1

Chapter - 1

CHAPTER 1

A Brief Overview of Synthesis and Pharmacological Activities of Substituted Hydrazones, Sulphonamides and Sulphonates

Chapter - 1

CHAPTER 1 1. A Brief Overview of Synthesis and Pharmacological Activities of Substituted Hydrazones, Sulphonamides and Sulphonates 1.1 Section-1 A brief review on Substituted Hydrazones

1.1.1 Introduction to substituted hydrazones This section presents an overview of literature survey on the natural occurrence, medicinal importance, use and synthesis of acyl hydrazones as important tool in organic chemistry. Acyl hydrazones are a very old class of molecules: the first example of N-acylhydrazines was mentioned in 18501, and a number of N-unsubstituted, mono-and disubstituted acylhydrazines are now commercially available. Acyl hydrazones are a versatile class of nitrogen-substituted molecules with a high degree of chemical reactivity, used as precursors and intermediates of many important organic molecules such as heterocycles,

pharmaceuticals, polymers, dyestuffs and photographic products.2 Their use for analytical purposes is well known, and allows the detection of aldehydes, ketones and carboxylic acids. The chemiluminescence of both cyclic and acyclic acyl hydrazones when they undergo oxidation is another interesting and useful property.3 Acylhydrazones have been

Chapter - 1

extensively investigated in recent years as they were found to be associated with various biological activities have promising analytical properties and can be used as catalysts. The cyclic products of acylhydrazones are an important class of heterocyclic compounds with a wide range of biological activities.4-8 They are synthesized by simply refluxing acid hydrazide (AH) with various carbonyl compounds in methanol or ethanol. Due to the simplest reaction conditions, diversified chemical libraries may be constructed for discovering potential bioactive molecules. The resulting double bond between C and N of the hydrazones contributes to the formation of geometrical isomers (syn and anti). Geometrical isomerism may have some important role in the bioactivity of the acyl hydrazones hence their studies are very crucial to develop synthetic methods for selective synthesis of a particular isomer. 1.1.2 Chemistry and nomenclature of substituted hydrazones Compounds of general formula ArCONHN=C(R) Ar are known as N-acyl hydrazones. Hydrazones containing an azomethine CH=NNHhydrogen are obtained from the action of acid hydrazide with aldehyde or ketones either in various solvents or under solvent free conditions. Over all, the acylhydrazone derivatives can exist in four possible forms due to collective effect of configurational stereochemistry E and Z as well as conformational stereoisomers or rotamers i.e antiperiplaner (ap) and syn periplaner conformers (sp).

Chapter - 1

H N O

H N Ar O

H N

Ar N H HN

O N

O H Ar HN N

Ar H

E-Isomer ap-rotamer

Z-Isomer ap-rotamer

E-Isomer sp-rotamer

Z-Isomer sp-rotamer

1.1.3 Medicinal importance Substituted acyl hydrazones show a variety of biological activity, such as analgesic, antiinflammatory, anti-microbial, anti-convulsant, anti-platelet, anti-tubercular, anti-viral, schistomiasis and anti-tumoral activities.9,10 Isoniazid or isonicotinic acid hydrazide (INH) is the first-line anti-tuberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis. Isoniazid also has an anti depressant effect, and it was one of the first antidepressants discovered. It has high in vivo inhibitory activity towards M.tuberculosis H37Rv. Hydrazones of 1NH were

synthesized which have inhibitory activity in mice infected with various strains of M. tuberculosis. Hydrazones show less toxicity than hydrazides because of the blockage of NH2 group. These findings further support the growing importance of the synthesis of hydrazide-hydrazones compound.11-13 Nifuroxazide (INN), 4-hydroxy-N'-[(5-nitrofuran-2-yl)

methylene] benzohydrazide is an oral hydrazone based nitrofuran antibiotic used to treat colitis and diarrhea. Some of the representative examples are given below

5 1.1.3a Anticonvulsant Activity

Chapter - 1

Epilepsy is a common neurological disorder and a collective term given to a group of syndromes that involve spontaneous, intermittent, abnormal electrical activity in the brain. The pharmacotherapy of epilepsy has been archived during the last decade. Furthermore, although for the last twenty years new antiepileptic drugs have been introduced into clinical practice, the maximal electroshock (MES) test and the subcutaneous pentylenetetrazole (scPTZ) test are the most widely used animal models of epilepsy to characterize the anticonvulsant activity. The biological results revealed that in general, the acetyl hydrazones14 provided good protection. The biological revealed that in general, the acetyl hydrazones 1 provided good protection against convulsions while the oxamoylhydrazones 2 were significantly less active.

R1 R2
R2

R1

O H3C C H N C N R3

O O H2N C C

H N N

R3

1 1.1.3b Antidepressant Activity

Iproniazide, isocarboxazide and nialamide, which are hydrazide derivatives, exert their action by inhibiting the enzyme monoamine oxidase (MAO). Inhibition results in increased levels of nor epinephrine, dopamine, tyramine and serotonin in brain neurons and in various other

Chapter - 1

tissues. There have been many reports on the antidepressant / MAOinhibiting the activity of hydrazones derived from substituted hydrazides and reduction products. Ten new arylidenehydrazides15 3-phenyl-2,3dihydro-1H-indole-2-corboxylic acid benzylidene-hydrazide (3) which were synthesized by reacting 3-Phenyl-5-sulfonamidoindole-2-carboxylic acid hydrazide with various aldehydes, evaluated for their antidepressant activity. 3-Phenyl-5-sulfonamidoindole-2-carboxylic acid 3,4-

methylenedioxy / 4-methyl / 4-nitrobenzylidene-hydrazide showed Antidepressant activity8,9 at 100 mg/k.

O N NH N H

3 1.1.3c Analgesic, Anti-inflammatory and Antiplatelet Activity Todeschini and his team has derived the most important anti inflammatory derivative16 2-(2-formylfuryl) pyridylhydrazone, it presented 79% inhibition of pleurisy at a dose of 80.1 mol/kg. The results concerning the mechanism of the action of these series of N-heterocyclic derivatives in platelet aggregation that suggests a Ca+2 scavenger mechanism, this compound (4) was able to complex Ca+2 in in vitro experiments at 100 m concentration, indicating that these series of

Chapter - 1

compounds can act as Ca+2 scavenger depending on the nature of the aryl moiety present at the imine subunit.

N O H

NH

4 1.1.3d Antiplatelet activity. Novel tricyclic acylhydrazone derivative 17 (5) was given by Fraga and his team and evaluated their ability to inhibit platelet aggregation of rabbit platelet-rich plasma induced by platelet-activating factor at 50nM. Benzylidene-/4-bromobenzylidene 3-hydroxy-8-methyl-6-phenylpyrazolo [3,4-b]theino-[2,3-d]pyridine-2-carbohydrazode were evaluated at 10M, presenting respectively 10.4 and 13.6% of inhibition of the PAF-induced platelet aggregation.
O H3C N N S N N H OH H Ar

5 1.1.3e Antimalarial Activity Walcourt and his co-workers has derived novel aroylhydrazone and thiosemicarbazone iron chelators and tested anti-malarial activity against chloroquine-resistant and sensitive parasites. In these derivatives

Chapter - 1

the aroylhydrazone chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone18 hydrazyde Isonicotinic ( 6) showed acid greater (2-hydroxy-naphthalen-1-ylmethylene)anti malarial agent activity than

desferrioxamine against chloroquine-resistant and sensitive parasites.

N OH

H N O

6 1.1.3f Antimicrobial Activity A series of Ethyl 2-arylhydrazono-3-oxobutyrates19 were

synthesized by Kucukguzel and his team in order to determine their antimicrobial properties. Compound 7 showed significant activity against S. aureus whereas the others had no remarkable activity on this strain and compound was found to be more active than the others against Mycobacterium fortuitism at a MIC value of 32 g/ml.

HN N S N

O HN N O CH3 O C2H5

HN N O N

O HN N O CH3 O C2H5

7 1.1.3g Cytotoxic Activity

1-aroyl-2-(alkenyl/aryl)idene hydrazines20 were prepared by Reddy and his team from mefenamic acid moiety which were found to be

Chapter - 1

cytotoxically active, in which the acid moiety in mefenamic acid was replaced by azomethine group moiety and were tested against human lung adenocarcinoma cell line (A549) in vitro, all the compounds showed moderate cytotoxic activities particularly at higher dose. 2-(2,3-Dimethylphenylamino)-benzoic acid(2-hydroxy-benzylidene)-hydrazide (10) was found to be the most active.

N H O NH N OH

Me Me

10 1.1.3h Analgesic activity A series of 2-phenoxybenzoic acid and N-phenylanthranilic acid hydrazides21 were prepared by Ali Almasirad and his team by taking a mixture of hydrazide and corresponding aldehyde or acetophenone in absolute ethanol and was stirred at room temperature in the presence of hydrochloric acid as a catalyst, most of the synthesized compounds were significantly more potent than mefenamic acid and diclofenac in abdominal constriction and formalin tests.

10
O N N H R' X R Ar

Chapter - 1

X = O, NH R = H, Cl R' = H, CH3 Ar = Cl/OCH3 /OH substituted phenyl

11 1.1.3i Selective Agonists for Estrogen-Related Orphan nuclear Receptors The first small molecule agonists (12) of the estrogen related receptors have been identified by William J. Zuercher and his coworkers. A solid-phase approach was developed using the phenol building block as an anchor point and a solution-phase route was also developed.22 The compounds synthesized when screened showed activity in the ERR FRET assay with an 40-55% increase in coactivator peptide recruitment. The ERR activity is highly sensitive to substitution at R1. The optimal substituents were 4- iPr and 4-NEt2.

O R2 N H N R3

R1

R1 R2 R3

iPr

OtBu 4-NH2 Me 12

N-Et2 H

4-OH H

11 1.1.3j Antimycobacterial activity

Chapter - 1

Cocco and his team has reacted Isonicotinoylhydrazones further pyridinecarboxaldehydes pyridymethyleneamino to derivatives23 give (13) the The new corresponding synthesized

hydrazones and their pyridylmethyleneamino derivatives were tested for their activity against mycobacteria, Gram +ve and Gram ve bacteria. The cytotoxicity was also tested. Several compounds showed a good activity against M. tuberculosis H37Rv and some

isonicotinoylhydrazones showed a moderate activity against a clinically isolated M. tuberculosis (6.25-50 g/mL) which was 1NH resistant.

Py R O N N NH N O

13 1.1.3k Antitumor activity Pandey and his team has derived several hydrazones24 having antitumoral activity. Some of diphenolic hydrazones showed maximum uterotrophic inhibition of 70%, where as compound (no) exhibited cytotoxicity in the range of 50-70% against MCF-7 and ZR-75-1 human malignant breast cell lines.

12
HO N N H NO2

Chapter - 1

NO2

14 1.1.3l Vasodilator activity A new bioactive compound of the N-acylhydrazone25 class, 3,4methylenedioxybenzoyl-2-thienyl hydrazone (15) named LASSBio-294, was shown to have inotropic and vasodilatory effects. New derivatives of LASSBio-294 were designed by Silva and his team and tested on the contractile responses of rat vascular smooth muscle in vitro. Most of the compounds has shown the vasodilator activity.

O O O N H N S R

15 1.1.4 Synthetic utility: use as intermediates Although hydrazide hydrazones are pharmacologically active they are also used as intermediates for many important organic hetero cyclic molecules possessing wide range of biological activity, as intermediates, coupling products26, N-alkylhydrazides27, 1, 3, 4-oxadiazolines28-30, 2azetidinones31 and 4-thiazolidinones.32,
33

N-Acylhydrazones are often

crystalline, can be purified by sometimes simple recrystallization but organic chemists have recently focused on their utility as electrophiles in

13

Chapter - 1

reactions with nucleophiles to get aza compounds. N-Acylhydrazones can be readily prepared, stored and act as stable imine surrogates in these reactions. N-Acylhydrazones act as good template for metal catalysts which improves stereo chemical control. N-Acyl hydrazones (16a) give N-acyl (17) and N-alkylhydrazines (18) along with derivatives34 according to the following (Scheme 1). Scheme 1

O Ar N H N R

LAH, THF Ar

O N H

H N

Ar

N H

H N

16a

17

18

N-Acyl

hydrazones

(16b)

give

only

N-alkylhydrazines

(19)35

according to the following Scheme 2 by using milder reducing agent sodium borohydride in place of lithium aluminium hydride. Scheme 2
O Ar N H N Ar SBH Ar O N H H N

Ar

16b Many effective (21), compounds, are such by as

19 iproniazide of (20) and

isocarboxazide

synthesized

reduction

hydrazide-

hydrazones. Iproniazide (20), like INH, is used in the treatment of

14

Chapter - 1

tuberculosis. It also displays an antidepressant effect and patients appear to have a better mood during the treatment.

HN NH O N O Me

H N

Me N H Me

Iproniazide (20)

Isocarboxazide (21)

Reductions of N-acylhydrazones to N-alkyl-N-acylhydrazines have also been accomplished with catalytic hydrogenation, reducing metals and boron, silicon or tin reagents.36 A variety of N-acylhydrazones can be allylated by tetra allyltin (22) in the presence of a Lewis acid catalyst. This reaction is tolerant to many functional groups, and homoallylic hydrazides (23) were obtained in high yield (Scheme 3). Scheme 3
R1 H N NHCOAr Sc(OTf)3 MeCN , RT HN R1 NHBz

Sn-(CH2-CH=CH2)4

16b

22

23

15

Chapter - 1

N-Acylhydrazones (24 and 25) can serve as azadienes in Aza-Diels Alder reactions and can participate in both intra and inter molecular [4+2] cycloaddition at high temperature ( Scheme 4) 37 to produce 26 and 27 respectively. Scheme 4
Me N MeN O 24 R N MeN O 25
1,2-Dichlorobenzene Reflux, 48 h 1,2-Dichlorobenzene Reflux, 48 h

Me N MeN O 26 O MeHN N MeN O 27 N

Cyclocondensation of arylidine hydrazones 16b with thioglycolic acid and thiolactic acid in dry benzene gives thiazolidinone derivatives 28 and thiazolidine derivatives respectively (Scheme 5). Scheme 5
38, 39

in 60-70% yield according to

O Ar N H N Ar Thiolactic acid Ar

O HN N

Ar S

O
16b 28

16

Chapter - 1

Substituted benzoic acid hydrazones 1b undergo cyclisation with phenoxy acetic acid in presence of thionyl chloride in dry benzene to furnish 3-phenoxy-2-azetidinones (29) (Scheme 6).40 Scheme 6
O O Ar N H N Ar PhOCH2COOH HN N Ar O Ar OPh

16b

29

Substituted 1, 3, 4-oxadiazolines 30 can be synthesized when hydrazones are heated in the presence of acetic anhydride (Scheme 7).41-43 Scheme 7
O Ar N H N Ar Ac2O Ar O N N Ar H

COCH3

1b

30

N-Acyl hydrazones (16b) give only N-alkylhydrazines (31)44 according to the following Scheme 8 by using milder reducing agent sodium borohydride in place of lithium aluminium hydride. Scheme 8
O Ar N H N Ar SBH Ar O N H H N

Ar

16b

31

17

Chapter - 1

The hydrocyanation of N-acylhydrazones (32) enables a practical access to - hydrazino acids (33) (Scheme 9). It was reported in 1990 that addition of hydrogen cyanide generated in situ to N- acylhydrazones proceeds efficiently in the presence of a phase transfer catalyst.45 Scheme 9
R1 R2 HN + NHCOR3 NaCN PTC, AcOH, H2O/hexane R1 NHCOR3 CN R2

32

33

Hydrazones are better radical acceptors than imines. Friested and Qin reported the diastereoselective reaction of chiral N-acylhydrazones (34) to give 35 with secondary and tertiary alkyl radicals in presence of a stoichiometric amount of zinc chloride as an activator and

tributylstannane as a radical mediator (Scheme 10). 46 Scheme 10

O N N Bn R1 H O O

R2I, ZnCl2, BEt3 Bu3SnH, -780C

R1 HN N

Bn R2

34

35

Trichloroacetic

acid

hydrazones

(36),

prepared

from

the

condensation of carbonyl derivatives mainly aromatic and , unsaturated aldehydes with trichloroacetic acid hydrazide are easily

transformed in 1, 3, 4 oxadiazole (37) derivatives when treated with

18

Chapter - 1

potassium carbonate (Scheme 11). 47 There is growing interest in 1, 3, 4oxadiazole derivatives as they possess broad spectrum biological activity. Scheme 11
H N O R N H
Dioxane, reflux,2 hr K2CO3 (3 EQV), TEBA (2% mol)

Cl2HC

O N N

Cl3C

36 1.1.5 Synthesis of Substituted hydrazones

37

The older methods for the synthesis of N-acylhydrazones involve the intermolecular dehydration of suitably substituted acid hydrazide and carbonyl compounds. The conditions for the dehydration are variable. Some of these methods are described below. All these approaches involve classic organic synthetic methodology and display typical organic reactivity patterns and selectivities. Recently, however, a number of new and potentially quite versatile methods have been developed for the synthesis of substituted N-acylhydrazones. A number of pyrazole analogues with 1, 3, 4-substitution pattern 38 were synthesized according to the following (Scheme 12) by A. H. Abadi and his co-workers48 and evaluated for their antitumor and

antiangiogenic properties.

19 Scheme 12
X O O N O N NH2 H NO2 NO2 X= H, X=Br 38 N N NH N N X

Chapter - 1

1-Phenyl-1H-pyrazole-4-carboxaldehyde (40) was obtained via Vilsmeier-Haack formylation of (39) in 65% yield. Condensation of 40 with phenyl acetic acid afforded the acid (41). The methyl ester of 41 reacted with hydrazide hydrate to obtain carbohydrazide (42) in 68% yields. It was dissolved in ethanol, different aldehydes were added and at the end of the reaction, the mixture was poured in ice to get the desired carbohydrazides (43) (Scheme 13).49 Scheme 13
Ar1 COOH CHO Ar N N N N N N MeOH, H
+

CONHNH2 Ar N N N Ar 1CHO N

CONHN Ar

NH2NH2 ,H2SO4

39

40

41

42

43

20

Chapter - 1

Acyl hydrazone derivaties of 7-hydroxy-2-oxo-2H-chromen-4-yl)acetic hydrazide (45) was prepared from acid hydrazide 44 according to the Scheme 14. 50 Scheme 14
O NHNH2 + O O OH ArCHO EtOH O N N CHAr H

OH

44

45

V.K Panday and his co workers synthesized acylhydrazones 47 by refluxing a mixture of acid hydrazide 46 and aromatic aldehydes in glacial acetic acid for few hours. The desired hydrazones 47 were isolated by pouring the crude mixture in cold methanol. The solid was filtered and recrystallised from ethanol (Scheme 15).51 Scheme 15
NH2 HN O R R1 R1 R O N H N H Ph

46 R H
O

47 Et
OH

H
OH

R1

CONH
N O

CONH

CONH

21

Chapter - 1

A series of N- aryl hydrazone derivatives of mefenamic acid (49), a known NSAID were synthesized by Ali Almasirad and co-workers.52 The hydrazide of mefenamic acid (48) was prepared by the following literature method.42,
43

An equimolar mixture of the hydrazide (48) and aldehydes

were dissolved in ethanol and stirred at room temperature for 0.5-1 hr in presence of two drops of conc. HCl. The hydrazones (49) were isolated by removing solvent under reduced pressure, followed by neutralization with 10% aqueous sodium bicarbonate (Scheme 16). Scheme 16
O NHNH2 NH Me Me EtOH + ArCHO Two drops of conc.HCl Me Me O NH N H NH Ar

48

49

Similarly, 2-phenoxybenzoic acid and N- phenylanthranilic acid hydrazides were synthesized and evaluated for the analgesic activities by treating equimolar mixture of hydrazides and aldehydes or ketones in ethanol in presence of 2 drops of HCl.53 The target compound (52) was prepared by acid catalysed condensation of aldehyde and ketone in high overall yield by synthetic sequence depicted in the Scheme 14. The regioselective condensation of 2-aminopyridine (50) with 2-chloroethylacetoacetate (51) produced

22

Chapter - 1

functionalized methyl ester imidazo [1, 2 ] pyridine 52 derivative in 93% yield. Treatment of methanolic solution of the ester with hydrazine hydrate at reflux gave desired acylhydrazine which underwent

condensation with aldehydes and ketones in ethanol using hydrochloric acid as catalyst (Scheme 17).54 Scheme 17
O N
52

Me N
50

NH2

O Cl
51

1.EtOH O Reflux, 20hr H N OEt 2.NH2NH2.H2O Reflux, MeOH

3.Ar-CHO

Me

N H

H Ar

The new N-acylarylhydrazone compounds 56 were obtained in diasteromeric form and the E form being major one. The base catalysed isomerisation of the double bond of safrole (53) followed by oxidative cleavage, it was converted into methyl ester 54 by treatment with 2.6 eqv of KOH and 1.3 eqv of iodine in methanol. The acylhydrazine intermediate 55 was obtained in 70% yield by treatment of an ethanolic solution of the ester 54 with hydrazine hydrate at reflux for 3.5 hr (Scheme 18).55

23 Scheme 18

Chapter - 1

O O

a) KOH, nBuOH b) O3 , AcOH,00C

O O

CHO I / KOH, 2 MeOH

O O

COOMe

53

54

N2H4.H2O
EtOH, Reflux

O O O NH N H ArCHO EtOH/HCl O O CONHNH2

55

Ar

56

Olsson and his co workers reported the discovery and initial SAR of potent and selective nonpeptidic small molecule PAR-2 agonists

(proteinase activated receptor). The hydrazide 58 was formed by adding hydrazine in ethyl ester 57 under microwave conditions. Finally the hydrazide 58 was condensed with 3-bromoacetophenone to get desired product 59 (Scheme 19).56 Scheme 19
Br Br O N2H4. H2O OEt MW, 1400C 20 min O 57 58 Br O O NHNH2 HN O 59 Br HN EtOH, AcOH O 10:1, 500C,16h Me NH N

HN

24

Chapter - 1

A library of 156 acyl hydrazones ( 62) was designed from commercially available aldehydes and hydrazides. The acyl hydrazones 62 synthesized in deep well plates at 10mol scale according to Scheme 20. In deep well plates different aldehydes 60 and hydrazides 61 were stirred at room temperature in DMF.57 Scheme 20
HO + OHC 60 R R1 NHNH2 O 61 OH DMF RT R N N H O R1

62

1.2 Section B A brief review on Sulphonamides 1.2.1 Introduction This section presents an introduction on the medicinal importance, synthesis and use of sulphonamides as synthetic tools in organic chemistry. The sulfonamide functionality is much more widespread in pharmaceuticals than just in an early class of antibiotics. Sulfonamides have been the subject of pharmaceutical interest as a result of their potent biological activities58 such as antihypertensive agent bosentan,59 phophodiesterase-5 inhibitor sildenafil60 and antiviral HIV protease inhibitor amprenavir61, anticancer, anti-inflammatory and antiviral gents.62

25 1.2.2 Chemistry and nomenclature of sulphonamides Sulphonamides are the derivatives of sulfonic

Chapter - 1

acids.

Sulphonamides are chemically quite stable, these are weak acids compared to carboxylic acid amides. The acidic nature results from the ability of the SO2 moiety to stabilize the nitrogen anion through resonance. The sulphonamide functional group is S(=O)2-NH2, a sulfonyl group connected to an imine group. The general formula is RSO 2NH2. Where R is some organic group. Any sulfonamide can be considered as derived from a sulfonic acid by replacing a hydroxyl group with an amine group. In medicine, the

term "sulfonamide" is sometimes used as a synonym for sulfa drug, a derivative or variation of sulfanilamide. 1.2.3 Medicinal importance of sulfonamides Sulfonamide scaffold is well known for the design of many synthetic compounds with diverse pharmacological properties. The presence of the Benzene ring that allows sulfonamides to partition through bacterial cell walls, Once inside of the bacterial cells, Sulfonamides must be ionizable, and contain both a positive and negative charge on opposite sides of its structure, which further resembles the structure of PABA and results in Binding of Sulfonamides

26 1.2.3a Antibacterial activity

Chapter - 1

Kumar and his team have given the synthesis of some Schiff bases63 of sulfonamides by condensing 4-amino benzene sulfonamide with different aromatic aldehydes in the presence of glacial acetic acid and ethanol at 50-600C. The antimicrobial activity of these compounds was evaluated by Agar diffusion method. Several Schiff bases derived from sulphonamide as shown good antibacterial activity.

SO2NH2 Ar-HC N

Ar = substituted aldehydes

63 1.2.3b Anti inflammatory activity Benzenesulfonamide64 derivatives carrying a pyrazole moiety were prepared by Abdel Aal et al which were structurally related to the COX-2 inhibitor celecoxib (Celebrex) and were found to be potent antiinflammatory agents with no or less tendency to evoke gastric ulceration. In these derivatives N-Ethyl-2-(3-methyl-5-oxo-4,5-dihydro-pyrazole-1carbonyl)-benzenesulfonamide (64) was found to be more active.

27

Chapter - 1

CH3 O N N

O SO2NHC2H5

64 1.2.3c Hepatitis C virus NS3 protease inhibitor Aryl bromide moiety65 represents a building block of a class of HCV NS3 protease inhibitors these were prepared by using Mo(CO)6 as a convenient CO-releasing group from aryl bromides with a primary sulfonamide exemplifying the use of amidocarbonylation method for potential analogue generation. When evaluated in an in vitro assay comprising the full-length NS3 protein, N-(4-Methoxy-benzoyl)-4-methylbenzenesulfonamide ( ) proved to be highly potent inhibitor with Ki value 85 7nM.
O O N H O S O

65 1.2.3d Growth Harmone Secretagogue Receptor High specific activity sulfur-35-labeled sulfonamide66 radioligand (66) has been developed by Dean and his co-workers for the

identification of a GH secretagogue receptor. [35S]-MK-0677 was found to

28

Chapter - 1

possess the necessary combination of high selectivity, affinity and specific activity required for utilization as a radioligand in the study of this newly discovered receptor.

H H N CO N O

NH2

SO2CH3

66 1.2.3e Antiglaucoma drugs A new series of sulfonamide67 (CA) inhibitors by reacting arylsulfonyl chlorides with aromatic/heterocyclic sulfonamides

possessing a free amino/imino/hydroxyl group were given by Andrea and his co-workers. Sulfonamide 67 showed strong affinities toward isozymes I, II, and IV of carbonicanhydrase (CA), and also showed strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomtous rabbit eye, as 2% water solutions.

H2NO2S

O H 2N S NH O

67

29 1.2.3f Cancer-Associated Carbonic Anhydrases (CAs)

Chapter - 1

Neoglucoconjugate68 a new class of sulfonamide (68) link was designed by Marie and his co-workers to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. The

carbohydrate fragment in these compounds is linked to the classical aromatic sulfonamide CA pharmacore to target inhibition of cancerassociated CAs. The CA inhibitors designed were very good CA IX inhibitors and potent CA XII inhibitors.

OR RO RO O X OR N H SO2NH2

X= R=

SO2 H 68

S Ac

1.2.3g Antimicrobial activity Iqbal and his team synthesized benzene sulphonamides69 bearing 2,5-distubstituted-1,3,4-oxadiazole moiety and tested for antimicrobial and antifungal activity for all the compopunds. Compound 69 exhibited significant antibacterial and antifungal activities due to the presence of a chloro group on position 4 of the phenyl substitutent, free SH group at position 5 of the oxadiazole ring, the free NH2 group of the sulphonamido moiety.

30

Chapter - 1

O Cl O H2N N S O N

SH

69 1.2.3h -Lactamase inhibitors Eidam and his team has given new sulfonamide boronic acids70 (70) derived from the conversion of the canonical R1 carboxamide retain substantial inhibition activity against -lactamases, they also rescued antibiotic resistance when used in combination with third generation antibiotics in bacterial cell cultures. This superficially modest

substitution changes the geometry of the inhibitors enough to scramble the SAR observed in the analogue carboxamides.

H N R O S O B HO OH

R=

CH3

Ph

Substituted phenyls

70 1.2.3i Protein Kinase Inhibitors The isoquinoline sulphonamide derivatives (71) given by Hidaka and his team had ability to inhibit protein kinases, Some of the derivatives71 exhibited selective inhibition toward a certain protein

31

Chapter - 1

kinase. The inhibitors were freely reversible and of the noncompetitive type with respect to the phosphate acceptor. . The

isoquinolinesulphonamides structurally unrelated to ATP, compete with ATP for free enzyme but do not interact with same enzyme form as does the phosphate acceptor.

O S N O R

R=

N NH

H N

H2N
NH

HN

N NH

71 1.2.4 Synthesis of sulphonamides Gopalsamy and his co-workers has prepared diarylsulfone

sulfonamides 73, from diarylsulfonyl chlorides 72 and phenylethyl amine in the presence of Et3N and CH2Cl2 at 370C for 16 hr to yield 82% of diarylsulfone sulfonamides72 (Scheme 21). Scheme 21
O S O O S O Cl O Phenylethyl amine Et3N, CH2Cl2, 370C S O O S O NH

72

73

32

Chapter - 1

A two step synthesis of pentadentate tetraionic based ligands 74 based on sulfonamide, amide and pyridyl groups is reported by Karno and his team. These ligands are easily accessible in good to excellent yield from commercially available materials (Scheme 22). Scheme 22
R O2S NH NH2 Cl O O Cl N Et3 N, CH 2Cl2
73

NH3 tartrate NH3 ClSO2 R

2 equiv NaOH

O N H HN SO2R

H N O

HN SO2R

74

Bahrami and his co-workers has given the direct oxidative conversion of thiol derivatives to the corresponding sulfonyl chlorides through oxidative chlorination, using valuable reagent H2O2-SOCl2, this upon reaction with amines to yield sulfonamides 75 in excellent yields (Scheme 23).
74

Scheme 23
R S H2O2 - SOCl2 H CH3CN, rt O O S R Cl R'NH2 Et3N O O S R' R N H 75

R = alkyl, aryl

33

Chapter - 1

A series of novel disulfonamide derivatives 77 were synthesized by Behmadi and his co-workers and characterized by FT-IR, 1HNMR and MS techniques. In order to prepare new disulfonamides, at first they have synthesized new diamines containing a pyridine ring 76. Then, they have been reacted with sulfonyl chlorides to give corresponding

disulfonamides (Scheme 24).75 Scheme 24

R R

R'SO2Cl
N H2N
76

Et3N, THF
RT HN O S O R' N NH O S O R'

NH2

77

-fluorosulfonamides 79 were prepared by Taylor, Yong and Bryan by electrophilic florination of tertiary sulfonamides using N-

fluorobenzenesulfonimide as fluorinating agent. First benzene sulfonyl chloride was reacted with secondary amines in the presence of Et3N and cat. DMAP in THF and then florination (Scheme 25). Scheme 25
O S Cl Et3N O DMAP, THF R N H R' O R S N R' NHMDS O NFSi, THF R2 O R S N R' O 79
76

34

Chapter - 1

One-Pot synthesis of aromatic and heteroaromatic sulfonamides77 was given by pandya and is co-worders, analogues were prepared from aryl and heteroaryl bromides 80 by converting to Grignard reagent using isopropylmagnesium chloride or magnesium bromide and reacting with sulfuryl chloride, sulfur dioxide and an amine to give sulfonamide 81 analogues (Scheme 26). Scheme 26
Mg, Et2O, iPrMgCl SO2, SO2Cl2, NHR2

O Ar

Ar Br 80

O NR2

R = alkyl, aryl

81

Deng and Mani has given an environmentally benign synthesis of sulfonamide 82 in water by reacting amino and aminobenzoic acids with sulfonyl chlorides by maintaining the PH at 8.0 using 1 Mol L-1 Na2CO3 in water and to get the yield PH was adjusted to 2.0 by using Conc. HCl to get 98% yield using 5% Bu4N+Br- as a phase transfer catalyst as the amines are less soluble in water (Scheme 27). Scheme 27
5% Bu4N+Br H2O, PH 8.0 SO2Ar SO2Ar
78

R1 NH2

Ar

SO2Cl

H R1 N SO2Ar 82

R1 N

R1 = amine, aminoacid

35

Chapter - 1

A series of arene and alkane sulfonamides 83 were prepared by Kataoka by treating the sodium sulfonates with triphenylphosphine dibromide followed by treating wit amines in the presence of sulfonyl halides and triethylamine to yield sulfonamides (Scheme 28).79 Scheme 28
PhSO3Na Ph3P.Br2 CH3CN R1 = PhCH2, Et, H R2 = H, Et PhSO2Br R1R2NH Et3N, O0, rt PhSO2NR1R2 83

A series of aryl N-aminosulfonamides80 84 was given by Nguyen and his team With palladium-catalyzed three-component coupling of aryl iodides, hydrazines and a crystalline solid DABCO.(SO2)2 as a convenient source of sulfur dioxide which is easy to handle and employ only a slight excess of sulfur dioxide (Scheme 29). Scheme 29
O S O N H N O

I H2N Me (DABCO).(SO2)2 N O

Pd(OAc)2, P Bu3 700C

Me

81 Wright and Hallstrom as reported the conversion of heteroaryl thiols to heteroaryl heteroaryl sulfonyl chlorides by using NaOCl, HCl

36

Chapter - 1

and by reacting with excess of benzylamine at -50 to -250C to sulfonamides81 (Scheme 30). Scheme 30

N N

NaOCl, HCl Bz NH2

N N O S

H N O

82 An easy and handy synthesis of sulfonamides 83 directly from sulfonic acids or its sodium salts is reported by Luca and Giacomelli. 2,4,6-Trichloro-[1,3,5]-triazine was added at room temperature to a solution of benzenesulfonic acid sodium salt in acetone dry and 18crown-6 and the mixture was irradiated to 800C for few min in sealed tube to yield sulfonamides (Scheme 31).
82

Scheme 31
O S O ONa O 1. TCT, 18-crown-6, acetone 2. HNR1R2 NaOH , THF S O NR 1R 2

84

85

A mild and efficient reaction of amine derived sulfonate salts in the presence of cyanuric chloride, triethylamine as base, and anhydrous acetonitrile as solvent at room temperature gives the corresponding sulfonamides 86 in good to excellent yields (Scheme 32).
83

37 Scheme 32

Chapter - 1

86

1.3 Section C A brief review on Sulphonates 1.3.1 Introduction to sulphonates Sulfonic esters are used as reagents in organic synthesis, chiefly because the RSO2O- group is a good leaving group in Sn1, Sn2, E1 and E2 reactions. Methyl triflate, for example, is a strong methylating reagent. They are commonly used to lend water solubility to protein crosslinkers such as N-hydroxysulfosuccinimide (Sulfo-NHS), BS3, SulfoSMCC, etc. 1.3.2 Chemistry and nomenclature of sulphonates Esters with the general formula R1SO2OR2 are as a category called sulfonic esters, with individual members of the category being named analogously to how ordinary carboxyl esters are named. For example, if the R2 group is a methyl group and the R1 group is a trifluoromethyl group, the resulting compound is methyl trifluoromethane sulfonate.

38 1.3.3 Synthesis of sulphonates Enantiopure -substituted sodium sulfonates

Chapter - 1

without

any

racemization using polymer bound triazenes based on triazene T2* linker was performed by Vignola and his co-workers in the presence of alkylating resin. Without any purification all products 87 were obtained in good yield and in excellent purities (Scheme 33). Scheme 33
84

87 Alkyl trifluoromethyl sulfonates85 (triflates) 89 are prepared by taking a solution of phenol 88 and phenyl bis[(trifluoromethyl)sulfonyl] amine in dichloromethane is triethylamine is added keeping in an ice bath, and stirred for 1hr at 0 0 C and warmed to room temperature and the reaction is stopped by addition of diethyl ether, and the organic layer washed with water (Scheme 34).

39 Scheme 34
OH SO2CF3 Ph N SO2CF3 CO2Me HN Boc HN CH2Cl2 CO2Me Boc TEA O SO2CF3

Chapter - 1

88

89

To a cooled solution of dry pyridine in alcohol triflic anhydride was added dropwise at a rate to maintain a reaction temperature of 0-20C and after the addition it was stirred at 00C for 30 min at room temperature and the volatiles are removed in vacuo, and residue obtained was extracted with ether (Scheme 35) to get the

trifluoromethane sulfonates 90 (triflates).87 Scheme 35

F R OH F F O S O O O F S Pyridine O F F F F

O S O O R

90

The triethylamine and alcohol were dissolved in dichloromethane and cooled to 00C and methane sulfonyl chloride taken in CH2Cl2 was added dropwise over 30 min and stirred at room temperature until the reaction was completed it was poured into 0.5 M NaHCO3 and it was extracted with CH2Cl2 and washed with brine to get the methyl sulfonates 91 (mesylates) (Scheme 36).87

40 Scheme 36

Chapter - 1

91 The useful protecting group for the construction of sulfonate88 containing analogs 92 of nucleosides was found to be isobutyl ester. Synthesis of useful uridine or adenosine 3-C-methanesulfonate analogs were readily achieved with the isobutyl ester as a protecting group (Scheme 37). Scheme 37

92 The regioselective 1,3-dipolar cycloaddition of -bromo-

pentafluorophenyl vinyl sulfonate with nitrile oxides has been used to rapidly access a range of 3,5-isoxazoles which could be converted directly to their corresponding sulfonates (Scheme 39).89 Scheme 39

41

Chapter - 1

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