A convenient [hydroxy(tosyloxy)iodo]benzene-mediated one-pot synthesis of 2-arylimidazo[2,1-b[benzothiazoles

Article abstract of DOI:10.1080/17415993.2014.996221

Several 2-arylimidazo[2,1-b]benzothiazoles (4) have been conveniently synthesized in one-pot reactions via α-tosyloxylation of enolizable ketones (1) using [hydroxy(tosyloxy)iodo]benzene 2 in acetonitrile, followed by treatment with 2-amino-6-(substituted

Full text of DOI:10.1080/17415993.2014.996221

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A convenient
[hydroxy(tosyloxy)iodo]benzene-
mediated one-pot synthesis of 2-
arylimidazo[2,1-b]benzothiazoles
Garima Sumrana & Ranjana Aggarwalb
a Department of Chemistry, D. A. V. College (Lahore), Ambala
City, Haryana 134 002, India
b Department of Chemistry, Kurukshetra University, Kurukshetra,
Haryana 136119, India
Published online: 02 Jan 2015.
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To cite this article: Garima Sumran & Ranjana Aggarwal (2015) A convenient
[hydroxy(tosyloxy)iodo]benzene-mediated one-pot synthesis of 2-arylimidazo[2,1-b]benzothiazoles,
Journal of Sulfur Chemistry, 36:2, 170-177, DOI: 10.1080/17415993.2014.996221
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Journal of Sulfur Chemistry, 2015
Vol. 36, No. 2, 170–177, http://dx.doi.org/10.1080/17415993.2014.996221
A convenient [hydroxy(tosyloxy)iodo]benzene-mediated one-pot
synthesis of 2-arylimidazo[2,1-b]benzothiazoles
Garima Sumrana∗ and Ranjana Aggarwalb
aDepartment of Chemistry, D. A. V. College (Lahore), Ambala City, Haryana 134 002, India; bDepartment
of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India
(Received 8 September 2014; accepted 3 December 2014)
Several 2-arylimidazo[2,1-b]benzothiazoles (4) have been conveniently synthesized in one-pot reactions
via α-tosyloxylation of enolizable ketones (1) using [hydroxy(tosyloxy)iodo]benzene 2 in acetonitrile,
followed by treatment with 2-amino-6-(substituted)benzothiazoles (3). The present protocol offers sev-
eral advantages towards general access of 2-arylimidazo[2,1-b]benzothiazoles, including an intriguing
alternative to the literature protocols, a readily available nontoxic reagent, operational simplicity and an
environmentally benign procedure.
OH
Ph
I
i)
Ar
O
OTs
2
N
N
Ar
CH3
N
S
S
4a-h
R
1
ii)
R
NH2
3
Abs. EtOH
Keywords: α-tosyloxyketones; [hydroxy(tosyloxy)iodo]benzene; imidazo[2,1-b]benzothiazoles; hyper-
valent iodine; 2-amino-6-(substituted)benzothiazoles
1. Introduction
The imidazo[2,1-b]benzothiazole structural motif may be found in a large number of phar-
maceutical agents with a diverse range of physiological activities, namely, antitumor,[1]
antibacterial,[2,3] antifungal [4] and immunosuppressive.[5] A series of substituted imidazo[2,1-
b]benzothiazoles possess inverse-agonist profiles toward the central benzodiazepine [6] and
5-hydroxytryptamine3 receptors.[7] As shown in Figure 1, imidazo[2,1-b]benzothiazole deriva-
tive (AC220) I was identified as one of the most potent and selective FMS-like tyrosine kinase-3
inhibitor.[8] Furthermore, imidazo[2,1-b]benzothiazoles can be synthetically manipulated easily
*Corresponding author. Email: garimasumran@gmail.com
This article makes reference to supplementary material available on the publisher’s website at http://dx.doi.org/
10.1080/17415993.2014.996221.
c
ꢀ 2014 Taylor & Francis

Journal of Sulfur Chemistry 171
NEt2.HCl
O
N
O
O
N
S
N
O
O
N
S
N
.
N
I
N
N
H
HCl
H
II
AC220
YM-201627
H3CO
S
H2NO2S
S
S
N
N
N
N
N
N
V
III
NH CH3
11
PFT-β
IV
R
Figure 1. 2-Arylimidazo[2,1-b]benzothiazoles and related compounds with biological and medicinal activity.
by Mannich, substitution and addition reactions for preparing a wide range of compounds that
have immense pharmaceutical value.[9–11]
In particular, 2-arylimidazo[2,1-b]benzothiazole derivative (YM-201627) II has proven
to be a potent and orally active antitumor agent (Figure 1).[12] 11C-labeled imidazo[2,1-
b]benzothiazole III has been shown to be a superb fluoroprobe in positron emission
tomography analysis of Alzheimer’s disease.[13] Imidazobenzothiazoles IV are well-known
inhibitors of apoptosis following the p-53 independent pathway in contrast to the well-
known standard drug piffithrin-α (PFT-α or PFT-β V).[14] It has recently been reported
that Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles possess potential anti-cancer
activities.[11]
Mainly two distinct routes have been employed in the literature for the synthesis of
imidazo[2,1-b]benzothiazoles (Scheme 1). The first one involves the construction of a imidazole
ring on the starting 2-aminobenzothiazole by condensation with 1,2-difunctionalized units, such
as α-haloketones,[1,4,5,8,9,11,14–16] α-haloester,[6] and γ -bromodypnone [17]; a multicom-
ponent reaction between 2-aminobenzothiazoles, benzaldehydes and imidazoline-2,4,5-trione
under solvent-free conditions [18]; and Groebke–Blackburn multicomponent reaction of 2-
aminobenzothiazoles with aldehydes and isocynides (route a).[2,19] The second approach
involves appending the thiazole ring by reacting 1-(m-chlorophenyl)-2-mercaptoimidazole with
potassium amide in liquid ammonia (route b).[20] Other synthetic routes for the preparation of
these compounds involve annulation reactions of amidines with substituted bromomethyl com-
pounds, acid chlorides and acrylic dienophiles [21] and Pd/Cu catalyzed Sonogashira coupling
reaction of iodobenzenes with 2-imino-3-(2-propynyl)-1,3-benzothiazole.[22,23]
However, many of these procedures require sometimes multistep synthesis, harsh reac-
tion conditions, cumbersome product isolation procedure, unsatisfactory yields, special care
in handling and storing the toxic and expensive reagents. Therefore, a need still exists for
further development of a versatile and convenient synthetic protocol for the synthesis of
2-arylimidazo[2,1-b]benzothiazoles. Our ongoing program on the development of greener
protocols in heterocyclic synthesis coupled with significant biological importance,[24–28]
prompted us to extend the versatility of [hydroxy(tosyloxy)iodo]benzene HTIB for the syn-
thesis of 2-arylimidazo[2,1-b]benzothiazoles involving the intermediacy of α-tosyloxyketones
(α-TK).

172 G. Sumran and R. Aggarwal
N
S
route a
NH2
(i) or (ii) or (iii)
R
+
R
a
R
N
N
R
S
(iv)
+
Cl
N
b
route b
HS
N
Ph
reagents
(i) =
O
or
Br
or
BrCH2COCOOC2H5
O
Ph
Br
R
O
O
HN
NH
+
RCHO
(ii) =
O
RCHO
+
R
N C
(iii) =
(iv) =
KNH2, liquid NH3
Scheme 1. Retrosynthetic routes for imidazo[2,1-b]benzothiazoles.
2. Results and discussion
α-TK, readily accessible through oxidation of enolizable ketones with HTIB, offer an attrac-
tive alternative due to their versatility in organic synthesis, as these are relatively stable
chemical entities, have ready accessibility, site-selectivity in the reaction and provide a safe
eco-friendly alternative route to conventional toxic and lachrymatory α-haloketones for clean
synthesis.[29–32]
The starting material, 2-amino-6-(substituted)benzothiazoles (3), was synthesized by the reac-
tion of appropriate aniline with potassium thiocyanate which resulted in the formation of
substituted phenylthiourea. The ensuing reaction of substituted phenylthiourea in the presence
of bromine in chloroform followed by neutralization with aqueous ammonia afforded 3.[33]
A one-pot HTIB-mediated sequential synthesis of title compounds is depicted in Scheme 2.
Initially, acetophenone (1a) was oxidized with one equivalent of HTIB 2 in acetonitrile under
reflux condition for 2 h and subsequently the α-TK so generated in situ was treated with 2-
aminobenzothiazole (3a) in absolute ethanol. The progress of the reaction was monitored by thin
layer chromatography (TLC) which indicated the formation of α-TK after 2 h and a single spot
for 4a after 5 h. Simple workup of the reaction resulted in the formation of 2-phenylimidazo[2,1-
b]benzothiazole (4a) in 62% yield (Scheme 2). 1H NMR spectrum of compound 4a exhibited a
characteristic singlet at δ 7.87 due to the C3-H of the imidazole ring confirming the cyclization.
In order to study the scope of this approach, various enolizable ketones (1b–d)
were subjected to α-tosyloxylation with HTIB 2 and ensuing reaction with 2-amino-6-
(substituted)benzothiazoles (3a–c) under the above conditions in order to achieve the synthesis of
4b–h. In all the cases, the corresponding 2-arylimidazo[2,1-b]benzothiazoles (4b–h) (Scheme 2)
were obtained in excellent yields ranging from 60% to 72% (Table 1). The synthesized com-
pounds 4 were characterized by comparing their mps [5,15] and spectral properties with those
reported in the literature.[11] The versatility of the present protocol was further proved by the fact
that when the reaction was scaled from milligram to gram level under the same conditions, it took

Journal of Sulfur Chemistry 173
OH
Ph
I
i)
Ar
O
OTs
2
N
N
Ar
CH3
N
S
S
4a-h
R
1
ii)
R
NH2
1a: Ar = C6H5
3
Abs. EtOH
1b: Ar = 4-Cl-C6H4
1c: Ar = 4-Br-C6H4
1d: Ar = 4-F-C6H4
3a: R = H
3b: R = CH3
3c: R = OCH3
Scheme 2. Synthesis of 2-arylimidazo[2,1-b]benzothiazoles (4).
Table 1. Yield and characterization of 2-arylimidazo[2,1-b]benzothiazoles (4).
3
Ar
5
2
N
N
S
6
1
R
7
8
Product
Ar
R
M.p. (°C)
Lit. M.p. (°C)
Yielda (%) one pot
Lit. yieldb (%)
4a
4b
4c
4d
4e
4f
H
H
102
160
164
151
165
212
164
217
100 [5,15]
159 [5,15]
161[5,15]
148 [15]
165 [15]
215 [15]
164 [15]
217 [15]
62
65
60
72
63
66
67
70
30 [5], N.R.c [15]
44 [5], 28.1 [15]
16 [5], 36.47 [15]
26.11 [15]
Cl
Br
F
H
H
CH3
CH3
OCH3
OCH3
41.4 [15]
Cl
Cl
43.95 [15]
4g
4h
N.R. [15]
57.2 [15]
aYield of isolated product.
bYield of isolated pure product based on amount of appropriate 2-aminobenzothiazole used.
cN.R.: not reported.
place successfully to give the 2-arylimidazo[2,1-b]benzothiazoles 4. The process is environmen-
tally benign and the reaction conditions and workup procedure are mild, simple and convenient.
The results summarized in Table 1 clearly indicate that the new one-pot synthesis affords much
better overall yields (60–72%) as compared with the literature procedure (16–57%) involving
the lachrymatory α-haloketones.[5,15]

174 G. Sumran and R. Aggarwal
3. Conclusions
In a nutshell, the noteworthy features of present study are:
(i) HTIB-mediated one-pot sequential protocol offers general applicability for synthesis of 2-
arylimidazo[2,1-b]benzothiazoles, which have diverse synthetic applications.
(ii) α-TK, generated in situ as intermediate, provide a safe eco-friendly alternative approach
which avoids the use of highly toxic, unstable and lachrymatory α-haloketones.
4. Experimental
Melting points were determined in open capillaries in an electrical apparatus and are uncorrected.
The homogeneity of the compounds was checked by TLC using silica gel-G (Acme). IR spectra
were recorded on a Buck Scientific IR M-500 spectrophotometer in KBr discs (νmax in cm−1),
1H NMR spectra in CDCl3 on a Bruker (300 and 400 MHz) spectrophotometer; chemical shifts
are expressed in δ-scale downfield from TMS as an internal standard.
4.1. General procedure for one-pot synthesis of 2-arylimidazo[2,1-b]benzothiazoles (4a–h)
from ketones 1
A mixture of appropriate methyl ketone 1 (5 mmol) and HTIB 2 (1.95 g, 5 mmol) in acetonitrile
(20 mL) was heated under reflux for 2 h. Excess of acetonitrile was distilled off. The forma-
tion of α-TK was confirmed by TLC monitoring of the reaction mixture. Then a solution of
2-amino-6-(substituted)benzothiazole 3 (5 mmol) in absolute ethanol (10 mL) was added drop-
wise to the reaction mixture. The resultant reaction mixture was heated under reflux for 4–5 h.
The progress of the reaction was accomplished by TLC using pet ether:ethyl acetate (8:2) as the
solvent system. After completion of the reaction, the excess of solvent was distilled in vacuo,
and a solid product separated out on cooling. The solid thus separated was filtered, neutralized
with aq. sodium bicarbonate solution, washed with water and purified by recrystallization from
ethanol to afford 4. The spectroscopic data were consistent with literature.
4.1.1. 2-Phenylimidazo[2,1-b]benzothiazole (4a)
1H NMR (CDCl3, 300 MHz): δ 7.03 (t, 1H, ArH), 7.32–7.37 (m, 4H, ArH), 7.47 (m, 1H, ArH),
7.49–7.59 (m, 2H, ArH), 7.80–7.83 (m, 1H, ArH), 7.87 (s, 1H, Imidazole-H).
4.1.2. 2-(4-Chlorophenyl)imidazo[2,1-b]benzothiazole (4b)
Synthesis of this compound was accomplished on gram scale following the same procedure,
employing appropriate methyl ketone 1 (0.01 mol), HTIB 2 (3.9 g, 0.01 mol) and compound 3a
(0.01 mol) to obtain pure product 4b as a white solid.
1H NMR (CDCl3, 300 MHz): δ 7.23–7.26 (t, 1H, C7-H), 7.27–7.30 (d, 2H, Jo = 8.4 Hz, Ph-2ꢁ,
6ꢁ-H), 7.33–7.39 (t, 1H, J = 7.8 Hz, C6-H), 7.48–7.51 (d, 1H, J = 7.8 Hz, C8-H), 7.59–7.62 (d,
1H, J = 7.8 Hz, C5-H), 7.69–7.72 (d, 2H, Jo = 8.4 Hz, Ph-3ꢁ, 5ꢁ-H), 7.84 (s, 1H, Imidazole-H).

Journal of Sulfur Chemistry 175
4.1.3. 2-(4-Bromophenyl)imidazo[2,1-b]benzothiazole (4c)
1H NMR (CDCl3, 400 MHz): δ 7.37 (dt, 1H, J = 7.96 Hz, J = 1.0 Hz, C7-H), 7.47 (dt, 1H,
J = 7.82 Hz, J = 1.04 Hz, C6-H), 7.54 (m, 2H, J = 8.52 Hz, J = 1.72 Hz, Ph-2ꢁ, 6ꢁ-H), 7.61
(d, 1H, J = 7.68 Hz, C8-H), 7.72 (d, 1H, J = 7.96 Hz, C5-H), 7.75 (m, 2H, J = 8.56 Hz,
J = 1.8 Hz, Ph-3ꢁ, 5ꢁ-H), 7.96 (s, 1H, Imidazole-H).
4.1.4. 2-(4-Fluorophenyl)imidazo[2,1-b]benzothiazole (4d)
1H NMR (CDCl3, 400 MHz): δ 7.12 (t, 2H, J = 8.72 Hz, Ph-3ꢁ, 5ꢁ-H), 7.35 (dt, 1H, J = 7.8 Hz,
J = 0.88 Hz, C7-H), 7.46 (dt, 1H, J = 7.72 Hz, J = 0.88 Hz, C6-H), 7.60 (d, 1H, J = 7.92 Hz,
C8-H), 7.70 (d, 1H, J = 7.92 Hz, C5-H), 7.84 (m, 2H, J = 7.72 Hz, J = 5.4 Hz, Ph-2ꢁ, 6ꢁ-H),
7.90 (s, 1H, Imidazole-H).
4.1.5. 7-Methyl-2-phenylimidazo[2,1-b]benzothiazole (4e)
1H NMR (CDCl3, 300 MHz): δ 2.47 (s, 3H, CH3), 7.24 (d, 1H, J = 7.6 Hz, C6-H), 7.29 (t, 1H,
J = 7.16 Hz, Ph-4ꢁ-H), 7.39 (t, 2H, Ph-3ꢁ, 5ꢁ-H), 7.4–7.52 (m, 2H , C8, C5-H), 7.72–7.74 (m, 2H,
phenyl-2ꢁ, 6ꢁ-H), 7.88 (s, 1H, Imidazole-H).
4.1.6. 2-(4-Chlorophenyl)-7-methylimidazo[2,1-b]benzothiazole (4f)
1H NMR (CDCl3, 400 MHz): δ 2.47 (s, 3H, CH3), 7.25 (d, 1H, J = 7.6 Hz, C6-H), 7.38 (m,
2H, Jo = 8.52 Hz, Jm = 2.48 Hz, Jp = 1.8 Hz, Ph-2ꢁ, 6ꢁ-H), 7.46 (m, 1H, C8-H), 7.49 (m,
1H, C5-H), 7.79 (m, 2H, Jo = 8.52 Hz, Jm = 2.48 Hz, Jp = 1.8 Hz, Ph-3ꢁ, 5ꢁ-H), 7.90 (s, 1H,
Imidazole-H).
4.1.7. 7-Methoxy-2-phenyl imidazo[2,1-b]benzothiazole (4g)
1H NMR (CDCl3, 400 MHz): δ 3.88 (s, 3H, OCH3), 7.01 (dd, 1H, J = 8.78 Hz, J = 2.44
Hz, C6-H), 7.21 (d, 1H, J = 2.44 Hz, C8-H), 7.32 (t, 1H, J = 7.40 Hz, Ph-4ꢁ-H), 7.43 (t, 2H,
J = 7.48 Hz, Ph-3ꢁ, 5ꢁ-H), 7.50 (d, 1H, J = 8.76 Hz, C5-H), 7.88 (d, 2H, J = 7.24 Hz, Ph-2ꢁ,
6ꢁ-H), 7.91 (s, 1H, Imidazole-H).
4.1.8. 2-(4-Chlorophenyl)-7-methoxyimidazo[2,1-b]benzothiazole (4h)
1H NMR (CDCl3, 400 MHz): δ 3.90 (s, 3H, OCH3), 7.03 (dd, 1H, J = 8.84 Hz, J = 2.44 Hz,
C6-H), 7.23 (d, 1H, J = 2.44 Hz, C8-H), 7.39 (m, 2H, Jo = 8.56 Hz, Jm = 2.44 Hz, Jp = 1.76
Hz, Ph-2ꢁ, 6ꢁ-H), 7.52 (d, 1H, J = 8.8 Hz, C5-H), 7.80 (m, 2H, Jo = 8.56 Hz, Jm = 2.48 Hz,
Jp = 1.76 Hz, Ph-3ꢁ, 5ꢁ-H), 7.90 (s, 1H, Imidazole-H).
Acknowledgements
Support to this research by authorities of D.A.V. College, Ambala City for providing laboratory facilities is gratefully
acknowledged. Thanks are also due to Prof. Devinder Kumar, Department of Chemistry and Central Instrumentation
Laboratory, Guru Jambheshwar University of Science & Technology, Hisar for providing NMR data.

176 G. Sumran and R. Aggarwal
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplemental material
Supplemental data for this article can be accessed at doi:10.1080/17415993.2014.996221.
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