Cytotoxin- Inhibits DNA-topoisomerase enzymes

Happy Tree
(China)

CO-301 Heterocyclic
Chemistry
Convenor
Dr. Fawaz Aldabbagh
http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm
 Definition: Heterocyclic compounds are organic
compounds that contain a ring structure containing atoms
in addition to carbon, such as sulfur, oxygen or nitrogen,
as the heteroatom. The ring may be aromatic or non-
aromatic

Significance – Two thirds of all organic compounds are

aromatic heterocycles. Most pharmaceuticals are heterocycles.

Examples
Pfizer: Viagra

Quinine
Erectile dysfunction
Treatment of malaria for 400 years (Peru)
 H
N NHMe
N
N
Me NC
N
H Treating stomach & intestinal ulcers

Camptothecin Analogues

Pfizer - Irinotecan GSK - Topotecan

Ovarian & lung cancer

More soluble & less side-effects
 When Is A Molecule Aromatic?
• For a molecule to be aromatic it must:
• Be cyclic
• Have a p-orbital on every atom in ring
• Be planar
• Posses 4n+2 p electrons (n = any integer)

benzene naphthalene

Erich Hückel
+

[14]-Annulene
cyclopropenyl cation
 Six Membered Heterocycles: Pyridine

N N
H
pyridine piperidine

Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)

Hybridization = sp2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
Pyridinium ion: pKa = 5.5
1
H NMR: δ Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
H 7.5
H H 7.1 Pyridine is a weak base
Pyridine is π-electron deficient
H N H 8.5 Electrophilic aromatic substitution is
difficult
pyridine Nucleophilic aromatic substitution is easy
 Pyridine as a nucleophile

Me I
_
N N+ I
Me

Use Pyridine as a solvent to make esters

O O
Pyr 1
+ R1-OH R
R X R O

X = OAc, Cl, Br
N+
E.g.
O O OH
Pyr
O O R
+
O O Acyl pyridinium ion
Reactive intermediate
 H3 C CH3
DMAP (DimethylAminoPyridine) N
Whereas acylations “catalyzed” by pyridine are
normally carried out in pyridine as the reaction
solvent. Only small amounts of DMAP are required
to do acylations
N

Attempted Electrophilic Aromatic Substitution

i
i NO2

N+ N N
H i, HNO3, H2SO4
Unreactive, Stable
O
ii
ii R

N+ N N
_ ii, AlCl3, RCOCl
AlCl3
How can we nitrate pyridine?
NO2
H2O2, AcOH HNO3, H2SO4

N N+ N+
_ _
O O
Pyridine N-oxide
85%
We now have an activating and protecting group
_
O N O O
+ +
Mechanism O N H

N+ N+
_
O O

NO2 NO2
PPh3
+ O PPh3
N+ N
_
O 75%
 Nucleophilic Substitution at 2- and 4-positions of
pyridine is most favoured
_
Nu
Nu
N Cl N
_ Cl N Nu

E.g. PhSH, NEt3

N Cl N SPh
93%

Br NH2
Br Br
NH3 (aq)

N N
65%
 Five Membered Heterocycles: Pyrrole

Aromatic: Thus, 6π electrons

1
H NMR: δ Sp2 hybridised and planar
Lone pair tied up in aromatic ring
H H 6.2
Pyridine is π-electron excessive
Thus, Electrophilic Aromatic Substitution is Easy
H N H 6.5
Nucleophilic Substitution is Difficult
H
Pyrrole
 Electrophilic Aromatic Substitution preferred at the 2-position
NO2
AcONO2, AcOH/ -10 C
+
NO2
N N N
H H H
Normal acidic nitration causes polymerization 51% 13%

Vilsmeier Reaction
1. POCl3
O 2. Na2CO3, H2O
+ H
N H NMe2
N
H O
H
59%

O O
Me Me
Ac2O, AlCl3 NaOH (aq)
rt
N N N
SO2Ph SO2Ph 82%
H
Electron-withdrawing group allows substitution at the 3-position
Organic Synthesis with Pyrrole should avoid strong acids

H
H+
H N+ N
N
H H
H
H
reaction continues to give polymer

H N N+
H H

N N Cl
H H 80%
i; 1 X SO2Cl2, Et2O
Cl Cl
ii; 4 X SO2Cl2, Et2O
ii
N Cl N Cl
H H 80%
 Indole
Aromatic due to 10 π-electrons
Benzene part is non-reactive
N Electrophilic aromatic substitution
H occurs at the 3-position
CHO
Indole Vilsmeier

N N
55%
H H
Indole Alkaloids

O OCONH2
H 2N OMe

Me N NH

O
Lysergic acid (LSD) Strychnine Mitomycin C
 Other Five Membered Heterocycles

N S O
H Thiophene Furan
Pyrrole

The least aromatic:

Least reactive The O atom is too electronegative

More aromatic than Furan Less reactive than pyrrole,

but substitution always at 2-
position

Electrophilic Substitution, not addition

Can give addition, as well as substitution products when

reacted with E+

Thiophene has similar reactivity to benzene

 Electrophilic Aromatic Substitution of Thiophene
Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

HNO3, AcOH, Ac2O / -10 C

NO2
S S
85%
1. POCl3
O 2. Na2CO3, H2O
+ H
S H NMe2
S
68% O

Cl
SO2Cl2, heat
Cl Cl
S S S
43% 10%
 Some Reactions of Furan
ZnCl2, 100 C
O
+
S S
O O
83% O
Furan is more reactive than thiophene
O
ZnCl2, 0 C
+
O O
O O
O
95%

Br Br
Br2, CCl4 Br2, MeOH MeO OMe
Br O Br O
O H H
not a clean reaction
Addition product
H+, H2O Wittig reaction
OHC CHO
Ph3P OHC
_
Hydrolysis of acetal + O CHO
Furan is easily cleaved to dicarbonyls
OHC
CHO
 The Diels-Alder Reaction

O O

100 C
+ O O
benzene
Diene
4π system O 100% O
dienophile
2π system 4+2π cycloaddition Otto Diels

Electron rich
Electron poor
O O

30 C
H H
+

100% Kurt Alder

Noble Prize in 1950
 The configuration of the dienophile is retained
O
H
H CO2Me
OMe
+
OMe
H CO2Me
H
O
Always reacts via the cis-diene
O
H
H CO2Me
+ MeO
OMe
H CO2Me
H
O
O H O

25 C
+ O O

100%
H O
O

H
H endo product
O (100%)

O O Under kinetic control

 Furan readily undergoes the Diels-Alder reaction with maleic anhydride
O

Thermodynamic
endo-product O exo-product forms as the
O
temperature is raised
O
More stable due to steric reasons

Aromaticity prevents thiophene from taking part in the Diels-Alder reaction

O
S O
O - SO2
S +
O X
X
X

This sulfone is not aromatic & very reactive

 Five-membered Rings with Two or More Nitrogens

N pKa = 14.5
Diazoles
N (imidazole)
N N pKa = 16.5
H H (pyrrole)

Pyrazole Imidazole
Imidazole is more basic than pyridine, but more acidic than pyrrole

H H
N+ N
Imidazole + H+
N N
H H

N _
NaOH N
Imidazole - H+
- H 2O _
N N

Properties: Very stable cation and anion of imidazole is formed

 Some Natural Imidazole Compounds
Histidine

Important ligand to many metalloproteins

Is one of the essential amino acids.

A relatively small change in cellular pH can result in a change in its charge

Body neurotransmitter & local immune response

histamine
histidine carboxylase

Dipeptide in high concentrations in the brain & muscles

- Improves social interactions & treatment of autism
Carnosine
 Synthesis of 2- and 5-Nitroimidazole Antibiotics

2-Nitroimidazole, “azomycin”

N N N N
(i) (ii) (iii)

N N N NO2 NO2
N
H CPh3 CPh3 H 30%

• ClCPh3, NEt3 (ii) Bu-Li, n-PrONO2 (iii) HCl (aq), MeOH

5-Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections

O2N O O2N
4
N (i) N N N
+
Me N Me O2N 5 Me Me
N 80% N N
H H
Two tautomeric forms
OH OH
metronidazole inactive
(i) HNO3, H2SO4
Triazoles Weakly basic like pyridine, but more acidic than imidazole
H
H
N N N N N
N
N N
N N N
N
H 1,2,4-Triazole
H
1,2,3-Triazole
pKa = 10.3

Tetrazoles Only one isomer now possible

H
N N N N
N N
R R
N N
pKa ~ 5 ~ RCOOH
H
_
N N N N N N
etc
N N N
R R R
N N N
_
H
 Tetrazoles are used in drugs as replacements for CO2H

H
O H N N
N
O N
Me
Me O
N
N
O
O
Cl
Indomethacin Cl
Tetrazole derivative

Anti-arthritis drug
- Non steroidal anti-inflammatory drug –
reduces fever, pain, stiffness, delays
premature labour & other uses
 Bioreductive Anti-Tumour Agents
O OCONH2 O
10
O
H2N OMe N N
1 OR
Me N NH Me N

O O
Mitomycin C Pyrrolo[1,2-a]benzimidazole (PBI)
IC50 ≈ 1.0 µM E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211
K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235

O O
More selective to hypoxia
Hypersensitive to Fanconi Anemia
N N

N N N Tr
( )n
O O

IC50 ≈ 0.001 µM L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.

M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218

S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196
Targeting Hypoxic Cells
 Mitomycin C (MMC)
SET - activation

O 10 OCONH2 O OCONH2 O
H2N OMe H2N steps H2N DNA
+ 1 e- OMe - 1 e-
1
Me N NH - 1 e- Me N NH N
Me
O O. DNA alkylation O NH2
CY P450 reductase

Two electron activation

O OCONH2 OH OCONH2 OH
H2N OMe H2N OMe H2N DNA
-
+2e
Me N NH + 2 H+ Me N NH Me N
DNA alkylation
O OH OH NH2
DT-diaphorase

S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477