Synthesis of Benzo[4,5]imidazo[2,1-b]thiazole by Copper(II)-Catalyzed Thioamination of Nitroalkene with 1H-Benzo[d]imidazole-2-thiol

Article abstract of DOI:10.1002/adsc.201800393

A Copper(II)-catalyzed thioamination of β-nitroalkene with 1H-benzo[d]imidazole-2-thiol has been developed for the synthesis of benzo[4,5]imidazo[2,1-b]thiazole derivatives. A variety of N-fused benzoimidazothiazole derivatives are obtained in high yields through successive C?N and C?S bond formations. This protocol is also applicable to β-substituted β-nitroalkenes to afford 2,3-disubstituted benzoimidazothiazoles. (Figure presented.).

Full text of DOI:10.1002/adsc.201800393

Title: Synthesis of Benzo[4,5]imidazo[2,1-b]thiazole by Cu(II)-catalyzed
Thioamination of Nitroalkene with 1H-Benzo[d]imidazole-2-thiol
Authors: Alakananda Hajra, Sourav Jana, Amrita Chakraborty, and
Valerii Z. Shirinian
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800393
Link to VoR: http://dx.doi.org/10.1002/adsc.201800393

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Benzo[4,5]imidazo[2,1-b]thiazole by Copper(II)-
Catalyzed Thioamination of Nitroalkene with 1H-
Benzo[d]imidazole-2-thiol
Sourav Jana,a Amrita Chakraborty,b Valerii Z. Shirinianc and Alakananda Hajraa*
a Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
b Anugrah Narayan College, Boring Road, Patna, Bihar 800013, India.
c Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky prosp., 119991, Moscow, Russian Federation.
Email: alakananda.hajra@visva-bharati.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A Copper(II)-catalyzed thioamination of β- benzo[4,5]imidazo[2,1-b]thiazole derivatives, new
nitroalkene with 1H-benzo[d]imidazole-2-thiol has been
developed for the synthesis of benzo[4,5]imidazo[2,1-
strategy for their preparation from readily accessible
and less expensive precursors is desirable.
b]thiazole
derivatives.
A
variety
of
N-fused
Owing to the ability to take part in a wide range of
organic reactions and easy accessibility through nitro-
aldol condensation, nitroalkenes have been used to
synthesize a number of heterocycles[12] such as
benzoimidazothiazole derivatives are obtained in high
yields through successive C-N and C-S bond formations.
This protocol is also applicable to β-substituted β-
nitroalkenes
to
afford
2,3-disubstituted
furan,[13a,14a,b]
imidazole,[14c]
pyridine,[13b]
benzoimidazothiazoles.
pyrimidine,[13c] indole,[13d] imidazopyridine,[13e,f,14d]
etc[13g-k]. Notably, nitroalkene is bielectrophilic in
nature and could serve as potential precursor to form
heterocycles by reacting with binucleophiles via
cascade hetero-Michael addition reaction.[14d]
However, study for the coupling between nitroalkene
and N, S –binucleophile to prepare thiazole moiety[15]
via C-N and C-S bond formations is unexplored. In
continuation of our ongoing program to explore the
nitroalkene as bielectrophile to synthesize several
heterocycles,[14] herein we disclose a Cu(II)-catalyzed
coupling between nitroalkene and commercially
available 1H-benzo[d]imidazole-2-thiol to afford
imidazo[2,1-b]thiazoles (Scheme 1).
Keywords: N-fused benzoimidazothiazole; nitroalkene;
regioselectivity; Michael addition; thioamination
Introduction
Imidazo[2,1-b]thiazole constitutes an important
class of fused heterocycles because of their
pharmacological activities such as calcium channel
antagonistic,[1]
acetylcholinesterase
inhibitor,[2]
SIRT1 activator[3] and also for their antifungal,[4] anti-
inflammatory,[5]
antitubercular
antitumor,[6]
activities[8] etc.[9]
antidiabetic,[7]
Particularly,
benzo[4,5]imidazo[2,1-b]thiazole
moiety
offers
promising immunomodulating and antimetastatic
properties which have been studied extensively for
drug development.[10] There are few synthetic
methods
for
the
construction
of
benzo[4,5]imidazo[2,1-b]thiazole which are based on
coupling between 1H-benzo[d]imidazole-2-thiol and
1,1-dibromoalkenes/alkynes/trans-1,2-diiodoalkenes
in presence of Cu-salts (Scheme 1).[11] However,
these starting materials are not convenient to prepare
and also most of reported methods afford 2-
unsubstituted
benzo[4,5]imidazo[2,1-b]thiazoles.
Because of the significant biological aspects of
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
the basis of 1H NMR spectra in which the
characteristic peak for thiazole (sp2-H) is observed as
singlet at 6.55 ppm and also by comparing with
literature.[11a,b,d] In order to determine the optimal
conditions, the reaction was screened with several
solvents like MeCN, DMF, DMA, toluene,
nitrobenzene, NMP, DCB and AcOH (Table 1,
entries 2 to 9). Among them DMF was found to be
the best to give the product 3aa in 68% yield (Table 1,
entry 3). Further increasing catalyst loading to 15%,
the yield of 3aa was improved to 87% (Table 1, entry
10). An almost similar result was obtained with 20
mol% of Cu(OAc)2.H2O (Table 1, entry 11). Other
metal acetates like Zn(OAc)2.2H2O and AgOAc were
employed as the catalyst, however these were not so
effective like Cu(OAc)2.H2O (Table 1, entries 12 and
13). Treatment with other common Cu salts such as
CuCl2, CuBr2, CuSO4.5H2O and Cu(OTf)2 as catalyst
were found to be less effective for this process (Table
1, entries 14 to 17). FeCl3 was also tested but it did
not produce any desired product (Table 1, entry 18).
o
Scheme 1. Synthesis of benzo[4,5]imidazo[2,1-b]thiazoles.
With increasing the reaction temperature to 100 C,
no observable change of the yield was noticed (Table
1, entry 19); but at lower temperature (60 oC), a much
lower yield was obtained (Table 1, entry 20). Thus, a
combination of 15 mol% Cu(OAc)2.H2O in DMF at
80 °C for 8 h was found to be optimal reaction
conditions for this thioamination process (Table 1,
entry 10).
Results and Discussion
We commenced our study by reacting 1H-
benzo[d]imidazole-2-thiol (1a) with (E)-1-methyl-4-
(2-nitrovinyl)benzene (2a) in presence of 10 mol%
Cu(OAc)2.H2O in DMSO at 80 °C (Table 1, entry 1).
Interestingly, the desired product 3aa was isolated in
35% yield after 8 h. The structure was confirmed on
Table 1. Evaluation of the reaction condition.[a]
Entry
1
2
3
4
5
6
7
8
Catalyst (mol%)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (10)
Cu(OAc)2.H2O (15)
Cu(OAc)2.H2O (20)
Zn(OAc)2.2H2O (15)
AgOAc (15)
Solvent
DMSO
MeCN
DMF
DMA
toluene
PhNO2
NMP
Temperature
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
Yield[b]
35%
Trace
68%
Trace
ND[c]
36%
Trace
32%
52%
87%
87%
25%
21%
ND
DCB
9
AcOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10
11
12
13
14
15
16
17
18
CuCl2 (15)
CuBr2 (15)
CuSO4.5H2O (15)
Cu(OTf)2 (15)
ND
20%
27%
ND
FeCl3 (15)
DMF
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
19
20
Cu(OAc)2.H2O (15)
Cu(OAc)2.H2O (15)
DMF
DMF
100 °C
60 °C
85%
26%
[a] Reaction conditions: 0.3 mmol of 1a, 0.3 mmol of 2a and catalyst in 1.5 mL solvent at 80 °C for 8 h.
[b] Isolated yields.
[c] ND = Not detected.
After getting the optimized reaction conditions,
the scope of β-nitroalkene (2a-2o) was examined, and
the results are shown in Table 2. β-Nitroalkenes
having both electron donating substituents like -Me, -
OMe and electron withdrawing group like -NO2 on
the phenyl ring responded well to give the
corresponding 3-substituted benzo[4,5]imidazo[2,1-
b]thiazoles (3aa-3ae) with 78-87% yields. Different
halogens like -F, -Cl and -Br containing β-
nitroalkenes reacted very smoothly with 1H-
benzo[d]imidazole-2-thiol to give the respective
products in significant yields (3af-3ai). The position
of substitution in the phenyl ring of β-nitroalkenes
did not affect the yield of the reactions (3ac-3ai).
Interestingly, β-nitroalkene bearing an acid sensitive
dioxole unit also afforded the respective product (3aj)
without any difficulties. Furthermore, (E)-1-(2-
nitrovinyl)naphthalene
and
(E)-2-(2-
nitrovinyl)thiophene provided good yields of the
corresponding products (3ak and 3al). However, the
current methodology is not applicable for
nitroalkenes having aliphatic substituents at -
position (2m, 2n and 2o).
Table 2. Substrate scope: Variation of β-nitroalkenes.[a]
[a] Reaction conditions: 0.3 mmol of 1a, 0.3 mmol of 2 and 15 mol% Cu(OAc)2.H2O in 1.5 mL DMF at 80 °C for 8 h.
[b] Reaction time 24 h.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
Table 4. Substrate scope: Variation of substituents on 1H-
benzo[d]imidazole-2-thiol.[a]
Moreover, β-substituted β-nitroalkene such as β-
methyl β-nitroalkene, β-ethyl β-nitroalkene and β-
phenyl β-nitroalkene derivatives were also
successfully employed as the coupling partner with
1H-benzo[d]imidazole-2-thiol under the optimized
reaction conditions (Table 3). In all the cases,
cyclization occurred with good yields to furnish 3,4-
disubtituted benzo[4,5]imidazo[2,1-b]thiazoles (5a-
5h).
Table 3. Substrate scope: Reaction with β-substitute-β-
nitroalkenes.[a]
[a] Reaction conditions: 0.3 mmol of 1, 0.3 mmol of 2a and
15 mol% Cu(OAc)2.H2O in 1.5 mL DMF at 80 °C for 8 h.
[b] The isomeric ratio was determined by 1H NMR.
Gram scale applicability of the present
methodology was also demonstrated in Scheme 2.
The reaction between 1H-benzo[d]imidazole-2-thiol
(1a) and (E)-1-methyl-4-(2-nitrovinyl)benzene (2a)
afforded the thiazole product in 74% (1.172 g, 3aa)
yield under the ordinary reaction set-up.
[a] Reaction conditions: 0.3 mmol of 1a, 0.3 mmol of 4 and
15 mol% Cu(OAc)2.H2O in 1.5 mL DMF at 80 °C for 8 h.
[b] Reaction time 16 h.
[c] Reaction time 24 h.
Scheme 2. Practical applicability of the present protocol.
On the basis of the literature report and our
previous work,[14a,d] the probable mechanism of the
present protocol is outlined in Scheme 3. Initially the
intermediate A is formed via Michael addition of 1H-
benzo[d]imidazole-2-thiol (1a) to (E)-1-methyl-4-(2-
nitrovinyl)benzene (2a). Subsequently B intermediate
is generated from the intermediate A through
intramolecular cyclization via C-S bond formation in
presence of Cu(OAc)2.H2O. Finally the product (3aa)
was obtained by the elimination of water and
HNO.[13h,14d] It is worthy to mention that initial
Michael addition occurs through N-atom under the
reaction conditions although S-atom is more
nucleophilic than N-atom. It might be due to the
complexation of S-atom with Cu(II)-catalyst.
Next, the compatibility of this method with 1H-
benzo[d]imidazole-2-thiols having substituents like -
Me and -OMe on the phenyl ring as shown in Table 4
was studied. In both the cases mixture of two
regioisomers (3ba+3b'a) and (3ca+3c'a) were
isolated with almost equal ratios. However,
benzo[d]imidazole-2-thiols
having
electron
withdrawing substituents such as -Cl and -NO2 on
benzene ring were not suitable substrates for this
annulation.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
1
118−121 °C); H NMR (CDCl3, 400 MHz): δ 7.78 (d, J =
8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.6 Hz,
2H), 7.32 (t, J = 8.4 Hz, 1H), 7.08-7.06 (m, 1H), 6.99-6.96
(m, 1H), 6.55 (s, 1H), 2.49 (s, 3H); 13C{1H} NMR (CDCl3,
100 MHz): δ 157.3, 148.6, 140.4, 134.4, 130.2, 129.7,
128.8, 126.5, 123.4, 120.4, 119.2, 111.8, 106.8, 21.6.
3-Phenylbenzo[4,5]imidazo[2,1-b]thiazole (3ab):[11a,b,d]
Yellow solid (64 mg, 85%), mp 138−139 °C (lit. mp
1
138−140 °C); H NMR (CDCl3, 400 MHz): δ 7.80 (d, J =
8.0 Hz, 1H), 7.67-7.64 (m, 2H), 7.59-7.56 (m, 3H), 7.32 (t,
J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 8.0
Hz, 1H), 6.60 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ
157.3, 148.7, 134.4, 130.2, 129.5, 129.1, 129.0, 128.4,
123.5, 120.6, 119.3, 111.8, 107.3.
3-(4-Methoxyphenyl)benzo[4,5]imidazo[2,1-b]thiazole
(3ac):[11a,b] Yellow solid (69 mg, 82%), mp 148−149 °C (lit.
mp 148−150 °C); 1H NMR (CDCl3, 400 MHz): δ 7.78 (d, J
= 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 8.4 Hz,
1H), 7.23 (d, J = 8.4 Hz, 1H), 7.09-7.06 (m, 3H), 6.52 (s,
1H), 3.92 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ
161.0, 157.3, 148.6, 134.2, 130.4, 130.2, 123.4, 121.6,
120.4, 119.2, 114.4, 111.7, 106.5, 55.6.
Scheme 3. Possible mechanistic pathway.
We have developed a new Cu(II)-catalyzed
methodology
for
the
synthesis
of
benzo[4,5]imidazo[2,1-b]thiazole derivatives by the
reaction between 1H-benzo[d]imidazole-2-thiol and
β-nitroalkene. This transformation shows broad
substrate scope and a wide range of functional group
tolerance. Moreover, starting materials are readily
available. To the best of our knowledge there is no
report on synthesis of benzo[4,5]imidazo[2,1-
b]thiazole ring via 1,2-aminothiolation of β-
nitroalkene which acts as a bielectrophile. We believe
3-(3,4,5-Trimethoxyphenyl)benzo[4,5]imidazo[2,1-
b]thiazole (3ad): White solid (71 mg, 70%), mp 165-
166 °C; 1H NMR (CDCl3, 400 MHz): δ 7.83 (d, J = 8.0 Hz,
1H), 7.35-7.32 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.85 (s,
2H), 6.63 (s, 1H), 3.92 (s, 3H), 3.89 (s, 6H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 157.4, 153.7, 124.1, 123.8, 123.2,
122.6, 120.8, 119.2, 115.1, 111.9, 109.6, 107.4, 106.3, 61.2,
56.5; Anal. Calcd for C18H16N2O3S: C, 63.51; H, 4.74; N,
8.23; Found C, 63.62; H, 4.68; N, 8.11%.
3-(3-Nitrophenyl)benzo[4,5]imidazo[2,1-b]thiazole
1
(3ae): Yellow solid (69 mg, 78%), mp 134-135 °C; H
the present protocol is very convenient and will open NMR (CDCl3, 400 MHz): δ 8.86 (t, J = 2.0 Hz, 1H), 8.54 (t,
the door to synthesize various heterocycles.
J = 2.0 Hz, 1H), 8.49-8.47 (m, 1H), 8.39-8.37 (m, 1H),
8.31-8.29 (m, 1H), 7.98-7.95 (m, 1H), 7.76 (t, J = 8.0 Hz,
1H), 7.68-7.63 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 143.7, 139.2, 139.0, 136.2, 134.5, 134.2, 130.3, 130.2,
Experimental section
127.6, 125.6, 125.3, 123.5, 123.4, 122.9, 122.4; Anal.
Calcd for C15H9N3O2S: C, 61.01; H, 3.07; N, 14.23; Found
General Information: Reagents were purchased from C, 61.23; H, 3.10; N, 14.16%.
commercial sources and used without further purification.
1H and13C{1H} NMR spectra were determined on 400 MHz
3-(4-Fluorophenyl)benzo[4,5]imidazo[2,1-b]thiazole
1
(3af):[11b,d] Yellow solid (72 mg, 89%), mp 173−174 °C (lit.
mp 174−177 °C); 1H NMR (CDCl3, 400 MHz): δ 7.82 (d, J
= 8.0 Hz, 1H), 7.66-7.62 (m, 2H), 7.36-7.26 (m, 3H), 7.15
(d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.62 (s, 1H);
13C{1H} NMR (CDCl3, 100 MHz): δ 163.8 (d, J = 232 Hz),
157.2, 148.3, 132.8, 131.0 (d, J = 8 Hz), 125.5 (d, J = 3 Hz),
123.7, 120.8, 119.3, 116.4 (d, J = 22 Hz), 115.8, 111.6,
107.9.
spectrometer. H NMR spectra were determined on 400
MHz spectrometer as solutions in CDCl3. Chemical shifts
are expressed in parts per million (δ) and the signals were
reported as s (singlet), d (doublet), t (triplet), m (multiplet),
q (quartet), dd (double doublet), dq (double quartet) and
coupling constants (J) were given in Hz. 13C{1H} NMR
spectra were recorded at 100 MHz in CDCl3 solution.
Chemical shifts as internal standard are referenced to
CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as
internal standard. TLC was done on silica gel coated glass
slide. Commercially available solvents were freshly
distilled before the reaction. All reactions involving
moisture sensitive reactants were executed using oven
dried glassware.
3-(4-Chlorophenyl)benzo[4,5]imidazo[2,1-b]thiazole
(3ag):[11a,d] Yellow solid (79 mg, 93%), mp 200-201 °C (lit.
mp 199−202 °C); 1H NMR (CDCl3, 400 MHz): δ 7.80 (d, J
= 8.0 Hz, 1H), 7.62-7.54 (m, 4H), 7.34 (t, J = 8.4 Hz, 1H),
7.21 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.62 (s,
1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 157.2, 148.7,
136.5, 133.0, 132.8, 130.2, 129.5, 127.8, 123.7, 120.8,
119.4, 111.6, 108.0.
General Procedure for the Synthesis of Table 2 to Table
4: A mixture of 1H-benzo[d]imidazole-2-thiol (1, 0.30
mmol), β-Nitroalkene (2, 0.30 mmol) and Cu(OAc)2.H2O
(15 mol %, 9 mg, 0.045 mmol) in DMF (1.5 mL) was taken
in a reaction tube and the reaction mixture was stirred at
80 °C for 8 h. After completion of the reaction it was
allowed to cool at room temperature and extracted with
ethyl acetate and water. The organic phase was dried over
anhydrous Na2SO4. The crude residue was obtained after
evaporating the solvent under reduced pressure and finally
it was purified by column chromatography on silica gel
(60-120 mesh) using petroleum ether/ethyl acetate = 9:1 as
an eluent to afford the pure product.
3-(2,6-Dichlorophenyl)benzo[4,5]imidazo[2,1-b]thiazole
1
(3ah): Yellow solid (84 mg, 88%), mp 184-186 °C; H
NMR (CDCl3, 400 MHz): δ 7.79 (d, J = 8.0 Hz, 1H), 7.57-
7.49 (m, 3H), 7.31 (t, J = 8.4 Hz, 1H), 7.04 (t, J = 8.0 Hz,
1H), 6.78 (s, 1H), 6.68 (d, J = 8.0 Hz, 1H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 157.1, 148.0, 137.2, 132.3, 128.6,
127.1, 125.5, 123.5, 121.1, 119.3, 110.5, 110.1, 106.0;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H9Cl2N2S:
318.9858; found: 318.9861.
3-(p-Tolyl)benzo[4,5]imidazo[2,1-b]thiazole (3aa):[11a,b,d]
Yellow solid (69 mg, 87%), mp 118−120 °C (lit. mp
3-(4-Bromophenyl)benzo[4,5]imidazo[2,1-b]thiazole
(3ai):[11a] Yellow solid (84 mg, 85%), mp 205-206 °C (lit.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
mp 205-206 °C); 1H NMR (CDCl3, 400 MHz): δ 7.81 (d, J 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 154.3, 147.8,
= 8.0 Hz, 1H), 7.73-7.71 (m, 2H), 7.55-7.52 (m, 2H), 7.34 131.0, 130.1, 129.1, 127.8, 123.4, 123.1, 121.7, 120.6,
(t, J = 7.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 8.4 119.1, 111.0, 109.5, 13.6; Anal. Calcd for C14H10N2S2: C,
Hz, 1H), 6.64 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 62.19; H, 3.73; N, 10.36; Found C, 62.02; H, 3.70; N,
157.2, 148.5, 132.4, 131.8, 131.7, 130.4, 128.4, 124.7, 10.48%.
123.7, 120.8, 119.4, 111.6, 108.1.
2-Ethyl-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (5e):
1
3-(Benzo[d][1,3]dioxol-5-yl)benzo[4,5]imidazo[2,1-
Yellow solid (68 mg, 81%), mp 132-134 °C; H NMR
b]thiazole (3aj): White solid (83 mg, 94%), mp 171- (CDCl3, 400 MHz): δ 7.74 (d, J = 8.4 Hz, 1H), 7.59-7.56
172 °C; 1H NMR (CDCl3, 400 MHz): δ 7.79 (d, J = 8.4 Hz, (m, 3H), 7.53-7.49 (m, 2H), 7.26-7.22 (m, 1H), 6.96-6.92
1H), 7.47-7.41 (m, 1H), 7.34-7.28 (m, 2H), 7.14-7.11 (m, (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 2.68 (q, J = 7.6 Hz, 2H),
1H), 7.09-7.08 (m, 1H), 6.54 (s, 1H), 6.14 (s, 1H), 6.10 (s, 1.26 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
2H); 13C{1H} NMR (CDCl3, 100 MHz): δ 157.2, 149.3, δ 155.1, 147.8, 132.6, 130.3, 130.0, 129.2, 128.8, 128.3,
148.6, 148.2, 133.9, 130.1, 124.1, 123.5, 123.2, 120.6, 127.4, 123.0, 120.4, 118.9, 111.2, 21.2, 15.8; Anal. Calcd
119.3, 116.2, 111.8, 108.9, 106.9, 101.9; Anal. Calcd for for C17H14N2S: C, 73.35; H, 5.07; N, 10.06; Found C,
C16H10N2O2S: C, 65.29; H, 3.42; N, 9.52; Found C, 65.43; 73.11; H, 5.13; N, 10.08%.
H, 3.31; N, 9.59%.
2-Ethyl-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (5f):
1
3-(Naphthalen-1-yl)benzo[4,5]imidazo[2,1-b]thiazole
Yellow oil (76 mg, 87%); H NMR (CDCl3, 400 MHz): δ
(3ak): White solid (76 mg, 84%), mp 205-206 °C; 1H NMR 7.75 (d, J = 8.0 Hz, 1H), 7.42-7.37 (m, 4H), 7.25-7.23 (m,
(CDCl3, 400 MHz): δ 8.11 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 1H), 6.99-6.94 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 2.68 (q, J
8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.71-7.69 (m, 1H), = 7.6 Hz, 2H), 2.51 (s, 3H) 1.26 (t, J = 7.6 Hz, 3H);
7.63 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.42 (t, J 13C{1H} NMR (CDCl3, 100 MHz): δ 155.2, 148.0, 140.2,
= 8.4 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.81-6.79 (m, 1H), 130.2, 129.9, 125.8, 124.3, 123.0, 120.3, 119.0, 116.6,
6.77 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 13C{1H} NMR 111.3, 109.5, 21.6, 21.3, 15.9; Anal. Calcd for C18H16N2S:
(CDCl3, 100 MHz): δ 157.0, 148.6, 133.7, 132.2, 132.1, C, 73.94; H, 5.52; N, 9.58; Found C, 74.08; H, 5.47; N,
131.0, 130.2, 129.1, 128.8, 127.7, 127.0, 126.8, 125.5, 9.51%.
125.2, 123.4, 120.7, 119.0, 111.5, 108.7; Anal. Calcd for
C19H12N2S: C, 75.97; H, 4.03; N, 9.33; Found C, 75.76; H,
2-Ethyl-3-(4-methoxyphenyl)benzo[4,5]imidazo[2,1-
b]thiazole (5g): Yellow semi solid (73 mg, 79%); 1H NMR
(CDCl3, 400 MHz): δ 7.73 (d, J = 8.4 Hz, 1H), 7.60-7.56
(m, 1H), 7.37 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.25-7.21 (m,
3.90; N, 9.47%.
3-(Thiophen-2-yl)benzo[4,5]imidazo[2,1-b]thiazole
(3al):[11a,b] White solid (55 mg, 72%), mp 95-96 °C (lit. mp 1H), 7.15-7.09 (m, 2H), 6.96-6.92 (m, 1H), 6.69 (d, J = 8.4
94−95 °C); 1H NMR (CDCl3, 400 MHz): δ 7.80 (d, J = 8.4 Hz, 1H), 3.70 (s, 3H), 2.65 (dq, J = 7.6 Hz, 2.4 Hz, 2H),
Hz, 1H), 7.67-7.62 (m, 2H), 7.35-7.31 (m, 1H), 7.29 (d, J = 1.26 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
8.8 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, δ 158.5, 155.3, 147.9, 132.3, 131.9, 127.6, 122.7, 121.0,
1H), 6.59 (s, 1H), 13C{1H} NMR (CDCl3, 100 MHz): δ 120.2, 118.8, 111.3, 110.8, 109.6, 55.6, 21.4, 15.6; Anal.
157.5, 146.1, 131.09, 131.01, 123.6, 120.7, 119.8, 119.5, Calcd for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08; Found
116.6, 116.5, 116.3, 111.5, 107.5.
C, 70.36; H, 5.16; N, 9.01%.
2-Methyl-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole
2,3-Diphenylbenzo[4,5]imidazo[2,1-b]thiazole (5h):[11d]
(5a): White solid (72 mg, 86%), mp 168−169 °C; 1H NMR White solid (64 mg, 65%), mp 195-197 °C (lit. mp 196-
(CDCl3, 400 MHz): δ 7.74 (d, J = 8.0 Hz, 1H), 7.43-7.37 197 °C); 1H NMR (CDCl3, 400 MHz): δ 7.81 (d, J = 8.4 Hz,
(m, 4H), 7.27-7.23 (m, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.88 1H), 7.59-7.55 (m, 5H), 7.32-7.27 (m, 6H), 6.99 (t, J = 8.0
(d, J = 8.0 Hz, 1H), 2.50 (s, 3H), 2.32 (s, 3H); 13C{1H} Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (CDCl3,
NMR (CDCl3, 100 MHz): δ 155.1, 148.0, 140.1, 130.2, 100 MHz): δ 154.7, 147.6, 131.4, 130.6, 130.4, 130.3,
129.8, 125.6, 123.0, 120.3, 119.5, 119.4, 119.0, 111.3,
110.6, 21.6, 13.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C17H15N2S: 279.0950; found: 279.0953.
129.5, 129.1, 128.87, 128.83, 128.47, 128.44, 123.6, 123.4,
120.8, 119.0, 111.5.
6-Methyl-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole
3-(4-Chlorophenyl)-2-methylbenzo[4,5]imidazo[2,1-
compound
with
7-methyl-3-(p-
b]thiazole (5b): Yellow solid (80 mg, 89%), mp tolyl)benzo[4,5]imidazo[2,1-b]thiazole
(1:1):
1
1
183−1853 °C; H NMR (CDCl3, 400 MHz): δ 7.76 (d, J = (3ba+3b'a):[11d] Yellow solid (72 mg, 86%); H NMR
8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, (CDCl3, 400 MHz): δ 7.66 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H),
2H), 7.29 (d, J = 8.8 Hz, 1H), 7.03-6.99 (m, 1H), 6.86 (d, J 7.54-7.52 (m, 4H), 7.38-7.35 (m, 4H), 7.14 (d, J = 8.4 Hz,
= 8.0 Hz, 1H), 2.33 (s, 3H); 13C{1H} NMR (CDCl3, 100 2H), 7.05 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.52-6.51 (m,
MHz): δ 155.0, 147.8, 136.3, 131.6, 131.5, 130.0, 129.6, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H);
128.7, 127.0, 123.3, 120.6, 119.2, 111.1, 13.3; Anal. Calcd 13C{1H} NMR (CDCl3, 100 MHz): δ 157.2, 156.8, 149.1,
for C16H11ClN2S: C, 64.32; H, 3.71; N, 9.38; Found C, 148.4, 140.4, 133.2, 129.75, 129.72, 128.83, 128.80, 126.7,
64.17; H, 3.78; N, 9.31%.
124.9, 121.8, 119.1, 118.7, 117.1, 111.8, 111.3, 106.6,
106.4, 21.9, 21.7, 21.67, 21.64; Anal. Calcd for C17H14N2S:
C, 73.35; H, 5.07; N, 10.06; Found C, 73.21; H, 5.16; N,
10.01%.
2-Methyl-3-(naphthalen-2-yl)benzo[4,5]imidazo[2,1-
b]thiazole (5c): Yellow solid (86 mg, 91%), mp
1
150−152 °C; H NMR (CDCl3, 400 MHz): δ 8.07-7.98 (m,
3H), 7.94-7.92 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66-7.59 6-Methoxy-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole
(m, 3H), 7.27-7.22 (m, 1H), 6.93-6.89 (m, 1H), 6.83 (d, J = compound
with
7-methoxy-3-(p-
8.0 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (CDCl3, 100 tolyl)benzo[4,5]imidazo[2,1-b]thiazole
(1:1.1):
1
MHz): δ 155.1, 148.1, 133.7, 133.2, 130.3, 130.1, 129.0, (3ca+3c'a): Yellow solid (74 mg, 84%); H NMR (CDCl3,
128.9, 128.4, 128.1, 127.5, 127.2, 127.0, 125.9, 123.0, 400 MHz): δ 7.67 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 8.0 Hz,
120.4, 120.0, 119.1, 111.3, 13.4; HRMS (ESI-TOF) m/z: 4H), 7.35 (d, J = 7.6 Hz, 4H), 7.28-7.26 (m, 1H), 7.12 (d, J
[M + H]+ Calcd for C20H15N2S: 315.0950; found: 315.0948. = 8.8 Hz, 1H), 6.96 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.74-6.67
(m, 2H), 6.52 (s, 2H), 3.85 (s, 3H), 3.68 (s, 3H), 2.47 (s,
6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 164.3, 157.4,
2-Methyl-3-(thiophen-2-yl)benzo[4,5]imidazo[2,1-
156.8, 154.5, 145.9, 140.4, 134.4, 134.1, 131.4, 129.7,
b]thiazole (5d): Yellow solid (61 mg, 75%), mp 107-
108 °C; 1H NMR (CDCl3, 400 MHz): δ 7.69 (d, J = 8.4 Hz,
1H), 7.58 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.27-7.19 (m, 3H),
6.96 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 2.31 (s,
129.6, 129.4, 128.9, 128.7, 126.5, 119.4, 112.2, 111.9,
110.3, 106.9, 106.4, 101.3, 55.9, 55.8, 22.0, 21.6; Anal.
Calcd for C17H14N2OS: C, 69.36; H, 4.79; N, 9.52; Found
C, 69.47; H, 4.71; N, 9.61%.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
Acknowledgments
[11] a) H. Xu, Y. Zhang, J. Huang, W. Chen, Org. Lett.
2010, 12, 3704; b) D. Xiao, L. Han, Q. Sun, Q. Chen, N.
Gong, Y. Lv, F. Suzenet, G. Guillaumet, T. Cheng, R.
Li, RSC Adv. 2012, 2, 5054; c) M. A. Omar, W. Frey, J.
Conrad, U. Beifuss, J. Org. Chem. 2014, 79, 10367; d)
G. Shen, B. Yang, X. Huang, Y. Hou, H. Gao, J. Cui, C.
Cui, T. Zhang, J. Org. Chem. 2017, 82, 3798.
A.H. and V. Z. S. acknowledge the financial support from DST,
New Delhi (Indo-Russian joint project # INT/RUS/RFBR/P-295)
and Russian Foundation for Basic Research, Russia (Ref. # 17-
53-45127).
References
[12] a) N. Ono, The Nitro Group in Organic Synthesis
Wiley-VCH, New York, 2001; b) A. Z. Halimehjani, I.
N. N. Namboothiri, S. E. Hooshmanda, RSC Adv. 2014,
4, 48022; c) A. Z. Halimehjani, I. N. N. Namboothiri, S.
E. Hooshmanda, RSC Adv. 2014, 4, 51794.
[1] A. Balkan, S. Uma, M. Ertan, W. Wiegrebe, Pharmazie
1992, 47, 687.
[2] H. Zhi, L. Chen, L. Zhang, S. Liu, Z. Wen, H. Lin, C.
Hu, Chin. J. Med. Chem. 2008, 18, 340.
[13] a) C. M. Simpkins, D. A. Hunt, Tetrahedron Lett.
2013, 54, 5544; b) A. Diaz-Ortiz, J. R. Carrillo, F. P.
Cossio, M. J. Gomez-Escalonilla, A. DelaHoz, A.
Moreno, P. Prieto, Tetrahedron 2000, 56, 1569; c) V.
A. Zapol'skii, J. C. Namyslo, C. Altug, M. Gjikaj, D. E.
Kaufmann, Synthesis 2008, 304; d) M. Singsardar, A.
Chakraborty, S. Jana, A. Hajra, Chemistry Select 2017,
2, 8893; e) K. Monir, A. K. Bagdi, M. Ghosh, A. Hajra,
Org. Lett. 2014, 16, 4630; f) R.-L. Yan, H. Yan, C. Ma,
Z.-Y. Ren, X.-A. Gao, G.-S. Huang, Y.-M. Liang, J.
Org. Chem. 2012, 77, 2024; g) M.-S. Xie, Z.-L. Chu,
H.-Y. Niu, G.-R. Qu, H.-M. Guo, J. Org. Chem. 2014,
79, 1093; h) H. Shiraishi, T. Nishitani, S. Sakaguchi, Y.
Ishii, J. Org. Chem. 1998, 63, 6234; i) S. Maiti, S.
Biswas, U. Jana, J. Org. Chem. 2010, 75, 1674; j) P. V.
Santhini, A. K. R, S. A. Babu, B. S. Simethy, G. Das, V.
K. Praveen, S. Varughese, J. John, J. Org.
Chem. 2017, 82, 10537; k) P. V. Santhini, S. A. Babu,
A. K. R, E. Suresh, J. John, Org. Lett. 2017, 19, 2458.
[3] J. C. Milne, P. D. Lambert, S. Schenk, D. P. Carney, J.
J. Smith, D. J. Gagne, L. Jin, O. Boss, R. B. Perni, C. B.
Vu, J. E. Bemis, R. Xie, J. S. Disch, P. Y. Ng, J. J.
Nunes, A. V. Lynch, H. Yang, H. Galonek, K. Israelian,
W. Choy, A. Iffland, S. Lavu, O. Medvedik, D. A.
Sinclair, J. M. Olefsky, M. R. Jirousek, P. J. Elliott, C.
H. Westphal, Nature 2007, 450, 712.
[4] M. M. Ghorab, Y. A. Mohamad, S. A. Mohamed, Y. A.
Ammar, Phosphorus, Sulfur Silicon Relat. Elem. 1996,
108, 249.
[5] B. Tozkoparan, M. Ertan, P. Kelicen, R. Demirdamar,
Farmaco 1999, 54, 588.
[6] a) J. H. Park, M. I. El-Gamal, Y. S. Lee, C. H. Oh, Eur.
J. Med. Chem. 2011, 46, 5769; b) A. Andreani, M.
Rambaldi, A. Locatelli, R. Bossa, A. Fraccari, I.
Galatulas, J. Med. Chem. 1992, 35, 4634; c) A. Furlan,
F. Colombo, A. Kover, N. Issaly, Eur. J. Med. Chem.
2012, 47, 239; d) R. Duval, S. Kolb, E. Braud, D.
Genest, C. Garbay, J. Comb. Chem. 2009, 11, 947; e) A.
Andreani, S. Burnelli, M. Granaiola, A. Leoni, J. Med.
Chem. 2008, 51, 7508; f) T. U. Mayer, T. M. Kapoor, S.
J. Haggarty, R. W. King, S. L. Schreiber, T. J.
Mitchison, Science 1999, 286, 971.
[14] a) M. Ghosh, S. Santra, P. Mondal, D. Kundu, A.
Hajra, Chem. Asian J. 2015, 10, 2525; b) D. Kundu, M.
Samim, A. Majee, A. Hajra, Chem. Asian J. 2011, 6,
406; c) S. Mitra, A. K. Bagdi, A. Majee, A. Hajra,
Tetrahedron Lett. 2013, 54, 4982; d) S. Santra, A. K.
Bagdi, A. Majee, A. Hajra, Adv. Synth. Catal. 2013,
355, 1065; e) M. Ghosh, A. Hajra, Eur. J. Org. Chem.
2015, 2015, 7836; f) B. C. Ranu, A. Hajra, Tetrahedron
2001, 57, 4767.
[7] C. B. Vu, J. E. Bemis, J. S. Disch, P. Y. Ng, J. J. Nunes,
J. C. Milne, D. P. Carney, A. V. Lynch, J. J. Smith, S.
Lavu, P. D. Lambert, D. J. Gagne, M. R. Jirousek, S.
Schenk, J. M. Olefsky, R. B. Perni, J. Med. Chem. 2009,
52, 1275.
[15] K. M. Weiß, S. Wei, S. B. Tsogoeva, Org. Biomol.
Chem. 2011, 9, 345.
[8] G. C. Moraski, L. D. Markley, M. Chang, S. Cho, S. G.
Franzblau, C. H. Hwang, H. Boshoff, M. Miller, J.
Bioorg. Med. Chem. 2012, 20, 2214.
[9] N. Pietrancosta, A. Moumen, R. Dono, P. Lingor, V.
Planchamp, F. Lamballe, M. Bahr, J. L. Kraus, F.
Maina, J. Med. Chem. 2006, 49, 3645.
[10] a) S. Ambethkar, M. Vellimalai, V. Padmini, N.
Bhuvanesh, New J. Chem. 2017, 41, 75; b) W. S.
Hamama, A. E. Hassanien, M. G. El-Fedawy, H. H.
Zoorob, Journal of Heterocyclic Chemistry 2015, 52,
492; c) D. Thienpont, O. F. J. Vanparijs, A. H. M.
Raeymaekers, J. Vandenberk, P. J. A. Demoen, F. T. N.
Allewijn, R. P. H. Marsboom, C. J. E. Niemegeers, K.
H. L. Schellekens, P. A. J. Janssen, Nature 1966, 209,
1084.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800393
Advanced Synthesis & Catalysis
UPDATE
Synthesis of Benzo[4,5]imidazo[2,1-b]thiazole by
Cu(II)-catalyzed Thioamination of Nitroalkene
with 1H-Benzo[d]imidazole-2-thiol
Adv. Synth. Catal. Year, Volume, Page – Page
Sourav Jana, Amrita Chakraborty, Valerii Z.
Shirinian and Alakananda Hajra*
8
This article is protected by copyright. All rights reserved.