3 . ACTIVATION OF CARBOXYL GROUPS USING

2-MERCAPTOBENZOTHIAZOLE

3.1 Introduction

Activation of carboxyl group is one of the important

steps in peptide synthesis. l5 This is usually done by

converting the acids to azides, 20 mixed anhydrides, 25 acid

halides, l8 active esters 3 3 atc. These usual classical

methods require rigorous conditions such as the use of a

base, temperature etc. which make the synthesis much more

difficult. To activate carboxyl group with a mild precursor

for peptide synthesis is a real task, nowadays.

Photochemical activation approach is a mode of

activating carboxyl group in a mild way. For this approach

excited state behaviour of the functional group is utilised.

A chromophore which is sensitive to light at the same time

stable to most t>f the wide variety of chemical reagents used

in common organic synthesis, is suitable for photochemical

activation. Here, the wavelength of light used is absorbed

only by the activating group without affecting the integrity

of the other parts of the molecule. Moreover, the

photoreaction of the activating chromophore poses no

problems to the substrate and photoproduct

separable. Therefore, in order to achieve

activating carboxyl group under mild and neu

a number of groups have been designed a

applied in the synthesis of peptides, 7 5 , 7 6

and carbohydrates 79780. However, no attemp

for the easily accessible heterocyclic thiol

benzothiazole - which in principle could be successfully

used for the photochemical mode of activation.

Thus, this chapter is mainly devoted to investigate the

usefulness of 2-mercaptobenzothiazole (1) as a mild carboxyl

activating group.

This chapter also describes

i) the derivatization of compound 1 with different

carboxylic acids, both aliphatic and aromatic.

ii) characterisation of this derivatized 3-acyl

benzothiazoline-2-thione using different analytical and

spectral techniques.

iii) aminolysis and alcoholysis of 3-acyl benzothiazoline-2-

thione under different experimental conditions, the

main purpose of this reaction is not the preparation

of simple amides and esters through a complicated

route, but to illustrate the suitability of 3-acyl

benzothiazoline-2-thiones as carboxyl activated

component.

iv) selective aminolysis of 3-acyl benzothiazoline-2-thione

using amino alcohol.

V ) delineating mechanistic pathway for the formation of

amides and esters under different conditions.

3.2 Results and Discussion

3.2.1 Synthesis of 3-benzoyl benzothiazoline-2-thione (ha)

The derivatization of 2-mercaptobenzothiazole (1) was

carried out by the DCC coupling method 51 (Scheme 3.1).

Here, to an equimolar solution of benzoic acid (3a) and 2-

mercaptobenzothiazole (1) in THF and methylene chloride

mixture (1:4), an equivalent amount of DCC in methylene

chloride was added with stirring in an ice bath for half an

hour. The precipitated dicyclohexyl urea (DCU) was filtered

off. The concentrated mixture was separated using silica

gel column. The separated product as evidenced by tlc was

recrystallised from alcohol to afford yellow crystals with

m.p. 125 OC in 78% yield. This was characterised as 3-

benzoyl benzothiazoline-2-thione ( h a ) from different

analytical and spectral methods.

Both N-acyl and S-acyl derivatives are possible during

DCC coupling reaction. In analogous coupling reaction with

thiazolidine-2-thione it was proposed that S-acyl

derivatives first formed undergo S-->N thermal rearrangement

and the thermodynamically more stable N-acyl derivatives are

obtained. Thus, in close analogy with thiazolidine-2-

thi~nes,'~ the mechanism of DCC coupling reaction can be

proposed as in Scheme 3.1.

Scheme 3.1

U V a b s o r p t i o n s p e c t r u m o f t h e p r o d u c t i n c h l o r o f o r m

s o l u t i o n showed h max a t 296 nm (Fig. 5 . 2 in Chapter 5 ) .

I t g a v e I R a b s o r p t i o n b a n d s f o r t h e c a r b o n y l a n d

t h i o c a r b o n y l g roups a t 1680 cm-I and 1 1 2 0 c m - I r e s p e c t i v e l y .

'H NMR (DMSO-d6) s p e c t r u m g a v e s i g n a l s f o r t h e p h e n y l

p r o t o n s a t d 7 . 9 5 ( 4 H , m) and 7 . 6 (5H, m ) ( F i g . 3 . 2 ) .

m o o

LO. 6

4 0 . 0

20.0

Wave number ( cm-I )

Fig. 3.1. IR ( K B r ) spectrum of 3-benzoyl benzothiazoline-2- thione (ha)

3.2.l.(i) Reaction of 3-benzoyl benzothiazoline-2-thione

(4a) with amines (6): Formation of amides

When a dilute ( 2 mmol) solution of 3-benzoyl

benzothiazoline-2-thione (4a) in chloroform was mixed with a

solution of (2 mmol) freshly distilled aniline (6a), the

yellow colour of the solution disappeared gradually. The

reaction mixture was stirred for 10 minutes. The completion

of the reaction was followed by tlc and spectro-

photometrically. The mixture was concentrated and separated

by column chromatography (alumina). The compound eluted

first was recrystallised from benzene and was characterised

as benzanilide (7a). Yield: 95%; m.p.: 162 OC (lit. m.p.

163 o~)102. In addition to this product, 2-mercapto-

benzothiazole ( 1 ) was obtained as the last fraction in

nearly quantitative yield. The above aminolysis reaction

was found to be general. When the reaction was repeated

using benzylamine (6b), 2-methylaniline (6c), 4-methyl-

aniline (6d), methylamine ( 6 e ) and glycine (6f), the

respective amides, N-benzyl benzamide (7b), N-(g-tolyl)

benzamide ( 7 ~ ) . N-(g-tolyl) benzamide (7d), N-methyl

benzamide (7e) and N-glycyl benzamide (7f) were obtained in

85-95%, together with 2-mercaptobenzothiazole (1) in almost

quantitative yield (Scheme 3.2). Details of the reaction

conditions and the characterisation data.of the products are

given in Table 3.1.

Scheme 3.2

3 2 1 i i Reaction bf 3-benzoyl benzothiazoline-2-thione

(4a) with alcohols ( 8 )

The ease of aminolysis of 3-benzoyl benzothiazoline-2-

thione with different amines and the formation of amides

prompted to exploit this nucleophilic reaction using other

weak nucleophiles such as alcohols under identical

conditions. But even after stirring for a long time, 3-

benzoyl benzothiazoline-2-thione failed to react with all

the alcohols tried. This may probably be due to the weak

nucleophilic nature of alcohols when compared with that of

Table 3.1. Reaction of 3-benzoyl benzothiazoline-2-thione

(4a) with amines (6)

-

Amine Time of b i d e m.p. Yield reaction (lit

102 ( X ) (min) m . ~ . )

Oc

Aniline (6a) 10

Benzylamine (6b) 15

Methylamine (6e) 15

Glycine (6f) 25

Benzanilide (7a)

N-Benzyl benz- amide (7b)

N-(p-Tolyl) benzamide ( 7 C )

N-(p-Tolyl) benzamide (7d)

N-Methyl benzamide (7e)

N-Glycyl benzamide (7f)

amines. The possible acyl transfer reaction under

photochemical condition was also tried by irradiating a

dilute solution of 3-benzoyl benzothiazoline-2-thione (ha)

and benzyl alcohol using UV-visible light for about 10 h.

However no products could be isolated.

3 2 1 i i i ) Reaction of 3-benzoyl benzothiazoline-2-thione

(4a) with amino alcohols (10)

Since 3-benzoyl benzothiazoline-2-thione (4a) has

reacted only with amino nucleophiles and the reaction with

alcohols is lacking, selective aminolysis using amino

alcohols was tried. Thus, when an equimolar solution of 3-

benzoyl benzothiazoline-2-thione ( h a ) and ethanolamine (10a)

in chloroform was stirred for 15 minutes, the yellow colour

of the solution gradually disappeared. The reaction was

monitored by tlc and spectrophotometrically. After the

completion of the reaction, the mixture was chromatographed

over a neutral alumina column. The separated product was

recrystallised from alcohol to afford pale yellow crystals

of N-(2-hydroxyethyl) benzamide (lla) in 85% yield. m.p.:

160 OC. In the IR (KBr) spectrum (Fig. 3.3) there is no

peak above 1700 cm-I which shows the absence of ester

linkage and the broad peak at 3500 cm-I clearly points to

the presence of -OH group in the product.

The above selective aminolysis of 3-benzoyl

benzothiazoline-2-thione was generalised by extending the

reaction to other amino alcohols and aminophenols. Thus, 3-

aminopropan-1-01 (lob), diethanolnminc (10~). 4-aminophenol

(10d) and 2-aminophenol (10e) when added to a dilute

solution of 3-benzoyl b e n z o t h i a z o l i n e - 2 - t h i o n e and stirred

Wave number ( cm-' )

Fig. IR (KBr) spectrum of N-(2-hydroxyethyl) benzamide (lla)

for 20-30 minutes, the respective hydroxy substituted

amides. N-(3-hydroxypropyl) benzamide ( l l b ) , N,N-bis( 2 -

hydroxyethyl) benzamide (llc), N-(4-hydroxyphenyl) benzamide

(lld) and N-(2-hydroxyphenyl) benzamide (lle) were obtained

in 75-85% yields (Scheme 3.3). 2-Mercaptobenzothiazole (1)

was regenerated in all cases which helps to monitor the

reaction spectrophotometrically. The products obtained were

characterised by mixed m.p.'s or by analytical and spectral

techniques. The details of the selective aminolysis

reaction are described in Table 3.2.

Scheme 3.3

3.2.2 Synthesis of 3-(phenylacetyl) benzothiazoline-2-

thione (4b)

An equimolar mixture of phenylacetic acid (3b) and 2-

mercaptobenzothiazole (1) was dissolved in a mixture of THF

and methylene chloride (1:4], an equivalent amount of DCC in

methylene chloride was added to it, stirred for half an hour

and the precipitated DCU was filtered off. The resultant

product was chromatographed using silica gel column and

finally purified by recrystallisation from alcohol. 3 -

(Phenylacetyl) benzothiazo1in~~-2-thione (4b) was obtained as

Table 3.2. Reaction of 3-benzoyl benzothiazoline-2-thione

(4a) with amino alcohols (10)

Amino Time of Amide m.p. Yield I R alcohol reaction (lit ( % I ( KBf I

104 (min) m . ~ . ) cm- O c

Ethanol- amine (10a)

Diethanol- amine (10c)

4-Amino- phenol (10d)

15 N-(2-Hydroxy- 160 ethyl) benz- (163) amide (lla)

2 0 N-(3-Hydroxy- 142 propyl) benz- amide (llb)

30 N,N-Bis(2- 155 hydroxyethyl) (153) benzamide ( llc)

25 N-(4-Hydroxy- 231 phenyl) (234)

- benzamide (lld)

2 5 N-(2-Hydroxy- 181 phenyl) benz- (18.L) amide (lle)

orange yellow crystals in 75% yield with m.p. 90 OC. UV

spectrum in chloroform gave a band at 292 nm. IR (KBr)

spectrum (Fig. 3.4) of the compound gave peaks for carbonyl

and thiocaronyl frequencies at 1690 cm- and 1160 cm-I

respectively. 'H NMR (DMSO-d6) spectrum is given in Fig.

3.5. The different signals obtained are at & 7.95 (4H,m),

7.5 (5H.m) - phenyl protons and 2.5 (2H,s) - CH2 protons.

Wave number ( cm-' )

Fig. 3.4. IR (KBr) spectrum of 3-(phenylacety1)benzothi- 1 azoline-2-thione (4b) I

3.2.2.(i) Reaction of 3-(phenylacetyl) benzothiazoline-2-

thione (4b) with amines: Formation of amides

Analogous to the reaction of 3-benzoyl benzothiazoline-

2-thione ( 4 ~ 1 1 , when equimolar amount of 3-(phenylacetyl)

b e n z o t h i a z o l i n e - 2 - t h i o n e ( 4 b ) and freshly distilled aniline

(6a) were dissolved in chloroform and stirred for about 15

minutes, the colour of the solution disappeared gradually.

The reaction was monitored by tlc and also

spectrophotometrically. After the completion of the

reaction, the reaction mixture was worked up by column

chromatography using alumina column. The product eluted,

first was recrystallised from benzene and was identified as

phenylacetyl aminobenzene (12a). Yield: 93%; m.p. : 117 OC.

Mixed m.p. with authentic sample did not show any

depression.

The reaction was found to be general by repeating the

reaction with benzylamine (6b), 2-methylaniline (6c), 4 -

methylaniline ( b d ) , methylamine (be) and glycine (6f). The

respective amides, phenylacetyl amino(N-methy1)benzene

(12b), phenylacetyl amino(2-methy1)benzene (12c)

phenylacetyl amino(4-methyl) benzene (12d). phenylacetyl

aminomethane (12e) and N-(phenylacetyl) glycine (12f) were

obtained in 75-90% yield in addition to the isolation of 2-

mercaptobenzothiazole (1) in almost quantitative yield.

Details of the reaction and the characterisation datasof the

products are given in Table 3.3.

Table 3.3. Reaction of 3-(phenylacetyl) benzothiazoline-2-

thione (4b) with amines

Amine Time of Amide m.p. Yield reaction (lit. ( % ) (min)

Aniline (6a) 10

Benzylamine (6b) 15

Methylamine 2 0 (6e)

Glycine (6f) 3 0

Phenylacetyl 117 93 aminobenzene (118) ( 12a

Phenylacetyl 122 90 amino(N-methyl)- (122) benzene (12b)

Phenylacetyl 159 7 7 amino(2-methyl)- (159) benzene ( 12c)

Phenylacetyl 133 8 0 amino(&-methyl)- (136) benzene ( 12d)

Phenylacetyl 5 9 92 aminome thane (58) (12e)

N-(Phenylacetyl) 141 7 5 glycine (12f l (143)

3.2.2.(ii) Reaction of 3-(phenylacetyl) benzothiazoline-2-

thione (4b) with alcohols: Formation of esters

The facile arninolysis of 3-(phenylacetyl) benzo-

thiazoline-2-thione (4b) with different amines and the

formation of amides in very good yield paved the way to

extend this reaction to other weak nucleophiles such as

alcohols under identical conditions. Similar to 3-benzoyl

benzothiazoline-2-thione, even after stirring for a long

time, 3-(phenylacetyl) benzothiazoline-2-thione failed to

react with all the alcohols used. Therefore, the possible

acyl transfer reaction under photochemical condition was

tried by exposing a dilute solution of 3-(phenylacetyl)

benzothiazoline-2-thione and benzyl alcohol under direct

sunlight. The colour of the solution gradually diminished.

On a preparative scale, a dilute solution (2 m o l ) of 3-

(phenylacetyl) benzothiazoline-2-thione (4b) in methylene

chloride together with an equivalent quantity of benzyl

alcohol (8a) was irradiated in a pyrex photochemical reactor

using a Philips 125 W mercury-quartz lamp for 2 h. The

reaction was also monitored by tlc. When the reaction was

completed,the mixture was concentrated and chromatographed

over a neutral alumina column. The first fraction eluted

was purified to afford benzyl phenylacetate (9a) in 85%

yield. b.p. : ) 300 OC. IR (KBr) spectrum showed characte-

1 ristic ester peak at 1720 cm- .

In order to generalise the esterification reaction, the

reaction was carried out using different alcohols like

methanol (8b), ethanol (8c), 1-pentanol (8d) and 1-propan01

(8e). The respective esters, methyl phenylacetate (9b),

ethyl phenylacetate (9c), pentyl phenylacetate ( 9 d ) and

propyl phenylacetate (9e) were formed in about 85-92% yield

together with 2-mercaptobenzothiazole (1) (Scheme 3.4).

Details of the photolysis reaction and the characterisation

data of the products are presented in Table 3.4.

Scheme 3.4

3.2.2.(iii) Reaction of 3-(phenylacetyl) benzothiazoline-

2-thione (4b) with amino alcohols (10)

Since 3-(phenylacetyl) benzothiazoline-2-thione (4b)

Table 3.4. Irradiation of 3-(phenylacetyl) benzothiazoline

-2-thione (4b) in presence of alcohols (8)

Alcohol Time of Esters b.p. yield* irradia- (lit. ( % 1 tion (h) b.p. )Io3

Oc

Benzyl alcohol 2 Benzyl phenyl- 300 8 5 (8a) acetate (9a) (317)

Methanol (8b) 1 Methyl phenyl- 210 9 2 acetate (9b) (215)

Ethanol (8c) 1 Ethyl phenyl- 225 90 acetate (9c) (227 1

1-Pentanol (8d) 2 Pentyl phenyl- 262 90 acetate (9d) (265)

1-Propanol (8e) 2 Propyl phenyl- 237 . 90 acetate (9e) (238

* Yield calculated on the basis of the amount of 2- mercaptobenzothiazole regenerated.

has reacted only with amines under normal conditions and the

esterification reaction with alcohols took place only under

photochemical conditions, selective aminolysis using amino

alcohols was carried out. Thus, when an equimolar amount of

3-(phenylacetyl) benzothiazoline-2-thione (4b) and ethanol-

amine (10a) in chloroform was stirred for 20 minutes, the

yellow colour of the solution gradually disappeared. The

reaction was monitored by tlc and spectrophotometrically.

After the completion of the reaction, the mixture was

chromatographed over an alumina column and the product was

recrystallised from alcohol to afford white crystals of N-

(2-hydroxyethyl) phenylacetamide (13a) in 85% yield. m.p.:

152 OC. IR (KBr) spectrum of the compound gave characte-

ristic OH stretching frequency at 3400 cm-' and carbonyl

frequencies at 1683 cm-l.

The above selective aminolysis of 3-(phenylacetyl)

benzothiazoline-2-thione (4b) was repeated using different

amino alcohols and phenols. Thus, 3-aminopropan-1-01 (lob),

diethanolamine (lOc), 4-aminophenol (10d) and 2-aminophenol

(10e) when added to a dilute solution (equimolar) of 3 -

(phenylacetyl) beniothiazoline-2-thione and stirred for 15-

30 minutes the respective hydroxy substituted amides N-(3-

hydroxypropyl) phenylacetamide (13b), N,N-bis(2-hydroxy

ethyl) phenylacetamide (13c), N-(4-hydroxyphenyl) phenyl-

acetamide (13d) and N-(2-hydroxyphenyl) phenylacetamide

(13e) were obtained in 70-85% yield. 2-Mercapto-

benzothiazole (1) was regenerated in all cases which helps

in monitoring the reaction spectrophotometrically. The

products obtained were characterised by different analytical

and spectral techniques. The details of the selective

aminolysis carried out are described in Table 3.5.

Table 3.5. Reaction of 3-(phenylacetyl) benzothiazoline-

2-thione with amino alcohols

Amino Time of Amide m6p. Yield IR alcohol reaction ( C) ( 9 ) ( K B f

(min) cm

Ethanol- 20 N-(2-Hydroxy- 152 85 3400 amine (10a) ethyl) phenyl- (OH)

acetamide (13a) 1683 (C=O)

3-Amino- 25 N-(3-Hydroxy- 140 8 2 3440 propan-1-01 propyl) phenyl- (OH)

( lob) acetamide (13b) 1640 (C=O)

Diethanol- 30 N,N-Bis(2- 137 7 0 3470 amine (10c) hydroxyethyl) (OH)

phenylaceta- 1690 mide (13c) (c=O)

4-Amino- 30 . N-(4-Hydroxy- 186 7 5 3500 phenol (10d) phenyl) phenyl- (OH)

acetamide ( 13d) 1680 (C=O)

2-Amino- 30 N-(2-Hydroxy- 161 7 2 3480 phenol (10e) phenyl) phenyl- (OH)

acetamide (13e) 1696 (C=O)

3.2.3 Synthesis of 3-acetyl benzothiazoline-2-thione (4c)

To equimolar mixture of acetic acid (3c) and 2-

mercaptobenzothiazole (1) dissolved in a mixture of THF and

methylene chloride (1:4) an equivalent amount of DCC in

methylene chloride was added. Stirred for half an hour and

the precipitated DCU was removed by filtration. The

concentrated mixture was run through silica gel column and

the separated product as evidenced by tlc was recrystallised

from alcohol to afford yellow crystals of 3-acetyl

benzothiazoline-2-thione (4c) with m.p. 105 OC. Yield: 82%.

UV spectrum gave A max at 291 nm. IR (KBr) spectrum (Fig.

3.6) of the compound showed characteristic carbonyl and

thiocarbonyl frequencies at 1666 and 1135 cm-I respectively.

'H NMR in DMSO (90 MHz) showed aromatic proton signals at

d 7.4 (4H,m) and methyl protons at 6 1.7 (3H,s) (Fig. 3.7).

W o o - 0 3000 0 4 W ' O >coo 0 SDOO 0 900.0

Wave number (cm-l)

Fig. 3.6. IR ( K B r ) spectrum of 3-acetyl benzothiazoline-2- thione (4c)

3.2.3.(i) Reaction of 3-acetyl benzothiazoline-2-thione (4c)

with amines: Formation of amides

When equimolar amount ( 2 mmol) of 3-acetyl

benzothiazoline-2-thione (4c) and freshly distilled aniline

(2 mmol) were dissolved in chloroform and stirred for 15

minutes, the colour of the solution disappeared gradually.

The reaction was monitored by tlc and also by the usual

spectrophotometric method. Working up of the reaction

mixture followed by column chromatography (alumina) and

recrystallisation from benzene, the product separated first

was identified as acetanilide (14a) with very good yield

(95%) m.p.: 112 OC. Mixed melting point with authentic

sample did not show any depression

The reaction was also extended to other amines such as

benzylamine (6b), 2-methylaniline (6c), l-methylaniline

(6d), methylamine (6e) and glycine (6f). The respective

amides N-benzyl acetamide (14b), N- (g-tolyl) acetamide

(14c), N-(E-tolyl) acetamide (14d), N-methyl acetamide (14e)

and N-glycyl acetamide (14f) were obtained in 80-9596 yield

along with 2-mercaptobenzothiazole (1) in almost

quantitative yield. The characterisation data of the

products are given in Table 3.6.

Table 3.6. Reaction of 3-acetyl benzothiazoline-2-thione

(4c) with amines

Amine Time of Amide m.p. Yield reaction (lit.

102 ( % ) (min) m.p. )

Oc

Aniline (6a) 15 Acetanilide 111 95 (14a) (114)

Benzylamine (6b) 15 N-Benzyl acet- 6 0 9 2 amide (14b) (60)

2-Methylaniline 2 0 N-(o-Tolyl) 114 80 ( 6 ~ ) acetamide ( 1 4 ~ ) (112)

4-Methylaniline 15 N-(p-Tolyl) 152 82 (6d) acetamide (14d) (154)

Methylamine 20 N-Methyl (6e) acetamide (14e) Oil 90

Glycine (6f) 2 0 N-Glycyl 200 85 acetamide (14f) (204)

3.2.3.(ii) Reaction of 3-acetyl benzothiazoline-2-thione

(4c) with alcohols: Formation of esters

Since the aminolysis of 3-acetyl benzothiazoline-2-

thione (4c) with different amines which eventually results

to the formation of amides is a nucleophilic reaction, the

reaction was carried out using other weak nucleophiles such

as alcohols under identical condition. Even after prolonged

stirring, 3-acetyl benzothiazoline-2-thione failed to react

with all the alcohols used. This may probably due to the

weak nucleophilic nature of alcohols. However, similar to

3-(phenylacetyl) benzothiazoline-2-thione (4b), 3-acetyl

benzothiazoline-2-thione (4c) also underwent reaction with

alcohols under photochemical conditions. Here, a dilute

solution of 3-acetyl benzothiazoline-2-thione (4c) in

methylene chloride together with an equimolar quantity ( 2

mmol) of benzyl alcohol (8a) was irradiated in a preparative

pyrex photochemical reactor using a Philips 125 W mercury-

quartz lamp for 2 h. During irradiation the colour of the

solution was gradually diminished. The reaction was also

monitored by tlc. Concentration of the reaction mixture and

separation using a neutral alumina column, the first

fraction obtained was evaporated to dryness to afford benzyl

acetate (15a) in 88% yield. b.p.: 212 O C . The identity of

the compound was also checked thin layer chromato-

graphically.

The above ester synthesis was found to be general.

When the reaction was performed using methanol (Sb), ethanol

(Sc), 1-pentanol ( 8 d ) and 1-propanol (Be), the respective

products methyl acetate (15b1, ethyl acetate ( 15c), pentyl

acetate (15d), and propyl acetate (15e) were formed in 80-

90% yield. In addition to this, 2-mercaptobenzothiazole (1)

was isolated in quantitative yield. Thus showing the

generality of the esterification reaction under photo-

chemical conditions. Details of the esterification reaction

and the characterisation data: of the products are given in

Table 3.7.

Table 3.7. Irradiation of 3-acetyl benzothiazoline-2-thione

( 4 c ) in presence of alcohols (8)

Alcohol Time of Ester irradia- tion (h)

b . p . Y i e l d (lit. ( % I b.p. ) Io3 OC

Benzyl alcohol 2 Benzyl acetate (8a) ( 15a)

Methanol (8b) 2 Methyl acetate ( 15b)

Ethanol (8c) 1.5 Ethyl acetate ( 1 5 ~ )

I-Pentanol ( 8 d ) 2 Pentyl acetate (15d)

1-Propanol (8e) 2 Propyl acetate ( 15e)

3.2.3.(iii) Reaction of 3-acetyl benzothiazoline-2-thione

( 4 c ) with amino alcohols (10)

Since 3-acetyl benzothiazoline-2-thione ( 4 c ) has

reacted with alcohols only under photochemical conditions,

it is worthwhile to carry out the selective aminolysis using

amino alcohols or phenols. Thus, when an equimolar (2 mmol)

amount of 3-acetyl benzothiazoline-2-thione ( 4 c ) and

ethanolamine (10a) in chloroform was stirred for 15 minutes,

the yellow colour of the solution gradually disappeared.

After completion, the reaction mixture was chromatographed

over an alumina column. The product separated was

recrystallised from alcohol, which was identified as N-(2-

hydroxyethyl) acetamide ( 1 6 a ) from m . p . 164 O C and mixed

m . p .

The generality of the selective aminolysis was

established by extending the reaction using 3-aminopropan-l-

01 (lob), diethanolamine (10c), 4-aminophenol (10d) and 2 -

aminophenol (10e). The respective amides N-(3-hydroxy-

propyl) acetamide (16b), N,N-bis(2-hydroxyethyl) acetamide

(16c), N-(4-hydroxyphenyl) acetamide (16d) and N-(2-hydroxy

phenyl) acetamide (l6e) were obtained in 70-80% yield

together with 2-rnercaptobenzothiazole (1). The products

obtained were characterised by different analytical and

spectral t e c h n i q u e s . T h e d e t a i l s of the selective

aminolysis reaction are presented in Table 3.8.

Table 3.8. Reaction of 3-acetyl benzothiazoline-2-thione

(4c) with amino alcohols (10)

Amino Time of Amide m.p. Yield IR alcohol reaction (lit. ( % ( KBri

(min) rn-p. ) I o 4 ) cm- Oc

Ethanol- 15 N-(2-Hydroxy- 164 87 -- amine (10a) ethyl) acet- (166)

amide (l6a)

Diethanol- 30 amine (10c)

4-Amino- 30 phenol (IOd)

2-Amino- 30 phenol (10e)

N-(3-Hydroxy- 152 propyl) acet- amide (16b)

N,N-Bis(2- 139 hydroxyethyl) acetamide ( 16c)

N-(4-Hydroxy- 151 phenyl) acet- (150) amide ( 1 6 d )

N- ( 2-Hydroxy- 120 phenyl) acet- (124) amide (16e)

3.2-4. Synthesis of 3-propionyl benzothiazoline-2-thione

(4d)

3-Propionyl benzothiazoline-2-thione ( 4 d ) was prepared

just similar to that of 4 a , 4b and 4c. Here an equimolar

solution of propionic acid ( 3 6 ) and 2-mercaptobenzothiazole

(1) in THE and methylene chloride mixture (1:4), was stirred

with an equivalent amount of DCC in methylene chloride in an

ice bath for half an hour. The precipitated DCU was

filtered off. The concentrated mixture was separated using

silica gel column. The separated product as evidenced by

tlc was recrystallised from alcohol to afford yellow

crystals with m.p. 110 O C in 80% yield. This was

characterised as 3--propionyl benzothiazoline-2-thione ( 4 d )

from different spectral methods.

UV spectrum in chloroform gave h ,,, at 296 nm. IR

(KBr) spectrum (Fig. 3.8) of the compound gave carbonyl

frequencies at 1710 crn-I and thiocarbonyl frequencies at

1170 cm". 'H nmr (DMSO) showed proton signals at A 7.4

(4H,m), - phenyl protons , 3.5 (2H,m) and 1.1 (3H,t) -

methyl protons (Fig. 3.9).

3.2.4.(i). Reaction of 3-propionyl benzothiazoline-2-thione

(4d) with amines: Formation of amides

When 3-propionyl benzothiazoline-2-thione ( 4 d ) and

freshly distilled aniline (6a) were dissolved in chloroform

and stirred for about 15 minutes in equimolar proportions,

the colour of the solution gradually diminished. After the

completion of the reaction as indicated by tlc, the mixture

was worked up by column chromatography using alumina column.

The first fraction eluted was evaporated to dryness and on

recrystallisation from benzene gave white crystals of N -

phenyl propionarnide (6a) in 80% yield with m.p. 105 OC.

Wave number ( cm-' )

Fig. 3.8. IR (KBr) spectrum of 3-propionyl benzothiazoline-2- thione (4d)

When the reaction was repeated with benzylamine (6b),

2-methylaniline (6c), &-methylaniline (6d) and methylamine

(6e), the respective amides, N-benzyl propionamide (17b), N-

(g-tolyl) propionamide (17c), N-(p-tolyl) propionamide (17d)

and N-methyl propionamide (17e) were obtained in 80-90%

yield in addition to the isolation of 2-

mercaptobenzothiazole (1) in almost quantitative yield,

which establishes the generality of the reaction. Details

of the reaction and the characterisation data of the

products are given in Table 3.9.

3.2.4.(ii) Reaction of 3-propionyl benzothiazoline-2-thione

(4d) with alcohols: Formation of esters

The ease of aminolysis of 3-propionyl benzothiazoline-

2-thione (4d) with different amines and the formation of

amides inspired to extend this reaction to alcohols under

identical conditions. Just like 3-acetyl benzothiazoline-2-

thione the reaction failed, but under photochemical

conditions the reaction was very smooth. Here when a

dilute solution (2 mmol) of 3-propionyl benzothiazoline-2-

thione ( 4 d ) in methylene chloride together with an

equivalent amount of benzyl alcohol (8a) was irradiated in a

preparative pyrex photochemical reactor using a Philips 125W

mercury-quartz lamp for 3 h, the colour of the solution was

found to be diminished. The reaction mixture was

concentrated and chromatographed over an alumina column.

The first fraction was purified to afford benzyl propionate

(18a) in 90% yield. b.p.: 215 OC.

Table 3 . 9 . Reaction of 3-propionyl benzothiazoline-2-thione

with amines

Amine Time of Amide m.p. Yield I R reaction (lit. ( % ) (KBf)

102 (min) cm-

Aniline (6a)

Benzylamine (6b)

2-Methyl- aniline

(6c)

&-Methyl- aniline

(6d)

Methyl- amine (6e)

20 . N-Phenyl propionamide ( 17a)

2 5 N-Benzyl propionamide (17b)

3 0 N-(g-Tolyl) propionamide ( 1 7 ~ )

2 5 N-(p-Tolyl) propionamide ( 17d)

20 N-Methyl propionamide ( 17e)

The above ester formation was found to be general, when

the reaction was performed using methanol (8b), ethanol

(8c), 1-pentanol (8d), cyclohexanol (8f) and 2-propanol

(8g). The respective esters methyl propionate (18b). ethyl

propionate (18~). pentyl propionate (18d), cyclohexyl

propionate (18f) and 2-propyl propionate (18g) were obtained

in 85-92% yield in addition to the isolation of 2-

mercaptobenzothiaozle (1). Table 3.10 gives the characteri-

sation data of the products.

Table 3.10. Irradiation of 3-propionyl benzothiazoline-2- thione (4d) in presence of alcohols

Alcohol Time of Ester b.p. Yield irradia- (lit

102 ( % ) tian (h)

Benzyl alcohol (8a)

Methanol (Bb)

Ethanol (8c)

Cyclohexanol (Sf)

3 Benzyl propio- nate (18a)

1.5 Methyl propio- nate (18b)

2 Ethyl propio- nate (18c) .

2 Pentyl propio- nate (18d)

1.5 Cyclohexyl pro- pionate ( 18f)

2 2-Propyl pro- pionate (18g)

3.2.4.(iii). Reaction of 3-propionyl benzothiazoline-2-

thione (4d) with amino alcohols (10)

Analogous to compounds 4b and 4c selective aminolysis

of 3-propionyl b e n z o t h i a z o l i n e - 2 - t h i o n e (4d) was tried using

amino alcohols and phenols. Thus, when an equimolar mixture

of 3-propionyl benzothiazoline-2-thione (4d) and ethanol-

amine (10a) in chloroform was stirred for 20 minutes, the

yellow colour of the solution gradually disappeared. The

reaction w a s monitored by tlc and also spectro-

photometrically. Column chromatographic separation of the

mixture gave a product which was recrystallised from

alcohol. The product was identified as N-(2-hydroxyethyl)

propionamide (19a) in 80% yield. m.p.: 145 OC. IR (KBr)

spectrum of the compound gave stretching frequencies at 3400

(OH), 3310 (NH) and 1660 cm-I (C=O).

In order to establish the general nature of the

reaction, the selective aminolysis was repeated using 3 -

aminopropan-1-01 (lob), diethanolamine (loc), 4-aminophenol

(10d) and 2-aminophenol (10e). The respective N-(3-

hydroxypropyl) propionamide (19b), N,NT-bis(2-hydroxyethyl)

propionamide (19c), N-(4-hydroxyphenyl) propionamide (19d)

and N-(2-hydroxyphenyl) propionamide (19e) were formed along

with 2-mercaptobenzothiazole (1). The products obtained are

described in Table 3.11.

Table 3.11. Reaction of 3-propionyl benzothiazoline-2-thione

(4d) with amino alcohols

Amino Time of Amide m.p. Yield IR alcohol reaction (lit. ( % 1 ( KBf )

104 (min) cm-

Ethanol- 20 N- ( 2-Hydroxy- 145 80 amine (10a) ethyl) propio-

namide (19a)

3-Amino- 2 5 N-(3-Hydroxy- 135 7 8 propan-1-01 . propyl) propio-

(lob) namide (19b)

Diethanol- 30 N,N'-Bis(2- amine (10c) hydroxyethyl)

propionamide ( 19c)

4-Aminophenol 25 N-(4-Hydroxy- ( 10d) pheny 1 )

propionamide (19d)

2-Aminophenol 30 N-(2-Hydroxy- (10e) phenyl)

propionamide ( 19e)

From the number of reactions carried out with amines

and amino alcohols it is observed that 3-acyl

benzothiazoline-2-thiones (4) invariably undergo aminolysis

leading to the formation of amides in good yield and the

quantitative regeneration of 2-mercaptobenzothiazole.

Again, under normal conditions 3-acyl benzothiazoline-2-

thiones do not react with alcohols, which points to the weak

nucleophilic nature of -OH groups. Though, the electronic

structure of amines has a profound influence on the rate of

aminolysis (discussed in Chapter 5), the initial step of the

reaction will be the attack of nucleophilic amino group on

the activated acyl group of 3-acyl benzothiazoline-2-thione.

Through a cyclic transition state and electronic

reorganisation the-formation of amides and 2-mercaptobenzo-

thiazole can be explained. Thus, the possible pathway

leading to the formation of amides and 2-mercaptobenzo-

thiazole can be explained as in Scheme 3.5.

Scheme 3 . 5

Ester synthesis under photochemical conditions renders

through a different mechanistic pathway. From the foregoing

experimental observations, it is found that ester synthesis

under photochemical means occurs only in those 3-acyl

benzothiazoline-2-thiones where there is an d-hydrogen atom

adjacent to the carboxyl carbon atom. Thus, from

observations and by comparison with thiazolidine-2-thione 92

a mechanistic pathway involving a 'ketene' intermediate is

proposed, though not conclusive (Scheme 3.6).

Scheme 3.6

3.3. Experimental

3.3.1 General

The reagents 2-mercaptobenzothiazole (1) and 2-

mercaptobenzoxazole (2) were purchased from E. Merck, West

Germany. Different amines, alcohols, phenols and

amino alcohols were commercially available samples and were

purified by recrystallisation or distillation.

The solvents used were purified following literature

procedures. Melting points were determined in open

capillaries on a hot-stage melting point apparatus.

Irradiations were carried out with a Philips HPK 125 W high

pressure mercury-vapour lamp in a pyrex photochemical

reactor of 150 ml capacity. The lamp was surrounded by a

jacket containing the solution to be irradiated.

I R spectra were recorded on Shimadzu I R - 4 7 0

spectrophotometer using KBr discs. Shimadzu U V - 1 6 0 A

spectrophotorneter was used for UV spectral measurements. 'H

NMR ( 9 0 MHz) spectra were recorded from R S I C , I I T Madras and

R R L Trivandrum.

Pre-coated silica gel plates were used for analytical

tlc. Column chromatography was performed on a column of

size 100 cm length x 2 cm diameter. Silica gel and neutral

alumina were used as absorbants and the solvent systems used

were Petroleum ether-ethyl acetate (4:l) and chloroform-

methanol (3:l).

3.3.2 Synthesis of 3-benzoyl benzothiazoline-2-thione (4a)

The preparation of 3-benzoyl benzothiazoline-2-thione

(4a) was carried out by the usual DCC coupling method5'. In

a typical procedure a solution of DCC (10 mmol) in methylene

chloride (5 ml) was added to a solution of benzoic acid

(1.22 g, 10 mmol) and 2-mercaptobenzothiazole (1.68 g, 10

mmol) in THF and methylene chloride ( 1 : while stirring

in an ice bath. The reaction mixture was stirred at 0 OC

for 15 min and at room temp. for another 15 min. The

precipitated dicyclohexyl urea (DCU) was filtered off and

washed vith a little methylene chloride. The concentrated

reaction mixture was separated using silica gel column. The

product obtained was recrystallised from alcohol to afford

Pale yellow crystals of 3-benzoyl benzothiazoline-2-thione

(ha). Yield: 2.10 g (78%), m.p.: 125 OC.

3.3.2.(i) Reaction of 3-benzoyl b e n z o t h i a z o l i n e - 2 - t h i o n e

(ha) with amines : Formation of amides

Freshly distilled aniline (0.2 ml, 2 mmol) was added

to a solution of 3-benzoyl benzothiazoline-2-thione (0.55 g,

2 mmol) in chloroform (25 ml). The mixture was stirred for

10 min. The completion of the reaction was monitored by tlc

and spectrophotometrically. The mixture was separated using

neutral alumina column. The fraction eluted was evaporated

to dryness and was recrystallised from benzene to afford

white crystals of benzanilide (7a). Yield: 0.37 g (95%),

m.p.: 162 OC. Concentration of the other fraction followed

by recrystallisation from alcohol gave dull white crystals

of 2-mercatobenzothiazole (1). Yield 95%.

The same procedure was used in the conversion of amides

such as N-benzyl benzamide (7b), N-(Q-tolyl) benzamide (7c),

N-(p-tolyl) benzamide ( 7 d ) , N-methyl benzamide (7e) and N-

glycyl benzamide (7f), from 3-benzoyl benzothiazoline-2-

thione and respectively with benzylamine (bb) 2-

methylaniline (bc), 4-methylaniline (bd), methylamine (be)

and glycine (6f). In all cases, 2-mercaptobenzothiazole was

isolated in very good yield. The characterisation dataof

the different compounds are already described in Table 3.1.

3.3.2(ii) Reaction of 3-benzoyl benzothiazoline-2-thione

(4a) with amino alcohols

To a solution of 3-benzoyl benzothiazoline-2-thione

(4a, 0.55 g, 2 mmol) in chloroform (25 ml), ethanolamine

(0.12 rnl, 2 mmol) was added. Shaken well for 2 5 min and the

completion of the reaction was followed by tlc and

spectrophotometrically. The product was then separated

using neutral alumina column. The fraction collected first

was concentrated and recrystallised from alcohol to afford

white crystals of N-(2-hydroxyethyl) benzamide (lla).

Yield: 0.14 g (85%), m.p.: 160 OC. The other fraction on

crystallisation from alcohol afforded dull white crystals of

2-mercaptobenzothiazole (1). Yield: 85%.

N-(3-Hydroxypropyl) benzamide (llb), N,N-bis (2-hydroxy-

ethyl) benzamide (llc), N-(4-hydroxyphenyl) benzamide (lld)

and N-(2-hydroxyphenyl) benzamide (lle) were similarly

prepared, when 3-benzoyl benzothiazoline-2-thione was

treated respectively with 3-aminopropan-1-01 (lob),

diethanolamine (loc), 4-aminophenol (10d). and 2-aminophenol

(10e). 2-Mercaptobenzothiazole was isolated in all cases

with very good yield. Analytical and spectral details of

the compounds were presented in table 3.2.

3.3.3 Synthesis of 3-(phenylacetyl) benzothiazoline-2-

thione (4b)

To a solution of phenylacetic acid (1.34 g, 10 mmol)

and 2-mercaptobenzothiazole (1.68 g , 10 mmol) in THE and

methylene chloride mixture (1: 4), a solution of DCC (10

mmol) in methylene chloride (5 ml) was added while stirring

in an ice bath. The reaction mixture was stirred for 30 min

first at OOC and finally at room temperature. DCU formed

was filtered off and washed with a little methylene

chloride. Separation of the concentrate using silica gel

column followed by recrystallisation from alcohol afforded

orange yellow crystals of 3-(phenylacetyl) benzothiazoline-

2-thione ( 4 b ) . Yield: 2.1 g (75%); m.p.: 90 OC.

3.3.3.(i) Reaction of 3-(phenylacetyl) benzothiazoline-2-

thione (4b) with amines: Formation of amides

0.2 M1 (2 mmol) of freshly distilled aniline was added

to a solution of 3-(phenylacetyl) benzothiazoline-2-thione

(2 mmol) in chloroform (25 ml). Stirred the mixture for 10

min. After the completion of the reaction as evidenced by

the disappearance of the yellow colour, the mixture was

separated using alumina column. Two fractions were

obtained. The first fraction on concentration, followed by

recrystallisation from benzene afforded white crystals of

phenylacetyl aminobenzene (12a). Yield: 0.39 g (93%); m.p.:

117 OC. The other fraction was evaporated to dryness to get

dull white crystals of 2-mercaptobenzothiazole (1). Yield:

93%.

The above procedure was extended also to the

preparation of phenylacetyl amino(N-methy1)benzene (12b),

phenylacetyl amino(2-methy1)benzene ( 1 2 ~ 1 , phenylacetyl

amino(4-methy1)benzene (12d), phenylacetyl aminomethane

(12e) and N-(phenylacetyl) glycine. Here, 3-phenylacetyl

benzothiazoline-2-thione was treated with benzylamine (6b),

2-methylaniline (6c), 4-methylaniline (6d), 4-methylamine

(6e) and glycine (6f) respectively. The characterisation

data of the products are already given in Table 3.3.

3.3.3(ii) Irradiation of 3-(phenylacetyl) benzothiazoline-

2-thione (4b) with alcohols: Formation of esters

A mixture of 3-(phenylacetyl) benzothiazoline-2-thione

(0.57 g, 2 mmol) and benzyl alcohol (2 mmol) in methylene

chloride (150 ml) was irradiated with UV-visible light in a

preparative pyrex photochemical reactor for 2 h. The yellow

colour of the solution was found to be diminished. The

reaction mixture was worked up by distillation and the

residue was separated by column chromatography (neutral

alumina). The first fraction collected was concentrated and

purified to afford benzyl phenylacetate (9a). Yield: 85%;

b.p. : > 300 OC.

Similar irradiations were carried out with 3-(phenyl-

acetyl) benzothiazoline-2-thione using methanol tab),

ethanol (8c) , 1-pentanol (ad) and 1-propanol (Be),

respective esters, methyl phenylacetate (9b), ethyl

phenylacetate (9c), pentyl phenylacetate (9d) and propyl

phenylacetate (9e) were formed in 85-92% yield. 2-

Mercaptobenzothiazole (1) was isolated in all the

experiments (Table 3.4).

3.3.3ciii) Reaction of 3-(phenylacetyl) benzothiazoline-2-

thione (4b) with amino alcohols: Formation of

hydroxy amides

To a solution of 3-(phenylacetyl) benzothiazoline-2-

thione (0.57 g, 2 mmol) in chloroform (25 ml), ethanolamine

(0.12 ml, 2 mmol) was added. The mixture was shaken well

for 20 min. After the completion of the reaction, the

mixture was chromatographed over an alumina column. The

product separated first was recrystallised from alcohol to

afford white crystals of N-(2-hydroxyethyl) phenylacetamide

(13a). Yield : 0.3 g (85%); m.p. : 152 OC.

Similar procedure was adopted for the preparation of N-

(3-hydroxypropyl) phenylacetamide (13b), N,N-bis(2-hydroxy-

ethyl) phenylacetamide (13c), N-(4-hydroxyphenyl) phenyl-

acetamide (13d) and N-(2-hydroxyphenyl) phenylacetamide

(13e), from 3-aminopropan-1-01 (lob), diethanolamine (10~).

4-aminophenol (10d) and 2-aminophenol (10e) respectively.

2-Mercaptobenzothiazole was regenerated in all cases.

3.3.4 Synthesis of 3-acetyl benzothiazoline-2-thione (4c)

A solution of DCC (10 mmol) in methylene chloride (5

ml) was added to a solution of acetic acid (0.6 ml, 10 mmol)

and benzothiazoline-2-thione (1.68 g, 10 mmol) in a mixture

of THF and methylene chloride (1:4) while stirring in an

ice bath. The precipitated DCU was filtered off and washed

with a little methylene chloride. The product was separated

using silica gel column. The separated product as evidenced

by tlc was recrystallised from alcohol to afford yellow

crystals of 3-acetyl benzothiazoline-2-thione (4c). Yield:

1.65 g (82%), m.p.: 105 OC.

3.3.4(i) Reaction of 3-acetyl b e n z o t h i a z o l i n e - 2 - t h i o n e (4c)

with amines: Formation of amides

Freshly distilled aniline (0.2 ml, 2 mmol) was added to

a solution of 3-acetyl b e n z o t h i a z o l i n e - 2 - t h i o n e (0.42 g, 2

mmol) in chloroform (25 ml). Stirred for 15 min. The

completion of the reaction was evidenced by tlc and

spectrophotometrically. The mixture was then separated

using a neutral alumina column. The first fraction eluted

was concentrated and recrystallised from benzene to afford

white crystals of acetanilide (14a). Yield: 0.25 g ( 9 5 % ) ,

m.p.: 112 OC. The other fraction on concentration followed

by recrystallisation gave 2-mercaptobenzothiazole (1).

N-Benzyl acetamide (14b), N-(p-tolyl) acetamide (14c),

N-(p-tolyl) acetamide (14d), N-methyl acetamide (14e) and N-

glycyl acetamide (14f) were formed when 3-acetyl

benzothiazoline-2-thione was treated respectively with

benzylamine (6b), 2-methylaniline (6c), l-methylaniline

(6d), methylamine (6e) and glycine (6f) (Table 3.6).

3.3.4(ii) Irradiation of 3-acetyl benzothiazoline-2-thione

(4c) in presence of alcohols: Formation of esters

A solution of 3-acetyl benzothiazoline-2-thione (0.42

g , 2 mmol) and benzyl alcohol (2 mmol) in methylene chloride

(150 ml) was irradiated with UV-visible light using a pyrex

photochemical reactor for 2 h. The reaction was followed by

tlc. The solvent was distilled off and the residue was

separated by alumina column. The first fraction collected

was concentrated and the product was purified to afford

benzyl acetate (15a). Yield: 88%, b.p.: 212 OC.

When 3-acetyl benzothiazoline-2-thione (4c) and the

alcohols methanol (8b), ethanol (8c), 1-pentanol (8d) and 1-

propanol (8e) were irradiated under similar conditions

afforded methyl acetate (15b), ethyl acetate (15c), pentyl

acetate (15d) and propyl acetate (15e) respectively. In all

cases 2-mer~a~tobenzothiazole was also isolated. ".LA I 'le

characterisation data of the compounds were given in Table

3.7.

3.3.4(iii) Reactions of 3-acetyl benzothiazoline-2-thione

(4c) with amino alcohols: Formation of hydroxy

amides

To a chloroform solution of 3-acetyl benzothiazoline-2-

thione (0.42 g, 2 mmol), ethanolamine (0.12 ml, 2 mmol) was

added. The mixture was well shaken for 15 min. The yellow

colour of the solution gradually disappeared. The reaction

was monitored by tlc. The mixture on column chromatography

(neutral alumina) gave the product which was recrystallised

from alcohol. The product was identified as N-(2-hydroxy-

ethyl) acetamide (16a). Yield: 0.18 g (87%), m.p. 164 OC.

The above method was extended to the preparation of N-

(3-hydroxypropyl) acetamide (16b), N,N-bis(2-hydroxyethyl)

acetamide (16c), N-(4-hydroxyphenyl) acetamide (16d) and N-

(2-hydroxyphenyl) acetamide (16e), from 3-acetyl

benzothiazoline-2-thione (4c) and 3-aminopropan-1-01 (lob),

diethanolamine (lOc), 4-aminophenol (10d) and 2-aminophenol

(10e) respectively. The products formed were characterised

by analytical and spectral technique (Table 3.8).

3.3.5 Synthesis of 3-propionyl benzothiazoline-2-thione (4d)

To a solution of propionic acid (0.75 ml, 10 mmol) and

benzothiazoline-2-thione (1.68 g, 10 mmol) in a mixture of

THF and methylene chloride ( 1 : 4 ) , a solution of DCC (10

mmol) in methylene chloride (5 ml) was added with stirring

in an ice bath. the reaction mixture was stirred for half

an hour. DCU was filtered off and the product was separated

by column chromatography (silica gel), the separated product

was recrystallised from alcohol to afford pale yellow

crystals of 3-propionyl benzothiazoline-2-thione (4d).

Yield: 0.18 g (SO%), m.p.: 110 OC.

3.3.5(i) Reaction of 3-propionyl benzothiazoline-2-thione

(4d) with amines: Formation of amides

0.2 M1 (2 mmol) of freshly distilled aniline was added

to a solution of 3-propionyl benzothiazoline-2-thione (0.46

g, 2 mmol) in chloroform (25 ml). The mixture was stirred

for 15 min. The completion of the reaction was evidenced by

the disappearance of the yellow colour and by tlc. The

mixture was separated using an alumina column. The

initially eluted fraction was concentrated. The separated

product was recrystallised from benzene to afford white

crystals of N-phenyl propionamide (17a). Yield: 0.12 g

(go%), m.p.: 105 OC. 2-Mercaptobenzothiazole (1) was

regenerated in quantitative yield (90%).

The above procedure was also used in the preparation of

N-benzyl propionamide (17b), N-(g-tolyl) propionamide ( 1 7 ~ 1 ,

N-(p-tolyl) propionamide (17d) and N-methyl propionamide

(17e) from benzylamine (6b), 2-methylaniline (6c), 4-

methylaniline (6d) and methylamine (6e) respectively. 2-

Mercaptobenzothiazole ( 1 ) was also isolated. The

characterisation data of the products are already given in

Table 3.9.

3.3.5(ii) Irradiation of 3-propionyl benzothiazoline-2-

thione (4d) in presence of alcohols

A mixture of 3-propionyl benzothiazoline-2-thione (0.46

g, 2 mmol) and benzyl alcohol (2 mmol) in methylene chloride

(150 ml) was irradiated with UV-visible light for 3 h. The

reaction was followed by tlc. After the completion of the

reaction, the yellow colour of the solution disappeared. The

solvent was distilled off and the residue was separated by

column chromatography (alumina column). The first fraction

was concentrated and the product was purified to afford

benzy: propionate (18a). Yield: 0.27 g (go%), b.p.: 215 OC.

Second fraction gave 2-mercaptobenzothiazole (90%).

The above procedure was extended to the formation of

esters such as methyl propionate (18b), ethyl propionate

(18c), pentyl propionate (18d), cyclohexyl propionate (18f)

and 2-propyl propionate (18g) from methanol (8b), ethanol

(8c), 1-pentanol (8d), cyclohexanol (8f) and 2-propanol

(8g) respectively. 2-Mercaptobenzothiazole (1) was

regenerated in all the cases. The characterisation data of

the products were given in Table 3.10.

3.3.5(iii) Reaction of 3-propionyl benzothiazoline-2-thione

(4d) with amino alcohols: Selective aminolysis

Ethanolamine (2 mmol) and 3-propionyl benzothiazoline-

2-thione (0.46 g, 2 mmol) were dissolved in chloroform (25

ml) and well stirred for 20 min. The reaction mixture was

separated by column chromatography (alumina column). The

initially eluted fraction was concentrated. The product was

then recrystallised from alcohol to afford white powdery N-

(2-hydroxyethyl) propionamide (19a). Yield: 0.26 g (BOX),

m.p.: 145 OC. 2-Mercaptobenzothiazole (1) was regenerated

in quantitative yield (80%).

The above react5on was extended to the preparation of

N-(3-hydroxypropyl) propionamide (lqb), N-NT-bis-(2-hydroxy-

ethyl) propionamide (19c), N-(4-hydroxyphenyl) propionamide

(19d) and N-(2-hydroxyphenyl) propionamide (19e) respec-

tively from 3-aminopropan-1-01 (lob), diethanolamine (lOc),

4-aminophenol (10d) and 2-aminophenol (10e). 2-Mercapto-

benzothiazole was also isolated. The products were

characterised by analytical and spectral techniques (Table

3.11).

ACTIVATION OF CARBOXYL GROUPS USING 2-MERCAPTOBENZOXAZOLE