Design, Synthesis and Evaluation of Bioactive

Design, Synthesis and Evaluation of Bioactive Privileged Structures for Drug
Discovery
THESIS SUBMITTED TO
JADAVPUR UNIVERSITY
JADAVPUR (KOLKATA)
WEST-BENGAL
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY
BY
Maloy Kumar Parai

MEDICINAL AND PROCESS CHEMISTRY DIVISION
CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001, INDIA
2008
Dedicated
To
My
Beloved Parents
CERTIFICATE FROM THE SUPERVISOR

This is to certify that the thesis entitled Design, Synthesis and
Evaluation of Bio-active Privileged Structures for Drug Discovery
submitted by Sri Maloy Kumar Parai who got his name registered on
21st November, 2005 for the award of Ph.D. (Science) degree of
Jadavpur University, is absolutely based upon his own work under joint
supervision of Dr. Umesh Chandra Halder and Dr. Gautam Panda
and that neither this thesis nor any part of it has been submitted for any
degree/diploma or any other academic award anywhere before.
(Dr. Umesh Chandra Halder)

Lecturer
Organic Chemistry Section
Department of Chemistry
Jadavpur University
Kolkata 700032
West Bengal, India
E-mail: uhalder2002@yahoo.com
Phone: 91 033 24146223
Telephone : 91-033-2414-6223
Internet: http : // www.jadhavpur.edu
Fax : 91-033-2414-6484
CERTIFICATE FROM THE SUPERVISOR

This is to certify that the thesis entitled Design, Synthesis and
Evaluation of Bio-active Privileged Structures for Drug Discovery
submitted by Sri Maloy Kumar Parai who got his name registered on
21st November, 2005 for the award of Ph.D. (Science) degree of
Jadavpur University, is absolutely based upon his own work under the
joint supervision of Dr. Umesh Chandra Halder and Dr. Gautam
Panda and that neither this thesis nor any part of it has been submitted
for any degree/diploma or any other academic award anywhere before.
(Dr. Gautam Panda)

Scientist
Medicinal and Process Chemistry Division
Central Drug Research Institute
Lucknow 226001
Uttar Pradesh, India
E-mail: gautam_panda@cdri.res.in
Phone: +91 522 2612411-18, Ext. 4385, 4469
CERTIFICATE FROM THE SUPERVISORS

This is to certify that the thesis entitled Design, Synthesis and Evaluation of Bioactive Privileged Structures for Drug Discovery submitted by Sri Maloy Kumar
Parai who got his name registered on 21.11.2005 for the award of Ph.D. (Science)
degree of Jadavpur University, is absolutely based upon his own work under the joint
supervision of Dr. Umesh Chandra Halder and Dr. Gautam Panda and that neither
this nor any part of it has been submitted for any degree/ diploma or any other academic
award anywhere before.
(Signatures of the Supervisors & date with official seal)
Acknowledgements
It gives me great pleasure to express my deep sense of esteem
and gratitude to my research supervisor Dr. Gautam Panda, Scientist,
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, for his inspiring guidance, never diminishing encouragement,
support and constructive comments. He was always there when I had
problems, questions or new ideas during the formative period of my research
life. It would have been impossible to accomplish this work, without his able
supervision and perseverance in the quest for success. For this I will be
forever grateful to him.
I would like to express deep and sincere gratitude to my supervisor Dr.
Umesh Chandra Halder, (Ph.D), Lecturer, Department of Chemistry, Jadavpur
University, Kolkata for his spontaneous encouragement, richest supervision
and personal guidance throughout my study.
I am highly grateful to Dr. C. M. Gupta (past Director) and Dr. R. Tuli
(present Director), Central Drug Research Institute, Lucknow for providing the
laboratory and excellent library facilities.
I sincerely thank Dr. Chandan Singh, (past HOD) and Dr. A. K. Saxena
(present HOD), Medicinal and Process Chemistry Division, for their
encouragement, constant inspiration, help and co-operation whenever
needed.
I sincerely acknowledge the help of the members of SAIF and glass
blowing section.
I also wish to express my sincere thanks to Drs., K. Raj, D. P. Sahu, A.
K. Misra, A. K. Shaw, Y. S. Prabhakar, Atul Goel, Atul Kumar, D. K. Dikshit
and T. Narender for their valuable advice, encouragement and constant
inspiration during the entire course of this study.
I am also highly thankful to Drs., U. Bandyopadhyay, V. Chaturvedi, S.
Sinha, Y.K. Manju and A. Gaikwad for providing the biological activity results.
I wish to convey my thanks to Mrs. V. Mehrotra, Mrs. M. Sharma, Mr. J.
C. Rajan, and Mr. A. K. Srivastava for their help, encouragement and support.
It is indeed a great pleasure working with my past and present

colleagues Tanveer, Pradeep, Dimpy, Sharad, Alok, Ravi, Umasharan,
Naveen, Rajesh, Chinmoy, Raghava, Vikas, Saquib, Pintu, Shweta, Poonam,
Jyoti, Biswajit, Somnath, Devesh, Ajay, Nidhi, Raja, Rishi, Noopur and all
other colleagues with whom I enjoyed my research tenure.
The warm and friendly attitude of my colleagues Manish Sinha, Satish,
Namita, Manish, Shreekant, Meenakshi, Ravi, Pratibha, Ankita and Sandip,
provided a congenital and cheerful atmosphere in the laboratory. My
acknowledgement will remain incomplete without recognizing their ever-willing
help, enthusiastic encouragement and constructive criticism of my labmates
Shagufta, Jitendra, Ajay, Sajal, Krishna, Subal, Ritesh, Sanjit and Priyanka
during this period. I extend my heartfelt thanks to them. My special thanks go
to Ajay and Sajal for their help to triumph over many tough moments of my
personal and professional life in the last five years.
It is impossible to express my deep sense of gratitude to my parents,
elder sister (Didi) in mere words for their commitment to my ambitions and
their selfless sacrifices without which I would not have reached this status. I
am invariably full short of words for the support and encouragement rendered
by little Anirban. I would also like to thank all my relative and friends specially
to Lakhsmikanta for their support and encouragement.
I am also thankful to CSIR, New Delhi for the financial assistance (in
the form of fellowship).
Finally and most importantly I bow my head to lord Shiva and goddess
Saraswati by whom grace I acquired the wealthy knowledge especially in
chemistry and wonderful family members.
(Maloy Kumar Parai)
TABLE OF CONTENTS
S. No
Chapter 1.
Chapter 2
Title
Page
List of Abbreviations
Preface
An Overview on Privileged Structures in Drug Discovery
1.1 Introduction
1.2 Application of Privileged Structures in Drug Discovery
1.2.1 The concept of privileged structures in GPCR ligands design
i-iii
iv-vi
1-46
1
3
5
1.3 Characteristics of Privileged Substructures

1.4 Phenyl-Substituted Monocycles
1.4.1 Biphenyls:
1.4.2 Arylpiperidines
1.4.3 Arylpiperazines
1.4.4 Dihydropyridines
1.4.5 Dihydropyrimidones
1.5 Fused [7-6] Ring Systems
1.5.1 1,4-Benzodiazepin-2-ones
1.5.2 1,5-Benzodiazepin-2-ones
1.5.3
1,4-Benzodiazepin-2,5-diones
and
Pyrrolo[2,1c][1,4]benzodiazepin-5,11-diones
1.5.4 1,5-Benzothiazepin-4-ones
1.5.5 5,11-Dihydro-benzo[e]pyrido[3,2-b][1,4]- diazepin-6-ones
1.5.6 Benzodiazepine-quinazolinones
1.6.1 Benzopyrans, Chromones, Coumarins and Pyranocoumarins
1.6.1.1 Benzopyrans
1.6.1.2 Chromones
1.6.1.3 Coumarins
1.6.1.4 Pyranocoumarins
1.6.2 Quinoxalines/Quinazolines
1.6.2.1 Quinoxalines
1.6.2.2 Quinazolines
1.6.2.3 3,4-Dihydroquinoxalin-2-ones (Benzopiperazinones)
1.6.2.4 Quinazolinones
1.6.2.5 Imidazoquinoxalines
1.7.1 Indoles
1.7.2 Benzimidazoles
1.7.3 Benzofurans
1.7.4 Benzothiophenes
1.8 Conclusion
1.9 References
An Unexpected reaction of phosphorous tribromide on (chromen-4-
6
7
8
10
11
12
13
14
15
17
18
21
23
23
24
24
24
25
26
27
29
29
30
30
31
32
33
33
34
35
35
37
37
47-82
yl)-aryl-methanols, (thiochromen-4-yl)-aryl-methanols and (2,3dihydro-benzo [b] thiepin-5-yl)-aryl-methanols: A case study
Chapter 3
2.1 Introduction.
2.2 Initial Observations
2.2.1 Reaction of Phosphorous Bromide on 7-methoxy-2,2-dimethyl
chromanone derived allyl alcohols
2.2.1.1 Plausible Reaction Mechanism
2.3 Reaction of PBr3 on tetrasubstituted 2,2-dimethyl-chromanone
derived Allylic alcohols
2.4 Reaction of PBr3 on 2,2-dimethyl-thiochromanone and
thiochromanone derived Allylic alcohols
2.4.1 Plausible Reaction Mechanism
2.5 Reaction of PBr3 on benzo [b] thiepinone and 8-methoxy-benzo [b]
thiepinone derived Allylic alcohols
2.5.1 Plausible Reaction mechanism for the formation of bromo
products
2.6 Reaction of PBr3 on benzo[b]oxepinone derived Allylic alcohols
2.7 Experimental Section
2.7.1 General Methods
2.7.2 Chemistry
2.7.2.1 Preparation of allylic alcohols
2.7.2.2 Preparation of saturated carbonyls, exocyclic olefins,
rearranged products and bromo derivatives.
2.8 Conclusion
2.9 References
2.10 Spectra
Design, Synthesis and Antitubercular Activity of Biaryl and
Triarylmethane Derivatives
3.1 Introduction
3.2 Antitubercular Drugs
3.3 Small Molecules as Chemical Probes and Drug Leads for TB
3.4 Basis of Present Work
3.5 Results and Disscussion
3.6 Antitubercular Screening of {33a-b, 43a-e, 44a-f, 45a-d, (50-51)a-d,
(52-56)a-g, and 58a-k)} and their Structure-Activity Relationships.
3.7 Conclusion
3.8 Experimental Section.
3.8.2 Preparation of carbinols
3.8.3 Preparation of phenols
3.8.4 Preparation of Triarylmethaneoxy Ethylamines
3.8.5 Preparation of 2-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]phenoxymethyl}-oxirane
3.8.6 Preparation of 2-hydroxy amino alkyl derivatives
3.8.7 Biological Activity
47
48
48
48
49
50
51
54
54
55
55
55
56
56
66
74
75
77
83-136
83
84
86
88
89
95
95
96
96
96
99
102
122
123
127
Chapter 4
Chapter 5
3.8.7.1 Agar Micro Dilution Method

3.9 References
3.10 Spectra
Design, Synthesis and Antimalarial Activity of Benzene and
Isoquinoline Sulfonamide Derivatives.
4.1. Introduction
4.2 Life cycle of malaria parasite
4.3 Treatment of malaria
4.4 Mechanism of action of antimalarial drugs
4.4.1 Quinoline analogues
4.4.2 Artemisinin and their derivatives
4.4.3 Antifolates
4.4.4 Atovaquone
4.5 New targets and ligands for malaria
4.6 Basis of present work
4.7 Results and Discussion
4.7.1 Chemistry
4.7.2 Structure activity relationships
4.8 Conclusion
4.9 Experimental section
4.9.1 Chemistry
4.9.1.1 General procedure for the preparation of Preparation of
benzenesulfonamides
4.9.1.2
General
procedure
for
the
preparation
of
Isoquinolinesulfonamides
4.10 Biology
4.11 References
4.12 Spectra
A convenient synthesis of chiral amino acid derived 3,4-dihydro-2Hbenzo[b][1,4]thiazine derivatives
5.1 Introduction
5.2 Reported methods for the synthesis of 1,4-benzothiazines
5.2.1 Solution phase synthesis of 1,4 benzothiazines
5.2.2 Solid phase synthesis of 1,4 benzothiazines
5.3 Basis of work
5.4 Synthesis of chiral 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives
6a-g from chiral pool S-amino acids
5.4.1 Retrosynthesis of prototype 6
5.4.1.1 Synthesis of N-Boc amino alcohol tosylates 10
5.4.1.2 Synthesis of (S)-1-(2-bromophenylthio)propan-2-amine 7
5.4.1.3 Synthesis of S-amino acids incorporated (S)-3,4-dihydro-2Hbenzo[b][1,4]thiazine derivatives 6a-g
5.5.2 Preparation of N-Boc (S)-1-(2-bromophenylthio) amine
derivatives 8a-g
127
127
131
137-168
137
137
139
141
141
142
142
143
144
145
146
146
149
149
150
150
150
156
161
162
164
169-190
169
169
170
172
173
173
174
174
175
175
177
177
177
5.5.3 Boc deprotection of 8a-g to furnish 7a-g

5.5.4 Cyclization of 2-bromophenylthio-amine derivatives
5.6 Conclusion
5.7 References
5.8 Spectra
List of publications
180
180
183
183
186
191
List of Abbreviations
AcOH
AlCl3
ARG
bs
Bn
(Boc)2O
o
C
Calcd.
CDCl3
C NMR
CNS
1
H-1H COSY
d
DCM
dd
DEAD
DIC
DIPEA
DIPP-AA
DMF
DMSO
DOS
eq
FCS
g
GABA
GLU
Gly
h
HCl
HIV
HMBC
HOBT
HSQC
H2SO4
HOMO
HTS
Hz
IC50
IR
J
acetic acid
aluminium trichloride
arginine
broad singlet (in NMR)
benzyl
Di-tert-butyldicarbonate
degree celcius
calculated in analysis
deuterated chloroform
carbon nuclear magnetic resonance
central nervous system
proton proton correlated spectroscopy
doublet (in NMR)
dichloromethane
double doublet (in NMR)
diethyl azodicarboxylate
N, N-diisopropylcarbodiimide
diisopropyl ethyl amine
N-diisopropylamino acids
N,N-dimethylformamide
dimethyl sulfoxide
diversity-oriented synthesis
equivalent
fecal colf serum
gram (s)
Gama amino butyric acid
glutamine
glycine
hour (s)
hydrochloric acid
human immunodeficiency virus
heteronuclear multiple bond correlation
1-hydroxybenzo triazole
heteronuclear single quantum coherence
sulfuric acid
highest occupied molecular orbital
high throughput screening
hertz
inhibitory concentration required for 50% inhibition
infrared
coupling constant (in NMR)
i
K2CO3
LAH
Lys
m
MDR
Met
mg
mL
mmole
m/z
M+
MDR
MeI
MHz
MIC
mp
MS (FAB)
MST
MTT
MW
N
NaHCO3
NaOH
Na2SO4
NH4Cl
NMDA
NMR
H NMR
OD
OHT
Pd/C
PBS
PDB
PKC
PPA
PPh3
ppm
Py
q
RC
Rf
RIF
rt
s
potassium carbonate
lithium aluminum hydride
Lysine
multiplet (in NMR)
multi drug-resistant
methionine
milligram
millilitre (s)
millimole (s)
mass to charge ratio (in Mass Spectrometry)
molecular ion peak
multi drug resistance
methyl iodide
megahertz
minimum inhibitory concentration
melting point
mass spectroscopy (Fast atom bombardment)
mean survival time
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
microwave
normality
sodium bicarbonate
sodium hydroxide
sodium sulphate
ammonium chloride
N-methyl-D-aspartate
nuclear magnetic resonance
proton nuclear magnetic resonance
optical density
4-hydroxytamoxifen
palladium on charcoal
phosphate buffer saline
protein data bank
protein kinase C
polyphosphoric acid
triphenylphosphine
parts per million (in NMR)
pyridine
quartet (in NMR)
reaction complex
retardation factor
rifampicin
room temperature
singlet (in NMR)
ii
TEA
Ser
SnCl4
t
TB
TBDMS
TAE
tert
THF
TLC
TMS
Ts
UV
M
WHO
triethyl amine
serine
stannic chloride
triplet (in NMR)
tuberculosis
tert-Butyldimethylsilyl chloride
triaryl ethylene
tertiary
tetrahydrofuran
thin layer chromatography
tetra methyl silane
p-toluenesulfonyl Chloride
ultraviolet
micromolar
world health organization
iii
Preface
The drug discovery process mainly depends on the discovery of compounds
that cure or help to treat diseases. One of the major goals in drug discovery research is
to identify high affinity and specific ligands for receptors and enzymes. The
identification of such ligands is an important step in the development of new and
better therapeutic agents. Despite the recent developments in small scale and high
throughput synthesis on solid supports and in solution for the generation of focussed
libraries, the total output of new pharmaceutical entities has not increased
significantly and modification in existing strategies for drug discovery are warranted.
Besides the screening of sets of new compounds by selected biological assays, the
structural modification and improvement of existing active molecules is very
attractive, since it deals with compounds that are druglike in humans. In this
direction, the use of privileged structures, a single molecular framework able to
provide ligands for diverse receptors, concept may be of immense importance to
accelerate drug discovery, especially by identifying different targets with unknown
3D structure, i.e. the G-protein coupled receptors. The understanding of the molecular
determinants that underline the privileged structure-target relationships should be the
key to apply the full potential of the privileged structure concept in the design of
novel targeted compounds libraries.
Privileged structures have been successfully exploited across and within different
target families and promises to be an effective approach to the discovery and
optimization of novel bioactive molecules. Moreover, the combination of the concept
of privileged structure with the combinatorial chemistry approach can allow a faster
identification of a new lead. In alternative to the use of privileged structures, several
studies appeared dealing with the preparation of libraries based on the concept of
diversity-oriented synthesis. Following this approach, libraries of compounds with
rich skeletal and stereochemical diversity were created in order to gain a diverse
display of chemical information in three dimensional space. However, no encouraging
results are available yet implying that the use of privileged structures in the
discovery of new drugs can be successfully employed.
The thesis entitled Design, Synthesis and Evaluation of Bio-active Privileged
Structures for Drug Discovery describes our synthetic endeavors towards finding
iv
new bioactive molecules. In this direction our prime objective was to design and
synthesis of several triarylmethane derivatives as antitubercular agents. Their
synthesis and biological evaluation has been described. In another effort, various
benzene and isoquinoline sulfonamides were synthesized and evaluated as
antimalarials against biological taregts.
The work embodied in this thesis has been organized under five main chaptersChapter I. An Overview on Privileged Structures in Drug Discovery.
Chapter II. An Unexpected reaction of phosphorous tribromide on (chromen-4-yl)aryl-methanols,
(thiochromen-4-yl)-aryl-methanols
and
(2,3-dihydro-benzo[b]
thiepin-5-yl)-aryl-methanols: A case study.

Chapter III. Design, Synthesis and Antitubercular Activity of Biaryl and
Triarylmethane Derivatives.
Chapter IV. Design, Synthesis and Antimalarial Activity of Benzene and
Isoquinoline Sulfonamide Derivatives.
Chapter V. A convenient synthesis of chiral amino acid derived 3,4-dihydro-2Hbenzo[b][1,4]thiazine derivatives.
In the Chapter I a brief review on Privileged Structures and its significance
in drug discovery process has been described. The Chapter describes modern drug
discovery process along with its different tools.
In the Chaper II
a novel observation during the reaction of phosphorous
tribromide on chroman, thiochroman, 2,3-dihydrobenzo[b]thiepine derived allylic

alcohols leading to some unusual products, saturated ketones, exocyclic olefins, and
rearranged products is reported. The mechanistic investigation of these unexpected
reactions has been described.
The Chapter III of the thesis deals with the study which has identified
triarylmethane derivatives (TRAMs) as a new class of antitubercular in vitro and in
vivo. It was observed that thiophene containing TRAMs exhibited better
antitubercular activity.
In Chapter IV design, synthesis and antimalarial activity of a series of benzene
and isoquinoline sulfonamide derivatives is described. Selected isoquinoline
derivatives with chlorine substitutent on benzene ring exhibited good in vitro
antimalarial activity.
In Chapter V, a short and facile synthetic route for the preparation of S-amino
acid
derived
chiral
benzothiazine
derivatives
involving
copper-catalyzed
intramolecular aryl amination reaction has been described.

Brief summary, experimental procedures, spectra of some of the important
compounds and appropriate literature citations are given in the text of each chapter of
the thesis.
vi
Chapter 1
An Overview on Privileged Structures in Drug
Discovery
Chapter 1: An Overview on Privileged Structures in Drug Discovery
1.1 Introduction:
The concept of privileged structure has widely been used for the discovery of
novel biologically active molecules during the past two decades. The term privileged
structure was first coined by Evans et al. in 1988 in relation to the heterocycle 1, 4benzodiazepine-2- one, and was defined as a single molecular framework able to
provide ligands for diverse receptors.1 The molecular scaffolds of privileged
structure will have versatile binding properties which will enable them to provide
potent and selective ligands for a range of different biological targets. In addition,
privileged structures typically represent more drug-like compound libraries and leads
having drug-like properties. It often consists of a semi-rigid scaffold, which is able to
present multiple hydrophobic residues without undergoing hydrophobic collapse2.
The net result is the production of high quality leads that provide a solid foundation
for further development. This understanding allows privileged structure based
libraries to be targeted at distinct target families (e.g. GPCRs, LGIC, enzymes/
kinases). Privileged structures have been successfully exploited across and within
different target families and promises to be an effective approach to the discovery and
optimization of novel bioactive molecules. Currently in market, a significant amount
of drugs possess a privilieged structure in their molecules. e.g. Atorvastatin, Sildenafil
and Erlotinib (Figure 1.1).
O
OH
N
H
OH
CO2H
O
N
N
2; Sildenafil
N
N
F
1; Atorvastatin
HN
F
N
O
HN
N
Cl
N
MeO
N
3; Erlotinib
Figure 1.1 Representative examples of privileged structure containing drugs.

Evans et al. noted the ability of 1, 4- benzodiazepin-2-ones to bind to
cholecystokinin (CCK) (4), gastrin, and central benzodiazepine receptors (5). In
addition to these, the benzodiazepine scaffold is also act as neurokinin-1 antagonists
(6), as enzyme inhibitors such as k-secretase inhibitors (7) and farnesyl: protein
transferase inhibitors (8), and as ion channel ligands such as the delayed rectifier K+
current modulator (9) (Figure 1.2).3,4
H
N
OO
N
N
Cl
5; Lorazepam,
(Benzodiazepine Agonist)
CF3
6; (Neurokinin-1 Antagonist)
H3CS
O O
CF3
N
Cl
4; Devazepide,
(CCK-A Antagonist)
OH
N
H
NH
H
N
HN
O
HN
O
NH
N
7; K-Secretase Inhibitor
CO2H
OO
H
N
NH2
N
N
O
NH
N
HS
F
8; Farnesyl:
Protein Transferase Inhibitor
9; Delayed Rectifier
K+ Current Modulator
Figure 1.2 Examples of biologically active benzodiazepines based on a single privileged

structure.
The term privileged structure has not arrived suddenly. Early on, various
groups had recognized the presence of common structural units in many ligands but
possess different biological activity. Their observed multiple actions was explained on
the basis of conformational flexibility.5 Subsequently, Andrews and Lloyd described a
number of common topological arrangements for biogenic amine antagonists.6 They
concluded that a common pharmacophore existed throughout diverse drug classes,
and that specificity resulted from secondary binding groups attached to the basic
pharmacophore.6
Since the privileged structure term was introduced, an increasing number of
substructural frameworks have been described as privileged structures, including
phenylsubstituted monocycles such as biphenyls,7,8 diphenylmethane derivatives,7,9
1,4-dihydropyridines, aryl piperazines, benzylpiperidines,7,9 fused [7-6] ring systems
such as benzodiazepines, benzothiazepines, fused [6-6] ring systems such as
chromones, quinoxalines/quinazolines, 2-benzoxazolones, benzopyrans,10-12 1,4dihydropyridine,9 pyranocoumarin,10-12 and fused [5-6] ring systems such as indoles,
benzimidazoles, and benzofurans spiroindoline sulfonamide,7,13
These privileged structures have since then, deliberate or not, been used
extensively in medicinal chemistry programs to identify new ligands, especially for
G-protein coupled receptors (GPCR's). The application of the privileged structure
approach, both in traditional medicinal chemistry and in the design of focused

libraries, will be discussed with the aid of illustrative examples.
1.2 Application of Privileged Structures in Drug Discovery:
The development of a clinically useful drug which provides either a cure for a
particular disease or symptomatic relief from a physiological disorder involves years
of cumulative research. The drug discovery process is organized into different phases,
starting from the proposal of a biological target and passing through various stages
and finally launching of a product (Figure 1.3). The long process by which a new drug
is brought to market stage from the starting point is referred to by a number of names
most commonly as the development chain or pipeline. The time from drug
discovery to approval can take up to 15 years, and the average cost of bringing a
pharmaceutical product to market is US $800 million and growing. Each journey from
one phase to the next one is a critical milestone that may affect the overall potential
for the development of a clinically useful drug.
Figure 1.3 Schematic presentation of drug discovery research.

The success rate of the drug discovery program is quite low despite a
considerable amount of money and energy has been spent over the past few years in
pharmaceutical industry. With approximately 500 known biological targets,14
alongwith thousands more from genomic research15 the situation grows worse.
Despite the successful introduction of protein therapeutics and the promise of gene
therapy, major pharmaceutical companies are still focused on the discovery and
3
manufacture of low molecular weight compounds (<500 Da) for clinical use. Thus,
the pressure to access small molecule library for drug discovery process will increase
substantially over the next few years.
Several techniques have been utilized in an effort to accelerate this process.
One aspect was the introduction of combinatorial chemistry16 and high-throughput
screening (HTS). Despite some success with these techniques, it rapidly became
apparent that they did not produce their expected results.15,17-19 This was believed to
be resulted from the immaturity of the technology, the inability to make the right
types of molecules, and a lack of understanding of what types of molecules to be
synthesized.17 As a consequence, much more effort has gone into rational design of
new molecules to be synthesized.
Among the probable strategies that can lead to the discovery of new drugs,
the proper identification and use of privileged structures gained particular attention.
Privileged substructures represent an ideal source of lead compounds. As described
previously (in Figure 1.2), a single library based upon privileged substructures can
lead to active compounds at a variety of receptors. Several groups have utilized these
structures in this manner. For example, combinatorial libraries based upon privileged
substructures have been synthesized by Nicolaou and colleagues, who utilized a
benzopyran scaffold,10-12 Schultz and coworkers, who made use of the purine
scaffold,20-23 and Hirschmann and Smith, who have worked with glycosides.24-26
While not every group intends to use these scaffolds in such a fashion, several
groups have focused on privileged substructures to improve the efficiency of drug
discovery. For example, Hirschmann, Smith, and colleagues have actively pursued the
design and development of new privileged scaffolds27 and have made hybrids of
existing privileged substructures.28 There has been significant interest in the
identification of new privileged substructures, and many groups have utilized
computational procedures to aid this endeavor. For example, Nilson et al. explored
databases of drugs to identify structural motifs that have broad biological activities
and developed synthetic processes to prepare arrays of such compounds.29 Another
example is RECAP, a computational technique that has been developed to identify
privileged substructures from biologically active molecules for use in library
development.30 Mason et al. has also developed a four-point pharmacophore method
for the design of focused combinatorial libraries of molecules with privileged
substructure characteristics.31
4
1.2.1 The concept of privileged structures in GPCR ligands design:

The G-protein-coupled receptors (GPCRs) form a large protein family that
distributed widely in the body and plays an important role in many physiological and
pathophysiological processes have been historically among the most popular targets
for drug discovery.32 Over 50% of the current marketed drugs target this class of
receptor in many therapeutic areas.33 The sequencing of the human genome
34,35
has
significantly expanded the number of GPCR targets for drug discovery: from the 30
targets of currently marketed drugs to an estimated 300 new potential targets.36,37
Recognizing this tremendous therapeutic and commercial opportunity, many
pharmaceutical companies today devote up to 30% of their drug discovery efforts
toward the GPCR target family. Over the past 20 years, conventional SAR methods
in medicinal chemistry have been highly successful in generating new generations of
drugs.The increasing knowledge of GPCRs (biological target space) and their ligands
(chemical ligand space) enables novel drug design strategies to accelerate the finding
and optimization of GPCR leads. However, to date, the only crystal structure
available is for bovine rhodopsin, which shares variable sequence and functional
similarity to the many hundreds of possible target proteins. It is thus very difficult to
construct accurate models of the active site of a GPCR target.38 Some hints about
which amino acids are important in the active site can be derived from binding data
for ligands with mutated receptors, sufficient in some cases to generate models of the
target against which to guide virtual screening and compound design.39,
40
Historically, the discovery of ligands for new GPCR's has been dependent on highthroughput screening (HTS) of large compound libraries and/or on ligand based
design. Privileged structures, with their inherent affinity for diverse biological
receptors, represent an ideal source for the design and synthesis of combinatorial
libraries targeting a wide variety of enzymes and receptors41 and in particular, the
GPCR family of proteins. The idea is that the incorporation of privileged structures
into combinatorial libraries, combined with information from homology modeling of
a specific receptor or from known ligands, will increase the probability of finding
valuable hits. The privileged structure will thus provide affinity while selectivity is
introduced by the variation in the rest of the molecule. Ultimately, a single, large
combinatorial library of privileged structures might provide ligands for a whole series
of receptors.
Toward this goal, the privileged structure based approach has been used
5
extensively to design libraries that possess both a high probability of producing lead
compounds against a variety of targets and good drug-like properties that allow
ready elaboration into a drug molecule. Numerous privileged structure-based
combinatorial libraries41 have been designed and synthesized, and these libraries have
proved to be an extremely powerful tool to aid the rapid discovery and optimization of
potent and selective ligands for a wide variety of GPCR targets. After developing the
synthetic route for the combinatorial synthesis of a series of 1,4-benzodiazepin-2-ones
(7), Bunin et al. synthesized a small library of 192 molecules.41 Screening these
compounds against the cholecystokinin A receptor yielded active compounds.
Subsequently, a larger library of 1680 1,4-benzodiazepines was synthesized and
screened against a number of receptor and enzyme targets. Inhibitors of pp60s-src
tyrosine kinase and ligands that block an autoimmune DNA-antibody interaction
implicated in systemic lupus erythematosus were identified.
1.3 Characteristics of Privileged Substructures:
It is subjective to define the privileged structure, although in general, it is stated
that they contain at least two ring systems connected either by fusion, such as
benzodiazepines, or through one or two single bonds, such as biaryls or diaryl
ethers.41 Privileged structures are generally having rigid ring systems which are able
to project multiple side-chain substituents in a well defined three-dimensional space
so that they may interact with a wide variety of biological receptors. Moreover, the
rigid molecular frameworks of privileged structures may impart good oral
bioavailability. In fact, Veber and co-workers at GlaxoSmithKline recently
demonstrated, by analyzing 1,100 drug candidates in the GlaxoSmithKline corporate
database, that rigid molecules containing rotatable bonds generally display better oral
bioavailability than more flexible molecules. Therefore, it's logical to think that by
replacing the privileged structure of a drug molecule while keeping those functional
groups unchanged, we might find a better drug.
Hirschmann, Smith, and colleagues24 have also suggested that the side-chain
projections of privileged scaffolds are recognized by structural motifs in G-protein
coupled receptors, therefore suggesting that the receptor active site geometry is
complementary to the privileged scaffold architecture. A molecular recognition event
is dependent on the electrostatic and steric surface complementarity of ligand and
receptor. Hann and colleagues42 imply that keeping the ligand surface simple may
result in broad binding activities. To some degree, it would appear that the binding
6
surface of the molecule is dependent on both the geometry in which the scaffold can
project its substituents and the functionality of the substituents thus employed.
However, in most cases folds that are capable of doing this will account for a fair
proportion of the total molecular weight before any substituents are appended,
especially if the molecular weight is to stay below 500 Da. As a result, the scaffold
will ideally be functional and form favorable interactions with the receptor. It is
possible to speculate that privileged substructures form favorable noncovalent
interactions with proteinaceous receptors which give rise to their broad binding
capacities. It is also possible that the ability of privileged substructures to bind to
proteins may result from the biosynthetic processes used in their preparation. Critics
of the privileged substructure concept may well argue that many of these structures
have limited utility due to their promiscuous nature. There are certain molecules that
show broad binding activities and have proven very difficult to optimize.41 In these
cases, it has been suggested that the promiscuous nature of these molecules is due to
aggregation (micelle or vesicle formation), and as a result, identification of these
molecules could avoid false positives in biological screening. Although it is certainly
worthwhile stating that the compounds reviewed here may bind to multiple receptors
through aggregation phenomena, the effectiveness of the privileged substructure
concept may amply be illustrated by the biphenyl framework. It has been described as
a preferred substructure for protein binding and appears in 4.3% of all known drugs.
Bicyclic and tricyclic scaffolds are therefore an ideal size for library synthesis.
They have a small enough molecular weight to provide scope for improved specificity
and affinity through the attachment of suitable substituents (which will consequently
increase molecular weight, yet retain drug-like character) in a wide variety of
topologies. The size of the privileged substructure relative to the entire molecule is an
important factor. Hence, a privileged substructure should constitute a significant
portion of the total mass of the molecule and represent its core element. However, it
was noted that many privileged substructures larger than bicycles were merely
combinations or hybrids of two or more bicyclic privileged substructures. Hence,
bicyclic privileged substructures may represent the core elements of an entire suite of
privileged substructures.
1.4 Phenyl-Substituted Monocycles
Phenyl-substituted monocycles have been utilized frequently in medicinal
chemistry. This basic framework is commonly observed in many different scaffolds,
7
from biphenyls to arylpiperazines. Unsurprisingly, many of these frameworks have

been observed to be a core element of molecules that bind to multiple, unrelated
classes of receptor with high affinity.
1.4.1 Biphenyls:
The biphenyl scaffold has received increased attention as a privileged
structure by the pharmaceutical industry. This motif has shown activity across a wide
range of therapeutic classes,41 which include antiamebic, antifungal, antiinfective,
antihypercholesteremic,
ntihyperlipoproteinemic,
fasciolicide,
antirheumatic,
analgesic, antiinflammatory, antithrombotic, uricosuric, and antiarrhythmic antitumor,

antihypertensive, and antiatherosclerotic agents. It also has shown the potential to
treat infertility as a follicle-stimulating hormone (FSH) receptor agonist.43
In
addition to this, the biphenyl substructure is found in 4.3% of all known drugs
(Figure 1.4).
H3 C
CH3
H3 C
HOOC
N
O
H3C
10; Antiarthritic Non-steroidal Anti-inflammatory Drug
HN
N
11; Antihypertensive Drug N N
Figure 1.4 Examples of biologically active biphenyls.

This diversity in receptor selectivity is not overly surprising when one considers
that aromatic moieties have long been considered as major players in molecular
recognition. When drugs that contain the biaryl moiety attach to proteins, they are
dominated by interactions with aromatic and hydrophobic residues. Furthermore, it
has been shown that the biaryls interact favorably with polar groups such as amides
and hydroxyl groups. They have also combined with positively charged moieties.
Since the biaryl is able to interact with these numerous binding sites, it is prevalent in
pharmaceuticals.
Recent literature has highlighted the use of the biaryl scaffold as a selective
Histamine H3 receptor antagonist (Figure 1.5). The H3 receptors which control the
production and release of histamine are presynaptic receptors and are mainly found in
the central nervous system. Because the majority of the receptors are located in the
central nervous system, it has been proposed that controlling this receptor could be a
drug development target for neurological disorders such as Alzheimers disease,
Parkinson's disease, and epilepsy.44 Besides biaryls also have exhibited antibacterial
activity against Gram-positive bacteria.45
O
N
O
H3C
N
O
12
CH3
Figure 1.5 Histamine H3 Receptor Antagonist

Heterocyclic biaryls have also exhibited biological activity. They have been
shown to be useful as antibacterial agents by inhibiting Gram-positive and Gramnegative
bacteria46
and
as
an
anti-inflammatory.
2-Amino-4-(p-
arylthio)phenylthiazoles have shown to be potential antagonists of LFA-1/ICAM-1

binding sites. Controlling LFA-1/ICAM-1 binding inhibits the over activation of
leukocytes to a site where an injury or infection has occurred. The over activation
may occur during a stroke or myocardial infarction and could lead to untoward tissue
damage (Figure 1.6).
HN
O
H
N
HN
N
O
O
H3C
CH3
CF3
S
N
CH3
N
CH3
13; Gram-positive and Gram-negative
inhibitor
O
R1
R2
X= O,S
14; LFA-1/ICAM-1 antagonist
Figure 1.6 Examples of biologically active biphenyls.

Several synthetic methodologies exist for the synthesis of biphenyls, including
the Ullmann synthesis for the creation of symmetrical biaryls and the Suzuki coupling
involving organoboron reagents, the Stille coupling using orgaanotin and the Negishi
coupling with organozinc reagents and the use of organosilicates for the creation of
unsymmetrical biaryls. The Grignard reaction has also been utilized for the creation of
unsymmetrical biaryls, but there are few examples of combinatorial library of
biphenyls by use of Grignard reagents .
The most versatile procedures for the stereospecific and regioselective synthesis of
biphenyl systems are the Stille and Suzuki reactions (Scheme 1).41
I + Rn M
Catalyst
R2
Base
R1
R2
R1
Stille Reaction: M=Sn; Catalyst= PdLn

Suzuki Reaction: M=B; Catalyst= PdLn
Negishi Reaction: M=Zn, Al, Zr, Catalyst= Ni(PPh3)4, PdCl2(PPh3)2
Scheme 1
1.4.2 Arylpiperidines:
The arylpiperidine scaffolds are found in many compounds that have distinct
pharmacological and therapeutic profiles.41 For example, the arylpiperidines are highaffinity neurokinin-1 receptor (NK1) antagonists. For example, the cis-(2S, 3S)piperidine framework (8) has been reported to be a basic framework for high-affinity
neurokinin-1 receptor (NK1) antagonists (Figure 1.7). Neurokinin antagonists are
implicated in a variety of disease states, including migraine, emesis, pain, arthritis,
asthma, depression, and anxiety. Possible applications of drugs specific for these
receptors include the treatment of asthma, as well as psychosis and anxiety.
R1
N
H
15
Figure 1.7 The cis-(2S,3S)-piperidine framework is a basic framework for highaffinity neurokinin-1 receptor (NK1) antagonists.
The arylpiperidine scaffold is also
found in some neuropeptide Y (NPY)
inhibitors, thus implying the role of this particular molecular scaffold for the potential
design of new anti-obesity drugs, the dopamine transporter (cocaine antagonist),
somatostatin (inhibition of tumor cell growth), the CCR2B receptor (antifungal
properties), the opioid receptor (substance abuse, analgesic), the serotonin receptor,
and serotonin reuptake inhibitor (antidepressant) and as a reversible inhibitor of
monoamine oxidase A (antidepressant), e.g. Fluoxetine(16) and (R,S) Paroxetine (17)
are potent antidepressant drugs47a-b which exerts its therapeutic action by selectively
inhibiting 5-HT reuptake.
F
OMe
O
N
H
16; Fluoxetine
O
O
N
H
17; (R,S) Paroxetine
Figure 1.8 Examples of biologically active arylpiperidines.

10
Three different types strategies has been chosen to synthesize these compounds,
synthesis in which the piperidine ring is attached to the aryl group through the ring
nitrogen,41 carbon-carbon bond formation between the two cyclic structures, and
synthesis in which the piperidine ring is formed during the synthesis48 (Figure 1.9).
N
NH
19
18
Figure 1.9
H
N
Arylpiperidines
Base or
+
Metal catalyst
X
X= F,Cl, Br, I
18
Scheme 2 Synthesis of Arylpiperidines of Type 18

1.4.3 Arylpiperazines:
Arylpiperazine is a core fragment of many bioactive compounds exhibiting a
variety of pharmacological effects. It has been shown that their action can be
mediated by different subpopulations of serotonin41 (5-hydroxytryptamine, 5-HT
including the 5-HT1A and 5-HT1D receptors, 5-HT2B and 5-HT2C receptors, and the 5HT6 receptor), dopamine, and adrenergic receptors. Such a multireceptor potential
implicates their frequent use as a source of new agents with different therapeutic
properties. This includes antibacterials, R1-adrenergic blockers, R2-adrenergic
agonists, antidepressants, serotonin receptor (5-HT1A) antagonists, phosphodiesterase
III inhibitors, antitussives, antifungals, antivirals, anxiolytics, antipsychotics,
antimycobacterials,
antidepressants,
lipooxygenase
inhibitors,
analgesics,
antiaggregants, endothelin antagonists, hypolipidemic compounds, and also molecules

that treat cognition disorders. The most thoroughly studied group of arylpiperazine
derivatives, called long-chain arylpiperazines (LCAPs), have been found as serotonin
receptor ligands, in particular 5-HT1A and 5-HT2A ones (Figure 1.10).49
11
OH
H
N
N
N
N
19; Flesinoxan
O
OMe
S
21; Ipsapirone
N
H
22; (S)-WAY-100135
OMe
N
N
N
N
N
O
N
N
N
20; Buspirone
O
N
23 ; BMY 7378
Figure 1.10 Structures of Several 5-HT1A-Agonists.

Their general chemical structure contains an alkyl chain (two to four methylene
units) attached to the N4 atom of the piperazine moiety and a terminal amide or an
imide fragment. The significance of the respective parts of LCAPs for 5-HT1A
receptor affinity, intrinsic activity, and selectivity has been the subject of many
structure activity relationship studies.50 In particular, much effort has been devoted to
the role of the terminal part in a ligand-receptor interaction; in consequence, a great
many different fragments were used.
Classically,
arylpiperazines
were
synthesized
through
ring
closure
of
appropriately substituted anilines and bis-(2-chloroethyl)amine hydrochloride in the

presence of base or acids (Scheme 3).51
Ar NH2
Cl
Cl
K2CO3 ,PhCl
NH
or p-TsOH, PhCl
NH
Ar
Scheme 3. Synthesis of arylpiperazine framework

In 1995 Dankwardt et al. published a novel route for arylpiperazine synthesis
through nucleophilic aromatic substitution.52 Nucleophilic aromatic substitution
reactions for aryl piperazine library synthesis has also been accomplished in the
liquid phase under similar conditions, or on solid phase with the aid of a palladium
catalyst.41
1.4.4 1,4-Dihydropyridines:
1,4-Dihydropyridines are versatile compounds because their derivatives play
important roles in medicinal chemistry,41 for example, nifedipine, amlodipine and
other antihypertensive agents (Figure 1.11). 1,4-DHPs are the most studied class of
12
organic calcium channel modulators and, since their introduction into clinical
medicine in 1975, have become almost indispensable for the treatment of
cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.
CF3
CO2 Me
NO 2
CO2 Me O2N
MeO2 C
N
H
Me
Me
N
H
Me
Me
Figure 1.11 Nifedipine (24) and BAY K 8644 (25)

1,4-Dihydropyridines have also been reported to be vasodilators, bronchodilators
and
possess
antimutagenic,
activities.
41
antiatherosclerotic,
antidiabetic,
antioxidant,
geroprotective,
hepatoprotective,
herbicidal,
and
antitumor,
photosensitizing
These molecules can also be utilized to promote drug transfer across the
blood-brain barrier. Other 1,4-dihydropyridines have been reported to be active at P2

receptors and to inhibit platelet aggregation. The 1,4-dihydropyridine Cerebrocrast
has also recently been introduced as a neuroprotectant and cognition enhancer lacking
neuronal- specific calcium antagonist properties.
Among the numerous methods,41 developed for the synthesis of 1,4-dihydropyridines,
Hantzsch condensation is one of the most well-accepted methods and much effort has
been made to modify this reaction53 (Scheme 4).
R
EtO 2C
H
O
O O
NH3
R
CO 2Et EtO 2C
Base
CO 2Et
N
H
Scheme 4. 1,4-dihydropyridines Synthesis by Hantzsch condensation.

1.4.5 Dihydropyrimidones:
Dihydropyrimidones are have attracted immense interest as calcium channel
modulators, antihypertensive agents, -1a-antagonists, mitotic kinesin Eg5 inhibitors,
neuropeptide Y (NPY) antagonists and melanin concentrating hormone receptor
antagonists (Figure 1.12).54
13
F
F
O
HN
HN
OMe
NO 2
MeO
EtO
O
OH
MeO
EtO
MeO
N
H
N
H
OMe
28; SNAP-7941
MCH1 receptor antagonist
27; Monastrol,
Kinesin Inhibitor
26; Calcium channel blocker
NH
H
N
O
Figure 1.12 Representative bioactive dihydropyrimidones.

Compounds containing this scaffold are also known to exhibit a wide range of
biological activities such as antiviral, antitumour, antibacterial and anti-inflammatory
actions. Several marine alkaloids containing the DHPM core unit have shown
interesting biological properties. In particular, batzelladine alkaloids have been found
to be potent HIV gp-120-CD4 inhibitors (Figure 1.13).
Ar
R2
NH
R2
N
X
H
R1, R2 =alkyl group, X = O, S, Ar = substituted aryl
Figure 1.13
As a result of their medicinal properties, synthesis of the dihydropyrimidone
nucleus has received much attention. The initial synthesis of dihydropyrimidone is
Biginelli condensation,41 involves the acid-catalyzed cyclocondensation reaction of a
-keto ester, aldehyde and derivatives of urea or thioureas (Scheme 5).
Ar
E
R2
Ar
H
NH2
HN
R1
H+
EtOH
R2
X = O, S
E = ester, amide, acyl group
Ar = substituted aryl group
NH
N
R1
Scheme 5. The Biginelli Reaction for Dihydropyrimidone Synthesis.

Several recent modifications of the classical Biginellis approach have been
developed for high-throughput screening during past few years.41 Basically, these
methods are all similar, using different Lewis acid catalysts.
1.5. Fused [7-6] Ring Systems
Among heterocyclic structures, benzodiazepines and benzothiazepines are the
unique privileged structures, owing to its presence in so many compounds of
pharmaceutical significance that it is nearly impossible to catalog their complete
14
range of biological activity. Presently, there are numerous types of benzodiazepines

and benzothiazepines (Figure 1.14) including 1,4-benzodiazepin-2-ones (29), 1,5benzodiazepin-2-ones (30), 1,4-benzodiazepin-2,5-diones (31), 1,4-benzothiazepin2,5-diones (32), pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones (33), and 5,11-dihydrobenzo[e]pyrido[3,2-b][1,4]diazepin-6-ones (34), all of which have been synthesized
combinatorically both in solution and solid phase.
H
N
H
N
H
N
NH
N
29
N
H
N
30
NH
32 O
31 O
H
N
NH
33
34 O
Figure 1.14 Fused [7-6] privileged ring systems based on benzodiazepine and
benzothiazepine frameworks.
1.5.1 1,4-Benzodiazepin-2-ones:
These benzannulated scaffolds display a wide range of pharmacological activities41
and regarded as the Privileged Heterocyclic Scaffolds in drug discovery.
Representative members of this class have shown activity as anxiolytics and as
antagonists of CCK-A, GABAA receptor, human bradykinin B2, and HIV-1 Tat
receptors. These drugs have also proven useful as inhibitors of Ras farnesylation and
Src protein tyrosine kinase and have shown anti-arrhythmic activity.
According to the report of Selnik et al.55, the (R)-2-(2,4-Trifluoromethyl)-N-[2oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3yl]acetamide (35)(Figure 1.15) possesess class III antiarrhythmic activity in vivo by
selective blockade of the slowly activating cardiac delayed rectifier potassium current
Iks.
O
CH3
n
NH
HN
N
35
Figure 1.15
Numerous
new
1,4-benzodiazepin-2-one-based
gastrin/CCK-B
receptor
antagonists related to the typical analogue L-386,760, (36) and more closely to the
15
recently reported compound YM022, (37), has been synthesized by them and
evaluated for its biological activity and shown to be potent and selective ligands for
the gastrin/CCK-B receptor (Figure 1.16).
H3C
O
CH3
N
O
O
N
H
O
O
HN
N
CH 3
36; L-386,760
N
H
CH 3
HN
37; YM022
Figure 1.16
Recently it was shown that the benzodiazepine derivatives (38) and (39) posses
bradykinin B1 antagonistic property. Wood and coworker have identified novel
bradykinin B1 receptor antagonists,56 with the most potent members demonstrating
subnanomolar binding affinity and low-nanomolar functional activity (Figure 1.17).
H3C
O
O
N
N
O
N
H
NH
H3C
NH COOH
N
O
N
H
R 38; R = CH3 , 39; R = C6H5
40; R = Alkyl group
Figure 1.17
Many 1,4-benzodiazepine derivatives (40) are reported to have endothelin
receptor antagonistic properties by Bolli et al.57 They designed a novel class of ET
receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo [e][1,4]diazepin-2-one
scaffold.
Recently 1,4-benzodiazepine derivatives are reported to have inhibitory effect
on respiratory syncytial virus (RSV) by Carter et al.58 They investigated the antiviral
SAR of approximately 650 closely related 1,4-benzodiazepines and found that omethoxybenzamide containing a suitably positioned electron-withdrawing group gave
both excellent in vitro activity and good pharmacokinetic properties.
H
N
H
N
R
R
NHR
N
Cl
H
N
NHBoc
*
N
O
41; R = COCH 3
42 ; R = NHC6 H4 CH3
43; R = alkyl side chain from amino acids
Figure 1.18
16
3-Amino-1,4-benzodiazepines as well as chemically related diverse amines

were synthesized from oxazepam by Offel et al.59 and screened on the
cholecystokinin receptor in a radiolabel binding assay. The substituted 3-anilino-1,4benzodiazepine structure was identified as lead structure in a diverse series of 3amino-1,4-benzodiazepines (41) and the full SAR (structure-activity relationship)
optimization provided 3-anilinobenzodiazepines with CCK1 receptor selectivity to
CCK2. In 2003, Herrenz and coworker60 reported 1,4-benzodiazepine derivatives (43)
as a novel scaffold for peptidomimetics buildings (Figure 1.18).
1,4-benzodiazepine derivative BZ-423 (44) is a pro-apoptotic 1,4benzodiazepine with potent activity in two clinically relevant animal models of
systemic lupus erythematosus. Bz-423 binds to the oligomycin sensitivity conferring
protein component of the mitochondrial FoF1-ATPase. Bz-423 inhibits the enzyme,
which produces a state 3 to state 4 transitions within the mitochondrial respiratory
chain (MRC), ultimately resulting in production of superoxide (O2-) from MRC
complex III. This reactive oxygen species act as an upstream signal, initiating a
tightly regulated apoptotic process. Previous studies revealed that a hydrophobic
aromatic substituent at C3 along with the phenolic hydroxyl group is required for the
cytotoxic activity of Bz-423. The compounds (45)-(47) have been synthesized and
shown to have similar toxicity effect (Figure 1.19). 61-63
H3C
N
O
H3 C
O
R
NH
Cl
46 ; R =
43 O
Cl
OH
45; R =
47 ; R =
H
N
44; BZ-423
Figure 1.19
1.5.2
1,5-Benzodiazepin-2-ones:
1,5-Benzodiazepine-2-one (30) (Figure 2.4) is associated with wide range of
biological activity including interleukin-1 converting enzyme (ICE) inhibitors and

delay rectifier potassium current blocker (IK).64 Schwarz et al.65 synthesized 1,5benzodiazepine-2-one from resin bound 4-fluoronitrobenzoic acid (Scheme 3).
Nucleophilic substitution with amino acids followed by reduction and treatment with
DEPC and DIEA afforded the cyclic product. Regioselective N-5 alkylation by alkyl
17
halide followed by final alkylation of N-1 with lithiated 4-benzyl-2-oxazolidinone as

a base gave the resin bound desired product.
O
R2
NH
i. DEPC, DIEA
2
ii. R X/ 500C
HN
R
NH 2
COOH
O
N
NH2
N
iii. R3X/ Lithiated-4-Bz-2O
Oxozolidinone
R3
iv. TFA
Scheme 6: Synthesis of 1,5-benzodiazepin-2-ones.

1.5.3
1,4-Benzodiazepin-2,5-diones and Pyrrolo[2,1-c][1,4]benzodiazepin-5,11-
diones:
1,4-benzodiazepin- 2,5-diones continue to attract enormous interest, due to a
broad and ever evolving spectrum of biological activities.66 Amongst the 1,4benzodiazepin-5-ones, most attention has been paid to tricyclic systems, such as the
antitumour pyrrolo-1,4-benzodiazepin-5-ones, the biologically active quinazolinofused circumdatin and asperlicin natural products,5 the pyrido- and benzofused nonnucleosidic reverse transcriptase inhibitors, muscarinic receptor ligands, and the
clinically used anti-depressant, cognition enhancing imidazolo-fused flumazenil, and
positron emission tomography tracers derived from flumazenil. Bicyclic 1,4benzodiazepin-5-ones have attracted attention as simplified analogues and precursors
of these tricyclic systems, are of specific interest as anti-convulsants, anti-anxiety
agents, antidepressants, sedatives, hypnotics, muscle relaxants, analgesics, antitumour agents and fibrinogenic receptor antagonists. Use of the Ugi reaction67 to
produce 1,4-benzodiazepin- 2,5-diones is potentially more versatile than several
reported methods,41 accomplishing the entire synthesis in fewer steps and
circumventing many drawbacks.
Pyrrolo [2,1-c][1,4] benzodiazepine-5,11-dione (PBDs) are merely prolin
substituted 1,4-benzodiazepin-2,5-dione. All of the drugs belonging to PBDs group
are extremely potent compounds. Almost all of them exhibit antibiotic, antitumor, and
antiviral activities.68-70 Natural compounds showed a wide antibacterial
in vitro
activity.71-72 However, in vivo they were found to be with weak or no

chemotherapeutic activity against infections caused by bacteria, fungi, viruses, and
other protozoan and helminthic infections.73 Meerpoel and coworker74 reported
Pyrrolo[1,2-a][1,4]benzodiazepines (48) and (49) as a novel class of non-azole antidermatophyte anti-fungal agent (Figure 1.20).
18
R2
CH 3
N
R1
48; R 1 = Cl, R 2 = H
49; R 1 = H, R 2 = Cl
Figure 1.20
Research on PBDs is of considerable interest due to their potential as antitumour
agents, gene regulators and DNA probes. The PBD ring systems are also produced by
various Streptomyces Species, members include anthramycin (50), porothramycin B
(51), tomaymycin (52), chicamycin A (53) and abbeymycin (54). The potent
antitumor activity of all of the members of PBD series is probably one of the most
potential clinical significance. Anthramycin (50) and related compounds have been
shown to have broad antitumor activity against a variety of transplanted tumors.Both
anthramycin (50) and sibiromycin (55) have been used clinically.
Lown et al. have reviewed a number of compounds, which possess varying
substituents in the aromatic A-ring, along with the related biological studies.75 A new
7,8-methylenedioxy analog of (p)-porothramycin B (57) and its water-soluble sodium
bisulfite derivative (59) have shown to exhibit high cytotoxic activities (IC50 950
nM) against several tumor cell lines. The most interesting feature is the fact that (58)
is equally active on doxorubicin-resistant cell lines as on sensitive cell lines (Figure
1.21).76
OR 3 H
N
R4
OCH 3
H
N
CON
R1
HO
O
53; Chicamycin A
HO
OH
H
N
H3CO
O
OCH3
H
HO
OCH3H
N
56; DC-81
OMe
H
N
OCH3
H
N
OH H
N
54; Abbeymycin
OMe H
N
CH 3
O
52; Tomaymycin
H3CO
H
N
OCH3
H
H
N
H 3CO
R2
50; Anthramycin (R4=CH 3, R3= R 2=R 1=H)

51; Porothramycin B (R4 =H, R 3 = R 2=R1 =CH 3)
H
N
HO
55; Sibiromycin
H
R
N
H
CONMe2
O
57; (+)- Porothramycin, 99
N
O
CONMe2
58; R = OMe, 100

59; R = SO3Na, 101
19
Figure 1.21
Variety of A-ring heterosubstituted PBD analogs have been reported by Thurston
and other groups in the last few years.77-81 The rationale for heterocyclic-PBD
synthesis was based on the following features: (a) retention of cytotoxicity against
tumor cell lines; (b) obtain compounds with low cardiotoxicity; (c) modulate the
reactivity of carbinolamine (or its equivalent). A class of pyrazolo[4,3-e]pyrrolo[1,2a][1,4] diazepinones of general formula (60), (61) and (62), (63)
have been
synthesized and some of the synthesized compounds showed a cytotoxicity against

L1210 leukemia cell lines, comparable to DC-81 (56) (mM range) (Figure 1.22).
R1
R1
N
N
R2
R2 N
O
62 ; R 1 = Me, i-Pr
2
63 ; R = Me, Et, Bn, subtituted benzyl
60 ; R 1 = Me, COOMe, i-Pr

61 ; R 2 = Me, Et, Bn
Figure 1.22
Some other heterocyclic analogs of PBDs were also prepared, including pyridine
(64), pyrimidine (65), and pyrazine (66). Regarding these latter derivatives, a
significant decrease of activity (10100-fold less active) was observed with the
respect to pyrazolic analogs and DC-81. These results suggested that the presence of
electron withdrawing nitrogens in the A-ring of PBDs produces an increase in the
carbinolamine reactivity, which could react with non-specific endogenous
nucleophilic agents, with a consequent loss of DNA-specificity (Figure 1.23).
N
H
N
OMe
H
N
O
64
N
MeO
OMe H
N
OMe
H
N
N
O
65
H
N
OMe
H
N
N
O
66
Figure 1.23
Kamals group has developed mixed imine-amide pyrrolobenzodiazepine dimers
with general structure (67) and they exhibit potent antitumor activity and significant
binding (Figure 1.24). These PBD-dimers are joined through their C8-position by an
alkanedioxy spacer (comprised of three to five and eight carbons), wherein one ring of
PBD has the imino function (DC-81) while the other has an amide group (dilactam of
DC-81).82-83
20
H
N
O
H
OCH 3
O
OCH 3
N
O
67; n = 3-5 and 8
Figure 1.24
1.5.4 1,5-Benzothiazepin-4-ones:
Seven membered benzofused ring systems containing nitrogen and sulfur as
heteroatoms are termed as benzothiazepines.There are different types of
benzothiazepine derivatives and exhibit diverse biological activities,41 among them
1,5-benzothiazepine derivatives constitute an important area of drug discovery with a
large member of 1,5-benzothiazepines exhibiting a variety of pharmacological
activities.84a-b For example, Diltiazem(68), Clemtiazem, and Siratiazem are important
cardiovascular drugs of this family, which have been introduced for the treatment of a
variety of cardiac ailments. Some members of this class of compounds act as potent
bradykinin agonists, growth hormone secretagogues, ligands for Src H2 protein,
spasmolytics, and squalene synthetase inhibitors, antihypertensive, blood platelet
aggregation inhibitors, anti-arrhythmic, antithrombotic, antianginal and antiischemic,
antitumor.
OMe
H
S
NMe
S
H
OAc
N
H O
69; R = Me
70; R = 2-OMe
71; R = 4-OMe
H3C N 68
CH3
Figure 1.25
Another well-known benzothiazepine derivative called BTM-1086 (69), (70) and (71)
are shown to have antiulcer and antisecretary property (Figure 1.25).85
Benzothiazepine compound, 2164U90, (72) has also been shown to efficiently block
bile acid uptake via the ileal transporter in both in vitro and in vivo models. It is potent
inhibitor of the ileal bile acid active transport system.86
CH3
N
O O
S
NH
H
CH3
CH3
S
N
N
Cl
N
72
73
H3C N
CH3
74
21
Figure 1.26
Thiazesim (73) is benzothiazepine derivative having antidepressant property87-90
The Pyrrolo[1,3]benzothiazepine derivative ST1469, (74) and related analogues were
found to have antipsychotic serotonine and dopamine antagonistic properties as
described by Campiani et al (Figure 1.26).91 The benzothiazepine derivatives were
also known for their potentiality as angiotensin converting enzyme inhibitors,92 the
compound (75) was most potent having an IC50 of 2.95 nm, the compound (76) was
found to inhibit AI pressor response. Additionally (77) lowered blood pressure in
spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/Kg (Figure
1.27).
Ph
S
S
COOR
NH
N
OTf
N
1
75; R = H; R = CH3
77
COOR 76; R = CH3; R1 = H
NMe
Figure 1.27
(5-{4-[(Biphenyl-2-carbonyl)-amino]-benzoyl}-2,3,4,5-tetrahydro-benzo[b][1,4]
thiazepin-2-yl)-acetic acid (78) is a potent and selective V2 arginine vasopressin
receptor antagonist. The compound was orally active in vivo, showing aquaretic
activity at doses as low as 3 mg/kg.93 The benzothiazepine derivative (79) was known
to possess bradykinin agonistic properties as described by Amblard and colleagues
(Figure 1.28).94
O
S
OH
S
NH-Ser-Thi-Gly-Hyp-Pru-Arg-D-Arg-H
N
O
N
H
O
79
O
Arg-OH
78
Figure 1.28
The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1d][1,5]-benzothiazepine derivatives such as (80) are described by Campiani et al. The
PBR affinity is associated to potent calcium antagonist activity, and this property
supports the hypothesis that the cardiovascular action of PBR ligands is a calcium
dependent process through DHP-sensitive voltage-dependent channels.95,96 Several
22
other thiazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (81) was found to be an apomorphine
antagonist (Figure 1.29).97
Me
Me
N
OCOMe
N
OH
N
80
81
Figure 1.29
1.5.5 5,11-Dihydro-benzo[e]pyrido[3,2-b][1,4]- diazepin-6-ones:
5,11-Dihydro-benzo[e]pyrido[3,2-b][1,4]diazepin-6-ones (82) possess diverse
therapeutic activities41 which include inhibition of HIV-1 reverse transcriptase292 and
muscarinic receptor inhibition (including the prototypical M1-selective muscarinic
receptor inhibitor, pirenzipine (Figure 1.30), which is used for ulcer treatment).
N
N
O
N
NH
O
Figure 1.30
In 1997, Semple and coworker98 reported (3R)-N-(1-(tert-Butylcarbonylmethyl)2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N-(3(methylamino)phenyl)urea (YF476) having gastrin/CCK-B antagonistic properties.
Unsurprisingly, combinatorial syntheses41 of these molecules usually employ a similar
strategy to that of the 1,4-benzodiazepines. Ring closure is usually affected via amide
bond formation between N4 and C5. A good example of this was reported by
Woolard et al. Other combinatorial libraries of these molecules have also been
reported using a similar strategy for solution-phase synthesis.
1.5.6 Benzodiazepine-quinazolinones:
Privileged 1,4-benzodiazepine-2,5-dione ring systems are the key intermediates
for the synthesis of benzodiazepinequinazolinone alkaloids. Sclerotigenin was
isolated from the sclerotia of Penicillium sclerotigenum and has shown a promising
antiinsectan activity.99 It is the simplest member of the benzodiazepinequinazolinone
natural alkaloid family. Other members in this family such as circumdatins AG
23
isolated from terrestrial fungus Aspergillus ochraceus and benzomalvins AC isolated

from fungus Penicillium sp. also possess interesting biological activities (Figure
1.31).
O
O
N
N
HO
N
N
O
N
H
83; Sclerotigenin
N
O
Me
N
H H
84; Circumdatin C
N
CH3H
N
H
HO
Ph
85; Benzomalvin A
H
N
N
i-Bu
O
86; (-) Asperlicin
Figure 1.31 Examples of biologically active benzodiazepine-quinazolinones.

Recently Zhan et al100 reported a new synthetic protocol for sclerotigenin-type
benzodiazepinequinazolinone library scaflold. A fluorous benzyl protecting group is
used for the synthesis of 4-benzodiazepine-2,5-dione intermediate.
1.6.1 Benzopyrans, Chromones, Coumarins, and Pyranocoumarins:
Benzopyran (87), chromone (88), and coumarin (89) all possess a similar core
structure. They are all seen frequently in a broad range of natural products, and each
display a wide diversity in the types of receptors to which they bind.
O
O
87
O
88
O
89
1.6.1.1 Benzopyrans:
The benzopyran structural motif observed in many biologically active natural
products, and it plays an important role in binding with broad range of receptors.101
For example, vitamin E (90) and its analogues trolox (91) and MDL-73404 (92) are
important lipophilic antioxidants. MDL-73404 (92) also exhibits cardioprotective
effects during a myocardial infarction. Conocurvone, a naphthoquinone trimer
isolated from a Conospermum sp. in 1993, prevents the cytopathic effects and
replication of HIV in human T-lymphoblastic cells (CEM-SS). Centchroman (93), an
estrogen antagonist, is an antifertility agent. Clusifoliol (94) was a component isolated
from Peperomia species which have been used to treat malignant tumors.
Daurichromenic acid (95) and rhododaurichromanic acid A (96) have also shown
potent anti-HIV activity. Nebivolol (97) is an anti-hypertensive agent. Siccanin (98) is
a potent antifungal agent and used clinically in Asia (Figure 1.32).
24
HO
OTs+
N
HO
HO
COOH
O
90; vitamin E
91; Trolox
92; MDL-73404
OH
OH H
OH
HO2 C
HO2 C
O
MeO
O
93; Centchroman
94; Clusifoliol
F
O
OH
N
H
95; Daurichromenic acid
OH
96; Rhododaurichromanic
acid A
OH
98; Siccanin
97; Nebivolol
Figure 1.32 Representative examples of biologically active chromans and chromens.

They are also known serotonin (5-HT3) receptor antagonists, inhibit aldosterone
biosynthesis and phosphodiesterase IV, activate potassium channels, and have
bradycardia activity. Despite this wealth of activity, few combinatorial libraries
containing this core structure involving numerous prenylation and cyclization
reactions have been reported.41 Nicolaou et al have reported two combinatorial
synthesis of a benzopyran libraries. The core benzopyran framework was assembled
in solution phase through coupling 2-methyl-3-butyn- 2-ol to a variety of phenols.
Park and co-workers also developed a branching synthesis of a natural product-like
small molecule library embedded with a privileged benzopyran motif.102
1.6.1.2 Chromones:
Chromones (88) are a group of naturally occurring compounds that are widely
distributed in nature, especially in the plant kingdom. In the family of flavones,
chromone derivatives, nobiletin (99) inhibits the enzymatic activity of MMP-9103
whereas, at 0.3 _ 10-3 M, baicalein (100) inhibits the ectopeptidases APN/CD13 and
neutral endopeptidase (NEP/CD10; EC 3.4.24.11) by 57% and 36%, respectively.104
At the same concentration, flavanol derivatives, quercetin (101) inhibit the activities
of NEP/CD10 (73%) and APN/CD13 (49%).104
OMe O
OH
MeO
MeO
OH
O
99; Nobiletin
OMe
OMe
HO
HO
OH
O
100; Baicalein
HO
O
CH 2CO2 H
O
OH
101; Quercetin
102; FAA
OH
Figure 1.33 Examples of biologically active chromone derivatives.
25
Several therapeutically interesting biological activities41 of certain molecules

containing benzopyranone ring have been reported. For example, Flavone-8-acetic
acid105 (FAA, 102) has been considered a very interesting compound because of its
peculiar antitumor profile, They have been shown to be tyrosine and protein kinase C
inhibitors, as well as antifungal, antiviral, antitubulin, and antihypertensive agents.
Chromone derivatives are also active at benzodiazepine receptors and on
lipoxygenase and cyclooxygenase. In addition to this, they have been shown to be
anticancer agents, possessing antimutagenic properties as well as the ability to inhibit
electron transport through inhibition at NADH:ubiquinone oxidoreductase and
phorbol ester-inducedornithinedecarboxylase.
Chromones may be synthesized under either acidic or basic conditions. The
classical 2,3- disubstituted benzopyranone
(103) synthesis utilizes Baker-
Venkataraman rearrangement (Scheme 7) or Claisen ester condensation in acidic

conditions and is by far the most common method.313
O
O
R1
O
R2
Baker-Venkatarama
rearrangement
O
R2
OH
R1
R1
H+
O
103
R2
Scheme 7. Classical Synthesis of the Benzopyranone

1.6.1.3 Coumarins:
Coumarins (2H-1-benzopyran-2-ones) (89) are well-known natural products
displaying a broad range of biological activities.106 Coumarin derivatives have been
extensively used as therapeutic agents.107
26
R
R
HO
O
OH
N
H
O
MeO
O
O
108; warfarin
OH
104; Novobiocin; R = H R1 = NH2

105; Clorobiocin; R = Cl R1 =
Me N
H
R1
OH
OH
HN
H
N
MeO
O
HO
CH3
OH
R1
O
O
H
N
HO O
OHO
O
106; Courmycine A1; R1 =
Me N
H
O
Me
O
OH H
O
O
N
O
2
O
O
O
107; Simocyclinone
OMe
O
O
O HO
OH
OH
OH
OH
Figure 1.34 Coumarin-containing antibiotics and drug.

Coumarin is the parent molecule of warfarin (108, Figure 1.34), used clinically
as an anticoagulant and as a rodenticide. Coumarins have been reported41 to exhibit
antibacterial, antifungal, antiinflammatory, antioxidant and immunosuppressive
activities and to act as diuretics and analgesics. Coumarins also display a variety of
anticancer, antimutagenic, antitumor activities. Other biological activities of the
coumarins include inhibitors of HIV-1 protease, monoamine oxidase, caspase-1
(interleukin-1 converting enzyme, anti-inflammatory
applications), a variety of
proteases (includes cathepsin B, elastase, Factor Xa, urokinase, thrombin), reversible

inhibitors of thyrotropin- releasing hormone degrading ectoenzyme (possible use in
the treatment of brain and spinal injury and central nervous system disorders
including spinocerebellar degeneration, cognitive deficits and spinal cord pain
transmission). Multicyclic molecules containing the coumarin scaffold include
furanocoumarins, pyranocoumarins, and psoralens, which also have a broad range of
biological activities. A variety of combinatorial libraries containing the coumarin ring
have appeared in the literature,108-111 in which the coumarin scaffolds were synthesize
by using the Knoevenagel condensation.
1.6.1.4 Pyranocoumarins:
27
Pyranocoumarins are a naturally occurring framework that has been used for
many centuries in medicine. They are an active chemical in many plants that have
been used in traditional medicines. Examples of this include Bai-Hua Qian-Hu, which
was used in traditional Chinese medicine for the treat ment of certain respiratory
diseases and pulmonary hypertension,41
O
O
O
109; Pteryxin
110; Luvangetin
111 ; Decursin
Figure 1.35
41
Bio-active natural products e.g Pteryxin (109), which has been shown to relax the
smooth muscle of tracheas and pulmonary arteries, luvangetin (110), which displayed
gastroprotective activity, and decursin (111) which was reported to have cyctotoxic
activity and activate protein kinase C, respectively (Figure 1.35). Potentially they
have also immense value in cancer therapy, as they can inhibit NADH:ubiquinone
oxidoreductase (also known as complex Isthis enzyme has also been implicated in the
pathogenesis of diseases such as Parkinsons, focal dystonia, and Lebers hereditary
opticneuropathy e.g.,deguelin (112), inhibits phorbol ester-induced ornithine
decarboxylase (this enzyme is responsible for the biosynthesis of polyamine growth
factors required for normal cellular proliferation; possible use in cancer therapy),
shows some
application in preventing benzo(a)pyrene and hydrogen peroxide
induced mutagenesis,325 and activates protein kinase C.338 Another area in which.
Deguelin (112), DCK (113), and seselin (114).112-114 these compounds display great
potential is as anti- HIV drugs (Figure 1.36).
O
MeO
MeO
O
H
O
H
O
112; Deguelin
O
O
O
O
O
O 113; DCK
114; Seselin
Figure 1.36
Dipyranocoumarins from the Calophyllum genus exhibit HIV-1 specific reverse
transcriptase inhibitor activity, antibacterial and antifungal activity, and antiulcer
activity, are hemorrhagic toxins, antiprotozoans, and uterotonics, and are used to
promote smooth muscle relaxation (tracheal and pulmonary artery relaxation). Other
28
pyranocoumarins, such as seselin (114) are also clinically used as photoactive drugs
in the photochemotherapy of the skin, to treat vitiligo and to prevent sun burning. Due
to the importance of this class of heterocyclic compounds, many efforts have been
devoted to the preparation of such scaffold but few combinatorial syntheses of
pyranocoumarins have appeared in the literature.115,116 Nicolaou et al. have reported
the synthesis of a 10 000-membered benzyopyran library using Knoevanagel
condensation, a condensation reaction, or a Wittig reaction.41
1.6.2 Quinoxalines/Quinazolines:
There are numerous biologically active molecules whose framework includes a sixmembered ring containing two nitrogen atoms fused to a phenyl ring. Most of these
molecules are based on the quinoxaline (115) or quinazoline (116) framework.
However, many of the biologically active molecules of this class contain a carbonyl
group, such as the quinoxalinones (117), quinazolinones (118), and quinazolindiones
(119), or possess a fused imidazole ring (120).
O
O
N
N
115
N
H
117
116
N
N
H
119
N
H
118
N
NH
O
N
N
H
120
1.6.2.1 Quinoxalines:
Quinoxaline (115) is an important class of benzoheterocycles1 displaying a broad
spectrum of biological activities which have made them privileged structures in
combinatorial drug discovery libraries.117 The importance of quinoxalines as
pharmaceutical agents118 is manifested by the marketing of Brimonidine [5-bromo-N(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] as an antiglucoma agent. Many
drug candidates bearing quinoxaline core structures are in clinical trials in antiviral,
anticancer, antibacterial, and CNS therapeutic areas.
In addition, quinoxaline
derivatives also have been evaluated as anthelmintic, antibacterial, anti-inflammatory,

antifungal, insecticidal agents. Oxidation of both nitrogens of the quinoxaline ring
dramatically increased the diversity of certain biological properties,119 such as
antibacterial activity, hypoxia-selective anticancer activity. They also act as platelet
derived growth factor (PDGF) Inhibitors (121, 122) (Figure 1.37).120
Me
Me
121
MeO
MeO
122
29
Figure 1.37 Quinoxaline-Based Inhibitors of PDGF Receptor Tyrosine Kinase.

Although a number of methods are available for the synthesis of substituted
quinoxalines,41 probably the most widely used method for the preparation of
quinoxaline derivatives is by condensation of aryl-1,2-diamines with R-diketones,
usually R-dicarbonyl compounds (Hinsberg condensation) or their equivalents.
1.6.2.2 Quinazolines:
Quinazolines are widely used as antitumorals, for example (123)121,122
although they exhibit also a wide range of biological properties as potent nonnucleoside reverse transcriptase inhibitors of HIV-1,123 antibacterial agents (124),124
phosphodiesterase 5 inhibitors125 and antagonist for the human adenosine A(3)
receptor126 with potential action as anti-inflammatory, anti-asthmatic or anti-ischemic
agents. This heterocycle is present also in the agent for the treatment of Pneumocystis
carinii pneumonia Trimetrexate (125),127 in Anagrelide128 that can be used for the
treatment of thrombocythaemia,129 in Prazosin (126)130 (Figure 1.38) used in benign
prostatic hyperplasia, and in the antihypertensive agent Ketanserin.131
F
NH2
MeO
HN
N
NH2 O
N
N
N
H
124
123
OMe
N
Cl
NH2
MeO
MeO
MeO
MeO
OMe
Cl
Me
NH2
MeO
MeO
N
H
N
N
N
125; Trimetrexate
O
N
NH2
126; Prazosin
Figure 1.38 Relevant bio-active molecules with quinazoline moiety.

There are three different pathways described for the synthesis of quinazolines.
Cobb et al., Zhang et al. and Makino et al. took a cyclocondensation as the key
step.132 As shown in scheme 10, Makino also used a cycloaddition for the
construction of the quinazoline skeleton.
1.6.2.3 3,4-Dihydroquinoxalin-2-ones (Benzopiperazinones):
The benzopiperazinone (3,4-dihydroquinoxalin- 2-one) (127), (Figure 3.0) ring

system is structurally related to the widely employed benzodiazepine nucleus and yet
has been less widely used in drug discovery.133
30
H
N
N
H
N
HO2 C
N
H
127
N
H
O
CH 3 O
128
Figure 1.39 Representative examples of biologically active benzopiperazinones.

Examples of biologically active benzopiperazinones include inhibitors of aldose
reductase (128), PDGF receptor tyrosine kinase, partial agonists and antagonists of
the aminobutyric acid (GABA)/benzodiazepine receptor complex, and angiotensin II
receptor antagonists. Also, two patents have described the synthesis of 4(acyloxy)benzopiperazinone derivatives with antiviral activity, as associated with
HIV. This framework may also be useful in cancer treatment as Pgp production is
often increased in tumor cells from patients undergoing chemotherapy.
The simplest strategy used for the combinatorial synthesis of benzopiperazinone
scaffold is through the addition of an amino acid to a nitro analogue followed by
reduction and cyclization. Many groups have utilized this methodology for
combinatorial synthesis.41 The most common aniline analogue used for library
synthesis is derived from ortho-fluoronitrobenzene, (Scheme 8).134
R1
NO2 H 2N
F
CO2 R
DIEA , DMF
NO2
N
H
R1
Reduction
CO2 R
Cyclization
H
N
N
H
R1
Scheme 8.
1.6.2.4 Quinazolinones:
4(3H)-Quinazolinones are an important class of fused heterocycles found in
numerous of bio-active natural products and synthetic compounds (Figure 3.1). and
possess broad range of biological activities135-136 such as anti- HIV, anti-cancer, antiinflammatory, anti-convulsant, anti-hypertensive and anti-malarial activity. For
example, DPC 961 (129) and DPC 083 (130) are nonnucleoside reverse transcriptase
inhibitors (NNRTIs) that show promise for the treatment of HIV as well as new
mutant strains of the virus.137 Bio-active natural products febrifugine(131) which is an
ingredient of a traditional Chinese herbal remedy, effective against malaria.138 Several
alkaloids having this scaffold have been reported to possess Cytotoxicity property,139
as exemplified by luotonin A (132), luotonin F (133) and fumiquinazoline A (134).
31
Cl
F3 C
NH
F3C
Cl
O
N
NH
O
HO
N
O
H
130; DPC 083
N
O
H
129; DPC 961
H
N
NH
131; Febrifugine
H
O HN
N
H
OH
N
N
N
N
132; Luotonin A
O
O
N
N
O
O
133; Luotonin F
N
135; Methaqualone
134; Fumiquinazoline A
Figure 1.40 Quinazolinone bio-active natural products and synthetic drugs.

These compounds also act as psychotropic, hypnotic, cardiotonic, and
antihistamine agents.41 Methaqualone (135) it is the most well-known synthetic
quinazolinone drug, famous for its sedativehypnotic effects (Figure 1.40).138
Quinazolinones also inhibit41 monoamine oxidase, aldose reductase, tumor necrosis
factor R, thymidylate synthase, pyruvic acid oxidation, and acetylcholine-esterase
activity and are antitumor, antiulcer, antiplatelet aggregation (glycoprotein IIb/ IIIa
inhibitors). The Niementowski synthesis is majorly used for the synthesis of
quinazoline core which involves chemical reaction of anthranilic acids with amides to
form 4-oxo-3,4-dihydroquinazolines. 140a-c
1.6.2.5 Imidazoquinoxalines:
Compounds
containing
azole-fused
dihydroimidazo[1,5-a]quinoxalines
(137),
(136),
quinoxalines
such
as
4,5-
4,5-dihydroimidazo[1,2-a]quinoxalines
4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxalines
(138)
and
4,5-
dihydro[1,2,4]triazolo[1,5-a]quinoxalines (139) are known to exhibit a wide range of

biological activities.141
N
N
N
N N
N
N
O
N
N
H
N
H
N
H
N
H
N
H
136
137
138
139
140
R
N
O
O
Among these compounds, imidazo- [1,5-a]quinoxalines and the related

imidazo[1,5-a]quinoxalin- 4-ones are common structural arrays that are found in a
number of biologically important and therapeutically useful agents.142 Thus, they have
been used as a template for the synthesis of GABA/ benzodiazepine receptor
agonists/antagonists, cAMP and cGMP phosphodiesterase inhibitors, A1- and A2aadenosine receptor agonists, inhibit cAMP and cGMP phosphodiesterase, and IgEmediated passive cutaneous anaphylaxis (PCA) (antiallergic properties) and several
32
other
pharmacologically
methylphenyl)-
active
compounds.
More
recently,
amino]-7,8-dimethoxyimidazo[1,5-a]quinoxaline
4-[(2-chloro-6(BMS-238497)
(141) and its analogues (142, 143) have emerged as a novel and potent inhibitor of
Src-family kinase p56Lck, displaying excellent enzymatic activity against Lck (IC50 )
2 nM) and good potency in blocking T-cell proliferation (IC50) 0.67 M).(Figure
1.41)141-143
N
MeO
MeO
N
Me
N
H
Cl
141 ; BMS-238497
N
N
142
N
H
Me2 N
Br
MeO
N
H
N
143
Me
N
H
Cl
Figure 1.41
All of these scaffolds have been synthesized combinatorially (136, 137, 138 and
139).144 A small combinatorial library of molecules based on the scaffold (140) has
also yielded glycine/ NMDA receptor antagonists and AMPA receptor antagonists.145
Three different strategies have been reported for the combinatorial synthesis of
imidazo[1,5-a]quinoxalines.146-148
1.7 Fused [56] Ring Systems:
Numerous fused [5,6] ring systems exhibit broad range biological activity and
being used therapeutically. Among them the indole ring is one of the most ubiquitous
heterocyclic structures found in nature. Other fused [5,6] ring systems discussed here
include benzimidazole, benzofuran and benzothiophene.
1.7.1 Indoles:
The indole substructure is a basic element for a number of biologically active
natural and synthetic products. Since January 2003, there have been more than 400
drugs and 3000 patents in which the indole motif has been present.149 The range of
applications for these therapeutically relevant compounds includes protein kinase C
inhibitors, 5-HT agonists, melatonin agonists, and glucocorticoid receptor modulators.
For example, the 2-phenyl-indole derived ligands (144) and (145) that target the 5hydroxytryptamine-6 (5HT6) and melanocortin-4 (MC4) receptors, respectively. The
hallucinogen D-lysergic acid diethylamide (LSD) (146) also contains an indole ring
and is a potent nonselective serotonin receptor agonist. The discovery of Sumatriptan
(147),146 a selective serotonin 5-HT1D receptor agonist, as an effective acute treatment
for migraine headache has intensified research in this area, and over the past years
several related compounds, including Mercks Rizatriptan (MK-462, 148),150 have
33
entered late phases of clinical development. In addition to this, molecules containing

an indole scaffold also acts as selective estrogen receptor modulator (SERM)151 (149,
150) and selective factor Xa inhibitors. Many other indole alkaloids with biological
activity also exist, including those that cause cell cycle arrest at the G2/M transition
(Figure 1.42).
COOH
N
5N
H
N
H
N
H
145
N
H
Cl
147; Sumatriptan
146; Indomethacine
NMe2
Br
144
CH 3 MeHN S
O O
Br
NMe2
MeO
N
4
N
N
H
OH
OH
HO
HO
148; Rizatriptan
150
149
Figure 1.42 Some examples of biologically active indoles.

In addition to several synthetic strategies152 both in solution and solid phase in
1996, Hutchins and Chapman reported
41
the application of Fischer indole synthesis
for the solid-phase synthesis of indole from ketone attached to a polystyrene resin
through the 4-hydroxymethylbenzoic acid (HMB) linker. The indole ring may also be
synthesized through the palladium-catalyzed coupling of alkynes. This has been
achieved many times in the synthesis of solidphase combinatorial libraries.41
1.7.2 Benzimidazoles:
The benzimidazole scaffold has received extensive attention in medicinal
chemistry,153 especially after the commercialization of the anthelmintics albendazole
(151), fenbendazole (152), thiabendazole(153), Astemizole (154), antiulcerative
Omeprazole(155), and
several others e.g oxfenbendazole, antihistamine (Figure
1.45).
S
H
N
H
N
O
NH
N
151; Albendazole
O
NH
152; Fenbendazole
H
N
N
N
153; Thiabendazole
34
F
H
N
N
NH
MeO
O
N
OMe
MeO
Me
X R
155; Omeprazole
154; Astemizole
OMe
R2
S
N
Me
R1
N
157
156
Substituted
X=NH, NR' or S
Substituted 2-amino and 2-alkylthiobenzimidazoles
thio-methylbenzimidazoles (proton-pump inhibitors,
antiulcer, antiviral)
(antiarrythmic, antiviral)
Figure 1.45 (A) Structures of drugs based on the benzimidazole scaffold; (B) trisubstituted
benzimidazoles and analogs with diverse biological activities.
It encompasses a diverse range of biological activities including antiarrhythmic,

antiulcer, anticancer, anthelmintical, inotropic, antihistamine, antifungal, antiviral,
and cytotoxicity.154 In addition to this, benzimidazoles also show other diverse
biological activities,41 inhibiting phosphodiesterase IV and the integrin RIIb3
receptor,
and
antagonism
of
angiotensin
and
neuropeptide
Y.
2-
Alkylthiobenzimidazoles and their corresponding sulfoxides have also been shown to

be proton-pump inhibitors, antiulcer compounds and antivirals. In addition to this, the
purine framework, which is one of the key structures in DNA, is also closely related
to the benzimidazole framework.
Various protocols have been reported for combinatorial synthesis of
benzimidazole motif.41
in which different aldehydes have been used to cyclize
the imidazole ring. An intramolecular cyclization strategy through amides is also

common in both solution- and solid-phase155 combinatorial synthesis.
1.7.3 Benzofurans:
The benzofuran scaffold is ubiquitous in the realms of pharmacologically active
agents and in isolated natural products. Prescribed agents156 featuring this nucleus
include the antidepressant (-)-BPAP (158), antifungals, selective opioid receptor
analgesics, and the antiarrythmic Amiodarone.
O
NH
158
Figure 1.46 (-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP).

BPAP has been shown to have neuroprotective effects similar to those of
selegiline, and has been researched for the treatment of Alzheimer's disease,
Parkinson's disease and clinical depression. Some benzofuran derivatives are also
known as 5-lipoxygenase inhibitors, angiotensin II inhibitors,4 calcium entry blockers,
and antitumor agents. Benzofuran-containing natural products include frondosin B7
35
and the eupomatenoid family. Due to their small size, the benzofuran group has also
been appended to other scaffolds to form molecules that inhibit tubulin (antimitotic
activity),157 sodiumindependent atypical dopamine D-2 receptors (antipsychotic
activity),41 and EP3 prostanoid receptors.41 The benzofuran group is also present in
larger heterocyclic structures41 such as the furochromones, whose analogues inhibit
cyclic
AMP
phosphodiesterase
(inhibiting
platelet
aggregation),
and
acyl
CoA:cholesterol O-acyltransferase (ACAT) inhibitors (antiatherosclerotic activity).

Benzo[b]- furo[3,4-d]furan-1-ones also are a common scaffold found in many
naturally occurring products, which have a wide range of biological effects.
Thus synthetic access to benzofurans is of considerable interest, and numerous
approaches to this scaffold have been disclosed in the literature.158 Combinatorial
syntheses of these molecules have also been achieved in a number of ways.41 These
methodologies generally involves a palladium catalyzed heteroannulation reaction or
the Mitsunobu reaction.
1.7.4 Benzothiophenes:
The benzothiophene scaffold have attracted considerable attention due to their
profound biological activities.41,159 They act as inhibitors of herpes simplex virus type
I (HSV-1) replication, tubulin
(antimitotic activity), cysteine proteases such as
cathepsins K and L, serine proteases such as thrombin, and selective opioid receptor
analgesics and when used in conjunction with an arylpiperazine moiety are 5-HT6
antagonists (potential roles in schizophrenia and depression). Benzothiophenes also
form the core component of several pharmaceutical drugs such as raloxifene (159),
zileuton (160), and sertaconazole (161) (Figure 1.47).
O
HO
N
N
OH
HO
NH2
S
Cl
Me
S
159; Raloxifene
160; Zileuton
S
Cl
Cl 161; Sertaconazole
Figure 1.47
Raloxifene is an oral selective estrogen receptor modulator (SERM) 160,161 that has
oestrogenic actions on bone and anti-oestrogenic actions on the uterus and breast. It is
used in the prevention of osteoporosis in postmenopausal women. It has been
investigated that raloxifene is as effective as tamoxifen in reducing the incidence of
breast-cancer in certain high risk groups of females. Recently Antonio Monge et al.162
36
has reported that the benzo[b]thiophene derivatives (162) and (163) which showed
moderate to high affinity at 5-HT transporter and 5-HT1A receptors (Figure 1.48).
F
HO
HO
MeO
MeO
N
163
162
Figure 1.48
Several strategies 163a-b for the synthesis of this bicyclic ring have been reported,
and these may be amenable to synthesis in a combinatorial fashion. One strategy has
utilized a Friedel-Crafts aroylation as the key synthetic step.
1.8 Conclusion:
The research on privileged structures are of immense importance in medicinal
chemistry and have been successfully exploited across and within different target
families and promises to be an effective approach to the discovery and optimization of
novel bioactive molecules. Privileged scaffolds increase hit rates for biological targets
of interest, leading to the discovery of other biologically active targets and generating
leads with enhanced drug-like properties. Consequently, from medicinal chemists
point of view, privileged structures remain as core scaffolds for viable starting points
in library design and synthesis. This approach permits the identification of increased
numbers of active compounds from screens against a variety of receptors.
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46
Chapter 2
An Unexpected reaction of phosphorous
tribromide on (chromen-4-yl)-aryl-methanols,
(thiochromen-4-yl)-aryl-methanols and (2,3dihydro-benzo [b] thiepin-5-yl)-aryl-methanols:
A case study
Chapter 2: An Unexpected Reaction of phosphorous tribromide on (chromen-4-yl)-aryl-methanols,..
2.1 Introduction
The reaction of allylic alcohols with phosphorus tribromide to furnish bromo
derivatives is an important transformation in organic synthesis1. In this reaction, the
hydroxy of allylic alcohol is replaced by bromide through stereo- and regioselective
manner leading to the formation of corresponding bromo derivatives or the allylic
alcohol rearranges into the terminal bromides involving migration of the double
bond.2 In this section, we explain some of our novel observations during the reaction
of cyclic allylic alcohols with phosphorous tribromide. Initially in an effort towards
accessing chromene containing bioactive agents3 we needed an advanced intermediate
of prototype 2, which could be obtained from carbinols 1 on treatment of PBr3. But
instead of furnishing bromo derivatives 2, to our surprise, carbinols 1 underwent
isomerization to give saturated carbonyls of prototype 3 and exocyclic olefins 4
(Scheme 2.1).4
R2
Br
HO
R2
R1
PBr3
O
0 0C
R1
1 O
+
R1
HO
R2
R2
3 O
R2
R1
PBr 3
R1
00 C
5
R 1 = OCH 3, H
R 2 = alkyl, aryl, heteroaryl
R1
Scheme 2.1
This unusual transformation of allylic alcohols to saturated carbonyls and
exocyclic olefins encouraged us to study the reaction of PBr3 on a set of allylic
alcohols as this type of disproportionation reactions are highly important in organic
synthesis5 and very few one step synthetic methods are reported in literature for such
transformations.6 From close analysis of the structures of allylic alcohols of prototype
1 and the ratio of their products, saturated ketone 3 and exocyclic olefin 4 depends on
the nature and substituent position of R2. Further to elaborate the effect of R1 and
47
heteroatom of the ring on the polarizibility of the unsymmetrical allylic double bond,
we became interested to replace the heteroatom of the ring with the carbon atom.
Surprisingly the tetralone and 6-methoxytetralone derived allylic alcohols rearranged
to the 1-aryl methyl naphthalenes 5 via aromatigation of ring B.7
Further in continuation to our previous work, we became interested to study the
mechanistic details of the reaction along with studying the effect of substituents at
various positions and ring size on the formation of products. Towards this objective,
several related analogs varying in ring size, substituents at various positions were
synthesized and studied. A detailed mechanistic investigation is presented in this
chapter.
2.2 Initial Observations

2.2.1 Reaction of Phosphorous Bromide on 7-methoxy-2,2-dimethyl chromanone
derived allyl alcohols:
During the bromination reaction of chromanone derived allylic alcohols it was
observed that the allylic alcohols were rearranged to saturated carbonyls and
exocyclic olefins depending on the substituent R2. To elaborate the methodology
several allylic alcohols were synthesized and treated with phosphorous tribromide. It
was observed that if R2 contains strong electron withdrawing group the product was
exclusively ketone and whereas exocyclic olefins were formed when R2 is having
strong electron donating group. In the case of R2 with moderate effect mixture of both
the products were obtained. Keeping all these results in mind, it was anticipated that
the reaction mainly depends upon the acidity of proton Ha. Mechanism is described
afterwards.
2.2.1.1 Plausible Reaction Mechanism:
Based on the observed results,4 a probable mechanism has been proposed taking
into account the role of both 7-methoxy substituent and substituents at R2. Treatment
of 1 with PBr3 furnished 7 with formation of HBr. The double bond in 7 got
protonated due to the extended conjugation of 7-methoxy in aromatic ring giving rise
to a quinonoid structure like 8. In presence of electronegative substituents in R2, Ha
proton is more acidic and thus bromide anion in the solution abstracts it giving rise to
11, which on hydrolysis furnished saturated carbonyls 3. On the other hand, in
48
presence of electrondonating substituents in R2, acidity of proton Ha is reduced and

thus bromide anion attacks POBr2 group resulting into formation of POBr3 and
exocyclic olefin 4.
Ha
R4
HO
PBr 3
MeO
Ha
R4
Br 2 P O
Ha
R4
Br 2P O
H Br
MeO
MeO
Ha: more acidic

( R4:with -I Inductive
effect)
Ha: less acidic

( R4:with +I Inductive ef fect)
Br
R4
Ha
H
MeO
-Br3 PO
MeO
Br
Ha
R4
Br2 P O
Ha
R4
Br 2P O
H
MeO
10
O
9
-HaBr
R4
Br 2P
H
MeO
O
3
R4
H
Hydrolysis
MeO
O
11
Scheme 1.2
2.3
Reaction of PBr3 on tetrasubstituted 2,2-dimethyl-chromanone derived
Allylic alcohols:
Further to elaborate this methodology, we were interested to explore the reaction
of PBr3 on tetra substituted allylic alcohols. From literature reports it was observed
that the isomerization of allylic alcohols using known methods depends largely upon
the substitution on the double bond.6a The reaction becomes more difficult as the
number of substituents on double bond increases. A handful of examples are known
for the transposition of trisubstituted and conjugated allylic alcohols into saturated
carbonyls.8 Not a single example of conversion of tetrasubstituted allylic alcohols into
saturated carbonyls by using metal catalyst or any other regents in one step is known;
perhaps due to steric hindrance present in double bond having four substituents. To
explore the possibility of this reaction, tetrasubstituted allylic alcohols 14a-g were
synthesized from 3-methyl-7-methoxy-2,2-dimethyl-chroman-4-one 129 and were
49
treated with PBr3 in benzene at 00C. To our delight, the saturated ketones 15a-e and
exocyclic olefins 16, 17 were isolated in good yields, (Scheme 2.3 and Table 2.1).
Br
H3 CO
Br
H3 CO
13
O
12
PBr3, Benzene
reflux, 24 h
H3 CO
HO
n-BuLi, THF
-780 C
R 2CHO, 1h
H 3 CO
O
13
R2
PBr3
O
14a-g
00 C
H3 CO
R2
R2
+
O
15a-e
H 3 CO
O
16-17
Scheme 2.3
Table 2.1 Transformation of tetrasubstituted allylic alcohols 14a-g to saturated
ketones 15a-e and exocyclic olefins 16,17.
Entry
R2
Alcohol
Ketone
Yield
Olefin
(%)
Yield
(%)
14a
C6H5
15a
84
14b
C6H4-(3-OCH3)
15b
79
14c
C6H4-(4-F)
15c
83
14d
C3H7
15d
75
14e
C6H4-(4-Cl)
15e
87
14f
C6H4-(4-OCH3)
16
71
14g
C6H4-{4-N(CH3)2}
17
73
2.4 Reaction of PBr3 on 2,2-dimethyl-thiochromanone and thiochromanone

derived Allylic alcohols:
We further wanted to predict the role of heteroatom in this transformation reaction
of allylic alcohols and thus 7-Methoxy-2,2-dimethyl-thiochroman-4-one 18a was
converted into bromo derivative 19a which on subsequent reaction with n-BuLi and
R2CHO afforded allylic alcohols 20a-c following reported procedures.5,10 The
resulting compounds 20a-c with 7-methoxy substituent on reaction with PBr3 at 0C
furnished saturated ketones 21a-c in good yields (Table 1.2). On the contrary, on
treatment with PBr3, the corresponding allylic alcohols without 7-methoxy substituent
50
22a-h, furnished rearranged products 23a-h instead of giving saturated carbonyls. On

the other hand, thiochromanone derived bromo derivative 25 was not stable and hence
further reaction was not performed on it, Scheme 1.4.
R2
PBr 3
R1
S
18a ;
OCH 3
18b; R1 = H
R1 =
650 C
R1
R2
HO
Br
PBr 3
n-BuLi,-780C
R2 CHO
S
19a; R 1 = OCH 3
19b; R 1 = H
R1
R1
S
21a-c; R 1 = OCH 3
R2
R1
20a-c;
= OCH 3
22a-h; R1 = H
R1
S
23a-h; R 1 = H
HO
d+
H 3CO
S
20a-c
R2
Br
PBr 3,65 0C
dS
24
4 days
S
25
Highly unstable
Scheme 2.4
2.4.1 Plausible Reaction Mechanism:
The sulfur of 20a-c having vacant 3d orbital might induce inverse polarization on
double bond through attracting the electron cloud of benzene ring. On the other hand,
the electron donating effect of OCH3 at benzene nucleus nullifies the effect of sulphur
and causes the polarization of double bond of 20a-c as depicted above (Scheme 1.4)
similar to the one observed in chroman containing allylic alcohols4. Thus it was
observed that donating effect of OCH3 in 20a-c plays a role in retaining the
polarization of double bond, which eventually furnished the saturated ketones 21a-c
might following same mechanism (Scheme 2.2). Further to ascertain the role of 7OCH3 at benzene ring on polarization of double bond, PBr3 reaction was performed
on allylic alcohols 22a-h without 7-OCH3 substituent.
51
R2
+
30
R2
HO
dS
d+
PBr 3
CH 3
d-
CH 3
22a-h
d+
CH3
CH3
)
Br - (
CH3
a
H 2C
CH3
CH3
H
27
R2
H
H3C
R2
26
33
Not isolated
CH 3
Br 2 PO
26
Path a : migration of
one of the gem-dimethyl
groups
Path b : Nucleophilic
addition of bromide
Path c: Through episulfonium intermediate
32
31
R2
Br2 PO
S
Path c
R2
R2
R2
S
H
S
H 2C
23a-h
H
CH 3
29
R2
R2
)(
A1,3
H
+
S
H 3C
H
CH3
R2
28
Scheme 2.5
This reaction can be thought to proceed via an intermediate 26 formed during the
reaction of 22a-h with PBr3 followed by elimination of HBr. The double bond in 22ah is not similarly polarized owing to absence of 7-OCH3 as it was observed in 20a-c
(Scheme 2.4). Moreover, the tendency of leaving group ability of OPBr2 and the
ability of accommodating electron cloud in vacant 3d orbital of sulphur atom in 26
caused the inverse polarization of double bond in 26. This resulted into an additional
+ve charge on trisubstituted carbon atom of double bond where nucleophilic addition
of bromide anion (path b) can take place or one of the gem-dimethyl groups can
migrate (path a) or the reaction may follow through epi-sulfonium intermediate11 to
furnish 29 (path c); (Scheme 1.5). Close inspection of six membered half-chair like
transition state5 of 26 revealed that the nucleophilic approach of bromide ion was
obstructed due to the steric hindrance of one of the gem-dimethyl groups at
pseudoaxial () position. Thus the reaction followed path a and migratory aptitude of
-methyl prevailed over nucleophilic attack of bromide ion and afforded 27.
Moreover, the driving force of migration of one of the gem-dimethyl groups is the
formation of sulfonium ion due to the lone pair participation of sulfur atom in the
stabilization of an intermediate positive charge on carbon atom bearing methyl group
in 28. Further, 28 with methyl at equatorial rearranged to 29 with methyl at axial due
to the existence of severe 1,3-allylic strain (A1,3)11,12 between equatorial-methyl and
R2 in 28. 28 got deprotonated to furnish 29, which again rearranged for an extended
52
double bond delocalization in presence of acidic medium (PBr3/benzene) to furnish

23a-h.
All the compounds 23a-h were characterized by spectroscopic techniques. The
rearranged product 23a and 23a showed M+ peaks at m/z 309 and 294 respectively in
FABMS spectrum. The IR spectrum of 23a and 23b showed characteristic absorption
at 1529 cm-1 and 1523cm-1 due to the conjugated ethylene group respectively. The 1H
NMR spectrum of 23a showed characteristic peaks i.e. a multiplet at 5.23 and 5.06
for two ethylene protons along with one singlet at 2.10 for three methyl protons.
Most importantly, in the 1H NMR spectrum of 22a two characteristic singlet peaks at
1.39 and 1.37 for six protons of two methyl groups disappeared in its rearranged
product 23a. The 1H NMR spectrum of other compounds also showed the similar
pattern as 23a with slightly downfield or upfield shift of signals. The
13
C NMR of
these products were also in full agreement with the assigned structures. The
possibility of formation of 33 has been ruled out from the incisive analysis of COSY,
NOESY and HMBC spectra of the rearranged product.
6'
6
7
5'
7'
4' O
8'
3'
9' 1'
2'
10 4 3 10'
2
9 S
8
11'
1
O
H
H
H
H
H
H
S
H
Figure 2.1: HMBC correlation of compound 23b.

Table 2.2 List of final products 21a-c and 23a-h during treatment of PBr3 on allylic
alcohols 20a-c, 22a-h containing thiochromene ring
Entry
R1, R4
Alcohol
Ketone
Yield
Rearranged
Yield
(%)
product
(%)
20a
OCH3, C6H4-(4-Cl)
21a
50
20b
OCH3, C6H5
21b
51
20c
OCH3, C6H4-(3-NO2)
21c
60
22a
H, C6H4-(3-NO2)
23a
63
22b
H, C6H4-(4-OCH3)
23b
53
22c
H, C6H4-{4-N(CH3)2}
23c
59
22d
H, C6H5
23d
52
22e
H, C6H4-(4-Cl)
23e
62
53
22f
H, C6H4-(4-CN)
23f
65
10
22g
H, C6H3-(2,4-Cl)
23g
61
11
22h
H, C6H4-(4-CH3)
23h
57
2.5 Reaction of PBr3 on benzo [b] thiepinone and 8-methoxy-benzo [b] thiepinone
derived Allylic alcohols:
Again, we became interested in executing the reaction of PBr3 on benzo [b]
thiepinone13 derived allylic alcohols without gem-dimethyl substituents to acertain the
effect of ring size. On treatment with PBr3 36-38 furnished bromo derivative 39-41.
Reaction of 39 with PBr3 gave an twist-chair14 like intermediate 42 with elimination
of HBr. Nucleophilic addition of bromide anion and migration of double bond gave
39. On the other hand, allylic alcohols 37 and 38 with 7-methoxy substituent afforded
bromide 44 through migration of double bond and elimination of POBr2.
Isomerization of exocyclic double bond to endocyclic leads to 40 and 41 perhaps due
to A1,3 strain11,12 and increased electron density on R2 from +R effect of 8-methoxy of
45 (Scheme 2.6, 2.7 and Table 2.3).
R2
Br
HO
Br
ii) R2 CHO
reflux 1
R
S
34a; R1 = H
34b; R1 = OMe
R1
i) n-BuLi, THF
-78 0C
PBr3
R1
R2
S
35a-b
R1
PBr 3
39;
R1
0 0C
36; R1 = H, R 2 = C 6H 4 -(4-F)
37; R1 = OCH 3, R2 =C 6H 4-(3OCH3 )
38 ; R1 = OCH 3, R2 = C 6H 5
= H, R 2 = C 6H 4 -(4-F)
R2
Br
R1
S
OCH 3 , R2 = C 6H 4-(3-OCH 3)
40;
41 ; R 1 = OCH 3 , R2 = C 6H 5
R1 =
Scheme 2.6
2.5.1 Plausible Reaction mechanism for the formation of bromo products:
F
b Br
HO
-
S
36
HO
-HBr
36
PBr3
-POBr2
Br 2 PO
S
)(
Br A1,3
H
43
F
42
Path b: Nucleophilic addition
of bromide anion
F
H
Br
S
H
Br
39
39
54
HO
PBr 3
Br 2PO
Br
Br
Br -
-HBr
H 3CO
S
37; R = H
38; R = OMe
H 3 CO
H 3 CO
S
45
H 3CO
S
40; R = H
41; R = OMe
S
45
Scheme 2.7
Table 2.3: Formation of bromo derivatives 39-41 from alcohols 36-38
Entry
Alcohol
R1, R4
Product
Yield (%)
36
H, C6H4-(4-F)
39
51
37
OCH3, C6H4-(3-OCH3)
40
53
38
OCH3, C6H5
41
57
2.6 Reaction of PBr3 on benzo[b]oxepinone derived Allylic alcohols: Similar

reaction of PBr3 on allylic alcohols 46 derived from benzo[b]oxepinone13 gave noncharacterizable products and allylic alcohols 46 was also unstable (Scheme 2.8).
HO
R
PBr3
Non-characterizable
products
O
46
Unstable
Scheme 2.8

2.7.1 General Method
All melting points were recorded in open capillaries on Remi MP-1, 4/98 melting
point apparatus and were uncorrected. IR spectra were recorded on a Perkin-Elmer
RX1 and FTIR 8201 PC Shimadzu spectrophotometers and values are expressed in
cm-1. Solid samples were recorded as KBr wafers and liquid samples as their film
between NaCl plates. Proton Nuclear Magnetic Resonance (1H NMR) and Carbon
Nuclear Magnetic Resonance
(13C NMR) spectra were generally recorded on
Advance DPX200 Bruker 200 MHz and Advance DRX200 Bruker 300 MHz
spectrometer unless otherwise mentioned. NMR samples were generally made in
chloroform-D solvent and chemical shifts were reported in scale in parts per million
(ppm) using tetramethyl-silane (TMS, Me4Si) as the internal standard. Standard
55
abbreviations s, d, t, m and dd were used to refer singlet, doublet, triplet, multiplet and
double doublet respectively. Coupling constants were reported in Hertz.
13
C NMR
assignments differing by only 2-3 ppm can in some cases be interchanged. FABMS
spectra are recorded on JEOL SX 102 Mass Spectrometer using Argon/Xenon (6kV,
10 mA) as the FAB gas. Elemental analyses were performed on Vario EL III and
Carlo Erba 1108 CHN Analyzer. All the compounds were dried in abderhalden.
Analytical thin layer chromatography (TLC) were carried out on (10 cm x 5 cm) glass
plates coated with Mercks silica gel G or GF254 (containing 13% calcium sulphate as
binder) or Mercks aluminium oxide 60 GF254 neutral or 60 HF254 basic. Visualization
of spots on TLC plates was achieved either by exposure to iodine vapour or UV light
or by spraying sulphuric acid and heating the plate at 120oC. Column chromatography
was performed using Qualigens silica gel (100-200 mesh) and basic alumina. The
amount of adsorbent used is approximately in the ratio of 1: 35 and elution was
usually done using ethyl acetate-hexane unless otherwise mentioned.
All reactions were monitored by employing TLC technique using appropriate solvent
system for development. Reactions involving oxygen sensitive reagents employed
degassed solvents. Transfer of moisture sensitive materials were carried out in a glove
box, using standard syringe-septum techniques and reaction mixtures were maintained
under nitrogen until work up. Unless otherwise mentioned all materials were obtained
from commercial suppliers. Tetrahydrofuran (THF) was distilled over sodium
benzophenone ketyl freshly prior to use. Benzene, pentane and toluene were dried
over sodium metal wire. Dichloromethanes and chloroform were distilled over P2O5.
Ethyl acetate was distilled over potassium carbonate. Dimethylsulphoxide and
dimethyl formamide were distilled over CaH2. All solvent extracts were washed
successively with water, brine and dried over anhydrous Na2SO4 and concentrated at
reduced pressure on a Buchi-E1 rotary evaporated. Yields reported are isolated yields
of materials judged homogeneous by TLC and NMR spectroscopy.
2.7.2 Chemistry
2.7.2.1 Preparation of allylic alcohols
(7-Methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-phenyl-methanol 14a:
56
To a stirred solution of 4-bromo-7-methoxy-2,2,3-trimethyl-2H-chromene 13

(0.76 g, 2.68 mmol) in dry THF (15mL) at -780C and under N2, n-butyl lithium (2.5
mL of 1.6M in hexane, 4.02 mmol), was added via a syringe in a
single portion. The resulting orange solution was stirred at -780C
HO
for 5-6 minutes after which the benzaldehyde (0.29 g, 3.35

mmol) in THF (2mL) was added in a single portion at the same
14a
temperature. This gave a pale yellow solution which was stirred
at room temperature for 1h. After quenching with water, THF was removed in vacuo.
The mixture was extracted with ethylacetate, the extract was washed with brine and
dried over sodium sulphate. The concentrated extract was subjected to column
chromatography on silica gel and elution with 10% ethyl acetate in hexane (Rf = 0.4)
furnishing 14a (0.56 g, 67%) as a white solid; mp-1350C. IR (KBr): 3471, 2929, 2362,
1606, 1503, 1361, 1198, 1029, 704 cm-1. H NMR (200 MHz, CDCl3): 7.45-7.25
(m, 5H, ArH), 6.97 (d, 1H, J = 8.6 Hz, ArH), 6.40 (d, 1H, J = 2.6 Hz, ArH), 6.24 (dd,
1H, J1= 8.6 Hz, J2= 2.6 Hz, ArH), 6.06 (s, 1H, CHOH), 3.69 (s, 3H, OCH3), 2.27 (bs,
1H, CHOH), 1.87 (s, 3H, =CCH3), 1.42 {s, 3H, C(CH3)2},1.40{s, 3H, C(CH3)2}. 13C
NMR (50 MHz, CDCl3): 160.0, 154.5, 142.7, 134.4, 128.8, 128.1, 127.3, 126.4,
125.7, 114.7, 106.8, 102.8, 79.1, 70.4, 55.5, 25.8, 25.2, 14.6. MS (FAB): m/z (%) :
310 (70, [M+]), 295 (100, [M+-CH3]), 293 (50, [M+-OH]. Anal. Calcd. C20H22O3: C,
77.39; H, 7.14. Found: C, 77.47; H, 7.17.
(3-methoxy-phenyl)-(7-methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-methanol
14b:
As described for 14a, 13 (0.72 g, 2.51 mmol) in dry THF (15mL), n-Butyl
lithium (2.38 mL of 1.6M in hexane, 3,816 mmol), 3-methoxy benzaldehyde (0.35 g,
2.54 mmol) in THF (2mL) furnished 14b (0.52 g, 60%) as a
HO
light yellow liquid; Rf = 0.4 (10% ethyl acetate in hexane). IR

(Neat): 3465, 3013, 1610, 1503, 1263, 1217, 1159, 767 cm-
O
14b
. H NMR (200 MHz, CDCl3): 7.25-7.19 (m, 1H, ArH),
11
7.03-6.90 (m, 3H, ArH), 6.80-6.79 (m, 1H, ArH), 6.39 (d, 1H, J = 2.5 Hz, ArH), 6.25
(dd, 1H, J1 = 8.6 Hz, J2 = 2.6 Hz, ArH), 6.01 (s, 1H, CHOH), 3.77 (s, 3H, OCH3), 3.67
(s, 3H, OCH3), 1.86 (s, 3H, =CCH3), 1.48 {s, 3H, C(CH3)2},1.41{s, 3H, C(CH3)2}.MS
57
(FAB): m/z (%) : 340 (90, [M+]), 325 (100, [M+-CH3]), 323 (60, [M+-OH]). Anal.
Calcd. C21H24O4: C, 74.09; H, 7.11. Found: C, 74.03; H, 7.07.
(4-Fluoro-phenyl)-(7-methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-methanol 14c:
lithium (3.3 mL of 1.6M in hexane, 5.30 mmol), 4-fluoro benzaldehyde (0.44 g, 3.53
F
HO
mmol) in THF (2mL) furnished 14c (0.65 g, 56%) as a white

solid; mp-1270C (dichloromethane); Rf = 0.4 (10% ethyl
acetate in hexane). IR (Neat): 3453, 2961, 1613, 1503, 1160,
O
14c
758 cm-1. H NMR (200 MHz, CDCl3): 7.64 (d, 1H, J = 8.2
Hz, ArH), 6.45-6.39 (m, 2H, ArH), 4.93 (t, 1H, J = 7.3 Hz,
CHOH), 3.75 (s, 3H, OCH3), 2.01 (bs, 1H, CHOH), 1.88-1.84 (m, 2H,
CHCH2CH2CH3) 1.81 (s, 3H, =CCH3), 1.51-1.67 (m, 2H, CHCH2CH2CH3), 1.41 {s,
3H, C(CH3)2},1.27{s, 3H, C(CH3)2}, 0.90 (t, 3H, J = 7.2 Hz, CHCH2CH2CH3).
13
NMR (50 MHz, CDCl3): 159.8, 154.3, 132.6, 128.6, 126.3, 115.4, 106.7, 102.7,
78.7, 55.5, 28.2, 26.0, 25.0, 19.9, 14.4. MS (FAB): m/z (%): 276 (80, [M+]), 261 (100,
[M+-CH3]), 259 (20, [M+-OH]). Anal. Calcd. C20H21FO3: C, 73.15; H, 6.45. Found: C,
73.12; H, 6.48.
1-(7-Methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-butan-1-ol 14d:
lithium (2.3 mL of 1.6M in hexane, 3.71 mmol), n butanal (0.18 g, 2.47 mmol) in
THF (2mL) furnished 14d (0.36 g, 52 %) as pale yellow oil; Rf =
HO
0.4 (10% ethyl acetate in hexane). IR (Neat): 3453, 2961, 1613,

1503, 1160, 758 cm-1. H NMR (200 MHz, CDCl3): 7.64 (d,
MeO
O
14d
1H, J= 8.2 Hz, ArH), 6.45-6.39 (m, 2H, ArH), 4.93 (t, 1H, J= 7.3
Hz, CHOH), 3.75 (s, 3H, OCH3), 2.01 (bs, 1H, CHOH), 1.88-1.84 (m, 2H,
CHCH2CH2CH3) 1.81 (s, 3H, =CCH3), 1.51-1.67 (m, 2H, CHCH2CH2CH3), 1.41 {s,
3H, C(CH3)2},1.27{s, 3H, C(CH3)2}, 0.90 (t, 3H, J= 7.2 Hz, CHCH2CH2CH3).
13
NMR (50 MHz, CDCl3): 159.8, 154.3, 132.6, 128.6, 126.3, 115.4, 106.7, 102.7,
78.7, 55.5, 28.2, 26.0, 25.0, 19.9, 14.4. MS (FAB): m/z (%): 276 (80, [M+]), 261 (100,
[M+-CH3]), 259 (20, [M+-OH]).
(4-Chloro-phenyl)-(7-methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-methanol 14e:
58
lithium (2.31 mL of 1.6M in hexane, 3.71 mmol), 4-chlorobenzaldehyde (0.35 g, 2.47
Cl
mmol) in THF (2mL) furnished 14e (0.56 g, 66%) as a white

solid; mp- 1300C (dichloromethane); Rf = 0.4 (10% ethyl acetate
HO
in hexane). IR (Neat): 3465, 2978, 1611, 1576, 1501, 1157,

O
O
14e
1085, 811 cm-1.1H NMR (200 MHz, CDCl3): 7.37-7.25 (m,
4H, ArH), 6.94 (d, 1H, J = 8.6 Hz, ArH), 6.39 (d, 1H, J = 2.5 Hz, ArH), 6.25 (dd, 1H,
J1 = 8.6 Hz, J2= 2.5 Hz, ArH), 6.00 (s, 1H, CHOH), 3.73 (s, 3H, OCH3), 2.37 (bs, 1H,
CHOH), 1.85 (s, 3H, =CCH3), 1.46 {s, 3H, C(CH3)2},1.41{s, 3H, C(CH3)2}.
13
NMR (50 MHz, CDCl3): 160.1, 154.5, 141.2, 134.7, 133.1, 128.9, 127.8, 127.2,
126.3, 114.4, 106.9, 102.9, 79.0, 69.9,55.6, 25.7, 25.2, 14.6. MS (FAB): m/z (%): 344
(90, [M+]), 331 (60, [M+-CH3]), 329 (100, [M+-OH]). Anal. Calcd. C20H21ClO3: C,
69.66; H, 6.14. Found: C, 69.57; H, 6.05.
(4-Methoxy-phenyl)-(7-methoxy-2,2,3-trimethyl-2H-chromen-4-yl)-methanol 14f:
As described for 14a, 13 (1 g, 3.53 mmol) in dry THF (15mL), n-Butyl
lithium (3.31 mL of 1.6M in hexane, 5.30 mmol), 4-methoxy benzaldehyde (0.58 g,
O
HO
4.24 mmol) in THF (2mL) furnished 14f (0.74 g, 62%) as a pale

yellow viscous oil; Rf = 0.4 (10% ethyl acetate in hexane). IR
(Neat): 3474, 2931, 1599, 1507, 1166, 1020, 831 cm-1. 1H NMR
O
14f
(200 MHz, CDCl3): 7.33 (d, 2H, J = 8.8 Hz, ArH), 6.98 (d, 1H,
J = 8.6 Hz, ArH), 6.87 (d, 2H, J = 8.8 Hz, ArH), 6.40 (d, 1H, J = 2.5 Hz, ArH), 6.26
(dd, 1H, J1 = 8.6 Hz, J2 = 2.5 Hz, ArH), 6.01 (s, 1H, CHOH), 3.79 (s, 3H, OCH3), 2.24
(bs, 1H, CHOH), 1.86 (s, 3H, =CCH3), 1.48 {s, 3H, C(CH3)2},1.42{s, 3H, C(CH3)2}.
13
C NMR (50 MHz, CDCl3): 160.0, 159.0, 154.5, 134.7, 134.2, 128.0, 127.1, 126.5,
114.7, 114.2, 106.8, 102.8, 79.1, 70.2, 55.6, 25.8, 25.21, 14.6. MS (FAB): m/z (%):
340 (50, [M+]), 323 (100, [M+-OH]). Anal. Calcd. C21H24O4: C, 74.09; H, 7.11.
Found: C, 74.22; H, 7.09.
(4-Dimethylamino-phenyl)-(7-methoxy-2,2,3-trimethyl-2H-chromen-4-yl)methanol 14g:
As described for 14a, 13 (1 g, 3.53 mmol) in dry THF (15mL), n-Butyl lithium
(3.31 mL of 1.6M in hexane, 5.30 mmol), 4-dimethylamino-benzaldehyde (0.63 g,
59
4.24 mmol) in THF (2mL) furnished 14g (0.73 g, 59%) as a white solid; mp- 1420C
(dichloromethane); Rf = 0.5 (15% ethyl acetate in hexane). IR (KBr): 3444, 2926,
N
1594, 1351, 1160, 765 cm-1. 1H NMR (200 MHz, CDCl3):

7.27 (d, 1H, J = 8.4 Hz, ArH), 7.03 (d, 1H, J = 8.6 Hz, ArH),
HO
O
6.27 (dd, 1H, J1 = 8.6 Hz, J2 = 2.5 Hz, ArH), 5.98 (s, 1H,
O
14g
CHOH), 3.70 (s, 3H, OCH3), 2.92 (s, 6H, N-(CH3)2, 1.84 (s,
3H, =CCH3), 1.48 {s, 3H, C(CH3)2}, 1.40 {s, 3H, C(CH3)2}.
13
C NMR (50 MHz,
CDCl3): 159.9, 154.4, 150.1, 133.9, 130.4, 128.1, 126.9, 126.6, 115.1, 113.0, 106.8,
102.8, 79.1, 70.5, 55.6, 41.0, 30.1, 25.9, 25.1, 14.6. MS (FAB): m/z (%): 354 (100,
[M+]). Anal. Calcd. C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: C, 74.70; H, 7.68;
N, 4.02
(4-Chloro-phenyl)-(7-methoxy-2,2-dimethyl-2H-thiochromen-4-yl)-methanol
20a:
As described for 14a, 4-bromo-7-methoxy-2,2-dimethyl-2H-thiochromene 19a (1.0 g,
3.51 mmol) in dry THF (30 mL), n-Butyl lithium (3.28 mL of 1.6M in hexane, 5.26
Cl
HO
mmol), 4-chloro benzaldehyde (0.49 g, 3.51 mmol) in THF

(2mL) furnished 20a (0.65 g, 53%) as a brown viscous yellow
oil; Rf = 0.5 (15% ethyl acetate in hexane). IR (Neat): 3417,
S
20a
2364, 1596, 1277, 1224, 1051, 770 cm-1. 1H NMR (200
MHz, CDCl3): 7.28-7.18 (m, 5H, ArH), 7.06 (d, 1H, J = 8.7, ArH), 6.75 (d, 1H, J =
2.4, ArH), 6.44 (dd, 1H, J1 =8.7, J2 = 2.4, ArH), 5.83 (s, 1H, =CH), 5.58 (s, 1H,
CHOH), 3.67 (s, 3H, OCH3), 2.20 (bs, 1H, CHOH), 1.37 {s, 6H, C(CH3)2}. 13C
NMR (50 MHz, CDCl3): 157.5, 139.6, 135.3, 133.8, 132.4, 130.3, 127.6, 127.2,
125.6, 122.4, 111.77, 110.2, 73.2, 54.2, 39.6, 27.9. MS (FAB): m/z ( %): 346 (40,
[M+]), 329 (100, [M+-OH]). Anal. Calcd. C19H19ClO2S: C, 65.79; H, 5.52. Found: C,
65.66; H, 5.61.
(7-Methoxy-2,2-dimethyl-2H-thiochromen-4-yl)-phenyl-methanol 20b:
As described for 14a, 19a (1 g, 3.51 mmol) in dry THF (30 mL), n-butyl lithium
(3.28 mL of 1.6M in hexane, 5.26 mmol), benzaldehyde (0.36 mL, 3.51 mmol) in
THF (2 mL) furnished 20b (0.59 g, 56%) as a yellow viscous yellow oil; Rf = 0.5
60
(15% ethyl acetate in hexane). IR (Neat): 3441, 2366, 1500, 1351, 670 cm-1. 1H NMR
(200 MHz, CDCl3): 7.34-7.17 (m, 5H, ArH), 7.08 (d, 1H, J =
8.7 Hz, ArH), 6.75 (d, 1H, J = 2.4 Hz, ArH), 6.44 (dd, 1H, J1
HO
=8.7 Hz, J2 = 2.4 Hz, ArH), 5.87 (s, 1H, =CH), 5.61 (s, 1H,
O
CHOH), 3.65 (s, 3H, OCH3), 2.09 (bs, 1H, CHOH), 1.37 {s, 6H,
S
20b
C(CH3)2}.
13
C NMR (50 MHz, CDCl3): 158.9, 142.5, 136.9, 135.1, 131.3, 129.0,
128.2, 127.3, 127.0, 124.2, 113.1, 111.6, 75.1, 55.6, 41.0, 29.5. MS (FAB): m/z (%):
312 (50, [M+]), 295 (100, [M+-OH]). Anal. Calcd. C19H20O2S: C, 73.04; H, 6.45.
Found: C, 73.09; H, 6.39.
(7-Methoxy-2,2-dimethyl-2H-thiochromen-4-yl)-(3-nitro-phenyl)-methanol 20c:
Yield= 53% as a brown oil; Rf = 0.5 (25% ethyl acetate in hexane). As described for
14a, 19a (1.0 g, 3.51 mmol) in dry THF (30 mL), n-butyl lithium (3.28 mL of 1.6M in
hexane, 5.26 mmol), 3-nitro benzaldehyde (0.71 g, 5.20
HO
20c
N+
O-
mmol) in THF (2 mL) furnished 20c (0.66 g, 53%) as a

brown oil; Rf = 0.5 (15% ethyl acetate in hexane). IR (Neat):
3434, 2970, 1718, 1610, 1270, 1148, 1051, 771 cm-1. 1H
NMR (200 MHz, CDCl3): 8.22 (s, 1H, ArH), 8.02 (d, 1H,
J = 2.5 Hz, ArH), 7.58 (d, 1H, J = 7.7 Hz, ArH), 7.38 (t, 1H, J = 7.9 Hz, ArH), 7.07
(d, 1H, J = 8.7 Hz, ArH), 6.70 (d, 1H, J = 2.5 Hz, ArH), 6.40 (dd, 1H, J1 = 8.7 Hz, J2
= 2.5 Hz, ArH), 5.78 (s, 1H, =CH), 5.62 (s, 1H, CHOH), 3.66 (s, 3H, OCH3), 2.52
(bs, 1H, CHOH), 1.38 {s, 6H, C(CH3)2}. 13C NMR (50 MHz, CDCl3): 159.1, 148.8,
144.7, 136.5, 135.5, 133.1, 132.9, 129.8, 127.1, 123.3, 123.0, 122.1, 113.3, 111.8,
74.9, 55.6, 41.0, 29.3. MS (FAB): m/z (%): 357 (60, [M+]), 342 (100, [M+-CH3]), 340
(50, [M+-OH]). Anal. Calcd. C19H19NO4S: C, 63.85; H, 5.36; N, 3.92. Found: C,
63.91; H, 5.43; N, 3.78.
(2,2-Dimethyl-2H-thiochromen-4-yl)-(3-nitro-phenyl)-methanol 22a:
As described for 14a, 19b (1.0 g, 3.92 mmol) in dry THF (30 mL), n-butyl lithium
(3.67 mL of 1.6M in hexane, 5.88 mmol), 3-nitroHO
22a
N+
O
S
O-
benzaldehyde (0.59 g, 3.92 mmol) in THF (2mL) furnished

22a (0.69 g, 52%) as brown oil; Rf = 0.5 (15% ethyl acetate
in hexane). IR (Neat): 3431, 2925, 2362, 1529, 1349, 768cm1 1
. H NMR (200 MHz, CDCl3): 8.25 (s, 1H, ArH), 8.05 (d,
61
1H, J = 8.1 Hz, ArH), 7.59 (d, 1H, J = 7.6 Hz, ArH), 7.44-7.36 (m, 1H, ArH), 7.18 (t,
2H, J = 9.2 Hz, ArH), 7.04-6.89 (m, 1H, ArH), 5.94 (s, 1H, =CH), 5.69 (s, 1H,
CHOH), 2.35 (bs, 1H, CHOH), 1.39 {s, 3H, C(CH3)2}, 1.37 {s, 3H, C(CH3)2} .
13
NMR (50 MHz, CDCl3): 149.2, 145.7, 137.2, 135.6, 134.7, 133.2, 131.1, 131.0,
129.2, 129.3, 126.3, 126.1, 123.8, 123.3, 96.5, 73.0, 40.5, 28.7. MS (FAB): m/z (%):
327 (40, [M+]), 312 (100, [M+-CH3]), 310 (80, [M+-OH]). Anal. Calcd. C18H17NO3S:
C, 66.03; H, 5.23; N, 4.28. Found: C, 65.91; H, 5.29; N, 4.34.
(2,2-Dimethyl-2H-thiochromen-4-yl)-(4-methoxy-phenyl)-methanol 22b:
As described for 14a, 19b (1.0 g, 3.92 mmol) in dry THF (25 mL), n-Butyl lithium
(3.67 mL of 1.6M in hexane, 5.88 mmol), 4-methoxybenzaldehyde (0.47 mL, 3.92
mmol) in THF (2mL) furnished 22b (0.67 g, 56%) as brown
O
HO
viscous oil; Rf = 0.5 (15% ethyl acetate in hexane).IR (Neat):

3379, 2923, 2361, 1612, 1352, 770 cm-1. 1H NMR (200 MHz,
CDCl3): 7.24 (d, 2H, J = 8.5 Hz, ArH), 7.16-7.12 (m, 1H, ArH),
22b
7.02-6.90 (m, 3H, ArH), 6.79 (d, 2H, J = 8.6 Hz, ArH), 6.06 (s,
1H, =CH), 5.60 (s, 1H, CHOH), 3.74 (s, 3H, OCH3 ), 1.45{s, 3H, (CH3)2}, 1.43 {s,
3H, (CH3)2}. 13C NMR (50 MHz, CDCl3): 159.4, 137.5, 134.8, 133.5, 133.1, 131.2,
129.4, 128.8, 128.3, 127.7, 125.8, 125.4, 114.8, 114.4, 74.2, 55.6, 40.7, 30.1. MS
(FAB): m/z (%): 312 (40, [M+]), 306 (100, [M+-CH3]), 304 (20, [M+-OH]). Anal.
Calcd. C19H20O2S: C, 73.04; H, 6.45. Found: C, 73.14; H, 6.51.
(4-Dimethylamino-phenyl)-(2,2-dimethyl-2H-thiochromen-4-yl)-methanol 22c:
As described for 14a, 19b (1.0 g, 3.92 mmol) in dry THF (30 mL), n-Butyl lithium
(3.67 mL of 1.6M in hexane, 5.88 mmol), 4-Dimethylamino-benzaldehyde (0.59 g,
3.92 mmol) in THF (2mL) furnished 22c (0.64 g, 51%) as a dark
N
brown oil; Rf = 0.5 (15% ethyl acetate in hexane). IR (Neat):

3405, 2922, 1611, 1520, 1354, 761cm-1. 1H NMR (200 MHz,
HO
CDCl3): 7.18-7.04 (m, 4H, ArH), 6.90-6.83 (m, 2H, ArH), 6.54
S
22c
(d, 2H, J = 8.6 Hz, ArH), 6.04 (s, 1H, =CH), 5.48 (s, 1H,
CHOH), 2.82 {s, 6H, -N(CH3)2}, 2.02 (bs, 1H, CHOH), 1.38 {d, 6H, J = 4.6 Hz,
C(CH3)2}.
13
C NMR (50 MHz, CDCl3): 159.3, 137.5, 134.8, 133.6, 129.4, 128.8,
128.3, 127.9, 127.7, 126.5, 125.8, 125.4, 114.3, 113.1, 74.2, 40.7, 38.2, 30.1. MS
62
(FAB): m/z (%): 325 (50, [M+]), 308 (100, [M+-OH]). Anal. Calcd. C20H23NOS: C,
73.81; H, 7.12; N, 4.30. Found: C, 73.97; H, 7.17; N, 4.23.
(2,2-Dimethyl-2H-thiochromen-4-yl)-phenyl-methanol 22d:
As described for 14a, 19b (1 g, 3.92 mmol) in dry THF (25 mL), n-butyl lithium (3.67
mL of 1.6M in hexane, 5.88 mmol), benzaldehyde (0.398 mL, 3.92 mmol) in THF
(2mL) furnished 22d (0.59 g, 54%) as a yellow oil; Rf = 0.5 (15%
ethyl acetate in hexane). IR (Neat): 3530, 2958, 1502, 1359, 1005,
HO
688 cm-1. 1H NMR (200 MHz, CDCl3): 7.42-7.24 (m, 7H, ArH),
7.19-6.91 (m, 2H, ArH), 6.09 (s, 1H, =CH), 5.82 (s, 1H, CHOH),
S
22d
2.15 (bs, 1H, CHOH), 1.46 {d, 6H, J= 8.6, C (CH3)2}. 13C NMR (75 MHz, CDCl3):
142,2, 136.9, 133.2, 133.1, 130.7, 128.5, 127.9, 127.7, 127.3, 126.9, 125.4, 125.0,
74.4, 40.2, 29.0, 28.9. MS (FAB): m/z (%): 282 (50, [M+]), 265 (100, [M+-OH]).
Anal. Calcd. C18H18OS: C, 76.56; H, 6.42. Found: C, 76.41; H, 6.49.
(4-Chloro-phenyl)-(2,2-dimethyl-2H-thiochromen-4-yl)-methanol 22e:
As described for 14a, 19b (0.5 g, 1.96 mmol) in dry THF (15 mL), n-butyl
lithium (1.35 mL of 1.6M in hexane, 2.15 mmol), 4-Chloro benzaldehyde (0.28 g,
1.96 mmol) in THF (2mL) furnished 22e (0.42 g, 68%) as a colourless viscous oil; Rf
= 0.5 (15% ethyl acetate in hexane).
Cl
IR (Neat): 3430, 1601,
-1 1
1463, 1436, 1257, 1218, 758 cm . H NMR (200 MHz, CDCl3):
HO
7.31-7.17 (m, 6H, ArH), 7.07-6.96 (m, 2H, ArH), 6.03 (s, 1H,
=CH), 5.68 (d, 1H, J = 2.8, CHOH), 2.27 (d, 1H, J = 2.8, CHOH),
S
22e
1.45 {s, 3H, C (CH3)2}, 1.43 {s, 3H, C(CH3)2}.
13
C NMR (50
MHz, CDCl3): 140.9, 137.1, 134.1, 133.9, 133.6, 130.8, 129.1, 128.7, 128.4, 128.0,
125.7, 125.5, 40.6, 29.3. MS (FAB): m/z (%):
316 (100, [M+]). Anal. Calcd.
C18H17ClOS: C, 68.23; H, 5.41. Found: C, 68.31; H, 5.46.

4-[(2,2-Dimethyl-2H-thiochromen-4-yl)-hydroxy-methyl]-benzonitrile 22f:
N
lithium (1.35 mL of 1.6M in hexane, 2.15 mmol), 4formylbenzonitrile (0.26 g, 1.96 mmol) in THF (2mL) furnished
HO
22f (0.39 g, 64%) as a pale yellow semi-solid; Rf = 0.5 (20%

S
22f
ethyl acetate in hexane). IR (Neat): 3433, 2231, 1606, 1217, 758

cm-1. 1H NMR (200 MHz, CDCl3): 7.61-7.48 (m, 4H, ArH),
63
7.30-7.21 (m, 2H, ArH), 7.11-6.96 (m, 2H, ArH), 5.98 (s, 1H, =CH), 5.73 (d, 1H, J =
2.4, CHOH), 2.59 (bs, 1H, CHOH), 1.44 {s, 3H, C (CH3)2}, 1.43 {s, 3H, C(CH3)2}.
13C NMR (50 MHz, CDCl3): 147.8, 136.8, 135.3, 133.8, 132.7, 130.4, 128.5,
128.2, 127.7, 125.8, 125.5, 119.1, 111.7, 75.0, 40.6, 29.2. MS (FAB): m/z (%): 307
(100, [M+]). Anal. Calcd. C19H17NOS: C, 74.23; H, 5.57; N, 4.56. Found: C, 74.31; H,
5.53; N, 4.61.
(2,4-Dichloro-phenyl)-(2,2-dimethyl-2H-thiochromen-4-yl)-methanol 22g :
lithium (1.35 mL of 1.6M in hexane, 2.15 mmol), 2,4-dichlorobenzaldehyde (0.37 g,
1.96 mmol) in THF (2mL) furnished 22g (0.45 g, 63%) as a pale
Cl
HO
yellow semi-solid; Rf = 0.5 (20% ethyl acetate in hexane). IR

(Neat): 3404, 1587, 1466, 1217, 759 cm-1. 1H NMR (200 MHz,
Cl
S
22g
{s, 3H, C(CH3)2}.
CDCl3): 7.32-6.96 (m, 7H, ArH), 6.07 (s, 1H, =CH), 5.84 (s,
1H, CHOH), 2.24 (bs, 1H, CHOH), 1.36 {s, 3H, C(CH3)2}, 1.31
13
C NMR (50 MHz, CDCl3): 138.4, 136.1, 134.7, 134.6, 133.6,
131.0, 129.8, 128.5, 128.0, 127.9, 125.8, 124.8, 69.8, 40.1, 29.2. MS (FAB): m/z (%):
350 (100, [M+]). Anal. Calcd. C18H16Cl2OS: C, 61.54; H, 4.59. Found: C, 61.48; H,
4.55.
(2,2-Dimethyl-2H-thiochromen-4-yl)-p-tolyl-methanol 22h :
lithium (1.35 mL of 1.6M in hexane, 2.15 mmol), p-tolualdehyde (0.25 mL, 2.15
mmol) in THF (2mL) furnished 22h (0.35 g, 61%) as a pale yellow
viscous oil; Rf = 0.6 (15% ethyl acetate in hexane). IR (Neat):
HO
3399, 1594, 1437, 760 cm-1. 1H NMR (200 MHz, CDCl3):

22h
7.30-6.95 (m, 8H, ArH), 6.11 (s, 1H, =CH), 5.69 (d, 1H, J = 3.4,
CHOH), 2.31 (s, 3H, CH3), 2.07 (d, 1H, J = 3.4, CHOH), 1.47 {s,
3H, C(CH3)2}, 1.45 {s, 3H, C(CH3)2}. 13C NMR (75 MHz, CDCl3): 139.6, 138.0,
137.2, 133.5, 133.3, 131.2, 130.2, 129.7, 129.3, 128.3, 127.7, 127.4, 125.7, 125.4,
74.6, 40.6, 29.4, 21.5. MS (FAB): m/z (%):
295 (100, [M+-H]). Anal. Calcd.
C19H20OS: C, 76.98; H, 6.80. Found: C, 76.91; H, 6.75.

(2,3-Dihydro-benzo[b]thiepin-5-yl)-(4-fluoro-phenyl)-methanol 36:
64
As described for 14a, 35a (1 g, 4.15 mmol) in dry THF (30mL), n-Butyl lithium
(3.89 mL of 1.6M in hexane, 6.22 mmol), 4-flurobenzaldehyde (0.45 mL, 4.15 mmol)
F
OH
in THF (2mL) furnished 36 (0.62 g, 59%) as light yellow viscous

oil; Rf = 0.5 (15% ethyl acetate in hexane).IR (Neat): 3399, 2926,
2362, 1604, 1508, 1222, 765 cm-1. 1H NMR (200 MHz, CDCl3):
36
7.48-7.44 (m, 1H, ArH), 7.36-7.28 (m, 2H, ArH), 7.16-7.14 (m,
2H, ArH), 7.08-7.04 (m, 1H, ArH), 6.91-6.82 (m, 2H, ArH), 6.35 (t, 1H, J= 7.8 Hz,
=CH), 5.52 (s, 1H, CHOH), 3.37-3.26 (m, 2H, SCH2CH2), 2.48 (bs, 1H, CHOH),
2.21-1.98 (m, 2H, SCH2CH2).
13
C NMR (50 MHz, CDCl3): 165.0, 160.1, 144.3,
143.6, 138.1, 135.6, 134.4, 129.6, 129.3, 129.1, 128.6, 128.2, 128.0, 115.6, 115.2,
76.6, 43.6, 26.2. MS (FAB): m/z (%): 286 (100, [M+]). Anal. Calcd. C17H15FOS: C,
71.30; H, 5.28. Found: C, 71.38; H, 5.23.
(E)-(8-methoxy-2,3-dihydrobenzo[b]thiepin-5-yl)(3-methoxyphenyl)methanol 37:
As described for 14a, 35b (1.0 g, 3.68 mmol) in dry THF (30mL), n-Butyl lithium
(2.5 mL of 1.6M in hexane, 4.05 mmol), 3-methoxybenzaldehyde (0.55 g, 4.10 mmol)
in THF (2mL) furnished 37 (0.77 g, 64%) as yellow viscous oil; Rf
OH
= 0.4 (15% ethyl acetate in hexane). IR (Neat): 3429, 2931, 2839,

1595, 1485, 1283, 1045, 758 cm-1. 1H NMR (200 MHz, CDCl3):
O
O
37
7.19-7.11 (m, 2H, ArH), 7.03-6.99 (m, 2H, ArH), 6.80-6.73(m, 2H,
ArH), 6.40 (t, 1H, J = 8.7, ArH), 5.58(s, 1H), 3.76 (s, 3H,
OCH3),3.75 (s, 3H, OCH3), 3.45-3.35(m, 2H), 2.25-2.15(m, 2H). 13C NMR (50 MHz,
CDCl3): 160.0, 158.6, 144.2, 143.9, 135.7, 129.6, 129.2, 129.0, 128.7, 120.2, 119.9,
114.7, 113.9, 112.5, 55.7, 43.5, 26.4. MS (FAB): m/z (%) :329 (90, M+1), 311 (45,
M-17). Anal. Calcd. C19H20O3S: C, 69.48; H, 6.14. Found: C, 69.57; H, 6.17.
(E)-(8-methoxy-2,3-dihydrobenzo[b]thiepin-5-yl)(phenyl)methanol 38:
As described for 14a, 35b (1.0 g, 3.68 mmol) in dry THF (30mL), n-Butyl
lithium (2.5 mL of 1.6M in hexane, 4.05 mmol), benzaldehyde (0.43 g, 4.10 mmol) in
THF (2mL) furnished 38 (0.68 g, 62%) as colourless viscous oil,
OH
Rf = 0.4 (10% ethyl acetate in hexane). IR (Neat): 3423, 2928,

2368, 1594, 1487, 1286, 1228, 1046, 758 cm-1. 1H NMR (200
38
MHz, CDCl3): 7.38-7.34 (m, 2H, ArH), 7.25-7.03 (m, 5H, ArH),
6.69 (dd, 1H, J1 = 2.64, J2 = 8.5, ArH), 6.29(t, 1H, J = 7.7, ArH),
65
5.51(s, 1H), 3.66 (s, 3H, OCH3), 3.35-3.26 (m, 2H), 2.18-1.95 (m, 2H). 13C NMR (50
MHz, CDCl3): 159.6, 144.2, 143.9, 135.7, 129.6, 129.5, 128.8, 128.2, 127.7, 114.7,
113.9, 112.5, 75.7, 55.7, 43.5, 26.4. MS (FAB): m/z (%): 281 (100, M-17). Anal.
Calcd. C18H18O2S: C, 72.45; H, 6.08. Found: C, 72.57; H, 6.01.
2.7.2.2 Preparation of saturated carbonyls, exocyclic olefins, rearranged
products and bromo derivatives
(7-Methoxy-2,2,3-trimethyl-chroman-4-yl)-phenyl-methanone 15a:
To a solution of carbinol 14a (0.2 g, 0.645 mmol) in dry benzene (5mL) at 00C
was added PBr3 phosphorous tribromide (0.26 g, 0.97 mmol) and mixture was stirred
for 10-15 min. at same temperature. After completion of the
reaction, reaction mixture was poured into ice cold water and
extracted with ethyl acetate. The extract was washed with brine,
O
15a
dried over anhydrous sodium sulphate and concentrated under
vacuo. The residue was chromatographed over silica gel and
elution with 10% ethyl acetate in hexane, Rf = 0.5, furnished 15a (0.17 g, 84%) as
white solid; mp-1050C (dichloromethane). IR (KBr): 2957, 1673, 1617, 1160, 1125,
702cm-1. 1H NMR (200 MHz, CDCl3): 7.81 (d, 2H, J = 7.4 Hz, ArH), 7.54-7.38 (m,
3H, ArH), 6.72 (d, 1H, J = 8.4 Hz, ArH), 6.44 (d, 1H, J = 1.9 Hz, ArH), 6.36 (d, 1H, J
= 8.4 Hz, ArH), 4.19 (d, 1H, J = 11.3 Hz, ArCH), 3.74 (s, 3H, OCH3), 2.51-2.42 (m,
1H, CHCH3), 1.45 {s, 3H, C(CH3)2}, 1.21 {s, 3H, C(CH3)2}, 0.92 (d, 3H, J = 6.7 Hz,
CHCH3).
13
C NMR (50 MHz, CDCl3): 202.67, 160.3, 154.3, 137.6, 133.4, 129.5,
129.1, 113.6, 108.0, 102.7, 78.3, 55.6, 50.9, 40.2, 28.1, 19.6, 15.7. MS (FAB): m/z
(%): 311 (70, [M++H]), 310 (40, [M+]), 205 (100, [M+-COC6H5]). Anal. Calcd.
C20H22O3: C, 77.39; H, 7.14. Found: C, 77.47; H, 7.10.
(3-Methoxy-phenyl)-(7-methoxy-2,2,3-trimethyl-chroman-4-yl)-methanone 15b:
As described for 15a, 14b (0.10 g, 0.29 mmol) in dry benzene (2.5mL),
phosphorous tribromide (0.12 g, 0.441mmol) furnished 15b (0.08 g, 79%) as
colourless oil; Rf = 0.6 (10% ethyl acetate in hexane). IR
O
(Neat): 2973, 2935, 1677, 1615, 1548, 1261, 1165, 1037, 761
O
15b
66
6.43 (d, 1H, J = 2.5 Hz, ArH), 6.35 (dd, 1H, J1 = 8.4 Hz, J2 = 2.5 Hz, ArH), 4.18 (d,
1H, J = 11.3 Hz, ArCH), 3.81 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.32-2.61 (m, 1H,
CHCH3), 1.45 {s, 3H, C(CH3)2}, 1.25 {s, 3H, C(CH3)2}, 0.93 (d, 3H, J = 6.8 Hz,
C NMR (50 MHz, CDCl3): 202.5, 160.3, 160.2, 154.4, 139.0, 130.0,
13
CHCH3).
129.1, 122.2, 120.1, 113.6, 108.0, 102.7, 78.4, 55.7, 55.6, 50.8, 40.2, 28.1, 19.6, 15.7.
MS (FAB): m/z (%): 341(50, [M++H]), 205 (100, [M+-COC6H4OCH3]). Anal. Calcd.
C21H24O4: C, 74.09; H, 7.11. Found: C, 74.00; H, 7.09.
(4-Fluoro-phenyl)-(7-methoxy-2,2,3-trimethyl-chroman-4-yl)-methanone 15c:
As described for 15a, 14c (0.25 g, 0.76 mmol) in dry benzene (5mL),
phosphorous tribromide (0.31 g, 1.14 mmol) furnished 15c (0.21 g, 83%) as light
yellow solid; mp-1200C (dichloromethane); Rf = 0.5 (5% ethyl
F
acetate in hexane). IR (KBr): 2960, 1674, 1618, 1594, 1507,
1161, 1126, 779 cm-1. 1H NMR (200 MHz, CDCl3): 7.917.84 (m, 2H, ArH), 7.12-7.03 (t, 2H, ArH), 6.69 (d, 1H, J =
O
15c
8.7 Hz, ArH), 6.43 (d, 1H, J = 2.5 Hz, ArH), 6.35 (dd, 1H, J1
= 8.4 Hz, J2 = 2.5 Hz, ArH), 4.12 (d, 1H, J = 11.2 Hz, ArCH), 3.74 (s, 3H, OCH3),
2.48-2.39 (m, 1H, CHCH3), 1.45 {s, 3H, C(CH3)2}, 1.20 {s, 3H, C(CH3)2}, 0.92 (d,
3H, J = 6.8 Hz, CHCH3). 13C NMR (50 MHz, CDCl3): 200.9, 168.5, 163.4, 160.4,
154.2, 133.6, 132.4, 132.2, 128.9, 116.3, 115.9, 113.3, 108.1, 102.8, 78.4, 55.6, 51.3,
40.2, 28.1, 19.5, 15.6. MS (FAB): m/z (%): 329 (50, [M++H]), 205 (100, [M+COC6H4F]). Anal. Calcd. C20H21FO3 C, 73.15; H, 6.45. Found: C, 73.08; H, 6.42.
1-(7-Methoxy-2,2,3-trimethyl-chroman-4-yl)-butan-1-one 15d:
As described for 15a, 14d (0.10 g, 0.36 mmol) in dry benzene (2.5 mL),
phosphorous tribromide (0.15 g, 0.55 mmol) furnished 15d (0.08 g, 75%) as light
O
(Neat): 2970, 1703, 1618, 1504, 1267, 1162, 1128, 759 cm-1.
1
MeO
O
15d
H NMR (200 MHz, CDCl3): 6.63 (d, 1H, J = 7.9 Hz, ArH),
6.38-6.32 (m, 2H, ArH), 3.67(s, 3H, OCH3), 3.26 (d, 1H, J =
11.2 Hz, ArCH), 2.18 (t, 2H, J = 7.27 Hz, COCH2CH2CH3), 2.09-2.05 (m, 1H,
CHCH3), 1.55-1.43 (m, 2H, COCH2CH2CH3), 1.36 {s, 3H, C(CH3)2}, 1.01 {s, 3H,
C(CH3)2},
0.92 (d, 3H, J = 6.8 Hz, CHCH3), 0.76 (t, 3H, J = 7.3 Hz,
COCH2CH2CH3).
13
C NMR (50 MHz, CDCl3): 212.3, 160.4, 154.6, 128.9, 111.8,

67
108.0, 102.7, 78.1, 56.0, 55.5, 40.6, 39.0, 28.2, 19.1, 17.7, 15.4, 14.1. MS (FAB): m/z
(%): 277 (20, [M++H]), 205 (100, [M+- COCH2CH2CH3]). Anal. Calcd. C16H22O3: C,
73.25; H, 8.45. Found: C, 73.12; H, 8.38.
(4-chloro-phenyl)-(7-methoxy-2,2,3-trimethyl-chroman-4-yl)-methanone 15e:
As described for 15a, 14e (0.10 g, 0.29 mmol) in dry benzene (5mL),
phosphorous tribromide (0.12 g, 0.44 mmol) furnished 15e (0.09 g, 87%) as light
Cl
yellow solid; mp-1070C (dichloromethane); Rf = 0.5 (5% ethyl

1201, 1162, 1096, 763cm-1. 1H NMR (200 MHz, CDCl3):

O
O
15e
6.68 (d, 1H, J = 8.5 Hz, ArH), 6.45 (d, 1H, J = 2.4 Hz, ArH), 6.35 (dd, 1H, J1 = 8.5
Hz, J2 = 2.5 Hz, ArH), 4.09 (d, 1H, J = 11.2 Hz, ArCH), 3.74 (s, 3H, OCH3), 2.462.37 (m, 1H, CHCH3), 1.44 {s, 3H, C(CH3)2}, 1.19 {s, 3H, C(CH3)2}, 0.92 (d, 3H, J
= 6.7 Hz, CHCH3).13C NMR (50 MHz, CDCl3): 201.2, 160.4, 154.2, 139.8, 135.5,
131.0, 129.3, 128.9, 113.2, 108.1, 102.9, 78.4, 55.6, 51.5, 40.2, 28.1, 19.1, 15.5. MS
(FAB): m/z (%): 345 (90, [M++H]), 205 (100, [M+-COC6H4Cl]). Anal. Calcd.
C20H21ClO3 C, 69.66; H, 6.14. Found: C, 69.77; H, 6.13.
(4-Chloro-phenyl)-(7-methoxy-2,2-dimethyl-thiochroman-4-yl)-methanone 21a:
As described for 15a, 20a (0.1 g, 0.29 mmol) in dry benzene (2.5mL),
phosphorous tribromide (0.12 g, 0.43 mmol) furnished 21a (0.05 g, 50%) as light
Cl
yellow oil; Rf = 0.6 (10% ethyl acetate in hexane). IR (Neat):

2926, 2373, 1650, 1479, 1224, 769 cm-1. 1H NMR (200 MHz,
CDCl3): 7.81 (d, 2H, J = 8.3, ArH), 7.37 (d, 2H, J = 8.3,
O
21a
ArH), 7.25 (d, 1H, J= 8.5, ArH), 6.71 (d, 1H, J = 2.4, ArH),
6.53 (dd, 1H, J1 = 8.5, J2 = 2.4, ArH), 4.61-4.52 (m, 1H, ArCH), 3.79 (s, 3H, OCH3),
2.29-2.07 (m, 2H, ArCHCH2), 1.51 {s, 3H, C(CH3)2}, 1.42 {s, 3H, C(CH3)2}. 13C
NMR (75 MHz, CDCl3): 199.3, 159.2, 138.9, 134.1, 134.0, 130.4, 130.2, 129.9,
127.5, 127.1, 126.7, 120.8, 114.4, 55.2, 49.0, 42.1, 31.0, 30.2, 28.1. MS (FAB): m/z
(%): 347 (100, [M++H]). Anal. Calcd. C19H19ClO2S: C, 65.79; H, 5.52. Found: C,
65.73; H, 5.49.
(7-Methoxy-2,2-dimethyl-thiochroman-4-yl)-phenyl-methanone 21b:
68
As described for 15a, 20b (0.10 g, 0.32 mmol) in dry benzene (2.5 mL),
phosphorous tribromide (0.13 g, 0.48 mmol) furnished 21b (0.05 g, 51%) as pale
yellow semi solid; Rf = 0.5 (10% ethyl acetate in hexane). IR
(Neat): 2931, 2363, 1678, 1596, 1223, 1045, 771 cm-1. 1H NMR
(200 MHz, CDCl3): 7.83 (d, 2H, J = 8.5, ArH), 7.47-7.32 (m,
O
21b
3H, ArH), 6.78 (d, 1H, J = 8.5, ArH), 6.64 (d, 1H, J = 2.6, ArH),
6.46 (dd, 1H, J1 = 8.5, J2 = 2.6, ArH), 4.61-4.55 (m, 1H, ArCH), 3.68 (s, 3H, OCH3),
2.23-2.04 (m, 2H, ArCHCH2), 1.41 {s, 3H, C(CH3)2}, 1.33 {s, 3H, C(CH3)2}.
13
NMR (75 MHz, CDCl3): 198.3, 159.2, 136.1, 134.5, 133.4, 131.2, 128.9, 127.5,
127.1, 121.8, 114.4, 55.6, 48.7, 42.0, 31.4, 30.2, 28.6. MS (FAB): m/z (%): 312 (100,
[M+]). Anal. Calcd. C19H20O2S; C, 73.04; H, 6.45. Found: C, 72.91; H, 6.44.
(7-Methoxy-2,2-dimethyl-thiochroman-4-yl)-(3-nitro-phenyl)-methanone 21c:
As described for 15a, 20c (0.10 g, 0.28 mmol) in dry benzene (2.5 mL),
phosphorous tribromide (0.11 g, 0.42 mmol) furnished 21c (0.06 g, 60%) as brown
viscous oil; Rf = 0.5 (10% ethyl acetate in hexane).
O
21c
N+
O-
IR
-1 1
(Neat): 2925, 1670, 1600, 1348, 1238, 1033, 711 cm . H

NMR (200 MHz, CDCl3): 8.65 (s, 1H, ArH), 8.27 (d, 1H, J
= 8.1, ArH), 8.01 (d, 1H, J = 7.7, ArH), 7.51 (t, 1H, J = 7.9,
ArH), 6.74 (d, 1H, J = 8.5, ArH), 6.66 (d, 1H, J = 2.6, ArH), 6.45 (dd, 1H, J1 = 8.5, J2
= 2.6, ArH), 4.59-4.50 (m, 1H, ArCH), 3.67 (s, 3H, OCH3), 2.23-1.96 (m, 2H,
ArCHCH2), 1.40 {d, 6H, J = 7.3, C(CH3)2}.
13
C NMR (50 MHz, CDCl3): 199.8,
159.0, 148.9, 137.1, 135.2, 130.4, 130.2, 127.5, 124.6, 122.7, 112.8, 112.4, 55.6, 49.0,
42.7, 31.0, 30.0, 28.8. MS (FAB): m/z (%):
358 (100, [M+]). Anal. Calcd.
C19H19NO4S: C, 63.85; H, 5.36; N, 3.92. Found: C, 63.97; H, 5.36; N, 3.90.

7-Methoxy-4-(4-methoxy-benzylidene)-2,2,3-trimethyl-chroman 16:
As described for 15a, 14f (0.10 g, 0.29 mmol) in dry benzene (5mL),
phosphorous tribromide (0.12 g, 0.44 mmol) furnished 16 (0.67
O
g, 71%) as colourless liquid; Rf = 0.8 (5% ethyl acetate in

hexane). IR (Neat): 2928, 1609, 1509, 1457, 1248, 1157, 1036,
16
830cm-1. 1H NMR (200 MHz, CDCl3): 7.41 (d, 1H, J = 8.7 Hz,
ArH), 7.17 (d, 2H, J = 7.4 Hz, ArH), 6.87-6.75 (m, 3H, ArH,
69
=CH-Ar), 6.45 (dd, 1H, J1 = 8.7 Hz, J2 = 2.5 Hz, ArH), 6.31 (d, 1H, J = 2.5 Hz, ArH),
3.76 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.76-2.70 (m, 1H, CHCH3), 1.44 {s, 3H,
C(CH3)2}, 1.30 {s, 3H, C(CH3)2}, 1.03 (d, 3H, J = 6.8 Hz, CHCH3). MS (FAB): m/z
(%): 329 (50, [M++H]), 205 (100, [M+-COC6H4F]). Anal. Calcd. C21H24O3: C, 77.75;
H, 7.46. Found: C, 77.82; H, 7.56.
[4-(7-Methoxy-2,2,3-trimethyl-chroman-4-ylidenemethyl)-phenyl]-dimethylamine 17:
As described for 15a, 14g (0.10 g, 0.28 mmol) in dry benzene (5mL),
phosphorous tribromide (0.11 g, 0.42 mmol) furnished 17 (0.07 g, 73%) as pale
N
(Neat): 2920, 1595, 1433, 1348, 1158, 1115, 1056, 613 cm-1.
1
17
H NMR (200 MHz, CDCl3): 7.41 (d, 1H, J = 8.7 Hz, ArH),
7.17 (d, 1H, J = 8.8 Hz, ArH), 6.73-6.67 (m, 3H, ArH, =CH-
Ar), 6.44 (dd, 1H, J1 = 8.7 Hz, J2 = 2.5 Hz, ArH), 6.30 (d, 1H,
J = 2.5 Hz, ArH), 3.71 (s, 3H, OCH3), 2.92 {s, 6H, N(CH3)2}, 2.82-2.78 (m, 1H,
CHCH3), 1.30 {s, 3H, C(CH3)2}, 1.18 {s, 3H, C(CH3)2}, 1.12 (d, 3H, J = 6.8 Hz,
CHCH3). MS (FAB): m/z (%): 338 (100, [M++H]). Anal. Calcd. C22H27NO2: C, 78.30;
H, 8.06; N, 4.15. Found: C, 78.22; H, 8.09; N, 4.23.
3-Methyl-2-methylene-4-(3-nitro-benzyl)-2H-thiochromene 23a:
As described for 15a, 22a (0.10 g, 0.31 mmol) in dry benzene (25 mL),
phosphorus tribromide (0.124 g, 0.458 mmol) furnished 23a (0.06 g, 63%) as pale
ON+
O
S
23a
3451, 2924, 2368, 1529, 1349, 1218, 768 cm-1. 1H NMR (200
MHz, CDCl3): 7.97-7.93 (m, 2H, ArH), 7.76-7.71 (m, 1H,
ArH), 7.36-7.17 (m, 2H, ArH), 5.23 (s, 1H, =CH2), 5.06 (s, 1H,
=CH2), 4.32 (s, 2H, CH2Ar), 2.10 (s, 3H, CH3).
13
C NMR (50 MHz, CDCl3): 148.9,
143.7, 142.7, 140.2, 139.0, 138.3, 134.4, 129.8, 127.7, 124.9, 124.8, 123.4, 122.8,
122.5, 121.7, 118.1, 32.9, 25.4. MS (FAB): m/z (%): 309 (60, [M+]). Anal. Calcd.
4-(4-Methoxy-benzyl)-3-methyl-2-methylene-2H-thiochromene 23b:
70
As described for 15a, 22b (0.10 g, 0.34 mmol) in dry benzene (25 mL),
phosphorus tribromide (0.14 g, 0.52 mmol) furnished 23b (0.05 g, 53%) as white
solid; Rf = 0.5 (10% ethyl acetate in hexane). IR (KBr): 3415,
2929, 2362, 1523, 1247, 1035, 743 cm-1. 1H NMR (200 MHz,
CDCl3): 7.72-7.69 (m, 1H, ArH), 7.40-7.39 (m, 1H, ArH), 7.217.16 (m, 2H, ArH), 6.97-6.92 (m, 2H, ArH), 6.72-6.66 (m, 2H,
S
23b
ArH), 5.19 (s, 1H, =CH2), 5.10 (s, 1H, =CH2), 4.17 (s, 2H,
CH2Ar), 3.67 (s, 3H, OCH3), 2.10 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3): 158.2,
140.9, 138.8, 138.4, 132.5, 129.9, 129.3, 124.6, 124.5, 123.0, 122.5, 117.7, 114.3,
55.6, 32.4, 25.4. MS (FAB): m/z (%): 294 (30, [M+]), 279 (100, [M+-CH3]). Anal.
Calcd. C19H18OS: C, 77.51; H, 6.16. Found: C, 77.55; H, 6.11.
Dimethyl-[4-(3-methyl-2-methylene-2H-thiochromen-4-ylmethyl)-phenyl]-amine
23c:
As described for 15a, 22c (0.10 g, 0.3 mmol) in dry benzene (2.5mL), phosphorus
tribromide (0.12 g, 0.46 mmol) furnished 23c (0.06 g, 59%) as light orange viscous
oil; Rf = 0.5 (10% ethyl acetate in hexane). IR (Neat): 3406,
N
2928, 2367, 1519, 1218, 769 cm-1. 1H NMR (200 MHz,

CDCl3): 7.72-7.61 (m, 1H, ArH), 7.45-7.32 (m, 1H, ArH),
7.16-7.12 (m, 2H, ArH), 6.86 (d, 2H, J = 8.6, ArH), 6.52 (d,
S
23c
2H, J = 8.6, ArH), 5.20-5.12 (m, 2H, =CH2), 4.12 (s, 2H,
CH2Ar), 2.80 {s, 6H, N(CH3)2}, 2.11 (s, 3H, CH3).
13
C NMR (50 MHz, CDCl3):
148.2, 138.8, 138.3, 130.1, 128.9, 124.4, 123.2, 122.3, 117.6, 113.8, 41.8, 32.3, 25.4.
MS (FAB): m/z (%): 307 (100, [M+]), 292 (60, [M+-CH3]). Anal. Calcd. C20H21NS: C,
78.13; H, 6.88; N, 4.56. Found: C, 78.20; H, 6.94; N, 4.55.
4-Benzyl-3-methyl-2-methylene-2H-thiochromene 23d:
As described for 15a, 22d (0.1 g, 0.35 mmol) in dry benzene (2.5 mL), phosphorus
tribromide (0.14 g, 0.53 mmol) furnished 23d (0.05 g, 52%) as
colourless oil; Rf = 0.5 (10% ethyl acetate in hexane). IR (Neat):
3462, 2927, 1596, 1434, 730 cm-1. 1H NMR (200 MHz, CDCl3):
S
23d
7.81-7.77 (m, 1H, ArH), 7.50-7.45 (m, 1H, ArH ), 7.28-7.09 (m,
7H, ArH ), 5.27 (s, 1H, =CH2), 5.17 (s, 1H, =CH2), 4.31 (s, 2H,
71
CH2Ar), 2.17 (s, 3H, CH3}. 13C NMR (50 MHz, CDCl3): 142.7, 140.9, 140.5, 138.8,
138.4, 129.5, 128.8, 128.4, 126.3, 124.6, 124.5, 123.0, 122.5, 117.7, 33.3, 30.1, 25.4.
MS (FAB): m/z (%) : 264 (100, [M+]). Anal. Calcd. C18H16S: C, 81.77; H, 6.10.
Found: C, 81.74; H, 6.19.
4-(4-Chloro-benzyl)-3-methyl-2-methylene-2H-thiochromene 23e:
As described for 15a, 22e (0.10 g, 0.32 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.04 mL, 0.38 mmol) furnished 23e (0.06 g, 62%) as
Cl
colourless viscous oil; Rf = 0.5 (10% ethyl acetate in hexane). IR

(Neat): 3406, 2924, 1593, 1216, 759 cm-1. 1H NMR (300 MHz,
CDCl3): 7.83 (d, 1H, J = 8.0, ArH), 7.50 (d, 1H, J = 8.0, ArH),
23e
7.40-7.20 (m, 2H, ArH), 7.19 (d, 2H, J = 8.1, ArH), 7.10 (d, 2H, J
= 8.1, ArH), 5.30 (s, 1H, =CH2), 5.17 (s, 1H, =CH2), 4.29 (s, 2H,
CH2Ar), 2.17 (s, 3H, CH3}. 13C NMR (50 MHz, CDCl3): 142.6, 140.2, 138.5, 138.4,
137.8, 131.7, 129.3, 128.5, 124.3, 124.2, 122.4, 122.1, 117.4, 32.2, 25.0. MS (FAB):
m/z (%) : 297 (30, [M+-H]). Anal. Calcd. C18H15ClS: C, 72.35; H, 5.06. Found: C,
72.22; H, 4.88.
4-(3-Methyl-2-methylene-2H-thiochromen-4-ylmethyl)-benzonitrile 23f:
As described for 15a, 22f (0.10 g, 0.33 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.04 mL, 0.39 mmol) furnished 23f (0.06 g, 65%) as pale
CN
yellow viscous oil. Rf = 0.6 (10% ethyl acetate in hexane).
IR
(Neat): 3405, 1728, 1608, 1216, 759 cm-1. 1H NMR (300 MHz,
CDCl3): 7.85 (d, 1H, J = 8.0, ArH), 7.54 (d, 2H, J = 8, ArH),
23f
7.42-7.20 (m, 5H, ArH), 5.29 (s, 1H, =CH2), 5.09 (s, 1H, =CH2),
4.35 (s, 2H, CH2Ar), 2.16 (s, 3H, CH3}. 13C NMR (50 MHz, CDCl3): 145.8, 139.9,
138.5, 137.8, 132.3, 128.7, 127.3, 124.5, 124.3, 122.3, 122.1, 117.5, 110.0, 32.9, 29.6,
25.0. MS (FAB): m/z (%) : 288 (40, [M+-H]). Anal. Calcd. C19H15NS: C, 78.86; H,
5.22; N, 4.84. Found: C, 78.71; H, 5.28; N, 4.83.
4-(2,4-Dichloro-benzyl)-3-methyl-2-methylene-2H-thiochromene 23g:
As described for 15a, 22g (0.10 g, 0.26 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.03 mL, 0.34 mmol) furnished 23g (0.06 g, 61%) as
colourless vicous oil; Rf = 0.5 (10% ethyl acetate in hexane). IR (Neat): 3422, 1649,
1517, 1216, 761 cm-1. 1H NMR (300 MHz, CDCl3): 7.82 (d, 1H, J = 7.8, ArH), 7.60
72
(d, 2H, J = 8.0, ArH), 7.48-7.26 (m, 5H, ArH), 5.26 (s, 1H,
Cl
Cl
=CH2), 5.06 (s, 1H, =CH2), 4.30 (s, 2H, CH2Ar), 2.16 (s, 3H,
CH3). 13C NMR (50 MHz, CDCl3): 143.2, 140.0, 138.4, 138.3,
137.6, 132.5, 129.8, 129.0, 127.1, 124.5, 124.4, 122.3, 122.2,
23g
117.4, 30.2, 24.9. MS (FAB): m/z (%) : 333 (100, [M+-H]). Anal.
Calcd. C18H14Cl2S; calcd. C, 64.87; H, 4.23; Found: C, 64.93; H, 4.24.

3-Methyl-4-(4-methyl-benzyl)-2-methylene-2H-thiochromene 23h:
As described for 15a, 22h (0.10 g, 0.34 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.04 mL, 0.40 mmol) furnished 23h (0.06 g, 57%) as pale
yellow viscous oil; Rf = 0.7 (5% ethyl acetate in hexane).
IR
-1 1
(Neat): 3432, 1216, 760 cm . H NMR (200 MHz, CDCl3): 7.80

(d, 1H, J = 7.8, ArH), 7.51 (d, 1H, J = 8.0, ArH), 7.38-7.26 (m,
23h
2H, ArH), 7.15-6.90 (m, 4H, ArH), 5.26 (s, 1H, =CH2), 5.18 (s,
1H, =CH2), 4.27 (s, 2H, CH2Ar), 2.28 (s, 3H, CH3), 2.17 (s, 3H, CH3). 13C NMR (75
MHz, CDCl3): 143.0, 141.1, 140.8, 139.2, 138.8, 129.1, 128.7, 128.3, 126.6, 124.5,
124.3, 123.4, 122.9, 117.6, 33.5, 31.2, 23.1. MS (FAB): m/z (%) : 277 (90, [M+-H]).
Anal. Calcd. C19H18S: C, 81.97; H, 6.52. Found: C, 81.94; H, 6.45.
4-Bromo-5-(4-fluoro-benzylidene)-2,3,4,5-tetrahydro-benzo[b]thiepine 39:
As described for 15a, 36 (0.2 g, 0.79 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.32 g, 1.18 mmol) furnished 97 (0.14 g, 51%) as brown
F
viscous oil; Rf = 0.5 (10% ethyl acetate in hexane). IR (Neat): 3442,

2360, 1651, 1525, 1217, 1022, 771 cm-1. 1H NMR (200 MHz,
Br
CDCl3): 7.47-7.38 (m, 3H, ArH), 7.18-6.97 (m, 5H, ArH), 6.86
(s, 1H, =CHAr), 4.99-4.94 (m, 1H, CHBr), 3.58-3.48 (m, 2H,
39
SCH2), 2.29-2.21 (m, 1H, SCH2CH2), 2.06-1.98 (m, 1H,

13
SCH2CH2). C NMR (50 MHz, CDCl3): 161.3, 140.3, 138.5, 134.4, 134.1, 130.3,
129.8, 128.8, 126.4, 126.1, 125.7, 123.4, 114.3, 113.0, 39.3, 32.4, 31.3. MS (FAB):
m/z (%): 349 (100, [M+]). Anal. Calcd. C17H14BrFS C, 58.46; H, 4.04. Found: C,
58.60; H, 4.11.
(E)-4-bromo-8-methoxy-5-(3-methoxybenzyl)-2,3-dihydrobenzo[b]thiepine
40:
As described for 15a, 38 (0.10 g, 0.30 mmol) in dry benzene (2.5 mL), phosphorus
73
tribromide (0.03 mL, 0.37 mmol) furnished 97 (0.06 g, 53%) as brown viscous oil; Rf
= 0.7 (10% ethyl acetate in hexane). IR (Neat):3012, 2937, 2369, 1600, 1477, 1219,
1042, 768 cm-1. 1H NMR (300 MHz, CDCl3): 7.44 (d, 1H, J =
8.7, ArH), 7.29 (s, 1H, ArH), 7.18 (t, 1H, J = 7.8, ArH), 6.92 (dd,
Br
1H, J1 = 2.1, J2 = 9.0 ArH), 6.72 (t, 3H, J = 7.8, ArH), 4.15 (s,
2H, Ar-CH2), 3.86 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.58-3.51
40
(m, 2H, SCH2), 3.44-3.36 (m, 2H). 13C NMR (75 MHz, CDCl3):
159.8, 157.4, 141.0, 139.8, 134.4, 134.0, 130.5, 129.5, 122.8, 120.4, 114.1,114.0,
111.3, 105.0, 55.5, 55.0, 32.3, 32.1, 31.3. MS (FAB): m/z (%): 390(97, M+), 391(78,
M+1), 392(100, M+2), 393(22, M+3). Anal. Calcd. C19H19BrO2S: C, 58.32; H, 4.89.
Found: C, 58.37; H, 4.86.
(E)-5-benzyl-4-bromo-8-methoxy-2,3-dihydrobenzo[b]thiepine 41:
As described for 15a, 38 (0.10 g, 0.36 mmol) in dry benzene (2.5 mL),
phosphorus tribromide (0.04 mL, 0.40 mmol) furnished 97 (0.07 g, 57%) as pale
3062, 2995, 2835, 2366, 1602, 1478, 1268, 1233, 1059, 760cm-1.
Br
O
41
H NMR (300 MHz, CDCl3): 7.39 (d, 1H, J = 8.7, ArH), 7.24 (t,
3H, J = 9.6, ArH), 7.17 (d, 1H, J = 6.9, ArH), 7.11 (d, 2H, J = 7.5,
ArH), 6.89(dd, 1H, J1 = 2.1, J2 = 9.0, ArH), 4.15 (s, 2H, ArCH2),
3.83 (s, 3H, OCH3), 3.49 (t, 2H, J = 6.2, SCH2), 3.38 (d, 2H, J = 6.3). 13C NMR (50
MHz, CDCl3): 158.6, 141.8, 138.4, 134.4, 134.1, 132.5, 128.5, 127.2, 124.8, 114.0,
111.3, 108.0, 55.5, 33.3, 32.6, 31.0. MS (FAB): m/z (%): 360(98, M+), 361(42, M+1),
362(100, M+2), 363(32, M+3). Anal. Calcd. C18H17BrOS: C, 59.84; H, 4.74. Found:
C, 59.88; H, 4.75.
2.8 Conclusion
Herein, we report some facile and straightforward reactions of phosphorus tribromide
on chroman, thiochroman, 2,3-dihydrobenzo[b]thiepine derived allylic alcohols
leading to the formation of saturated ketones, exocyclic olefins, methyl migrated
products 23a-h, bromo derivatives 39-41 The mechanisms involved in these reactions
are also well demonstrated by elaborating the effect of R1, R2 and heteroatom
substituent on polarization of the double bond in allylic alcohols. The chromene
containing allylic alcohols having high electron-donating substituent both at R1 and
74
R2 furnished exocyclic olefins. While saturated carbonyls are obtained when high
electron-withdrawing substituent at R2 are present in the allylic alcohols containing
chromene ring. The thiochromene containing allylic alcohols 20a-c having OCH3 at
R1 and electron withdrawing substituent at R2 also furnished satutated carbonyls 21ac. When electron-donating group (OCH3) is absent at R1 like in 22a-h, the reaction
involves a sequence of rearrangement reactions.
2.9 References
1. (a) Miyaura, N.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992, 33, 2571-2574.
(b) Effenberger, F.; Kesmarszky, T. Chem. Ber. 1992, 125, 2103 and references
therein..
2. Corey, E. J.; Kirst, H. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1970, 92,
6314-6320..
3. (a) Shi, Y.-L.; Shi. M. Org. Lett. 2005, 7, 3057-3060 and references cited there in.
(b) Jang, K. H.; Lee, B. H.; Choi, B. W.; Lee, H.-S.; Shin, J. J. Nat. Prod. 2005, 68,
716-723..
4. (a) Shagufta, Parai, M. K.; Panda, G. Tetrahedron Lett. 2005, 46, 8849-8852. (b)
Shagufta, Srivastava, A. K.; Panda, G. Tetrahedron Lett. 2006, 47, 1065-1070.
5. (a) Van der Drift, R.C.; Bouwman, E.; Drent, E. J. Organomet. Chem. 2002, 650,
1-27. (b) Uma, R.; Crvisy, C.; Gre, R. Chem. Rev. 2003, 103, 27 and references
therein. (c) Trost, B.M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259..
6. (a) Andrist, A.H.; Slivon, L.E.; Graas, J. E. J. Org. Chem. 1978, 43, 634-637. (b)
Otsuka, S.; Tani, K. Synthesis 1991, 665. (c) Tanaka, K.; Fu, G. C. J. Org. Chem.
2001, 66, 8177-8186 and references therein. (d) Kitamura, M.; Manabe, K. Noyori, R.
Takaya, H. Tetrahedron Lett. 1987, 28, 4719-4720. (e) Larson, G. L.; Prieto, J. A.;
Hernandez, A. Tetrahedron Lett. 1981, 22, 1575-1578. (g) Bankston, D.; Fang, F.;
Huie, E.; Xie, S. J. Org. Chem. 1999, 64, 3461-3466. (h) Negishi, E.; Zhang, Y.;
Bagheri, V. Tetrahedron Lett. 1987, 28, 5793-5796. (i) Denmark, S. E.; Rivera, I. J.
Org. Chem. 1994, 59, 6887-6889. (j) Hanessian, S.; Delorme, D.; Beaudoin, S.;
Leblanc, Y. J. Am. Chem. Soc. 1984, 106, 5754-5756. (k) Denmark, S. E.; Amburgey,
J. J. Am. Chem. Soc. 1993, 115, 10386-10387. (l) Corey, E. J.; Seibel, W. L.
Tetrahedron Lett. 1986, 27, 905-908. (m) Liebeskind, L. S.; Mitchell, D.; Foster, B. S.
75
J. Am. Chem. Soc. 1987, 109, 7908-7910. (n) Hutchinson, D. K.; Fuchs, P. L. J. Am.
Chem. Soc. 1987, 109, 4755-4756. (o) Shibasaki, M.; Sodeoka, M.; Ogawa, Y. J. Org.
Chem. 1984, 49, 4096-4098. (p) Negishi, E.; Zhang, Y.; Cederbaum, F. E.; Webb, M.
B.; J. Org. Chem. 1986, 51, 4080-4082. (q) Cho, S. H.; Liebeskind, L. S. J. Org.
Chem. 1987, 52, 2631-2634.
7. Shagufta, Raghunandan, R.; Maulik, P. R.; Panda, G. Tetrahedron Lett. 2005, 46,
5337-5341.
8. (a) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.;
Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 52085217. (b) Otsuka, S.; Tani, K. Synthesis 1991, 665. (c) Chapuis, C.; Barthe, M.; de
Saint Laumer, J.-Y. Helv. Chim. Acta. 2001, 84, 230.
9. Akuamoah, R. K.; Brown, P. E.; Marcus, W. Y.; Steele, J. E. J. Chem. Soc. Perkin
Trans 1. 1995, 197..
10. (a) Gabbutt, C.D.; Hartley, D.J.; Hepworth, J.D.; Heron, B.M.; Kanjia, M.;
Rahman, M.M. Tetrahedron, 1994, 50, 2507-2522. (b) Gabbutt, C.D.; Hepworth,
J.D.; Heron, B.M. J. Chem. Soc. Perkin Trans 1, 1994, 653.
11. (a) Johnson, F. Chem. Rev. 1968, 68, 375; (b) Hoffman, R.W. Chem. Rev. 1989,
89, 1841-1860. (c) Rabideau, P. W.; "The Conformational Analysis of 1,4Cyclohexadienes and Related Hydroaromatics," in The Conformational Analysis
of Cyclohexenes, Cyclohexadienes and Related Hydroaromatic Compounds,
VCH, 1989a, p. 47-63. (d) Gundermann, K.D. Angew. Chem. Int. Ed. 1963, 2.
674-683. (e) Smith, D.G. J. Chem. Soc. Perkin Trans 1, 1990, 3187-3191. (f)
Mackenzie, N.E.; Thomson, R.H. J. Chem. Soc. Perkin Trans 1, 1982, 395-402.
12.
Rabideau,
P.
W.;
The
Conformational
Cyclohexadienes
and
Related
Analysis
ydroaromatic
of
Compounds,
Cyclohexenes,
Methods
in
Stereochemical Analysis, VCH Publishers, 1989, p1.

13. Tondon, V. K.; Khanna, J. M.; Anand, N.; Srimal, R. C.; Prasad, C. R.; Kar, K.
Ind. J. Chem. 1975, 13, 1-8.
14. (a) Dsilets, S.; St-Jacques, M. J. Am. Chem. Soc. 1987, 109, 1641-1648. (b)
Dsilets, S.; St-Jacques, M. Tetrahedron 1988, 44, 7027-7036. (c) Mnard, D. ; StJacques, M. Tetrahedron 1983, 39, 1041-1060. (d) Lachapelle, A.; St-Jacques, M.
Can. J. Chem. 1987, 65, 2575.
76
2.10 Spectra
N
HO
S
22c
Figure 2.2 1H NMR (200 MHz, CDCl3) spectrum of 22c.
23c

77
23c
Figure 2.4 13C NMR (50 MHz, CDCl3) spectrum of 23c.
N+
O-
S
21c
78
21c
N+
O-
Figure 2.6
13
C NMR (50 MHz, CDCl3) spectrum of 21c.
F
HO
O
14c
79
F
HO
O
14c
Figure 2.8
13
F
O
15c
80
F
O
15c
Figure 2.10
13
OH
36
Figure 2.11 1H NMR (200 MHz, CDCl3) spectrum of 36.
81
OH
36
Figure 2.12
13
C NMR (50 MHz, CDCl3) spectrum of 36.
Br
39
Figure 2.13 1H NMR (200 MHz, CDCl3) spectrum of 39.
82
Chapter 3
Design, Synthesis and Antitubercular Activity of
Biaryl and Triarylmethane Derivatives
Chapter 3: Design, Synthesis and Antitubercular Activity of Biaryl and Triarylmethane Derivatives
3.1 Introduction
Tuberculosis (TB) is an age-old disease known to civilization since pre-historic
times and it is caused by a germ called Mycobacterium tuberculosis which is
transmitted from person to person by airborne droplets. Even now, it is the worlds
second commonest cause of death from infectious disease, after HIV/AIDS.1 The
current survey says that nearly 32 per cent of the human population (nearly 1.9 billion
people) is infected with the TB pathogen. Approximately 9 million of these infected
people develop active disease and more than two million of these patients die from it
each year.2 In India alone one person dies of TB every minute. Approximately 50% of
Indias population is reported to be tuberculin test positive. Despite the fact that it is
treatable and preventable, the disease has been spreading at a steady rate over the past
decade. The main reason for gloomy picture of this disease is the malnutrition leading
to reduced immunity.3 In many cases of the association of TB and HIV infections
nearly two-thirds of the patients diagnosed with TB are also HIV-1 seropositive.4
Furthermore, numerous studies have shown that TB is a cofactor in the progression of
HIV infection.5 The resurgence of TB infection is further complicated by an increase
in cases that are resistant to all five first line clinically prescribed antitubercular
drugs.6,7 In the developing world, probably 50% of HIV seropositive individuals are
co-infected with TB. Tuberculosis usually affects the lungs (as pulmonary TB), but it
can spread to the kidneys, bones, spine, brain and other parts of the human body.
Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium canetti, and Mycobacterium microti also cause tuberculosis, but these
species are less common. Symptoms of TB in the lungs may include a bad cough that
lasts 3 weeks or longer, weight loss, coughing up blood or mucus, weakness or
fatigue, fever and chills, night sweats etc.
Antitubercular drug therapy is more problematic especially in those countries
which lack the necessary health care organization to provide the long and costly
treatment adapted to patients. Thus, new drugs are necessary to enhance better
antitubercular activity and to shorten the treatment regimen. In the last several years,
the research on M. tuberculosis has undergone much progress. Regimens have been
optimized along with the implementation of the Directly Observed Therapy
Shortcourse (DOTS) initiative. The genome of M. tuberculosis was unraveled at the
83
laboratory level8,9 and much work provided insights into the mechanisms of action of
the antituberculosis drugs currently used.
3.2 Antitubercular Drugs

Although tuberculosis has co-evolved with humans for many thousands of years,
until 50 years ago there were no medicines to cure TB. The first breakthrough in the
chemotherapy of tuberculosis was the introduction of streptomycin in 1946.
Streptomycin 7 (Figure 3.1) is an aminoglycoside antibiotic derived from
Streptomyces griseus. It is made up of three components, streptidine, streptose and Nmethyl-L-glucosamine. It is poorly absorbed from gastrointestinal tract and thus
administered intramuscularly. Concentration of streptomycin of the order of 1 g/ml
inhibits the growth of M. tuberculosis H37Rv. The drug exerts its effect by interfering
with bacterial protein synthesis. It penetrates the inner membrane of M. tuberculosis
and binds to the 30S subunit of the ribosome.10
Latent TB treatment usually requires a single antibiotic, while active TB disease is
best treated with combinations of several antibiotics, to reduce the risk of the bacteria
developing antibiotic resistance. The drugs that have been used to fight tuberculosis
include rifampin 1, isoniazid 2, ethambutol 3, pyrazinamide 4, kanamycin 5, amikacin
6, capreomycin 1A 8, levofloxacin 9, p-aminosalicylic acid 10, ethionamide 11 and
cycloserine 12. Among them, the first line tuberculosis drugs include rifampin 1,
isoniazid 2, ethambutol 3 and pyrazinamide 4 (Figure 3.1).
Rifampin
Rifampin (RIF) 1 is extremely effective against MTB with very low MICs of
0.1 to 0.2 g/ml.11 RIF had long been believed to target the mycobacterial RNA
polymerase and thereby kill the organism by interfering in the transcription process.
RIF specifically inhibits the transition from synthesis of short oligoribonucleotides to
full-length transcripts.
Isoniazid (INH)
Isoniazid (INH) 2 is a prodrug that requires activation by the mycobacterial
catalase peroxidase enzyme (katG) to an active form, which then exerts a lethal effect
on intracellular targets. INH is highly active against the MTB complex pathogens (M.
tuberculosis, M. bovis, M. africanum and M. microti) with very low MICs (0.02 to
0.06 g/ml).12 INH enters the organism through diffusion and oxygen-dependent
84
active transport.13 The drug has been reported to affect virtually every aspect of
mycobacterial metabolism. Many components of M. tuberculosis have been proposed
as possible targets of INH. It inhibits the synthesis of mycolic acids (long chain
branched hydroxylated fatty acids) in M. tuberculosis by affecting an enzyme
mycolase synthase, which is unique for mycobacteria.14
Figure 3.1 Structures of currently used first-line and second-line drugs for treating TB.
Pyrazinamide (PZA)
Pyrazinamide (PZA) 3, a structural analog of nicotinamide, is a first-line drug
for short-course tuberculosis therapy. It is active against semidormant a bacillus
which is not affected by any other drug. It has strong synergy with INH and RIF and
shortens the therapy period for tuberculosis treatment up to 6 months. It shows no
significant bactericidal effect and is primarily considered a sterilizing drug.15
Ethambutol (EMB)
Ethambutol (EMB) 4, a synthetic compound with profound antimycobacterial
activity, is a first line anti-TB drug. The core of the mycobacterial cell wall is the
complex mycolylarabinogalactanpeptidoglycan formed by three covalently attached
macromolecules, viz. mycolic acid, peptidoglycan and arabinogalactan. The target of
the ethambutol lies in the pathway for the biosynthesis of cell wall arabinogalactan.16
These first-line antituberculosis drugs INZ, RIF, EMB and PZA can be given as
single-drug formulations or as fixed-dose combination (FDC) formulations where two
or more drugs are present in fixed proportions in the same formulation. This
recommended treatment regimen is highly effective and the rates of severe adverse
85
reactions are low. However, unpleasant side effects and relatively long course of
treatment are the drawbacks, which increase the rate of non-compliance to treatment
regimen. Such non-adherence with the course of treatment leads to treatment failure
and the development of drug resistance.
3.3 Small Molecules as Chemical Probes and Drug Leads for TB

In addition to their long standing value as drugs and therapeutics, natural and
synthetic small molecules have found great utility as chemical probes for identifying
protein targets, unraveling mechanisms of action, and studying biological systems on
a global scale. In tuberculosis research, besides target identification and validation,
recent efforts have been focused on discovery of new classes of antibiotics and
improving the pharmacologic properties of those already in use to shorten treatment
duration and expand efficacy to MDR-TB and XDR-TB. A variety of approaches
have been taken in attempts to identify new drug classes; the successful outcomes of
some of these studies have in turn provided new chemical probes for further study of
Mtb.
Two related nitroimidazole derivatives 18 (PA-824)17 and 19 (OPC-67863)18 are
among the most promising current anti-TB drug candidates. Both compounds have
been shown to be prodrugs requiring activation by the same F420-dependent enzyme
(Rv3547)18,19 and to inhibit the growth of Mtb and MDR-TB by inhibiting mycolic
acid biosynthesis and protein synthesis. However, the active species and ultimate
targets of each remain unknown. Both 18 and 19 are currently being evaluated in
phase II clinical trials.
Recently, diarylquinoline 20 (TMC 207)20 was reported as a potent inhibitor of
Mtb, M. smegmatis, and MDR-TB with ATP synthase target that appears to be
essential to mycobacteria.20 Compound 20 was identified from a library of
diarylquinolines using a whole cell screen on M. smegmatis and it appeared to be
more potent than both INH and RIF and showed no cross resistance with other
antimycobacterials. In mouse studies, combinations of 20 with any two of the drugs
INH, RIF and PZA was more effective than the standard combination of INH, RIF,
and PZA suggesting that substitution of one of them by 20 has the potential to shorten
current TB therapies. Compound 20 is currently in phase II development.
Compound 17 (LL-3858 or Sudoterb)21 represents a new class of anti-TB
compound being developed by Lupin Limited (India). 17 was reported to be active
86
against both sensitive and drug-resistant Mtb, suggesting a new mechanism of action.
In mice studies, 17 showed similar activity as INH and in combination with INH, RIF,
and PZA was effective in eradicating sensitive and resistant Mtb within two months.
Compound 17 is now in multidose phase I clinical development.
Figure 3.2 Structures of promising antitubercular lead compounds in various stages of

development.
Several derivatives of currently used antibiotics are also exhibiting promising

antitubercular activity. Gatifloxacin (GAT, 21) and moxifloxacin (MXF, 22) are new
fluoroquinolone DNA gyrase inhibitors that offer advantages over currently used
second line fluoroquinolines ofloxacin and ciprofloxacin. Compound 22 displayed
anti-TB activity comparable to INH in a mouse model and has been shown to kill
rifampin-resistant Mtb populations and when administered with INH, RIF, and PZA,
to be more effective at killing Mtb than the 3-drug treatment on its own.22
Fluoroquinolines 21 and 22, currently in phase III, are the most advanced anti-TB
compounds in clinical development showing promise to be the first new anti-TB
drugs in nearly 30 years. Rifapentin, rifabutin, rifalazil, and rifametane, all
semisynthetic derivatives of the natural product rifamycin, are in various phases of
clinical trials showing enhanced activity toward Mtb and improved pharmacokinetic
properties.23,24
87
Compound 16 (SQ109) is a derivative of ethambutol,25 and was reported to act

synergistically with INH and RIF and to exhibit improved pharmacokinetic profiles.
Although 16 is a second generation EMB derivative, it does not appear to inhibit cell
wall biosynthesis as does its parent compound. Compound 16 is currently in phase I
evaluation. Other new classes of anti-TB compounds currently in preclinical testing
include derivatives of the natural product capuramycin, oxazolidinones and sulfonylcarboxamides. Capuramycins inhibit translocase I, an enzyme involved in the
biosynthesis of peptidoglycan, a key component of the cell wall. The most active
capuramycin derivative identified todate is 13 (RS-118641).26 Linezolid27 (14) is a
synthetic oxazolidinone that acts by inhibiting protein synthesis. The compound was
approved by the FDA and has been used on occasion in patients with MDR-TB. Sulfonylcarboxamide 15 (FAS20013),28 shown to be active against MDR- and latent
TB, was designed to be a transition state mimic for -ketoacyl synthase, the
condensing enzyme required for fatty acid biosynthesis. The synthesis was inspired by
the activities of the natural products cerulenin and thiolactomycin which inhibit the
two-carbon homologation catalyzed by -ketoacyl synthase.
3.4 Basis of Present Work

Towards an ongoing program for developing new antitubercular agents, the
antitubercular activity of several diaryloxy methanophenanthrene derivatives 23 and
24 and 4-[10-(methoxybenzyl)-9-anthryl]phenol derivatives 25 (Figure 3.3) with
basic amino alkyl or amino hydroxyl alkyl side chains was reported.29 These
compounds are phenanthrene and anthracene containing triarylmethane derivatives
and exhibited 1.56-25 g/mL antitubercular activity in vitro. Most importantly, in
case of phenanthrene containing triarylmethane derivatives, one compound was
reported to have significant in vivo antitubercular activity in a mouse model of
tuberculosis infection but it was toxic.29a
OMe
OMe
23
OMe
R
O
R= 2o or 3o Amines, NMe2, NEt2 , N
OH
24
,N
25
and N
Figure 3.3 Structures of diaryloxy methanophenanthrenes and 4-[10-(methoxybenzyl)-9anthryl]-phenols with basic amino alkyl or amino hydroxy alkyl side chains.
88
It is also reported that some of the biphenyl methanone derivatives are known to
possess antimycobacterial activity.30 In order to understand and determine SAR of
triarylmethane derivatives, necessary for enhanced anti-TB activity, we first
embarked on the design, synthesis and antitubercular activity of diarylmethane
derivatives with alkylaminoethyl chains.
Simultaneously, we also paid our attention towards the synthesis of certain
focused libraries of new triarylmethane derivatives (TRAMs) through the
incorporation of heteroaryl moiety such as thiophene, indole, pyridine, pyrrole as one
of the aryl substituents in triarylmethane nucleus. We also intend to incorporate
chlorine, fluorine, methoxy and thiomethoxy substituted phenyl ring since it is
observed that the presence of these substituents in a molecule can profoundly affect
its biological properties.31-33 Moreover, several amino alcohol derivatives such as
ethambutol are well known to exhibit antitubercular activity.34 Thus in our program
also, we intended to incorporate 2-hydroxy-amino functionality on thiophene
containing pharmacophore for further diversification and thus designed to synthesize
26, 27, and 28 as our target molecules (Figure 3.4).
R2
O
OMe
1
Ar
OH
R2
O
R2
O
26 OCH3
27
28
Ar = 2-Thiophenyl,
o
o
i
R= 2 or 3 Amines, NMe2, NEt2, N( Pr)2 (1-Benzenesulf onyl-1H-Indole-3-yl ),
Pyridine-3-yl,(1-Benzyl-1H- Pyrrole-2-yl)
N O
N
N
N
R1 = OMe, SMe, Cl, F.
Figure 3.4 General structures of designed molecules
3.5 Results and Disscussion

Initially synthesis of aminoalkyl derivatives of unsubstituted diarylmethane
derivatives was carried out. The reaction of Grignard reagent derived from 4bromoanisole 29 with 4-benzyloxybenzaldehyde 30 furnished carbinol 31 which was
dehydrogenated under H2, Pd/C conditions. It was found that the above reaction
resulted into the simultaneous debenzylation and removal of hydroxyl functionality of
31 to furnish diarylmethane 32. The reaction of 32 with two alkylamine hydrochloride
chains in the presence of anhydrous K2CO3 and dry acetone led to the formation of
compounds 33a and 33b in 66% and 71% yields respectively (Scheme 3.1). By
89
treatment of amines 33a and 33b with ethanolic hydrogen chloride the corresponding
salts were prepared.
R2
OCH3
OH
OBn
CHO
b
Mg/ THF
+
Br
OBn
29
30
HO
r.t
OCH3
OCH3
OCH 3
32
31
33
Scheme 3.1
Reagents and Conditions: a) Mg, THF, RT, 2 h, 73 % b) Pd/C, H2, RT, 1h, 95 % c)
ClCH2CH2NRR.HCl, K2CO3, acetone, 66-71%
Next, we became interested in synthesizing TRAMs containing indole, pyridine,
pyrrole and thiophene rings. The designed compounds were synthesized essentially
following the steps as depicted in (Scheme 3.3 and Scheme 3.4).
Initially triarylmethane (TRAMs) containing indole, pyrrole and pyridine
heteroaryl moieties were synthesized to evaluate their antimycobacterial activity.
Nucleophilic addition of Grignard reagents generated from 29 onto different
heteroaryl carbaldehyde 34-36 in THF furnished the carbinol derivatives 37-39 in
excellent yields. The resulting alcohols 37-39 were well characterised by IR, NMR
and MS spectra. Subsequent Friedel-Crafts arylation of carbinols 37-39 with phenol in
the presence of conc. H2SO4 or anhydrous AlCl3 provided 40-42 as major product by
nucleophilic attack of phenol through para carbon atom of benzene ring. The reaction
of 40, 41 and 42 with different dialkylaminoethyl chloride hydrochlorides in the
presence of anhydrous K2CO3 and dry acetone led to the formation of aminoalkyl
derivatives 43a-e, 44a-f and 45a-d in good yields respectively (Scheme 3.3). The
ethanolic HCl salts of 43a-e, 44a-f and 45a-d were found to be moderate active
against M. Tuberculosis H37Rv in vitro with MIC in the range of 6.25, 12.5 and 25
g/mL (Table 3.1).
H3CO
+ ArCHO
Br
H3CO
a
OH
29
37-39
Ar = (1-Benzenesulfonyl-1H-Indole-3-yl ), 34
= (1-Benzyl-1H- Pyrrole-2-yl), 35
= Pyridin-3-yl, 36
OHH3CO
c
H3CO
Ar
Ar
40-42
Major
R2
Ar
43a-e, 44a-f, 45a-d
Scheme 3.2
0
Reagents and conditions: (a) Mg, THF, 0 C-rt, 2 h, 37 (72%), 38 (68%), 39 (63%). (b)
phenol, conc. H2SO4 (cat.) or anhy. AlCl3, dry benzene, reflux, 2 h, 40 (60%), 41
90
(62%), 42 (52%) (c) alkylaminoethyl hydrochloride (ClCH2CH2R2.HCl), anhy.

K2CO3, dry acetone, reflux, 6-7 h, (yields given in Table 3.1)
Next, we focused to synthesize a library of triarylmethanes (TRAMs) containing
thiophene nucleous. Compounds in this series were synthesized essentially following
the same route as depicted above (Scheme 3.2). The compounds 49a-e were
characterized from its deshielded doublet aromatic protons and singlet methine proton
resonances respectively than corresponding para isomers 50a-e due to the presence of
I inductive effect of ortho-hydroxy group. The structural identity of 49a-e and 50a-e
were further confirmed by their 13C NMR and mass spectrum fragmentation analysis.
In this competitive reaction, the generation of compound 49a-e and 50a-e could be
attributed to the fact that Friedel-Crafts alkylation occurs via attack of phenol at both
ortho and para position of the benzene nucleus with the carbinol 49a-e.
Aminoethylated products 51a-e, 52a-g, 53a-g, 54a-g 55a-g and 56a-g were
synthesized in good yields (Scheme 2.3). The corresponding salts were obtained after
treating the amines with ethanolic HCl. Initial bioevaluation of the compounds 51a-e,
52a-g, 53a-g, 54a-g 55a-g and 56a-g gave interesting antitubercular activity results in
vitro with MIC in the range of 12.5 to 0.56 g/mL (Table 3.1).
To evaluate the anti-TB activity of 2-hydroxy amino alkyl derivatives of 50b the
compound 50b was reacted with epichlorohydrin in presence of K2CO3 to furnish the
oxirane 57 in good yield (86%). The oxirane was then reacted with selected primary
and secondary amines to furnish a variety of 2-hydroxy amino alkyl derivatives (58ak), (Scheme 3.3).
91
R1
R1
S
R2
a
+ Y
S
X
1
R = m-OCH3 , X = Br, 46a Y= CHO, 47a
= Br,
47b
= p-OCH 3 , X = Br, 29
= p-SCH 3, X = Br, 46b
= p-Cl,
X = CHO, 46c
= p-F,
X = CHO, 46d
R1
R2
51a-e
R1
R1
OH
48a-e
S
c
R2
50a-e
OCH 3
K2CO3
R 1= m-OCH 3, 52a-g
= p-OCH3 , 53a-g
= p-SCH 3, 54a-g
55a-g
= p-Cl,
= p-F,
56a-g
OCH 3
OCH3
Amines (R2 H)
Epichlorohydrin S
Reflux, 86%
OH
50b
R2
Ethanol
Reflux
O
57
49a-e
R1
S
c
OH
O
58 a-k
R2
Scheme 3.3
Reagents and conditions: (a) Mg, THF, 0 C-rt, 2 h, 48a (69%), 48b (71%), 48c (74%)
48d (79%) and 48e (81% ); (b) phenol, conc. H2SO4(cat.), dry benzene, reflux, 2 h,
49a (12%), 49b (9%), 49c (11%), 49d (12%), and 49e (8% ) (c) alkylaminoethyl
hydrochloride (ClCH2CH2R2.HCl), anhy. K2CO3, dry acetone, reflux, 6-7 h, (yields
given in table 3.1)
Table 3.1
Entr
y
Compound
No.
R1
R2
Yield
(%)a
1
2
33a
33b
p-OCH3
p-OCH3
N(CH3)2
66
71
MIC (g/mL)
Agar micro
dilution
method35
>25
>25
3
4
5
43a
43b
43c
p-OCH3
p-OCH3
p-OCH3
N(CH3)2
N(CH2CH3)2
81
78
67
>12.5
12.5
12.5
43d
p-OCH3
71
12.5
43e
p-OCH3
69
12.5
8
9
44a
44b
p-OCH3
p-OCH3
N(CH3)2
76
73
12.5
12.5
10
11
44c
44d
p-OCH3
p-OCH3
N{CH(CH3)2}2
79
77
12.5
12.5
12
44e
p-OCH3
87
12.5
92
13
44f
p-OCH3
14
15
16
45a
45b
45c
p-OCH3
p-OCH3
p-OCH3
17
45d
p-OCH3
18
19
20
21
22
23
24
50a
50b
50c
50d
51a
51b
51c
m-OCH3
p-OCH3
p-SCH3
p-Cl
p-OCH3
p-OCH3
p-OCH3
25
51d
p-OCH3
26
51e
p-OCH3
27
52a
m-OCH3
28
29
52b
52c
m-OCH3
m-OCH3
30
52d
m-OCH3
31
52e
m-OCH3
32
52f
m-OCH3
33
52g
m-OCH3
34
35
36
53a
53b
53c
p-OCH3
p-OCH3
p-OCH3
37
53d
p-OCH3
38
53e
p-OCH3
39
53f
p-OCH3
40
53g
p-OCH3
41
54a
p-SCH3
42
54b
43
44
81
12.5
74
66
63
>25
>25
>25
65
>25
61
59
63
58
71
76
78
>12.5
3.12
>12.5
>12.5
>12.5
>12.5
>12.5
73
>12.5
68
>12.5
N(CH3)2
71
N(CH2CH3)2
N{CH(CH3)2}2
78
69
12.5
3.12
3.12
83
6.25
77
3.12
82
12.5
79
3.12
79
72
75
12.5
6.25
1.56
73
3.25
76
0.78
76
>12.5
72
12.5
N(CH3)2
70
>12.5
p-SCH3
N(CH2CH3)2
71
3.12
54c
p-SCH3
N{CH(CH3)2}2
74
1.56
54d
p-SCH3
74
3.12
N(CH3)2
NCH(CH3)2
N
OH
OH
OH
OH
N(CH3)2
N(CH2CH3)2
N
N(CH3)2
N(CH2CH3)2
N{CH(CH3)2}2
N
93
45
54e
p-SCH3
46
54f
p-SCH3
47
54g
p-SCH3
48
49
55a
55b
p-Cl
p-Cl
50
55c
p-Cl
51
55d
p-Cl
52
55e
p-Cl
53
55f
p-Cl
54
55g
p-Cl
55
56a
p-F
56
56b
57
81
3.12
76
>12.5
78
3.12
N(CH3)2
N(CH2CH3)2
71
76
6.25
3.12
N{CH(CH3)2}2
73
0.56
73
3.12
75
3.12
69
12.5
81
3.12
N(CH3)2
78
6.25
p-F
N(CH2CH3)2
85
3.12
56c
p-F
N{CH(CH3)2}2
81
1.56
58
56d
p-F
83
1.56
59
56e
p-F
77
0.78
60
56f
p-F
83
6.25
61
56g
p-F
81
1.56
62
58a
p-OCH3
80
>12.5
77
>12.5
83
>12.5
70
>12.5
86
>12.5
N CH 3
81
>12.5
77
>12.5
76
12.5
N
N
N
N
63
58b
p-OCH3
64
58c
p-OCH3
HN
N
O
65
58d
p-OCH3
OCH 3
HN
OCH 3
66
58e
p-OCH3
67
58f
p-OCH3
68
58g
p-OCH3
69
58h
p-OCH3
70
58i
p-OCH3
79
12.5
71
58j
p-OCH3
85
>12.5
HN
HN
94
72
58k
p-OCH3
HN
81
>12.5
3.6 Antitubercular Screening of {33a-b, 43a-e, 44a-f, 45a-d, (50-51)ad, (52-56)a-g, and 58a-k)} and their Structure-Activity Relationships
All the synthesized final molecules were evaluated against M. tuberculosis H37Rv
strains following agar micro dilution technique35 and their results are shown in Table
3.1. Out of seventy two molecules tested, triarylmethane derivatives (TRAMs)
containing thiophene nucleous (52-56)a-g showed promising in vitro antitubercular
activity, MIC of 0.56-12.5 g/mL. Other compounds of the series showed MIC of
12.5g/mL or above. A closer look into the structure-activity relationship of the above
compounds revealed that in a given diarylmethylphenol series (50a-d), compound
50b containing p-OCH3 showed better activity than other compounds with m-OCH3,
p-SCH3 and p-Cl groups. Compounds 51a-e containing alkoxy chain at ortho position
did not exhibit good activity. Among the pair of compounds 52a, 52b; 53a, 53b; 54a,
54b, 55a, 55b and 56a, 56b, increasing the alkyl chain on nitrogen gave better
activity. Increase in polarity of the side chain reduced antimycobacterial activity for
the compounds (52f, 53f, 54f, 55f and 56f). The compounds 58a-k containing polar 2hydroxy-amino alkyl group also did not show better potency as well. Among
copounds (52-56)a-g, some compounds containing diisopropyl and piperidine
aminoethyl side chain with a chloro or fluoro substituent on the para- position of a
phenyl ring are most potent antimycobial. Compounds 53(c,e) and 55(c,e) also have
demonstrated significant in vivo antitubercular activity in a mouse model of
tuberculosis infection. Further in vivo experiments of these lead compounds is in
process. This SAR analysis reveled that rational and logical modification of thiophene
containing compounds with enough hydrophobicity might lead to have better
antitubercular lead. It is noteworthy, synthesis of the compounds and their biological
evaluation towards this direction is currently underway.
3.7 Conclusion
In
conclusion,
aminoalkyl
derivatives
of
diarylmethane
and
several
triarylmethane (TRAMs) containing heteroaryl moieties were synthesized using

Friedel-Crafts alkylation of biaryl carbinols obtained by Grignard reaction. 2hydroxy-aminoalkyl derivatives of triarylmethane (TRAMs) containing thiophene
95
moiety have also been synthesized. Among all the triarylmethane (TRAMs)
derivatives, compounds containing thiophene heterocycle showed promising in vitro
activity in the range of 0.56-12.5 g/mL against Mycobacterium tuberculosis H37Rv
than other (TRAMs) containing indole, pyrrole, pyridine. Introduction of 2-hydroxyaminoalkyl moiety on the thiophene containing pharmacophore diminished its
antitubercular activity. It is conceivable that these triarylmethane derivatives
containing thiophene ring might act as a lead for optimizing antitubercular activity.
All these results suggest that it would be interesting to prepare the analogus of active
molecules for finding new compounds that possess better activity and bioavailability.

3.8.1 General Methods:
Same as that described in the Chapter 2.
3.8.2 Preparation of carbinols (31, 37-39 and 48a-e):
(4-Benzyloxy-phenyl)-(4-methoxy-phenyl)-methanol 31:
To a solution of 4-bromoanisole 29 (8.2 mL, 70.74 mmol) in dry THF (30 mL)
was added activated magnesium (1.93 g, 80.2 mmol) and was stirred at room
OBn
temperature under dry nitrogen for 2 h. To Grignard reagent thus

formed was added 4-benzyloxy benzaldehyde 30 (5 g, 23.58 mmol) in
THF (10 mL) and stirring was continued for another 3-4 hrs. The
HO
reaction mixture was quenched by gradual addition of saturated

31 OCH3
NH4Cl (~10mL) and THF was removed in vacuo. The mixture was
extracted thrice with ethyl acetate, washed with brine and dried over sodium sulphate.
It was concentrated and charged over silica gel. Elution with 10% ethyl acetate in
hexane furnished carbinol product 31 (5.5 g, 73.3%) as white solid, m.p. 93-95C. IR
(KBr): 3402, 1592, 1585, 1365, 1145, 780 cm-1. 1H NMR (CDCl3, 200 MHz): 7.437.24 (m, 9 H), 6.94-6.83 (m, 4H), 5.75 (s, 1H), 5.03 (s, 2H), 3.77 (s, 3H) 3.11 (bs,
1H). 13C NMR (50 MHz, CDCl3): 158.9, 156.1, 142.3, 141.6, 138.3, 130.7, 129.2,
128.7, 127.9, 127.3, 118.1, 117.3, 79.5, 75.4, 58.9. MS (ESI): m/z 320 (M+). Anal.
Calcd for C21H20O3: C, 78.73; H, 6.29. Found: C, 78.79; H, 6.35.
(1-Benzenesulfonyl-1H-indol-3-yl)-(4-methoxy-phenyl)-methanol 37:
As described for 31, 4-bromoanisole 29 (1.31 mL, 10.52 mmol) in dry THF
(25mL), magnesium (0.31 g, 12.842 mmol), 1-benzenesulfonyl-1H-indole-396
carbaldehyde 34 (2.0 g, 7.01 mmol) in THF (5 mL) furnished 37 (1.98 g, 72%) as

brown semi-solid. IR (KBr): 3402, 2927, 1607, 1508, 1247, 1175, 1032, 767 cm-1. 1H
NMR (CDCl3, 200 MHz): 7.94-7.84 (m, 3H), 7.47-7.25 (m,
9H), 6.85 (m, 2H), 5.95 (s, 1H), 3.79 (s, 3H). 13C NMR (50
MeO
N SO2
MHz, CDCl3): 161.8, 142.9, 138.6, 138.1, 136.6, 136.2,
OH
37
129.0, 128.7, 128.4, 127.5, 124.19, 118.3, 79.7, 59.9. MS

+
(ESI): m/z 393 (M ). Anal. Calcd for C22H19NO4S: C, 67.16; H, 4.87; N, 3.56. Found:
C, 67.19; H, 4.83; N, 3.60.
(1-benzyl-1H-pyrrol-2-yl)(4-methoxyphenyl)methanol 38:
As described for 31, 4-bromoanisole 29 (3 g, 16.18 mmol) in dry THF (25mL),
magnesium (0.51 g, 21.60 mmol), 1-benzyl-1H-pyrrole-2-carbaldehyde 35 (2.0 g,
10.80 mmol) in THF (5 mL) furnished 38 (2.15 g, 68%) as orange
MeO
OH
N
Bn
viscous oil. This compound is unstable and used as such for the
next step.
38
(4-Methoxy-phenyl)-pyridin-3yl-methanol 39:
As described for 31, 4-bromoanisole 29 (3.50 mL, 28.00 mmol) in dry THF (30 mL),
magnesium (0.896 g, 37.34 mmol), pyridine 3-carboxaldehyde 36 (1.75 mL, 18.67
MeO
mmol) in THF (5 mL) furnished 39 (2.5 g, 63%) as white solid,

m.p. 70-71C. IR (KBr): 3402, 1592, 1585, 1365, 1145, 780 cm-1.
OH
39
H NMR (CDCl3, 200 MHz): 8.43 (d, 1H, J = 1.6), 8.29 (dd,
1H, J1 = 1.3, J2 = 4.8), 7.66 (d, 1H, J = 7.8), 7.26-7.15 (m, 3H), 6.84 ( d, 2H, J = 8.6),
5.74 (s, 1H), 3.76 (s, 3H). MS (ESI): m/z 215 (M+). Anal. Calcd for C13H13NO2: C,
72.54; H, 6.09; N, 6.51. Found: C, 72.59; H, 6.05; N, 6.84.
(3-Methoxy-phenyl)-thiophen-2-yl-methanol 48a :
As described for 31, m-bromoanisole 46a (1.69 mL, 13.37 mmol) in dry THF
(20mL) magnesium (0.42 g, 17.83 mmol) and thiophen-2-aldehyde 47a (1 g, 8.91
mmol) in THF furnished carbinol 48a (2.0 g, 69%) as light yellow
S
MeO
OH
48a
oil. IR (Neat): 3436, 2926, 1597, 1352, 1039, 703 cm-1. 1H NMR
(CDCl3, 200 MHz): 7.27-7.21 (m, 2H), 7.05-7.02 (m, 2H), 6.97-
6.92 (m, 2H), 6.88-6.84 (m, 1H), 6.03 (s, 1H), 3.82 (s, 3H).
13
C NMR (CDCl3, 50
MHz): 158.5, 146.6, 143.4, 128.2, 125.3, 124.1, 123.6, 117.3, 112.3, 110.5, 71.0,
97
53.9. MS (ESI): m/z 203 (M+-OH). Anal. Calcd for C12H12O2S: C, 65.43; H, 5.49.
Found: C, 65.46; H, 5.43.
(4-Methoxy-phenyl)-thiophen-2-yl-methanol 48b:
As described for 31, 4-bromoanisole 29 (1.7 mL, 13.4 mmol) in dry THF (20
mL), magnesium (0.43 g, 17.9 mmol), thiophene-2-carboxaldehyde 47a (0.82 mL,
8.91 mmol) in THF (5 mL) furnished 48b (1.40 g, 71%) as yellow
MeO
oil. IR (Neat): 3402, 1592, 1585, 1365, 1145, 780 cm-1. 1H NMR
S
OH
48b
(200 MHz, CDCl3): 7.17-7.05 (m, 3H), 6.78-6.64 (m, 4H), 5.74
(s, 1H), 3.60 (s, 3H). MS (ESI): m/z 220 (M+). Anal. Calcd for C12H12O2S: C, 65.43;
H, 5.49. Found: C, 65.52; H, 5.41.
(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methanol 48c:
As described for 31, 4-bromothioanisole 49b (2.716 g, 13.37 mmol) in dry THF (25
mL), magnesium (0.42g, 17.83 mmol), thiophene-2-carboxaldehyde 47a (0.82 mL,
8.91 mmol) in THF (7 mL) furnished 48c (2.30 g, 74%) as pale yellow semi solid. IR
(Neat): 3419, 2373, 1596, 1353, 1016, 702 cm-1. 1H NMR (200
MeS
MHz, CDCl3): 7.24 (d, 2H, J = 8.3), 7.19-7.13 (m, 3H), 6.88-
S
OH
48c
6.79 (m, 2H), 5.92(s, 1H), 2.42 (s, 3H).
13
CNMR (CDCl3,
50MHz): 51.2, 148.4, 140.4, 138.6, 127.2, 127.1, 126.9, 125.8, 125.3, 109.9, 72.4,
16.1. MS (ESI): m/z 219 (M+-OH, 100%). Anal. Calcd for C12H12OS2: C, 60.98; H,
5.12. Found: C, 61.05; H, 5.18.
(4-Chloro-phenyl)-thiophen-2-yl-methanol 48d:
As described for 31, p-chlorobenzaldehyde 49c (1.0 g, 7.11 mmol) in dry THF,
magnesium (0.59 g, 24.18 mmol), 2-bromo-thiophene 47b (2.07
Cl
mL, 21.34 mmol) in THF (25 mL) furnished 48d (3.77 g, 79%) as
S
yellow oil. IR (Neat): 3291, 2925, 2364, 1595, 1354, 1088, 1035,
OH
48d
822, 755, 695 cm-1. 1H NMR (200 MHz, CDCl3): 7.38-7.24 (m,
5H), 6.95-6.84 (m, 2H), 5.97 (s, 1H). MS (ESI): m/z 207 (M+-OH). Anal. Calcd for
C11H9ClOS: C, 58.80; H, 4.04. Found: C, 58.87; H, 4.07.
(4-fluorophenyl)(thiophen-2-yl)methanol 48e:
As described for 31, 4-fluorobenzaldehyde 46d (2.0 g,
F
16.12 mmol) in dry THF, magnesium (0.77 g, 32.25 mmol), 2S

OH
48e
bromo-thiophene 47b (3.90 g, 24.18 mmol) in THF (25 mL)

furnished 48e (2.28 g, 68%) as pale yellow oil. IR (Neat):
98
3309, 2927, 2348, 1606, 1064, 835, 755 cm-1. 1H NMR (200 MHz, CDCl3): 7.39
(dd, 2H, J1 = 5.4, J2 = 8.5), 7.26 (dd, 1H, J1 = 1.22, J2 = 5.02), 7.08-6.86 (m, 4H),
6.01 (s, 1H), 2.62 (bs, 1H).
13
C NMR (CDCl3, 50 MHz): 164.8, 159.9, 148.0,
139.0, 138.9, 128.1, 128.0, 126.7, 125.6, 124.9, 115.6, 115.1, 71.7. MS (ESI): m/z 191
(M+-OH). Anal. Calcd for C11H9FOS: C, 63.44; H, 4.36. Found: C, 63.39; H, 4.34.
3.8.3 Preparation of phenols (32, 49a-e and 50a-e):
4-(4-Methoxy-benzyl)-phenol 32:
The compound 31 (0.5 g, 0.84 mmol) was hydrogenated over
OH
10% Pd/C (0.05 g) and after usual work-up and purification furnished 32
(0.32 g, 95.8%) as white semi- solid. IR (neat): 3390, 1510, 1258, 759
cm-1. 1H NMR (CDCl3, 200 MHz): 7.03-6.93 (m, 4H), 6.78-6.64 (m,
32 OCH3
4H), 3.80 (s, 2H), 3.72 (s, 3H).
13
C NMR (50 MHz, CDCl3): 159.2,
155.7, 135.3, 133.8, 130.1, 129.0, 118.7, 116.4, 59.5, 45.3. MS (ESI): m/z 214 (M+).
Anal. Calcd for (C14H14O2): C, 78.48; H, 6.59. Found: C, 78.42; H, 6.45.
4-[(1-Benzenesulfonyl-1H-indol-3-yl)-(4-methoxy-phenyl)-methyl]-phenol 40:
To a solution of carbinol 37 (1.77 g, 4.51 mmol) and phenol (0.52 mL, 6.32 mmol) in
dry benzene (20 mL) was added aluminium trichloride (0.601 g, 4.51 mmol) and the
mixture was heated at 80 C for 1h. After cooling, the reaction
MeO
N SO2
mixture was neutralized with saturated aq. NaHCO3 and

extracted with ethyl acetate. The concentrated extract was
OH
40
subjected to column chromatography on silica gel and elution

with 15% ethyl acetate in hexane furnishing 40 (1.25 g, 60%) as
brown viscous oil. IR (Neat): 3431, 2368, 1712, 1591, 1510, 1170, 1105, 1025, 769
cm-1. 1H NMR (CDCl3, 200 MHz): 7.95 (d, 1H, J = 8.2) 7.77 (d, 2H, J = 8.6), 7.297.21 (m, 3H), 6.99-6.72 (m, 12H), 5.39 (s, 1H), 4.95 (bs, 1H), 3.79 (s, 3H). 13C NMR
(50 MHz, CDCl3): 161.5, 159.7, 141.7, 139.7, 138.8, 137.5, 137.0, 135.4, 135.0,
129.5, 129.3, 128.2, 127.8, 127.6, 126.4, 124.1, 122.7, 121.8, 120.3, 118.3, 66.5, 58.3.
MS (ESI): m/z 469 (M+). Anal. Calcd for C28H23NO4S: C, 71.62; H, 4.94; N, 2.98.
Found: C, 71.66; H, 4.98; N, 2.89.
4-((1-benzyl-1H-pyrrol-2-yl)(4- methoxyphenyl)methyl)phenol 41:
As described for 40 carbinol 38 (1.77 g, 4.51 mmol) and phenol (0.52 mL, 6.32
mmol) in dry benzene (20 mL) in presence of cat. amount conc. H2SO4 furnished 41
(1.31 g, 62%) as brown viscous oil. IR (Neat): 3021, 2361, 1601, 1427, 1216, 762 cm99
1
. 1H NMR (CDCl3, 200 MHz): 7.31-7.25 (m, 3H), 6.95-
MeO
N
Bn
6.65(m, 11H), 6.11-6.08 (m, 1H), 5.57 (d, 1H, J = 1.8), 5.04 (s,
1H), 4.78 (s, 2H), 3.78 (s, 3H). MS: 369 (M+). Anal. Calcd for
(C25H23NO2): C, 81.27; H, 6.27; N, 3.79. Found: C, 81.19; H,
OH
41
6.31; N, 3.73.
4-[(4-Methoxy-phenyl)-pyridin-3-yl-methyl]-phenol 42:
As described for 40 carbinol 39 (2.6 g, 12.09 mmol) and phenol (1.59 g, 16.93
mmol) in dry benzene (30 mL) furnished 42 (1.8 g, 52%) as dark yellow viscous oil.
IR (Neat): 3431, 1605, 1507, 1443, 1245, 1172, 1028 cm1. 1H
MeO
N
NMR (200MHz, CDCl3): 8.43- 8.37 (m, 2H), 7.44-7.39 (m, 1H),
7.27 -7.24 (m, 1H), 7.00 (d, 2H, J = 8.6), 6.89-6.73 (m, 6H), 5.41 (s,
1H), 3.76 (s, 3H). MS (ESI): m/z 292 (M++1). Anal. Calcd for
OH
42
C19H17NO2: C, 78.33; H, 5.88, N, 4.81. Found: C, 78.36; H, 5.96, N, 4.75

4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenol 50a:
As described for 40, Carbinol 48a (1.0 g, 4.54 mmol) and phenol (0.47 g, 4.99
mmol) in presence of conc. H2SO4 furnished 50a (0.82 g, 61%) as major product
alongwith 49a as minor one (0.16g, 12%) as oil. IR (Neat): 3334,
S
MeO
2369, 1600, 1510, 1259 cm-1, 1H NMR (200 MHz, CDCl3): 7.247.18 (m, 2H), 7.05 (d, 2H, J = 8.2), 6.92-6.88 (m, 1H), 6.81-6.69 (m,
OH
50a
5H), 6.77 (s, 1H), 5.56 (s, 1H), 5.24 (s, 1H), 3.73 (s, 3H). 13C NMR
(CDCl3, 50 MHz): 158.3, 153.0, 146.8, 144.4, 134.8, 128.7, 128.0, 125.3, 124.9,
123.2, 120.1, 113.9, 113.6, 110.5, 53.9, 50.0, MS (ESI): m/z 296 (M+). Anal. Calcd
for C18H16O2S: C, 72.94; H, 5.44. Found: C, 72.87; H, 5.47.
2-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenol 49a:
IR (Neat): 3399, 2932, 2365, 1597, 1454, 1264, 1043, 758 cm-1. 1H NMR (200
MHz, CDCl3): 7.27-7.20 (m, 3H), 7.14-7.00 (m, 3H), 6.96-6.74 (m, 5H), 5.90 (s,
1H), 4.91 (bs, 1H), 3.74 (s, 3H). 13CNMR (CDCl3, 50Hz): 160.1,
S
MeO
HO
153.5, 146.8, 144.6, 130.6, 130.2, 129.9, 128.6, 127.1, 126.9, 125.3,
121.6, 121.3, 116.4, 115.2, 112.5, 55.6, 46.2. MS (ESI): m/z 297
49a
(M++1). Anal. Calcd for C18H16O2S: C, 72.94; H, 5.44. Found: C,
72.97; H, 5.40.
4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenol 50b:
100
As described for 40, carbinol 48b (2.0 g, 9.09 mmol) and phenol (1.025g, 10.90
mmol) in dry benzene (25mL) furnished 50b (1.60 g, 59%) as major product
alongwith 49b as minor one (0.24g, 9%) as blackish viscous oil. IR
MeO
(Neat): 3409, 1597, 1485, 1256, 1045, 760 cm-1. 1H NMR (CDCl3,
200 MHz): 7.24-7.03 (m, 5H), 6.93-6.64 (m, 6H), 5.55 (s, 1H), 3.7
OH
50b
(s, 3H). MS (ESI): m/z 296 (M+). Anal. Calcd for C18H16O2S: C,
72.94; H, 5.44. Found: C, 72.86; H, 5.43.

2-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenol 49b:
IR (Neat): 3389, 1607, 1489, 1247, 1048, 757 cm-1. 1H NMR (200
MeO
S
MHz, CDCl3): 7.22-7.12 (m, 4H), 6.95-6.70 (m, 7H), 5.86 (s,
1H), 3.78 (s, 3H). MS (ESI): m/z 296 (M+). Anal. Calcd for
HO
C18H16O2S: C, 72.94; H, 5.44. Found: C, 72.99; H, 5.38.
49b
4-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenol 50c:
As described for 40, carbinol 48c (1.0 g, 4.23 mmol) and phenol (0.44g, 4.66
mmol) in dry benzene (20 mL) furnished 50c (0.83 g, 63%) as major product
alongwith 49c as minor one (0.09 g, 7%) as reddish viscous oil. IR
MeS
(Neat): 3432, 2368, 1596, 1351, 1236, 700 cm-1. 1H NMR (200
MHz, CDCl3): 7.20-7.16 (m, 5H), 7.12-7.07 (m, 3H), 6.94-6.65

(m, 3H), 5.56 (s, 1H), 5.02 (bs, 1H), 2.45 (s, 3H). 13C NMR (CDCl3,
OH
50c
50MHz):
154.7, 148.6, 141.5, 136.9, 136.4, 130.3, 129.6, 127.0, 126.6, 124.9,
115.6, 53.8, 51.1, 16.3. MS (ESI): m/z 312 (M++1, 30%), 311 (M+-1, 90%). Anal.
Calcd for C18H16OS2: C, 69.19; H, 5.16. Found: C, 69.13; H, 5.20.
2-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenol 49c:
IR (Neat): 3256, 2922, 2365, 1594, 1453, 1232, 1089, 756, cm-1.
MeS
1
S
H NMR (200 MHz, CDCl3): 7.25-7.15 (m, 6H), 6.96-6.69 (m,
5H), 5.90 (s, 1H), 2.47 (s, 3H). MS (ESI): m/z 312 (M+, 100%).
HO
49c
Anal. Calcd for C18H16OS2: C, 69.19; H, 5.16. Found: C, 69.15; H,
5.23.
4-[(4-Chloro -phenyl)-thiophen-2-yl-methyl]-phenol 50d:
As described for 40, carbinol 48d (1.0 g, 4.45 mmol) and phenol (0.50 g, 5.32
mmol) in dry benzene (20 mL) furnished 50d (0.77 g, 58%) as major product
alongwith 49d as minor one (0.08 g, 6%) as orange viscous oil. IR (neat): 3428, 1594,
101
Cl
1351 cm-1. 1H NMR (200 MHz, CDCl3): 7.41-6.95 (m, 7H),

S
6.80-6.66 (m, 4H), 5.59 (s, 1H). MS (ESI): m/z 301 (M++1). Anal.
Calcd for C17H13ClOS: C, 67.88; H, 4.36. Found: C, 67.85; H,
OH
50d
4.40.
2-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenol 49d:
IR (Neat): 3421, 2377, 1590, 1353, 1014 cm-1. 1H NMR (200
Cl
MHz, CDCl3): 7.39-7.27 (m, 3H), 7.19-7.12 (m, 4H), 6.92-6.77

S
HO
(m, 4H), 5.92 (s, 1H), 4.97 (bs, 1H). MS (ESI): m/z 301 (M++1).
Anal. Calcd for C17H13ClOS: C, 67.88; H, 4.36. Found: C, 67.83;
49d
H, 4.32.
4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenol 50e:
As described for 40, Carbinol 48e (2.1 g, 10.09 mmol) and
F
S
phenol (1.0 g, 10.61 mmol) in presence of conc. H2SO4 furnished

50e (1.60 g, 57%) as major product alongwith 49e as minor one
(0.21 g, 8%) as dark brown viscous oil. IR (Neat): 3406, 2926,
OH
50e
1601, 1506, 1455, 1228, 1026, 758 cm-1. 1H NMR (200 MHz,
CDCl3): 7.25-7.11(m, 6H), 7.07-6.78 (m, 2H), 6.76 (d, 2H, J = 8.6), 6.07 (d, 1H, J
= 5.7), 5.60 (s, 1H). 1.69 (bs, 1H).
13
C NMR (CDCl3, 50 MHz): 154.8, 148.6,
140.2, 136.4, 130.7, 130.5, 130.3, 127.0, 126.6, 126.0, 125.0, 116.0, 115.8, 115.7,
115.4, 50.9. MS (ESI): m/z 284 (M+), 233. Anal. Calcd for C17H13FOS: C, 71.81; H,
4.61. Found: C, 71.78; H, 4.65.
2-((4-fluorophenyl)(thiophen-2-yl)methyl)phenol 49e
IR (Neat): 3411, 2929, 1607, 1512, 1460, 1225, 1029, 757 cm-1. 1H NMR (200
MHz, CDCl3): 7.21-7.09 (m, 6H), 7.05-6.77 (m, 2H), 6.74 (d, 2H, J = 8.5), 6.10 (d,
1H, J = 5.6), 5.87 (s, 1H). 1.78 (bs, 1H).
F
S
13
C NMR (CDCl3, 50
MHz): 153.4, 147.1, 136.8, 131.0, 130.8, 130.6, 130.1, 128.7,

127.3, 127.1, 126.9, 125.3, 121.3, 116.4, 115.9, 115.5, 109.9, 45.4.
HO
49e
MS (ESI): m/z 284 (M+). Anal. Calcd for C17H13FOS: C, 71.81; H,

4.61. Found: C, 71.83; H, 4.67.
3.8.4 Preparation of Triarylmethaneoxy Ethylamines (33a-b, 43a-e, 44a-f, 45a-d,

51a-d, 52a-g, 53a-g, 54a-g, 55a-g, 56a-g and 58a-k)
{2-[4-(4-Methoxy-benzyl)-phenoxy]-ethyl}-dimethylamine 33a:
102
A mixture of compounds 32 (0.22 g, 1.03 mmol), anhy. K2CO3 (0.71 g, 5.14

mmol), 1-(2-chloroethyl)-dimethyl amine hydrochloride (0.28 g, 1.54 mmol) and dry
acetone (20 mL) was refluxed for 7 hrs. K2CO3 was filtered off and
acetone was removed. The residue was diluted with water and
extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over anhy. Na2SO4. Column chromatography
over basic alumina and elution with 35% ethyl acetate in hexane
OCH 3
33a
furnished the compound 33a (0.20 g, 66%) as yellow semi-solid. IR
(Neat): 2928, 1501, 1256, 759 cm-1. 1H NMR (CDCl3, 200 MHz): 7.10-7.04 (m,
4H), 6.85-6.79 (m, 4H), 4.05 (t, 2H, J = 7.1), 3.85 (s, 2H), 3.77 (s, 3H), 2.74 (t, 2H, J
= 7.0), 2.34 (s, 6H). 13C NMR (50 MHz, CDCl3): 159.4, 158.9, 136.8, 136.5, 132.2,
132.1, 119.4, 118.7, 74.0, 66.2, 59.2, 51.0, 45.3. MS (ESI): m/z 286 (M++1). Anal.
Calcd for (C18H23NO2): C, 75.76; H, 8.12; N, 4.91. Found: C, 75.72; H, 8.18; N, 4.95.
1-{2-[4-(4-Methoxy-benzyl)-phenoxy]-ethyl}-piperidine 33b:
As described for 33a, compound 32 (0.2 g, 1.02 mmol),
N
O
K2CO3
(0.71
g,
5.14
mmol),
1-(2-chloroethyl)-piperidine
hydrochloride (0.22 g, 1.54 mmol) furnished 33b (0.19 g, 71%) as

light yellow semi solid. IR (Neat): 3440, 1635, 1245, 770 cm-1. 1H
NMR (CDCl3, 200 MHz): 7.10-7.04 (m, 4H), 6.85-6.79 (m, 4H),
OCH3
33b
4.07 (t, 2H, J = 7.0), 3.85 (s, 2H), 3.79 (s, 3H), 2.75 (t, 2H, J = 7.0),
2.52-2.47 (m, 4H), 1.62-1.55 (m, 4H), 1.45-1.43 (m, 2H).
13
C NMR (50 MHz,
CDCl3): 159.6, 158.7, 136.5, 136.7, 133.5, 132.8, 120.1, 119.3, 75.6, 67.4, 59.0,
57.7, 57.3, 51.0, 45.3. 34.0, 29.8. MS (ESI): m/z 326 (M++1). Anal. Calcd for
(C21H27NO2): C, 77.50; H, 8.36; N, 4.30. Found: C, 77.55; H, 8.34; N, 4.37.
(2-{4-[(1-Benzenesulfonyl-1H-indol-3-yl)-(4-methoxy-phenyl)-methyl]-phenoxy}ethyl)-dimethyl-amine 43a:
As described for 33a, compound 40 (0.18 g, 0.37 mmol), K2CO3 (0.26 g, 1.86
mmol), 1-(2-chloroethyl)-dimethyl amine hydrochloride (0.06 g, 0.45 mmol)
furnished 43a (0.16 g, 81%) as orange viscous liquid. IR
MeO
N SO2
(Neat): 3394, 2361, 1592, 1463, 1242, 1033, 768 cm-1. 1H

NMR (CDCl3, 200 MHz): 7.96 (s, 1H), 7.28-6.71 (m 16H),
O
43a
6.46 (s, 1H), 5.48 (s, 1H), 3.96 (t, 2H, J = 5.2), 3.70 (s, 3H),
N
2.65 (t, 2H, J = 5.2), 2.26 (s, 6H). 13C NMR (50 MHz, CDCl3):
103
160.8, 159.3, 142.6, 140.6, 138.8, 137.5, 137.0, 135.4, 135.0, 129.5, 129.3, 128.2,
127.8, 127.6, 126.4, 124.1, 122,7, 121.8, 120.3, 118.3, 71.2, 64.7, 58.3, 53.1, 49.4.
MS (ESI): m/z 540 (M+). Anal. Calcd for C32H32N2O4S: C, 71.09; H, 5.97; N, 5.18.
Found: C, 71.02; H, 5.93; N, 5.25.
(2-{4-[(1-Benzenesulfonyl-1H-indol-3-yl)-(4-methoxy-phenyl)-methyl]-phenoxy}ethyl)-diethyl-amine 43b :
mmol), 1-(2-chloroethyl)-diethyl amine hydrochloride (0.08 g, 0.44 mmol) furnished
43b (0.17 g, 78%) as yellow viscous oil. IR (Neat): 3413,
MeO
N SO2
2926, 2360, 1607, 1507, 1245, 1033, 768 cm-1. 1H NMR

(CDCl3, 200 MHz): 7.96 (d, 1H, J = 8.2), 7.75 (d, 2H, J=
8.5), 7.55-7.32 (m, 3H), 7.18-6.71 (m, 12H), 5.42 (s, 1H), 3.97
O
43b
(t, 2H, J = 5.9), 3.70 (s, 3H), 2.79 (t, 2H, J = 5.9), 2.58-2.55
(m, 4H), 0.99 (t, 4H, J = 7.1). 13C NMR (50 MHz, CDCl3): 161.4, 159.1, 141.2,
140.7, 139.3, 137.5, 136.6, 135.2, 134.6, 129.8, 129.7, 128.5, 127.3, 127.0, 126.7,
125.2, 122,4, 121.6, 120.3, 119.0, 70.8, 63.6, 57.7, 52.5, 50.3, 24.3. MS (ESI): m/z
569 (M++1). Anal. Calcd for C34H36N2O4S: C, 71.80; H, 6.38; N, 4.93. Found: C,
71.88; H, 6.34; N, 4.99.
1-Benzenesulfonyl-3-{(4-methoxy-phenyl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]methyl}-1H-indole 43c :
mmol), 1-(2-chloroethyl)-pyrrolidine amine hydrochloride (0.075 g, 0.447 mmol)
furnished 43c (0.140 g, 67%) as brown viscous liquid. IR
(Neat): 3413, 2926, 2360, 1607, 1507, 1245, 1033, 768 cm-1.
MeO
N SO2
H NMR (CDCl3, 200 MHz): 7.96 (d, 1H, J = 8.2), 7.77 (d,
2H, J = 8.5), 7.65-7.31 (m, 3H), 7.09-6.08 (m, 6.92-6.78 (m,

O
43c
12H), 5.39 (s, 1H), 4.08 (t, 2H, J = 6.0), 3.78 (s, 3H), 2.89 (t,
2H, J = 5.9), 2.61-2.45 (m, 4H), 1.92-1.81 (m, 4H). MS (ESI): m/z 567 (M++1). Anal.
Calcd for C34H34N2O4S: C, 72.06; H, 6.05; N, 4.94. Found: C, 72.01; H, 6.12; N,
4.90.
1-Benzenesulfonyl-3-{(4-methoxy-phenyl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]methyl}-1H-indole 43d :
104
mmol), 1-(2-chloroethyl)-piperidine hydrochloride (0.088 g, 0.44 mmol) furnished
43d (0.15 g, 71%) as yellow viscous liquid. IR (Neat): 3431,
MeO
N SO2
2933, 2363, 1603, 1509, 1371, 1248, 1177, 753, 580 cm-1. 1H
NMR (CDCl3, 200 MHz): 7.89 (d, 1H, J = 8.2), 7.71 (d, 2H, J
O
43d
= 8.5), 7.38-7.35 (m, 3H), 7.01-6.71 (m, 12H), 5.32 (s, 1H),
N
4.00 (t, 2H, J = 6.1), 3.71 (s, 3H), 2.69 (t, 2H, J = 6.1), 2.45-
2.40 (m, 4H), 1.55-1.48 (m, 4H), 1.21-1.14 (m, 2H). MS (ESI): m/z 581 (M++1).
Anal. Calcd for C35H36N2O4S: C, 72.39; H, 6.25; N, 4.82. Found: C, 72.33; H, 6.23;
N, 4.80.
3-[[4-(2-Azepan-1-yl-ethoxy)-phenyl]-(4-methoxy-phenyl)-methyl]-1benzenesulfonyl-1H-indole 43e :
MeO
N SO2
K2CO3 (0.26 g, 1.9 mmol), 1-(2-Chloro-ethyl)-azepane (0.09 g,

0.44 mmol) furnished 43e (0.15 g, 69%) as brown viscous
O
43e
liquid. IR (Neat): 3432, 2928, 2362, 1596, 1352, 766 cm-1. 1H
NMR (CDCl3, 200 MHz): 7.97 (d, 1H, J = 8.2), 7.79 (d, 2H,
J = 8.5), 7.59-7.41 (m, 3H), 7.11-6.81 (m, 12H), 5.41 (s, 1H), 4.06 (t, 2H, J = 6.0),
3.80 (s, 3H), 2.96 (t, 2H, J = 6.0), 2.82-2.79 (m, 4H), 1.69-1.61 (m, 8H). MS (ESI):
m/z 595 (M++1). Anal. Calcd for C36H38N2O4S: C, 72.70; H, 6.44; N, 4.71. Found: C,
72.73; H, 6.48; N, 4.69.
2-(4-((1-benzyl-1H-pyrrol-2-yl)(4-methoxyphenyl)methyl)phenoxy)-N,Ndimethylethanamine 44a :
As described for 33a, compound 41 (0.10 g, 0.271 mmol), anhy. K2CO3 (0.75 g,
0.542 mmol), 1-(2-chloroethyl)-dimethyl amine hydrochloride (0.040g, 0.271 mmol)
furnished the compound 44a (0.08 g, 71%) as brown viscous oil.
MeO
N
Bn
IR (Neat): 3021, 2360, 1601, 1430, 1216, 760 cm-1. 1H NMR

(CDCl3, 200 MHz): 7.32-7.24 (m, 3H), 6.93-6.88 (m, 6H),
O
44a
6.77-6.72 (m, 4H), 6.64-6.63 (m, 1H), 6.07 (t, 1H, J = 3.11),
5.57-5.56 (m, 1H), 5.05 (s, 1H), 4.78 (s, 2H), 4.04 (t, 2H, J =
6.2), 3.77 (s, 3H). 2.89 (t, 2H, J = 6.2), 2.32 (s, 2H). MS (ESI): m/z 441 (M++1).
Anal. Calcd for C29H32N2O2: C, 79.06; H, 7.32; N, 6.36. Found: C, 79.12; H, 7.19; N,
6.27.
105
1-benzyl-2-((4-methoxyphenyl)(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)methyl)-1Hpyrrole 44b :
0.54 mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (0.05 g, 0.27 mmol)
furnished the compound 44b (0.09 g, 73%) as brown viscous oil.
MeO
IR (Neat): 2924, 2372 1606, 1508, 1246, 1035, 757 cm-1. 1H
N
Bn
NMR (CDCl3, 200 MHz): 7.34-7.25 (m, 3H), 6.94-6.89 (m,

O
44b
6H), 6.80-6.76 (m, 4H), 6.67-6.65 (m, 1H), 6.09 (t, 1H, J =
3.10), 5.58-5.57 (m, 1H), 5.04 (s, 1H), 4.79 (s, 2H), 4.04 (t, 2H,
J = 6.1), 3.77(s, 3H). 2.89 (t, 2H, J = 6.2), 2.72-2.61 (m, 4H), 1.08 (t, 4H, J =7.12).
13
C NMR (50 MHz, CDCl3): 158.5, 157.7, 139.0, 136.0, 135.7, 135.6, 130.1, 129.1,
127.7, 126.8, 122.3, 114.6, 114.0, 110.2, 107.1, 66.6, 55.6, 52.0, 50.9, 48.2, 47.9,
30.0. MS (ESI): m/z 467 (M++1). Anal. Calcd for C31H34N2O2: C, 79.79; H, 7.34; N,
6.00. Found: C, 79.84; H, 7.29; N, 6.08.
N-(2-(4-((1-benzyl-1H-pyrrol-2-yl)(4-methoxyphenyl)methyl)phenoxy)ethyl)-Nisopropylpropan-2-amine 44c :
As described for 33a, compound 41 (0.10 g, 0.271 mmol), anhy. K2CO3 (0.075
g, 0.542 mmol), (2-Chloro-ethyl)-diisopropyl-amine hydrochloride (0.054g, 0.271
mmol) furnished the compound 44c (0.10 g, 73%) as brown
MeO
viscous oil. IR (Neat): 3021, 2360, 1599, 1425, 1216, 1044, 761
N
Bn
cm-1. 1H NMR (CDCl3, 200 MHz): 7.32-7.26 (m, 3H), 6.95O
6.88 (m, 6H), 6.80-6.75 (m, 4H), 6.67-6.65 (m, 1H), 6.10 (t,
44c
1H, J = 3.10), 5.56-5.55 (m, 1H), 5.04 (s, 1H), 4.79 (s, 2H), 4.01
(t, 2H, J = 6.9), 3.77(s, 3H), 3.07-3.00 (m, 2H), 2.80 (t, 2H, J = 6.9), 2.72-2.61 (m,
4H), 1.04 (d, 12H, J = 6.4). MS (ESI): m/z 497 (M++1). Anal. Calcd for C33H40N2O2:
C, 79.80; H, 8.12; N, 5.64. Found: C, 79.69; H, 8.16; N, 5.61.
1-(2-(4-((1-benzyl-1H-pyrrol-2-yl)(4methoxyphenyl)methyl)phenoxy)ethyl)piperidine 44d :
MeO
N
Bn
anhy. K2CO3 (0.08 g, 0.54 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.05 g, 0.271 mmol) furnished the
O
43d
compound 44d (0.09 g, 72%) as blackish red viscous oil. IR

(Neat): 3020, 2401, 1643, 1423, 1216, 1040, 760 cm-1. 1H
106
NMR (CDCl3, 200 MHz): 7.31-7.25 (m, 3H), 6.93-6.88 (m, 6H), 6.80-6.75 (m,
4H), 6.66-6.65 (m, 1H), 6.09 (t, 1H, J = 3.1), 5.56-5.55 (m, 1H), 5.05 (s, 1H), 4.79(s,
2H), 4.08 (t, 2H, J = 6.0), 3.77 (s, 3H). 2.78 (t, 2H, J = 5.9), 2.53 (t, 4H, J = 4.5),
1.68-1.59 (m, 4H), 1.46-1.44 (m, 2H).
13
C NMR (50 MHz, CDCl3): 158.6, 157.8,
139.0, 136.0, 135.8, 135.7, 130.1, 129.1, 128.9, 127.7, 126.8, 122.3, 114.8, 114.0,
110.3, 107.2, 66.2, 58.3, 55.6, 55.4, 51.0, 50.9, 48.0, 30.1, 26.2, 24.5. MS (ESI): m/z
481 (M++1). Anal. Calcd for C32H36N2O2: C, 79.96; H, 7.55; N, 5.83. Found: C,
79.91; H, 7.56; N, 5.75.
1-(2-(4-((1-benzyl-1H-pyrrol-2-yl)(4methoxyphenyl)methyl)phenoxy)ethyl)azepane 44e :
0.54 mmol), 1-(2-Chloro-ethyl)-azepane hydrochloride (0.05 g, 0.27 mmol) furnished
the compound 44e (0.10 g, 76%) as orange red viscous oil. IR
MeO
(Neat): 3020, 2401, 1642, 1510, 1216, 1038, 760 cm-1. 1H NMR
N
Bn
(CDCl3, 200 MHz): 7.31-7.25 (m, 3H), 6.94-6.88 (m, 6H),

6.80-6.76 (m, 4H), 6.66-6.64 (m, 1H), 6.10 (t, 1H, J = 3.0),
44e
5.58-5.56 (m, 1H), 5.05 (s, 1H), 4.79 (s, 2H), 4.03 (t, 2H, J =
6.2), 3.77(s, 3H). 2.93 (t, 2H, J = 6.2), 2.79-2.74 (m, 4H), 1.61-1.38 (m, 8H). MS
(ESI): m/z 495 (M++H). Anal. Calcd for C33H38N2O2: C, 80.13; H, 7.74; N, 5.66.
Found: C, 80.07; H, 7.80; N, 5.58.
4-(2-(4-((1-benzyl-1H-pyrrol-2-yl)(4methoxyphenyl)methyl)phenoxy)ethyl)morpholine 44f:
0.542 mmol), 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.051 g, 0.271 mmol)
furnished the compound 44f (0.09 g, 72%) as brown semi solid.
MeO
IR (Neat): 3020, 2400, 1638, 1510, 1216, 1041, 758 cm-1. 1H
N
Bn
NMR (CDCl3, 200 MHz): 7.32-7.21 (m, 3H), 6.95-6.89 (m,

O
44f
6H), 6.80-6.76 (m, 4H), 6.67-6.65 (m, 1H), 6.21-6.16 (m, 1H),
N
O
6.09 (t, 2H, J = 3.1), 5.05 (s, 1H), 4.79(s, 2H), 4.07 (t, 2H, J =
6.1), 3.77(s, 3H). 3.75-3.71 (m, 4H), 2.78 (t, 2H, J = 6.1), 2.59-2.25 (m, 4H). MS
(ESI): m/z 483 (M++1). Anal. Calcd for C31H34N2O3: C, 77.15; H, 7.10; N, 5.80.
Found: C, 77.08; H, 7.05; N, 5.86.
107
(2-{4-[(4-Methoxy-phenyl)-pyridin-3-yl-methyl]-phenoxy}-ethyl)-dimethyl amine
45a:
furnished 45a as yellow viscous oil (0.185 g, 74%). IR (Neat):
MeO
N
3440, 1635, 1245, 770 cm-1. 1H NMR (CDCl3, 200 MHz): 8.338.30 (m, 2H), 7.25 (d, 1H, J = 7.8), 7.08-7.04 (m, 1H), 6.90-6.68
45a
(m, 8H), 5.32 (s, 1H), 3.91 (t, 2H, J = 6.1), 3.63 (s, 3H), 2.59 (t,
2H, J = 6.1), 2.20 (s, 6H). MS (ESI): m/z 363 (M++1). Anal.
Calcd for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found C, 76.35; H, 7.34; N, 7.85.
Diethyl-(2-{4-[(4-methoxy-phenyl)-pyridin-3-yl-methyl]-phenoxy}-ethyl)-amine
45b :
MeO
K2CO3 (0.474 g, 3.43 mmol), 1-(2-chloroethyl)-diethylamine
hydrochloride (0.18 g, 1.03 mmol) furnished 45b as yellow

O
viscous oil (0.17 g, 66%). IR (Neat): 3440, 1635, 1245, 770 cm-
45b
. H NMR (CDCl3, 200 MHz): 8.37-8.33 (m, 2H), 7.29 (d,
1 1
1H, J = 7.7), 7.18-6.72 (m, 9H), 5.35 (s, 1H), 3.97 (t, 2H, J = 6.0), 3.68 (s, 3H), 2.78
(t, 2H, J = 6.0), 2.55 (m, 4H), 1.00 (t, 6H, J = 7.2). MS (ESI): m/z 391 (M++1). Anal.
Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found C, 76.75; H, 7.64; N, 7.29.
3-{(4-Methoxy-phenyl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methyl}-pyridine
45c:
mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (0.17 g, 1.03 mmol) furnished
45c as yellow viscous oil (0.17 g, 63%). IR (Neat): 3440, 1635,
MeO
N
1245, 770 cm-1. 1H NMR (CDCl3, 200 MHz): 8.32-8.30 (m,

2H), 7.27 (d, 1H, J = 7.8), 7.07-6.67 (m, 9H), 5.31 (s, 1H), 3.95
O
45c
(t, 2H, J = 6.1), 3.61(s, 3H), 2.75 (t, 2H, J = 6.1), 2.49-2.47 (m,
4H), 1.65-1.58 (m, 4H). MS (ESI): m/z 389 (M++1). Anal. Calcd
for C25H28N2O2: C, 77.29; H, 7.26; N, 7.21. Found C, 77.35; H, 7.34; N, 7.14.

3-{(4-Methoxy-phenyl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-pyridine
45d :
108
mmol), 1-(2-chloroethyl)-piperidine hydrochloride (0.19 g, 1.03 mmol) furnished 45d
as yellow viscous oil (0.18 g, 65%). IR (Neat): 3440, 1635,
MeO
1245, 770 cm-1. 1H NMR (CDCl3, 200 MHz): 8.36-8.31 (m,
2H), 7.29 (d, 1H, J = 7.8), 7.19-6.72 (m, 9H), 5.35 (s, 1H), 4.02
O
(t, 2H, J = 6.1), 3.67 (s, 3H), 2.71 (t, 2H, J = 6.0), 2.48-2.43 (m,
45d
4H), 1.56-1.49 (m, 4H), 1.37-1.39 (m, 2H). MS (ESI): m/z 403
(M++1). Anal. Calcd for C26H30N2O2: Calc. C, 77.58; H, 7.51; N, 6.96. Found C,
77.65; H, 7.60; N, 6.85.
(2-{4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-dimethylamine 52a:
As described for 33a, compound 50a (0.10 g, 0.33 mmol), K2CO3 (0.14 g, 1.01
furnished 52a (0.09 g, 71%) as a light yellow semi solid. IR
(Neat): 3434, 2820, 1595, 1351 cm-1. 1H NMR (CDCl3, 200
MeO
MHz): 7.12-7.02 (m, 4H), 6.86-6.61 (m, 7H), 5.51 (s, 1H),
O
52a
3.98 (t, 2H, J = 6.4), 3.67 (s, 3H), 2.67 (t, 2H, J = 6.4), 2.27 (s,
6H). MS (ESI): m/z 368 (M++1). Anal. Calcd for C22H25NO2S:
C, 71.90; H, 6.86; N, 3.81. Found: C, 71.87; H, 6.82; N, 3.84.

Diethyl-(2-{4-[(3-methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-amine
52b :
As described for 33a, compound 50a (0.10 g, 0.33 mmol),
S
MeO
K2CO3 (0.14 g, 1.01 mmol), 1-(2-chloroethyl)-diethyl amine

hydrochloride (0.06 g, 0.37 mmol) furnished 52b (0.10 g, 78%)
O
52b
as a light yellow semi solid. IR (Neat): 2926, 1597, 1351 cm-1.

1
H NMR (CDCl3, 200 MHz): 7.18-7.01 (m, 4H), 6.87-6.62
(m, 5H), 6.62 (s, 1H), 6.60 (m, 1H), 5.51 (s, 1H), 3.95 (t, 2H, J = 6.4), 3.67 (s, 3H),
2.80 (t, 2H, J = 6.4), 2.62-2.51 (m, 4H), 1.18-0.96 (m, 6H). MS (ESI): m/z 396
(M++1). Anal. Calcd for C24H29NO2S: C, 72.87; H, 7.39; N, 3.54. Found: C, 72.95; H,
7.43; N, 3.49.
Diisopropyl-(2-{4-[(3-methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)amine 52c:
109
mmol), (2-Chloro-ethyl)-diisopropyl-amine hydrochloride (0.07g, 0.37 mmol)
furnished 52c as yellow viscous oil (0.95 g, 69%). IR (Neat):
2926, 1646, 1512, 1012 cm-1. 1H NMR (CDCl3, 200 MHz):
MeO
7.18-7.01 (m, 4H), 6.86-6.82 (m, 1H), 6.76-6.60 (m, 6H), 5.51
O
52c
(s, 1H), 3.80 (t, 2H, J = 7.4), 3.67 (s, 3H), 2.99-2.93 (m, 2H),
2.73 (t, 2H, J = 7.4), 0.96 (d, 12H, J = 6.4 ). MS (ESI): m/z 424
(M++1). Anal. Calcd for C26H33NO2S: C, 73.72; H, 7.85; N, 3.31. Found: C, 73.66; H,
7.87; N, 3.29.
1-(2-{4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-pyrrolidine
52d:
52d (0.11g, 83%) as a brown semi solid. IR (Neat): 2932, 1603,
1508, 1248 cm-1. 1H NMR (CDCl3, 200 MHz): 7.25-7.09 (m,
MeO
4H), 6.94-6.09 (m, 7H), 5.58 (s, 1H), 4.09 (t, 2H, J = 5.8), 3.74
O
52d
(s, 3H), 2.90 (t, 2H, J = 5.8), 2.65-2.63 (m, 4H), 2.03-1.81 (m,
C, 73.25; H, 6.92; N, 3.56. Found: C, 73.27; H, 6.88; N, 3.63.

1-(2-{4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-piperidine
52e:
mmol), 1-(2-chloroethyl)-piperidine hydrochloride (0.07g, 0.37 mmol) furnished 52e
(0.10 g, 77%) as a red semi solid. IR (Neat): 2927, 1596, 1351
cm-1. 1H NMR (CDCl3, 200 MHz): 7.25-7.08 (m, 4H), 6.93-
MeO
6.89 (m, 1H), 6.84-6.74 (m, 5H), 6.69 (m, 1H), 5.58 (s, 1H),
O
52e
4.08 (t, 2H, J = 6.2), 3.74 (s, 3H), 2.76 (t, 2H, J = 6.2), 2.502.48 (m, 4H), 1.60-1.25 (m, 6H). MS (ESI): m/z 408 (M++1).
Anal. Calcd for C25H29NO2S: C, 73.67; H, 7.17; N, 3.44. Found: C, 73.72; H, 7.23; N,
3.51.
4-(2-{4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-morpholine
52f:
mmol), 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.07 g, 0.37 mmol) furnished
110
52f (0.11 g, 82%) as a brown viscous liquid. IR (Neat): 2949, 1601, 1508, 1250 cm-1.
IR (Neat): 2931, 1597, 1513, 1243 cm-1. 1H NMR (CDCl3, 200
MHz): 7.25-7.19 (m, 2H), 7.13 (d, 2H, J = 8.0), 6.95-6.92
S
MeO
(m, 1H), 6.87-6.72 (m, 4H), 6.71 (s, 1H), 6.70 (d, 1H, J = 6.8),
5.60 (s, 1H), 4.08 (t, 2H, J = 6.3), 3.77 (s, 3H), 2.97 (t, 2H, J =
O
52f
N
O
6.3), 2.82-2.79 (m, 4H), 1.68-1.61 (m, 8H). MS (ESI): m/z 410
(M +1). Anal. Calcd for C24H27NO3S: C, 70.39; H, 6.65; N, 3.42. Found: C, 70.46; H,
6.67; N, 3.47.
1-(2-{4-[(3-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-azepane
52g:
mmol), 1-(2-Chloro-ethyl)-azepane hydrochloride (0.07g, 0.37 mmol) furnished 52g
( 0.11 g, 79 %) as a orange semi solid. IR (Neat): 2931, 2356,
1597, 1253 cm-1. 1H NMR (CDCl3, 200 MHz): 7.25-7.19 (m,
MeO
2H), 7.13 (d, 2H, J = 8.0), 6.95-6.92 (m, 1H), 6.87-6.72 (m, 4H),
O
52g
6.71 (s, 1H), 6.70 (d, 1H, J = 6.8), 5.60 (s, 1H), 4.08 (t, 2H, J =
6.3), 3.77 (s, 3H), 2.97 (t, 2H, J = 6.3), 2.82-2.79 (m, 4H), 1.68-1.61 (m, 8H). MS
(ESI): m/z 422 (M++1). Anal. Calcd for C26H31NO2S : C, 74.07; H, 7.41; N, 3.32.
Found: C, 74.13; H, 7.44; N, 3.29.
2-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-dimethylamine 53a:
As described for 33a, compound 50b (0.10 g, 0.34 mmol), K2CO3 (0.14 g, 1.01
furnished 53a (0.95 g, 79%) as red viscous liquid. IR (Neat): 2923,
MeO
2361, 1508, 1244, 1035, 765 cm-1. 1H NMR (CDCl3, 200 MHz):
7.16-6.99 (m, 5H), 6.92-6.56 (m, 6H), 5.47 (s, 1H), 4.03 (t, 2H, J =
O
53a
7.1), 3.77 (s, 3H), 2.74 (t, 2H, J = 7.2), 2.34 (s, 6H). MS (ESI): m/z
368 (M++1). Anal. Calcd for C22H25NO2S: C, 71.90; H, 6.86; N,
3.81. Found: C, 71.84; H, 6.82; N, 3.87.

Diethyl-(2-{4-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]-phenyoxy}-ethyl)amine 53b:
111
53b (0.09 g, 72%) as brown viscous oil. IR (Neat): 2928, 2367,

MeO
1590, 1233, 762 cm-1.
H NMR (CDCl3, 200 MHz): 7.72-
7.69 (m, 3H), 7.18-6.66 (m, 8H), 5.61 (s, 1H), 3.92 (t, 2H, J =
7.1), 3.81 (s, 3H), 3.79 (t, 2H, J = 6.9), 2.57-2.50 (m, 4H) 1.00
O
53b
(t, 6H). MS (ESI): m/z 396 (M++1). Anal. Calcd for

Diisopropyl-(2-{4-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)amine 53c:
mmol), (2-Chloro-ethyl)-diisopropyl-amine hydrochloride (0.07g, 0.37 mmol)
MeO
2964, 1654, 1611, 1509 cm-1. 1H NMR (CDCl3, 200 MHz):
7.12-7.00 (m, 5H), 6.86-6.82 (m, 1H), 6.75 (d, 4H, J = 8.0),
O
53c
6.59-6.58 (m, 1H), 5.49 (s, 1H), 3.79 (t, 2H, J = 7.4), 3.71 (s,
3H), 2.99-2.93 (m, 2H), 2.73 (t, 2H, J = 7.4), 0.96 (d, 12H). MS
+
(ESI): m/z 424 (M +1). Anal. Calcd for C26H33NO2S: C, 73.72; H, 7.85; N, 3.31.
Found: C, 73.79; H, 7.79; N, 3.29.
1-(2-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-pyrrolidine
53d:
mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (0.06g, 0.37 mmol) furnished 53d
MeO
1245, 770 cm-1. 1H NMR (CDCl3, 200 MHz): 7.08-7.00 (m,
5H), 6.78-6.72 (m, 6H), 5.48 (s, 1H), 3.98 (t, 2H), 3.69 (s, 3H),
O
53d
2.79 (t, 2H), 2.61-2.56 (m, 4H), 1.92-1.73 (m, 4H). MS (ESI):
m/z 394 (M++1). Anal. Calcd for C24H27NO2S: C, 73.25; H,
6.92; N, 3.56. Found: C, 73.28; H, 6.94; N, 3.61.

53e:
mmol), 1-(2-chloroethyl)-piperidine hydrochloride (0.07 g, 0.38 mmol) furnished 53e
(0.10 g, 76%) as rose red viscous oil. IR (Neat): 3440, 1635, 1245, 770 cm-1. 1H NMR
(CDCl3, 200 MHz): 7.21-7.01 (m, 5H), 6.99-6.57 (m, 6H), 5.48 (s, 1H), 3.99 (t, 2H),
112
3.69 (s, 3H), 2.55 (t, 2H), 2.43-2.34 (m, 4H), 1.57-1.37 (m, 4H),
MeO
1.35-1.18 (m, 2H). MS (ESI): m/z 408 (M++1). Anal. Calcd for
C25H29NO2S: C, 73.67; H, 7.17; N, 3.44. Found: C, 73.73; H,

O
53e
7.15; N, 3.49.
4-(2-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-morpholine
53f:
53f (0.10 g, 76%) as light yellow semi solid. IR (Neat): 2929,
MeO
1608, 1509, 1247 cm-1. 1H NMR (CDCl3, 200 MHz): 7.50-
7.07 (m, 7H), 6.99-6.60 (m, 4H), 5.52 (s, 1H), 4.05 (t, 2H, J =
O
53f
7.4), 3.71 (s, 3H), 3.70-3.54 (m, 4H), 2.79-2.75 (m, 2H), 2.53-
N
O
2.42 (m, 4H).
13
C NMR (CDCl3, 50 MHz): 136.5, 130.1,
129.6, 127.0, 126.5, 124.9, 114.8, 67.2, 66.0, 58.0, 54.4, 51.2, 30.9, 16.2. MS (ESI):
m/z 410 (M++1). Anal. Calcd for C24H27NO3S: C, 70.39; H, 6.65; N, 3.42. Found: C,
70.43; H, 6.72; N, 3.43.
53g:
mmol), 1-(2-Chloro-ethyl)-azepane hydrochloride (0.08 g, 0.38 mmol) furnished 53g
MeO
1517, 1247 cm-1. 1H NMR (CDCl3, 200 MHz): 7.26-6.87 (m,
7H), 6.76 (d, 4H, J = 8.2), 5.39 (s, 1H), 4.03 (t, J = 6.0 Hz,
O
53g
2H), 3.77 (s, 3H), 2.93 (t, 2H, J = 6.1), 2.79-2.74 (m, 4H),
N
1.78-1.61 (m, 8H). MS (ESI): m/z 446 (M++Na). Anal. Calcd
for C26H31NO2S: C, 74.07; H, 7.41; N, 3.32. Found: C, 74.05; H, 7.39; N, 3.39.

(2-{2-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-dimethylamine 51a:
As described for 33a, compound 49b (0.20 g, 0.67 mmol), anhy. K2CO3 (0.28 g,
2.02 mmol), 1-(2-chloroethyl)-dimethyl amine hydrochloride (0.12 g, 0.81mmol) in
dry acetone furnished the compound 51a (0.18 g, 71%) as light yellow oil. IR (Neat):
2927, 2367, 1517, 1251, 1045, 767 cm-1. 1H NMR (CDCl3, 200 MHz): 7.17-6.90
113
(m, 5H), 6.84-6.71 (m, 5H), 6.54 (d, 1H, J = 3.3), 5.94 (s, 1H),
MeO
3.94 (t, 2H, J = 5.3), 3.69 (s, 3H), 2.57 (t, 2H, J = 5.3), 2.20 (s,
C, 71.90; H, 6.86; N, 3.81. Found: C, 71.92; H, 6.83; N, 3.85.
51a
Diethyl-(2-{2-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-amine
54b:
mmol), 1-(2-chloroethyl)-diethyl amine hydrochloride (0.14 g, 0.81mmol) furnished
51b (0.20 g, 76%) as yellow viscous oil. IR (Neat): 2933, 2360,
MeO
1598, 1242, 760 cm-1. 1H NMR (CDCl3, 200 MHz): 7.17-6.91
S
O
(m, 5H), 6.84-6.71 (m, 5H), 6.55 (d, 1H, J = 3.3), 5.95 (s, 1H),
3.92-3.86 (m, 2H), 3.69 (s, 3H), 2.64 (t, 2H, J = 6.2), 2.52-2.36
51b
(m, 4H), 0.96-0.82 (m, 6H). MS (ESI): m/z 396 (M++1). Anal. Calcd for C24H29NO2S:
C, 72.87; H, 7.39; N, 3.54. Found: C, 72.95; H, 7.36; N, 3.58.
1-(2-{2-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)pyrrolidine 51c:
As described for 33a, compound 49b (0.20 g, 0.674
MeO
mmol), K2CO3 (0.28 g, 2.02 mmol), 1-(2-chloroethyl)S
pyrrolidine hydrochloride (0.140 g, 0.81 mmol) furnished 51c as
yellow viscous oil (0.21 g, 78%). IR (Neat): 2935, 2361, 1610,
51c
1227, 769 cm . H NMR (CDCl3, 200 MHz): 7.25-6.97 (m, 5H), 6.92-6.78 (m,
-1 1
5H), 6.61 (d, 1H, J = 3.42), 6.02 (s, 1H), 4.07 (t, 2H, J = 5.5), 3.77 (s, 3H), 2.82 (t,
2H, J = 5.5), 2.56-2.54 (m, 4H), 1.75-1.73 (m, 4H). MS (ESI): m/z 394 (M++1). Anal.
Calcd for C24H27NO2S: C, 73.25; H, 6.92; N, 3.56. Found: C, 73.18; H, 6.95; N, 3.54.
51d:
As described for 33a, compound 49b (0.20 g, 0.67 mmol), K2CO3 (0.28g, 2.02
mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (0.15 g,
MeO
0.81 mmol) furnished 51d as pink semi solid (0.20 g, 73%). IR

S
51d
(Neat): 2928, 2366, 1592, 1351 cm-1, 1H NMR (200 MHz,

CDCl3): 7.24-6.96 (m, 5H), 6.91-6.77 (m, 5H), 6.58 (d, 1H, J
= 3.42), 6.00 (s, 1H), 4.00 (t, 2H, J = 5.5), 3.71 (s, 3H), 2.62 (t,
114
2H, J = 5.5), 2.46-2.34 (m, 4H), 1.75-1.70 (m, 6H). MS (ESI): m/z 408 (M+). Anal.
Calcd for C25H29NO2S: C, 73.67; H, 7.17; N, 3.44. Found: C, 73.62; H, 7.23; N, 3.39.
11e:
mmol), 1-(2-Chloro-ethyl)-azepane hydrochloride (0.16g, 0.81 mmol) furnished 51e
1509, 1245, 754 cm-1. 1H NMR (CDCl3, 200 MHz): 7.18-
MeO
S
N
6.72 (m, 5H), 6.85-6.71 (m, 5H), 6.56 (d, 1H, J = 3.46), 5.95
(s, 1H), 3.93 (t, 2H, J = 7.0), 3.70 (s, 3H), 2.73 (t, 2H, J = 7.0),
51e
2.58-2.56 (m, 4H), 1.56-1.47 (m, 8H). MS (ESI): m/z 422
(M +1). Anal. Calcd for C26H31NO2S: C, 74.07; H, 7.41; N, 3.32. Found: C, 74.02; H,
7.39; N, 3.33.
Dimethyl-(2-{4-[(4-methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}ethyl)- amine 54a:
As described for 33a, compound 50c (0.10 g, 0.35 mmol),
MeS
K2CO3 (0.135 g, 0.96 mmol), 1-(2-chloroethyl)-dimethyl amine
hydrochloride (0.05 g, 0.35 mmol) furnished 54a (0.06 g, 70%)

as brown viscous liquid. IR (Neat): 2924, 1608, 1506, 1243 cmO
54a
. H NMR (CDCl3, 200 MHz): 7.21-7.07 (m, 7H), 6.94-6.90
1 1
(m, 1H), 6.84 (d, 2H, J = 8), 6.66 (d, 1H, J = 3.6), 5.57 (s, 1H), 4.07 (t, 2H, J = 6.2),
2.76 (t, 2H, J = 6.2), 2.46 (s, 3H), 2.36 (s, 6H).
13
C NMR (CDCl3, 50 MHz): 148.6,
136.4, 130.1, 129.6, 127.0, 126.9, 126.5, 124.8, 114.8, 66.1, 58.5, 51.2, 46.1, 16.3.
MS (ESI): m/z 384 (M++1). Anal. Calcd for C22H25NOS2: C, 68.89; H, 6.57; N, 3.65.
Found: C, 68.84; H, 6.61; N, 3.71.
Diethyl-(2-{4-[(4-methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)amine 54b:
As described for 33a, compound 50c (0.10 g, 0.35
MeS
mmol), K2CO3 (0.135 g, 0.96 mmol), 1-(2-chloroethyl)-
diethyl amine hydrochloride (0.06 g, 0.35 mmol) furnished

O
54b
54b (0.10 g, 71%) as a pale yellow viscous oil. IR (Neat):

N
2924, 1607, 1461, 1245 cm-1. 1H NMR (CDCl3, 200 MHz):
7.20-7.08 (m, 7H), 6.94-6.92 (m, 1H), 6.83 (d, 2H, J = 8.1), 6.66 (d, 1H, J = 3.6), 5.57
115
(s, 1H), 4.03 (t, 2H, J = 6.4), 2.87 (t, 2H, J = 6.4), 2.70-2.59 (m, 4H), 2.46 (s, 3H),
1.07 (t, 6H, J = 7.2). 13C NMR (CDCl3, 50 MHz): 136.9, 130.1, 129.6, 127.0, 126.9,
126.5, 124.8, 114.7, 66.8, 52.1, 51.2, 48.1, 16.3, 12.1. MS (ESI): m/z 412 (M++1).
Anal. Calcd for C24H29NOS2 : C, 70.03; H, 7.10; N, 3.40. Found: C, 70.11; H, 7.04;
N, 3.45.
Diisopropyl-(2-{4-[(4-methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}ethyl)-amine 54c:
As described for 33a, compound 50c (0.10 g, 0.35 mmol), K2CO3 (0.135 g, 0.96
mmol), (2-Chloro-ethyl)-diisopropyl-amine hydrochloride (0.07 g, 0.35 mmol)
furnished 54c as a light yellow viscous oil (0.105 g, 74%). IR
MeS
(Neat): 2964, 1608, 1505, 1248 cm-1. 1H NMR (CDCl3, 200
MHz): 7.18-6.99 (m, 7H), 6.86-6.85 (m, 1H), 6.74 (d, 2H, J
O
54c
= 8.1), 6.60 (d, 1H, J = 3.6), 5.49 (s, 1H), 3.80 (t, 2H, J = 7.4),
2.99-2.93 (m, 1H), 2.73 (t, 2H, J = 7.4), 2.38 (s, 3H), 0.96 (d,
12H, J=6.4). 13C NMR (CDCl3, 50 MHz): 158.1, 148.7, 141.5, 136.8, 136.1, 130.1,
129.6, 127.0, 126.5, 124.8, 114.6, 69.5, 51.2, 50.1, 44.8, 21.1, 16.3. MS (ESI): m/z
440 (M++1). Anal. Calcd for C26H33NOS2 : C, 71.02; H, 7.57; N, 3.19. Found: C,
71.04; H, 7.63; N, 3.24.
1-(2-{4-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)pyrrolidine 54d:
As described for 33a, compound 50c ( 0.10 g, 0.35 mmol), K2CO3 ( 0.14 g, 0.96
mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride ( 0.06g,
MeS
0.35 mmol) furnished 54d as a orange viscous oil ( 0.10 g,
74%). IR (Neat): 2925, 1602, 1351 cm-1. 1H NMR (CDCl3, 200

O
54d
MHz): 7.26-7.07 (m, 7H), 6.94-6.90 (m, 1H), 6.84 (d, 2H, J
N
= 8.0), 6.66 (d, 1H, J = 3.6), 5.57 (s, 1H), 4.10 (t, 2H, J = 5.8),
2.91 (t, 2H, J = 5.8), 2.94-2.88 (m, 4H), 2.46 (s, 3H), 1.98-1.82 (m, 4H).
13
C NMR
(CDCl3, 50 MHz): 157.9, 148.6, 141.5, 136.9, 130.1, 129.6, 127.0, 126.9, 126.5,
124.8, 114.8, 67.2, 55.4, 55.0, 51.2, 23.8, 16.3. MS (ESI): m/z 410 (M++1). Anal.
Calcd for C24H27NOS2: C, 70.37; H, 6.64; N, 3.42. Found: C, 70.43; H, 6.66; N, 3.37.
1-(2-{4-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)piperidine 54e:
116
(0.11 g, 81%) as a brick red semi solid. IR (Neat): 2930, 1607,
MeS
1506, 1245 cm-1. 1H NMR (CDCl3, 200 MHz): 7.19-7.00 (m,

S
7H), 6.87-6.85 (m, 1H), 6.75 (d, 2H, J = 8.0), 6.60-6.58 (m,
1H), 5.50 (s, 1H), 4.03 (t, 2H, J = 5.8), 2.72 (t, 2H, J = 5.8),
O
54e
2.47-2.45 (m, 4H), 2.38 (s, 3H), 1.56-1.18 (m, 6H). MS (ESI):
m/z 424 (M++1). Anal. Calcd for C25H29NOS2: C, 70.88; H,
6.90; N, 3.31. Found: C, 70.94; H, 6.87; N, 3.37.

4-(2-{4-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)morpholine 54f:
mmol), 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.065g, 0.35 mmol) furnished
54f (0.10 g, 76%) as pale red semi solid. IR (Neat): 2924,
MeS
1590, 1459, 1222 cm-1. 1H NMR (CDCl3, 200 MHz): 7.18-
7.08 (m, 7H), 6.84-6.82 (m, 1H), 6.77 (d, 2H, J=8), 6.62 (d,
O
54f
1H, J = 3.6), 5.53 (s, 1H), 4.05 (t, 2H, J = 7.4), 3.69-3.68 (m,
N
O
4H), 2.79-2.75 (m, 2H), 2.53-2.42 (m, 4H). 13C NMR (CDCl3,
50 MHz): 136.5, 130.1, 129.6, 127.0, 126.5, 124.9, 114.8, 67.2, 66.0, 58.0, 54.4,
51.2, 30.9, 16.2. MS (ESI): m/z 426 (M++1). Anal. Calcd for C24H27NO2S2: C, 67.73;
H, 6.39; N, 3.29. Found: C, 67.74; H, 6.45; N, 3.27.
1-(2-{4-[(4-Methylsulfanyl-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)azepane 54g:
(0.10 g, 78%) as a brown semi solid. IR (Neat): 2927, 1600,
MeS
1512, 1352 cm-1. 1H NMR (CDCl3, 200 MHz): 7.21-7.10 (m,
7H), 6.95-6.92 (m, 1H), 6.85 (d, 2H, J = 8.1), 6.67 (d, 1H, J =
O
54g
3.7), 5.59 (s, 1H), 4.15 (t, 2H, J = 6.1), 3.06 (t, 2H, J = 6.1),
2.92-2.89 (m, 4H), 2.48 (s, 3H), 1.74-1.51 (m, 8H). MS (ESI):
m/z 438 (M++1). Anal. Calcd for C26H31NOS2: C, 71.35; H, 7.14; N, 3.20. Found: C,
71.39; H, 7.08; N, 3.21.
117
(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-dimethyl-amine
55a:
As described for 33a, compound 50d (0.20 g, 0.67 mmol), K2CO3 (0.28 g, 2.00
furnished 55a (0.18 g, 71%) as pale yellow viscous oil. IR
Cl
(Neat): 2932, 1596, 1510, 1351 cm-1. 1H NMR (CDCl3, 200
MHz): 7.28-7.18 (m, 3H), 7.14-7.05 (m, 4H), 6.93-6.87 (m,

1H), 6.86 (d, 2H, J = 8.1), 6.66-6.64 (m, 1H), 5.58 (s, 1H), 4.04
O
55a
(t, 2H, J = 5.9), 2.71 (t, 2H, J = 5.9), 2.32 (s, 6H).
13
C NMR
(CDCl3, 50 MHz): 158.1, 148.2, 143.0, 135.9, 132.8, 130.5, 130.0, 128.9, 127.0,
126.7, 125.0, 114.8, 66.3, 58.7, 51.0, 46.3. MS (ESI): m/z 372 (M++1). Anal. Calcd
for C21H22ClNOS: C, 67.82; H, 5.96; N, 3.77. Found: C, 67.79; H, 6.02; N, 3.79.
(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-diethyl-amine
55b:
55b (0.20 g, 76%) as pale yellow viscous oil. IR (Neat): 2968,
Cl
1595, 1511, 1351 cm-1. 1H NMR (CDCl3, 200 MHz): 7.27 (d,
S
2H, J = 8.2), 7.23-7.08 (m, 5H), 6.96-6.93 (m, 1H), 6.86 (d,
2H, J = 8.1), 6.69-6.68 (m, 1H), 5.61 (s, 1H), 4.05 (t, 2H, J =
6.6), 2.88 (t, 2H, J = 6.6), 2.69-2.61 (m, 4H), 1.11-1.06 (m,
55b
6H). MS (ESI): m/z 400 (M++1). Anal. Calcd for

C23H26ClNOS: C, 69.07; H, 6.55; N, 3.50. Found: C, 69.04; H, 6.62; N, 3.51.
(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-diisopropylamine 55c:
Cl
3312, 2967, 1602, 1446, 1353, 1023, 759 cm-1. 1H NMR
(CDCl3, 200 MHz): 7.28-7.19 (m, 4H), 7.14-7.05 (m, 3H),

O
55c
6.94-6.93 (m, 1H), 6.86 (d, 2H, J = 8.2), 6.66-6.65 (m, 1H),
5.58 (s, 1H), 3.87 (t, 2H, J = 7.4), 3.06-3.00 (m, 2H), 2.80 (t,
2H, J = 7.4), 1.03 (d, 12H). 13C NMR (CDCl3, 50 MHz): 156.6, 146.5, 141.4, 134.0,
118
131.1, 128.8, 128.4, 127.2, 125.3, 124.9, 123.3, 113.1, 67.9, 49.4, 48.2, 43.1, 19.5.
MS (ESI): m/z 428 (M++1). Anal. Calcd for C25H30ClNOS: C, 70.15; H, 7.06; N, 3.27.
Found: C, 70.13; H, 7.13; N, 3.31.
1-(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-pyrrolidine
55d :
55d (0.19 g, 73%) as brown semi solid. IR (Neat): 2929, 1595,
Cl
1511, 1351 cm-1. 1H NMR (CDCl3, 200 MHz): 7.28-7.05 (m,
7H), 6.94-6.82 (m, 3H), 6.66-6.64 (m, 1H), 5.58 (s, 1H), 4.13
(t, 2H, J = 5.6), 2.95 (t, 2H, J = 5.6), 2.71-2.69 (m, 4H), 1.88-
O
55d
1.84 (m, 4H), 1.33-1.25 (m, 2H). MS (ESI): m/z 398 (M++1).
Anal. Calcd for C23H24ClNOS: C, 69.42; H, 6.08; N, 3.52. Found: C, 69.38; H, 6.14;
N, 3.53.
1-(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-piperidine
55e:
mmol), 1-(2-chloroethyl)-piperidine hydrochloride (0.135 g,
Cl
0.734 mmol) furnished 55e (0.205 g, 75%) as wine red viscous
liquid. IR (Neat): 2822, 1594, 1351, 764 cm-1. 1H NMR

O
55e
(CDCl3, 200 MHz): 7.29-7.21 (m, 3H), 7.16-7.08 (m, 4H),

N
6.99-6.93 (m, 1H), 6.87-6.84 (m, 2H), 6.69-6.67 (m, 1H), 5.60
(s, 1H), 4.10 (t, 2H, J = 6.2), 2.78 (t, 2H, J = 6.2), 2.54-2.50
(m, 4H), 1.66-1.58 (m, 4H), 1.48-1.44 (m, 2H). 13C NMR (CDCl3, 50 MHz): 158.1,
148.1, 143.0, 135.8, 132.8, 130.4, 130.0, 128.9, 126.9, 126.6, 125.0, 114.8, 77.4, 66.2,
58.3, 55.4, 51.0, 30.1, 26.3, 24.6. MS (ESI): m/z 412 (M+). Anal. Calcd for
C24H26ClNOS: C, 69.97; H, 6.36; N, 3.40. Found: C, 70.04; H, 6.34; N, 3.46.
4-(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-morpholine
55f:
55f (0.19 g, 69%) as light red semi solid. IR (Neat): 2925, 2857, 1610, 1508, 1459
cm-1. 1H NMR (CDCl3, 200 MHz): 7.27-7.06 (m, 7H), 6.94-6.92 (m, 1H), 6.83 (d,
119
2H, J = 8.1), 6.66-6.64 (m, 1H), 5.58 (s, 1H), 4.08 (t, 2H, J
Cl
= 5.8), 3.75-3.70 (m, 4H), 2.79 (t, 2H, J = 5.8), 2.59-2.55

S
(m, 4H). 13C NMR (CDCl3, 50 MHz): 158.0, 148.1, 143.0,

136.1, 132.8, 130.5, 130.1, 128.9, 127.0, 126.7, 125.0,
55f
114.9, 67.3, 66.1, 58.0, 54.4, 51.0. MS (ESI): m/z 414 (M+).
Anal. Calcd for C23H24ClNO2S: C, 66.73; H, 5.84; N, 3.38.
Found: C, 66.77; H, 5.81; N, 3.40.

1-(2-{4-[(4-Chloro-phenyl)-thiophen-2-yl-methyl]-phenoxy}-ethyl)-azepane
55g:
as brown viscous oil (0.23 g, 81%). IR (Neat): 2926, 1601,
Cl
1509, 1352, 1247 cm-1. 1H NMR (CDCl3, 200 MHz): 7.28-
7.05 (m, 7H), 6.94-6.81 (m, 3H), 6.66-6.64 (m, 1H), 5.58 (s,
O
55g
1H), 4.11 (t, 2H, J = 6.2), 2.75 (t, 2H, J = 6.2), 2.69-2.47 (m,
4H), 1.65-1.25 (m, 8H). 13C NMR (CDCl3, 50 MHz): 158.1,
148.1, 143.0, 135.8, 132.8, 130.4, 130.0, 128.9, 126.9, 126.6, 125.0, 114.8, 77.4, 66.6,
56.8, 56.2, 51.0, 28.2, 27.4. MS (ESI): m/z 426 (M+). Anal. Calcd for C25H28ClNOS:
C, 70.48; H, 6.62; N, 3.29. Found: C, 70.55; H, 6.58; N, 3.35.
2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)-N,N-dimethylethanamine
56a:
As described for 33a, compound 50e (0.10 g, 0.35 mmol), K2CO3 (0.15 g, 1.05
furnished 56a (0.10 g, 78%) as brown viscous oil. IR (Neat): 2930,
1599, 1516, 1231, 759 cm-1. 1H NMR (CDCl3, 200 MHz): 7.32-
7.23 (m, 3H), 7.19-7.11 (m, 4H), 6.89-6.86 (m, 1H), 6.83 (d, 2H, J
O
56a
= 8.4), 6.69-6.67 (m, 1H), 5.57 (s, 1H), 4.08 (t, 2H, J = 5.7), 2.74 (t,
2H, J = 5.7), 2.33 (s, 6H).
13
C NMR (CDCl3, 50 MHz): 159.3,
147.6, 143.3, 136.0, 133.7, 130.9, 130.3, 129.2, 127.6, 127.0, 125.1, 115.8, 115.1,
66.3, 58.7, 51.0, 46.3. MS (ESI): m/z 356 (M++1). Anal. Calcd for C21H22FNOS: C,
70.96; H, 6.24. Found: C, 70.98; H, 6.31.
N,N-diethyl-2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethanamine
56b:
120
mmol), 1-(2-chloroethyl)-diethyl amine hydrochloride (0.07g, 0.39 mmol) furnished
56b (0.11 g, 85%) as yellow viscous oil. IR (Neat): 2968, 1595, 1511, 1351 cm-1. 1H
NMR (CDCl3, 200 MHz): 7.29-7.24 (m, 3H), 7.22-7.10 (m,
4H), 6.98-6.95 (m, 1H), 6.88 (d, 2H, J = 8.4), 6.70-6.69 (m, 1H),
5.63 (s, 1H), 4.06 (t, 2H, J = 6.1), 2.90 (t, J = 6.1 Hz, 2H), 2.70O
56b
2.64 (m, 4H), 1.13-1.08 (m, 6H). MS (ESI): m/z 384 (M++1).
Anal. Calcd for C23H26FNOS: C, 72.03; H, 6.83; N, 3.65. Found:
C, 72.11; H, 6.79; N, 3.67.

N-(2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethyl)-Nisopropylpropan-2-amine 56c:
furnished 56c as pale yellow viscous oil (0.12 g, 81%). IR
(Neat): 3402, 2967, 2362, 1606, 1508, 1228, 758 cm-1. 1H NMR
(CDCl3, 200 MHz): 7.21-7.10 (m, 6H), 7.06-6.93 (m, 2H),

6.82 (d, 2H, J = 8.7), 6.65 (d, 1H, J = 3.5), 5.60 (s, 1H), 3.87 (t,
56c
2H, J = 6.5), 3.10-3.03 (m, 2H), 2.80 (t, 2H, J = 6.6), 1.04 (d,
12H, J = 6.5). MS (ESI): m/z 412 (M++1). Anal. Calcd for C25H30FNOS: C, 72.96; H,
7.35; N, 3.40. Found: C, 72.94; H, 7.37; N, 3.36.
1-(2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethyl)pyrrolidine 59d:
56d (0.11 g, 83%) as dark brown viscous oil. IR (Neat): 2930,
1605, 1515, 1247, 761 cm-1. 1H NMR (CDCl3, 200 MHz):
7.32-7.08 (m, 7H), 6.97-6.85 (m, 3H), 6.69-6.67 (m, 1H), 5.60
O
56d
(s, 1H), 4.15 (t, 2H, J = 5.7), 2.96 (t, 2H, J = 5.7), 2.70-2.68 (m,
N
4H), 1.86-1.81 (m, 4H), 1.34-1.28 (m, 2H). MS (ESI): m/z 382
(M++1). Anal. Calcd for C23H24FNOS: C, 72.41; H, 6.34; N, 3.67. Found: C, 72.44;
H, 6.29; N, 3.69.
1-(2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethyl)piperidine 56e:
121
(0.11 g, 77%) as orange red viscous liquid. IR (Neat): 2928,

1599, 1511, 1246, 761 cm-1. 1H NMR (CDCl3, 200 MHz):
7.33-7.27 (m, 3H), 7.19-7.13 (m, 4H), 7.01-6.98 (m, 1H),
6.89-6.84 (m, 2H), 6.72-6.69 (m, 1H), 5.57 (s, 1H), 4.13 (t,
O
2H, J = 6.0), 2.76 (t, 2H, J = 6.0), 2.51-2.47 (m, 4H), 1.63-
56e
1.59 (m, 4H), 1.48-1.44 (m, 2H). MS (ESI): m/z 396 (M++1).
Anal. Calcd for C24H26FNOS: C, 72.88; H, 6.63; N, 3.54. Found: C, 72.94; H, 6.68;
N, 3.53.
4-(2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethyl)morpholine 56f:
mmol), 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.07 g,
F
0.39 mmol) furnished 56f (0.12 g, 83%) as light red semi solid.
S
IR (Neat): 3409, 2928, 2364, 1606, 1508, 1229, 1117, 757 cm-1.
1
56f
H NMR (CDCl3, 200 MHz): 7.21-7.01 (m, 6H), 6.97-6.81 (m,
2H), 6.67 (d, 2H, J = 8.6), 6.65 (d, 1H, J = 3.5), 5.60 (s, 1H),
4.08 (t, 2H, J = 5.7), 3.73 (t, 4H, J = 4.6), 2.87 (t, 2H, J = 5.7), 2.57 (t, 2H, J = 4.6).
13
C NMR (CDCl3, 50 MHz): 164.4, 159.6, 157.9, 148.6, 140.3, 140.2, 136.5, 130.7,
130.5, 130.1, 127.0, 126.6, 125.0, 115.8, 115.4, 114.9, 67.3, 66.1, 58.0, 54.5, 50.9.
MS (ESI): m/z 398 (M++1), 318. Anal. Calcd for C23H24FNO2S: C, 69.49; H, 6.09; N,
3.52. Found: C, 69.47; H, 6.04; N, 3.56.
1-(2-(4-((4-fluorophenyl)(thiophen-2-yl)methyl)phenoxy)ethyl)azepane 56g:
as brown viscous oil (0.12 g, 81%). IR (Neat): 3431, 2926,
2361, 1607, 1507, 1219, 1034, 760 cm-1. 1H NMR (CDCl3, 200
MHz): 7.14-7.03 (m, 6H), 6.98-6.83 (m, 2H), 6.76 (d, 2H, J =
O
56g
8.7), 6.58 (d, 1H, J = 3.4), 5.52 (s, 1H), 3.98 (t, 2H, J = 6.2),
2.87 (t, 2H, J = 6.2), 2.72-2.67 (m, 4H), 1.64-1.54 (m, 8H). 13C
NMR (CDCl3, 50 MHz): 164.4, 159.6, 158.1, 148.7, 140.3, 136.3, 130.7, 130.5,
130.0, 127.0, 126.6, 125.0, 115.8, 115.3, 114.9, 66.7, 56.8, 56.2, 51.0, 28.1, 27.4. MS
(ESI): m/z 410 (M++1). Anal. Calcd for C25H28FNOS: C, 73.31; H, 6.89; N, 3.42.
Found: C, 73.27; H, 6.92; N, 3.48.
122
3.8.5
Preparation
of
2-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-
phenoxymethyl}-oxirane 57:
A mixture of compound 49b (2.50 g, 8.43 mmol), anhydrous K2CO3 (3.50 g,
25.30 mmol) and epichlorohydrin (30 mL) was heated at reflux for 7 hrs. K2CO3 was
filtered off and epichlorohydrin was removed in vacuo. The residue was extracted
with ethyl acetate, washed with water, brine and dried (Na2SO4). Column
chromatography on silica gel and elution with 20%
ethylacetate in hexane (Rf = 0.6) furnished 57 (1.98 g, 67%) as
MeO
light yellow viscous oil. 1H NMR (CDCl3, 200 MHz): 7.16-
7.04 (m, 5H), 6.88-6.76 (m, 5H), 6.61 (d, 1H, J = 3.9), 5.54 (s,
O
1H), 4.11 (dd, 1H, J1 = 3.4, J2 = 11), 3.96 (dd, 1H, J1 = 3.4, J2 =
O
57d
11), 3.76 (s, 3H), 3.29 (m, 1H), 2.88 2.83 (m, 1H), 2.71-2.68
(m, 1H). MS (ESI): m/z 352 (M+). Anal. Calcd for C21H20O3S: C, 71.56; H, 5.72.
Found: C, 71.61; H, 5.65.
3.8.6 Preparation of 2-hydroxy amino alkyl derivatives
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-(4-pyridin-2-ylpiperazin-1-yl)-propan-2-ol 58a:
A mixture of 57 (0.30 g, 0.852 mmol), 1-Pyridin-2-yl-piperazine (0.15 mL, 1.00
mmol) in ethanol (8 mL) was heated at reflux for 6 hrs.
MeO
Ethanol was removed, and the residue was extracted
with ethyl acetate. The extract was washed with brine

OH
O
58a
and dried. Column chromatography on silica gel and

elution with 90% ethyl acetate in hexane (Rf = 0.4)
furnished 58a (0.35 g, 80%) as a brown semi solid. IR (Neat): 3419, 2924, 2370,
1619, 1514, 1249, 1037 cm-1. 1H NMR (CDCl3, 200 MHz): 8.01 (d, 1H, J = 6.2),
7.3-7.2 (m, 1H), 7.18-7.17 (m, 1H), 7.00 (d, 4H, J = 8.1), 6.77-6.72 (m, 2H), 6.72 (d,
4H, J = 8.2), 6.56-6.55 (m, 2H), 5.47 (s, 1H), 4.04-4.03 (m, 1H), 3.70-3.69 (m, 2H),
3.69 (s, 3H), 3.49-3.46 (m, 4H), 2.89-2.86 (m, 2H), 2.53-2.51 (m, 4H). MS (ESI): m/z
516 (M++1). Anal. Calcd for C30H33N3O3S: C, 69.87; H, 6.45; N, 8.15. Found: C,
69.85; H, 6.52; N, 8.13.
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-(3-morpholin-4-ylpropylamino)-propan-2-ol 58b:
123
As described for 58a, 57 (0.30 g, 0.85 mmol) and 3-Morpholin-4-yl-propylamine

(0.15 mL, 1.03 mmol) in ethanol (8 mL) furnished 58b (0.32 g, 77%) as a brown semi
solid. IR (Neat): 3370, 2924, 1608, 1508, 1246 cm-1. 1H
MeO
NMR (CDCl3, 200 MHz): 7.18-6.97 (m, 5H), 6.83-
OH
O
58b
H
N
6.79 (m, 1H), 6.72 (d, 4H, J = 8.0), 6.55 (d, 1H, J = 3.9),
O
N
5.46 (s, 1H), 3.99 (m, 1H), 3.88-3.83 (m, 2H), 3.70 (s,
3H), 3.62-3.58 (m, 4H), 2.97 (bs, 2H), 2.78-2.63 (m, 4H), 2.35-2.32 (m, 6H), 1.691.63 (m, 2H). MS (ESI): m/z 497 (M++1). Anal. Calcd for C28H36N2O4S: C, 67.71; H,
7.31; N, 5.64. Found: C, 67.69; H, 7.37; N, 5.70.
1-(4-Benzyl-piperazin-1-yl)-3-{4-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]phenoxy}-propan-2-ol 58c:
As described for 58a, 57 (0.30 g, 0.85 mmol) and 1-Benzyl-piperazine (0.18
mL, 1.04 mmol) in ethanol (8 mL) furnished 58c (0.37 g, 83%) as a brown semi solid.
IR (Neat): 3411, 2924, 2363, 1612, 1511, 1250, 1034 cm-1.
MeO
1
S
H NMR (CDCl3, 200 MHz): 7.27-7.21 (m, 4H), 7.12-7.09
(m, 1H), 7.05 (d, 4H, J = 8), 6.85-6.74 (m, 6H), 6.60 (d, 1H,
OH
O
NBn
N
58c
J = 3.9), 5.51(s, 1H), 4.04-4.03 (m, 1H), 3.91-3.88 (m, 2H),

3.72 (s, 3H), 3.38 (s, 2H), 3.27 (bs, 1H), 2.66-2.45 (m, 10H).
MS (ESI): m/z 529 (M++1). Anal. Calcd for C32H36N2O3S: C, 72.70; H, 6.86; N, 5.30.
Found: C, 72.72; H, 6.92; N, 5.27.
1-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-3-{4-[(4-methoxy-phenyl)-thiophen-2yl-methyl]-phenoxy}-propan-2-ol 58d:
As described for 58a, 57 (0.30 g, 0.85 mmol)
MeO
and 2-(3,4-Dimethoxy-phenyl)-ethylamine(0.16 mL,
1.02 mmol) in ethanol (8 mL) furnished 58d (0.32 g,

OH
O
NH
OMe
70%) as a brown semi solid. IR (Neat): 3397, 2925,
OMe
2357, 1607, 1511, 1246, 1030 cm-1. 1H NMR (200
58d
MHz, CDCl3): 7.10-6.94 (m, 5H), 6.85-6.62 (m, 9H), 5.43 (s, 1H), 3.95 (bs, 1H),
3.95-3.82 (m,4H), 7.76(s, 3H), 3.74(s, 3H), 3.72 (s, 3H), 3.56-3.49 (m, 2H), 3.19-3.16
(m, 4H).
CNMR (CDCl3, 50 MHz): 158.6, 157.3, 149.6, 149.0, 148.4, 137.4,
13
136.4, 130.1, 130.0, 126.8, 126.4, 124.7, 121.1, 114.7, 114.1, 112,6, 111.9, 96.5,
70.1, 66.3, 56.2, 56.1, 55.4, 51.4, 50.8, 50.5, 32.8 cm-1. MS (ESI): m/z 534
124
(M++1,100%), 382 (30%). Anal. Calcd for C31H35NO5S: C, 69.77; H, 6.61; N, 2.62.
Found: C, 69.83; H, 6.55; N, 2.67.
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-thiomorpholin-4-ylpropan-2-ol 58e:
As described for 58a, 57 (0.30 g, 0.85 mmol) and thiomorpholine (0.10 mL, 1.02
mmol) in ethanol (8 mL) furnished 58e (0.33 g, 86%) as a brown semi solid. IR
(Neat): 3416, 2920, 2367, 1608, 1508, 1246, 1034 cm-1. 1H
MeO
NMR (200 MHz, CDCl3): 7.19-7.08 (m, 5H), 6.93-6.80

S
(m, 5H), 6.65(d, 1H, J = 3.44), 5.57(s, 1H), 4.05- 3.98 (m,
OH
2.80-2.75 (m, 2H),2.70- 2.66 (m, 2H), 2.59-2.50 (m, 2H).
58e
13
2H), 3.95(d, 2H, J = 4.78), 3.78 (s, 3H), 2.94-2.91 (m, 2H),
CNMR (CDCl3, 50MHz): 158.6, 157.7, 149.2, 137.1, 136.5, 130.1, 130.0, 126.8,
126.4, 124.6, 114.7, 114.1, 96.6, 70.5, 65.8, 61.9, 55.8, 55.4, 50.9, 28.2. MS (ESI):
m/z 456 (M++1,100%), 454(M+-1, 60%), 203. Anal. Calcd for C25H29NO3S2: C, 65.90;
H, 6.42; N, 3.07. Found: C, 65.98; H, 6.37; N, 3.15.
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-(4-methylpiperazin-1-yl)-propan-2-ol 58f:
As described for 58a, 57 (0.30 g, 0.85 mmol) and 1-Methyl-piperazine (0.12 mL,
1.03 mmol) in ethanol (8 mL) furnished 58f (0.31 g, 81%) as a blackish semi solid. IR
(Neat): 3421, 2922, 2365, 1605, 1513, 1248, 1035 cm-1. 1H
MeO
NMR (200 MHz, CDCl3): 7.13-7.02 (m, 5H), 6.87- 6.74
(m, 5H), 6.60 (d, 1H, J = 3.32), 5.51 (s, 1H), 4.47(bs, 1H),
OH
O
58f
N
N
4.06-4.03 (m, 1H), 4.01- 3.83 (m, 2H), 3.73 (s, 3H), 3.663.63 (m, 2H), 2.70-2.63 (m, 8H), 2.29 (s, 3H).
13
CNMR
(CDCl3, 50M): 158.6, 157.7, 149.2, 137.1, 136.7, 130.1, 126.9, 126.4, 124.8, 114.7,
114.1, 70.6, 66.0, 60.7, 55.6, 54.9, 53.9, 52.9, 50.9, 45.7. MS (ESI): m/z 453 (M++1,
100%), 451(M+-1, 60%). Anal. Calcd for C26H32N2O3S: C, 69.00; H, 7.13; N, 6.19.
Found: C, 68.93; H, 7.17; N, 6.22.
1-(3-Diethylamino-propylamino)-3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl]-phenoxy}-propan-2-ol 58g:
As described for 58a, 57 (0.30 g, 0.85 mmol) and N1,N1-Diethyl-propane-1,3diamine (0.17 mL, 1.05 mmol) in ethanol (8 mL) furnished 58g (0.31 g, 77%) as a
brown oil. IR (Neat): 3407, 2923, 2360, 1615, 1510, 1247, 1033 cm-1. 1H NMR
125
(CDCl3, 200 MHz): 7.26-7.07 (m, 5H), 6.93-6.65

(m, 5H), 6.64 (d, 1H, J = 3.34), 5.55 (s, 1H), 4.13-
MeO
S
3.97 (m, 2H), 3.78 (s, 3H), 3.18-2.92 (m, 2H), 2.90-
OH
O
NH
2.85 (m, 4H), 2.30-2.27 (m, 2H), 2.20-2.02 (m, 4H),

1.62 (bs, 1H), 1.56-1.54 (m, 2H), 1.33-1.17 (m, 6H).
58g
MS (ESI): m/z 483 (M +1). Anal. Calcd for C28H38N2O3S: C, 69.67; H, 7.94; N, 5.80.
Found: C, 69.25; H, 7.90; N, 5.73.
1-Cyclohexylamino-3-{4-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}propan-2-ol 58h:
As described for 58a, 57 (0.30 g, 0.85 mmol) and Cyclohexylamine (0.12 mL,
1.06 mmol) in ethanol (8 mL) furnished 58h (0.29 g, 76%) as
MeO
a pale yellow oil. IR (Neat): 3419, 2926, 2367, 1603, 1518,
OH
O
1245, 1031 cm-1. 1H NMR (CDCl3, 200 MHz): 7.24-7.04

H
N
(m, 5H), 6.89-6.76 (m, 5H), 6.61 (d, 1H, J = 3.35), 5.53 (s,
58h
1H), 4.05-4.00 (m, 1H), 3.95-3.87 (m, 2H), 3.77 (s, 3H),
2.81-2.72 (m, 4H), 2.62-2.54 (m, 5H), 1.30-1.25 (m, 6H). MS (ESI): m/z 452 (M++1).
Anal. Calcd for C27H33NO3S: C, 71.81; H, 7.37; N, 3.10. Found: C, 71.83; H, 7.40; N,
3.03.
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-piperidin-1-ylpropan-2-ol 58i:
As described for 58a, 57 (0.30 g, 0.85 mmol) and piperidine (0.10 mL, 1.02 mmol) in
ethanol (8 mL) furnished 58i (0.30 g, 79%) as a brick red
MeO
semisolid. IR (Neat): 2925, 1608, 1508, 1246 cm-1. 1H NMR
(CDCl3, 200 MHz): 7.14-7.03 (m, 5H), 6.88-6.75 (m, 5H),

OH
O
58i
6.60 (d, 1H, J = 3.38 Hz), 5.52 (s, 1H), 4.06-3.98 (m, 1H),
3.94-3.85 (m, 2H), 3.75 (s, 3H), 2.62 (dd, 2H, J1 = 5.76, J2 =
10.6), 2.51-2.39 (m, 4H), 1.61-1.45 (m, 6H). MS (ESI): m/z 438 (M++1). Anal. Calcd
for C26H31NO3S: C, 71.36; H, 7.14; N, 3.20. Found: C, 71.40; H, 7.11; N, 3.26.
1-{4-[(4-Methoxy-phenyl)-thiophen-2-yl-methyl]-phenoxy}-3-pyrrolidin-1-ylpropan-2-ol 58j:
As described for 58a, 57 (0.30 g, 0.85 mmol) and pyrrolidine (0.085 mL, 1.02
mmol) in ethanol (8 mL) furnished 58j (0.305 g, 85%) as a pale yellow semi solid.
IR(Neat): 3409, 2921, 2367, 1611, 1516, 1249, 1036 cm-1. 1H NMR (CDCl3, 200
126
MHz): 7.25-7.08 (m, 5H), 6.91-6.80 (m, 5H), 6.65 (d, 1H,
MeO
J = 3.4), 5.56 (s, 1H), 4.13-4.10 (m, 2H), 3.95 (d, 2H, J =
S
5.2), 3.77 (s, 3H), 3.34 (bs, 1H), 2.85-2.75 (m, 3H), 2.642.56 (m, 3H), 1.84-1.82 (m, 4H). MS (ESI): m/z 424
OH
N
(M++1). Anal. Calcd for C25H29NO3S: C, 70.89; H, 6.90; N,
58j
3.31. Found: C, 70.93; H, 6.93; N, 3.24.

1-(3-Imidazol-1-yl-propylamino)-3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl]-phenoxy}-propan-2-ol 58k:
As described for 58a, 57 (0.30 g, 0.85 mmol) and 3-Imidazol-1-yl-propylamine (0.12
mL, 1.02 mmol) in ethanol (7 mL) furnished 58k (0.31 g, 81%) as a red viscous oil.
IR (Neat): 3421, 2935, 2362, 1616, 1517, 1247, 1033
MeO
cm-1. 1H NMR (CDCl3, 200 MHz): 7.49 (bs, 1H),
7.26-6.99 (m, 5H), 6.90-6.57 (m, 5H), 6.57-6.55 (m,

OH
O
H
N
58k
1H), 5.47 (s, 1H), 4.43-4.37 (m, 2H), 4.07 (bs, 1H),
3.92-3.74 (m, 4H), 3.71 (s, 3H), 2.77-2.63 (m, 2H),
2.59-2.51 (m, 2H), 2.02-1.90 (m, 2H). MS (ESI): m/z 478 (M++1). Anal. Calcd for
C27H31N3O3S: C, 67.90; H, 6.54; N, 8.80. Found: C, 67.87; H, 6.55; N, 8.77.
3.8.7 Biological Activity
3.8.7.1 Agar Micro Dilution Method
All the synthesized final molecules {33a-b, 43a-e, 44a-f, 45a-d, 50a-d, 51a-e
(52-56)a-g and 58a-k)} were evaluated against M. tuberculosis H37Rv strains
following agar micro dilution method where serial two fold dilutions of each test
compound were added into 7H10 agar and M. tuberculosis H37Rv was used as test
organism.35 MIC was the concentration of the compound that completely inhibited the
growth and colony forming ability of M. tuberculosis.
In 24 well plate 3 mL middle brook 7H11 agar medium with OADC supplement
is dispensed in each well. The test compound is added to the middle brook medium
agar before in duplicate so that final concentration of test compound in each well is
25, 12.5, 6.25, 3.125 and 1.56 g/mL respectively. The known CFU of H37Rv culture
was dispensed on top of agar in each well in negative pressure biosafety hood. The
plates are then incubated at 37C/5% CO2 incubator. The concentration at which
complete inhibition of colonies was observed was taken as MIC of test drug.
127
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Eds.; Academic: San Diego, 1982, p 95. (b) Farmer, P.; Bayona, J.; Becerra, M.;
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Tuberc. Lung Dis. 1998, 2, 869. (c) Chopra, I.; Brennan, P. Tubercle Lung Dis. 1998,
78, 89.
8. Camus, J. C.; Pryor, M. J.; Medigue, C.; Cole, S. T. Microbiology 2002, 148,
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Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.;
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Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J. E.;
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269. (b) Wimpenny, J. W. J. Gen. Microbiol. 1967, 47, 389.
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16.Heifets, L. B.; Lindholm-Levy, P. J. Am. Rev. Respir. Dis. 1992, 145, 1223.
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Kreiswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, 962.
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20. Andries, K.; Verhasselt, P.; Guillemont, J.; Ghlmann, H. W. H.; Neefs, J.-M.;
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D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. A.
Science 2005, 307, 223.
21. Arora, S. K.; Sinha, N.; Jain, S.; Upadhayaya, R. S.; Jana, G.; Ajay, S.; Sinha, R.
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22. Zhang, Y.; Post-Martens, K.; Denkin, S. Drug Discovery Today 2006, 11, 21.
23. Rothstein, D. M.; Shalish, C.; Murphy, C. K.; Sternlicht, A.; Campbell, L. A.
Expert Opin. Invest. Drugs 2006, 15, 603.
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Shagufta; Srivastava, A. K.; and Sinha, S. Bioorg. Med. Chem. Lett. 2005, 15, 5222.
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130
3.10 Spectra
MeO
S
N
51a
Figure 3.5 1H NMR (200 MHz, CDCl3) spectrum of 51a.
MeS
S
OH
48c
131
MeS
S
OH
50c
MeS
S
OH
50c
Figure 3.8
13
132
MeS
S
O
54d
Figure 3.9 1H NMR (200 MHz, CDCl3) spectrum of 54d.
MeO
N SO2
O
43a
Figure 3.10 1H NMR (200 MHz, CDCl3) spectrum of 43a.
133
MeO
N
Bn
44e
Figure 3.11 1H NMR (200 MHz, CDCl3) spectrum of 44e.
MeO
N
Bn
O
44b
Figure 3.12 1H NMR (200 MHz, CDCl3) spectrum of 44b.
134
MeO
N
Bn
O
44b
Figure 3.13 13C NMR (50 MHz, CDCl3) spectrum of 44b.
MeO
N
O
45c
135
MeO
S
O
53c
MeO
S
O
53c
Figure 3.16
13
136
Chapter 4
Design, Synthesis and Antimalarial Activity of
Benzene and Isoquinoline Sulfonamide
Derivatives
Chapter 4: Design, Synthesis and Antimalarial Activity of Benzene and Isoquinoline Sulfonamide Derivatives
4.1 Introduction
Malaria is a vector-borne infectious disease caused by protozoan parasites of
the genus Plasmodium. It is widespread in tropical and subtropical regions, including
parts of the Americas, Asia, and Africa. It is a particularly devastating health problem
in Africa, especially between the Sahara Desert and South Africa.1 According to
World Health Organization (WHO), malaria causes approximately 300 million
clinical cases every year. It is estimated that between 1.5 to 2.7 million people die
from malaria every year either directly or in association with anemia and upto one
million of those deaths are among children in the age group less then 5 years.2 Malaria
is commonly associated with poverty, but is also a cause of poverty and a major
hindrance to economic development. Only four types of the plasmodium parasite can
infect humans through entering in the intraerythrocytic cycle; the most serious forms
of the disease are caused by Plasmodium falciparum and Plasmodium vivax, but other
related species (Plasmodium ovale, Plasmodium malariae) can also affect humans.
Among these parasites, P. falciparum is responsible for about 80% of infections and
90% of deaths.3 Clinically, malaria manifests as fever, chills, prostration and anemia.
Severe form of the disease may lead to delirium, metabolic acidosis, cerebral malaria,
multi organ system failure, coma and death. The treatment of malaria depends solely
on chemotherapeutics and chemoprophylaxis due to the existence of limitations in
vaccine development and vector control. Malaria parasite, Plasmodium falciparum,
has developed resistance against almost all frontline antimalarials such as chloroquine
and antifolates (sulfadoxine + pyrimethamine) which made the situation more worse.4
The design and development of novel drugs for the comprehensive treatment of
malaria is highly necessary, intensive research warrants to eradicate this deadly
disease. Therefore, strong interest has been directed at the search for new antimalarial
agents.5
4.2 Life cycle of malaria parasite

The Lifecycle of the malaria parasite may be divided into two stages (i) the
definitive (vertebrate) host - e.g. man and (ii) the intermediate (invertebrate) host e.g. female anopheline mosquitoes. Malaria in humans develops via two phases: an
exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves
infection of the hepatic system, or liver, while the erythrocytic phase involves
infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a
137
person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the
bloodstream and migrate to the liver. Within 30 minutes of being introduced into the
human host, they infect hepatocytes, multiplying asexually and asymptomatically for
a period of 615 days. Once in the liver these organisms differentiate to yield
thousands of merozoites which, following rupture of their host cells, escape into the
blood and infect red blood cells, thus beginning the erythrocytic stage of the life
cycle. The parasite escapes from the liver undetected by wrapping itself in the cell
membrane of the infected host liver cell.
Within the red blood cells the parasites multiply further, again asexually,
periodically breaking out of their hosts to invade fresh red blood cells. Several such
amplification cycles occur. Thus, classical descriptions of waves of fever arise from
simultaneous waves of merozoites escaping and infecting red blood cells.
Figure 4.1. The life cycle of malaria parasite (adapted from MSN Encarta).
After several erythrocytic cycles some erythrocytic forms develop into sexual
gametocytes. It is ingestion of infected blood containing gametocytes by biting a
female mosquito which allows the lifecycle to be completed with the sexual phase in
the mosquito. Gametocytes in human blood are taken up by the mosquito leading to
fertilization and zygote formation in mosquito midgut. This produces an ookinete that
penetrates the gut lining and developed as an oocyst in the gut wall. When the oocyst
ruptures, it releases haploid sporozoites that invades the salivary glands of the
mosquito and is subsequently transmitted back to humans due to the bite. Only female
mosquitoes feed on blood, thus males do not transmit the disease. An outline of
lifecycle of malaria parasite is presented in Figure 4.1.6,7
138
4.3 Treatment of malaria5a

Human beings have been infected by malaria from long back ago, and may
have been a human pathogen for the entire history of our species. Scientific studies on
malaria made their first significant advance in 1880, when a French army doctor
proposed that malaria was caused by Plasmodium protozoan. However, it was Sir
Ronald Ross who finally proved in 1898 that malaria is transmitted by mosquitoes.
Treatment of malaria involves supportive measures as well as specific antimalarial
drugs. The first effective treatment for malaria was the bark of Cinchona tree
(originally found in the high altitudes of South America) and which had already been
used since the beginning of the 17th century. However, it was not known until 1820
that the active ingredient, extracted from the bark, is quinine. The structure of quinine
(1, Figure 4.2) was elucidated in 1908 and provided evidence that the quinoline
nucleus could be useful component of an antimalarial. However synthetic route of
quinine nucleus is very complex for commercial production and it is less effective and
more toxic as a blood schizonticidal agent. In the 1940s, as a result of large-scale
search for analogues of quinine, the 4-aminoquinolines chloroquine 2 and
amodiaquine 3 were produced. Later mefloquine 4, a synthetic analogue of quinine
and halofantrine 5, a phenanthrene methanol structurally related to quinine was
developed. The drugs available for the treatment of the liver forms of the parasite are
the primaquine 8 and dihyrofolate reductase inhibitors e.g., proguanil 12. Other
currently used drugs for malaria are antifolates sulfadoxine (10), pyrimethamine(11))
and the artemisinin derivatives.
In the early 1970s, isolation of artemisinin as the antimalarial principle of
Chinese traditional herb, Artemisia annua is a major milestone in the history of
malaria chemotherapy. Ever since its isolation, artemisinin has been a subject of
intense structure activity relationship studies. Because of the low solubility of
artemisinin, more hydrosoluble analogues, artemether 9a and arteether 9b were
developed and are active against multi drug resistance strains of plasmodium parasite.
The structures of clinically used antimalarial drugs are given in Figure 4.2. These
drugs act on different stages of the malaria life cycle, although most of them target the
intraerythrocytic phases of the parasite.14 In most cases, antimalarial drugs are
targeted against the asexual erythrocytic stage of the parasite. The parasite degrades
hemoglobin in its acidic food vacuole, producing free heme able to react with
139
molecular oxygen and thus to generate reactive oxygen species as toxic by-products.
A major pathway of detoxification of heme moieties is polymerization as malaria
pigment. Majority of antimalarial drugs act by disturbing the polymerization (and/or
the detoxification by any other way) of heme and killing the parasite with its own
metabolic waste. It should be noted that an antimalarial could be effective against one
Plasmodium species and completely ineffective against the others, thus making the
use of combinations of drugs an advisable strategy for malaria chemotherapy. All the
antimalarial drugs can be classified as
1) Schizonticidal drugs for clinical and parasitological cure
Chloroquine, Amodiaquine, Quinine, Quinidine, Pyrimethamine, Trimethoprim,
Proguanil,
sulfonamides
in
combination
with
Pyrimethamine,
Mefloquine,
Halofantrine, Artemisinine and its derivatives like Artesunate, Artemether, Arteether.

2) Gametocytocidal and anti-relapse drugs.
Primaquine, pamaquine, bulaquine, only compound having action on gametocytes
and hypnozoites.
OH
CH3
N
HO
HN
N(C2H5)2
HN
H
H3CO
Cl
Cl
HO
3, Amodiaquine
2, Chloroquine
1, Quinine
N
C4H9
HO
N
H H
Cl
F3C
N
Cl
Cl
CF3
CF3
Cl
Cl
4, Mefloquine
5, Halofantrine
6, Lumefantrine
H
OH
O O
O
NH2
HN
Cl
O
H3CO
7, Atovaquone
H2N
C4H9
HO
H3CO
O
S N
O H N
10, Sulfadoxine
RO
8, Primaquine
9a, Artemether R= CH3

9b, Arteether R = C2H5
9c, Artesunate R = COC2H4CO2H
NH2
OCH3
N
H2N
Cl
N
C2H5
11, Pyrimethamine
Cl
H3C CH3
N
NH
N
H2N
NH2
12, Proguanil
Figure 4.2. The structures of some clinically used antimalarial drugs.
140
4.4 Mechanism of action of antimalarial drugs5a

Despite years of use, not much is known about the mode of action of most of
the antimalarial drugs available today. Whilst this had not been perceived as a major
problem when such drugs performed satisfactorily, it is becoming evident that this
inadequate knowledge is limiting our ability to design new antimalarial agents.
However, different mechanisms have been proposed for the action of different
antimalarials.
4.4.1 Quinoline analogues. The mechanism of action of quinoline and its analogue
drugs is complicated and still unclear. Quinoline-containing antimalarial drugs act as
blood schizonticidal and weak gametocide against Plasmodium vivax and
Plasmodium malariae. These are accumulated in the food vacuoles of plasmodium
species, especially Plasmodium falciparum. Intra-erythrocytic stages of malaria
parasites consume and degrade huge quantities of hemoglobin in the food vacuole and
release a large quantities of redox active free heme as a by product. Free heme is very
toxic and parasites detoxify free heme by forming hemozoin, It is believed to reach
high concentrations in the vacuoles of the parasite, which, due to their alkaline nature,
raise the internal pH. It controls the conversion of cytotoxic heme to hemozoin by
inhibiting the biocrystallization of hemozoin thus poisoning the parasite that damage
parasitic food vacuoles through excess levels of toxicity. Other potential mechanisms
through which they may act include interfering with the biosynthesis of parasitic
nucleic acids by the formation of a quinoline-haem or quinoline-DNA complex.
Moreover, the inhibition of hemozoin formation is considered as a validated target to
develop new antimalarials.
Figure 4.3. Schematic of hemoglobin proteolysis.

141
4.4.2 Artemisinin and their derivatives: Artemesinin has a very different mode of
action than conventional anti-malarials, this makes is particularly useful in the
treatment of resistant infections, however in order to prevent the development of
resistance to this drug it is only recommended in combination with another nonartemesinin based therapy. Although the specific mechanism of action of artemisinin
13 and their derivatives is not still well understood, there is ongoing research directed
at elucidating it. According to most accepted mechanism when the malaria parasite
infects a red blood cell in human body, it consumes hemoglobin and liberates free
heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin
generating high-valent iron-oxo species, resulting in a cascade of reactions that
produce reactive oxygen radicals which damage the parasite leading to its death. Also,
the activated artemisinin and their derivatives specifically and irreversibly bind and
inhibit Pf-ATP6, and inhibits parasite growth (Figure 3.4). At present there is no
known resistance to Artemesinin and very few reported side-effects to drug usage,
however this data is limited.
H2C
+++
4
O
H
++
Fe
Fe
Fe
HO
+++
or
O
H
H
O
H
O
O
O
seco-C4 redical
C4 redical
13, Artemisinin
The activated artemisinin specifically and

irreversibly binds with cellular proteins,
inhibits PfATP6, and inhibits parasite growth.
Figure 4.4. Mode of action of artemisinin and their derivatives

4.4.3 Antifolates. They act primarily on the schizonts during the hepatic and
erythrocytic phases. The antifolates act by inhibition of dihydrofolate reductase
enzymes in the parasite thus preventing the biosynthesis of purines and pyrimidines
and halting the processes of DNA synthesis, cell division and reproduction.
Antifolates are classified into two classes:
(i) Type-1 antifolates (sulfonamides and sulfones) mimic p-aminobenzoic acid
(PABA)
and
prevent
the
formation
of
dihydropteroate
from
hydroxymethyldihydropterin catalyzed by dihydropteroate synthase (DHPS) which is
142
bifunctional
enzyme
in
plasmodia
coupled
with
2-amino-4-hydroxy-6-
hydroxymethyl-dihydropteridine pyrophosphokinase [PPPK].

(ii) Type-2 antifolates (pyrimethamine, biguanides and triazine metabolites,
quinazolines) inhibit dihydrofolate reductase (DHFR, also a bifunctional enzyme in
plasmodia coupled with thymidylate synthase [TS]), thus preventing the NADPHdependent reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) by DHFR.
THF is a necessary cofactor for the biosynthesis of thymidylate, purine nucleotides,
and certain amino acids.8
4.4.4 Atovaquone. Recently, this new type of antimalarial drug has proven to be very
effective as no mosquitos populations have already been able to generate resistance
due to exposure. Also, the drug produces has no side-effects such as the
cardiovascular effect with mefloquine which can trigger heart rhythm problems.
Atovaquone is used for both the treatment and prevention of malaria in a fixed
combination with proguanil. Whilst known to act primarily on mitochondrial
functions, its mode of action and synergy with proguanil are not completely
understood. The atovaquone acts on the mitochondrial electron transfer chain and
interfering with mitochondrial membrane potential. Atovaquone inhibit the
respiratory chain of malarial mitochondria. A brief summary of mode of action for the
main classes of antimalarial drugs is given in Table 4.1.
143
Table 4.1. Summary of mode of action for the main classes of antimalarial drugs
(adapted from Pharmacology & Therapeutics, Volume 89, 2001, Page 209).
4.5 New targets and ligands for malaria

The advances in the understanding of molecular and structural biology of
malaria parasite have led to the identification of various molecular targets for the
design of new antimalarials. These targets are various enzymes vital for the growth as
well as for the synthesis essential metabolites of parasite. The list of some of the
biological targets and their inhibitors are given in Table 4.2.9
Target
Parasite
Enzyme /
process
Plasmepsins,
proteases
falcipains
Mitochondrial Cytochrome c
system
oxidoreductase
Inhibitors
Structures
Leupeptin
Atovaquone
OH
Cl
15
Shikimate
pathway
Membrane
biosynthesis
5-enolpyruvyl
shikimate 3phosphate
synthase
Phospholipid
biosynthesis
Glyphosate
O
H
N
OH
16
G25
(CH2)16
CH3
CH3
17
Redox system
Apicoplast
Thioredoxin
reductase
Fab I
OH
HO
5,8Dihydroxy1,4naphthoquinone
Triclosan
HO
OH
18
Cl
OH
O
Cl
Cl
19
Parasite
transporters
Hexose
transporter
O-3-hexose
derivatives
CH 2OH
O
OCH2Ph
OH
20
Folic acid
dihydrofolate
reductase
OH
OH
NH2
N
N
H2N
21
144
Isoprenoid
biosynthesis
BMS214662
protein
farnesyltransfe
rase (PFT)
O
NC
S
O
N
NH
N
22
4.6 Basis of present work

Sulfonamides represent an important class of medicinally important molecules
and are known to possess wide range of biological activities which include
antimicrobial drugs, saluretics, carbonic anhydrase inhibitors, antithyroid agents,
antitumour drugs etc.10-20 Sulfonamides remain the most widely used antibacterial
agents in the world because of their low cost, low toxicity and excellent activity
against common bacterial diseases. It is noteworthy that some antifolate antimalarial
such as sulfadoxine (10), sulfadiazine (23) and sulfalene (24) are also benzene
sulfonamides21 (Figure 4.5). Isoquinoline sulfonamide (H-89) (25) is a potent
inhibitor of Pfmrk, one of the cyclin dependent protein kinases (CDKs) from
Plasmodium falciparum. Plasmodial CDKs play an essential role in the growth and
development of the parasite. Functional conservation among the CDKs suggests a role
in cell cycle control of the malaria parasite. Support for an essential role of plasmodial
CDKs comes from inhibitor studies in which mammalian CDK inhibitors possessed
anti-parasitic activity in vitro.17
O
N
S
N
O H
H 2N
OMe
OMe
O
O S
N
OMe
24; sulf alene
23; sulfadiazine
O
O S NRR
N
H
O
Br
N
O H
H 2N
H 2N
10; sulfadoxine
H
N
O
S
O
N
S
N
N
O H
25
H-89
R1
S O
NRR
N
27
26
R 1= H, CH 3, NO2
NRR = secondary, tertiary and cyclic amines
Figure 4.5 Representative examples of drugs and target molecules

In search of new antimalarials, these observations promoted us to synthesize
and evaluate a new series of benzene and isoquinoline sulfonamide derivatives for
antimalarial efficacy. Our work focused on the design and synthesis of benzene and
isoquinoline sulfonamide derivatives and to evaluate the efficassy of these compounds
145
as antimalaria. The structures of the target molecules 26 and 27 are given. Benzene
and isoquinoline sulfonyls are attached to secondary, tertiary and cyclic amines.
Substitution of benzene and isoquinoline sulfonyl chlorides with various amines is
expected to give the target molecule.
4.7 Results and Discussion

4.7.1 Chemistry
Reaction of commercially available benzene sulfonyl chlorides 28a-c with
primary amine 29a-c in presence of triethylamine and chloroform at room
temperature furnished 30a-g in 75-87% yield. Similarly 27a-c and isoquinoline
sulfonyl chloride 33 with secondary amine 31a-g under similar reaction condition
gave 32a-p and 33a-b respectively. To synthesize the -amino alcohol derivatives
38a-k of isoquinoline sulphonamide, 33 was reacted with methylamine hydrochloride
35 to furnish 36. The hydrogen atom attached to nitrogen in 36 is acidic and thus
reaction of 36 with NaH/DMF followed by epichlorohydrin furnished the epoxide 37.
Nucleophilic addition reaction of 37 with primary amines in MeOH gave a series of
-amino alcohol derivatives 38a-k regioselectively (Scheme 4.1).

O
S Cl
O
R1
+ H2 N
O
S Cl
Et3N
HN
CHCl3 , r.t, 2-3 hr
Et3 N
R2
n CHCl3, r.t, 2 hr
O
28a-c
O
O S N
+
HN
CHCl3
Et3N
CH 3
O
N
S
O
DMF, NaH
36
N
n
R2
R2
n
34a-b
CH 3 OH
O
N
S
O
NHR 2
NH 2R 2
Epichlorohydrin
CHCl3 N
R2
H
O
N
CH 3
O S
O
Cl
O S
Et3N
31d,31g
33
33
+
NH2 Me.HCl
35
R2
n
O
S N
O
32a-p
R1
31a-g
O
Cl
O S
S O
N
30a-g H
R1
29a-c
28a-c
R1
n R2
MeOH
N
37
N
38a-k
Scheme 4.1
All the synthesized sulfonamide derivatives with in vitro antimalarial activity against
Plasmodium falciparum are summarised in Table 4.2
Table 4.2
146
Serial
No.
Comp
ound
No.
30a
R1
Amines
CH3
Structures of sulfonamides
OCH3
H 2N
30b
N
O H
OCH3
NO2
OCH3
30c
OCH3
OCH3
OCH3
CH3
30e
CH3
S
N
O H
30f
S
N
O H
29c
NO2
30g
32a
NO2
HN
32b
CH3
HN
29c
32c
HN
32d
CH3
O
S N
O
CH3
13
32f
H 3C
31c
32g
CH3
HN
31c
N
32h
NO2
HN
H 3C
32i
H
HN
N
31d
O
S N
O
O 2N
OH
N
N
O
S N
O
O
S N
O
OH
OH
31d
16
10
71
10
73
ND
69
10
75
ND
81
10
76
10
83
10
76
10
OH
OH
31d
15
79
S N
O
O
S N
O
14
10
HN
87
O
H 3C
N
HN
10
H 3C
31b
32e
77
O
S
N
O
HN
12
10
O2 N
31a
11
78
O
S
N
O
31a
10
10
O
S
N
O H
31a
75
O 2N
H 2N
10
S
N
O H
29c
85
N
H 2N
10
H 3C
86
H 3C
N
H 2N
10
OCH3
N
O H
29b
OCH 3
H 2N
84
OCH 3
O
S
29a
30d
O2N
H 2N
OCH 3
O
S
N
O H
29a
MIC
(g/mL)
OCH 3
H 3C
H 2N
OCH 3
O
S
29a
Yield
(%)a
OH
O
S N
O
147
17
32j
NO2
Cl
Cl
O2 N
O
S N
O
O 2N
O
S N
O
N
HN
31e
18
32k
NO2
N
N
HN
19
32l
31c
O
S N
O
HN
31b
20
32m
CH3
N CH 3
HN
32n
NO2
N CH 3
HN
32o
31f
34a
O
S N
O
31d
24
34b
NH 2
25
38a
OH
38b
O
S
N
O
Me
83
10
79
10
82
10
88
50
84
10
69
50
71
10
66
10
65
10
72
50
67
10
N
H
OH
Cl
Cl
O
S
N
O
Me
38c
10
NH 2
H2N
27
80
OH
H2N
26
10
S N
O
79
OH
31g
10
N
HN
N Me
OH
HN
N Me
O
S N
O
N CH 3
HN
23
N Me
O
S N
O
O2N
31f
22
Cl
O
S N
O
H 3C
31f
21
73
OH
N
H
Cl
H2 N
28
38d
OCH3
H 2N
29
38e
OCH3
OCH3
O
S
N
Me
OH
N
H
Cl
N
OMe
O
S
N
O
Me
N
OH
N
H
OMe
OMe
H 2N
30
38f
O
S
N
O
Me
OH
N
H
H 2N
N
O
S
N
O
Me
OH
N
H
148
31
38g
64
10
74
69
62
10
67
10
H 2N
O
S
N
O
Me
32
38h
Cl
H 2N
33
38i
Cl
O
S
N
O
Me
38k
OH
N
H
Cl
H2 N
N
H
35
Cl
Cl
O
S
N
O
Me
H 2N
38j
Cl
N
H
OH
Cl
Cl
34
N
H
OH
O
S
N
O
Me
NH
OH
N
H
H2N
O
S
N
O
Me
OH
N
H
4.7.2 Structure activity relationships

All sulfonamide derivatives displayed in vitro activity against Plasmodium
falciparum with minimum inhibitory concentrations (MIC) ranging from 2-50 g/mL.
The analysis of the structures and antimalarial activity reveals that substitution in the
benzene ring among the series of benzene sulfonamides did not have any effect on
activity. However, isoquinoline derivatives showed better activity. Between 34a and
34b, compound containing amino group is more active than the hydroxyl group.
Isoquinoline sulfonamides with 2-hydroxy-propyl amines (38a-k) exhibited lower
inhibitory potential than benzene sulfonamides. The analysis reveals that isoquinoline
sulfonamide derivatives with disubstituted phenyl ring showed better inhibitory
activity than other mono substituted phenyl derivatives.
Increasing hydrophilic
moiety on propyl amine did not exhibit better activity. Isoquinoline sulfonamides 34a,
38a, 38e containing piperazine, 4-(2-amino-ethyl)-phenol and 3-imidazol-1-ylpropylamine group respectively did not show good activity. However, 2-hydroxy
propyl amines with isoquinoline on one side and dichloro phenyl ring on another side
showed better antimalarial activity.
4.8 Conclusion
In conclusion, in the present study a series of benzene and isoquinoline
sulfonamides were synthesized from corresponding sulfonyl chlorides using
nucleophilic addition reaction in moderate to high yields. Our work indicated that
149
among all the sulfonamides synthesized, only some of the isoquinoline derivatives
with chlorine substitutent on benzene ring exhibit good in vitro antimalarial activity.
Further optimization on these leads obtained might result into potent antimalarial
agents.
4.9 Experimental section

4.9.1 Chemistry
4.9.1.1
General
procedure
for
the
preparation
of
Preparation
of
benzenesulfonamides:
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-methyl-benzenesulfonamide 30a:
To a solution of 3, 4-dimethoxy-phenyl)-ethyl 29a (0.14 g, 0.79 mmol) in dry
chloroform (5 mL) was added triethyl amine (0.09 mL, 0.63
OCH3
O
S
N
O H
H 3C
30a
OCH3
mmol) followed by 4-methyl-benzenesulfonyl chloride 28a

(0.10 g, 0.52 mmol) and was stirred at room temperature for
2h. The mixture was extracted thrice with chloroform, washed with brine and dried
over sodium sulphate. It was concentrated and charged over silica gel. Elution with
40% ethyl acetate in hexane (Rf = 0.5) furnished 30a (0.14 g, 84%), as grey crystalline
solid Rf= 0.5 (40% ethyl acetate in hexane). mp- 132-134C. IR (KBr): 3268, 2967,
2840, 1595, 1516, 1437, 1327, 1260, 1160, 1023, 883, 676 cm-1 . 1H NMR (CDCl3,
200 MHz): 7.68 (d, 2H, J = 8.3), 7.26 (d, 2H, J = 8.0), 6.74 (d, 1H, J = 8.0), 6.646.58 (m, 1H), 6.58 (s, 1H), 4.80 (m, 1H ), 3.83 (s, 3H), 3.79 (s, 3H), 3.22-3.12 (m,
2H), 2.70 (t, 2H, J = 6.9), 2.41 (s, 3H). 13C NMR (50 MHz, CDCl3): 151.6, 148.1,
138.7, 138.2, 133.0, 130.3, 129.8, 128.6, 128.4, 124.3, 115.7, 115.0, 58.3, 43.8, 36.4,
24.7. MS (ESI): m/z 335 (M+, 90%). Anal. Calcd for C17H20NO4S: C, 60.87; H, 6.31;
N, 4.18. Found: C, 60.93; H, 6.27; N, 4.15.
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-nitro-benzenesulfonamide 30b:
As described for 30a, compound 30b was prepared as pale yellow solid, 0.14 g,
(86%), Rf= 0.4 (50% ethyl acetate in hexane). M.p.:120-122C. IR (KBr): 3436, 3285,
2927, 2365, 2339, 1524, 1461, 1349, 1220, 1161, 1026,
O2 N
O
S
N
O H
30b
OCH 3
OCH3
854, 771 cm-1. 1H NMR (CDCl3, 200 MHz): 8.29 (d,

2H, J = 7.1) 7.93 (d, 2H, J = 7.0), 6.73 (d, 1H, J = 7.9),
6.61 (d, 1H, J = 7.8), 6.58 (s, 1H), 4.96 ( m, 1H ), 3.82
(s, 3H ), 3.80 (s, 3H), 3.32-3.22 (m, 2H), 2.74 ( t, 2H, J = 6.8). 13C NMR (50 MHz,
CDCl3): 154.3, 152.3, 150.1, 148.6, 133.8, 129.5, 127.3, 124.7, 115.8, 115.4, 57.2,
150
39.5, 35.2. MS (ESI): m/z 366 (M+, 100%). Anal. Calcd for C16H18N2O6S: C, 52.45;
H, 4.95; N, 7.65. Found: C, 52.38; H, 4.98; N, 7.57.
N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-benzenesulfonamide 30c:
As described for 30a, compound 30c was prepared as pale brown solid, 0.15 g,
(85%), Rf= 0.4 (40% ethyl acetate in hexane). mp- 72 C. IR (KBr): 3287, 2999,
O
S
N
O H
OCH 3
2836, 1592, 1517, 1462, 1418, 1318, 1261, 1154, 1027,
OCH 3
936, 720, 598 cm-1. 1H NMR (CDCl3, 200 MHz): 7.80

(d, 2H, J = 7.6), 7.56-7.47 (m, 3H), 6.74 (d, 1H, J = 7.9),
30c
6.61 (d, 1H, J = 7.9), 6.58 (s, 1H), 4.85 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.24-3.14
(m, 2H), 2.70 (m, 2H). MS (ESI): m/z
321 (M++1, 95%). Anal. Calcd for

N-(3-(1H-imidazol-1-yl)propyl)-4-methylbenzenesulfonamide 30d:
As described for 30a, compound 30d, was prepared as pale yellow oil, 0.11 g,
(75%), Rf= 0.4 (1% methanol in chloroform). IR (Neat): 3420, 2935, 2362, 1596,
H 3C
O
S
N
O H
30d
1350, 1158, 1090 cm-1. 1H NMR (CDCl3, 200 MHz):

N
N
7.67 (d, 2H, J = 8.1) 7.43 (s, 1H) 7.22 (d, 2H, J = 8.0), 6.92
(s, 1H), 6.84 (s, 1H), 4.0 (t, 2H, J = 6.5), 2.79 (t, 2H, J =
5.8), 2.37 (s, 3H), 1.97-1.85 (m, 2H). MS (ESI): m/z 280 (M++1, 90%). Anal. Calcd
for C13H17N3O2S: C, 55.89; H, 6.13; N, 15.04. Found: C, 55.96; H, 6.15; N, 14.97.
4-Methyl-N-(3-morpholin-4-yl-propyl)-benzenesulfonamide 30e:
As described for 30a, compound 30e was prepared as pale yellow solid, 0.12 g,
(78%), Rf= 0.3 (70% ethyl acetate in hexane). mp-89-93C. IR (KBr): 3345, 2948,
O
S
N
O H
H 3C
2847, 2363, 1596, 1453, 1330, 1156, 1115, 1006, 815, 663,
N
O
548 cm-1. 1H NMR (CDCl3, 200 MHz): 7.65 (d, 2H, J =

8.1), 7.22 (d, 2H, J = 8.0), 3.62 (t, 4H, J = 4.6), 2.96 (t, 2H,
30e
J = 6.0), 2.34 (s, 3H), 2.31-2.28 (m, 6H ), 1.58-1.52 (m, 2H). MS (ESI): m/z 299
(M++1, 100%). Anal. Calcd for C14H22N2O3S: C, 56.35; H, 7.43; N, 9.39. Found: C,
56.32; H, 7.41; N, 9.45.
N-(3-Morpholin-4-yl-propyl)-4-nitro-benzenesulfonamide 30f:
As described for 30a, compound 30f was prepared as brown crystalline solid, 0.11 g,
(77%), Rf= 0.3 (70% ethyl acetate in hexane ), mp-106-108C. IR (KBr): 3430, 2965,
2822, 2364, 1599, 1532, 1441, 1353, 1159, 1117, 979, 857 cm-1. 1H NMR (CDCl3,
O
S
N
O H
O2 N
30f
200 MHz): 8.38 (d, 2H, J = 8.8), 8.04 (d, 2H, J = 2.1),
N
O
151
3.73 (t, 4H, J = 4.6), 3.14 (t, 2H, J = 5.7), 2.51-2.43 (m, 6H), 1.76-1.64 (m, 2H). MS
(ESI): m/z 330 (M++1, 100%). Anal. Calcd for C13H19N3O5S: C, 47.41; H, 5.81; N,
12.76. Found: C, 47.47; H, 5.84; N, 12.71.
N-(3-Morpholin-4-yl-propyl)-benzenesulfonamide 30g:
As described for 30a, compound 30g, was prepared as brown viscous oil, 0.14 g,
(87%), Rf= 0.3 (60% ethyl acetate in hexane). IR (Neat): 3407, 2931, 2857, 2363,
1596, 1449, 1330, 1160, 1115, 758, cm-1. 1H NMR (CDCl3, 200
O
S
N
O H
MHz): 7.78 (d, 2H, J = 1.6), 7.54- 7.38 (m, 3H), 3.61 (t, 4H, J
N
O
30g
= 4.6), 2.99 (t, 2H, J = 6.0), 2.33-2.28 (m, 6H), 1.61-1.49 (m,
2H). MS (ESI): m/z 285 (M++1, 100%). Anal. Calcd for C13H20N2O3S: C, 54.91; H,
7.09; N, 9.85. Found: C, 54.98; H, 7.12; N, 9.82.
1-Benzyl-4-(4-nitro-benzenesulfonyl)-piperazine 32a:
As described for 30a, compound32a was prepared as grey crystalline solid 0.26 g,
(79%), Rf= 0.5 (20% ethyl acetate in hexane). mp-138C. IR (KBr): 3423, 2923,
2366, 1597, 1354, 1167, 1129, 956, 747, 598 cm-1.
O
S
N
O
NMR (CDCl3, 200 MHz): 8.38 (d, 2H, J = 7.0), 7.94 (d,
O 2N
2H, J = 7.0), 7.27-7.24 (m, 5H), 3.50 (s, 2H), 3.03 (t, 4H, J
32a
= 4.8 Hz), 2.54 (t, 4H, J = 7.2). MS (ESI): m/z 362 (M+, 100%). Anal. Calcd for
1-Benzyl-4-(toluene-4-sulfonyl)-piperazine 32b:
As described for 30a, compound 32b, was prepared as colorless crystalline solid,
0.12 g, (71%) Rf= 0.5 (20% ethyl acetate in hexane) mp
O
S
N
O
H3C
85-87C. IR (KBr): 3443, 2939, 2820, 2365, 1595, 1449,

1347, 1162 cm-1. 1H NMR (CDCl3, 200 MHz): 7.62 (d,
32b
2H, J = 8.2), 7.32- 7.24 (m, 7H ), 3.47 (s, 2H ), 3.99 (t, 4H, J = 4.6), 2.51 (t, 4H, J =
4.8), 2.42 (s, 3H). MS (ESI): m/z 331 (M+, 100%). Anal. Calcd for C18H22N2O2S: C,
65.42; H, 6.71; N, 8.48. Found: C, 65.43; H, 6.77; N, 8.41.
1-benzyl-4-(phenylsulfonyl)piperazine 32c:
As described for 30a, compound 32c, was prepared as pale brown solid, 0.13
g, (73%), Rf= 0.4 (20% ethyl acetate in hexane). mp 155-157C. IR (KBr): 3432,
2913, 2824, 2365, 1595, 1446, 1170, 939 cm-1. 1H NMR
O
S N
O
N
32c
(CDCl3, 200 MHz): 7.77 (m, 2H), 7.60-7.54 (m, 3H),

7.27-7.24 (m, 5H), 3.47 (s, 2H), 3.03 (t, 4H, J = 4.8), 2.51
152
(t, 4H, J = 7.2). MS (ESI): m/z 317 (M++1, 100%). Anal. Calcd for C17H20N2O2S: C,
64.53; H, 6.37; N, 8.85. Found: C, 64.49; H, 6.45; N, 8.87.
1-(4-Chloro-phenyl)-4-(toluene-4-sulfonyl)-piperazine 32d:
As described for 30a, compound 32d was prepared as grey powder, 0.12 g, (69%)
Rf= 0.3 (40% ethyl acetate in hexane). mp-206-208C. IR (KBr): 3413, 2832, 2366,
H 3C
O
S N
O
32d
1594, 1495, 1451, 1349, 1231, 1162, 946, 731 cm-1. 1H

N
Cl
NMR (CDCl3, 200 MHz): 7.63 (d, 2H, J = 8.19), 7.36

(d, 2H, J = 7.1), 7.12 (d, 2H, J = 6.7), 6.97 (d, 2H, J =
6.7), 4.16 (s, 3H). MS (ESI): m/z 350 (M++1). Anal. Calcd for C17H19ClN2O2S : C,
58.19; H, 5.46; N, 7.98. Found: C, 58.16; H, 5.51; N, 8.06.
1-Pyridin-2-yl-4-(toluene-4-sulfonyl)-piperazine 32e:
As described for 30a, compound 32e was prepared as white crystalline solid, 0.12
g, (75%), Rf= 0.6 (40% ethyl acetate in hexane). white solid, mp-162-163C. IR
N
H3 C
O
S N
O
32e
(KBr):
3431, 3083, 2856, 2391, 1596, 1436, 1349,
1241, 1169, 957, 743, 571 cm-1. 1H NMR (CDCl3, 200
MHz): 8.07-8.03 (m, 1H), 7.56 (d, 2H, J = 8.3), 7.37-
7.33 (m, 1H), 7.31 (d, 2H, J = 8.3), 6.57-6.48 (m, 2H), 3.64 (t, 4H, J = 5.0), 2.99 (t,
4H, J = 5.0), 2.32 (s, 3H). MS (ESI): m/z 318 (M+, 100%). Anal. Calcd for
C16H19N3O2S: C, 60.54; H, 6.03; N, 13.24. Found: C, C, 60.57; H, 6.11; N, 13.17.
1-(phenylsulfonyl)-4-(pyridine-2-yl)piperazine 32f:
As described for 30a, compound 32f was prepared in 0.14 g, (81%) as white powder,
Rf= 0.4 (60% ethyl acetate in hexane). mp- 140-142C. IR (KBr): 3436, 2853, 2362,
O
N
S N
O
32f
1592, 1483, 1439, 1347, 1247, 1166, 951 cm-1. 1H NMR
(CDCl3, 200 MHz): 8.15-8.12 (m, 2H), 7.77 (d, 2H, J =

1.59), 7.57-7.47 (m, 4H), 6.66-6.57 (m, 2H), 3.64 (d, 4H, J =
5.0), 3.12 (d, 4H, J = 5.06). MS (ESI): m/z 304 (M++1, 100%). Anal. Calcd for
2-[4-(Toluene-4-sulfonyl)-piperazin-1-yl]-ethanol 32g:
As described for 30a, compound 32g was prepared as white solid, 0.11 g, (76%),
Rf= 0.3 (80% ethyl acetate in hexane). mp- 86-88C. IR (KBr): 3193, 2920,2840,
OH
H3 C
O
S N
O
32g
2364, 1450, 1349, 1169, 955, 736 cm-1. 1H NMR (CDCl3,

200 MHz): 7.63 (d, 2H, J = 8.2), 7.33 (d, 2H, J = 8.1),
3.56 (t, 2H, J = 5.3), 3.02 (t, 4H, J = 4.8), 2.60-2.47 (m,
153
6H), 2.44 (s, 3H). MS (ESI): m/z 285 (M++1, 100%). Anal. Calcd for C13H20N2O3S:
C, 54.91; H, 7.09; N, 9.85. Found: C, 54.83; H, 7.06; N, 9.87.
2-[4-(4-Nitro-benzenesulfonyl)-piperazin-1-yl]-ethanol 32h:
As described for 30a, compound 32h was prepared as colourless solid, 0.12 g,
(83%), Rf= 0.3 (70% ethyl acetate in hexane). mp-135-137C. IR (KBr): 3344, 3102,
OH
O
S N
O
32h
O 2N
2966, 2823, 1601, 1526, 1404, 1350, 1167, 1090, 958, 750,
599 cm-1. 1H NMR (CDCl3, 200 MHz): 8.39 (dd, 2H, J1
= 2.1, J2 = 7.4), 7.95 (dd, 2H, J1 = 1.9, J2 = 7.2), 3.59 (t,
2H, J = 5.3), 3.11 (m, 4H), 2.64-2.53 (m, 6H). MS (ESI): m/z 316 (M++1, 100%).
N, 13.35.
2-(4-Benzenesulfonyl-piperazin-1-yl)-ethanol 32i:
As described for 30a, compound 32i was prepared as cream coloured solid, 0.11 g,
(76%), Rf= 0.4 (70% ethyl acetate in hexane). mp- 76-79C. IR (KBr): 3569, 2814,
1451, 1325, 1282, 1166, 1089, 748 cm-1 . 1H NMR (CDCl3,
OH
O
S N
O
32i
200 MHz): 7.77-7.72 (m, 2H), 7.66-7.49 (m, 3H), 3.55 (t,
2H, J = 5.4), 3.03 (t, 4H, J = 4.8), 2.63-2.48 (m, 6H). MS
(ESI): m/z 271 (M++1, 100%). Anal. Calcd for C12H18N2O3S: C, 53.31; H, 6.71; N,
10.36. Found: C, 53.39; H, 6.69; N, 10.41.
1-(3-Chloro-phenyl)-4-(4-nitro-benzenesulfonyl)-piperazine 32j:
As described for 30a, compound 32j was prepared as brown crystalline solid,
0.12 g, (73%) Rf= 0.4 (70% ethyl acetate in hexane). mp- 142-145C. IR (KBr): 3449,
Cl
O2 N
O
S N
O
32j
3103, 2842, 2366, 1598, 1533, 1453, 1352, 1245, 1173,

1112, 757 cm-1. 1H NMR (CDCl3, 200 MHz): 8.41 (d, 2H,
J = 7.0), 7.97 (d, 2H, J = 7.0), 7.19-7.11(m, 1H), 6.87-669
(m, 2H), 6.82 (s, 1H), 3.28-3.23 (m, 8H). MS (ESI): m/z 381 (M+). Anal. Calcd for
C16H16ClN3O4S: C, 50.33; H, 4.22; N, 11.00. Found: C, 50.40; H, 4.13; N, 10.96.
1-(4-Nitro-benzenesulfonyl)-4-pyridin-2-yl-piperazine 32k :
As described for 30a, compound 32k was prepared as yellow powder, 0.12 g,
(79%), Rf= 0.3 (60% ethyl acetate in hexane ). mp- 236-237C. IR (KBr): 3440,
O2N
O
N
S N
O
32k
2839, 2361, 1594, 1529, 1438, 1347, 1245, 1164, 948,

758 cm-1. 1H NMR (CDCl3, 200 MHz): 8.41 (d, 2H, J
= 7.0), 7.96 (d, 2H, J = 6.9), 7.37-7.33 (m, 1H), 6.56154
6.49 (m, 2H). MS (ESI): m/z 349 (M++1, 100%,). Anal. Calcd for C15H16N4O4S: C,
51.71; H, 4.63; N, 16.08. Found: C, 51.66; H, 4.65; N, 16.00.
1-Benzenesulfonyl-4-(4-chloro-phenyl)-piperazine 32l:
As described for 30a, compound 32l, was prepared as white crystalline solid, 0.15
g, (80%), Rf= 0.3 (20% ethyl acetate in hexane): mp- 126 C. IR (KBr): 3416, 3094,
2835, 2362, 1593, 1495, 1449, 1352, 1232, 1167, 946
O
S N
O
Cl
32l
cm-1. 1H NMR (CDCl3, 200 MHz): 7.78 (d, 2H, J =

1.6), 7.62-7.54 (m, 3H), 7.18 (d, 2H, J = 2.1), 6.77 (d,
2H, J = 2.07 Hz), 3.17 ( s, 8H). MS (ESI): m/z 336 (M+, 100%). Anal. Calcd for
C16H17ClN2O2S: C, 57.05; H, 5.09; N, 8.32. Found: C, 57.11; H, 5.02; N, 8.39.
1-Methyl-4-(toluene-4-sulfonyl)-piperazine 32m: MKP-98:
As described for 30a, compound 32m, was prepared as white crystalline solid,
0.11 g, (83%), Rf= 0.3 (60% ethyl acetate in hexane). mp- 139-141C. IR (KBr):
3421, 2942, 2797, 1595, 1451, 1347, 1285, 1168, 1094,
H 3C
O
S N
O
32m
N Me
941 cm-1. 1H NMR (CDCl3, 200 MHz): 7.62 (d, 2H, J =

8.2), 7.31 (d, 2H, J = 8.0), 3.01 (m, 3H), 2.48-2.41 (m,
6H). MS (ESI): m/z 255 (M++1, 100%). Anal. Calcd for C12H18N2O2S: C, 56.67; H,
7.13; N, 11.01. Found: C, 56.75; H, 7.16; N, 10.95.
1-Methyl-4-(4-nitro-benzenesulfonyl)-piperazine 32n:
As described for 30a, compound 32n, was prepared as colorless crystalline
solid, 0.10 g, (79%), Rf= 0.3 (50% ethyl acetate in hexane). mp- 140-141C. IR
O2 N
O
S N
O
32n
(KBr): 3426, 3121, 2855, 1607, 1537, 1459, 1287, 757

N Me
cm-1. 1H NMR (CDCl3, 200 MHz): 8.40 (d, 2H, J =

6.9), 7.96 (d, 2H, J = 6.1), 3.10 (m, 4H), 2.49 (t, 4H, J =
4.9), 2.27 (s, 3H). MS (ESI): m/z 286 (M++1, 100%) , 284 (M+-1, 90%). Anal. Calcd
for C11H15N3O4S: C, 46.31; H, 5.30; N, 14.73. Found: C, 46.34; H, 5.34; N, 14.73.
1-Benzenesulfonyl-4-methyl-piperazine 32o:
As described for 30a, compound 32o was prepared as colorless solid, 0.11 g,
(82%) Rf= 0.3 (50% ethyl acetate in hexane). mp- 103-106C. IR (KBr): 3427, 3055,
O
S N
O
32o
N Me
2943, 2808, 2369, 1594, 1452, 1349, 1171, 1093, 937, 748, 578
cm-1 . 1H NMR (CDCl3, 200 MHz): 7.75 (d, 2H, J = 6.3),
7.60-7.52 (m, 3H), 3.04 (m, 4H), 2.47 (m, 4H), 2.26 (s, 3H).
155
MS (ESI): m/z 241 (M++1, 100%). Anal. Calcd for C11H16N2O2S: C, 54.98; H, 6.71;
N, 11.66. Found: C, 54.91; H, 6.77; N, 11.59.
4.9.1.2 General procedure for the preparation of Isoquinolinesulfonamides:
2-[4-(Isoquinoline-5-sulfonyl)-piperazin-1-yl]-ethanol 34a:
As described for 30a, compound 33 (0.10 g, 0.44 mmol), piperazinyl ethanol 9a
(0.06 mL, 0.53 mmol) and triethylamine ( 0.09 mL, 0.66 mmol) furnished 34a as pale
brown
N
O
S N
O
34a
crystalline solid, 0.12 g, (88%), Rf= 0.3 (10%
methanol in chloroform).
N
OH
mp- 68-71C. IR (KBr): 3337,
2815, 2366, 1613, 1460, 1134, 1066, 734, cm-1. 1H NMR
(CDCl3, 200 MHz): 9.35 (s, 1H), 8.68 (d, 1H, J = 6.2), 8.54 (d, 1H, J = 6.2), 8.37
(d, 1H, J = 7.4), 8.24 (d, 1H, J = 8.2 ), 7.73 (t, 1H, J = 7.8 ), 3.56 (t, 2H, J = 5.3),
3.20 (t, 4H, J = 4.9 ), 2.58-2.41 (m, 6H). 13C NMR (50 MHz, CDCl3): 155.3, 144.6,
137.3, 133.0, 129.4, 129.1, 128.6, 127.9, 127.0, 67.7, 58.2, 51.6, 38.3, MS (ESI): m/z
322 (M++1, 100%). Anal. Calcd for C15H19N3O3S: C, 56.06; H, 5.96; N, 13.07 Found:
C, 56.1; H, 5.89; N, 13.01.
2-[4-(Isoquinoline-5-sulfonyl)-piperazin-1-yl]-ethylamine 34b:
As described for 30a, compound 33 (0.10 g, 0.44 mmol), piperazinyl ethylamine
31b (0.17 g, 1.31 mmol) and triethylamine (0.09 mL, 0.66 mmol) furnished 34b as
brown solid, 0.115 gm, (84%), Rf= 0.3 (25% methanol in
N
O
S N
O
34b
N
NH 2
chloroform). mp-73-75C. IR (KBr): 3442, 2949, 2373, 1626,

1456, 768 cm-1. 1H NMR (CDCl3, 200 MHz): 9.47 (s, 1H),
8.62 (d, 1H, J = 6.2), 8.61 (d, 1H, J = 6.2), 8.39 (d, 1H, J = 7.4), 8.28 (d, 1H, J = 8.2),
7.68 (t, 1H, J = 8.0), 3.78 (bs, 2H), 3.56 (t, 2H, J = 5.4), 3.26 (t, 4H, J = 4.9), 2.612.43 (m, 6H). 13C NMR (50 MHz, CDCl3): 153.9, 143.7, 137.8, 133.2, 129.8, 128.1,
127.7, 127.3, 65.8, 51.0, 38.9. MS (ESI): m/z 321 (M++1, 100%), 319 (M+-1, 45 %).
N, 17.42.
Isoquinoline-5-sulfonic acid {2-hydroxy-3-[2-(4-hydroxy-phenyl)-ethylamino]propyl}-methyl-amide 38a :
To a solution of isoquinoline epoxide 27 (0.10 g, 0.36 mmol ) in dry ethanol, 4hydroxy-phenyl)-ethylamine (0.07 g, 0.43 mmol) was added and then it was allowed
to stirr for 6-7 h. After completion of reaction, ethanol was
N
OH
O
S
N
O
Me OH
38a
evaporated, extracted with ethyl acetate, concentrated,
N
H
156
purified by column chromatography and isolated 38a, 0.10 g, (69%) pale colorless
solid, Rf= 0.3 (6% methanol in chloroform) mp-67-70C. IR (KBr): 3183, 2936, 2366,
1618, 1488, 1317, 1218, 1129, 970, 762 cm-1 . 1H NMR (CDCl3, 200 MHz): 9.42 (s,
1H), 8.71-8.61 (m, 4H), 8.54-8.43 (m, 4H), 7.92-7.84 (m, 1H), 4.03 (bs, 1H), 3.613.55 (m, 2H), 3.40-3.29 (m, 6H), 3.01 (s, 3H). 13C NMR (50 MHz, CDCl3): 154.9,
140.8, 137.6, 137.0, 133.0, 130.4, 129.4, 128.9, 128.5, 127.9, 127.4, 126.8, 124.0,
69.9, 57.1, 50.9, 38.4. MS (ESI): m/z 416 (M++1 , 90%). Anal. Calcd for
C21H25N3O4S: C, 60.70; H, 6.06; N, 10.11. Found: C, 60.74; H, 5.99; N, 10.13
Isoquinoline-5-sulfonic
acid
[3-(2-chloro-benzylamino)-2-hydroxy-propyl]-
methyl-amide 38b :
As described for 38a, isoquinoline epoxide 27 (0.10 g,
N
Me OH
38b
0.36 mmol), 2-chloro-benzylamine (0.06 g, 0.44 mmol) in
Cl
O
S
ethanol furnished 38b as pale yellow solid, 0.170 g,
N
H
(71%) Rf= 0.4 (7% methanol in chloroform). mp- 67-
70C. IR (KBr): 3429, 2931, 2363, 1598, 1465, 1348, 1207, 1133, 983, 748 cm-1. 1H
NMR (CDCl3, 200 MHz): 9.40 (s, 1H), 8.73 (d, 1H, J = 7.4), 8.55 (d, 1H, J = 8.2),
8.40 (d, 1H, J = 7.4), 8.26 (d, 1H, J = 7.8), 7.76 (t, 1H, J = 7.7), 7.33-7.12 (m, 4H),
3.98-3.97 (m, 2H), 3.56 (m, 2H), 3.04 (s, 3H), 2.82-2.61 (m, 3H ), 2.31 (bs, 1H). 13C
NMR (50 MHz, CDCl3): 153.9, 143.8, 135.6, 135.0, 130.9, 129.3, 129.3, 128.7,
128.2, 127.0, 124.1, 67.0, 54.8, 43.2, 39.0. MS (ESI): m/z 420 (M+, 100%). Anal.
Calcd for C20H22ClN3O3S: C, 57.20; H, 5.28; N, 10.01. Found: C, 57.27; H, 5.30; N,
9.96.
acid
[3-(4-chloro-benzylamino)-2-hydroxy-propyl]-
methyl-amide 38c:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 4-chlorobenzylamine (0.05 mL, 0.43 mmol) in ethanol furnished 38c as pale brown semisolid, 0.10 g, (66%), Rf= 0.3 (10% methanol in chloroform).
IR (Neat): 3409, 2927, 2363, 1597, 1461,1351, 1212, 1132,
O
S
O
N
Me OH
38c
N
H
Cl
765 cm-1. 1H NMR (CDCl3, 200 MHz): 9.35 (s, 1H), 8.69
(d, 1H, J = 6.1), 8.48 (d, 1H, J = 6.2), 8.32 (d, 1H, J = 7.1),
8.21 (d, 1H, J = 8.4), 7.70 (t, 1H, J = 7.8), 7.28-7.24 (m, 2H), 7.14-7.03 (m, 2H),
3.89-3.88 (m, 1H), 3.31-3.10 (m, 2H), 2.94 (s, 3H), 2.91-2.87 (m, 2H), 2.81-2.56 (m,
4H). 13C NMR (50 MHz, CDCl3): 154.2, 144.0, 135.5, 133.1, 130.4, 129.6, 129.0,
157
128.9, 128.1, 127.2, 123.6, 66.9, 55.7, 46.1, 38.4. MS (ESI): m/z 420 (M+, 100%).
Anal. Calcd for C20H22ClN3O3S: C, 57.20; H, 5.28; N, 10.01. Found: C, 57.26; H,
5.25; N, 10.07
acid
{3-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-
hydroxy-propyl}-methyl-amide 38d:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 3,4dimethoxy-phenyl)-ethylamine (0.07 mL, 0.43 mmol) in ethanol furnished 38d as
brown viscous oil, 0.10 g, (65%), Rf= 0.3 (7% methanol
N
OMe
in chloroform). IR (Neat): 3404, 2933, 2832, 2362, 1597,
OMe
1460, 1153, 758 cm-1. 1H NMR (CDCl3, 200 MHz):
O
S
N
Me OH
38d
N
H
9.27 (s, 1H), 8.61 (d, 1H, J = 6.2), 8.41 (d, 1H, J = 6.2),
8.25 (d, 1H, J = 7.4), 8.14 (d, 1H, J = 8.2), 7.63 (t, 1H, J = 7.8), 6.75-6.65 (m, 4H),
3.80 (s, 3H), 3.78 (s, 3H), 3.19-3.11 (m, 2H), 2.87 (s, 3H), 2.71-2.59 (m, 6H ).
13
NMR (50 MHz, CDCl3): 154.3, 150.6, 149.2, 143.8, 137.5, 132.9, 130.3, 128.0,
127.5, 127.1, 124.7, 121.6, 115.3, 114.8, 68.7, 59.4, 58.9,53.4, 51.3, 48.7, 38.8, 36.0.
MS (ESI): m/z 460 (M++1, 100%). Anal. Calcd for C23H29N3O5S: C, 60.11; H, 6.36;
N, 9.14. Found: C, 60.09; H, 6.44; N, 9.11.
N-(2-hydroxy-3-(4-methoxyphenethylamino)propyl)-N-methylisoquinoline-5sulfonamide 38e:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 4methoxyphenyl methylamine (0.06 mL, 0.43 mmol) in ethanol furnished 38e as pale
yellow semi-solid, 0.11 gm, (72%), Rf= 0.5 (5% methanol
N
OMe
O
S
O
N
Me OH
38e
N
H
in chloroform), mp-105-106C. IR (Neat): 3425, 2928,

2361, 1598, 1352, 1248, 766 cm-1. 1H NMR (CDCl3, 200
MHz): 9.27 (s, 1H), 8.60 (d, 1H, J = 6.1), 8.41 (d, 1H, J =
5.9), 8.24 (d, 1H, J = 7.5), 8.13 (d, 1H, J = 8.1), 7.66-7.634 (m, 1H), 7.05 (d, 2H, J =
8.6), 6.75 (d, 2H, J = 8.6), 4.22 (bs, 1H), 4.06-4.00 (m, 1H), 3.70 (s, 3H), 3.42-3.35
(m, 2H), 3.21-3.12 (m, 4H), 2.79 (s, 3H). 13C NMR (50 MHz, CDCl3): 158.2, 154.0,
143.7, 137..5, 133.0, 130.1, 129.4, 128.4, 127.3, 127.0, 122.3, 121.0, 117.3, 68.1,
57.4, 56.8, 51.2, 48.5, 38.3, 35.7. MS (ESI): m/z 430 (M++1, 100%,). Anal. Calcd for
acid
[2-hydroxy-3-(3-imidazol-1-yl-propylamino)-
propyl]-methyl-amide 38f:
158
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 3-imidazol-1yl-propylamino)-propyl amine (0.05 mL, 0.43 mmol) in ethanol furnished 38f (0.10 g,
67%) as pale brown viscous oil, Rf= 0.4 (5% methanol in
chloroform). IR (Neat): 3399, 2935, 2364, 1653, 1458,
O
S
O
N
Me OH
38f
N
H
1328, 1227, 1134, 993, 758 cm-1. 1H NMR (CDCl3, 200

MHz): 9.28 (s, 1H), 8.61 (d, 1H, J = 6.1), 8.43 (d, 1H, J
= 6.1), 8.26 (d, 1H, J = 7.4), 8.14 (d, 1H, J = 8.2), 7.68-7.57 (m, 2H), 6.20 (d, 1H, J =
6.8), 6.14 (s, 1H), 6.08-5.96 (m, 1H), 4.03-3.90 (m, 6H), 3.19 (bs, 1H), 2.86 (s, 3H),
2.67-2.56 (m, 4H), 1.18 (bs, 1H). 13C NMR (50 MHz, CDCl3): 153.6, 144.1, 137.4,
136.0, 129.5, 128.3, 127.7, 127.2, 123.0, 121.7, 68.2, 54.6, 51,6, 48.1, 45.3, 38.3,
31.9. MS (ES1): m/z 404 (M++1, 100%,). Anal. Calcd for C19H25N5O3S: C, 56.56; H,
6.25; N, 17.36. Found: C, 56.59; H, 6.19; N, 17.33.
acid
(3-benzylamino-2-hydroxy-propyl)-methyl-amide
38g:
As described for 38a, isoquinoline epoxide 27(0.10 g, 0.36 mmol), benzyl amine
(0.05 g, 0.05 mmol) in ethanol furnished 38g as brown viscous oil, 0.09 g, (64%) Rf=
0.4 (2% methanol in chloroform). IR (Neat): 3404, 2928,
2364, 1599, 1135, 761, cm-1. 1H NMR (CDCl3, 200
O
S
O
N
Me OH
38g
MHz): 9.34 (s, 1H), 8.66 (d, 1H, J = 6.2), 8.48 (d, 1H, J
N
H
= 6.2), 8.33 (d, 1H, J = 7.2), 8.19 (d, 1H, J = 8.2), 7.69 (t,
1H, J = 7.8), 7.30-7.26 (m, 5H), 3.89-3.84 (m, 1H), 3.78 (s, 2H), 3.25-3.22 (m, 2H),
2.94 (s, 3H), 2.75-2.59 (m, 2H), 2.43 (bs, 2H). 13C NMR (50 MHz, CDCl3): 154.9,
140.8, 137.5, 137.1, 133.1, 130.4, 129.4, 129.0, 128.1, 127.4, 126.9, 124.1. MS (ESI):
m/z 386 (M+, 100%,). Anal. Calcd for C20H23N3O3S: C, 62.32; H, 6.01; N, 10.90.
Found: C, 62.36; H, 5.97; N, 10.84.
Isoquinoline-5-sulfonic acid [3-(3,4-dichloro-benzylamino)-2-hydroxy-propyl]methyl-amide 38h:
As described for 38a, isoquinoline epoxide 27 (0.10 g,
0.36 mmol),
O
S
O
N
Me OH
38h
N
H
Cl
3,4- dichloro-benzylamine (0.06 g, 0.36 mmol) in
Cl
ethanol furnished 38h as pale yellow viscous oil, 0.11 g, (74%), Rf= 0.4 (2% methanol
in chloroform). IR (Neat): 3415, 2929, 2365, 1598, 1350, 1132, 759 cm-1. 1H NMR
159
(CDCl3, 200 MHz): 9.23 ( s, 1H ), 8.58 (d, 1H, J = 6.1), 8.38 (d, 1H, J = 6.2), 8.22
(d, 1H, J = 6.6), 8.11 (d, 1H, J = 8.1), 7.61 (t, 1H, J = 7.8), 7.33 (d, 1H, J = 8.0), 7.31
(s, 1H), 7.07 (d, 1H, J = 8.0), 3.89-3.79 (m, 1H), 3.70 (s, 2H), 3.15-3.09 (m, 2H), 2.85
(s, 3H), 2.73-2.51 (m, 2H). 13C NMR (50 MHz, CDCl3): 153.9, 144.2, 141.6, 137.3,
130.4, 129.6, 128.7, 128.1, 127.5, 127. 3, 126.0, 118.1, 69.3, 57.3, 50.9, 39.8. MS
(ESI): m/z 454 (M+, 100%). Anal. Calcd for C20H21Cl2N3O3S: C, 52.87; H, 4.66; N,
9.25. Found: C, 52.83; H, 4.69; N, 9.21.
Isoquinoline-5-sulfonic acid [3-(2,4-dichloro- benzylamino)-2-hydroxy-propyl]methyl-amide 38i:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 2,4-dichlorobenzylamine (0.06 g, 0.36 mmol) in ethanol furnished 38i as colourless solid, 0.10 g,
(69%), Rf= 0.5 (1% methanol in chloroform). white solid, mp-63-65C. IR (KBr):
3425, 3282, 2925, 2362, 1593, 1467, 1341, 1147, 983, 832, 732 cm-1. 1H NMR
(CDCl3, 200 MHz): 9.34 (s, 1H ), 8.67 (d, 1H, J = 6.1),
8.49 (d, 1H, J = 6.2), 8.32 (d, 1H, J = 7.3), 8.20 (d, 1H, J =
Cl
O
S
O
N
Me OH
38i
N
H
Cl
8.1), 7.68 (t, 1H, J = 7.6), 7.36-7.18 (m, 3H), 3.89-3.81 (m,
3H), 3.26-3.21 (m, 2H), 2.95 (s, 3H), 2.73-2.58 (m, 2H), 2.37 (bs, 1H).
13
C NMR
(50 MHz, CDCl3): 154.3, 144.0, 141.3, 137.0, 130.3, 128.6, 128.0, 127.4, 127.3,
125.5, 118.0, 70.1, 58.1, 51.2, 39.6. MS (ESI): m/z 454 (M+, 100%). Anal. Calcd for
C20H21Cl2N3O3S: C, 52.87; H, 4.66; N, 9.25. Found: C, 52.92; H, 4.64; N, 9.28.
acid
{2-hydroxy-3-[2-(1H-indol-3-yl)-ethylamino]-
propyl}-methyl-amide 38j:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), 1H-indol-3-yl)ethylamine (0.07 g, 0.43 mmol) in ethanol furnished 38j
as pale yellow semi-solid, 0.10 g, (62%), Rf= 0.3 (5%
N
NH
O
S
O
N
Me OH
38j
N
H
methanol in chloroform).
mp-105-106C. IR (KBr):
3426, 2924, 2852, 2364, 1596, 1460, 1351, 1132, 764 cm. H NMR (CDCl3, 200 MHz): 9.33 (s, 1H), 8.67 (d,
1 1
1H, J = 6.2), 8.49 (d, 1H, J = 6.2), 8.29 (d, 1H, J = 7.3), 8.16 (d, 1H, J = 8.1), 8.14 (d,
1H, J = 8.1), 7.68-7.54 (m, 2H ), 7.33 (d, 1H, J = 7.2), 7.16-7.14 (m, 1H), 7.05-7.04
(m, 1H), 3.86-3.84 (m, 1H), 3.30-3.20 (m, 2H), 2.96-2.93 (m, 5H), 2.80-2.70 (m,
2H), 2.07 (s, 3H). 13C NMR (50 MHz, CDCl3): 155.1, 145.2, 141.3, 137.4, 133.1,
160
132.7, 131.9, 129.6, 127.8, 127.5, 124.2, 122.6, 121.8, 120.0, 119.4, 115.3, 115.0,
67.8, 55.7, 51.4, 39.7, 28.3. MS (ESI): m/z 439 (M++1, 100%). Anal. Calcd for
acid
{2-[(furan-2-ylmethyl)-amino]-2-hydroxy-ethyl}-
methyl-amide 38k:
As described for 38a, isoquinoline epoxide 27 (0.10 g, 0.36 mmol), furan-2ylmethanamine (0.04 g, 0.43 mmol) in ethanol furnished 38k as pale yellow semisolid, 0.10 g, (67%), Rf= 0.4 (2% methanol in
chloroform). IR (Neat): 3426, 2924, 2852, 2364, 1596,
O
S
O
N
Me OH
38k
N
H
1460, 1351, 1132, 764 cm-1. 1H NMR (CDCl3, 200 MHz):
9.35 (s, 1H), 8.68 (d, 1H, J = 6.2), 8.48 (d, 1H, J = 6.1),
8.33 (d, 1H, J = 7.4), 8.21 (d, 1H, J = 8.2), 7.71 (t, 1H, J= 7.4), 7.33 (d, 1H, J = 7.2),
6.31-6.23 (m, 2H), 3.90-3.88 (m, 1H), 3.76-3.74 (m, 1H), 3.20-3.13 (m, 2H), 2.94 (s,
3H), 2.71-2.51 (m, 4H).
13
C NMR (50 MHz, CDCl3): 154.3, 144.1, 141.5, 136.4,
135.7, 133.6, 131.8, 129.9, 127.8, 127.5, 124.2, 115.1, 114.8, 68.4, 56.1, 51.1, 38.7.
MS (ESI): m/z 347 (M+-28, 100%). Anal. Calcd for C18H21N3O4S: C, 57.58; H, 5.64;
N, 11.19. Found: C, 57.66; H, 5.62; N, 11.26.
4.10 Biology
Procedure for in vitro antimalarial activity evaluation:
The in vitro antimalarial assay was carried out in 96-well microtitre plates
according to the micro assay of Rieckmann et al. The culture of P. falciparum NF-54
strain is routinely being maintained in the RPMI-1640 medium supplemented with
25 mM HEPES, 1% d-glucose, 0.23% sodium bicarbonate and 10% heat-inactivated
human serum. The asynchronous parasite of P. falciparum was synchronized after 5%
d-sorbitol treatment to obtain parasitized cells harbouring only the ring stage. For
carrying out the assay, an initial ring-stage parasitaemia of 1% at 3% haematocrit in
total volume of 200 L of RPMI-1640 medium was uniformly maintained. The test
compound in 20 L volume at required concentration (ranging between 1.0 and
10 g/mL) in duplicate wells were incubated with parasitized cell preparation at 37 C
in candle jar. After 3640 h incubation, the blood smears from each well were
prepared and stained with Giemsa stain. The slides were microscopically observed to
record maturation of ring-stage parasites into trophozoites and schizonts in the
presence of different concentrations of compounds. The test concentration, which
161
inhibits the complete maturation into schizonts, was recorded as the minimum
inhibitory concentration (MIC). Pyrimethamine was used as the standard reference
drug. Activity of all the tested compounds is given in
4.11 References
1.
Snow, R. W.; Guerra, C. A.; Noor, A. M.; Myint, H. Y.; Hay, S. I. Nature 2005,
434, 214.
2. The World Health Report 2002, World Health Organization (WHO),
http://www.who.int/whr/2002/en/
3. Mendis, K.; Sina, B. J.; Marchesini, P.; Carter, R. Am. J. Trop. Med. Hyg. 2001, 64,
97.
4. (a) Peters, W. Br. Med. Bull. 1982, 38, 187. (b) Wernsdorfer, W. H.; Pyne, D.
Pharmacol. Ther. 1991, 50, 95.
5. (a) Rosenthal, P. J.; Miller, L. H. In Antimalarial Chemotherapy: Mechanisms of
Action, Resistance, and New Directions in Drug Discovery; Rosenthal, P. J., Ed.;
Humana Press Inc.: Totowa, NJ, 2001; pp 3-13. (b) Go, M.-L. Med. Res. Rev. 2003,
23, 456. (c) Thayer, A. M. Chem. Eng. News 2005, 83, 69.
6.
Tracy, J. W.; Webster, L. T., Jr. In Goodman & Gilman's The Pharmacological
Basis of Therapeutics, 9th ed.; Hardman, J. G.; Limbird, L. E.; Molinoff, P. B.,;
Ruddon, R. W.; Gilman, A. G.; Eds.; McGraw-Hill: New York, 1996; Chapter 40, pp
978.
7. Fullerton, D. S. Antimalarials. In Wilson and Gisvolds Textbook of Organic
Medicinal and Pharmaceutical Chemistr, 9th ed.; Delgado J. N.; Remers, W. A.; Eds.;
J. B. Lippincott Co., Philadelphia, 1996, pp. 205.
8. Frederich M.; Dogne JM.; Angenot L.; Mol P. De. Curr. Med. Chem. 2002, 15,
1435.
9. Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem., Int. Ed. 2003,
42, 5274 and references cited therin.
10. Campbel, P. Nature Insight 2002, 415, 6872.
11. Anand, N. In Burgers medicinal chemistry and drug discovery, 5th ed. In
Therapeutic Agents; Wolff, M. E., Ed.; J. Wiley & Sons: New York, 1996, 2, 527.
12. Bouissane, L.; El Kazzouli, S.; Leonce, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.
Bioorg. Med. Chem. 2006, 14, 1078.
13. Melagraki, G.; Afantitis, A.; Sarimveis, H.; Igglessi-Markopoulou, O.; Supuran,
162
C. T. Bioorg. Med. Chem. 2006, 14, 1108.

14. Mandloi, D.; Joshi, S.; Khadikar, P. V.; Khosla, N. Bioorg. Med. Chem. Lett.
2005, 17, 15.
15. Vullo, D.; Steffansen, B.; Brodin, B.; Supuran, C. T.; Scozzafava, A.; Nielsen, C.
U. Bioorg. Med. Chem. 2006, 14, 2418.
16. Sherif, A.; Rostom, F. Bioorg. Med. Chem. 2006, 14, 6475.
17. Santos, M. A.; Marques, S. M.; Tuccinardi, T.; Carelli, P.;Panelli, L.; Rossello, A.
Bioorg. Med. Chem. 2006, 14, 7539.
18. Joshi, S.; Khosla, N.; Tiwari, P. Bioorg. Med. Chem. 2004, 12, 571.
19. Ortqvist, P.; Peterson, S. D.; A kerblom, E.; Gossas, T.; Sabnis, Y. A.; Fransson,
R.; Lindeberg, G.; Danielson, U. H.; Karlen, A.; Sandstrom, A. Bioorg. Med. Chem.
2007, 15, 1448.
20. a) Johann, L.; Pegraro,S.; Dormeyer. M.; Michael,L.;
Aschenbrenner,A.;
Karmer.B. Bioorg. Med. Chem. Lett. 2004, 14 , 1979. b) Krungkrai, J.; Scozzafava,
A.; Reungprapavut, S.; Krungkrai, S.R.; Rattanajak, R.; Kamchonwongpaisan, S.;
Supuran, C.T. Bioorg. Med Chem. 2005, 13, 483.c) Krungkrai, S.R.; Suraveratum,N.;
Rochanakij, S.; Krungkrai, J. Int. J. Parasitol. 2001, 31, 661. d) Reungprapavut, S.;
Krungkrai, S.R.; Krungkrai, J. J. Enzym. Inhib. Med. Chem. 2004, 19 , 249.
21. Delfino, R. T.; Santos-Filho, O. A.; Figueroa-Villar, J. D. J. Braz. Chem. Soc., 2002.
13, 727.
22. Woodard, C. L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez,
M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer,
J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877.
163
4.10 Spectra
OCH 3
O
S
N
O H
H 3C
OCH 3
30a
Figure 4.6
O
S N
O
H NMR spectra (CDCl3, 200 MHz) of 30a.
Cl
32l
Figure 4.7
H NMR spectra (CDCl3, 200 MHz) of 32l.

164
O
S
N
O
Me OH
38i
Cl
N
H
Cl
Figure 4.8
H NMR spectra (CDCl3, 200 MHz) of 38i.
O
S
N
O
Me OH
38i
Cl
N
H
Cl
Figure 4.9
13
C NMR spectra (CDCl3, 50 MHz) of 38i.
165
O
S
N
Me OH
38g
N
H
Figure 4.10
H NMR spectra (CDCl3, 200 MHz) of 38g.
O
S
N
Me OH
38g
N
H
13
Figure 4.11 C NMR spectra (CDCl3, 50 MHz) of 38g.

166
N
O
S N
O
34a
N
OH
Figure 4.12
H NMR spectra (CDCl3, 200 MHz) of 34a.
N
O
S N
O
34a
Figure 4.13
OH
13
C NMR spectra (CDCl3, 75 MHz) of 34a.

167
N
OMe
O
S
N
O
Me
N
H
OH
38d
OMe
Figure 4.14 H NMR spectra (CDCl3, 200 MHz) of 38d.
O
S
O
N
Me OH
38c
N
H
Figure 4.15
Cl
13
C NMR spectra (CDCl3, 75 MHz) of 38c.
168
Chapter 5
A convenient synthesis of chiral amino acid
derived 3,4-dihydro-2H-benzo[b][1,4]thiazine
derivatives
Chapter 5: A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazine

derivatives
5.1 Introduction
Benzothiazine derivatives represent one of the most important classes of organic
molecules. Among several 1,2-, 2,1-, 1,4-, and 1,3-benzothiazine rings, 1,4benzothiazines (1,4-BT), in particular, are of significant interest and have been
extensively studied because of their profound biological activities1a-m including
antiinflammatory,
antihypertensive,
anticancer,
antifungal,
antitumour,
immunostimulating, antialdoso-reductase, antirheumatic, antiallergic, vasorelaxant,

anti-arrhythmic, neuroprotective, cytotoxic, KATP-Channel Openers and anti-HIV
activities. Most importantly, sulfone derivatives of benzothiazines form an interesting
series of heterocyclic compounds not only in industrial and medicinal point of view
but also for structural investigation.2 The diverse activities illustrate that 1,4-BT is a
template potentially useful in medicinal chemistry research and therapeutic
applications. Examples include antihypertensive drug3 semotiadil (1), antirheumatic
agent MX-68 (2), calcium antagonists (3),4 antifungal (4),5 -AR antagonists (5)
(Figure 5.1).
OMe
H 2N
O
O
S
N
Me
Me
N
N
N
1; Semotiadil
S
N
N
NH 2
H
N
O
OMe
COOH
2 ; MX-68
COOH
N
S
S
OH
O
NHR
N
O
O
3; calcium entry blockers
Cl
N
CH 3
4; antifungal agents
N
H 5
5; -AR antagonists
Figure 5.1. Representative examples of benzothiazine derived drugs and bioactive

analogues
5.2 Reported methods for the synthesis of 1,4-benzothiazines

The importance and utility of this family of compounds have led to the
development of a variety of efficient synthetic procedures affording compounds with
the 1,4-benzothiazine skeleton.7,8 Since, it is out of the scope
to cover
comprehensively all the synthesis of this scaffold that were reported in the literature,
only some general synthetic methodologies of benzothiazine derivatives are discussed
briefly.
169

derivatives
5.2.1 Solution phase synthesis of 1,4 benzothiazines:

The most of the synthetic strategies so far reported in literature involves the
nucleophilic reactions of 2-aminobenzenethiol. Several benzothiazine derivatives
have been synthesized (i) by condensation of 2-aminobenzenethiol with ,usaturated acids or esters,9 electron deficient alkyne,10 (ii) by treatment of Nunsubstituted and N,N-dialkyldithiodianilines with an enolizable dicarbonyl or ester,11
and (iii) by reaction of 2-aminobenzenethiol with -haloketone, -haloacetic acids,
acid chlorides or esters.12a,b Ring enlargement of 2-chloromethylbenzothiazole13 and
ring contraction of benzothiazepinones14 have also been reported to produce
benzothiazinones (Scheme 5.1).
COOH
H
H
Y
SH
C
Y=
C
H,
O2
r,
OA
NH
CO
Ar
CH2Y
N
H
N
S
Cl
O.
=H
R3
R2
X = Cl, Br; R2 = Cl,OH, OEt;
NH2
R3 = H
R1
R =
R
1
R=C
O M
R =
e
2
1
CO M
or CN
2 e or
CN, R
= Ph
R3
N
H
N
H
NH2
N
H
R
S
H2SO4, KBr, NaNO3

R3 = CH2Br
O
R
=C
NH2
O
2 Me
OEt
S
S
Scheme 5.1
NH2
15
Recently, Kobayashi et al.
have reported a new synthesis of 4H-1,4-benzothiazine
derivatives based on a deprotonationring-closure process of 2-cyano(phenylsulfinyl-,

p-nitrophenyl-, or o-nitrophenyl-)methylthiophenyl isocyanides, which are easily
prepared from 2-aminobenzenethiols with an appropriate base (Scheme 5.2).
SCH2Y
NaH, DMF,00C
R
NC
Electrophile (E)
R= H, CF3
Y= CN, S(O)Ph, C6H4NO2(p)
N
E
Scheme 5.2
In fact, this reaction sequence involves the deprotonation of the hydrogen adjacent to
the sulfur atom with sodium hydride generating the carbanion intermediate which
subsequently attacks on the isocyano carbon to give the imidoyl anion intermediate.
170

derivatives
Finally intra- or intermolecular proton migration resulted into the formation of

stabilized carbanion which gets trapped by an electrophile to give desired products.
The other synthetic pathway to 1,4-benzothiazines was described by Kundu et
16
al.
(Scheme 5.3). The synthesis of 2-alkyl(aryl)idene- 3,4-dihydro-2H-1,4-
benzothiazines was accomplished through the palladium-copper-catalyzed reactions

of S-[2-(N-prop-2-ynyl)aminophenyl]-N,N-dimethylthiocarbamate with aryl iodides
leading to the disubstituted alkynes followed by subsequent cyclization with KOH in
methanol.
NH2
H
N
H
N
SCONMe2
SCONMe2
SCONMe2
Ar
H
N
Ar
Scheme 5.3
Reaction conditions: (a) propargyl bromide, K2CO3 in acetone; (b) (PPh3)2PdCl2, CuI,
Et3N in CH3CN at room temperature, 24 h; (c) KOH in MeOH, reflux, 24 h.
Huang et al. reported a facile and highly efficient synthesis of 3-oxo-3,4-dihydro2H-1,4 benzothiazines by the reaction of equimolar amount of zinc salt of 2aminobenzenethiol and chloroacetyl chloride using benzyltriethylammonium chloride
(TEBF) as phase transfer catalyst in presence of solid sodium hydrogen carbonate
(Scheme 5.4).7c
O
S
Zn +
Cl
TEBF,NaHCO 3
Cl
NH2
CHCl3
R
N
H
Scheme 5.4
Another efficient synthesis of new benzothiazine derivatives has recently been
described by Biehl and co-workers.17 The reaction was accomplished through
aromatic nucleophilic elimination-addition reaction of 2-bromophenyl sulfenyl
derivative of ethyl amines with LDA, i,e through benzyne ring closure mechanism
(Scheme 5.5).
Br
+ H2N
R
SH
R = H, Me, OMe
Br
NaH
THF, r.t
Br
R
S
LDA
0
NH2-78 c
H
N
R
S
Scheme 5.5
171

derivatives
5.2.2 Solid phase synthesis of 1,4 benzothiazines:

Although a myriad of solution-phase synthesis of 1,4 benzothiazine have been
reported, solid-phase routes are few. G. Barany and co-workers developed18 an
efficient
solid-phase
preparation
of
substituted
of
3,4-dihydro-3-oxo-1,4-
benzothiazines and 3,4-dihydro-3-oxo-1,4-benzothiazine-1,1-dioxides in a minimal

number of steps (Scheme 5.6).
O
R
+
NH 3
H
N
SH
O
R1 b
R2
H
N
R1
R2
Scheme 5.6
Reagents and conditions: (a) -halo ketone (5 equiv), NaCNBH3 (5 equiv), DMF-HOAc
(99:1), 24 h; (b) TFA-TES (19:1), 1h.
The solid-phase nucleophilic aromatic substitution reaction again proved reliable

and afforded the corresponding o-nitroethers. Schwarz and Gallop19 described a
synthesis (Scheme 5.7) in which the fluoronitro resin was reacted with solutions of
thiocarboxylic acids. However, in reduction conditions, corresponding cyclic
hydroxamic acids were furnished instead of the expected corresponding 1,4benzothiazin- 3-ones.
NH
O
NO2
R
a
+
HS
CO2 H
F
N
H
CO2 H b H 2 N
S
OH
N
NO 2
Scheme 5.7
Reagents and conditions: (a) iPr2NEt, DMF, 250C; (b) i) SnCl2, H2O, DMF; ii) TFA-CH2Cl2
Another versatile solid-phase synthetic procedures affording libraries of

compounds with the 1,4-benzothiazine skeleton have been developed by Yulin Lam
and coworker that incorporate a variety of chemical functionalities (Scheme 5.8).20
SH
H
N
R2
+
OMe
Br
NO 2
O
R1
H
N
R1
NO2
O
2
CO2Me
R2 b
R1
R2
H 2N
O
N
H
Scheme 5.8
Reagents and conditions: (a) Et3N, DMF (2 equiv) 4 h; (b) i. SnCl2, H2O, AcONa, DMF; ii.
Anhy. toluene 1100C, 12h; iii. 20% TFA.
172

derivatives
5.3 Basis of work

As part of a continuing program in the development of novel synthetic
methodology for the preparation of biologically active substances, we were interested
in the synthesis of S-amino acid based benzofused heterocyclic structures bearing
nitrogen, oxygen and sulfur atoms21. Interest in the use of easily accessible and
versatile proteinogenic amino acids as a chiral pool for synthesis of optically active
heterocycles has been growing rapidly because of their response to the
enantiospecificity shown by most biological systems and the increased demand to
market chiral drugs as single enantiomers. With that objective, we recognized that the
copper-catalysed aryl amination approach for the formation of carbon-heteroatom
bond offers a better and more convenient route to the synthesis of benzannulated
medium ring heterocycles in optically pure form. Among the various synthetic
procedures to access 3,4-dihydro-2H-benzo[b][1,4]thiazine, we were particularly
interested towards an approach where naturally abundant amino acids can be
incorporated into the nucleus so that a number of 3-substituted chiral 3,4-dihydro-2Hbenzo[b][1,4]thiazine can be obtained easily. It is noteworthy, to the best of our
knowledge, amino acid based 1,4-benzothiazine derivatives are not reported so far.
5.4 Synthesis of chiral 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 6a-g
from chiral pool S-amino acids
We envisioned a direct access
to
chiral 3-substituted-3,4-dihydro-2H-
benzo[b][1,4]thiazine 6a-g from amino acid derived amines 7a-g. Amines 7a-g will
be obtained from the intermolecular nucleophilic substitution reaction of 2bromobenzenethiol 9 with amino acids derived 4-methylbenzenesulfonates 10a-g
(Scheme 1). Herein, we report a facile conversion of S-amino acid derivatives to
bicyclic amino acid-annulated 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives in
chiral form.
5.4.1 Retrosynthesis of prototype 6:

Retrosynthetic analysis of compound 6 furnished (S)-1-(2-bromophenylthio)
amine 7 as the precursor, which can be obtained from the N-Boc (S)-1-(2bromophenylthio) amine 8 by deprotection of Boc functionality. Compound 8 can be
synthesized by the coupling reaction between commercially available 2bromobenzenethiol 9 and amino alcohol derived tosylate 10 under NaH/THF
173

derivatives
condition. The precursor 12 can be synthesized by the reaction of amino ester 13 with
(Boc)2O in THF in presence of a base which on subsequent reduction may furnish NBoc amino alcohol 11 of naturally abundant S-amino acids (Scheme 5.9).21
H
N
Br BocHN
Br
Br
R
8
NH2
SH
9
NHBoc
ClHH2N
BocHN
10
BocHN
CO2Me
12
CO2Me
13
OTs
11
OH
Scheme 5.9
5.4.1.1 Synthesis of N-Boc amino alcohol tosylates 10:

The methyl esters of amino acid derivatives can easily be synthesized by the
literature procedure.21 The suspension of amino acid in methanol was stirred
overnight in presence of required amount of thionyl chloride to give the desired ester
hydrochloride 13 in quantitative yield. On treatment of (Boc)2O in presence of triethyl
amine in THF 13 furnished N-Boc amino esters which on subsequent reduction with
NaBH4 in THF/MeOH afforded corresponding amino alcohols. The tosylate
derivatives 10a-g of the amino alcohols 11a-g was synthesized by the reaction of
tosyl chloride and corresponding alcohols in presence of triethyl amine (Scheme
5.10).21
Me
ClHH 2N
BocHN
CO2 Me
13
Me b
CO2 Me
12
BocHN
Me
BocHN
OH
11
Me
OTs
10
Scheme 5.10
Reagents and conditions: (a) (Boc)2O, Et3N, THF rt, 4-5 hrs; (b) NaBH4 in
THF/MeOH; (c) TsCl, Et3N, 00C, overnight.
5.4.1.2 Synthesis of (S)-1-(2-bromophenylthio)propan-2-amine 7:
The effort to synthesize 2-bromophenylthio-2-amine 7 was started from 2bromo benzenethiol 9 and 4-methylbenzenesulfonate derivatives of amino acids 10ag. As for example, the reaction of 9 with 10a in presence of NaH under N2 in dry
THF at room temperature yielded N-Boc-(S)-1-(2-bromophenylthio) amines 8a in
72% isolated yield which on subsequent treatment with 50% TFA in dichloromethane
furnished 7a (Scheme 5.11).
174

derivatives
Br BocHN
Me
Br
+
SH
9
10a
Me
OTs
Br
NHBoc
S
7
Me
NH2
Scheme 5.11
Reagents and conditions: (a) NaH, THF, rt (b) 50% TFA in DCM
5.4.1.3
Synthesis
of
S-amino
acids
incorporated
(S)-3,4-dihydro-2H-
benzo[b][1,4]thiazine derivatives 6a-g:

To observe the feasibility of incorporation of S-amino acid into the 3,4dihydro-2H-benzo[b][1,4]thiazine derivative, arylation amination reaction of 2bromophenylthio-amine derivatives in inert atmosphere in presence of copper iodide
and anhydrous K2CO3 in N,N-dimethyl acetamide afforded enantiomerically pure 3,4dihydro-2H-benzo[b][1,4]thiazine derivatives 6a-g in 63-69% yields (Scheme 5.12,
Table 5.1).
Br
S
7a
H
N
Me
Me
NH2
6a
Scheme 5.12
Reagents and conditions: (a) 0.20 equiv. CuI, K2CO3, DMA, 100-1100C, 48 hrs.
All of these synthesized compounds were fully characterized by using
spectroscopic techniques i.e. IR, MS and NMR. The N-Boc (2-bromophenylthio)amines 8a and 8b thus obtained showed characteristic [M++H - Boc) peaks at m/z 246
and 274 respectively in ESI MS spectrum. The IR spectrum of 8a and 8b showed
characteristic absorption at 1498 cm-1 and 1508 cm-1 due to the N-Boc carbonyl group
respectively. The 1H NMR spectrum of 8a also showed characteristic peaks i.e. a
multiplet at 3.26-3.15 for one proton at C-2(-SCH2) and a multiplet at 3.00-2.94
for another proton. The 1H NMR spectrum of 8b also showed the similar pattern as
8a with slightly downfield or upfield shift of signals, except the presence of one
additional multiplet at 0.98-0.87 (m, 6H, CH3) for isopropyl group. The cyclized
products 6a and 6b also showed [M++H] peaks at m/z 166 and 194 respectively in ESI
MS spectra. The 1H NMR spectrum of these compounds showed characteristic broad
175

derivatives
singlets at 3.83 and 3.93 respectively for one proton of NH. The 13C NMR of these
products was also in full agreement with the assigned structures.
Table 5.1: List of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 6a-g and
intermediates 8a-g
Entry
Intermediates
Yield
(%)
Products
H
N
Br
Me
S
8a
72
6a
NHBoc
Br
2
S
8b
NHBoc
6b
Br
S
8c
NHBoc
4
S
8d
H
N
76
NHBoc
6e
64
95
69
94
63
97
65
96
69
NHBoc
H
N
OBn
73
Br
S
8f
99
H
N
76
Br
S
8e
6d
63
6c
Br
97
H
N
78
Yield
(%)
H
N
75
% ee
6f
OBn
NHBoc
Br
S
8g BocN
67
78
95
6g
5.5 Experimental
Same as that described in the Chapter 2.
5.5.2 Preparation of N-Boc (S)-1-(2-bromophenylthio) amine derivatives 8a-g
(S)-tert-butyl 1-(2-bromophenylthio)propan-2-ylcarbamate 8a:
176

derivatives
To a suspension of NaH (0.06 g, 2.64 mmol) in dry THF (10 mL) at 0C under
N2, 2-bromobenzenethiol (0.25 g, 1.33 mmol) was added slowly via a syringe. The
resulting solution was stirred at 0C for 5-10 minutes after
Br
8a
which
Me
NHBoc
the
(S)-2-(tert-butoxycarbonylamino)propyl
methylbenzenesulfonate
4-
10a (0.65 g, 1.98 mmol) in THF (5
mL) was added dropwise at the same temperature. The
resulted solution was stirred at room temperature for 1 h. The reaction mixture was
quenched by gradual addition of MeOH and THF was removed in vacuo. The mixture
was extracted thrice with ethylacetate, the extract was washed with brine, dried over
anhydrous Na2SO4 and concentrated under vacuo. The residue was chromatographed
over silica gel and elution with 15% ethyl acetate in hexane (Rf= 0.5) furnished 8a
(0.33 g, 72%) as colourless viscous oil. Rf = 0.5 (10% ethyl acetate in hexane). IR
(Neat): 3438, 3020, 2361, 1707, 1498, 1215, 770 cm-1. 1H NMR (300 MHz, CDCl3):
7.59-7.52, (m, 1H, ArH), 7.44 (d, 1H, J = 7.3 Hz, ArH), 7.30-7.26 (m, 1H, ArH),
7.05-7.00 (m, 1H, ArH), 4.70 (bs, 1H, NH), 3.95-3.94 (m, 1H,), 3.26-3.15 (m, 1H,
SCH), 3.00-2.94 (m, 1H, SCH), 1.43 (s, 9H, CCH3), 1.27 (d, 3H, J = 6.7 Hz, CH3).
13
C NMR (50 MHz, CDCl3): 155.0, 137.6, 133.0, 129.6, 127.0, 126.8, 79.5, 45.7,
39.6, 28.4, 21.5. MS (ESI): m/z (%): 246 (75, [M++H-Boc). Anal. Calcd for
(C14H20BrNO2S): C, 48.56; H, 5.82; N, 4.04;, Found: C, 48.49; H, 5.86; N, 4.05.
(S)-tert-butyl 1-(2-bromophenylthio)-3-methylbutan-2-ylcarbamate 8b:
As described for 8a, 2-bromobenzenethiol (0.25 g, 1.32 mmole), NaH (0.06 g,
2.64 mmol) in dry THF (15mL), 10b (0.94 g, 2.64 mmol) in THF (2mL) furnished 8b
as brown oil, (0.37 g, 75%); Rf = 0.4 (10% ethyl acetate in
Br
S
8b
hexane). IR (Neat): 3433, 2968, 2359, 1700, 1508, 1219, 758

NHBoc
7.36 (d, 1H, J = 6.2 Hz, ArH), 7.30-7.26 (m, 1H, ArH), 7.07-
7.02 (m, 1H, ArH),4.62 (bs, 1H, NH), 3.72-3.71 (m, 1H), 3.11-3.10 (m, 2H, SCH),
2.05-1.94 (m, 1H), 1.44 (s, 9H, CCH3), 0.98-0.87 (m, 6H, CH3). 13C NMR (50 MHz,
CDCl3): 155.3, 137.7, 132.9, 129.2, 127.7, 126.8, 124.3, 79.1, 54.7, 36.5, 30.6, 28.4,
19.6, 17.8. MS (ESI): m/z (%): 274 (70, [M+-Boc]), 276 (70, [M++2-Boc]). Anal.
Calcd for (C16H24BrNO2S): C, 51.34; H, 6.46; N, 3.74;, Found: C, 51.39; H, 6.40; N,
3.77.
tert-butyl (2S,3S)-1-(2-bromophenylthio)-3-methylpentan-2-ylcarbamate 8c:
177

derivatives

2.64 mmol) in dry THF (15mL), 10c (0.97 g, 2.64 mmol) in THF (2mL) furnished 8c
(0.40 g, 78%) as pale yellow oil; Rf = 0.5 (10% ethyl acetate
Br
in hexane). IR (Neat): 3437, 3019, 2962, 2361, 1703, 1499,

S
8c
NHBoc
1216, 760 cm-1. 1H NMR (300 MHz, CDCl3): 7.54 (dd,

1H, J1 = 0.9 Hz, J2 = 7.9 Hz, ArH), 7.42 (d, 1H, J = 7.1 Hz,
ArH), 7.30-7.25 (m, 1H, ArH), 7.06-7.01 (m, 1H, ArH), 4.60 (bs, 1H, NH), 3.96-3.94
(m, 1H), 3.16-3.11 (m, 1H, SCH), 1.68-1.70 (m, 1H), 1.46-1.45 (m, 2H), 1.44 (s, 9H,
CCH3), 0.93 (dd, 6H, J1 = 6.6 Hz, J2 = 9.0 Hz,).
13
C NMR (75 MHz, CDCl3):
155.0, 137.9, 132.9, 129.1, 127.7, 126.7, 124.1, 79.18, 48.0, 42.9, 39.1, 28.4, 24.9,
23.0, 22.1. MS (FAB): m/z (%): 288 (95, [M+-Boc]), 271 (30). Anal. Calcd for
(C17H26BrNO2S): C, 52.58; H, 6.75; N, 3.61, Found: C, 52.51; H, 6.72 N, 3.67.
(S)-tert-butyl 1-(2-bromophenylthio)-4-methylpentan-2-ylcarbamate 8d:
2.64 mmol) in dry THF (15mL), 10d (0.98 g, 2.64 mmol) in THF (2mL) furnished 8d
(0.36 g, 71%) as a light yellow liquid; Rf = 0.4 (10 % ethyl
Br
S
8d
acetate in hexane). brown oil, (0.31 g, 76%). IR (Neat): 3438,

3017, 2977, 2361, 1702, 1500, 1451, 1216, 757 cm-1. 1H NMR
NHBoc
(300 MHz, CDCl3): 7.55 (d, 1H, J = 7.9 Hz, ArH), 7.36 (d,
1H, J = 7.6 Hz, ArH), 7.28-7.24 (m, 1H, ArH), 7.07-7.01 (m, 1H, ArH), 4.69 (m, 1H,
NH), 3.72-3.77 (m, 1H), 3.17-3.07 (m, 2H, SCH2), 1.73-1.71 (m, 1H), 1.57-1.49 (m,
1H) 1.44 (s, 9H), 0.94-0.89 (m, 6H).
13
C NMR (50 MHz, CDCl3): 155.5, 137.7,
133.0, 129.2, 127.8, 126.9, 124.3, 53.8, 37.4, 36.3, 28.3, 24.9, 15.5, 11.5. MS (ESI):
m/z (%): 287 (98, [M+-Boc]). 289 (100, [M++2-Boc]). Anal.
Calcd for
(C17H26BrNO2S): C, 52.58; H, 6.75; N, 3.61; 4.04;, Found: C, 52.51; H, 6.77; N, 3.66.

(S)-tert-butyl 1-(2-bromophenylthio)-3-phenylpropan-2-ylcarbamate 8e:
2.64 mmol) in dry THF (15mL), 10e (1.07 g, 2.64 mmol) in
THF (2mL) furnished 8e (0.42 g, 76%) as grey oil, Rf = 0.5
Br
(10% ethyl acetate in hexane). IR (Neat): 3429, 3021, 2360,

S
8e
NHBoc
1707, 1495, 1428, 1215, 761 cm-1. 1H NMR (300 MHz,

CDCl3): 7.54 (d, 1H, J = 7.8 Hz, ArH), 7.34-7.20 (m, 7H,
ArH), 7.08-7.02 (m, 1H, ArH), 4.72-4.50 (bs, 1H, NH), 4.10-3.87 (m, 1H), 3.07 (d,
178

derivatives
2H, J = 5.4 Hz, SCH2), 2.95 (d, 1H, J = 6.6 Hz, CH2), 1.41 (s, 9H). 13C NMR (50
MHz, CDCl3): 155.2, 137.3, 133.0, 129.4, 129.1, 128.6, 128.0, 127.0, 126.7, 124.2,
116.4, 115.1, 79.3, 51.3, 39.1, 38.7, 28.3. MS (ESI): m/z (%): 322 (95, [M+-Boc]).
Anal. Calcd for (C20H24BrNO2S): C, 56.87; H, 5.73; N, 3.32, Found: C, 56.84; H,
5.67; N, 3.38.
(S)-tert-butyl
1-(4-(benzyloxy)phenyl)-3-(2-bromophenylthio)propan-2-
ylcarbamate 8f:
2.64 mmol) in dry THF (15mL), 10f (1.34 g, 2.64 mmol) in THF (2mL) furnished 8f
OBn
(0.51 g, 73%) as light yellow semi solid. Rf = 0.4 (10% ethyl

1215, 762 cm-1. 1H NMR (300 MHz, CDCl3): 7.31 (d, 1H,
Br
J = 7.56 Hz, ArH), 7.27-7.11 (m, 7H, ArH), 7.02 (d, 2H, J =
S
8f
NHBoc
7.53 Hz, ArH), 6.97-6.91 (m, 1H, ArH), 6.82 (d, 2H, J = 6.9
Hz, ArH), 4.95 (s, 2H), 4.61 (bs, 1H, NH), 4.05-3.89 (m, 1H),
2.95 (d, 1H, J = 4.72 Hz, SCH2), 2.81 (d, 1H, J = 4.63 Hz, CH2), 1.32 (s, 9H). 13C
NMR (75 MHz, CDCl3): 157.6, 154.9, 137.5, 137.0, 133.0, 130.4, 129.4, 128.9,
128.5, 127.9, 127.4, 126.8, 124.0, 115.0, 79.4, 69.9, 50.9, 38.3, 36.6, 28.4. MS (FAB):
m/z (%): 428 (100, [M+-Boc]). 430 (100, [M++2-Boc]). Anal. Calcd for
(C27H30BrNO3S): C, 61.36; H, 5.72 N, 2.65, Found: C, 61.43; H, 5.74; N, 2.58.
(S)-tert-butyl 2-((2-bromophenylthio)methyl)pyrrolidine-1-carboxylate 8g:
As described for 8a, 2-bromobenzenethiol (0.25 g, 1.32 mmol), NaH (0.06 g, 2.64
mmol) in dry THF (15mL), 10g (0.73 g, 2.64 mmol) in THF (2mL) furnished 8g (0.38
g, 78%) as colourless viscous oil; Rf = 0.4 (10 % ethyl acetate
Br
in hexane). IR (Neat): 3408, 3020, 2360, 1674, 1596, 1401,
S
8g BocN
1215, 761 cm-1. 1H NMR (200 MHz, CDCl3): 7.66-7.63 (m,

2H, ArH), 7.51-7.41 (m, 1H, ArH), 7.26-7.01 (m, 1H, ArH),
4.02 (bs, 1H, NH), 3.50-3.40 (m, 1H,), 2.76-2.71 (m, 1H), 2.01-1.89 (m, 1H), 1.861.74 (m, 1H, ArH), 1.46 (s, 9H, CCH3). 13C NMR (50 MHz, CDCl3): 154.7, 137.9,
133.5, 129.2, 128.1, 127.2, 126.5, 79.8, 56.3, 47.1, 36.8, 35.5, 29.0, 23.9. MS (ESI):
m/z (%):
272 (98, [M+-Boc]), 274 (98, [M++2-Boc]). Anal. Calcd for
(C16H22BrNO2S): C, 51.61; H, 5.96; N, 3.76, Found: C, 51.54; H, 5.89; N, 3.73.
179

derivatives
5.5.3 Boc deprotection from 8a-g to furnish 7a-g:

To the stirred solutions of 8a in dry DCM was added 50% TFA in DCM at
0
0 C and the mixture was stirred at RT for 0.5 h. After completion of the reaction, the
reaction mixture was neutralised by gradual addition of saturated aq. solution of
NaHCO3. The mixture was extracted thrice with dichloromethane, the extract was
washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuo
furnishing crude 7a which has been used as such for the next step.
5.5.4 Cyclization of 2-bromophenylthio-amine derivatives
(S)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 6a:
Seal tube was charged with (S)-1-(2-bromophenylthio)propan-2-amine 7a
(0.25 g, 1.01 mmol), anhy. K2CO3 (0.21 g, 1.52 mmol) and CuI (0.04 g, 0.20 mmol) in
H
N
6a
N,N-dimethyl acetamide (DMA) (4mL) under N2 gas. It was then

Me
heated at 100-1100C for about 48 hr. After completion of the

reaction it was then cooled to room temperature and poured into
ice-cooled water, acidified with conc. HCl till pH reached to 3.5.
The mixture was extracted thrice with ethylacetate, the extract
was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuo.
The residue was chromatographed over silica gel and elution with 5% ethyl acetate in
hexane, Rf = 0.7 (5% ethyl acetate in hexane), furnished 6a (0.11 gm, 66%) as viscous
brown oil. IR (Neat): 3394, 2921, 2358, 1650, 1482, 1307, 1038, 750 cm-1. 1H NMR
(200 MHz, CDCl3): 6.91-6.88 (m, 1H), 6.66-6.61 (m, 1H), 6.48 (dd, 6H, J1 = 0.7
Hz, J2 = 8.0 Hz), 3.83 (bs, 1H, NH), 3.76-3.67 (m, 1H), 2.93-2.80 (m, 2H), 1.33 (d,
3H, J = 6.3 Hz, CH3).
13
C NMR (75 MHz, CDCl3): 141.7, 127.3, 125.5, 118.0,
115.5, 115.2, 47.0, 32.3, 22.5.
MS (ESI): m/z (%): 166 (100, [M++1]). 124 (95).
Anal. Calcd for (C9H11NS): C, 65.41; H, 6.71; N, 8.48, Found: C, 65.33; H, 6.76; N,
8.53.
(S)-3-isopropyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 6b:
As described for 6a, 7b (0.25 g, 0.91 mmol), anhy. K2CO3 (0.19 g, 1.37 mmol)
and CuI (0.03 g, 0.18 mmol) in N,N-dimethyl acetamide (DMA)
6b
H
N
(4mL) under N2 gas furnished 6b (0.11 g, 63%) as dark brown
viscous oil; Rf = 0.7 (5% ethyl acetate in hexane). IR (Neat):

3696, 3020, 2965, 2361, 1593, 1480, 1216, 1023, 763 cm-1. 1H
180

derivatives
NMR (300 MHz, CDCl3): 6.97 (dd, 1H, J1 = 1.2, Hz, J2 = 7.7, Hz, ArH), 6.90-6.85
(m, 1H, ArH), 6.61-6.56 (m, 1H, ArH), 6.48-6.44 (m, 1H, ArH), 3.97 (bs, 1H, NH),
3.35-3.30 (m, 1H), 2.92 (d, 1H, J = 5.2 Hz), 1.97-1.86 (m, 1H), 1.09-1.02 (m, 1H,
13
ArH).
C NMR (75 MHz, CDCl3): 142.0, 134.0, 128.6, 126.3, 117.8, 115.2, 57.1,
32.5, 29.7, 18.0. MS (ESI): m/z (%): 194 (100, [M++H]. Anal. Calcd for (C11H15NS):
C, 68.35; H, 7.82; N, 7.25, Found: C, 68.43; H, 7.95; N, 7.19.
(S)-3-sec-butyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 6c:
As described for 6a, 7c (0.25 g, 0.87 mmol), anhy. K2CO3 (0.18 g, 1.30 mmol)
and CuI (0.03 g, 0.17 mmol) in N,N-dimethyl acetamide (DMA) (4mL) under N2 gas
furnished 6c (0.12 g, 69%) as reddish viscous oil; Rf = 0.6 (5%
H
N
S
6c
ethyl acetate in hexane). IR (Neat): 3441, 3020, 2360, 1649,

1461, 1216, 762 cm-1. 1H NMR (300 MHz, CDCl3): 6.98
(dd, 1H, J1 = 1.3 Hz, J2 = 7.7 Hz), 6.90-6.85 (m, 1H, ArH),
6.58 (dd, 1H, J1 = 1.1 Hz, J2 = 7.4 Hz), 6.46 (dd, 1H, J 1= 1.0 Hz, J2 = 8.0 Hz), 3.93
(bs, 1H, NH), 3.44-3.42 (m, 1H), 2.90-2.86 (m, 2H), 1.64-1.54 (m, 3H), 0.97-0.92 (m,
6H).
13
C NMR (50 MHz, CDCl3): 142.1, 127.3, 125.4, 117.6, 115.7, 115.1, 55.5,
39.2, 27.3, 25.5, 14.1, 11.5. MS (ESI): m/z (%): 208 (100, [M++H]), 124. Anal. Calcd
for (C12H17NS): C, 69.51; H, 8.26; N, 6.76, Found: C, 69.58; H, 8.23; N, 6.74.
(S)-3-isobutyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 6d:
As described for 6a, 7d (0.25 g, 0.87 mmol), anhy. K2CO3 (0.18 g, 1.30 mmol)
furnished 6d (0.11 g, 63%) as brown viscous oil; Rf = 0.6 (5%
H
N
6d

1589, 1480, 1216, 760 cm-1. 1H NMR (300 MHz, CDCl3):
7.02 (dd, 1H, J1 = 1.5 Hz, J2 = 7.6 Hz), 6.93-6.88 (m, 1H,
ArH), 6.65-6.60 (m, 1H, ArH), 6.48 (d, 1H, J = 8.0 Hz), 3.64-3.61 (m, 1H), 2.95 (dd,
1H, J1 = 2.6 Hz, J2 = 12.3 Hz), 2.85-2.78 (m, 1H), 1.82-1.75 (m, 1H), 1.51-1.44 (m,
2H), 0.99 (d, 6H, J=6.5 Hz).
13
C NMR (75 MHz, CDCl3): 141.7, 127.4, 125.4,
117.9, 115.8, 115.3, 49.3, 45.5, 31.7, 24.5, 22.9, 22.5. MS (ESI): m/z (%): 208 (100,
[M++H]), 124. Anal. Calcd for (C12H17NS): C, 69.51; H, 8.26; N, 6.76, Found: C,
69.56; H, 8.29; N, 6.69.
(S)-3-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine 6e:
181

derivatives
As described for 6a, 7e (0.25 g, 0.78 mmol), anhy. K2CO3 (0.16 g, 1.16 mmol)
6e
furnished 6e (0.12 g, 65%) as grey viscous oil; Rf = 0.6 (5%
H
N
1428, 1215, 764 cm-1. 1H NMR (300 MHz, CDCl3): 7.387.22 (m, 5H, ArH), 6.99 (dd, 1H, J1 = 1.4 Hz, J2 = 7.1 Hz,
ArH), 6.89-6.83 (m, 1H, ArH), 6.64-6.59 (m, 1H, ArH), 6.38 (d, 1H, J = 7.9 Hz),
3.83-3.81 (m, 1H), 3.05-2.83 (m, 4H).
13
C NMR (50 MHz, CDCl3): 140.8, 137.4,
129.2, 128.7, 127.4, 126.8, 125.4, 118.3, 116.0, 115.6, 52.1, 42.5, 30.4. MS (ESI): m/z
(%): 242 (100, [M++H]). Anal. Calcd for (C15H15NS): C, 74.65; H, 6.26; N, 5.80,
Found: C, 74.58; H, 6.23; N, 5.73.
(S)-3-(4-(benzyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine 6f:
As described for 6a, 7f (0.25 g, 0.58 mmol), anhy. K2CO3 (0.12 g, 0.88 mmol) and
CuI (0.02 g, 0.11 mmol) in N,N-dimethyl acetamide
H
N
6f
(DMA) (4mL) under N2 gas furnished 6f (0.13 g, 67%)

as blackish viscous oil; Rf = 0.7 (5% ethyl acetate in
OBn
hexane). IR (Neat): 3404, 3018, 2924, 2360, 2106,
-1 1
1592, 1481, 1217, 761 cm . H NMR (200 MHz, CDCl3): 7.50-7.36 (m, 5H, ArH),
7.18 (d, 2H, J = 8.5 Hz), 7.05-7.00 (m, 3H, ArH), 6.97-6.88 (m, 1H, ArH), 6.67-6.64
(m, 1H, ArH), 6.41 (dd, 1H, J1 = 1.0 Hz, J2 = 8.0 Hz), 5.10 (s, 2H), 3.93 (s, 1H), 3.813.76 (m, 1H), 3.03-2.80 (m, 4H). 13C NMR (50 MHz, CDCl3): 157.7, 141.3, 136.9,
130.2, 129.6, 128.5, 127.9, 127.4, 127.3, 125.4, 118.0, 115.8, 115.4, 115.1, 70.0, 52.2,
41.6, 30.4. MS (ESI): m/z (%): 348 (100, [M++H]). Anal. Calcd for (C22H21NOS): C,
76.04; H, 6.09; N, 4.03, Found: C, 75.96; H, 6.15; N, 4.10.
(S)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]thiazine 6g:
As described for 6a, 7g (0.25 g, 0.91 mmol), anhy. K2CO3 (0.19 g, 1.38 mmol)
furnished 6g (0.12 g, 67%) as orange red viscous oil;Rf = 0.6 (5%
N
6g
ethyl acetate in hexane). IR (Neat): 3404, 3020, 2857, 2360, 1589,

1482, 1216, 761 cm-1. 1H NMR (200 MHz, CDCl3): 7.08 (dd, 1H,
J1 = 1.2 Hz, J2 = 7.3 Hz), 7.03-6.98 (m, 1H), 6.61 (t, 1H, J = 7.4
Hz), 6.56 (d, 1H, J = 8.1 Hz), 3.78-3.75 (m, 1H), 3.41-3.33 (m, 2H), 3.02 (dd, 1H, J1
= 2.6 Hz, J2 = 12.2 Hz), 2.79-2.72 (m, 1H), 2.27-2.23 (m, 1H), 2.09-2.01 (m, 2H),
182

derivatives
1.63-1.60 (m, 1H).13C NMR (50 MHz, CDCl3): 142.0, 127.2, 126.0, 116.7, 116.0,
112.1, 58.4, 48.4, 32.9, 29.7, 23.0. MS (FAB): m/z (%): 192 (100, [M++H]). Anal.
Calcd for (C11H13NS): C, 69.07; H, 6.85; N, 7.32, Found: C, 69.03; H, 6.83; N, 7.26.
5.6 Conclusion
In conclusion, we have demonstrated an efficient method to synthesize a new
series of enantiomerically pure 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 6a-g
from naturally abundant chiral amino acids via- copper-catalysed intramolecular aryl
amination reaction. Ease of the reaction sequence gave an access to enantiomerically
pure chiral benzothiazines which could have interesting biological properties.
5.7 References:
1.
1,4-Benzothiazines (a) as antiinflammatory agents: (i) Lombardino, J. G.;
Wiseman, E. H. Med. Res. Rev. 1982, 2, 127. (ii) Turk, C. F. J. Med. Chem. 1973, 16,
776. (b) As antihypertensive agents: (i) Prasad, R. N. J. Med. Chem. 1969, 12, 290.
(ii) Cecchetti, V.; Fravolini, A.; Schiaffella, F.; DeRegis, M.; Orzalesi, G.; Volpato, I.
Farmaco. Ed. Sci. 1983, 38, 35. (c) As anticancer agents: (i) Gupta, R. R.; Dev, P.
K.; Sharma, M. L.; Rajoria, C. M.; Gupta, A.; Nyati, M. Anticancer Drugs 1993, 4,
589. (ii) Todorov, D. K.; Ilarionova, M. V.; Gupta, R. R.; Molnar, J.; Motohashi, N.
Heterocycl. Commun. 1995, 1, 153. (d) as anti-fungal agent: (i) Schiaffella. F;,
Macchiarulo. A;, Milanese. L;, Vecchiarell. A;, and Fringuell. R. Bioorg. Med. Chem.
2006, 14, 5196. (ii) Fringuelli . R ;, Schiaffella . F;, Bistoni F;,
Pitzurra . L;,
Vecchiarelli . A. Bioorg. Med. Chem. 1998, 6, 103.(iii) Baruffini A, Pagani G,

Amoretti L. I1 Farmaco 1967, 22, 528. (e) as anti-tumour agent: (i) Coughlin, S. A.;
Danz, D. W.; Robinson, R. G.; Klingbeil, K. M.; Wentland, M. P.; Corbett, T. H.;
Waud, W. R.; Zwelling, L. A.; Altsschuler, E. Biochem. Pharmacol. 1995, 50, 111.
(ii) Hasegawa, K.; Ito, S.; Inoue, S.; Wakamatsu, K.; Ozeki, H.; Ishiguro, I. Biochem.
Pharmacol. 1997, 53, 1435. (iii) Inoue, S.; Hasegawa, K.; Wakamatsu, K.; Ito, S.
Melanoma Res. 1998, 8, 105. (f) KATP-Channel Openers (i) Cecchetti, V.; Calderone,
V.; Tabarrini, O.; Sabatini, S.; Filipponi, E.; Testai, L.; Spogli, R.; Martinotti, E.;
Fravolini, A. J. Med. Chem. 2003, 46, 3670. (g) as anti-HIV agent: (i) Grandolini.G;,
Perioli.L;, Ambarogi, V. Euro. J. Med. Chem. 1999, 34, 701.
2. (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999,
40, 4761. (b) Chem. Abstr. 1985, 102, 605 (78901p, JP59164786). (c) Chem. Abstr.
183

derivatives
1992, 117, 748 (131207e, WO 9205164). (d) Chem. Abstr. 1990, 112, 585 (35887e,
JP 0161470). (e) Harmata, M.; Kahraman, M. J. Org. Chem. 1998, 63, 6845. (f)
Kaiser, E. M.; Knutson, P. L. A. J. Org. Chem. 1975, 40, 1342. (g) Cecchetti, V.;
Fravolini, A,; Schiaffella, F. J. Heterocycl. Chem. 1982, 19, 1045.
3. Morino, T.; Yamamoto, T. J. Chem. Eng. Jpn. 1997, 30, 1005.
4. 4. Corelli, F,; Manetti, F ,; Tafi, A,; Campiani, G,; Nacci, V,; Botta, M. J. Med.
Chem. 1997, 40, 125.
5. Macchiarulo, A,; Costantino, G,; Fringuelli, D,; Vecchiarelli, A,; chiaffella, F,;
Fringuelli, R. Bioorg. Med. Chem. 2002, 10, 3415.
6. Cecchetti, V.; Fravolini, A.; Fringuelli, R.; Schiaella, F.; Mascellani, G.; Pagella,
P. G.; Rugarli, P. L. Il Farmaco 1987, 42, 61.
7. (a) Babudri, F.; DiNunno, L.; Florio, S. Tetrahedron 1982, 38, 3059. (b) Babudri,
F.; DiNunno, L.; Florio, S. Synthesis 1983, 230. (c) Huang, X.; Chan, C.-C. Synthesis
1984, 851. (d) Marfat, A.; Carta, M. P. Synthesis 1987, 515. (e) Trapani, G.; Latrofa,
A.; Reho, A.; Liso, G. J. Heterocycl. Chem. 1989, 26, 721. (f) Singh, H.; Singh, D. J.;
Kumar, S. Indian J. Chem. Sect. B. 1992, 31B, 217. (g) Rai, D.; Gupta, V.; Gupta, R.
R. Heterocycl. Commun. 1996, 2, 273.
8. (a) Landquist, J. K. Sixmembered Ring Systems. In Comprehensive Organic
Chemistry; Heterocyclic Compounds; Barton, D., Ollis, W. D., Sammes, P. G., Eds.;
Pergamon Press: Oxford, 1979, 4, 1092. (b) Brown, C.; Davidson, R. M. 1,4Benzothiazines, dihydro-1,4-benzothiazines and related compounds. Adv. Heterocycl.
Chem. 1985, 38, 135. (c) Gupta, R. R., Ed. Phenothiazines and 1,4-Benzothiazines:
Chemical and Biomedical Aspects. In Bioactive Molecules; Elsevier: Amsterdam,
Neth, 1988, 4. (d) Sainsbury, M. 1,4-Thiazines, 1,4-Benzothiazines, Phenothiazines
and Related Compounds. In Rodds Chemistry of Carbon Compounds, 2nd ed.;
Publisher: Elsevier: Amsterdam, Neth, 1998; Vol. 4 (Part G (partial)/Part H), 575.
9. Kirchner, F. K.; Alexander, E. J. J. Am. Chem. Soc. 1959, 81, 1721.
11. Balasubramaniyan, V.; Balasubramaniyan, P.; Shaikh, A. S. Tetrahedron 1986,
42, 2731.
12. (a) Unger, O. Chem. Ber. 1897, 30, 607. (b) Unger, O.; Graff, G. Chem. Ber.
1897, 30, 2389.
13. Florio, S.; Capriati, V.; Colli, G. Tetrahedron 1997, 53, 5839.
14. Erker, T.; Bartsch, H. Liebigs Ann. Chem. 1992, 403.
184

derivatives
15. Kobayashi, K,; Hayashi, K,; Iitsuka, D,; Morikawa, O,; Konishi, H. Synthesis
2006, 07, 1077.
16. Kundu, N. G,; Bidisha Nandi, B. J. Org. Chem. 2001, 66, 4563.
17. Mukherjee, C,; Biehl, E. Heterocycles 2004, 63, 2309.
18. Yokum, T. S,; Alsina, J,; George Barany, G. J. Comb. Chem. 2000, 2, 282.
19. Burgess, K. Solid-phase Organic Synthesis; John Wiley & Sons: New York, 2000.
20. Lee, C. L.; Chan, K. P.; Lam, Y.; Lee, S. Y. Tetrahedron Lett. 2001, 42, 1167.
21. Mishra, J. K.; Panda G.; J. Comb. Chem. 2007, 9, 321.
185

derivatives
5.8 Spectra
Br
S
NHBoc
OBn
Figure 5.2 1H NMR (CDCl3, 300 MHz) spectrum of 8g.
H
N
OBn
Figure 5.3 1H NMR (CDCl3, 300 MHz) spectrum of 6g.
186

derivatives
H
N
Figure 5.4 1H NMR (CDCl3, 300 MHz) spectrum of 8d.
H
N
Figure 5.5
13
C NMR (CDCl3, 75 MHz) spectrum of 8d.
187

derivatives
Br
S
NHBoc
Figure 5.6 1H NMR (CDCl3, 300 MHz) spectrum of 8c.
Br
S
NHBoc
Figure 5.7 13C NMR (CDCl3, 75 MHz) spectrum of 8c.
188

derivatives
H
N
Figure 5.8 1H NMR (CDCl3, 300 MHz) spectrum of 6c.
H
N
Figure 5.9
13
C NMR (CDCl3, 50 MHz) spectrum of 6c.
189

derivatives
Br
S
NHBoc
Figure 5.10 1H NMR (CDCl3, 300 MHz) spectrum of 8a.
Br
S
NHBoc
Figure 5.11 1H NMR (CDCl3, 300 MHz) spectrum of 8b.
190
Vitae
Vitae
The author was born at Ghanashyambati, a small village in the district of Purba
Medinipore, West Bengal. After obtaining his M.Sc. degree from C.S.J.M University,
Kanpur, he joined Medicinal and Process Chemistry Division of Central Drug
Research Institute, Lucknow as Junior Research Fellow in January, 2004 and was
registered as Ph.D student from Jadavpur University, Kolkata, West Bengal
on
21.11.2005.
List of Publications
1. A new strategy for the synthesis of aryl- and heteroaryl- substituted exocyclic
olefins from allyl alcohols using PBr3, Shagufta, Maloy Kumar Parai and Gautam
Panda; Tetrahedron Letters, 2005 46, 8849-8852.
2. Effect of substituents on diarylmethanes for antitubercular activity; Gautam Panda,
Maloy Kumar Parai, Sajal Kumar Das, Shagufta, Manish Sinha, Vinita Chaturvedi,
Anil K. Srivastava, Y.S. Manju, Anil N. Gaikwad and Sudhir Sinha; European
Journal of Medicinal Chemistry, 2007, Volume 42, Pages 410-419.
3. Thiophene containing triarylmethanes as antitubercular agents, Maloy Kumar
Parai and Gautam Panda, V. Chaturvedi, Y. K. Manju, S. Sinha; Bioorganic &
Medicinal Chemistry Letters, 2008, 18, 289-292.
4. Design, synthesis and antimalarial activity of benzene and isoquinoline
sulfonamide derivatives. Maloy Kumar Parai, Gautam Panda, K. Srivastava, S. K.
Puri; Bioorg Med Chem Lett. 2008, 18, 776-781.
5.
Reaction
of
phosphorous
(thiochromen-4-yl)-aryl-methanols,
tribromide
on
(chromen-4-yl)-aryl-methanols,
(2,3-dihydro-benzo
[b]
thiepin-5-yl)-aryl-
methanols and [3,4]-dihydronaphthyl-aryl-methanols: A case study; Maloy K. Parai,

Shagufta, Ajay K. Srivastava, Matthias Kassack and Gautam Panda; Tetrahedron
2008, 64, 9962-9976.
6. Synthesis and Antitubercular activity of compounds comprising Aryl and
Heteroaryl moiety with Amino alkyl chains; Gautam Panda, Maloy Kumar Parai,
Ajay Kumar Srivastava, V. Chaturvedi, Y. K. Manju, Sudhir Sinha; Manuscript
submitted.
7. An efficient synthesis of benzothiazine derivatives from chiral amino acids: Maloy
Kumar Parai and Gautam Panda; Manuscript submitted.

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Design, Synthesis and Evaluation of Bioactive Privileged Structures for Drug

FOR THE DEGREE OF

Maloy Kumar Parai

CERTIFICATE FROM THE SUPERVISOR

(Dr. Umesh Chandra Halder)

Internet: http : // www.jadhavpur.edu

CERTIFICATE FROM THE SUPERVISOR

(Dr. Gautam Panda)

CERTIFICATE FROM THE SUPERVISORS

(Signatures of the Supervisors & date with official seal)

It is indeed a great pleasure working with my past and present

(Maloy Kumar Parai)

1.3 Characteristics of Privileged Substructures

yl)-aryl-methanols, (thiochromen-4-yl)-aryl-methanols and (2,3dihydro-benzo [b] thiepin-5-yl)-aryl-methanols: A case study

3.8.7.1 Agar Micro Dilution Method

5.5.3 Boc deprotection of 8a-g to furnish 7a-g

thiepin-5-yl)-aryl-methanols: A case study.

a novel observation during the reaction of phosphorous

tribromide on chroman, thiochroman, 2,3-dihydrobenzo[b]thiepine derived allylic

intramolecular aryl amination reaction has been described.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Figure 1.1 Representative examples of privileged structure containing drugs.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Figure 1.2 Examples of biologically active benzodiazepines based on a single privileged

Chapter 1: An Overview on Privileged Structures in Drug Discovery

approach, both in traditional medicinal chemistry and in the design of focused

Figure 1.3 Schematic presentation of drug discovery research.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Chapter 1: An Overview on Privileged Structures in Drug Discovery

1.2.1 The concept of privileged structures in GPCR ligands design:

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Chapter 1: An Overview on Privileged Structures in Drug Discovery

from biphenyls to arylpiperazines. Unsurprisingly, many of these frameworks have

analgesic, antiinflammatory, antithrombotic, uricosuric, and antiarrhythmic antitumor,

Figure 1.4 Examples of biologically active biphenyls.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Figure 1.5 Histamine H3 Receptor Antagonist

arylthio)phenylthiazoles have shown to be potential antagonists of LFA-1/ICAM-1

Figure 1.6 Examples of biologically active biphenyls.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Stille Reaction: M=Sn; Catalyst= PdLn

found in some neuropeptide Y (NPY)

Figure 1.8 Examples of biologically active arylpiperidines.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Scheme 2 Synthesis of Arylpiperidines of Type 18

antiaggregants, endothelin antagonists, hypolipidemic compounds, and also molecules

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Figure 1.10 Structures of Several 5-HT1A-Agonists.

appropriately substituted anilines and bis-(2-chloroethyl)amine hydrochloride in the

Scheme 3. Synthesis of arylpiperazine framework

Chapter 1: An Overview on Privileged Structures in Drug Discovery

Figure 1.11 Nifedipine (24) and BAY K 8644 (25)

blood-brain barrier. Other 1,4-dihydropyridines have been reported to be active at P2

Scheme 4. 1,4-dihydropyridines Synthesis by Hantzsch condensation.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

26; Calcium channel blocker

Figure 1.12 Representative bioactive dihydropyrimidones.

Scheme 5. The Biginelli Reaction for Dihydropyrimidone Synthesis.

Chapter 1: An Overview on Privileged Structures in Drug Discovery

range of biological activity. Presently, there are numerous types of benzodiazepines

Chapter 1: An Overview on Privileged Structures in Drug Discovery

R 38; R = CH3 , 39; R = C6H5

40; R = Alkyl group