1 Chapter - 1

CHAPTER 1

A Brief Overview of Synthesis and

Pharmacological Activities of

Substituted Hydrazones, Sulphonamides

and Sulphonates

2 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

3 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=NNH-

hydrogen 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).

4 Chapter - 1

HN

O

N

H

Ar

HN

O

N

Ar

H

E-Isomer Z-Isomer E-Isomer Z-Isomerap-rotamer ap-rotamer sp-rotamer sp-rotamer

HNN

HO

ArHN

N

ArO

H

1.1.3 Medicinal importance

Substituted acyl hydrazones show a variety of biological activity,

such as analgesic, anti–inflammatory, 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 Chapter - 1

1.1.3a Anticonvulsant Activity

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

CR3N

HNCH3C

O

R1

R2

CR3N

HNCC

O

H2N

O

1 2

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

6 Chapter - 1

tissues. There have been many reports on the antidepressant / MAO-

inhibiting the activity of hydrazones derived from substituted hydrazides

and reduction products. Ten new arylidenehydrazides15 3-phenyl-2,3-

dihydro-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.

N NH

O

NH

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 μmol/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 μm concentration, indicating that these series of

7 Chapter - 1

compounds can act as Ca+2 scavenger depending on the nature of the

aryl moiety present at the imine subunit.

NNHN

HO

4

1.1.3d Antiplatelet activity.

Novel tricyclic acylhydrazone derivative17 (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 10µM,

presenting respectively 10.4 and 13.6% of inhibition of the PAF-induced

platelet aggregation.

NN

SH3C

OH

O

NH

NAr

H

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

8 Chapter - 1

the aroylhydrazone chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl

hydrazone18 Isonicotinic acid (2-hydroxy-naphthalen-1-ylmethylene)-

hydrazyde (6) showed greater anti malarial agent activity than

desferrioxamine against chloroquine-resistant and sensitive parasites.

NHN

O

N

OH

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 μg/ml.

HN

N

N

S

O

HN N

CH3

C2H5

O

O

HN

N

N

O

O

HN N

CH3

C2H5

O

O

7 8

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

9 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-Dimethyl-

phenylamino)-benzoic acid(2-hydroxy-benzylidene)-hydrazide (10) was

found to be the most active.

NH

NHO

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 Chapter - 1

X

O

NH

N

R

Ar

R'

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 co-

workers. 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 ERRγ FRET assay with an 40-55% increase in coactivator peptide

recruitment. The ERRγ activity is highly sensitive to substitution at R1.

The optimal substituents were 4- iPr and 4-NEt2.

NH

O

N

R3R2

R1

R1 iPr OtBu N-Et2

R2 4-OH 4-NH2 H

R3 H Me

12

11 Chapter - 1

1.1.3j Antimycobacterial activity

Cocco and his team has reacted Isonicotinoylhydrazones further

pyridinecarboxaldehydes to give the corresponding

pyridymethyleneamino derivatives23 (13) The new 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 µg/mL) which was 1NH resistant.

O

N

N

NH

Py

O

N

R

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 Chapter - 1

NNH

HO NO2

NO2

14

1.1.3l Vasodilator activity

A new bioactive compound of the N-acylhydrazone25 class, 3,4-

methylenedioxybenzoyl-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

NH

O

N SR

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, 2-

azetidinones31 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

Ar

O

NH

N RAr

O

NH

HN R

Ar NH

HN R

+

LAH, THF

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

Ar

O

NH

N ArAr

O

NH

HN Ar

SBH

16b 19

Many effective compounds, such as iproniazide (20) and

isocarboxazide (21), are synthesized by reduction of 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.

N

OHN

NH

Me

Me

HN NH

N

O

O

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+

HNNHBz

R1

, RT

Sc(OTf)3

MeCNSn-(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

N

MeN

O

Me

1,2-DichlorobenzeneReflux, 48 h N

MeN

O

Me

N

MeN

O

R

1,2-DichlorobenzeneReflux, 48 h

N

MeN

O

R

N

O

MeHN

24 26

25

27

Cyclocondensation of arylidine hydrazones 16b with thioglycolic

acid and thiolactic acid in dry benzene gives thiazolidinone derivatives 28

and thiazolidine derivatives respectively 38, 39 in 60-70% yield according to

(Scheme 5).

Scheme 5

Ar

O

NH

N Ar Thiolactic acid Ar

O

HN NS

O

Ar

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

Ar

O

NH

N Ar Ar

O

HN N

O

OPh

Ar

PhOCH2COOH

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

Ar

O

NH

N ArN N

OAr

Ar

H

COCH3

Ac2O

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

Ar

O

NH

N ArAr

O

NH

HN Ar

SBH

16b 31

17 Chapter - 1

The hydrocyanation of N-acylhydrazones (32) enables a practical

access to α- 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

N

NHCOR3

+ NaCN

PTC, AcOH, H2O/hexane R1

CNR2

HNNHCOR3

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

N

OO

Bn

N

H

N

OO

Bn

HN

R1 R2R1

R2I, ZnCl2, BEt3

Bu3SnH, -780C

34 35

Trichloroacetic acid hydrazones (36), prepared from the

condensation of carbonyl derivatives mainly aromatic and α, β-

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, 4-

oxadiazole derivatives as they possess broad spectrum biological activity.

Scheme 11

Cl3C

O

NN

R

H

K2CO3 (3 EQV), TEBA (2% mol)

Dioxane, reflux,2 hr

N N

OCl2HC

RH

36 37

1.1.5 Synthesis of Substituted hydrazones

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 Chapter - 1

Scheme 12

NO2

NN

O

X

O

NH

NH2

NO2

NN

N

X

NHO

X= H, X=Br 38

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

NN

NN

CHO

NN

COOH

Ar

MeOH, H+ NN

CONHNH2

Ar

NN

CONHN

Ar

Ar1

Ar1CHONH2NH2 ,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

OO

O

NHNH2

+

OH OO

O

NH

OH

N CHAr

ArCHOEtOH

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

R

R1

O

HN

NH2

R

R1

O

NH

N

H

Ph

46 47

R H Et

H

R1

O

N

O

CONH

OH

CONH

OH

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

NH

Me

Me

O

NHNH2

+Two drops of conc.HCl

NH

Me

Me

O

NH

N H

Ar

ArCHOEtOH

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 α] 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

NNH2 O

Cl OEt

OMe 1.EtOH

Reflux, 20hr

2.NH2NH2.H2O NNH

MeN

O

50 51 52

H

Reflux, MeOH

3.Ar-CHO

Ar

H

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 Chapter - 1

Scheme 18

O

O

a) KOH, nBuOH

b) O3 , AcOH,00C

O

O

CHO I2/ KOH, O

O

COOMe

EtOH, Reflux

O

O

CONHNH2O

O

O

NH

N

Ar

H

5655

MeOH

N2H4.H2O

ArCHO

53 54

EtOH/HCl

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

HN

O

OEt

O

Br

HN

O

NHNH2

O

Br

HN

O

NH

O

N

Me

Br

MW, 1400C

20 min

EtOH, AcOH

10:1, 500C,16h

N2H4. H2O

595857

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 10µmol 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

R

HO

OHC

+

R1

NHNH2

O RN

NH

O

R1

OH

60 61 62

DMF

RT

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 Chapter - 1

1.2.2 Chemistry and nomenclature of sulphonamides

Sulphonamides are the derivatives of sulfonic 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 RSO2NH2.

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 Chapter - 1

1.2.3a Antibacterial activity

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

NAr-HC

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 anti-

inflammatory agents with no or less tendency to evoke gastric ulceration.

In these derivatives N-Ethyl-2-(3-methyl-5-oxo-4,5-dihydro-pyrazole-1-

carbonyl)-benzenesulfonamide (64) was found to be more active.

27 Chapter - 1

N

O N

CH3

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-methyl-

benzenesulfonamide ( ) proved to be highly potent inhibitor with Ki value

85 ± 7nM.

O

O

NH

SOO

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.

O

HN

NH2

CO

H

O

N

NSO2CH3

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.

H2N S NH

O

O

H2NO2S

67

29 Chapter - 1

1.2.3f Cancer-Associated Carbonic Anhydrases (CAs)

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 cancer-

associated CAs. The CA inhibitors designed were very good CA IX

inhibitors and potent CA XII inhibitors.

ORO

RO

OR

ORX

NH

SO2NH2

X = SO2 S

R = H Ac

68

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

Cl

NN

O

S

SH

O

O

H2N

69

1.2.3h β-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 β-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.

R S

HN

BOHHO

O O

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.

S

O

ONR

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

SO O

SCl

O O

Phenylethyl amine

Et3N, CH2Cl2, 370C

SO O

SNH

O O

72 73

R =

N

N

NH

HN

NH

H2N

HN

N

NH

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). 73

Scheme 22

NH3

NH3

tartrate ClSO2R

2 equiv NaOH

Et3N, CH2Cl2

NH

NH2

O2SR

N

O

Cl

O

Cl

NH

O

HN

O

HN

HN SO2R

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

RS

H

H2O2 - SOCl2

CH3CN, rt RS

Cl

O O R'NH2

Et3N RS

NH

O OR'

R = alkyl, aryl75

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

N

H2N NH2

R

R'SO2Cl Et3N, THF

RTN

HN NH

R

SS OO OO

R' R'76 77

α-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). 76

Scheme 25

S Cl

O

O DMAP, THF

N

H

R'R

Et3NS N

O

O

R

R' NHMDS

NFSi, THF

S N

O

O

R

R'

FR2

79

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

Ar BrMg, Et2O, iPrMgCl

SO2, SO2Cl2, NHR2

ArS

NR2

O O

R = alkyl, aryl81

80

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). 78

Scheme 27

R1 NH2 Ar SO2Cl R1

HN SO2Ar R1 N

SO2Ar

SO2Ar

5% Bu4N+Br -

H2O, PH 8.0

R1 = amine, aminoacid82

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

PhSO3NaPh3P.Br2

CH3CNPhSO2Br

R1R2NH

Et3N, O0, rtPhSO2NR1R2

R1 = PhCH2, Et, H

R2 = H, Et

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

Me

I

N OH2N

(DABCO).(SO2)2

SNH

N

OO O

Me

Pd(OAc)2, PtBu3

700C

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

S

HN

O 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 18-

crown-6 and the mixture was irradiated to 800C for few min in sealed

tube to yield sulfonamides (Scheme 31). 82

Scheme 31

SO

O

ONa

1. TCT, 18-crown-6, acetone

2. HNR1R2 NaOH , THF

SO

O

NR1R2

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 Chapter - 1

Scheme 32

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, Sulfo-

SMCC, 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 Chapter - 1

1.3.3 Synthesis of sulphonates

Enantiopure α-substituted sodium sulfonates 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). 84

Scheme 33

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 00 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 Chapter - 1

Scheme 34

OH

CO2Me

HN Boc

Ph N

SO2CF3

SO2CF3 TEA

CH2Cl2

O

CO2Me

HN Boc

SO2CF3

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

R OH S O

SO

O

OO F

FF

F

F

F PyridineF

F

F

S O

R

O

O

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 Chapter - 1

Scheme 36

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 α-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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