FeCl3/ZnI2-catalyzed synthesis of benzo[D]imidazo[2,1-b]thiazole through aerobic oxidative cyclization between 2-aminobenzothiazole and ketone

Article abstract of DOI:10.1021/ol5028893

The FeCl₃/ZnI₂-catalyzed aerobic oxidative cyclization between 2-aminobenzothiazole and ketone/chalcone for the synthesis of benzo[d]imidazo[2,1-b]thiazole is described. A variety of fused benzoimidazothiazole derivatives are obtained by this protocol.

Full text of DOI:10.1021/ol5028893

Letter
pubs.acs.org/OrgLett
FeCl3/ZnI2‑Catalyzed Synthesis of Benzo[d]imidazo[2,1‑b]thiazole
through Aerobic Oxidative Cyclization between
2‑Aminobenzothiazole and Ketone
Subhajit Mishra, Kamarul Monir, Shubhanjan Mitra, and Alakananda Hajra*
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
S
* Supporting Information
ABSTRACT: The FeCl3/ZnI2-catalyzed aerobic oxidative cyclization between 2-aminobenzothiazole and ketone/chalcone for
the synthesis of benzo[d]imidazo[2,1-b]thiazole is described. A variety of fused benzoimidazothiazole derivatives are obtained by
this protocol.
ulfur-containing heterocyclic compounds are frequently
found in naturally occurring compounds and generally
we need of a direct and practical method for the preparation of
these heterocycles from basic chemicals.
S
show various biological activities.1 Benzo[d]imidazo[2,1-b]-
thiazole is one of the important fused bicyclic sulfur containing
heterocycles and also an important chemical building block in
synthetic organic and biological chemistry (Figure 1). Various
The direct oxidative C−H bond functionalization offers an
excellent route to form C−C and C-heteroatom bonds avoiding
the prefunctionalization of the reactants.9 As a consequence
much attention has been drawn on the oxidative C−H bond
functionalization for the construction of various heterocycles
from the readily available reactants. Based on our experiences
on the synthesis of imidazopyridines,10 we envisaged that the
benzo[d]imidazo[2,1-b]thiazole could be directly synthesized
from 2-aminobenzothiazole and ketone via oxidative amination.
So far there is no such direct oxidative method for the synthesis
of this moiety from methyl ketones which are more easily
available compared to the α-halo/tosyloxy ketones. Herein we
report the synthesis of benzo[d]imidazo[2,1-b]thiazole deriva-
tives from ketones via FeCl3/ZnI2-catalyzed oxidative C−H
functionalization under aerobic conditions (Scheme 1).
Optimization of the reaction conditions was carried out by
taking 2-aminobenzothiazole (1a) and acetophenone (2a) as
the model substrates. Initially the reaction was carried out
employing a combination of FeCl3 (20 mol %) and ZnI2 (10
mol %) in acetonitrile under refluxing conditions, and to our
delight, the desired product was obtained in 10% yield (Table
1, entry 1). Other common solvents like 1,2-dichloroethane,
1,2-dichlorobenzene (DCB), DMF, DMSO, DMAc, and NMP
were also screened (Table 1, entries 2−7). 1,2-DCB was found
to be the most effective solvent. We also investigated the
catalytic activity of other iron salts such as FeBr3 and
Fe(NO3)3.9H2O. However, lower yields were obtained (Table
1, entries 8 and 9). No product was obtained either in absence
of the FeCl3 or ZnI2 (Table 1, entries 10 and 11). Thus, a
combination of both the catalysts is necessary for the reaction.
Figure 1. Biologically active benzo[d]imidazo[2,1-b]thiazole deriva-
tives.
benzo[d]imidazo[2,1-b]thiazoles have been used as antitumor
agents (I and II), antimicrobial agents, antibacterial agents, and
antiallergic agents.2−5 These derivatives are also found to be
particular kinase inhibitors and receptors (III) and employed
for PET imaging of Alzheimer’s patients brains (IV) as well as
β-amyloid plaques.6,7 Despite of having such important
biological activities, only a few methods have been developed
so far for the synthesis of this scaffold.8 The conventional
approach for the construction of benzo[d]imidazo[2,1-b]-
thiazole moiety is the condensation of 2-aminobenzothiazole
with α-halo/tosyloxy ketone. However, the utilization of
prefunctionalized as well as commercially less available starting
materials still limits the application of these procedures. Thus,
Received: September 30, 2014
© XXXX American Chemical Society
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dx.doi.org/10.1021/ol5028893 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
product was obtained by carrying out the reaction employing
20 mol % of FeCl3 and 10 mol % of ZnI2 in 1,2-DCB at 110 °C
for 15 h (Table 1, entry 3).
Scheme 1. Synthesis of Benzo[d]imidazo[2,1-b]thiazoles
With the optimal reaction conditions in hand, we
investigated the scope of the reaction (Scheme 2). First,
a b
,
Scheme 2. Substrate Scope
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
additive (mol %)
solvent
yield (%)
c
1
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeBr3 (20)
Fe(NO3)3·9H2O (20)
FeCl3 (20)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
CH3CN
1,2-DCE
1,2-DCB
DMF
10
24
88
21
20
10
17
72
60
c
2
3
4
5
DMSO
6
DMAc
7
NMP
8
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
9
10
11
12
13
14
15
16
17
18
19
20
21
ZnI2 (10)
ZnI2 (10)
ZnI2 (10)
ZnCl2 (10)
KI (10)
Cu(OAc)2.H2O (20)
99.99% FeCl3 (20)
FeCl3 (20)
15
86
trace
48
43
41
32
44
45
28
a
FeCl3 (20)
Reaction conditions: 0.6 mmol of 1 and 0.5 mmol of 2 in the
FeCl3 (20)
NaI (10)
TBAI (10)
I2 (10)
presence of FeCl3 (20 mol %) and ZnI2 (10 mol %) in 1,2-DCB at 110
b
°C for 15 h in air. Isolated yields.
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
HI (10)
different substituted 2-aminobenzothiazoles were employed
under the optimized reaction conditions. Satisfactorily, 2-
aminobenzothiazoles bearing electron-donating as well as
electron-withdrawing substituents afforded the corresponding
benzo[d]imidazo[2,1-b]thiazoles with high yields (3aa, 3bb,
3ca, and 3da). We then studied the scope and limitation of this
protocol by varying a wide range of aromatic, heteroaromatic,
and aliphatic ketones. Both the electron-donating and electron-
withdrawing groups like −Me, −OMe, −Cl, −Br, −I, and
−NO2 on the aromatic ring were compatible with this
transformation, and the corresponding benzo[d]imidazo[2,1-
b]thiazole derivatives were obtained in good to excellent yields
(3ab, 3ac, 3ad, 3ae, 3ag, 3ah, and 3bo). The halogen-
containing benzo[d]imidazo[2,1-b]thiazoles could be further
functionalized by the traditional cross-coupling reaction. The
CF3-containing acetophenone also afforded the product with
good yield (3af). 2-Phenylacetophenone gave the 2,3-
diphenylbenzo[d]imidazo[2,1-b]thiazole in good yield under
the optimized reaction conditions (3ai). The heteroaryl
ketones like 2-acetylfuran and 2-acetylthiophene also proceeded
well under the present reaction conditions (3aj, 3ak, and 3al).
The o-allyl group containing acetophenone afforded the
FeCl3 (10)
ZnI2 (5)
ZnI2 (2)
FeCl3 (5)
a
Reaction conditions: 0.6 mmol of 1a and 0.5 mmol of 2a in the
presence of catalyst and additive in solvent (2 mL) at 110 °C for 15 h
b
c
in air. Isolated yields. Reaction was carried out under refluxing
conditions.
The use of Cu(OAc)2·H2O instead of FeCl3 only afforded 15%
of the desired product (Table 1, entry 12). Furthermore, the
reaction was carried out employing analytically pure (>99.99%)
FeCl3 (20 mol %) and ZnI2 (10 mol %). A similar result (86%
yield) was obtained which proves that contamination of copper
does not act as the catalyst in the present methodology (Table
1, entry 13). ZnCl2 instead of ZnI2 diminished the formation of
desired product (Table 1, entry 14). It is notable to observe
that other iodide sources such as NaI, KI, TBAI, HI, and I2
were examined and found to be less effective compared to ZnI2
(Table 1, entries 15−19). Use of I2 produces a mixture of
undesired products. The decrease of catalyst loading of FeCl3/
ZnI2 decreased the yield of the product significantly (Table 1,
entries 20−21). Thus, the optimized yield of the desired
B
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Letter
corresponding product without affecting the allyl group (3am).
Furthermore, cyclohexyl methyl ketone, acetophenone, and
trifluoroacetophenone were also found to be suitable for this
transformation (3an, 3as, and 3at). Sterically hindered ortho-
substituted acetophones furnished the desired products in
moderate to good yields (3bo, 3ap, and 3aq). 1-Acetonaph-
thone also reacted well under the present reaction conditions
(3ar). However, the present methodology is not applicable for
methyl pyruvate, propiophenone, and isobutyl methyl ketone.
Next, we checked the feasibility of chalcone derivatives as the
coupling partner with 2-aminobenzothiazole under the
optimized reaction conditions for the synthesis of highly
substituted benzo[d]imidazo[2,1-b]thiazoles, which are difficult
to prepare through conventional methods (Scheme 3). To our
Scheme 4. Controlled Experiments
Scheme 3. Synthesis of 2-Aroylbenzo[d]imidazo[2,1-
b]thiazoles
Scheme 5. Plausible Mechanism
delight, the 2-aroylbenzo[d]imidazo[2,1-b]thiazoles were ob-
tained in high yields under oxygen atmosphere (5aa, 5ab, 5ac,
5ad). To the best of our knowledge this is the first reported
method for the synthesis of these aroyl substituted derivatives.
Some controlled experiments were carried out to understand
the probable mechanistic path of this oxidative cyclization
(Scheme 4). Only a trace amount of the desired product was
obtained under argon atmosphere, which indicates that the
presence of oxygen is required to fulfill the catalytic cycle
(Scheme 4, eq A). When the reaction was carried out in the
presence of AgOAc, a much lower yield was obtained (Scheme
4, eq B). From this observation, it seems that the in situ
generated iodine from the iodide source acts as the catalyst in
this reaction. However, the utilization of molecular iodine
resulted only 15% yield (Scheme 4, eq C). CuI is not effective
in this reaction, as it only produces 10% of the desired product
(Scheme 4, eq D). The combination of FeCl3 (20 mol %) and
CuI (10 mol %) is also not an effective catalyst for this
transformation. ZnI2 acts as an effective iodide source for this
reaction.
From these controlled experiments and the literature reports,
the probable mechanism of the reaction is represented in
Scheme 5. The Ortoleva−King reaction promoted by Lewis
acid is the key step for this reaction.11 The first step is the
generation of iodine by the oxidation of iodide anion with
aerobic oxygen in the presence of FeCl3. In the next step,
acetophenone reacts with this in situ generated iodine to
produce the α-iodoketone (A). The 2-aminobenzothiazole
reacts with this α-iodoketone (A) to form the intermediate B.
The subsequent intramolecular cyclization of the intermediate
B affords the 2-phenylbenzo[d]imidazo[2,1-b]thiazole. On the
basis of the experimental results, it seems that FeCl3 plays a
crucial role in aerial oxidation of iodide anion to iodine and
might help in the cyclization step as well. In the case of
chalcones, the reaction possibly proceeds through the
formation of iodonium intermediate. This intermediate on
sequential nucleophilic substitutions and aerobic oxidation
affords the 2-aroylbenzo[d]imidazo[2,1-b]thiazoles.
In summary, we have demonstrated FeCl3/ZnI2-catalyzed
direct synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives
through aerobic oxidative amination. The versatile method
shows broad functional group tolerance and is applicable to a
wide range of readily accessible ketones. This catalytic
combination is also effective for the construction of 2-
aroylbenzo[d]imidazo[2,1-b]thiazoles. The reaction probably
proceeds through in situ formation of α-iodo ketone followed
by intramolecular cyclization. We believe this operationally
simple protocol will find important applications in organic,
medicinal, and material chemistry.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Additional data, spectral data of all compounds, and scanned
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(10) (a) Monir, K.; Bagdi, A. K.; Ghosh, M.; Hajra, A. Org. Lett.
2014, 16, 4630. (b) Santra, S.; Mitra, S.; Bagdi, A. K.; Majee, A.; Hajra,
A. Tetrahedron Lett. 2014, 55, 5151. (c) Monir, K.; Bagdi, A. K.;
Mishra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2014, 356, 1105.
(d) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv.
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T. J. Org. Chem. 2012, 77, 5552. (b) Zhang, Y.; Chen, Z.; Wu, W.;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: alakananda.hajra@visva-bharati.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.H. acknowledges financial support from CSIR, New Delhi
(Grant No. 02(0168)/13/EMR-II). S.M. thanks UGC, and
K.M. thanks CSIR (SPM) for their fellowship.
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