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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)
* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.3(i) did not show any difference.
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)
* Mixed m.p. with the compounds prepared as described in Ch. 3, Sec. 3.2.4(i) did not show any difference.
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)
'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.3(ii).
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.
Table 4.8. Reaction of 3-propionyl benzoxazoline-2-thione
(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)
'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.4(ii).
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) phenyl- acetamide (13a)
3 0 N-(3-Hydroxy- propyl) phenyl- acetamide ( 1 3 b )
3 0 N,N-Bis(2- hydroxyethyl) phenylacetamide
. (13c)
3 0 N-(4-Hydroxy phenyl) phenyl- acetamide (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.
'A homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.3(iii).
Table 4.12. Reaction of 3-propionyl benzoxazoline-2-thione
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 homogeneous tlc was observed with the compound prepared as described in Ch. 3, Sec. 3.2.4(iii).
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)