Molecular iodine promoted divergent synthesis of benzimidazoles, benzothiazoles, and 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines

Article abstract of DOI:10.1021/jo5000797

An unprecedented formation of a new class of 2-benzyl-3-phenyl-3,4-dihydro- 2H-benzo[e][1,2,4]thiadiazines has been discovered during the course of benzimidazole and benzothiazole synthesis, through the molecular iodine-mediated oxidative cyclization with a new C-N and S-N bond formation at ambient temperature.

Full text of DOI:10.1021/jo5000797

Article
pubs.acs.org/joc
Molecular Iodine Promoted Divergent Synthesis of Benzimidazoles,
Benzothiazoles, and 2‑Benzyl-3-phenyl-3,4-
dihydro‑2H‑benzo[e][1,2,4]thiadiazines
Gunaganti Naresh,† Ruchir Kant,‡ and Tadigoppula Narender*,†
†Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India 226001
‡Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India 226001
S
* Supporting Information
ABSTRACT: An unprecedented formation of a new class of 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines has
been discovered during the course of benzimidazole and benzothiazole synthesis, through the molecular iodine-mediated
oxidative cyclization with a new C−N and S−N bond formation at ambient temperature.
INTRODUCTION
■
In recent years, carbon−heteroatom bond forming reactions
constituted the central theme of organic synthesis. Among
those, direct C−N bond forming reactions have engrossed
significant attention to construct the heterocycles.1 As a result,
a plethora of methods has been developed for C−N bond
formation. In those methods, copper-catalyzed C−N bond
formation reactions are more recognizable.2 For example
Buchwald,2j,3 Hartwig,2k,4 and Ma et. al2l synthesized bio-
logically active molecules through C−N bond formation
utilizing copper as a catalyst. However, these approaches
Figure 1. Representative drugs with benzimidazole, benzothiazole, and
1,2,4-benzothiadiazine skeletons.
require complex ligands, longer reaction times, and harsh
reaction conditions. In recent works, iodine-mediated ap-
proaches were found to be highly efficient alternatives for
zole skeletons.9 Development of efficient synthetic methods for
transition metal catalysts in C−N bond formation reactions
because iodine is low in cost, readily available, and nontoxic.5
Recently, we have also reported the synthesis of biologically
important oxazole and benzoxazolone heterocyclic motifs by
utilizing iodine through the C−N bond formation.6 In
continuation of this program, we synthesized benzimidazoles
and benzothiazoles using iodine.
construction of benzimidazoles and benzothiazoles is fascinat-
ing. Classical approaches for the synthesis of these compounds
involve condensation of aldehydes,10 acids,11 esters,12 and acid
chlorides13 with 2-amino-/mercaptoanilines (Scheme 1,
method A). Some transition-metal-catalyzed transformations
also gained considerable attention in recent years.14 Our
literature survey revealed that benzimidazoles and benzothia-
zoles were also synthesized by using hypervalent iodine and
Benzimidazoles and benzothiazoles are ubiquitous structural
motifs found in many therapeutically useful compounds (Figure
1).7 For example, Protonix, Prilosec, and Nexium are
representative drugs with benzimidazole skeletons,8 and
5F203 and PMX610 are representative drugs with benzothia-
Received: January 13, 2014
Published: April 1, 2014
© 2014 American Chemical Society
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Scheme 1
iodide as catalysts through C−H activation.15 Recently, Nguyen
and co-workers reported a novel route for the synthesis of
benzazoles from 1,2-diaminobenzene and benzylamine by using
sulfur/oxygen as an oxidizing agent and acetic acid as a
cyclizing catalyst (Scheme 1, Method B).16
Table 1. Optimization of Reaction Conditions for the
Synthesis of Benzimidazoles
a
However, for all these transformations, prefunctionalization
of starting materials or harsh reaction conditions such as high
temperature, strong acid catalysts, and longer reaction time are
required. It is therefore necessary to investigate simple and
efficient methods for the synthesis of benzimidazoles and
benzothiazoles. In this context, herein, we disclose the
divergent route for the construction of benzimidazoles and
benzothiazoles and a serendipitous discovery of a novel
straightforward route for biologically important heterocyclic
motif 1,2,4-benzothiadiazenes using molecular iodine.
1,2,4-Benzothiadiazine derivatives are a very interesting class
of heterocyclic motif17 and possess exciting biological activities.
Various benzothiadiazine derivatives such as chlorothiazide
(diuretic), cyclothiazide (diuretic and antihypertensive), and
bendroflumethiazide are used as pharmaceutical therapeutics.18
A majority of 1,2,4-benzothiadiazine derivatives are with
hexavalent sulfur, and, in contrast, very few divalent sulfur
derivatives are disclosed in literature.19,1 We therefore pursued
it further to develop a straightforward synthesis of 1,2,4-
benzothiadiazine derivatives.
b
c
entry
oxidant (equiv)
solvent
time (h)
yield (%)
1
I2 (3.0)
I2 (3.0)
0.25
0.25
0.25
0.25
0.5
1
45
60
65
75
80
78
78
50
70
30
NI
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EA
3
I2(2.7)
4
I2 (2.5)
5
I2 (2.0)
I2 (2.0)
6
7
I2 (2.0)
I2 (2.0)
0.5
1
8
DCE
9
I2 (2.0)
DMSO
CH3CN
CH3CN
1
10
11
NIS (2.0)
NCS (2.0)
1
1
a
The reaction was carried out with 1a (1.0 equiv), 2a (1.5 equiv), and
iodine (2.0 equiv) solvent (5 mL) by stirring at room temperature for
30 min. CH3CN = acetonitrile, EA = ethyl acetate. Isolated yields;
b
c
NI = not isolated.
similar effect on the product formation (entries 5 and 7, Table
1).
RESULTS AND DISCUSSION
■
Once we established the suitable solvent system for synthesis
of benzimidazoles, we then focused on the quantity of iodine.
Initially, we used 3.0 equiv of iodine and found the desired
benzimidazole (3a) formation in relatively low yield due to the
vigorous overoxidation of benzylamine (2a) and some complex
mixture formation. We therefore conducted a few experiments
with decreasing the quantity of iodine. After several experi-
ments, we attained the optimal conditions for the formation of
benzimidazole (3a) in good yield with 2.0 equiv of iodine
(entry 5, Table 1). Having optimized conditions, we screened
various 2-amino substituted anilines (1a−1n) and benzyl-
Our preliminary investigation began with the reaction of
benzene 1,2-diamine (1a) with benzylamine (2a) in the
presence of iodine (3.0 equiv) without using the solvent
(neat) at room temperature. We were delighted to observe the
formation of the desired product (3a), albeit in low yield
(45%). The poor yield of 3a might be due to the low solubility
of the reactants. Performing the same reaction in acetonitrile as
a solvent increased the yield to 60% (entry 2, Table 1). We
evaluated various solvents for further improvement in yield.
Among those, acetonitrile and ethyl acetate showed an almost
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a
Table 2. Substrate Scope of Benzimidazoles with Optimized Conditions
a
Conditions: 1a−1n (1.0 equiv), 2a−2i (1.5 equiv), and iodine (2.0 equiv) in acetonitrile (5 mL) were stirred at room temperature for 30 min.
Isolated yields are given in parentheses.
a
Table 3. Synthesis of Benzothiazoles with Optimized Conditions
a
Conditions: 2a−2k (1.5 equiv), 4a (1.0 equiv), and iodine (2.0 equiv) in acetonitrile (5 mL) were stirred at room temperature for 30 min. Isolated
yields are given in parentheses.
amines (2a−2i) to get the corresponding 2-aryl and heteroaryl
substituted benzimidazoles (3a−3n) in good yields. Electron-
rich and electron-poor substituents on the aromatic ring of
diamine and benzylamine were well tolerated in this tandem
reaction and furnished the desired benzimidazoles in good to
excellent yields (Table 2).
In light of our above successive results, we focused the scope
of this protocol toward the synthesis of benzothiazoles. For this
purpose, 2-aminoaniline (1a) was replaced with 2-mercaptoani-
line (4a) and reacted with benzylamine (2a) under similar
reaction conditions, which were optimized for benzimidazoles.
Surprisingly, we observed the unanticipated minor product 6a
along with the desired benzothiazole 5a (entry 1, Table 4) in
the ethyl acetate solvent. However, we initially focused on our
desired benzothiazole synthesis. Various solvents were screened
to reduce the formation of byproduct 6a and isolated the
desired benzothiazole 5a in excellent yield (80%) using
acetonitrile as the solvent system (entry 3, Table 4). We
explored the substrate scope with various substituted benzyl-
amines (2b−2k) and mercaptoaniline (4a) to produce 2-
substituted benzothiazoles (5a−5k) in good yields (Table 3)
using optimized conditions. Unfortunately, aliphatic amines
failed to provide benzimidazoles or benzothiazoles under
similar reaction conditions.
After successful implementation of this protocol for the
synthesis of benzimidazole and benzothiazoles, we shifted our
attention to establish the structure of the unanticipated product
(6a). In this context, our attempt to elucidate the structure of
minor product 6a with 2D-NMR was not fully successful.
However, its structure was confirmed as 2-benzyl-3-phenyl-3,4-
dihydro-H-benzo[e][1,2,4]thiadiazine (6a) by using single-
crystal X-ray analysis.20
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After we confirmed the structure of 2-benzyl-3-phenyl-3,4-
dihydro-H-benzo[e][1,2,4] thiadiazine (6a), we decided to
scrutinize the optimization conditions for the synthesis of
substituted 1,2,4-benzothiadiazenes. In this context, we
conducted an experiment with 2-mercaptoaniline (4a) (1.0
equiv) and benzylamine (2a) (2.0 equiv) in the presence of
iodine (2.0 equiv) as an oxidant in ethyl acetate solvent at room
temperature, which resulted in the formation of the unusual
heterocycle motif 6a in moderate yield due to the formation of
benzothiazole (5a) also along with 6a (entry 8, Table 4). When
we decreased the amount of benzylamine (2a) (entry 14, Table
4) in the reaction, the yield of the desired compound 6a also
intermediate I with 2-amino-/2-mercaptoaniline separately,
which furnished the benzimidazole/benzothiazole smoothly at
room temperature; however, our attempt to isolate the trans-
iminated intermediate (II or III) was not successful. With our
control experiment results and from earlier reports,16b,21 we
conclude that the pathway for the formation of benzimidazole/
benzothiazole is as shown in Scheme 3. In the case of 1,2,4-
benzothiadiazine formation, oxidized intermediate (IV) might
be generated from 2-mercaptoaniline in the presence of iodine.
In control experiments, we obtained intermediate (IV) from 2-
mercaptoaniline using I2 (Scheme 2). Kirihara and co-workers
also reported a similar intermediate from 2-mercaptoaniline.22
Further reaction between intermediates IV and I might have
resulted in 1,2,4- benzothiadiazine (6a) formation.
ab
,
Table 4. Optimization of Reaction Conditions
On the basis of previous literature reports16b,21 and our
experimental results, the possible reaction mechanism for the
formation of benzimidazoles and benzothiazoles is outlined in
Scheme 3, which starts from the oxidative dimerization of
benzylamine in the presence of iodine to produce the imine (I)
with the loss of ammonia. It might be easily converted into II or
III by the transimination with 2- amino-/2-mercaptoanilines
and subsequent cycloaddition gives the 2-phenyl-2,3-dihydro-
1H-benzo[d]imidazole/thiazole intermediate (VI/VII). Oxida-
tion of resultant intermediates VI/VII gives the benzimidazole/
thiazole. In the case of 2-benzyl-3-phenyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine formation, the oxidation of 2-
mercaptoaniline in the presence of iodine at optimized
conditions might give the 2,2′-disulfanediyldianiline (IV).21
Nucleophilic attack of IV on imine I and subsequent internal
nucleophlie (secondary amine) assisted cleavage of disulfide
bond might produce 6a.
c
d
oxidant
(equiv)
2a
time
(h)
yield 5a
yield 6a
c
entry
(equiv)
solvent
(%)
(%)
1
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (3.0)
I2 (2.0)
I2 (1.3)
I2 (2.0)
I2 (1.7)
I2 (1.5)
I2 (1.5)
I2 (1.3)
I2 (1.3)
I2 (1.3)
NIS
1.5
1.5
1.5
1.3
1.3
2
EA
EA
0.5
1
75
60
15
20
NI
NI
NI
NI
NI
50
50
62
75
78
81
40
NI
NI
2
3
CH3CN
CH3CN
CH3CN
DCE
DMSO
EA
0.5
0.5
0.5
0.5
0.5
0.5
1
80
60
4
5
50
6
50
7
2
65
8
2
<10
20
9
2
EA
10
11
12
13
14
15
16
2
EA
2
20
CONCLUSIONS
2
EA
3
10
■
2
EA
3
NI
NI
50
We have developed a simple and novel protocol for the iodine-
mediated synthesis of benzimidazole and benzothiazole from
readily available 2-amino-/2-mercaptosubstituted anilines and
various benzylamines. During this process, an unprecedented
formation of a new class of 2-benzyl-3-phenyl-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazines has been discovered. This method
involves metal-free C−N and S−N bond formation at ambient
temperature to produce the products in good to excellent
yields.
2
EA
4
1.5
2
EA
4
EA
4
30
NBS
2
EA
4
<10
a
Conditions for synthesis of 5a: 2a (1.5 equiv), 4a (1.0 equiv), and
iodine (2.0 equiv) in acetonitrile (5 mL) were stirred at room
temperature for 0.5 h. Conditions for synthesis of 6a: 2a (2.0 equiv),
4a (1.0 equiv), iodine (1.3 equiv), and ethyl acetate (5 mL) were
b
c
stirred at room temperature for 4 h. CH3CN = acetonitrile, EA =
ethyl acetate, DCE = 1, 2-dichloroethane, DMSO = dimethyl sulfoxide.
Isolated yields; NI = not isolated.
EXPERIMENTAL SECTION
d
■
General Information. All reagents and solvents were purchased
from commercial sources and used as received. The progress of the
reaction was monitored by analytical TLC on silica gel G/GF 254
plates. The column chromatography was performed with silica gel 60−
120 mesh. NMR (1H and 13C) spectra were recorded on either a 300
or 400 MHz NMR using TMS as an internal standard and chemical
shifts (δ ppm) (multiplicity, coupling constant (Hz), integration). The
abbreviations for multiplicity are as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; and dd, doublet of doublets. Melting
points are uncorrected and were determined in capillary tubes on a
hot-stage melting point apparatus containing silicon oil. High-
resolution mass spectra were taken with a 3000 mass spectrometer
and Q-TOF Analyzer. IR spectra were recorded using a FTIR
spectrophotometer.
General Procedure for Synthesis of Benzimidazoles (3a−3n). To
a stirred solution of benzylamine (1.5 equiv) and 2-aminoaniline (1.0
equiv) in acetonitrile (5 mL) at room temperature was added 2.0 equiv
of I2. We allowed for stirring at room temperature for 30 min, and the
progress of the reaction was monitored by TLC analysis. After
completion of the reaction, excess I2 was quenched with a saturated
aqueous solution of Na2S2O3. After separation of the organic layer,
decreased. After examining several experimental conditions, we
found that 1.3 equiv of iodine and a reaction time of 4 h are the
most effective conditions for the formation of 6a in excellent
yield (entry 3, Table 4). We also screened various solvents to
investigate the effect of the solvent system on the reaction
medium and found that ethyl acetate was most efficient to
increase the yield of 6a (entry 13, Table 4).
With these optimal conditions, we investigated the substrate
scope of this protocol with various substituted benzylamines
(2a−2f) and 2-mercaptoanilines (4a and 4b) and found the
formation of 6a−6j smoothly in good yields (Table 5).
Control Experiments. To establish the mechanism for the
formation of benzimidazole, benzothiazole, and 2-benzyl-3-
phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines, we carried
out a few control experiments (Scheme 2). In this context, we
isolated the imine intermediate I during the synthesis of
benzimidazole. We performed a reaction between imine
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a
Table 5. Synthesis of Various 2-Benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines Under Optimized Conditions
a
Conditions for synthesis of 6a−6j: 2a (2.0 equiv), 4a (1.0 equiv), and iodine (1.3 equiv) in ethyl acetate (5 mL) were stirred at room temperature
for 4 h. Isolated yields are given in parentheses.
Scheme 2
aqueous solution was then back-extracted with ethyl acetate (10 mL).
The combined organic layers were treated with saturated NaHCO3
solution (10 mL) and brine solution (10 mL) and dried over
anhydrous Na2SO4, evaporated to give a crude benzimidazole, and
purified by the silica gel column chromatography using hexane and
ethyl acetate (20:5) as eluent.
MHz, DMSO-d6) δ 12.755 (s, 1H), 8.162−8.155 (m, 2H), 7.641 (d, J
= 6.4 Hz, 2H), 7.196−7.102 (m, 4H), 3.874 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 161.1, 151.2, 144.4, 135.4, 128.5, 123.2,
122.5, 121.9, 119.0, 114.8, 111.5, 55.8 ppm.
2-(Benzo[d][1,3]dioxol-5-yl)-1H-benzo[d]imidazole (3c).23 White
1
solid; yield 79% (435 mg); ESI-MS (m/z) = 239 (M + H); H NMR
2-Phenyl-1H-benzo[d]imidazole (3a).23 White solid; yield 80%
(400 MHz, DMSO-d6) δ 7.732−7.687 (m, 2H) 7.561 (bs, 2H),
7.192−7.177 (m, 2H), 7.104 (d, J = 8.45 Hz, 1H), 6.165 (s, 2H) ppm;
13C NMR (100 MHz, DMSO-d6) δ 151.6, 149.2, 148.3, 124.6, 122.4,
121.4, 109.2, 106.9, 102.0 ppm.
1
(360 mg); ESI-MS (m/z) = 195 (M + H); H NMR (400 MHz,
DMSO-d6) δ 12.931 (bs, 1H), 8.212−8.188 (m, 2H), 7.683 (d, J =
7.41 Hz, 1H), 7.581−7.481 (m, 4H), 7.250−7.199 (m, 2H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 151.7, 144.3 135.5, 130.6, 130.3, 129.4,
126.9, 123.0, 122.1, 119.3, 111.8 ppm.
2-(4-Chlorophenyl)-1H-benzo[d]imidazole (3d).16a Pale white
solid; yield 80.2% (423 mg); ESI-MS (m/z) = 229 (M + H); 1H NMR
(400 MHz, DMSO-d6) δ 13.009, (s, 1H), 8.222−8.188 (m, 2H), 7.687
(d, J = 7.61 Hz, 1H) 7.650−7.615 (m, 2H), 7.552 (d, J = 7.47 Hz, 2H)
2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (3b).23 White solid;
yield 75.2% (390 mg); ESI-MS (m/z) = 225 (M + H); 1H NMR (400
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5, 6-Dimethyl-2-phenyl-1H-benzo[d]imidazole (3l).16a White
solid; yield 78.7% (320 mg); ESI-MS (m/z) = 223 (M + H); H
NMR (400 MHz, DMSO-d6) δ, 12.681 (bs, 1H), 8.173−8.159 (m,
2H), 7.551−7.329 (m, 5H), 2.329 (s, 6H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 150.8, 143.0, 134.0, 131.6, 130.9, 130.4, 129.9, 129.3,
126.7, 119.4, 111.8, 20.5 ppm.
Scheme 3. Possible Reaction Mechanism for the Formation
of Benzimidazole, Benzothiazole, and 2-Benzyl-3-phenyl-3,4-
dihydro-2H-benzo[e][1,2,4]thiadiazine
1
2-Phenyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (3m). Yellow
solid; yield 65.8% (245 mg); ESI-MS (m/z) = 263 (M + H); 1H NMR
(400 MHz, DMSO-d6) δ 13.37 (bs, 1H), 8.240−8.217 (m, 2H), 7.961
(bs, 1H), 7.792 (d, J = 8. 52 Hz, 1H), 7.612−7.522 (m, 4H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 154.6, 131.0, 129.9, 120.5, 127.3,
126.9, 124.2, 123.0, 119.3 ppm.
6-Nitro-2-phenyl-1H-benzo[d]imidazole (3n). Light red solid;
1
yield 58.2% (230 mg); ESI-MS (m/z) = 240 (M + H); H NMR
(400 MHz, DMSO-d6) δ 13.560 (bs, 1H), 8.451 (s, 1H), 8.195 (m,
2H), 8.122−8.095 (m, 1H), 7.750 (d, J = 8.86 Hz, 1H), 7.616−7.563
(m, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 156.2, 143.1, 131.3,
129.5, 127.4, 118.3, 112.7 ppm.
General Procedure for Synthesis of Benzothiazole (5a−5k). To a
stirred solution of benzylamine (1.5 equiv) and 2-mercaptoaniline (1.0
equiv) in acetonitrile (5 mL) at room temperature was added 2.0 equiv
of I2. We allowed for stirring at room temperature for 30 min, and the
progress of the reaction was monitored by TLC analysis. After
completion of the reaction, excess I2 was quenched with a saturated
aqueous solution of Na2S2O3. The organic layer was separated, and the
aqueous solution was then extracted by ethyl acetate (10 mL). The
combined organic layers were washed with saturated brine solution
(10 mL), dried over anhydrous Na2SO4, and evaporated to give a
crude benzothiazole. Residue was purified by the silica gel column
chromatography using hexane and ethyl acetate (90:1) as eluent to
give the desired benzothiazole.
7.245−7.204 (m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 150.6,
144.2, 135.5, 135.0, 129.5, 128.6, 123.2, 122.3, 119.4, 111.9 ppm.
2-(4-Fluorophenyl)-1H-benzo[d]imidazole (3e). White solid; yield
82.1% (403 mg); ESI-MS (m/z) = 213 (M + H); 1H NMR (400 MHz,
DMSO-d6) δ 12.916 (s, 1H), 8.250−8.207 (m, 2H) 7.661−7.532 (m,
2H), 7.432−7.380 (m, 2H), 7.212 (d, J =.3.53 Hz, 2H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 164.8, 162.3, 150.9, 129.7, 129.6,
129.2, 129.1, 127.3, 122.6 ppm.
2-Phenylbenzo[d]thiazole (5a).16a White solid; yield 80% (350
mg); ESI-MS (m/z) = 212 (M + H); 1H NMR (400 MHz, DMSO-d6)
δ 8.0973−8.0658 (m, 3H), 7.885 (d, J = 8.17 Hz, 1H), 7.502−7.460
(m, 4H), 7.389−7.349 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-
d6) δ 168.1, 154.2, 135.1, 133.6, 131.0, 129.0, 127.6, 126.3, 125.2,
123.2, 121.6 ppm.
2-p-Tolyl-1H-benzo[d]imidazole (3f).23 White solid; yield 80%
1
(385 mg); ESI-MS (m/z) = 209 (M + H); H NMR (400 MHz,
DMSO-d6) δ 12.828 (bs, 1H), 8.081 (d, J = 8.19 Hz, 2H), 7.586 (bs,
2H), 7.363 (d, J = 8.08 Hz, 2H), 7.216−7.183 (m, 2H), 2.386 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6 + CDCl3) δ 152.3, 140.3, 129.5,
126.9, 126.5, 122.5, 114.6, 20.9 ppm.
2-(4-Methoxyphenyl)benzo[d]thiazole (5b).16b White solid; yield
68.3% (328 mg); ESI-MS (m/z) = 242 (M + H), 1H NMR (400 MHz,
DMSO-d6) δ 8.096−8.005 (m, 4H), 7.541−7.401 (m, 2H), 7.125−
7.089 (m, 2H), 3.850 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6)
δ 167.5, 154.1, 134.7, 129.3, 126.9, 126.0, 125.5, 122.9, 122.6, 115.2,
55.9 ppm.
2-(Pyridin-3-yl)-1H-benzo[d]imidazole (3g).16a Pale white solid;
yield 78.7% (355 mg); ESI-MS (m/z) = 196 (M + H); 1H NMR (400
MHz, DMSO-d6) δ 13.11 (bs, 1H), 9.369 (d, J = 1.85 Hz, 1H), 8.696−
8.680 (m, 1H), 8.526−8.497 (m, 1H), 7.651−7.579 (m, 3H), 7.261−
7.239 (m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 151.0, 149.3,
148.0, 144.1, 135.4, 134.2, 126.6, 124.5, 123.4, 122.6, 119.5, 112.0
ppm.
2-(Benzo[d][1,3]dioxol-5-yl)benzo[d]thiazole (5c). Purple semi
1
solid; yield 70.6% (360 mg); ESI-MS (m/z) = 256 (M + H); H
NMR (400 MHz, CDCl3) δ 8.030−8.008 (m, 1H), 7.858−7.834 (m,
1H), 7.607−7.567 (m, 2H), 7.479−7.437 (m, 1H), 7.362−7.321 (m,
1H), 6.881 (d, J = 8.07 Hz, 1H), 6.027 (s, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 167.6, 154.1, 150.1, 148.4, 134.9, 128.0, 126.3, 125.0,
122.9, 122.5, 121.5, 108.6, 107.5, 101.7 ppm.
2-(Furan-2-yl)-1H-benzo[d]imidazole (3h).23 Pale yellow solid;
yield 68.2% (290 mg); ESI-MS (m/z) = 185 (M + H); 1H NMR (400
MHz, DMSO-d6) δ 12.961 (bs, 1H), 7.950−7.947 (m, 1H), 7.582 (bs,
2H), 7.224−7.198 (m, 3H), 6.738−6.725 (m, 1H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 146.0, 145.0, 144.1, 139.3, 122.7, 115.5,
112.8, 111.0 ppm.
2-(4-Chlorophenyl)benzo[d]thiazole (5d).24 Pale white solid; yield
81.5% (400 mg); ESI-MS (m/z) = 246 (M + H); 1H NMR (400 MHz,
DMSO-d6) δ 8.177−8.153 (m, 1H), 8.129−8.065 (m, 3H), 7.660−
7.625 (m, 2H), 7.589−7.548 (m, 1H), 7.508−7.467 (m,1H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 166.4, 154.0, 136.5, 135.0, 132.1,
129.9, 129.3, 127.2, 126.2, 123.4, 122.9 ppm.
2-(Thiophen-2-yl)-1H-benzo[d]imidazole (3i).23 Pale white solid;
yield 72.5% (335 mg); ESI-MS (m/z) = 201 (M + H); 1H NMR (400
MHz, DMSO-d6) δ 12.944 (bs, 1H), 7.837 (s, 1H), 7.722−7.709 (m,
1H), 7.544 (bs, 2H), 7.226−7.194 (m, 3H) ppm; 13C NMR (100
MHz, DMSO-d6) δ 147.5, 134.2, 129.2, 128.7, 127.1, 122.6 ppm.
Phenyl(2-phenyl-1H-benzo[d]imidazol-5-yl)methanone (3j): (CAS
number; 82326-53-2). Light red solid; yield 55.5% (195 mg); ESI-MS
(m/z) = 299 (M + H); 1H NMR (400 MHz, DMSO-d6) δ 13.307 (bs,
1H), 8.224 (d, J = 7.24 Hz, 2H), 7.981 (S, 1H), 7.791−7.669 (m, 5H),
7.608−7.534 (m, 5H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 196.1,
154.4, 138.6, 132.53, 131.5, 131.0, 130.0, 129.9, 129.6, 128.9, 127.2,
124.6 ppm.
2-(3,4-Dichlorophenyl)benzo[d]thiazole (5e). Pale white solid;
1
yield 78% (437 mg); ESI-MS (m/z) = 281(M + H), H NMR (400
MHz, CDCl3) δ 8.155 (d, J = 2.05 Hz, 1H), 8.049−8.027 (m, 1H),
7.868−7.810 (m, 2H), 7.503−7.462 (m, 2H), 7.400−7.359 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 165.1, 153.1, 135.1, 135.1,
133.5, 133.4, 130.1, 129.0, 126.7, 126.5, 125.7, 123.5, 121.7 ppm.
2-(4-Fluorophenyl)benzo[d]thiazole (5f).24 White solid; yield 81%
1
(370.8 mg); ESI-MS (m/z) = 230 (M + H), H NMR (400 MHz,
6-Methyl-2-phenyl-1H-benzo[d]imidazole (3k).16a White solid;
yield 80.9% (345 mg); ESI-MS (m/z) = 209 (M + H); 1H NMR (400
MHz, DMSO-d6)12.789 (s, 1H), δ 8.192−8.171 (m, 2H), 7.565−
7.460 (m, 4H), 7.395 (s, 1H), 7.033 (d, J = 8.32 Hz, 1H), 2.438 (s,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 151.3, 131.8, 130.7,
130.1, 129.8, 124.0, 116.0, 21.8 ppm.
CDCl3) δ 8.071−8.038 (m, 3H), 7.886−7.862 (m, 1H), 7.501−7.459
(m, 1H), 7.390−7.349 (m, 1H), 7.185−7.141 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3) δ 166.7, 163.2, 154.1, 135.1, 129.1, 129.6,
129.5, 126.4, 125.3, 123.2, 121.6, 116.3, 116.0 ppm.
2-p-Tolylbenzo[d]thiazole (5g).24 White solid; yield 72.2% (325
1
mg); ESI-MS (m/z) = 226 (M + H), H NMR (400 MHz, CDCl3) δ
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8.064−8.042 (m, 1H), 7.997 (d, J = 8.23 Hz, 2H), 7.887−7.865 (m,
1H), 7.492−7.450 (m, 1H), 7.378−7.337 (m, 1H), 7.295−7.274 (m,
2H), 2.413 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.3, 154.2,
141.4, 135.0, 131.0, 129.7, 127.5, 126.2, 125.0, 123.1, 121.6, 21.5 ppm.
2-(4-(Trifluoromethyl)phenyl)benzo[d]thiazole (5h).24 White
solid; yield 60.9% (340 mg); ESI-MS (m/z) = 280 (M+H); 1H
NMR (400 MHz, CDCl3) δ 8.166 (d, J = 8.15 Hz, 2H), 8.087 (d, J =
8.26 Hz, 1H), 7.890 (d, J = 7.92 Hz, 1H), 7.717 (d, J = 8.15 Hz, 2H),
7.505 (t, J = 7.69 Hz, 1H), 7.402 (t, J = 7.69 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 166.1, 154.0, 136.8, 136.7, 135.2, 132.6, 127.7,
126.6, 126.00, 126.0, 125.9, 125.8, 123.6, 121.7 ppm.
6.787−6.727 (m, 2H), 5.384 (d, J = 4.28 Hz, 1H), 4.519 (d, J = 4.14
Hz, 1H), 4.123 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 144.3,
140.1, 138.5, 134.4, 134.3, 129.9, 129.7, 129.1, 128.1, 128.0, 127.1,
126.5, 125.3, 125.1, 118.9, 116.2, 115.1, 72.1, 60.3 ppm; mass (ESI)
m/z = 387.3 (M + H)+; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H17Cl2N2S, 387.0489; found, 387.0478.
2-(4-Fluorobenzyl)-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[e]-
[1,2,4]thiadiazine (6d). White solid; yield 77% (550 mg); mp 155−
157 °C; FT-IR ν max (KBr) 1217.7 (C−N) cm−1, 3439.1 (N−H)
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.397−7.353 (m, 4H), 7.079−
7.000 (m, 5H), 6.855−6.832 (m, 1H), 6.759−6.692 (m, 2H), 5.367 (d,
J = 4.03 Hz, 1H), 4.482 (d, J = 3.97 Hz, 1H), 4.094 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3) δ 163.6, 163.5, 161.2, 161.1, 138.9, 138.2,
138.2, 138.2, 133.8, 133.8, 130.6, 130.6, 128.6, 128.5, 126.4, 125.2,
118.7, 116.4, 115.5, 115.3, 115.0, 115.0, 71.9, 60.1 ppm; mass (ESI)
m/z = 355.1 (M + H)+; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H17 F2N2S, 355.1081; found, 355.1073.
2-(4-(Trifluoromethoxy)phenyl)benzo[d]thiazole (5i). White solid;
1
yield 62.8% (370.6 mg); ESI-MS (m/z) = 296 (M + H); H NMR
(400 MHz, CDCl3) δ 8.146−8.071 (m, 3H), 7.920−7.899 (m, 1H),
7.531−7.490 (m, 1H), 7.426−7.385 (m, 1H), 7.338 (d, J = 8.06 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.2, 154.1, 151.0, 136.7,
135.1, 132.2, 129.1, 126.5, 125.5, 123.4, 121.7, 121.2 ppm.
2-(Pyridin-2-yl)benzo[d]thiazole (5j).16a White solid; yield 75.7%
2-Benzyl-6-chloro-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]-
1
thiadiazine (6e). White solid; yield 78.7% (435 mg); mp 160−161 °C;
(320.8 mg); ESI-MS (m/z) = 213 (M + H); H NMR (400 MHz,
1
FT-IR ν max (KBr) 1215.6 (C−N) cm−1, 3436.9 (N−H) cm−1; H
DMSO-d6) δ 8.747−8.728 (m, 1H), 8.351−8.327 (m, 1H), 8.184−
8.163 (m, 1H), 8.122−8.121 (m, 1H), 8.067- 8.024 (m, 1H), 7.616−
7.554 (m, 2H), 7.523−7.482 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 169.5, 154.2, 150.8, 150.4, 138.3, 135.9, 127.1, 126.6, 126.4,
123.8, 123.0, 120.8 ppm.
NMR (400 MHz, DMSO-d6) δ 7.412−7.348 (m, 8H), 7.327−7.248
(m, 3H), 6.848 (d, J = 2.12 Hz, 1H), 6.765 (d, J = 8.26 Hz, 1H),
6.597−6.571 (m, 1H), 5.431 (d, J = 4.25 Hz, 1H), 4.163 (d, J = 13.34
Hz, 1H), 3.922 (d, J = 13.58 Hz, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6) δ 143.4, 141.8, 138.5, 130.7, 129.3, 128.8, 128.6, 128.0,
127.9, 127.1, 126.5, 116.7, 113.7, 113.3, 72.0, 61.0 ppm; mass (ESI)
m/z = 353.0 (M + H)+; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H18ClN2S, 353.0879; found, 353.0872.
2-(Pyridin-4-yl)benzo[d]thiazole (5k). White solid; yield 76% (325
1
mg); ESI-MS (m/z) = 213(M + H); H NMR (400 MHz, CDCl3) δ
8.781−8.786 (m, 2H), 8.13 (d, J = 8.14 Hz, 1H), 7.962−7.937 (m,
3H), 7.570−7.528 (m, 1H), 7.481−7.440 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 165.1, 154.0, 150.7, 140.5, 135.2, 126.8, 126.2,
123.9, 121.9, 122.2 ppm.
6-Chloro-2-(4-methylbenzyl)-3-p-tolyl-3,4-dihydro-2H-benzo[e]-
[1,2,4]thiadiazine (6f). White solid; yield 72% (430 mg); mp 162−
163 °C; FT-IR νmax (KBr) 1215.6 (C−N) cm−1, 3439.09 (N−H)
General Procedure for Synthesis of 2-Benzyl-3-phenyl-3,4-
dihydro-2H-benzo[e][1,2,4]thiadiazines 6a−6j. To a stirred solution
of 2.0 equiv of benzylamine and 1.0 equiv of 2-mercaptoaniline in ethyl
acetate (5 mL) at room temperature was slowly added 1.3 equiv of I2.
We allowed for stirring at room temperature for 4 h, and the progress
of the reaction was monitored by TLC analysis. After completion of
the reaction, excess I2 was quenched with a saturated aqueous solution
of Na2S2O3. The organic layer was separated, and the aqueous solution
was then extracted by ethyl acetate (10 mL). The combined organic
layers were washed with brine solution (10 mL), dried over anhydrous
Na2SO4 and evaporated to yield a crude 1,2,4-benzothiadiazine
derivative. Residue was purified by the silica gel column chromatog-
raphy using hexane and ethyl acetate (80:2) as eluent.
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.338−7.286 (m, 4H), 7.223−
7.175 (m, 4H), 6.786−6.692 (m, 3H), 5.386 (d, J = 3.83 Hz, 1H),
4.539 (d, J = 3.83 Hz, 1H), 4.145−4.049 (m, 2H), 2.399 (s, 3H), 2.376
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.3, 139.3, 137.7,
137.4, 134.9, 131.4, 129.2, 129.1, 129.0, 126.6, 126.2, 118.3, 115.0,
114.2, 71.7, 60.5, 21.2 ppm; mass (ESI) m/z = 381.0 (M + H)+;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H22ClN2S, 381.1192;
found, 381.1185.
6-Chloro-2-(3-chlorobenzyl)-3-(3-chlorophenyl)-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine (6g). Pale pink solid; yield 73.4% (485
mg); mp 158−159 °C; FT-IR ν max (KBr) 1215.48 (C−N) cm−1,
1
3405.46 (N−H) cm−1; H NMR (400 MHz, DMSO-d6) δ 7.447−
7.323 (m, 9H), 6.884 (d, J = 2.11 Hz, 1H), 6.785 (d, J = 8.26 Hz, 1H),
6.612 (dd, J = 2.19 Hz 1H), 5.515 (d, J = 4.33 Hz, 1H), 4.214 (d, J =
13.52 Hz, 1H), 3.881 (d, J = 13.49 Hz, 1H) ppm; 13C NMR (100
MHz, DMSO-d6) δ 145.9, 141.3, 141.0, 133.5, 133.3, 131.0, 130.7,
129.1, 128.0, 128.0, 127.8, 127.1, 126.8, 126.0, 117.1, 114.0, 112.9,
72.1, 60.2 ppm; mass (ESI) m/z = 421.3 (M + H)+; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C20H16Cl3N2S 421.0100; found
421.0083.
2-Benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine
(6a). Pale pink solid; yield 81% (515 mg); mp 160−161 °C; FT-IR ν
1
max (KBr) 1294 (C−N) cm−1, 3396.4 (N−H) cm−1; H NMR (400
MHz, DMSO-d6) δ 7.422−7.238 (m, 10H), 7.008−6.947 (m, 2H),
6.821 (d, J = 8.11 Hz, 1H), 6.743−6.724 (m, 1H), 6.596−6.556 (m,
1H), 5.398 (d, J = 4.12 Hz, 1H), 4.168 (d, J = 13.43 Hz, 1H), 3.96 (d,
J = 13.31 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 143.7,
140.5, 138.8, 129.3, 128.8, 128.5, 127.8, 127.2, 126.6, 124.9, 117.3,
115.0, 114.5, 72.2, 61.0 ppm; mass (ESI-MS) m/z = 319 (M + H)+;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2S, 319.1269;
found, 319.1268.
6-Chloro-2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine (6h). White solid; yield 74.8% (456 mg);
mp 159−160 °C; FT-IR ν max (KBr) 1215.61 (C−N) cm−1, 3438.28
1
(N−H) cm−1; H NMR (400 MHz, DMSO-d6) δ 7.444−7.354, (m,
2-(4-Methylbenzyl)-3-p-tolyl-3,4-dihydro-2H-benzo[e][1,2,4]-
thiadiazine (6b). Pale pink solid; yield 70.8% (490 mg); mp 158−160
°C; FT-IR ν max (KBr) 1215.4 (C−N) cm−1, 3440.4 (N−H) cm−1;
1H NMR (400 MHz, CDCl3) δ 7.292−7.261 (m, 4H), 7.151−7.106
(m, 4H), 7.019−6.977 (m, 1H), 6.812−6.789 (m, 1H), 6.694−6.625
(m, 2H), 5.356 (d, J = 3.95 Hz, 1H), 4.391 (d, J = 3.95 Hz, 1H),
4.102−4.014 (dd, J = 13.22 Hz, J = 8.88 Hz, 2H), 2.332 (s, 3H), 2.308
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 139.6, 139.4, 135.3,
129.2, 129.0, 129.0, 126.7, 126.2, 125.2, 118.4, 116.7, 115.0, 72.1, 60.3,
21.2 ppm; mass (ESI) m/z = 347.1 (M+H)+; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C22H23N2S, 347.1582; found, 347.1579.
4H), 7.284 (d, J = 4.18 Hz, 1H), 7.213−7.151 (m, 4H), 6.842 (d, J =
2.16 Hz, 1H), 6.770 (d, J = 8.27 Hz, 1H), 6.591 (dd, J = 2.19 Hz, J =
6.0 Hz, 1H), 5.446 (d, J = 4.10 Hz, 1H), 4.156 (d, J = 13.43 Hz, 1H),
3.857 (d, J = 13.43 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
163.2, 160.8, 141.6, 139.7, 134.7, 131.3 (d, J = 8.22 Hz), 130.8, 129.2,
(d, J = 8.19 Hz), 126.6, 116.9, 115.6, 115.4, (d, J = 3.88 Hz) 115.2,
113.9, 113.1, 71.51, 60.17 ppm; mass (ESI) m/z = 389.0 (M + H)+;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H16ClF2N2S,
389.0691; found, 389.0679.
6-Chloro-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-
benzo[e][1,2,4]thiadiazine (6i). White solid; yield 71.1% (470 mg);
mp 142−143 °C; FT-IR ν max (KBr) 1215.54 (C−N) cm−1, 3439.01
(N−H) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.358−7.260 (m, 8H),
6.752−6.686 (m, 3H) 5.317 (d, J = 4.26 Hz 1H), 4.550 (d, J = 4.01
Hz, 1H), 4.063 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 140.49,
2-(3-Chlorobenzyl)-3-(3-chlorophenyl)-3,4-dihydro-2H-benzo[e]-
[1,2,4]thiadiazine (6c). White solid; yield 73% (565 mg); mp 135−
137 °C; FT-IR ν max (KBr) 1298.3 (C−N) cm−1, 3439.7 (N−H)
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.420−7.415 (m, 2H), 7.354−
7.279 (m, 6H), 7.104−6.7.062 (m, 1H), 6.870−6.848 (m, 1H),
3827
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139.55, 136.08, 133.95, 133.65, 131.73, 130.336, 128.79, 128.59,
128.17, 126.37, 118.79, 114.45, 71.62, 60.32 ppm; mass (ESI) m/z =
421.7 (M + H)+; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H16Cl3 N2S, 421.0100; found, 421.0083.
Nachtsheim, B. J. Org. Lett. 2011, 13, 3754. (c) Zhang, J. T.; Zhu, D.
P.; Yu, C. M.; Wan, C. F.; Wang, Z. Y. Org. Lett. 2010, 12, 284.
(d) Wu, W.-B.; Huang, J.-M. Org. Lett. 2012, 14, 5832. (e) Lamani, M.;
Prabhu, K. R. J. Org. Chem. 2011, 76, 7938. (f) Gao, W.-C.; Jiang, S.;
Wang, R.-L.; Zhang, C. Chem. Commun. 2013, 49, 4890. (g) Li, Y.-X.;
Wang, H.-X.; Ali, S.; Xia, X.-F.; Liang, Y.-M. Chem. Commun. 2012, 48,
2343. (h) Samanta, R.; Lategahn, J.; Antonchick, P. A. Chem. Commun.
2012, 48, 3194. (i) Batchu, H.; Bhattacharyya, S.; Batra, S. Org. Lett.
2012, 14, 6330. (j) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Adv. Synth.
Catal. 2013, 355, 170. (k) Xu, W.; Kloeckner, U.; Nachtsheim, B. J. J.
Org. Chem. 2013, 78, 6065. (l) Gao, W.-C.; Wang, R.-L.; Zhang, C.
Org. Biomol. Chem. 2013, 11, 7123.
6-Chloro-2-(3,4-dichlorobenzyl)-3-(3,4-dichlorophenyl)-3,4-dihy-
dro-2H-benzo[e][1,2,4]thiadiazine (6j). White solid; yield 72.8% (560
mg); mp 123−125 °C; FT-IR ν max (KBr) 1215.48 (C−N) cm−1,
1
3437.02 (N−H) cm−1; H NMR (400 MHz, CDCl3) δ 7.378−7.315
(m, 4H), 7.176−7.117 (m, 2H) 6.677−6.632 (m, 3H), 5.217 (d, J =
3.96 Hz, 1H), 4.512 (d, J = 3.96 Hz, 1H), 3.985−3.910 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3) δ 142.0, 139.0, 137.6, 132.7, 132.6,
132.2, 132.0, 132.0 130.8, 130.7, 130.5, 129.0, 128.3, 126.6, 126.2,
119.2, 114.6, 114.0, 71.7, 60.0 ppm; mass (ESI) m/z = 490.5 (M +
H)+; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H14Cl5N2S,
488.9320; found, 488.9317.
(6) (a) Naresh, G.; Narender, T. RSC Adv. 2014, 4, 11862.
(b) Rajendar, K.; Ruchir, K.; Narender, T. Adv. Synth. Catal. 2013,
355, 3591.
(7) Representative examples for the biological importance of
benzimidazoles: (a) Singh, S.; Bharti, N.; Mohapatra, P. P. Chem.
ASSOCIATED CONTENT
■
Rev. 2009, 109, 1900. (b) Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A.
̈
S
* Supporting Information
1
Copies of H NMR, 13C NMR spectra of all the compounds
M. Chem. Rev. 2011, 111, 5215. (c) Mieczkowski, A.; Roy, V.;
Agrofoglio, L. A. Chem. Rev. 2010, 110, 1828. (d) Alterio, V.; Fiore, A.
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(h) Kok, S. H. L.; Gambari, R.; Chui, C. H.; Yuen, M. C. W.; Lin, E.;
Wong, R. S. M.; Lau, F. Y.; Cheng, G. Y. M.; Lam, W. S.; Chan, S. H.;
Lam, K. H.; Cheng, C. H.; Lai, P. B. S.; Yu, M. W. Y.; Cheung, F.;
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(I) Liu, C.; Lin, J.; Pitt, S.; Zhang, R. F.; Sack, J. S.; Kiefer, S. E.; Kish,
K.; Doweyko, A. M.; Zhang, H.; Marathe, P. H.; Trzaskos, J.;
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(3a−3n, 5a−5k, and 6a−6j) and 2D-NMR spectra, X-ray
analysis data of compound 6a. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +91 522-2772450, 2772550; fax: +91 522 2623405; e-
mail: t_narendra@cdri.res.in, tnarender@rediffmail.com
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors are thankful to the Director, CDRI, Lucknow, India for
constant encouragement for the program on natural products
analogous and to the SAIF division for providing spectral data.
We thank Dr. Tejender S. Thakur, Molecular and Structural
Biology Division, Central Drug Research Institute (CSIR) for
supervising the X-ray data collection and structure determi-
nation of compound 6a. G. Naresh is thankful to the CSIR,
New Delhi, for the fellowship and research grant (BSC-0102:
THUNDER). This is CDRI communication no. 8649.
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