Three-component reaction of benzothiazole, acetylenic esters, phenoles; synthesis of dialkyl 2-benzo[d]thiazol derivatives under grinding

Article abstract of DOI:10.2174/1386207320666170502144317

Aim and Objective: Due to biological activity of a significant number of compounds containing benzothiazole ring system and in continuation of our interest in developing new environmentally benign methods for the synthesis of heterocyclic compounds by MCR

Full text of DOI:10.2174/1386207320666170502144317

3
38
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Combinatorial Chemistry & High Throughput Screening, 2017, 20, 338-345
RESEARCH ARTICLE
eISSN: 1 83 78 56 - 52 40 07 23
F
I 0ma . c9p
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:
Three-Component Reaction of Benzothiazole, Acetylenic Esters, Phenoles;
Synthesis of Dialkyl 2-benzo[d]thiazol Derivatives Under Grinding
SB EC N
I
E
T NH AC ME
1
2,*
1
Farzaneh Fatemi , Hoorieh Djahaniani and Bita Mohtat
1
2
Department of Chemistry, Karaj Branch, Islamic Azad University, Alborz, Iran; Department of Chemistry, East
Tehran Branch, Islamic Azad University, Tehran, Iran
Abstract: Aim and Objective: Due to biological activity of a significant number of compounds
containing benzothiazole ring system and in continuation of our interest in developing new
environmentally benign methods for the synthesis of heterocyclic compounds by MCRs in this study
we performed an efficient three-component from benzothiazole, acetylenic esters and hydroxyl
aromatics compounds to synthesize of 2- benzothiazole derivatives in high yield.
Materials and Methods: IR spectra were recorded using an FTIR apparatus. Melting points
measured on an Electrothermal 9100 apparatus. Spectra were obtained in solution of CDCl3 using
TMS as internal standard. Elemental analyses were carried out using a Heracus CHN–O– Rapid
A R T I C L E H I S T O R Y
analyzer. A mixture of benzothiazole, dimethyl acetylenedicarboxylate and phenol were placed in a
mortar. The mixture was ground with a mortar and pestle at room temperature for 12 min. After
completion of the reaction, as indicated by TLC (ethyl acetate: n-hexane, 1: 3), the solvent was
distilled off under reduced pressure and the residue was crystallized from diethyl ether.
Received: October 14, 2016
Revised: February 18, 2017
Accepted: March 2, 2017
Results: Treatment of benzothiazole and dialkyl acetylenedicarboxylates in presence of resorcinol
and ꢀ-naphthol led to products 4 (dialkyl (E)-2-(2-(2-hydroxyphenyl)benzo[d]thiazol-3(2H)-yl-3-
methylbut-2-enedioate), while we observed two isomer (Z) and (E) configurations (major and minor)
in nearly 70:30 ratio when the reaction was repeated in presence of 8-hydroxy quinolone and
DMAD. Also when we examined 2-nitro phenol, 4-nitrophenol, and 4-hydroxy quinoline, only one
product 5 was obtained. This indicates that the reaction proceeds efficiently with electron-releasing
substituted phenols.
DOI:
1
0.2174/1386207320666170502144317
Conclusion: The reaction between benzothiazole and dialkyl acetylenedicarboxylates in the presence
of some phenols without electron-withdraw substitution, presents a novel, one-pot, clean,
convenient, simple and inexpensive approach into the synthesis of 2-benzothiazole derivatives of
potential synthetic and pharmacologically interest. This procedure carries significant advantages
because of the minimization of labor, time, and cost.
Keywords Three-component reaction, benzothiazole (BZT), 2-benzothiazole derivatives, environmentally benign procedure,
solvent-free grinding, biological interesting compounds.
1
. INTRODUCTION
been used as a basic structure in therapeutically applications
such as antitumor [3], antifungal [4], anti-inflammatory [5],
antidiabetic [6], antimalarial [7], antimicrobial [8], antiviral
Benzothiazole and its derivatives exist in a variety of
natural products and pharmaceutical agents, and have a wide
range of pharmacological activities. Because of that,
benzothiazole and its derivatives are of great scientific
interest nowadays. Particularly, numerous BZT-based
compounds as clinical drugs have been extensively used in
practice to treat various types of diseases with high
therapeutic potency [1].
[
9], and enzyme inhibitory activity [10, 11]. Recently,
radiolabeling of some derivatives of benzothiazoles has been
developed for PET imaging in the diagnosis of Alzheimer’s
disease [12]. Benzothiazol derivatives which have hydroxyl
or alkoxy groups, substituted on phenyl-BZT moiety, were
synthesized and evaluated for their mushroom tyrosinase
inhibition activity [13].
Most of the benzothiazole analogs were reported for their
diverse biological and pharmaceutical properties [2]. 2-
Substitued benzothiazole such as 2-aryl benzothiazole has
In multicomponent reactions (MCRs), three or more
starting materials react to form a single product. Some
important aspects of MCRs include high atom economies,
mild reaction conditions, high yields, and the execution of
reactions in green reaction conditions offer many exciting
opportunities for both medicinal chemistry and industrial
research laboratories [14].
*
Address correspondence to this author at the Department of Chemistry,
East Tehran Branch, Islamic Azad University, PO Box 33955-163, Tehran,
Iran; Tel: +98-21-3359 4950; Fax: +98-21-3359 4332;
E-mail: jahanbani.ho@gmail.com
1
875-5402/17 $58.00+.00
© 2017 Bentham Science Publishers

Three-Component Reaction of Benzothiazole, Acetylenic Esters
Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4 339
RO C
H
2
CO R
2
RO C
C
N
C
2
CO R
2
CO R
2
N
2
CO R
N
+
+
+
OH
Ar
Ar
OH
S
S
CO R
S
2
CO R
2
4
5
2
3
1
Scheme 1. Synthesis of 4 and 5.
Due to biological activity of a significant number of
compounds containing benzothiazole ring system and in
continuation of our interest in developing new environ-
mentally benign methods for the synthesis of heterocyclic
compounds by MCRs [15, 16], herein we wish to report an
efficient three-component from BZT, acetylenic esters and
hydroxyl aromatics compounds to synthesize 2-
benzothiazole derivatives in high yield (Scheme 1).
(E)-diethyl
2-(2-(2-hydroxyphenyl)benzo[d]thiazol-
3(2H)-yl-3-methylbut-2-enedioate (4b): Yield 0.34 g (85%);
-
1
Red powder, mp 154-156 ºC. IR (KBr), (ʋmax/ cm ): 3240
(OH), 1735 and 1660 (C=O), 1620 (C-C), 1275, 1180 (C-O).
1
H NMR (400 MHz, CDCl
3
3
): δ 1.43 (t, 3H, J = 6.6, CH -
3
CH
CH
2
), 1.45 (t, 3H, J = 6.8, CH
3
-CH
), 4.11 (q, 2H, J = 6.7, CH
2
), 4.08 (q, 2H, J = 6.6,
3
3
-CH
2
3
-CH ), 6.28 (s, 1H,
2
3
4
CH), 6.42 (dd, 1H, J = 7.8 Hz and J = 1.2 Hz, Ar), 6.80
3
4
(
brs, 1H, OH), 6.84 (dd, 1H, J = 6.8 Hz and J = 0.8 Hz,
3 4
Ar), 6.89 (dd, 2H, J = 7.8 Hz and J = 1.2 Hz, Ar), 7.04 (dd,
2
. MATERIALS AND METHODS
3
4
3
1
H, J = 8.0 Hz and J = 1.6 Hz, Ar), 7.08 (1H, dd, J = 7.8
4
IR spectra were recorded using an FTIR apparatus.
Hz and J = 1.6 Hz, Ar), 7.15 (s, 1H, CHvinyl), 7.19 (1H, dd,
3
4
3
Melting points measured on an Electrothermal 9100
J = 7.8 Hz and J = 1.6 Hz, Ar), 7.28 (1H, dd, J = 8.0 Hz
4 13
apparatus. Spectra were obtained in solution of CDCl
3
using
and J = 1.2 Hz Ar); C NMR (100 MHz, CDCl
3
): δ 14.6
), 72.6
TMS as internal standard. Elemental analyses were carried
out using a Heracus CHN–O– Rapid analyzer. All chemicals
used in this work purchased from Merck or Aldrich and used
without further purification. The X-ray diffraction
measurement was made on a STOE IPDS-II diffracttometer.
and 14.8 (2CH -CH ), 64.3 and 64.7 (2CH -CH
3
2
3
2
(CH), 104.5 (CH), 110.6 (CH), 117.4 (CH), 118.7 (CH),
118.9 (CH), 119.9 (C), 122.8 (CH), 123.1 (CH), 125.9 (C),
126.9 (CH), 130.8 (CH), 131.0 (C), 137.7 (C), 143.1 (C),
5
156.8 and 164.1(2C=O) ppm. Anal. Calcd. for C21H21NO S
(
3
399.11): C 63.14, H 5.30, N 3.51; found: C 63.08, H 5.36, N
.47.
E)-dimethyl 2-(2-(2,4-dihydroxyphenyl)benzo[d]thiazol-
(2H)-yl)maleate (4c): Yield 0.33 g (85%); Orange powder;
3
. GENERAL PROCEDURE
(
A mixture of benzothiazole (0.22 g, 2.0 mmol), dimethyl
3
acetylenedicarboxylate (0.28 g, 2.0 mmol) and phenol (0.094
g, 2.0 mmol) was placed in a mortar. The mixture was
ground with a mortar and pestle at room temperature for 12
min. After completion of the reaction, as indicated by TLC
-1
mp 178-180 ºC, IR (KBr), (ʋmax/ cm ): 3479 and 3373
(
1
2OH), 1714 and 1692 (C=O), 1615 (C=C), 1259, 1079 and
1
024 (C-O). H NMR (400 MHz, CDCl
OCH ), 3.72 (s, 3H, OCH ), 5.30 (s, 1H, CH), 6.24 (dd, 1H,
J = 8.0 Hz and J = 0.8 Hz, Ar), 6.38 (brs, 1H, OH), 6.88
3
): δ 3.63 (s, 3H,
3
3
(
ethyl acetate: n-hexane, 1: 3), the solvent was distilled off
3
4
under reduced pressure and the residue was crystallized from
diethyl ether.
3
4
3
(
8
dd, 1H, J = 6.4 Hz and J = 0.8 Hz, Ar), 6.94 (dd, 2H, J =
4
3
4
.0 Hz and J = 1.6 Hz, Ar), 7.02 (dd, 1H, J = 8.0 Hz and J
3 4
(
E)-dimethyl
2-(2-(2-hydroxyphenyl)benzo[d]thiazol-
= 1.2 Hz, Ar), 7.04 (1H, dd, J = 8.0 Hz and J = 1.6 Hz, Ar),
3
4
3
(2H)-yl-3-methylbut-2-enedioate (4a): Red powder; Yield
7.06 (s, 1H, CHvinyl), 7.15 (1H, dd, J = 7.8 Hz and J = 1.6
3 4 13
-
1
0
.26 g (70%), mp 173-175 ºC. IR (KBr), (ʋmax/ cm ): 3200
Hz, Ar), 7.19 (dd, 1H, J = 7.8 Hz and J = 1.2 Ar);
C
(
OH), 1734 and 1679 (2 C=O), 1619 (C=C), 1270, 1177 (C-
3 3
NMR (100 MHz, CDCl ): δ 51.8 and 53.3 (2 OCH ), 67.4
1
O). H NMR (400 MHz, CDCl
s, 3H, OCH ), 6.26 (s, 1H, CH), 6.40 (dd, 1H, J = 8.0 Hz
3
): δ 3.66 (s, 3H, OCH
3
), 3.73
(CH), 103.0 (CH), 108.6 (CH), 112.1 (C), 117.2 (CH), 117.3
(CH), 122.5 (C), 122.6 (C), 125.9 (CH), 128.5 (CH), 131.6
(CH), 131.9 (CH), 138.7 (C), 142.7 (C), 157.6 (C), 160.0 and
3
(
3
4
3
and J = 0.8 Hz, CH), 6.83 (brs, 1H, OH), 6.86 (dd, 1H, J =
4
3
4
6
.4 Hz and J = 0.8 Hz, Ar), 6.92 (dd, 2H, J = 8.0 Hz and J
6
164.0 (2C=O) ppm. Anal. Calcd. for C19H17NO S (387.08):
3
4
=
0.1 Hz, Ar), 7.00 (dd, 1H, J = 8.0 Hz and J = 1.2 Hz, Ar),
C 58.62, H 4.47, N 3.60; found: C 58.56, H 4.58, N 3.55.
3
4
7
.10 (dd, 1H, J = 8.0 Hz and J = 1.6 Hz, Ar), 7.13 (s, 1H,
3 4
(E)-diethyl 2-(2-(2,4-dihydroxyphenyl)benzo[d]thiazol-
CHvinyl), 7.20 (dd, 1H, J = 7.8 Hz and J = 1.6 Hz, Ar),
1
3
3(2H)-yl)maleate (4d): Yield 0.37 g (90%). Cherry powder;
7
.26-7.32 (m, 1H, Ar); C NMR (100 MHz, CDCl
3
): δ 51.9
-1
mp 191-193 ºC. IR (KBr), (ʋmax/ cm ): 3487 and 3375
and 53.1(2OCH
3
), 72.2 (CH), 103.7 (CH), 111.8 (CH), 116.5
(
1
2OH), 1715 and 1687 (2C=O), 1625 (C=C), 1265, 1075 and
(
(
(
CH), 118.2 (CH), 118.4 (CH), 120.1(C), 122.6 (CH), 122.8
CH), 125.6 (C), 127.8 (CH), 131.5 (CH), 131.6 (C), 138.5
C), 142.7 (C), 156.4 and 164.7 (2C=O), ppm. Anal. Calcd.
1
025 (C-O). H NMR (400 MHz, CDCl
3
): δ 1.45 (t, 3H, J =
-CH ), 4.07 (q, 2H,
), 4.13 (q, 2H, J = 6.6, CH -CH ), 5.30 (s,
H, CH), 6.21 (dd, 1H, J = 8.0 Hz and J = 0.8 Hz, Ar), 6.33
3
6
.7, CH
3
-CH
2
), 1.48 (t, 3H, J = 6.6, CH
3
2
3
3
J = 6.7, CH
3
-CH
2
3
2
for C19
1.24, H 4.50, N 3.84.
H
17NO
5
S (371.11): C 61.28, H 4.56, N 3.80; found: C
3
4
1
(
6
3
4
brs, 1H, OH), 6.88 (dd, 1H, J = 6.4 Hz and J = 0.8 Hz,
Ar), 6.91 (dd, 2H, J = 8.0 Hz and J = 1.2 Hz, Ar), 7.00 (dd,
3 4

3
40 Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4
Fatemi et al.
3
4
3
1
H, J = 8.0 Hz and J = 1.2 Hz, Ar), 7.02 (1H, dd, J = 8.0
3 3
NMR (100 MHz, CDCl ): δ 52.0 and 53.1 (2OCH ), 65.7
4
Hz and J = 1.6 Hz, Ar), 7.05 (s, 1H, CHvinyl), 7.14 (1H, dd,
(CH), 113.3 (CH), 117.8 (CH), 117.9 (CH), 122.2 (CH),
3
4
3
J = 7.8 Hz and J = 1.6 Hz, Ar), 7.21 (dd, 1H, J = 7.8 Hz
122.9 (CH), 128.5 (C), 128.7 (CH), 128.9 (C), 129.1 (CH),
4
13
and J = 1.2 Ar); C NMR (100 MHz, CDCl
3
): δ 14.5and
), 67.3 (CH),
130.7 (CH), 133.6 (CH), 133.8 (C), 136.4 (C), 136.7 (C),
1
1
1
1
(
6
4.9 (2CH
3
-CH
2
), 64.5 and 64.8 (2CH
3
-CH
2
137.4 (C), 148.2 (C), 148.4 (CH), 164.1 and 164.8 (2C=O)
03.1 (CH), 108.5 (CH), 112.3 (C), 117.1 (CH), 117.2 (CH),
22.3 (C), 122.5 (C), 125.7 (CH), 128.4 (CH), 131.7 (CH),
32.0 (CH), 138.5 (C), 142.8 (C), 157.7 (C), 160.2 and 164.5
ppm.
1
Minor isomer (E)-4g (30%): H NMR (400 MHz, CDCl
3
):
), 6.15 (s, 1H, CH),
.39 (dt, 1H, J = 7.6 Hz and J = 0.8 Hz, Ar), 6.86 (dt, 1H,
δ 3.59 (s, 3H, OCH ), 3.72 (s, 3H, OCH
3
3
2C=O) ppm. Anal. Calcd. for C21
H
21NO
6
S (415.11): C
3
4
6
0.71, H 5.09, N 3.37; found: C 60.75, H 5.15, N 3.32.
E)-dimethyl 2-(2-(2-hydroxynaphtahlen-1-yl)benzo[d]
thiazol-3(2H)-yl)maleate (4e): Yield 0.33 g (80%). Orange
3
4
3
J = 8.0 Hz and J = 1.2 Hz, Ar), 6.98 (dt, 1H, J = 8.0 Hz
4
3
4
(
and J = 1.2 Hz, Ar), 7.13 (dd, 1H, J = 7.6 Hz and J = 0.8
3 3
Hz, Ar), 7.33 (d, 1H, J = 8.8 Hz, Ar), 7.45 (dd, 1H, J = 8.0
-
1
3
powder; mp 199-201 ºC. IR (KBr), (ʋmax/ cm ): 3488 (OH),
721 and 1680 (C=O), 1612 (C=C), 1271 and 1202 (C-O).
Hz and J = 4.4 Hz, Ar), 7.55 (s, 1H, CHvinyl), 7.99 (dd, 1H,
4
3
1
3J = 8.8 Hz and J = 0.8 Hz , Ar), 8.12 (dd, 1H, J = 8.4 Hz
4 3
1
H NMR (400 MHz, CDCl
3
): δ 3.66 (s, 3H, OCH
3
), 3.73 (s,
and J = 0.8 Hz, Ar), 8.59 (brs, 1H, OH), 8.78 (dd, 1H, J =
4 13
3
3
H, OCH ), 6.19 (s, 1H, CH), 6.44 (d, 1H, J = 7.6 Hz Hz,
3
4.4 Hz and J = 1.6 Hz, Ar); C NMR (100 MHz, CDCl
3
): δ
3
3
Ar), 6.94 (t, 1H, J = 7.2 Hz, Ar), 7.00 (t, 1H, J = 7.6 Hz,
51.7 and 53.4 (2OCH ), 65.9 (CH), 111.4 (CH), 116.1 (CH),
3
3
3
Ar), 7.22 (t, 1H, J = 7.2 Hz, Ar), 7.27 (t, 1H, J = 8.0 Hz,
118.1 (CH), 118.8 (CH), 121.9 (CH), 122.1 (C), 122.5 (C),
125.2 (CH), 127.5 (C), 127.8 (CH), 128.4 (CH), 136.2 (CH),
137.8 (CH), 139.2 (C), 142.8(C), 150.1 (C), 151.7 (CH),
164.0 and 165.1 (2C=O) ppm.
Ar), 7.34 (brs, 1H, OH), 7.35 (s, 1H, CHvinyl), 7.37 (1H, d,
3
3
J = 7.8 Hz, Ar), 7.48-7.55 (2H, m, Ar), 7.77 (d, 1H, J = 6.4
3
13
Hz, Ar), 8.34 (d, 1H, J = 7.6 Hz, Ar); C NMR (100 MHz,
3 3
CDCl ): δ 52.1 and 53.3 (2OCH ), 72.1 (CH), 111.3 (CH),
Diethyl
2-(2-(8-hydroxyquinolin-7-yl)benzo[d]thiazol-
1
1
1
1
12.0 (C), 115.9 (CH), 119.8 (CH), 122.6 (CH), 122.8 (CH),
3
(2H)-yl)maleate (4h): Yield 0.36 g (85%). Red powder;
23.1 (CH), 125.5 (C), 125.6 (CH), 125.7 (CH), 127.4 (CH),
27.5 (C), 127.6 (C), 128.2 (CH), 135.2 (CH), 138.6 (C),
42.8 (C), 152.9 (C), 164.7 and 165.0 (2 C=O) ppm. Anal.
-1
mp 238-240 ºC. IR (KBr), (ʋmax/ cm ): 3399 (OH), 1710 and
1
1
683 (C=O), 1622 and 1469 (C=C), 1267 (C-O). H NMR
3
(
(
400 MHz, CDCl
3
): δ 1.10 (t, 3H, J = 7.2, CH
3
-CH
), 4.05 (q, 2H, J = 7.2, CH
2
), 1.16
Calcd. for C23
found: C 65.48, H 4.51, N 3.26.
H
19NO
5
S (421.10): C 65.54, H 4.54, N 3.32;
3
3
t, 3H, J = 7.2, CH
3
-CH
2
3
-CH
-CH
2
),
),
3
4
4
.14 (ABquartet, 2H, J = 8.0 Hz and J = 1.2 Hz, CH
3
2
3 4
(
E)-diethyl 2-(2-(2-hydroxynaphtahlen-1-yl)benzo[d]
6.16 (s, 1H, CH), 6.43 (dt, 1H, J = 7.6 Hz and J = 0.8 Hz,
3
4
thiazol-3(2H)-yl)maleate (4f): Yield 0.38 g (85%). Yellow
Ar), 6.86 (dt, 1H, J = 8.0 Hz and J = 1.2 Hz, Ar), 6.97 (dt,
-
1
3
4
3
powder; mp 214-216-201 ºC. IR (KBr), (ʋmax/ cm ): 3475
OH), 17151 and 1687 (C=O), 1620 and 1460 (C=C), 1285
1H, J = 8.0 Hz and J = 1.2 Hz, Ar), 7.13 (dd, 1H, J = 7.6
4 3
(
Hz and J = 0.8 Hz, Ar), 7.33 (d, 1H, J = 8.8 Hz, Ar), 7.46
3 3
1
and 1198 (C-O). H NMR (400 MHz, CDCl
3
): δ 1.28 (t, 3H,
-CH ), 4.02 (q,
), 4.13 (q, 2H, J = 6.7, CH -CH ),
.20 (s, 1H, CH), 6.45 (d, 1H, J = 7.6 Hz Hz, Ar), 6.92 (t,
(dd, 1H, J = 8.0 Hz and J = 4.4 Hz, Ar), 7.73 (s, 1H,
3 3
3
J = 6.6, CH
3
-CH
2
), 1.32 (t, 3H, J = 6.8, CH
-CH
3
2
CHvinyl), 8.02 (d, 1H, J = 8.8 Hz, Ar), 8.12 (dd, 1H, J =
3
3
4
2
6
1
1
1
H, J = 6.6, CH
3
2
3
2
8.4 Hz and J = 1.6 Hz, Ar), 8.54 (brs, 1H, OH), 8.78 (dd,
3
3J
4
13
1H, = 4.0 Hz and J = 1.2 Hz, Ar); C NMR (100 MHz,
3
3
H, J = 7.2 Hz, Ar), 7.02 (t, 1H, J = 7.6 Hz, Ar), 7.24 (t,
CDCl
3 3 2 2
): δ 13.8 and 13.9 (2CH -CH ), 60.7 and 62.3 (2CH -
3
3
H, J = 7.2 Hz, Ar), 7.28 (t, 1H, J = 8.0 Hz, Ar), 7.32 (brs,
CH ), 65.8 (CH), 111.5 (CH), 116.3 (CH), 118.0 (CH), 118.2
3
3
H, OH), 7.34 (s, 1H, CHvinyl), 7.36 (1H, d, J = 7.8 Hz,
(CH), 121.8 (CH), 122.9 (C), 122.4 (C), 125.1 (CH), 127.6
(C), 127.8 (CH), 128.4 (CH), 136.1 (CH), 137.8 (C), 139.5
(C), 143.4 (C), 148.1 (C), 149.9 (CH), 163.9 and 164.5
3
Ar), 7.46-7.53 (2H, m, Ar), 7.78 (d, 1H, J = 6.4 Hz, Ar),
3
13
8
.32 (d, 1H, J = 7.6 Hz, Ar); C NMR (100 MHz, CDCl
δ 14.2 and 14.6 (2CH -CH ), 64.5 and 64.9 (2CH -CH
3
):
),
3
2
3
2
22 2 5
(2C=O) ppm. Anal. Calcd. for C24H N O S (450.12): C
7
1
1
1
(
6
2.2 (CH), 111.2 (CH), 112.9 (C), 115.8 (CH), 119.9 (CH),
22.5 (CH), 122.7 (CH), 123.0 (CH), 125.4 (C), 125.5 (CH),
25.6 (CH), 127.3 (CH), 127.5 (C), 127.7 (C), 128.1 (CH),
35.3 (CH), 138.7 (C), 142.9 (C), 153.0 (C), 164.5 and 165.2
63.98, H 4.92, N 6.22; found: C 63.92, H 4.85, N 6.16.
Tetramethyl 4aH-benzo[4,5]thiazolo[3,2-a]pyridine-1,2,
3
,4-tetracarboxylate (5a): Yield 0.36 g (85%). Yellow
-1
powder; mp 232-234 ºC (lit. [16], ºC). IR (KBr), (ʋmax/ cm ):
5
2 C=O) ppm. Anal. Calcd. for C25H23NO S (449.130): C
6.80, H 5.16, N 3.12; found: C 66.76, H 5.25, N 3.17.
1
1
739, 1715 1668, 1665 (C=O), 1584, 1475, 1448 (C=C),
1
228 (C-N). H NMR (400 MHz, CDCl
3
): δ 3.69 (s, 3H,
), 3.86 (s, 3H, OCH ), 3.94 (s, 3H,
), 6.43 (s, 1H, CH), 7.34-7.40 (m, 2H, Ar), 7.49 (dt,
Dimthyl 2-(2-(8-hydroxyquinolin-7-yl)benzo[d]thiazol-
OCH
OCH
3
), 3.83 (s, 3H, OCH
3
3
3
(2H)-yl)maleate (4g): Yield 0.36 g (85%). Yellow powder;
3
-
1
3
4
3
mp 220-222 ºC. IR (KBr), (ʋmax/ cm ): 3344 (OH), 1715 and
1H, J = 8.4 Hz and J = 1.2 Hz, Ar), 7.71 (d, 1H, J = 7.6
1
3
1
685 (C=O), 1623 (C=C), 1381 and 1275 (C-O). Anal.
Calcd. for C22 S (422.09): C 62.55, H 4.29, N 6.63;
found: C 62.58, H 4.34, N 6.58.
3
Hz, Ar); C NMR (100 MHz, CDCl ): δ 52.0, 52.4, 52.6, and
H
18
N
2
O
5
53.4 (4OMe), 55.5 (CH), 101.8 (C), 111.3 (C), 122.5 (C),
123.4 (C), 123.8 (C), 124.2 (C), 127.4 (C), 128.4 (C), 138.9
(C), 140.1 (C), 162.1, 163.9, 164.4, and 166.2 (4C=O) ppm.
1
Major isomer (Z)-4g (70%): H NMR (400 MHz, CDCl
3
):
8
Anal. Calcd. for C19H17NO S (419.07): C 54.41, H 4.09, N
δ 3.58 (s, 3H, OCH
3
), 3.75 (s, 3H, OCH ), 6.61 (s, 1H, CH),
3
3
3
3.34; found: C 54.45, H 4.12, N 3.38.
6
7
7
.80 (d, 1H, J = 8.4 Hz, Ar), 7.14 (t, 1H, J = 7.2 Hz, Ar),
3
.33 (1H, J = 4.4 Hz Hz, Ar), 7.36 (s, 1H, CH vinyl), 7.46-
Tetraethyl 4aH-benzo[4,5]thiazolo[3,2-a]pyridine-1,2,3,
3
.50 (m, 3H, Ar), 7.72 (br s, 1H, OH), 7.95 (dd, 1H, J = 8.0
4-tetracarboxylate (5b): Yield 0.36 g (85%). Yellow
4
3
4
-1
Hz and J = 0.8 , Ar), 8.15 (dd, 1H, J = 8.4 Hz and J = 1.6
powder; m p 200-202 ºC. IR (KBr, cm ): ʋmax 1733, 1720,
3
4
13
Hz, Ar), 8.81 (dd, 1H, J = 4.4 Hz and J = 1.2 Hz, Ar);
C
1665, and 1662 (C=O), 1586, 1470, and 1446 (C=C), 1230

Three-Component Reaction of Benzothiazole, Acetylenic Esters
Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4 341
1
3
(
C-N). H NMR (400 MHz, CDCl
3
): δ 1.18 (t, 3H, J = 6.8,
Table 1. Effect of different solvents and temperature
conditions on the synthesis of 4a.
3
3
CH
3
-CH
2
), 1.36 (t, 6H, J = 7.2, 2CH
-CH ), 4.14 (q, 2H, 3J = 7.2 Hz, CH
H, J = 7.2 Hz, 2 CH -CH ), 4.35-4.39 (m, 2H, CH
.41 (s, 1H, CH), 7.32-7.47 (m, 3H, Ar), 7.69 (d, 1H, J =
3
-CH
2
), 1.40 (t, 3H, J =
-CH ), 4.30 (q,
-CH ),
7
4
6
7
.2, CH
3
2
3
2
3
a
3
2
3
2
Entry
Solvent
CH Cl
CH Cl
Temp. (ºC)
Yield (%)
3
b
1
3
1
2
3
4
5
6
7
8
2
2
r.t
50
45
50
40
35
70
45
45
85
.6 Hz, Ar); C NMR (100 MHz, CDCl
-CH ), 55.7 (CH), 60.8, 61.1, 61.5, and 62.3
), 101.3 (C), 111.2 (C), 122.3 (C), 123.0 (C),
23.2 (C), 124.5 (C), 127.0 (C), 128.4 (C), 139.1 (C), 140.5
3
): δ 13.9, 13.9, 14.3,
b
and 14.3 (4CH
3
2
3
r.t
4
1
(
3 2
CH -CH
b
H
H
2
O
r.t
b
C), 162.6, 163.8, 164.7, and 167.6 (4C=O) ppm. Anal.
S (475.13): C 58.09, H 5.30, N 2.95;
found: C 58.12, H 5.27, N 2.98.
2
O
80
Calcd. for C23
H
25NO
8
b
THF
r.t
b
Solvent-Free
Solvent-Free
Solvent-Free
Grinding
r.t
b
80
4
4
. RESULTS AND DISCUSSION
b
100
.1. Chemical Synthesis
c
9
r.t
a
Isolated Yield
Reaction time = 12 h
Rreaction time = 15 m
We have previously reported the reaction between
b
c
benzothiazole, dialkyl acetylenedicarboxylates and 4-
hydroxycoumarin in which the newly formed compounds of
benzo[d]chromeno[3,4-h]oxathiazonine derivatives were
synthesized (Scheme 2) [16]. The consideration of previous
report encouraged us to investigate for the reaction of
bnzothiazole 1 and dialkyl acetylenedicarboxylates 2 in the
presence of some hydroxyl aromatic compounds such as
phenols, 4-hydroxy quinoline, and 8-hydroxy quinoline 3
To determine the scope and limitations of this reaction
further, we extended the optimal reaction to various phenols
such as resorcinol, 2-nitro phenol, 4-nitrophenol, β-naphthol,
4
-hydroxy quinoline and 8-hydroxy quinoline. We found that
treatment of BTA and dialkyl acetylenedicarboxylates in the
presence of resorcinol, β-naphthol and 8-hydroxy quinoline
led to products 4, but when we examined 2-nitro phenol, 4-
nitrophenol, and 4-hydroxy quinoline, only one product 5
(
Scheme 1). In this regard, we chose reaction between 1 and
dimethyl acetylenedicarboxylate (DMAD) 2a in the presence
2 2
of phenol 3a in CH Cl at room temperature. It was
interesting that based on the proposed mechanisms in our
recent report, the predicted product was not detected at all,
while dimethyl (E)-2-(2-(2-hydroxyphenyl)benzo[d]thiazol-
[
17] was obtained. This indicates that the reaction proceeds
efficiently with electron-releasing substituted phenols (Table
2
). Also 4-hydroxyquinoline is more stable in form of keton
3
(2H)-yl-3-methylbut-2-enedioate 4a was obtained.
rather than hydroxyl form.
The structures of 4a-h and 5a-b have been confirmed by
H
1
13
IR, H NMR, C NMR and mass spectroscopy. The
structural elucidation was clearly determined by X-ray
diffraction of single crystal of 4h [18, 19] (Fig. 2).
MeO C
2
CO Me
2
CO Me
2
N
S
N
S
1
In the H NMR spectrum of 4a, the two methoxy groups
were observed at δ = 3.66 and 3.73 ppm as two signal
singlet, the CH proton appeared at δ = 6.26 and OH proton
was observed at δ = 6.83, as broad singlet. The C=CH proton
signal was exhibited at about 7.13 ppm which confirmed (E)
CO Me
2
HO
OH
1
3
configuration [20, 21]. The C NMR spectrum of compound
4
a exhibited 19 distinct resonances in agreement with the
proposed structure.
H
S
The reaction 8-hydroxyquinoline with dimethyl
acetylenedicarboxylate (DMAD) in the presence of
benzothiazole afforded dimthyl 2-(2-(8-hydroxyquinolin-7-
yl)benzo[d]thiazol-3(2H)-yl)maleate 4g. The structure of 4g
O
CO Me
N
2
Me O C
2
H
H
ꢀ
1
13
1
was deduced from their H and C NMR spectra. The H
Scheme 2. Optimization of the reaction condition of BTA 1,
dimethyl acetylenedicarboxylate 2a and phenol 3a.
NMR spectrum of 4g displayed four signals for the methoxy
(
δ 3.58, 3.59, 3.72 and 3.75), two signals for CH aliphatic
groups (δ 6.15 and 6.61), a C=CH proton signal at about 7.36
ppm and a C=CH proton signal at about 7.55 ppm in
agreement with the presence of two isomer (Z) and (E)
configurations (major and minor) in nearly 70:30 ratio
Then we continued our investigation in various solvents
2 2 2
such as CH Cl , CHCl3, H O, THF, and also solvent-free
reaction conditions at room temperature for 12 h and also
grinding at room temperature for 15 m (Table 1). It was
found that the reaction under grinding reaction resulted in
higher yield (entry 9).
(
Scheme 3). The OH groups of two isomers exhibited two
13
broad lines at (δ 7.72 and 8.59). In fact, the C NMR
spectrum of 4g exhibits the major (M) and minor (m)
isomers of 4g, which display four sharp lines for the four

3
42 Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4
Fatemi et al.
Table 2. Synthesis of 4 and 5.
Entry
Ar
R
Product (4)
Product (5)
Yield %
H
2
MeO C
2
CO Me
-
85
1
Phenol
Me
N
S
4
HO
a
H
85
EtO C
-
2
2
CO Et
2
Phenol
Et
N
S
HO
4b
H
85
90
80
MeO C
2
-
2
Co Me
3
4
5
Resorcinol
Resorcinol
2-Naphtol
Me
Et
N
S
OH
HO
c
4
H
EtO C
2
2
CO Et
-
-
N
S
OH
4d
HO
H
MeO C
2
CO Me
2
Me
N
S
HO
H
4
e
85
85
2
EtO C
CO
2
Et
6
2-Naphtol
Et
-
N
S
HO
4
f
CO Me
2
MeO C
H
2
7
8
8-hydroxy Quinoline
8-hydroxy Quinoline
Me
Et
-
-
OH
N
N
S
4
g
H
8
5
EtO
2
C
2
CO Et
OH
N
N
S
4h
(
Table 2) Contd….

Three-Component Reaction of Benzothiazole, Acetylenic Esters
Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4 343
Entry
Ar
R
Product (4)
Product (5)
Yield %
2
CO Me
70
2
MeO C
-
2
CO Me
N
9
2-Nitrophenol
Me
S
CO Me
2
5a
CO
2
Et
CO
Et
75
80
85
2
EtO C
2
Et
N
S
1
1
1
0
1
2
2-Nitrophenol
4-Nitrophenol
4-Nitrophenol
Et
Me
Et
-
-
-
CO
2
5
b
CO
2
Me
CO
Me
2
MeO C
2
Me
N
S
CO
2
5a
ꢀ
CO
2
Et
CO
Et
2
EtO C
2
Et
N
S
CO
2
5b
ꢀ
a
Isolated Yield.
methoxy (δ 51.7, 52.0, 53.1 and 53.4) groups. Partial
assignment of these resonances is given in the General
procedure section.
compounds and leads to intermediate 8 which probably
undergoes tautomerism to produce product of 4 (Scheme 4).
S1
C5
H
2
CO Me
MeO
2
C
2
CO Me
C6
MeO
2
C
H
01
C4
C8
C13
OH
OH
N
C7
C12
N2
N
C9 C10
N
C16
N
C1
S
S
C3
N1
04
C11
C23
C14
C24
C2
C15
C22
Majour isomer (Z)-4g
Minor isomer (E)-4g
C17
C21
03
05
Scheme 3. Two isomers (E) and (Z) of 4g.
0
18
C20
C19
0
2
When diethyl acetylenedicarboxylate (DEAD) was
employed in this reaction, only the (E)-isomer of diethyl 2-
Fig. (1). ORTEP diagram of the X-ray crystal structure of 4h.
(
2-(8-hydroxyquinolin-7-yl)benzo[d]thiazol-3(2H)-
1
yl)maleate (4h) was isolated. The H NMR spectrum of the
compound 4h showed the vicinal methine proton signal at
1
The H NMR spectrum of 5a exhibited four methoxy
groups (δ = 3.69, 3.83, 3.86 and 3.94 ppm), a singlet for
methylene (CH) group (δ = 6.43 ppm) protons along with
resonances (δ = 7.34–7.71 ppm) for the aromatic protons.
7
.72 ppm which is confirmed the (E) configuration [20-21].
Moreover, the proposed structure of 4h was further
unequivocally determined by X-ray diffraction (Fig. 1).
1
3
The proton decoupled C NMR spectrum of 5a showed 19
1
13
A reasonable mechanistic postulate for the formation of 4
is given in Scheme 3. A plausible reaction scenario for this
one-pot reaction might be occurred via the initial formation
of 1:1 zwitterionic intermediate 6 from the reaction between
benzothiazole 1 and dialkyl acetylenedicarboxylates 2, and
subsequent protonation of the 1:1 adduct by hydroxyl
aromatic compounds. Then, the positively charged ion 7
might be attacked by the anion of the hydroxyl aromatic
distinct resonances. The H and C NMR spectra of 5b were
also similar to those for 5a except for the alkoxy moieties.
We have not established a mechanism for the formation
of tetraalkyl 4aH-benzo[4,5]thiazolo[3,2-a]pyridine 5 ring
systems, but a reasonable possibility is indicated in Scheme
5
.

3
44 Combinatorial Chemistry & High Throughput Screening, 2017, Vol. 20, No. 4
Fatemi et al.
2
RO C
O
RO C
2
C
H
CO R
RO C
2
2
CO R
C
C
N
2
C
N
S
N
S
C
C
3
+
S
CO R
2
6
7
1
2
RO C
2
C
H
2
CO R
RO
2
C
RO C
2
C
N
C
N
C
O
H
OH
H
S
S
4
8
Scheme 4. Proposed mechanism for the formation of compound 4.
CO Me
[2]
Nitti, A.; Po. R.; Bianchi, G.; Dario, P. Direct Arylation
Strategies in the Synthesis of π-Extended Monomers for Organic
Polymeric Solar Cells. Molecules, 2017, 22, 21- 31.
Masao, Y.; Ichiro, H.; Noriyuki, H.; Toshinori, A.; Youko, O.;
Fumie, T.; Shiho, I.; Kumiko, K.; Hidehiko, F.; Shinichi, K.;
Yuichi, S. Synthesis and biological evaluation of benzothiazole
derivatives as potent antitumor agents. Bioorg. Med. Chem., 2005,
2
S
N
S
N
2
[
3]
CO Me
2
MeO C
1
2
2
2
CO Me
5
, 3328-3332.
S
2
CO Me
S
N
CO Me
[4]
[5]
Sheng, C.; Che, X.; Wang, W.; Wang, S.; Cao, Y.; Yao, J.; Miao,
Z.; Zhang, W. Design and synthesis of antifungal benzoheterocyclic
derivatives by scaffold hopping. Eur. J. Med. Chem., 2011, 46,
2
N
C
2
CO Me
CO Me
2
1
706-1712.
MeO
2
CO
2
Me
MeO C
Gurupadayya, B.M.; Gopal, M.; Padmashali, B.; Vaidya, V.P.
Synthesis and bological activities of fuorobenzothiazoles. Ind. J.
Heterocy. Chem., 2005, 15, 169-172.
2
CO Me
2
Scheme 5. Proposed mechanism for the formation of compound 5.
[
6]
Pattan, S.R.; Suresh, Ch.; Pujar, V.D.; Reddy, V.V.K.; Rasal, V.P.;
Koti, B.C. Synthesis and antidiabetic activity of 2-amino [50(4-
sulphonylbenzylidene-2,4-thiazolidenedinone]-7-chloro-6-
flourobenzothiazole, Ind. J. Chem., 2005, 44B, 2404-2408.
A. Burger, S.N. Sawhey, Antimalarials. III. Benzothiazole amino
alcohols. J. Med. Chem., 1968, 11, 270-273.
Saeed, S.; Rashid, N.; Jones, P. G.; Ali, M.; Hussain, R. Synthesis,
characterization and biological evaluation of some thiourea
derivatives bearing benzothiazole moiety as potential antimicrobial
and anticancer agents. Eur. J. Med. Chem., 2010, 45, 1323-1331.
Akhtar, T.; Hameed, S.; Al-Masoudi, N.; Loddo, R.; Colla, P. In
vitro antitumor and antiviral activities of new benzothiazole and
CONCLUSION
In summary, the reaction between benzothiazole and
dialkyl acetylenedicarboxylates in the presence of some
phenols without electron-withdraw substitution, presents a
novel, one-pot, clean, convenient, simple and inexpensive
approach into the synthesis of 2-benzothiazole derivatives of
potential synthetic and pharmacologically interest. This
procedure carries significant advantages because of the
minimization of labor, time, and cost. Noteworthy, our work
introduces a very easy and simple one-pot multicomponent
reaction under the solvent-free grinding conditions, without
any catalyst, activation or modification.
[7]
8]
[
[9]
1
1
,3,4-oxadiazole-2-thione derivatives. Acta Pharm., 2008, 58, 135-
49.
[10]
[11]
[12]
[13]
Wang, X.; Sarris, K.; Kage, K.; Zhang, D.; Brown, S.P.; Kolasa, T.;
Surowy, C.; ElKouhen, O.F.; Muchmore, S.W.; Brioni, J.D.;
Stewart, A.O. Synthesis and evaluation of benzothiazole-based
analogues as novel, potent, and selective fatty acid amide hydrolase
inhibitors. J. Med. Chem., 2009, 52, 170-180.
CONFLICT OF INTEREST
Huang, L.; Su, T.; Shan, W.; Luo, Z.; Sun, Y.; He, F.; Li, X.
Inhibition of cholinesterase activity and amyloid aggregation by
The authors declare no conflict of interest, financial or
otherwise.
berberine-phenyl-benzoheterocyclic
and
tacrine-phenyl-
benzoheterocyclic hybrids. Bioorg. Med. Chem., 2012, 20, 3038–
048.
3
Cui, M. C.; Li, Z. J.; Tang, R. K.; Liu, B. L. Synthesis and
evaluation of novel benzothiazole derivatives based on the
bithiophene structure as potential radiotracers for beta-amyloid
plaques in Alzheimer's disease. Bioorg. Med. Chem., 2010, 18,
ACKNOWLEDGEMENTS
Declared none.
2
777-2784.
Ha, Y.M.; Park, J.Y.; Park, Y.J.; Park, D.; Choi, Y.J.; Kim, J.M.;
Lee, E.K.; Han, Y.K.; Kim, J.A.; Lee, J.Y.; Moon, H.R.; Chung,
H.Y. Synthesis and biological activity of hydroxy substituted
phenyl-benzo[d]thiazole analogues for antityrosinase activity in
B16 cells. Bioorg. Med. Chem. Lett., 2011, 21, 2445-2449.
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= 1.380 g cm , μ(Mo-Kα)= 0.189 mm , crystal dimension of
0.35×0.28×0.25 mm. The X-ray diffraction measurement was made
on a STOE IPDS 2T diffractometer with graphite monochromated
Mo-Kα radiation. The structure was solved by using SHELXS. The
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[18]. The non-hydrogen atoms were refined anisotropically by full
matrix least-squares on F values to final R
2
[
16]
1
= 0.0627, wR = 0.1469
2
and S = 1.044 with 295 parameters using 5782 independent
reflection (θ range = 2.69-29.13º). Hydrogen atoms were added in
idealized positions except hydrogen atom attached to oxygen atom.
The crystallographic information file has been deposited with the
Cambridge Data Centre, CCDC 1463836.
[
[
17]
18]
[19]
[20]
[21]
X-STEP32 Version 1.07b, Crystallographic Package; Stoe & Cie
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4
8, 1440-1444.
X-ray data for 4h: C24
group Pī, a = 9.2336(18), b = 10.336(2), c = 12.011(2) Å; α=
Eliel, E.L.; Wilen, S.H. Stereochemistry of Organic Compounds.
Wiley, New York, 1994, p 569.
H
22
N
2
O S, M = 450.50, triclinic system, space
5
Pretsch, E.; Buhlmann, P.; Badertscher, M. Structure Determination
of Organic Compounds. Springer Verlag, Berlin, 2009, p. 168.
3
1
07.79(3), β= 96.18(3), γ= 90.58(3)º, V = 1084.0(4) Å , Z = 2, Dcalcd