Iodine-catalyzed Csp3-H functionalization of methylhetarenes: One-pot synthesis and cytotoxic evaluation of heteroarenyl-benzimidazoles and benzothiazole

Article abstract of DOI:10.1016/j.bmcl.2017.07.051

An efficient one-pot synthetic procedure has been developed for the preparation of heteroarenyl-benzimidazoles via oxidative C_sp3-H functionalization with o-phenylenediamine using I₂-DMSO in open air from easily available starting materials. Based on a logical plan a spectrum of multi fundamental reactions like iodination, Kornblum oxidation and amination were brought into one-pot. By using this simple method a library of heteroarenyl-benzimidazoles derivatives (3a–t and 5a–g) and heteroarenyl-benzothiazole (3u) have been synthesized in good to excellent yield and screened for their cytotoxicity against a group of four human cancer cell lines. Among them 3h, 3q and 5b showed significant cytotoxic activities with an IC₅₀ of 1.69, 1.62 and 2.81 μM respectively against lung cancer (A549) cell line.[Figure presented]

Full text of DOI:10.1016/j.bmcl.2017.07.051

Bioorganic & Medicinal Chemistry Letters 27 (2017) 4039–4043
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Iodine-catalyzed Csp3-H functionalization of methylhetarenes: One-pot
synthesis and cytotoxic evaluation of heteroarenyl-benzimidazoles and
benzothiazole
Mirza Feroz Baig a,b, Siddiq Pasha Shaik a,b, V. Lakshma Nayak a, Abdullah Alarifi c, Ahmed Kamal a,b,c,
⇑
a Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India
b Academy of Scientific and Innovative Research, New Delhi 110 025, India
c Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthetic procedure has been developed for the preparation of heteroarenyl-benzim-
idazoles via oxidative Csp3-H functionalization with o-phenylenediamine using I2-DMSO in open air from
easily available starting materials. Based on a logical plan a spectrum of multi fundamental reactions like
iodination, Kornblum oxidation and amination were brought into one-pot. By using this simple method a
library of heteroarenyl-benzimidazoles derivatives (3a–t and 5a–g) and heteroarenyl-benzothiazole (3u)
have been synthesized in good to excellent yield and screened for their cytotoxicity against a group of
four human cancer cell lines. Among them 3h, 3q and 5b showed significant cytotoxic activities with
an IC50 of 1.69, 1.62 and 2.81 mM respectively against lung cancer (A549) cell line.
Received 28 April 2017
Revised 10 July 2017
Accepted 20 July 2017
Available online 21 July 2017
Keywords:
Heteroarenyl-benzimidazoles
C
sp3-H functionalization
Oxidation
Cytotoxicity
Molecular iodine
Ó 2017 Elsevier Ltd. All rights reserved.
Benzo-fused azoles containing heterocyclic compounds are bio-
logically active and medicinally significant compounds.1 Among
them, benzimidazole and benzothiazole structural motifs are
found in a wide range of natural products2,3 as well as in materi-
als.4 They also exhibit important biological activities such as anti-
cancer5, anti-HIV6 and antibacterial,7 (Fig. 1). In spite of their
biological importance, not many practical synthetic approaches
have been reported in the literature.8 Due to the importance of
these fused heterocyclic skeletons and inadequate synthetic
approaches, enlargement of competent methodologies for the syn-
thesis of these fused heterocycles is highly required. Direct func-
tionalization of Csp3-H bonds has promoted the formation of CAN
and C-heteroatom bonds and is one of the most striking and dom-
inant strategies in organic synthesis. Alternatively, one-pot domino
reactions have developed into powerful tools for the preparation of
fused heterocycles from comparatively simple building blocks
through atom and step monetary conversion by forming multiple
bonds in single process, which facilitate the formation of large
library of scaffolds for the high-throughput screening which is use-
ful during the drug discovery process.9,10
On the other hand, the improvement of metal free Csp3-H ami-
nation, especially iodine-mediated Csp3-H amination has recently
acquired extensive attention towards the construction of various
nitrogen containing heterocyclic compounds including benzimida-
zoles and benzothiazoles. In 2004, Chen described a protocol for
the preparation of 2-(1H-benzo[d]imidazol-2-yl)quinoline from
quinoline-2-carboxylic acid and o-phenylenediamine with
polyphosphoric acid (Scheme 1a).11 In 2015 Xiweiand co-workers
reported the synthesis of 2-(1H-benzo[d]imidazol-2-yl)quinoline
from 2-methylquinoline and o-phenylenediamine with octasulfur
⇑
Corresponding author at: Medicinal Chemistry and Biotechnology Division,
CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
http://dx.doi.org/10.1016/j.bmcl.2017.07.051
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.

4040
M.F. Baig et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4039–4043
Fig. 1. Biologically active benzimidazole and benzothiazole derivatives.
formation of quinoline-2-carbaldehyde; after this time the o-
phenylenediamine 2a (1 equiv) was added. After stirring for 8 h
under these conditions, the expected product 3a was obtained in
39% yield (Table 1, entry 1). Changing the solvent system from
DMF to DMSO resulted in enhancement of the yield of the product
(Table 1, entry 2). Moreover, solvents such as DCE, toluene and
CH3CN diminished the yield of the product (Table 1, entries 3, 4
and 5). Among the catalysts employed such as CuI, KI, TBAI and
I2 it was found that I2 was the best catalyst of choice for this trans-
formation at 10 mol% catalyst load (Table 1, entries 6, 7, 8 and 9).
Thus, in an attempt to increase the reaction yield, we verified the
influence of stoichiometry of the catalyst and noticed that the reac-
tion yield increased to 86% with the increase in amount of catalyst
from 10 mol% to 20 mol% (Table 1, entry 10). However, a further
increase in the amount of the catalyst has no effect on the reaction
yield; instead a decrease in the yield of the product is observed at
30 mol% catalyst load (Table 1, entry 11). With these results, we
then examined the effect of temperature on the yields of the pro-
duct, where decrease in the yield of the product is observed when
the reaction temperature is increased to 130 °C (Table 1, entry12).
Among the solvents screened, we observed that DMSO was the
best solvent for this transformation (Table 1, entries 13 and 14).
With the optimized reaction conditions in hand, the substrate
scope of this method was examined. A variety of 2-heteroaromatic
benzimidazole/benzothiazoles were synthesized in moderate to
good yield (Scheme 2). When 2-methylquinoline was used as the
Scheme 1. Synthesis of 2- heteroarenyl-benzimidazoles and benzothiazole.
(Scheme 1b),12 Gleaning from these reports, we envisioned a one-
pot process for the synthesis of 2-heteroarylbenzimidazole/ben-
zothiazole derivatives by the oxidative condensation of 2-methyl-
hetarenes with o-phenylenediamine/2-aminothiophenol under
mild conditions (Scheme 1c). And the results were reported herein.
Initially, we optimized the reaction conditions by performing
the reactions using 2-methylquinoline (1a) and o-phenylenedi-
amine (2a) as the model substrate (Table 1). In the first experi-
ment, 2-methylquinoline (1a, 1equiv) was solubilized in DMF
and NIS (20 mol%) was added. The mixture was stirred for 1 h at
110 °C under atmospheric pressure which resulted in the in situ
Table 1
Optimization of reaction conditions for synthesis of 3a.a
Entry
Catalyst (equiv)
Solvent
Temp (°C)/Time(h)
Yield%c
1
2
3
4
5
6
7
8
NIS(20%)
NIS(20%)
NIS(20%)
NIS(20%)
NIS(20%)
CuI(20%)
KI(20%)
TBAI(20%)
I2(10%)
I2(20%)
I2(30%)
I2(20%)
I2(20%)
I2(20%)
DMF
110/8
110/8
110/8
110/8
110/8
110/8
110/8
110/8
110/8
110/8
110/8
130/8
110/8
110/8
110/8
110/8
39
45
Trace
Trace
Trace
28
35
43
57
86
78
76
Trace
Trace
55
DMSO
Toluene
DCE
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
Toluene
DMSO
DMSO
9
10
11
12
13
14
15b
16b
I2(10%)
I2(20%)
81
a
b
c
All reactions were performed with 1a (1equiv), 2a (1 equiv), DMSO (2 ml) and catalyst according to Table 1 for 3a.
Under argon atmosphere.
Isolated yield.

M.F. Baig et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4039–4043
4041
Scheme 2. Scope of 2-methylquinoline and o-phenylenediamine. All reactions were performed with 1a (1 equiv), 2a (1 equiv), and I2 (20 mol%) in DMSO (2 ml) at 110 °C for
6 h. Isolated yield.
starting materials, the corresponding products were also obtained
in good yields (Scheme 2, 3a–g). 2-methylquinolines substituted
with both electron-donating and electron-withdrawing groups
smoothly reacted under the optimized reaction conditions to give
the target molecules. Generally, electron-donating groups on the
quinoline ring gave higher yields than those with electron-with-
drawing groups (Scheme 2, 3h–k). However, performing the reac-
tion with 3- and 7-methylquinolines did not resulted in fruitful
results leaving the reactants unreacted. This concludes that only
2-methylquinolines are suitable for this transformation.
We then turned our attention to explore the substrate scope of
various benzene-1, 2-diamines. Various substituted benzene-1,2-
diamines having substituents like Me, Cl, Br, CF3 and COPh reacted
well and afforded the corresponding products in 62–86% yields
(Scheme 2). To further explore the scope of this protocol, we inves-
tigated the compatibility of the reaction with 2-aminothiophenol
and 2-aminophenol. It is fortunate to observe that 2-aminothio-
phenol delivered corresponding product (3u) in good yields under
Scheme 3. Scope of 2-methylbenzo[d]thiazole and o-phenylenediamine. All reac-
tions were performed with 4a (1 equiv), 2a (1 equiv), and I2 (20 mol%) in DMSO
(2 ml) at 110 °C for 8 h. Isolated yield.
Scheme 4. Control experiments.

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M.F. Baig et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4039–4043
Scheme 5. Plausible mechanism.
the optimized reaction conditions. However, 2-aminophenol was
ineffective for this transformation resulting in formation of no
desired products.
Table 2
IC50valuesa (in
lM) for heteroarenyl-benzimidazoles (3a–t and 5a–g).
Compound
MDA MB231b
A549c
DU-145d
HCT-116e
Later, the scope of the study was also extended to substituted 2-
methylbenzothiazoles and the results were summarized in
Scheme 3. It is observed that various substituted 2-methylben-
zothiazole were found compatible with o-phenylenediamine for
this transformation and furnished corresponding products in good
to excellent yields. Gratifyingly, 2-methylbenzothiazoles substi-
tuted with both electron-rich as well as electron-deficient groups
on the phenyl ring were reacted smoothly and afforded the corre-
sponding products (5a–g) in good to excellent yields
(Scheme 3, 65–84%).
To elucidate the mechanistic pathway, few control experiments
were conducted as shown in Scheme 4. Accordingly, treatment of
2-methylquinoline (1) with I2 in presence of DMSO (optimized
conditions) delivered quinoline-2-carbaldehyde (B) in quantitative
yield which was isolated and characterised by spectroscopic stud-
ies, which upon exposure to o-phenylenediamine (2a) under stan-
dard conditions afforded the corresponding desired benzimidazole
product (3a) in good yield (Scheme 4b). In accordance with the
results, a possible mechanism for this reaction is illustrated in
Scheme 5. It is assumed that 2-methylquinoline (1a) may initially
undergo iodination to afford 2-iodomethylquinoline intermediate
(A) which further transforms into quinoline-2-carbaldehyde (B)
via Kornblum oxidation.13 the formed aldehyde then condenses
with o-phenylenediamine (2a) to give imine intermediate D. The
formed imine Intermediate after intramolecular nucleophilic addi-
tion by the free NH2 of the phenyl ring results in cyclic intermedi-
ate E. Finally, I2 mediated oxidation followed by aromatization
provides the desired product 3.14
Based on the results obtained from the Table 1, it is noticed that
the protocol also works even in the absence of DMSO which is
required for Kornblum oxidation (entry 1, Table 1). From these
results an alternate mechanism is depicted in Scheme 5 (path b),
where in 2-iodomethylquinoline intermediate (A) is formed after
iodination could directly undergo nucleophilic amination with o-
phenylenediamine (2) to generate the intermediate C, which in
the presence of I2 yields the imine D via oxidation. Finally,
intramolecular cyclization, oxidation followed by aromatisation
of D affords the benzimidazole product (3a).
It was considered of interest to evaluate these 2-(1H-benzo[d]
imidazol-2-yl)quinoline and 2-(1H-benzo[d]imidazol-2-yl)benzo
[d]thiazole analogues (3a–t and 5a–g) as potential cytotoxic
agents. And the results of MTT assay15 are summarized in Table 2.
The results obtained by this cytotoxicity assay indicated that some
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
5a
5b
5c
23.63
52.78
19.52
26.61
15.76
57.00
22.82
2.042
79.43
55.25
11.67
62.28
236.0
12.80
12.11
15.48
3.548
20.68
23.78
17.12
14.03
17.85
18.00
13.74
29.20
20.58
23.10
1.862
17.27
50.09
16.21
32.06
14.27
53.11
14.16
1.698
67.29
53.00
9.652
32.93
124.9
11.45
7.893
10.73
1.622
15.88
24.84
15.54
9.057
2.818
17.24
55.75
11.42
11.58
23.97
1.513
76.95
102.6
27.35
62.31
22.25
102.2
67.00
12.70
84.77
83.67
24.84
126.5
101.6
13.57
13.24
20.50
10.09
28.05
38.83
30.80
55.63
21.05
18.95
96.20
30.33
38.33
37.58
1.698
72.50
97.20
21.24
98.20
15.43
70.86
73.43
14.59
102.0
97.40
22.10
123.5
103.2
31.00
28.73
45.20
13.23
22.00
30.47
41.80
73.43
28.39
43.75
63.98
39.62
43.73
42.41
1.262
5d
5e
5f
5g
Nocodazole
a
50% Inhibitory concentration and the values are average of four individual
experiments after 48 h of drug treatment.
b
Breast cancer.
Lung cancer.
Prostate cancer.
Colon cancer.
c
d
e
of these compounds like 3h, 3q and 5b showed significant cyto-
toxic activity against lung cancer cell lines (A549) in comparison
to other tested cell lines with IC50 values of 1.69, 1.62 and
2.81 lM respectively. It is interesting to note that these results
are comparable to the nocodazole employed as the standard. In
order to investigate the structure activity relationship (SAR), we
have varied the substitution pattern of the both benzene rings of
heteroarenyl-benzimidazoles. The cytotoxicity data of most poten-
tial compounds i. e 3h and 3q deciphered that inductively electron
donating substituents (e.g., OMe) at 6th position as well as with-
drawing substituents at 7th position (e.g., Cl) on benzene ring of
quinoline and electron-neutral/withdrawing (H/CF3) substituents

M.F. Baig et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4039–4043
4043
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heteroarenyl-benzimidazoles by using methylhetarenes and sub-
stituted o-phenylenediamine in a one-pot open air reaction. It is
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with an IC50 of 1.69, 1.62 and 2.81
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lM respectively against A-549
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The authors thank CSIR and UGC for the award of fellowships.
We also thank funding received from the project entitled
‘Affordable Cancer Therapeutics (ACT)’ under XIIth five year plan
and extend our appreciation to the International Scientific
Partnership Program ISPP at King Saud University for funding this
research work through ISPP#0054.
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