ACTIVATION OF CARBOXYL GROUPS USING -...

4. ACTIVATION OF CARBOXYL GROUPS USING

2-MERCAPTOBENZOXAZOLE

4.1 Introduction

The importance of carboxyl activation strategy

principally lies in peptide synthesis. 7 5 , 7 6 The increase in

the number of publications 11-15 clearly demonstrates the

growth in this field. Researchers try to design more and

more carboxyl activating groups to cope with the

18 conventional activating groups such as acid halides ,

azides20, anhydrides2= which require rigorous operational

conditions. These drastic operational conditions are

minimised, to some extent in the case of heterocyclic thiol

systems - 2-mercaptobenzothiazole. The formation of amides

and esters in good yield in direct and photochemical

conditions from 3-acyl benzothiazoline-2-thione shows that

2-mercaptobenzothiazole is a potent carboxyl activating

group. With a view to searching for new or better carboxyl

activating group, the reactions of derivatized 2-

mercaptobenzoxazole are carried out. Hence this chapter is

mainly devoted to investigate the usefulness of 2-

mercaptobenzoxazole (2) as a mild carboxyl activating group.

This chapter also describes

i) the derivatization of compound 2 with different

carboxylic acids, both aliphatic and aromatic.

ii) characterisation of these derivtives 3-acyl benzoxa-

zoline-2-thiones using different analytical and

spectral techniques.

iii) arninolysis and alcoholysis of 3-acyl benzoxazoline-2-

thiones under different experimental conditions so as

to illustrate the suitability of 3-acyl benzoxazoline-

2-thione as carboxyl activated component.

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

using amino alcohols/phenols.

4.2 Results and Discussion

The activation strategy using 2-mercaptobenzoxazole is

almost in the same way as that of 2-mercaptobenzothiazole.

Initial step is, of course, the synthesis of different 3-

acyl benzoxazoline-2-thione. The synthesised 3-acyl benzo-

xazoline-2-thiones are then made to react with nucleophiles

such as amines, amino alcohols/phenols and alcohols both

under thermal and photochemical conditions.

4.2.1. Synthesis of 3-benzoyl benzoxazoline-2-thione (5a)

Analogous to the derivatization of Z-mercapto-

benzothiazole as explained in Ch. 3.2.1, 3-benzoyl

benzoxazoline-2-thione (5a) was synthesised by the effective

DCC coupling procedure. For this an equimolar solution of

benzoic acid (3a) and 2-mercaptobenzoxazole (2) in THE and

methylene chloride mixture (1:4) was stirred along with an

equivalent amount of DCC in methylene chloride. After

stirring for 1 h in an ice bath, the precipitated DCU was

filtered off and the mixture was separated using silica gel

column. The formation of new product was evidenced by tlc.

Recrystallisation from alcohol afforded pale brown crystals

with m.p. 142 OC in 80% yield. The product was

characterised as 3-benzoyl benzoxazoline-2-thione (5a) from

different spectral measurements.

The product gave UVmaX in chloroform solution at 293 nm

(Fig. 5.13 in Chapter 5) and IR absorption bands due to

carbony1 and thiocarbonyl frequencies at 1680 and 1120 cm-I

respectively (Fig. 4.1). 'H NMR (DMSO) shows signalsmfor

phenyl protons at 7.75 (4H,m) and 7.4 (5H,m) (Fig. 4.2).

Wave number (cm-l)

Fig. 4.1 IR (KBr) spectrum of 3-benzoyl benzoxazoline- 2-thione (5a)

During DCC coupling, similar to 3-acyl benzothiazo-

line-2-thiones the acyl derivatives formed may reasonably be

presumed as the thermodynamically more stable N-acyl

derivatives.

The derivatization of 2-mercaptobenzoxazole was also

done using different acids such as phenylacetic acid (3b),

acetic acid (3c), propionic acid ( 3 d ) and 2-chlorobenzoic

acid (3e). In all the cases DCC coupling method was found

to be very effective. The respective products 3-

phenylacetyl benzoxazoline-2-thione (Sb), 3-acetyl benzoxa-

zoline-2-thione (5c), 3-propionyl benzoxazoline-2-thione

(5d) and 3-(o-chlorobenzoyl) benzoxazoline-2-thione (5e)

were fotmed in 70-80% yield. The products obtained were

characterised by different analytical and spectral

techniques (Fig.4.3-4.10). Details are presented in ~ ~ b l ~ 4.1

4.2.2 Reactions of 3-acyl benzoxazoline-2-thiones with

amines

In order to test whether 3-acyl benzoxazoline-2-thione

a suitable candidate as activated carboxyl component it was

treated with different amines. Thus, when a dilute (2 mmol)

solution of 3-benzoyl benzoxazoline-2-thione (5a) in

chloroform was mixed with a solution of freshly distilled

aniline (6a), immediate decolourisation was the change

observed. The whole reaction mixture was stirred for 15

minutes. After completion of the reaction as evidenced by

tlc and spectrophotometrically, the mixture was

Table 4.1. Characterisation data of 3-acyl derivatives of

2-mercaptobenzoxazole

3-Acyl derivative m6p. Yield IR UV 'H NMR ( C ) (7: 1 ( K B f ) (nm)

cm -

3-Benzoyl benzoxa- 142 8 0 1680, 293 7.75 zoline-2-thione 1120 (4H,m), (5a) 7.6(5H,m)

3-Phenylacetyl 88 80 1690, 305 7.85 benzoxazoline-2- 1120 (4H,m), thione (5b) 7.5(5H,m)

2.3(2H,s)

3-Acetyl benzoxa- 113 83 1720, 302 7.4 zoline-2-thione 1150 (4H,m), ( 5 C ) 1.8(3H,s)

3-Propionyl benzo- 153 80 1670, 303 7.3 xazoline-2-thione 1150 (4H,m), (5d) 3.7(2H,m)

1.2(3H,t)

3-(2-Chlorobenzoyl) 161 7 2 1695, 300 7.80 benzoxazoline-2- 1140 (4H,m) thione (5e) 7.lr5(5H,m)

concentrated and then separated by column chromatography

(alumina column). The compound eluted first was

recrystallised from benzene and was characterised as

benzanilide (7a). Yield: 0.3 g (90%); m.p.: 162 OC (lit

m.p. 163 Oc)lo2. Mixed m.p. with the sample described in

Ch. 3, Sect. 3.2.l(i) did not show any appreciable change.

Along with this product 2-mercaptobenzoxazole (2) was also

eluted as the last fraction in quantitative yield.

The above aminolysis reaction was extended to different

amines such as benzylamine (6b), 2-methylaniline (6c), 4-

methylaniline (6d) and methylamine (6e). The respective

amides, N-benzyl benzamide (7b), N-(0-toly1)benzamide - (7c),

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

obtained in 80-90% yield in addition to the isolation of 2-

mercaptobenzoxazole (2) in almost quantitative yield (Scheme

4.1). Details of the reaction condition and characteri-

sation data of the products are given in Table 4.2.

Scheme 4.1

Table 4.2. Reaction of 3-benzoyl benzoxazoline-2-thione

with amines

Amine Time of Ami de m.p. Yield reaction (lit. 102

( % ) (min)

m.gc) *

Aniline (6a) 15 Benzanilide (7a) 162 (163) 9 0

Benzylamine (6b) 20 N-Benzyl benza- 104 (105) 88 mide (7b)

2-Methylaniline 2 0 N-(0-Tolyl) 143 (144) 79 ( 6 ~ ) benzamide (7c)

4-Methylaniline 2 5 N-(p-Tolyl) 156 (158) 8 2 (6d) benzamide (7d)

Methylamine (6e) 15 N-methyl benza- 80 (82) 92 mide (7e)

* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.l(i) did not show any difference.

The behaviour of 3-phenylacetyl benzoxazoline-2-thione

towards amines was also studied. This active form reacts

with different amines and the respective products were

obtained in very good yield. When different amines (6a-e)

were used the respective amides such as phenylacetyl amino-

benzene (12a), phenylacetyl amino(N-methy1)benzene (12b).

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

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

(12e) were formed in 75-90% yield. The products were

separated from the reaction mixture using column chromato-

graphy and were characterised. The characterisation data

are presented in Table 4.3.

Table 4.3. Reaction of 3-(phenylacetyl) benzoxazoline-2-

thione (5b) with amines

Amine Time of Amide m.p. Yield reaction

(liEb2 ( % ) (min) m.p. Oc *

Aniline (6a) 15. Phenylacetyl 116 (118) 90 aminobenzene (12a)

Benzylamine 20 (6b)

Methylamine 20 (6e)

Phenylacetyl 121 (122) 8 7 amino(N-methyl)- benzene (12b)

Phenylacetyl 158 (159) 7 5 amino(2-methyl)- benzene (12c)

Phenylacetyl 136 (136) 8 0 amino(4-methyl)- benzene (12d)

Phenylacetyl 141 (143) 90 aminomethane (12e)

* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.2(i) did not show any difference.

In order to generalise the aminolysis process, it was

proposed to extend the same reaction with another

derivatized thiol. Hence, the simple 3-acetyl benzo-

xazoline-2-thione was tried with different amines (6a-f) and

the respective products acetanilide (14a), N-benzyl

acetamide (llb), N-(2-tolyl) acetamide (14c), N-(~-tolylI

acetamide (14d), N-methyl acetamide (lle) and N-glycyl

acetamide (14f) were obtained in 75-9036 yield. 2 -

Mercaptobenzoxazole was also regenerated in all the cases.

The products were separated, recrystallised and characte-

rised using the analytical data (Table 4.4).

The aminolysis reaction was further established by

carrying out the same reaction with another derivatized 2-

mercaptobenzoxazole. Thus, when 3-propionyl benzoxazoline-

2-thione (5d) was treated with different amines (6a-e), the

corresponding products N-phenyl propionamide (17a), N-benzyl

propionamide (17b), N-(o-tolyl) propionamide ( 1 7 ~ 1 , N-(p-

tolyl) propionamide (17d), and N-methyl propionamide (17e)

were formed in very good yield. The products were

characterised by different analytical and spectral

measurements (Table 4.5).

Table 4.4. Reactions of 3-acetyl benzoxazoline-2-thione ( 5 ~ )

with amines

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

(min) O c *

Aniline (6a) 15 Acetanilide (14a) 113 (114) 9 3

Benzylamine (6b) 20 N-Benzyl acetamide 59 (60) 8 9 (14b)

2-Methylaniline 25 N-(2-Tolyl) aceta- 112 (112) 78 ( 6 ~ ) mide ( 1 4 ~ )

4-Methylaniline 25 N-(p-Tolyl) aceta- 152 (154) 8 0 (6d) mide (14d)

Methylamine (6e) 20 N-Methyl acetamide oil 85 ( 14e)

Glycine (6f) 25 N-Glycyl acetamide 202 (204) 70 ( 14f)


It is evident that the aminolysis reaction or rather

the reaction between the carboxyl activated 2-mercapto

benzoxazole and the amines was very successful and it

proceeds without showing any discrimination on the nature of

the carboxylate groups. Another major advantage in these

reaction was the regeneration of heterocyclic 2-mercapto-

Table 4.5. Reaction of 3-propionyl benzoxazoline-2-thione

(5d) with amines

Amine Time of Amide m.p. IR (Kfr) reaction (cm - (min)

*

Aniline 20 N-Phenyl propio- 104 (105) -- (6a) namide (17a)

Benzylamine 2 5 N-Benzyl propio- 132 (6b) namide (17b)

2-Methyl- 25 N-(9-~olyl) 103 aniline (6c) propionamide (17c)

4-Methyl- 25 . N-ip-Tolyl) 126 (126) -- aniline (6d) propionamide

(17d)

&-Methylamine 20 N-Methyl propio- 147 (148) -.

(be) namide (17e)


benzoxazole in quantitative yield which can be reused. The

products were formed in less than half an hour. However,

the method is not without problems, the main disadvantage

being the separation technique (required column

chromatography).

The success achieved in the reaction of 3-acyl

benzoxazoline-2-thione with amines and the regeneration of

2-mercaptobenzoxazole prompted to think of extending the

reaction with another nucleophile - alcohols. Thus, when a

dilute solution of 3-benzoyl benzoxazoline-2-thione (5a) was

treated with benzyl alcohol in chloroform and was stirred

for 1 h. Even after stirring for prolonged time or

repetition of the reaction with other activated carboxyl

component like 3-(phenylacetyl) benzoxazoline-2-thione, or

(g-chlorobenzoyl) benzoxazoline-2-thione and alcohols/

phenols did not give any product. The reason for this

behaviour may be attributed to the less nucleophilicity of

the alcoholic group compared to the amino.group.

4.2.3 Reaction of 3-acyl benzoxazoline-2-thione with

alcohols under photochemical conditions

The failure of the reaction between alcoho1s/phenols

and the derivatized thiols, diverted the attention to the

alternate pathway for the ester formation. Since the

activating group contains a thiol/thione function which is

light sensitive and the fact that weak nucleophiles require

more energy than amino group, possibility of reactions under

photochemical conditions was explored. Thus, when some

selected 3-acyl derivatives of 2-mercaptobenzoxazole were

made to react with alcohols in presence of UV-visible light

the course of the reaction was entirely different.

Here, in a typical photochemical reaction a dilute

solution (2 mmol) of 3-(phenylacetyl) benzoxazoline-2-thione

(5b) in chloroform together with an equivalent quantity of

benzyl alcohol (8a) was irradiated in a preparative pyrex

photochemical reactor using a Philips 125W mercury-quartz

lamp for 3 h. The brown colour of the solution gradually

diminished. The reaction was monitored by tlc. After

completion of the reaction, the mixture was concentrated and

chromatographed over an alumina coiumn. The first fraction

collected was purified to afford benzyl phenyl acetate (9a)

in 82% yield. b.p. > 300 OC. It gave a homogenous tlc with

the compound prepared as described in Ch. 3, Sec. 3.2.2(ii).

IR spectrum in KBr showed a characteristic ester carbonyl

frequency at 1720 cm-l.

The above esterification reaction was repeated using

different alcohols such as methanol (8b), ethanol ( B c ) , 1-

pentanol (8d) and 1-propanol (8e). The respective esters

methyl phenylacetate (9b), ethyl phenylacetate (9c), pentyl

phenylacetate (9d) and propyl phenylacetate (9e) were formed

in about 80-90% yield in addition to the isolation of the 2-

mercaptobenzoxazole (2) (Scheme 4.2). Details of the

reaction and the characterisation data of the products are

presented in Table 4.6.

Scheme 4.2

The esterification reaction by photochemical route was

generalised by repetition of the reaction with 3-acetyl

benzoxazoli.ne-2-thione (5c) and different alcohols (8a-e).

The respective products benzyl acetate (15a), methyl acetate

(15b), ethyl acetate (15c), pentyl acetate (15d) and propyl

acetate (15e) were obtained in 75-90% yield. In all the

cases, 2-mercaptobenzoxazole was regenerated. Products

Table 4.6 Reaction of 3-(phenylacetyl) benzoxazoline-2-

thione (5b) with alcohols

Alcohol Time of Ester b.p. Yield irradia-

( lf 6~ ( % ) tion (h) b.p.b C

Benzyl alcohol 3 Benzyl phenyl- >300 (317) 82 (8a) acetate (9a)

Methanol (8b) 2 Methyl phenyl- 210 (215) 88 acetate (9b)

Ethanol (8c) 2 Ethyl phenyl- 226 (227) 85 acetate (9c)

1-Pentanol 4 Pentyl phenyl- 261 (265) 75 (ad) acetate (9d)

1-Propanol (8e) 3.5 Propyl phenyl- 237 (238) 78 acetate (9e)

* The yield calculated by weighing the amount of 2-

mercaptobenzoxazole (2) regenerated.

'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.2(ii).

obtained were separated,identified by analytical methods and

by comparison with samples prepared as described in Ch. 3,

Sec. 3.2.3(ii). Table 4.7 gives the details of the

Table 4.7. Reaction of 3-acetyl benzoxazoline-2-th.#$i -

Alcohol Time of Ester b.p. Yield irradia- (lit. b.p.) lo2 ( % ) tion (h) O c

f

Benzyl alcohol 3 Benzyl acetate 213 (214) 85 (8a) (15a)

Methanol (8b) 3 Methyl acetate 57 (57) 90 ( 15b)

Ethanol (8c) 2 Ethyl acetate 76 (77) 8 5 ( 1 5 ~ )

1-Pentanol (8d) 3.5 Pentyl acetate 147 (148) 80 (15d)

1-Propanol (8e) 3 Propyl acetate 100 (101) 78 ( 15e)


The ester formation was further established by

repeating the reaction with another activated carboxyl

derivative. Thus, when 3-propionyl benzoxazoline-2-thione

(5d) was irradiated in presence of different alcohols (8a-

f), the respective esters, benzyl propionate (18a), methyl

propionate (18b), ethyl propionate (18c), pentyl propionate

(18d) and 2-propyl propionate (18f) were formed in 75-90%

yield. Details of the reaction and the characterisation

data of the products are given in Table 4.8.


(Sd) with alcohols

Alcohol Time of Ester b.p. Yield irradia- (lit. b.p.) lo4 ( % ) tion (h) OC

f

Benzyl alcohol 3 Benzyl propio- 220 (222) 88 (8a) nate (18a)

Methanol ( 8b) 2 Methyl propio- 79 (80) 90 nate (18b)

Ethanol (812) 2 Ethyl propionate 100 (100) 85 ( 1 8 ~ )

1-Pentanol (Ed) 2.5 Pentyl propio- 165 (168) 85 nate (18d)

2-Propanol (Sf) 2 2-Propyl pro- 109 (110) 80 pionate (18f)


The applicability of photochemical mode of esteri-

fication was critically examined by carrying out the

reaction using selected benzoxazole-2-thione derivatives of

aromatic carboxylic acids. As a typical example, when 3-

benzoyl benzoxazoline-2-thione (5a) was irradiated in

presence of alcohols like ethanol/methanol/benzyl alcohol

the reaction did not take place. This behaviour is

analogous to the reactions of 3-benzoyl benzothiazoline-2-

thione (4a) with alcohols under photochemical conditions.

The absence of &-hydrogen on the carboxyl carbon atom may

be the reason for this behaviour, which is already

established in the photochemical esterification using 2-

mercaptobenzothiaozle. Therefore, by close analogy with 2-

mercaptobenzothiazole similar type of mechanism can be

suggested in the photochemical esterification using 2-

mercaptobenzoxazole.

4.2.4 Reaction of 3-acyl benzoxazoline-2-thione with amino

alcohols

In the foregoing examples, it is observed that, 3-acyl

benzoxazoline-2-thione acts as a promising activated

carboxyl compound, but the behaviour towards different

nucleophiles is not identical. Reacts with amines readily -

even without heating and it reacts with alcohols only under

photochemical condition where a high energy of activation is

needed. Moreover, compounds devoid of d-hydrogen atoms at

the carboxyl group do not give rise to esters under these

conditions. With these varied aspects in mind, it was

thought of to undertake the selective aminolysis of 3-acyl

benzoxazoline-2-thiones using amino alcohols at ambient

temperature.

Thus, when an equimolar mixture of 3-benzoyl

benzoxazoline-2-thione (5a) and ethanolamine (10a) in

chloroform was stirred for 20 minutes, the colour of the

solution was disappeared. The reaction was also monitored

by tlc and spectrophotometrically. After the completion of

the reaction, the mixture was chromatographed over an

alumina column. The separated product was recrystallised

from alcohol to afford crystals of N-(2-hydroxyethyl)

benzamide (lla) in 85% yield. m.p.: 161 OC (165 OC)'~~. In

the IR (KBr) spectr;m, no peak was observed above 1700 cm-l,

which indicates the absence of ester carbonyl frequency and

the broad peak at 3460 cm-I clearly shows the presence of

-OH group in the product. The identity of the compound was

also established by a homogenous tlc and mixed m.p. with the

compound prepared as described in Ch. 3, Sec. 3.2.l(iii).

The generality of the above selective aminolysis of 3 -

benzoyl benzoxazoline-2-thione (5a) was established by

extending the reaction using different amino alcohols and

phenols. Thus, 3-aminopropan-1-01 (lob), diethanolamine

(10c), 4-aminophenol (10d) and 2-aminophenol (10e) when

added to a dilute solution of 3-benzoyl benzoxazoline-2-

thione and stirred for 20-30 minutes, the respective hydroxy

substituted amides, N-(3-hydroxypropyl) benzamide (llb),

N,N-bis(2-hydroxyethyl) benzamide (llc), N-(4-

hydroxyphenyl) benzamide (lld) and N-(2-hydroxyphenyl)

benzamide (lle) were obtained in 75-85% yield (Section 4.3).

The 2-mercaptobenzoxazole (2) was regenerated in all cases

which helps in monitoring the reaction spectrophoto-

metrically. The products obtained were characterised by

analytical and also by IR data (Table 4.9).

0 0 II /R1

NH --r R - C-N R2

1 1 - R = P h , 1 3 - R : P h c ~ ~ 16-R: CH, , R-R= CH2-13,

Scheme 4.3

Table 4.9. Reaction of 3-benzoyl benzoxazoline-2-thione (5a)

with amino alcohols

Amino Time of Amide m.p. Yield I R alcohol reac- ( litlo3 % ( K B f )

tion "%' cm (min)

* ,£

Ethanol- amine (10a)

Diethanol- amine ( 10c)

2 0 N-(2-Hydroxy- 161 ethyl) benzamide (163) (lla)

25 N-(3-Hydroxy- lbl propyl) benzamide (lib)

3 0 N,N-Bis(2- 150 hydroxyethyl) (153) benzamide (llc)

25 . N-(4-Hydroxy- 231 phenyl) [ 234) benzamide ( lld)

25 N-(2-Hydroxy- 180 phenyl) (183) benzamide ( lle)

* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.l(iii) did not show any difference.

'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.l(iii).

The selective aminolysis was further extended to

different acid derivatives. 3-(Phenylacetyl) benzoxazoline-

2-thione (5b) thus reacts with different amino alcohols and

phenols (10a-e) and the corresponding amides were formed.

N-(2-Hydroxyethyl) phenylacetamide (13a), N-(3-hydroxy-

propyl) phenylacetamide (13b), N,N-bis(2-hydroxyethyl)

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

(13d) and N-(2-hydroxyphenyl) phenylacetamide (13e) were

formed in 70-85% yield. The details of the aminolysis

reaction and the characterisation data of the products are

presented in Table 4.10.

Analogous selective aminolysis was also carried out

using some aliphatic acid derivatives of 3-

mercaptobenzoxazole. Thus 3-acetyl benzoxazoline-2-thione

(5c) and 3-propionyl benzoxazoline-2-thione (5d) were

treated with different amino alcohols (10a-e) the

corresponding amides such as N-(2-hydroxyethyl) acetamide

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

hydroxyethyl) acetamide (16c), N-(4-hydroxyphenyl) acetamide

(16d), N-(2-hydroxyphenyl) acetamide (16e), N-(2-

hydroxyethyl) propionamide (19a), N-(3-hydroxypropyl)

propionamide (19b), N,Nq-bis(2-hydroxyethyl) propionamide

(19~). N-(4-hydroxyphenyl) propionamide (19d), and N-(2-

hydroxyphenyl) propionamide (19e) were formed along with the

starting 2-mercaptobenzoxazole (2) in very good yield. The

details of the reaction and characterisation data are given

in Table 4.11 & 4.12.

Table 4.10. Reactions of 3-(phenylacetyl) benzoxazoline-2-

thione (5b) with amino alcohols

Amino Time of Amide m.p. Yield IR alcohol reac- ( O ) ( % ) (KBri

tion * , f cm- (min)

Ethanol- amine (10a)

Diethanol- amine (10c)

20 N-(2-Hydroxy- ethyl) phenylacetamide (13a)

3 0 N-(3-Hydroxy- propyl) phenylacetamide ( 1 3 b )

3 0 N,N-Bis(2- hydroxyethyl) phenylacetamide

. (13c)

3 0 N-(4-Hydroxy phenyl) phenylacetamide (13d)

138 7 2 3450 (OH) 1680 (C=O)

2-Aminophenol 25 N-(2-Hydroxy- 160 7 2 3480 ( 10e) phenyl) phenyl- (OH)

acetamide ( 13e) 1700 (C=O)

* . Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.2(iii) did not show any difference.

'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.2(iii).

Table 4.11. Reaction of 3-acetyl benzoxazoline-2-thione

(5d) with amino alcohols

Amino Time of Amide m.p. Yield IR alcohol reac- (lit. 103(%) ( KBf ti on m . ~ . ) cm -

(min) OC

* 9

Ethanol 2 0 N-(2-Hydroxy- 163 85 - - amine (10a) ethyl) acetamide (166)

(16a)

- - propyl) acetamide ( 16b)

Diethanol- 3 0 N,N-Bis(2- amine (10c) hydroxyethyl)

acetamide ( 1 6 ~ )

4-Aminophenol 30 N-(4-Hydroxy ( lod) pheny 1 )

acetamide ( 16d)

2-Aminophenol 25 N-(2-Hydroxy- ( 10e) phenyl)

acetamide (16e)

* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.3(iii) did not show any difference.



with aminoalcohols

Amino Time of Amide m.p. Yield IR alcohol reac- (lit.

103 % (KBri)

tion m . ~ . cm- (min) OC

*,f

Ethanol- 20 N-(2-Hydroxy- 143 8 0 3400 amine (10a) ethyl) propion- (OH)

amide (19a) 1650 (C=O)

3-Amino- 25 N-(3-Hydroxy- 152 75 3450 proan-1-01 propyl) propion- (OH)

(lob) amide (19b) 1675 (C.0)

Diethanol- 30 N,N-Bis(2- 175 70 3450 amine (10c) hydroxyethyl) (OH)

- propionamide (19c) 1670 (C=O)

4-hinophenol 25 N- ( 4-Hydroxy 154 7 5 -- (lad) phenyl) (156)

propionamide ( 19d)

2-hinophenol 25 N-(2-Hydroxy- 180 70 3500 ( lee) phenyl) (OH)

propionamide 1680 (19e) ( c=o)

* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.4(iii) did not show any difference.


A mechanistic pathway which is analogous to 3-acyl

benzothiazoline-2-thione could also be suggested for the

reactions of 3-acyl benzoxazoline-2-thione. Scheme 4.4

represents the reaction with amines and Scheme 4.5 explains

the reaction under photochemical conditions.

Scheme 4 - 4

Scheme 4.5

4.3 Experimental

4.3.1 Synthesis of 3-acyl benzoxazoline-2-thiones (5a-e):

General procedure

The preparation of 3-benzoyl benzoxazoline-2-thione

(5a) was carried out by the usual DCC coupling method.

Here, to a solution of benzoic acid (1.22 g, 10 mmol) and 2-

mercapto benzoxazole (1.52 g , 10 mmol) in THF and methylene

chloride ( 1 4 a solution of DCC (10 mmol) in methylene

chloride (5 ml) was added while stirring in an ice bath.

The mixture was stirred for 15 min at 0 OC and at room temp.

for another 15 min. The precipitated DCU was filtered off

and the concentrated reaction mixture was separated using

silica gel column. The product obtained was recrystallised

from alcohol to afford pale brown crystals of 3-benzoyl

benzoxazoline-2-thione (5a). Yield: 2g, (80%) ; m.p: 142 OC.

The above procedure was used for the derivatization of

2-mercaptobenzoxazole (2) using different acids such as

phenylacetic acid (3b), acetic acid (3c), propionic acid

(3d), and o-chlorobenzoic acid (3e). The respective

products 3-(phenylacetyl) benzoxazoline-2-thione (Sb), 3-

acetyl benzoxazoline-2-thione (5c), 3-propionyl benzoxazo-

line-2-thione (5d) and 3-(g-chlorobenzoyl) benzoxazoline-2-

thione (5e) were formed. The characterisation data of

different products are already given in Table 4.1.

4.3.2. Reaction of 3-acyl benzoxazoline-2-thiones with

amines: General procedure

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

a solution of 3-benzoyl benzoxazoline-2-thione (0.5 g ,

2 mmol) in chloroform (50 ml) and was stirred for 15 min.

The course of the reaction was monitored by tlc and

spectrophotometrically. The mixture was separated using

neutral alumina column. The first fraction eluted was

evaporated to dryness and was recrystallised from benzene to

afford white crystals of benzanilide (7a). Yield: 0.36g

(90%) m.p: 162 OC. Concentration of the other fraction

followed by recrystallisation from alcohol gave grey

crystals of 2-mercaptobenzoxazole (2) with 90% yield.

The same procedure was used in the preparation of

amides such as N-benzyl benzamide (7b), N-(e-tolyl)

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

benzamide (7c) from 3-benzoyl benzoxazoline-2-thione and

benzylamine (6b), 2-methylaniline (6c), 4-methylaniline (6d)

and methylamine (6e) respectively. 2-Mercaptobenzoxazole

(2) was regenerated in all the cases. The characterisation

data are already presented in Table 4.2.

Phenylacetyl aminobenzene (12a), phenylacetyl amino(N-

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

(12c) phenylacetyl amino(4-methy1)benzene (12d) and

phenylacetyl aminomethane (12e) were formed in good yields

when 3-phenylacetyl benzoxazoline-2-thione (5b) was treated

respectively with aniline (ba), benzylamine (6b), 2 -

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

(6e). 2-Mercapto benzoxazole was also isolated in

quantitative yield in all the cases. The characterisation

data of the products are already described in Table h . 3 .

When 3-acetyl benzoxazoline-2-thione (5c) was treated

with different amines such as aniline (6a), benzylamine

(6b), 2-methylaniline (bc), 4-methylaniline (6d),

methylamine (6e) and glycine (6f) , the respective products

acetanilide (14a), N-benzyl acetamide (14b) N-(2-tolyl)

acetamide (14c), N-(p.-tolyl) acetamide (14d), N-methyl

acetamide (14e) and N-glycyl acetamide (14f) were formed in

75-90% yield. 2-Mercaptobenzoxazole (2) was also isolated.

Characterisation data of the products are alreddy given in

Table 4.4.

The above procedure was also used for the formation of

amides such as N-phenyl propionamide (17a), N-benzyl

propionamide (17b), N-(Q-tolyl) propionamide ( 1 7 ~ 1 , N-(P-

tolyl) propionamide (17d), and N-methyl propionamide (17e)

from 3-propionyl benzoxazoline-2-thione (5d) and aniline

(6a), benzylamine (6b), 2-methylaniline ( d c ) , 4 -

methylaniline (6d) and 4-methylamine (6e) respectively. The

characterisation data of the products are already described

in Table 4.5. 2-Mercaptobenzothiazole (2) was also isolated

in quantitative yield.

4 . 3 . 3 . Reaction of 3-acyl benzoxazoline-2-thione with

alcohols: General procedure

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

! 0 . 5 7 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 3 h. The brown

colour of the solution was found to be diminished. Worked

up the reaction. , mixture 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.~.:

0 > 300 C. The other fraction gave 2-mercaptobenzoxaZ0le ( 2 )

in 85% yield.

Similar irradiations were carried out with 3-(phenyl-

acetyl) benzoxazoline-2-thione using methanol (8b). ethanol

(8c) 1-pentanol (8d) and 1-propanol (8e) . Respective

products methyl phenylacetate (9b) ethyl phenylacetate (9c),

pentyl phenylacetate (9d). and propyl phenylacetate (9e)

were formed in 75-85% yield. Details of the products are

described in Table 4.6. 2-Mercaptobenzoxazole (2) was

isolated in all the cases.

The above procedure was also used for the effective

preparation of esters, benzyl acetate (15a), methyl acetate

(15b1, ethyl acetate (15c), pentyl acetate (15d) and propyl

acetate (15e) from 3-acetyl benzoxazoline-2-thione (5c)

using benzyl alcohol (8a), methanol (8b), ethanol (8c), 1-

pentanol (ad) and 1-propanol (8e) respectively. The

characterisation data are given in Table 4.7. 2 -

Mercaptobenzoxazole (2) was isolated in quantitative yield.

When 3-propionyl benzoxazoline-2-thione (5d) was

treated with alcohols such as benzyl alcohol (8a), methanol

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

under the above experime~tal conditions, esters, benzoyl

propionate (18a), methyl propionate (lab), ethyl propionate

( 1 8 ~ 1 , pentyl propionate (18d) and 2-propyl propionate (18f)

were formed in 80-90% yield. The characterisation data of

the products are already given in Table 4.8. 2 -

Mercaptobenzoxazole (2) was obtained in quantitative yield.

4.3.4. Reaction of 3-acyl benzoxazoline-2-thione with amino

alcohols: General procedure

To a solution of 3-benzoyl benzoxazoline-2-thione (0.5

g, 2 mmol) in chloroform (50 ml), ethanolamine (0.12 ml, 2

mmol) was adddd. Shaken well for 20 min, the course of the

reaction was followed by tlc and spectrophotometrically.

The product was then separated from the reaction mixture

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.: 161 OC. The other fraction on

crystallisation from alcohol afforded grey crystals of 2-

mercaptobenzoxazole (2) in 85% yield.

Similarly N-(3-hydroxypropyl) benzamide (llb) N, N-his

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

benzamide (lld) and N-(2-hydroxyphenyl) benzamide (lie) were

formed when 3-benzoyl benzoxazoline-2-thione was treated

with amino alcohols such as 3-aminopropan-1-01 (lob),

diethanolamine (10~). 4-aminophenol (10d) and 2-aminophenol

(10e). The details are already given in Table 4.9. 2-

Mercaptobenzoxazole (2) was regenerated in all the cases.

The above selective aminolysis was also extended to 3-

(phenylacetyl) benzoxazoline-2-thione (5b) and amino

alcohols, ethanolamine (loa), 3-aminopropan-1-01 (lob),

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

(10e). The respective products N-(2-hydroxyethyl) phenyl-

acetamide (13a), N- (3-hydroxylpropyl) phenylacetamide (13b),

N,N-bis(2-hydroxyethyl) phenylacetamide (13c), N-(4-hydroxy-

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

phenylacetarnide (13e) formed were characterised and the

details are already given (Table 4.10).

The above procedure was also used in reactions between

3-acetyl benzoxazoline-2-thione (5c) and amino alcohols such

as ethanolamine (lOa), 3-aminopropan-1-01 (lob),

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

(10e). The respective products N-(2-hydroxyethyl) acetamide

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

hydroxyethyl) acetamide (16~). N-(O-hydroxyphenyl) acetamide

(16d) and N-(-2-hydroxyphenyl) acetamide (16e) were formed

and the characterisation data are already presented in Table

4.11. 2-Mercaptobenzoxazole (2) was also regenerated.

When 3-propionyl benzoxazoline-2-thione (5d) was

treated with different amino alcohols, ethanolamine (loa),

3-aminopropan-1-01 (lob), diethanolamine ( 1 0 ~ ) . 4 -

aminophenol (10d) and 2-aminophenol (loe), the respective

products N-(2-hydroxyethyl) propionamide (19a), N-(3-

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

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

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

characterisation data of the products are already presented

in Table 4.12.

- 0 . 0

IDO0.0 I M O . 0 1 D O D . O ,500.0 1000.0 900.0 w.0

Wave number (cm-l) Fig. 4.3 IR (KBrJ spectrum of 3-(phenylacetyl) benzo-

xazoline-2-thione (5b)

Wave number ( cm-' ) Fig. 4.5 IR (KBr) spectrum of 3-acetyl benzoxazoline-2-

thione ( 5 c )

Wave number ( cm-' ) Fig. 4.7 IR (KBr) spectrum of 3-propionyl benzoxazoline-

2-thione (5d) I

Wave number ( cm-' )

Fig. 4.9 .IR ( K B r ) spectrum of 3-(g-chlorobenzoyl) benzoxazoline-2-thione (5e)

MONITORING OF AMINOLYSIS REACTIONS - A SPECTROPHOTOMETRIC INVESTIGATION

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