An efficient conversion of phenolic esters to benzothiazoles under mild and virtually neutral conditions

Article abstract of DOI:10.1055/s-2004-829089

Phenolic esters are efficiently converted to 2-substituted benzothiazoles in a one-pot reaction by treatment with 2-aminothiophenol in the presence of a catalytic amount of K₂CO₃ in N-methyl-2-pyrrolidone (NMP) at 100°C.

Full text of DOI:10.1055/s-2004-829089

LETTER
1533
An Efficient Conversion of Phenolic Esters to Benzothiazoles under Mild and
Virtually Neutral Conditions
Conversion of
P
he
s
nolic
E
ste
i
rs to Be
t
nzothiazolesK. Chakraborti,* Santosh Rudrawar, Gurmeet Kaur, Lalima Sharma
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab – 160062, India
Fax +91(172)2214692; E-mail: akchakraborti@niper.ac.in
Received 24 February 2004
lothiobenzanilides in NMP or DMF at 150 °C for 2
Abstract: Phenolic esters are efficiently converted to 2-substituted
hours,28 and e) the Suzuki biaryl coupling of 2-bromoben-
benzothiazoles in a one-pot reaction by treatment with 2-ami-
nothiophenol in the presence of a catalytic amount of K2CO3 in N-
methyl-2-pyrrolidone (NMP) at 100 °C.
zothiazoles with arylboronic acids in the presence of
K2CO3 in DME–H2O at 100 °C for 6 hours.29 However,
these methodologies suffer from one or more of the disad-
vantages such as the lack of ease of availability/prepara-
tion of the starting material, prolonged reaction time (14 h
Key words: benzothiazoles, aryl esters, 2-aminothiophenol
to 4 d), use of costly, air sensitive, and toxic substances,
Benzothiazole moiety has emerged as a versatile pharma-
requirement of excess of reagents/catalysts, special appa-
cophore as compounds bearing benzothiazolyl group are
ratus, and harsh reaction conditions. Thus, the need for the
antitumour,1 antimicrobial2 and antiglutamate/anti-
development of alternate synthetic route to construct the
parkinsonism3 agents, wide spectrum Ca2+ channel
benzothiazolyl moiety is in high demand. Herein we re-
antagonists,4 inhibitors of several enzymes (e.g., aldose
port an efficient conversion of phenolic esters to 2-substi-
reductase,5 monoamine oxidase,6 lipoxygenase,7 cyclo-
tuted benzothiazoles.
oxygenase,8 acetylcholine esterase,9 thrombine,10 proteas-
es,11 H+-K+ ATPase,12 carbonic anhydrase,13 HCV
helicase,14) plant growth regulators,15 and find industrial
applications as antioxidants16 and vulcanization accelera-
tors.17
We reasoned that the treatment of a phenolic ester 2 with
2-aminothiophenol (1) in the presence of a catalytic
amount of base (e.g. K2CO3) should lead to the formation
of benzothiazole. An initial proton exchange between the
base and 1 generates the 2-aminothiophenolate anion (1a).
Nucleophilic attack by the in situ generated 1a on 2 forms
the S-acylated 2-aminothiophenol (3), which subsequent-
ly undergoes cyclodehydration to generate the benzothia-
zole. The liberated phenolate anion acts as base and
undergoes proton exchange with 1 to generate 1a consti-
tuting a ‘demand-based’ thiolate anion generation
protocol30 (Scheme 1). The use of catalytic amount of
K2CO3 makes the reaction operative under virtually neu-
tral condition and applicable for acid and base sensitive
substrates.
Various methods are available for the construction of
benzothiazolyl moiety involving the treatment of 2-ami-
nothiophenol (1) with carboxylic acid derivatives. These
include the reaction with selenoesters18 and seleno-
amides19 in ethanol for a prolonged period, aldehydes
through silica or montmorillonite clay catalyzed oxidative
cyclodehydration under microwave irradiation,20 carbox-
ylic acids in the presence of excess of polyphosphoric acid
at 150–220 °C for 2–4 hours14,21 or excess of P2O5–
MeSO3H at 70 °C for 10 hours.22 The synthesis of
benzothiazoles has also been achieved by the reaction of
1 with halo aromatics through palladium catalyzed carbo-
nylation under high pressure in the presence of 2,6-luti-
dine in dimethyl acetamide23 and with b-chloro-
cinnamaldehyde derivatives by p-TsOH catalyzed degra-
dative cyclization under microwave irradiation.24 The fol-
lowing other routes are reported for the synthesis of
benzothiazoles: a) The reaction of copper(I) thiobenzoate
with 2-iodoaniline in HMPT at 110 °C for 3 hours,25 b)
oxidative radical cyclization of thioanilides by treatment
with large excess of potassium ferricyanide at 90 °C under
basic conditions,21,26 c) demethylative cyclization of o-
(methylthio)anilides with phosphonitrile dichloride in di-
oxane under reflux for 8–10 hours,27 d) base promoted
intramolecular aromatic nucleophilic substitution of o-ha-
In order to determine the optimum reaction conditions, 2-
naphthyl benzoate and 2-naphthyl pivalate were treated
with 1 (1 equiv) in the presence of K2CO3 (5 mol%) under
SH
S–
K2CO3 (cat)
NMP
NH2
NH2
O
1
1a
R
Ar
O
2
S
R
S
– ArOH
– H2O
+ ArO–
R
O
N
NH2
3
SYNLETT 2004, No. 9, pp 1533–1536
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829089; Art ID: D04804ST
© Georg Thieme Verlag Stuttgart · New York
2
2.
0
7.
2
0
0
4
Scheme 1 Conversion of phenolic ester to benzothiazole via
demand-based thiolate anion generation.

1534
A. K. Chakraborti et al.
LETTER
Table 1 Reaction of 1 with Phenolic Esters 2 under Various Condi-
various conditions in NMP (Table 1). A quantitative con-
version to 2-phenylbenzothiazole took place in 45 min-
utes at 100 °C during the reaction involving 2-naphthyl
benzoate. No significant conversion to 2-phenylbenzothi-
azole took place in carrying out the reaction at room tem-
perature for 24 hours (entry 2). To determine the role of
K2CO3, an equimolar mixture of 1 and 2-naphthyl ben-
zoate was treated separately in NMP and under neat con-
ditions at 100 °C for 45 minutes in the absence of K2CO3
(entries 3 and 4). 2-Phenylbenzothiazole was formed in
18% yield when the reaction was carried out in NMP (en-
try 3). However, no significant amount of 2-phenylben-
zothiazole formation took place in carrying out the
reaction in the absence of solvent (entry 4). In each case,
the starting materials remained intact. A 39% yield of 2-
phenylbenzothiazole was formed when the equimolar
amount of 1 and 2-naphthyl benzoate was treated with
K2CO3 (5 mol%) under neat condition at 100 °C for 45
minutes indicating that NMP plays an important role for
in situ regeneration of 1a through proton exchange be-
tween 1 and the liberated 2-naphthoate anion. The reac-
tionsa
Entry
R
Ar
Time (h) Yield (%)b,c
0.75 100
20
5d
1
2
Ph
Ph
Ph
Ph
Ph
t-Bu
Ph
Ph
Ph
t-Bu
2-Naphthyl
2-Naphthyl
3
2-Naphthyl
0.75
0.75
0.75
3
18e
Nilf
39g
4
2-Naphthyl
5
2-Naphthyl
6
2-Naphthyl
100
100
100
100
100
7
4-Chlorophenyl
4-Nitrophenyl
2,4,6-Trichlorophenyl
4-Cyanophenyl
0.5
0.5
0.5
0.5
8
9
10
a The phenolic ester was treated with 1 (1 equiv) in the presence of
K2CO3 (5 mol%) (except for entries 3 and 4) in NMP (except for
tion with 2-naphthyl pivalate required 3 hours for the entries 4 and 5) at 100 °C (except for entry 2).
b GCMS yield of the corresponding 2-substituted benzothiazole.
complete conversion to the corresponding benzothiazole
under similar conditions. The longer time required during
the reaction with the pivalate was due to the steric hin-
drance offered by the tert-butyl group during the nucleo-
philic attack by the 2-aminothiophenolate anion on the
carbonyl carbon of the pivalate retarding the formation of
the intermediate S-acylated 2-aminothiophenol (3). As the
formation of the intermediate 3 should depend upon the
leaving group property of the aryloxide anion, we planned
to determine the most effective phenolic moiety of 2 for
the desired transformation. Thus, the benzoate and piv-
alate derivatives of various phenols were treated with 1 in
the presence of K2CO3 (5 mol%) in NMP at 100 °C. In the
case of 4-chlorophenyl, 4-nitrophenyl, and 2,4,6-trichlo-
rophenyl benzoates, complete conversion to 2-phenylben-
zothiazole took place in 0.5 hours (entries 7–9). The
distinct role of the leaving group property of the aryloxide
anion was revealed by the reaction of 4-cyanophenyl piv-
alate in which case the reaction was completed in 0.5
hours as compared to 3 hours required for the reaction
with 2-naphthyl pivalate (compare entries 6 and 10). To
further demonstrate the role of the aryloate moiety in 2,
methyl and ethyl benzoates were separately treated with 1
in the presence of K2CO3 (5 mol%) in NMP at 100 °C for
1 hour. In each occasion, the methyl/ethyl benzoate and 1
remained intact and no significant amount of 2-phenyl-
benzothiazole was formed (GC).31 The lack of formation
of benzothiazole from the alkyl esters may be explained
due to the poor leaving group property of the alkoxide
anion compared to that of the aryloxide anion.
c The unreacted phenolic ester was recovered, wherever applicable.
d The reaction was carried out at r.t.
e The reaction was carried out in the absence of K2CO3.
f The reaction was carried out in the absence of K2CO3 under neat
conditions.
g The reaction was carried out under neat conditions.
Cl
O
R
O
R
S
R
O
O
N
Cl
Cl
4
5
6
Figure 1 Various aryl esters and the corresponding benzothiazoles.
a) R = phenyl; b) R = 4-methoxyphenyl; c) R = 3,4-dimethoxyphe-
nyl; d) R = 3,4,5-trimethoxyphenyl; e) R = 4-chlorophenyl; f) R = 4-
nitrophenyl; g) R = trans-cinnamyl.
equiv) in the presence of K2CO3 (5 mol%) in NMP at
100 °C (Table 2). Comparable yields were obtained with
2-naphthyl and 2,4,6-trichlorophenyl esters but the reac-
tions were faster with the later substrates. Excellent
chemoselectivity was observed in the formation of the de-
sired product and no competitive side reactions such as
the methyl ether cleavage30a,f (entries 2–4 and 9–11), nu-
cleophilic aromatic substitution of the halogen atom32 (en-
tries 5 and 12) or the nitro group33 (entry 6), reduction of
the nitro group34 (entry 6) or the double bond35 (entry 7),
and Michael addition36 (entry 7) were observed.
Logically, we planned to extend this reaction to different
aryl esters in order to establish it as a general method for
conversion of aryl esters to benzothiazoles. Thus, various
acylated derivatives of 2-naphthol (4a–g) and 2,4,6-
trichlorophenol (5a–e) (Figure 1) were treated with 1 (1
In conclusion, this report describes an efficient chemose-
lective conversion of phenolic esters to benzothiazoles in
a one-pot reaction with 2-aminothiophenol under mild
and virtually neutral conditions.
Synlett 2004, No. 9, 1533–1536 © Thieme Stuttgart · New York

LETTER
Conversion of Phenolic Esters to Benzothiazoles
1535
2-(4-Nitrophenyl)benzothiazole (6f).20,24 Mp 228–230 °C. IR
Table 2 Conversion of Phenolic Esters to Benzothiazolesa
(KBr): 3350, 3050, 1674, 1596, 1522, 1443, 1431, 1342, 1311,
1
1250, 1219, 1107 cm–1. H NMR (300 MHz, CDCl3): d = 8.35 (d,
Entry
1
Aryl ester
Product
6a
Time (min) Yield (%)b
J = 8.86 Hz, 2 H), 8.26 (d, J = 8.83 Hz, 2 H), 8.13 (d, J = 8.83 Hz,
1 H), 7.96 (d, J = 7.84 Hz, 1 H), 8.26 (d, J = 8.83 Hz, 2 H), 7.58–
7.53 (m, 1 H), 7.49–7.44 (m, 1 H). 13C NMR (300 MHz, CDCl3):
d = 154.41, 149.40, 139.39, 135.73, 128.34, 126.94, 126.27,
124.30, 124.14, 121.85. MS (CI): m/z = 257 [MH+].
2-Styrylbenzothiazole (6g).38 Mp 98–100 °C. IR (KBr): 3050,
3029, 1628, 1490, 1445, 1314, 1190, 1071, 957 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.00 (d, J = 7.90 Hz, 1 H), 7.86 (d, J = 7.90 Hz,
1 H), 7.59–7.56 (m, 3 H), 7.50–7.33 (m, 6 H). MS (CI): m/z = 238
[MH+].
4a
4b
4c
4d
4e
4f
45
45
45
45
45
45
45
30
30
30
30
30
90
72
68
70
65
60
50
95
75
73
60
66
2
6b
6c
3
4
6d
6e
5
6
6f
The analytical data for the new compound are provided below.
7
4g
5a
5b
5c
5d
5e
6g
2-(3,4-Dimethoxyphenyl)benzothiazole (6c). Mp 132–134 °C. IR
(KBr): 2956, 2939, 2840, 1599, 1521, 1482, 1431, 1337, 1312,
1261, 1167, 1146, 1074, 1018 cm–1. 1H NMR (300 MHz, CDCl3):
d = 8.00 (d, J = 8.06 Hz, 1 H), 7.87 (d, J = 7.76 Hz, 1 H), 7.75 (s, 1
H), 7.62 (d, J = 8.32 Hz, 1 H), 7.48 (t, J = 7.31 Hz, 1 H), 7.37 (t,
J = 7.50 Hz, 1 H), 4.03 (s, 3 H), 3.96 (s, 3 H). 13C NMR (300 MHz,
CDCl3): d = 167.92, 154.03, 151.53, 149.29, 134.82, 126.57,
126.21, 124.85, 122.77, 121.47, 121.12, 110.96, 109.72, 56.00. MS
(CI): m/z = 272 [MH+]. Anal. Calcd for C15H13NO2S: C, 66.40; H,
4.83; N, 5.16. Found: C, 66.56; H, 4.78; N, 5.12.
8
6a
9
6b
6c
10
11
12
6d
6e
a The phenolic ester was treated with 1 (1 equiv) in the presence of
K2CO3 (5 mol%) at 100 °C in NMP.
b Isolated yield of the corresponding 2-substituted benzothiazole.
Acknowledgment
LS thanks CSIR, New Delhi for award of Senior Research Fel-
lowship.
Typical Procedure for the Conversion of Phenolic Ester to Ben-
zothiazole.
References
The magnetically stirred solution of 4a (620 mg, 2.5 mmol) in NMP
(2.5 mL) was treated with 1 (312.5 mg, 2.5 mmol) at 100 °C for 45
min in the presence of K2CO3 (17.5 mg, 0.125 mmol, 5 mol%)
under nitrogen. The reaction mixture was made alkaline with 5% aq
NaOH (15 mL) and extracted with CH2Cl2 (4 × 15 mL). The com-
bined organic extracts were washed with brine (15 mL), dried
(Na2SO4) and concentrated under reduced pressure to afford the
crude product which on passing through a column of silica gel (60–
120). Elution with 5% EtOAc in hexane (50 mL) afforded 2-phenyl-
benzothiazole (6a) (475 mg, 90%) identical [mp, IR, 1H NMR and
MS (EI)] of an authentic sample.19,20,29 The remaining reactions
were carried out following this general procedure. The mp and spec-
tral data (IR, 1H NMR and MS) of all known compounds were iden-
tical with those of the literature values, wherever applicable. New
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Synlett 2004, No. 9, 1533–1536 © Thieme Stuttgart · New York

1536
A. K. Chakraborti et al.
LETTER
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