2-MERCAPTOBENZOTHIAZOLE. methods require rigorous conditions such as the use of a. base, temperature etc. which make the synthesis much more

Transcription

1 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 33 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

2 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, 75,76 and carbohydrates 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-

3 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 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

4 recrystallised from alcohol to afford yellow crystals with m.p. 125 OC in 78% yield. This was characterised as 3- benzoyl benzothiazoline-2-thione (ha) 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

5 UV absorption spectrum of the product in chloroform solution showed h max at 296 nm (Fig. 5.2 in Chapter 5). It gave I R absorption bands for the carbonyl and thiocarbonyl groups at 1680 cm-i and 1120 cm-i respectively. 'H NMR (DMSO-d6) spectrum gave signals for the phenyl protons at d 7.95 (4H, m) and 7.6 (5H, m) (Fig. 3.2). moo LO Wave number ( cm-i ) Fig IR (KBr) spectrum of 3-benzoyl benzothiazoline-2- thione (ha)

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7 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. was found to be general. The above aminolysis reaction When the reaction was repeated using benzylamine (6b), 2-methylaniline (6c), 4-methyl- aniline (6d), methylamine (6e) 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

8 conditions and the characterisation data.of the products are given in Table 3.1. Scheme 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

9 Table 3.1. Reaction of 3-benzoyl benzothiazoline-2-thione (4a) with amines (6) - Amine Time of bide m.p. Yield reaction (lit 102 (X) (min) m. ~. ) Oc Aniline (6a) 10 Benzylamine (6b) 15 Benzanilide (7a) N-Benzyl benzamide (7b) N-(p-Tolyl) benzamide ( 7C) N-(p-Tolyl) benzamide (7d) Methylamine (6e) 15 Glycine (6f) 25 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.

10 321iii) 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 (ha) 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

11 (10d) and 2-aminophenol (10e) when added to a dilute solution of 3-benzoyl benzothiazoline-2-thione and stirred Wave number ( cm-' ) Fig. IR (KBr) spectrum of N-(2-hydroxyethyl) benzamide (lla) for 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% 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.

12 Scheme 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

13 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 (min) 104 m. ~. ) cm- O c Ethanolamine (10a) 15 N-(2-Hydroxy- 160 ethyl) benz- (163) amide (lla) 2 0 N-(3-Hydroxy- 142 propyl) benzamide (llb) Diethanolamine (10c) 4-Aminophenol (10d) 30 N,N-Bis(2-155 hydroxyethyl) (153) benzamide ( llc) 25 N-(4-Hydroxy- 231 phenyl) (234) - benzamide (lld) 25 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 The different signals obtained are at & 7.95 (4H,m), 7.5 (5H.m) - phenyl protons and 2.5 (2H,s) - CH2 protons.

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15 Wave number ( cm-' ) Fig IR (KBr) spectrum of 3-(phenylacety1)benzothi- 1 azoline-2-thione (4b) I (i) Reaction of 3-(phenylacetyl) benzothiazoline-2- thione (4b) with amines: Formation of amides Analogous to the reaction of 3-benzoyl benzothiazoline- 2-thione (4~11, when equimolar amount of 3-(phenylacetyl)

16 benzothiazoline-2-thione (4b) 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 ( bd), 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.

17 Table 3.3. Reaction of 3-(phenylacetyl) benzothiazoline-2- thione (4b) with amines Amine Time of Amide m.p. Yield reaction (min) (lit. (%) Aniline (6a) 10 Benzylamine (6b) 15 Phenylacetyl aminobenzene (118) ( 12a Phenylacetyl amino(n-methyl)- (122) benzene (12b) Phenylacetyl amino(2-methyl)- (159) benzene ( 12c) Phenylacetyl amino(&-methyl)- (136) benzene ( 12d) Methylamine 2 0 (6e) Glycine (6f) 3 0 Phenylacetyl aminome thane 59 (58) 92 (12e) N-(Phenylacetyl) glycine (12f l (143) (ii) Reaction of 3-(phenylacetyl) benzothiazoline-2- thione (4b) with alcohols: Formation of esters The facile arninolysis of 3-(phenylacetyl) benzo-

18 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 mol) 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 characteristic ester peak at 1720 cm- 1. In order to generalise the esterification reaction, the reaction was carried out using different alcohols like

19 methanol (8b), ethanol (8c), 1-pentanol (8d) and 1-propan01 (8e). The respective esters, methyl phenylacetate (9b), ethyl phenylacetate (9c), pentyl phenylacetate (9d) 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 (iii) Reaction of 3-(phenylacetyl) benzothiazoline- 2-thione (4b) with amino alcohols (10) Since 3-(phenylacetyl) benzothiazoline-2-thione (4b)

20 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 (8a) acetate (9a) (317) Methanol (8b) 1 Methyl phenyl acetate (9b) (215) Ethanol (8c) 1 Ethyl phenyl acetate (9c) ( Pentanol (8d) 2 Pentyl phenyl acetate (9d) (265) 1-Propanol (8e) 2 Propyl phenyl 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 ethanolamine (10a) in chloroform was stirred for 20 minutes, the yellow colour of the solution gradually disappeared. The reaction was monitored by tlc and spectrophotometrically.

21 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 characteristic 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 minutes the respective hydroxy substituted amides N-(3- hydroxypropyl) phenylacetamide (13b), N,N-bis(2-hydroxy ethyl) phenylacetamide (13c), N-(4-hydroxyphenyl) phenylacetamide (13d) and N-(2-hydroxyphenyl) phenylacetamide (13e) were obtained in 70-85% yield. 2-Mercaptobenzothiazole (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.

22 Table 3.5. Reaction of 3-(phenylacetyl) benzothiazoline- 2-thione with amino alcohols Amino Time of Amide m6p. Yield IR alcohol reaction ( C) (9) (KBf (min) cm Ethanol- 20 N-(2-Hydroxy amine (10a) ethyl) phenyl- (OH) acetamide (13a) 1683 (C=O) 3-Aminopropan N-(3-Hydroxypropyl) phenyl (OH) ( lob) acetamide (13b) 1640 (C=O) Diethanol- 30 N,N-Bis( amine (10c) hydroxyethyl) (OH) phenylaceta mide (13c) (c=o) 4-Amino- 30. N-(4-Hydroxy phenol (10d) phenyl) phenyl- (OH) acetamide ( 13d) 1680 (C=O) 2-Amino- 30 N-(2-Hydroxy phenol (10e) phenyl) phenyl- (OH) acetamide (13e) 1696 (C=O) 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

23 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 (3H,s) (Fig. 3.7). Woo W'O >coo 0 SDOO Wave number (cm-l) Fig IR (KBr) spectrum of 3-acetyl benzothiazoline-2- thione (4c)

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25 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 yield along with 2-mercaptobenzothiazole (1) in almost quantitative yield. The characterisation data of the products are given in Table 3.6.

26 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 (14a) (114) Benzylamine (6b) 15 N-Benzyl acet amide (14b) (60) 2-Methylaniline 2 0 N-(o-Tolyl) (6~) acetamide (14~) (112) 4-Methylaniline 15 N-(p-Tolyl) (6d) acetamide (14d) (154) Methylamine 20 N-Methyl (6e) acetamide (14e) Oil 90 Glycine (6f) 2 0 N-Glycyl acetamide (14f) (204) (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

27 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 mercuryquartz 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 OC. 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 (8d) and 1-propanol (Be), the respective products methyl acetate (15b1, ethyl acetate ( 15c), pentyl acetate (15d), and propyl acetate (15e) were formed in 80-

28 90% yield. In addition to this, 2-mercaptobenzothiazole (1) was isolated in quantitative yield. Thus showing the generality of the esterification reaction under photochemical 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 (4c) in presence of alcohols (8) Alcohol Time of Ester irradiation (h) b.p. Yield (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 (15~) I-Pentanol (8d) 2 Pentyl acetate (15d) 1-Propanol (8e) 2 Propyl acetate ( 15e)

29 3.2.3.(iii) Reaction of 3-acetyl benzothiazoline-2-thione (4c) with amino alcohols (10) Since 3-acetyl benzothiazoline-2-thione (4c) 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 (4c) 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 (16a) from m.p. 164 OC 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-hydroxypropyl) 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

30 obtained were characterised by different analytical and spectral techniques. The details 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. )Io4) cm- Oc Ethanol- 15 N-(2-Hydroxy amine (10a) ethyl) acet- (166) amide (l6a) N-(3-Hydroxy- 152 propyl) acetamide (16b) Diethanol- 30 amine (10c) N,N-Bis(2-139 hydroxyethyl) acetamide ( 16c) 4-Amino- 30 phenol (IOd) 2-Amino- 30 phenol (10e) N-(4-Hydroxy- 151 phenyl) acet- (150) amide (16d) N- ( 2-Hydroxy- 120 phenyl) acet- (124) amide (16e)

31 Synthesis of 3-propionyl benzothiazoline-2-thione (4d) 3-Propionyl benzothiazoline-2-thione (4d) was prepared just similar to that of 4a, 4b and 4c. Here an equimolar solution of propionic acid (36) 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 OC in 80% yield. This was characterised as 3--propionyl benzothiazoline-2-thione (4d) 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).

32

33 3.2.4.(i). Reaction of 3-propionyl benzothiazoline-2-thione (4d) with amines: Formation of amides When 3-propionyl benzothiazoline-2-thione (4d) 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 IR (KBr) spectrum of 3-propionyl benzothiazoline-2- thione (4d)

34 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 (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 (4d) in methylene chloride together with an equivalent amount of benzyl alcohol (8a) was irradiated in a preparative pyrex photochemical reactor using a Philips 125W

35 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) (min) 102 cm- Aniline (6a) Benzylamine (6b) 2-Methylaniline (6c) &-Methylaniline (6d) Methylamine (6e) 20. N-Phenyl propionamide ( 17a) 2 5 N-Benzyl propionamide (17b) 3 0 N-(g-Tolyl) propionamide (17~) 2 5 N-(p-Tolyl) propionamide ( 17d) 20 N-Methyl propionamide ( 17e)

36 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 characterisation data of the products. Table Irradiation of 3-propionyl benzothiazoline-2- thione (4d) in presence of alcohols Alcohol Time of Ester b.p. Yield irradiatian (h) (lit 102 (%) Benzyl alcohol (8a) Methanol (Bb) Ethanol (8c) 3 Benzyl propionate (18a) 1.5 Methyl propionate (18b) 2 Ethyl propionate (18c). 2 Pentyl propionate (18d) Cyclohexanol (Sf) 1.5 Cyclohexyl propionate ( 18f) 2 2-Propyl propionate (18g)

37 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 benzothiazoline-2-thione (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 was photometrically. monitored by tlc and also spectro- 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

38 with 2-mercaptobenzothiazole (1). The products obtained are described in Table Table Reaction of 3-propionyl benzothiazoline-2-thione (4d) with amino alcohols Amino Time of Amide m.p. Yield IR alcohol reaction (lit. (% 1 ( KBf ) (min) 104 cm- Ethanolamine (10a) 20 N- ( 2-Hydroxyethyl) propio namide (19a) 3-Amino- 25 N-(3-Hydroxy propan 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 (10e) N-(2-Hydroxyphenyl) propionamide ( 19e)

39 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

40 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

41 3.3. Experimental 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 IR-470 spectrophotometer using KBr discs. Shimadzu UV-160 A spectrophotorneter was used for UV spectral measurements. 'H NMR (90 MHz) spectra were recorded from R SIC, IIT Madras and RRL Trivandrum.

42 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 chloroformmethanol (3:l) 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.

43 3.3.2.(i) Reaction of 3-benzoyl benzothiazoline-2-thione (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 (7d), 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.

44 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 25 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-hydroxyethyl) 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.

45 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 (4b). Yield: 2.1 g (75%); m.p.: 90 OC (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

46 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 (12~1, 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 (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

47 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-(phenylacetyl) 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) ciii) 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

48 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 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.

49 3.3.4(i) Reaction of 3-acetyl benzothiazoline-2-thione (4c) with amines: Formation of amides Freshly distilled aniline (0.2 ml, 2 mmol) was added to a solution of 3-acetyl benzothiazoline-2-thione (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 (95%), 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) (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

50 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 (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

51 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) 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

52 crystals of 3-propionyl benzothiazoline-2-thione (4d). Yield: 0.18 g (SO%), m.p.: 110 OC (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. mixture was separated using an alumina column. The 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 (17~1, 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

53 characterisation data of the products are already given in Table (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.

54 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-hydroxyethyl) propionamide (19c), N-(4-hydroxyphenyl) propionamide (19d) and N-(2-hydroxyphenyl) propionamide (19e) respectively 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).

55 ACTIVATION OF CARBOXYL GROUPS USING 2-MERCAPTOBENZOXAZOLE