Synthesis of 1H-1,3-benzimidazoles, benzothiazoles and 3H-imidazo[4,5-c]pyridine using DMF in the presence of HMDS as a reagent under the transition-metal-free condition

Article abstract of DOI:10.1007/s11696-018-0540-5

An operationally simple method for synthesis of benzimidazole and 3H-imidazo[4,5-c]pyridine from o-phenylenediamine or pyridine-3, 4-diamine and N,N-dimethylformamide (DMF) in the presence of hexamethyldisilazane (HMDS) as a reagent is described. To evaluate the scope of application of this reagent, it was also used to prepare benzothiazole, 1H-perimidine, and benzoxazole, which was successful for benzothiazole and 1H-perimidine but benzoxazole was not formed. This reaction complies with the principles of green chemistry as it does not use toxic solvents, transition metals, or strong acids. The products are obtained in moderate to excellent yields.

Full text of DOI:10.1007/s11696-018-0540-5

Chemical Papers
https://doi.org/10.1007/s11696-018-0540-5
ORIGINAL PAPER
Synthesis of 1H‑1,3‑benzimidazoles, benzothiazoles
and 3H‑imidazo[4,5‑c]pyridine using DMF in the presence of HMDS
as a reagent under the transition‑metal‑free condition
Hamid Mostafavi1,2 · Mohammad Reza Islami1 · Ehsan Ghonchepour · Ahmad Momeni Tikdari
1
1
Received: 8 March 2018 / Accepted: 16 June 2018
©
Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
An operationally simple method for synthesis of benzimidazole and 3H-imidazo[4,5-c]pyridine from o-phenylenediamine
or pyridine-3, 4-diamine and N,N-dimethylformamide (DMF) in the presence of hexamethyldisilazane (HMDS) as a reagent
is described. To evaluate the scope of application of this reagent, it was also used to prepare benzothiazole, 1H-perimidine,
and benzoxazole, which was successful for benzothiazole and 1H-perimidine but benzoxazole was not formed. This reac-
tion complies with the principles of green chemistry as it does not use toxic solvents, transition metals, or strong acids. The
products are obtained in moderate to excellent yields.
Keywords Benzimidazole · Heterocyclic compounds · HMDS · DMF · Biological activities
Introduction
benzimidazole ring causes to exhibit a wide range of phar-
macological activities (Maryanoꢂ et al. 1995).
Benzimidazole is a bicyclic heteroaromatic compound con-
taining an imidazole ring, where a benzene ring fused to the
Today, diꢂerent strategies are used to synthesize organic
compounds (Yang et al. 2004, 2017). With regard to the
application of benzimidazole and its derivatives in chemis-
try and pharmacy, various methods have been used for the
synthesis of benzimidazole such as, reaction of 1,2-arylen-
ediamines with aldehydes, ketones, acid anhydrides, acid
chlorides, esters, amides, nitriles, urea, in the presence of
a catalyst such as In(OTF) (Trivedi et al. 2006), Na AlF
4
- and 5-position of the imidazole ring. The imidazole is an
important heterocyclic compound that is found in several
natural compounds such as purine, vitamins (B ), some of
1
2
the amino acids same as histidine. This compound shows a
vital role in the metabolism of all living cells. Benzimida-
zole derivatives exhibit numerous signiꢀcant medical and
biological activities such as antiallergic (Nakano et al. 1999),
anticancer (Tong et al. 2009), antibacterial (Menteşe et al.
3
3
6
(Grigorjeva et al. 2014), Zn(OTF) (Srinivasulu et al. 2014),
2
Na S O (Alaqeel 2017), CdCl (Sammaiah et al. 2012),
2
2
5
2
2
2
014), antiulcer (Iwahi et al. 1991), antifungal (Ke et al.
014), antihistaminic (Iemura et al. 1987), antiviral (Tonelli
NH OAc (Sharghi et al. 2008a), BF -etherate (Nagawade
4
3
and Shinde 2006), Au-CeO (Ruiz et al. 2010), NaHSO
2
3
et al. 2014), anti-inꢁammatory (Sondhi et al. 2006), anti-
depressant (Siddiqui et al. 2011), and antidiabetic (Bansal
and Silakari 2012) (Fig. 1). The literature survey reveals
that the presence of a substitution at 1, 2 and 5 positions of
(Austen and Kane 2001), MnO (Bhatnagar and George
2
1968), copper complex (Sharghi et al. 2008c), ceric ammo-
nium nitrate (CAN) (Kidwai et al. 2010), K [Fe(CN) ]
4
6
(Shaikh and Patil 2012), zinc chloride (Mahajan et al.
2
2
013), silica boron sulfonic acid (SBSA) (Sajjadifar et al.
012), lanthanum chloride (Venkateswarlu et al. 2013),
TsOH/graphite (Sharghi et al. 2008b), and hydrogen per-
oxide (Gadekar et al. 2010). Some of these methods suf-
fer from disadvantages such as environmental damage, the
use of strong acids, high temperatures, and use of toxic
metal catalysts and hazardous reagents that is in conꢁict
with green chemistry. Therefore, a research for new reagent
and the development of new methods are still of practical
*
Mohammad Reza Islami
mrislami@uk.ac.ir
1
2
Chemistry Department, Shahid Bahonar University
of Kerman, Kerman 76169, Iran
Kerman Agricultural and Natural Resource Research
and Education Center, (AREEO), Kerman, Iran
Vol.:(0
1
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Chemical Papers
Fig. 1 Drugs containing benzi-
midazole skeletons
importance in synthetic chemistry. Recently, DMF was used
for the synthesis of benzimidazole derivatives in the pres-
The products are known and the structures of those charac-
1
13
terized by IR, H NMR and C NMR. The FT-IR spectra
were recorded as KBr pellets by a Nicolet IR 100 instru-
ence of an activation reagent such as metal catalysts, PhSiH
3
1
13
(
Zhu et al. 2017), chlorotrimethylsilane (Ryabukhin et al.
ment. H NMR and C NMR spectra were recorded on
a Bruker INOVA 500 (500 and 125 MHz) spectrometer
2
006). N,N-Dimethylformamide (DMF) is a clear liquid that
has been widely used in industries as a solvent, an additive,
using TMS as internal standard and DMSO-d as a solvent
6
or an intermediate. N,N-Dimethylformamide (DMF) can
and chemical shifts are reported in ppm.
be easily synthesized from CO with dimethylamine in the
2
presence of H and suitable catalyst (Liu et al. 2010). This
2
compound has been employed as a widely utilized reactant
in organic transformations such as formylation, amination,
and cyanation reactions. (Ding and Jiao 2012). In one of
its main uses in organic synthesis, DMF is a reagent in the
Vilsmeier–Haack reaction, which is used to formylate aro-
matic compounds.
General procedure for the synthesis
of benzimidazole
HMDS (2 mmol) was added to in a 10-ml ꢁask contain-
ing 1,2-phenylenediamine (1 mmol) and 3 ml of DMF.
The reaction mixture was stirred and heated for 12 h at
120 °C and then was cooled to room temperature. The
excess DMF was removed under reduced pressure. The
benzimidazole was purified by silica chromatography
using 4:1 n-hexane/EtOAc as the eluent. All of the prod-
ucts are known. Their structures were veriꢀed by their IR,
Here we wish to report the synthesis of benzimidazole
by treatment of o-phenylenediamine with N,N-dimethyl-
formamide (DMF) or N,N-diethylformamide (DEF) in the
presence of hexamethyldisilazane (HMDS) as a new reagent
under solvent-free conditions at 120 °C (Scheme 1).
1
13
H NMR, and C NMR spectral data.
Experimental
Chemicals and methods
1H‑benzod]imidazole
1
The materials were purchased from commercial suppliers
and were of analytical grade. The progress of the reactions
was monitored by thin layer chromatography (TLC) using
a mixture of 80% n-hexane, 20% ethyl acetate as eluent.
All products were puriꢀed by column chromatography.
Yellow solid (114.6 mg, 97%); spectral data: H NMR
(500 MHz, DMSO-d ): δ 12.45 (s, 1H), 8.17 (s, 1H),
6
1
3
7.53 (t, J = 4 Hz, 2H), 7.11 (m, 2H), C NMR (125 MHz,
DMSO-d ): δ 142.42, 136.50, 122.19, and 115.93 ppm.
6
Scheme 1 Synthesis of
benzimidazole by reaction of
o-phenylenediamine with DMF
in the presence of HMDS
1
3

Chemical Papers
6‑Methyl‑1H‑benzo[d]imidazole
1H‑perimidine
1
1
Yellow solid (115 mg, 87%); spectral data: H NMR
Yellow solid (84.1 mg, 50%); spectral data: H NMR
(
500 MHz, DMSO-d ): δ 12.24 (s, 1H), 8.06 (s, 1H), 7.39
(500 MHz, DMSO-d ): δ 10.48 (s, 1H), 7.23 (s, 1H), 7.00 (t,
6
6
1
3
(
d, J=4 Hz, 1H), 7.29 (s, 1H), 6.92 (d, J=8 Hz 1H), 2.32
J=6 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 6.29 (s, 2H). C NMR
1
3
(
s, 1H, CH ), C NMR (125 MHz, DMSO-d ): δ 142.18,
(125 MHz, DMSO-d ) δ 146.96, 138.26, 135.91, 128.99,
3
6
6
1
38.37, 137.36, 131.44, 123.77, 115.96, 115.16, 21.85 ppm.
126.89, 123.57, 119.08 ppm.
Benzothiazole
6‑Nitro‑1H‑benzo[d]imidazole
1
Colorless liquid (121 mg, 90%); spectral data: H NMR
1
Yellow solid (110.9 mg, 68%); spectral data: H NMR
(500 MHz, CDCl ): δ 8.97 (s, 1H), 8.14 (d, J = 10 Hz,
3
(
(
500 MHz, DMSO-d ): δ 13.02 (s, 1H), 8.47 (s, 1H), 8.43
1H), 7.92 (d, J = 5 Hz, 1H), 7.49 (t, J = 5 Hz, 1H), 7.41
6
1
3
13
s, 1H), 8.03 (d, J = 8 Hz, 1H), 7.69 (d, J = 8 Hz, 1H).
C
(t, J=5 Hz, 1H), C NMR (125 MHz, CDCl ): δ 153.90,
3
NMR (125 MHz, DMSO-d ) δ 147.35, 134.23, 136.44,
153.23, 133.70, 126.15, 125.52, 123.62, 121.87 ppm.
6
1
33.86, 132.18, 126.96, 118.21 ppm.
Results and discussion
3
H‑imidazo[4,5‑c]pyridine
Initially, we performed the reaction of o-phenylenediamine
with DMF in the presence of SiO , PdCl , TEOS (tetraethyl
2
2
1
Yellow solid (53.6 mg, 45%); spectral data: H NMR
orthosilicate) as a catalyst and in the absence of any cata-
lyst. As shown in Table 1, no product was found in all four
cases (Table 1, entries 1–4). The yield of the same reaction
in the presence of HMDS (1 mmol) as a reagent at 85 °C
for 6 h was traced (Table 1, entry 5). The same reaction
(
(
500 MHz, DMSO-d ): δ 12.79 (s, 1H), 8.86 (s, 1H), 8.31
6
1
3
s, 1H), 8.22 (d, J = 4 Hz, 1H), 7.51 (d, J = 4 Hz, 1H),
C
NMR (125 MHz, DMSO-d ) δ 148.56, 144.56, 141.58,
6
1
33.17, 113.16, 107.92 ppm.
Table 1 Optimization of reaction conditions for synthesis of benzimidazole
Entry
Reagent
Eq.
Temp. (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
–
SiO2
–
1
1
1
1
1
2
3
2
2
2
2
120
120
120
120
85
120
120
120
120
130
120
120
6
6
6
6
6
6
6
6
12
12
15
12
0
0
0
0
PdCl2
TEOS
HMDS
HMDS
HMDS
HMDS
HMDS
HMDS
HMDS
HMDS
Trace
8
90
91
97
90
97
1
1
1
0
1
2
b
96
Reaction condition: o-phenylenediamine (1 mmol), DMF (3 ml)
The best reaction conditions for the synthesis of benzimidazole are in bold
a
Isolated yield
b
Isolated yield using o-phenylenediamine (3 mmol), DMF (9 ml)
1
3

Chemical Papers
was then carried out at 120 °C and the yield increased to
Table 2 Synthesis of benzimidazoles from 1,2-phenylenediamine and
DMF and DEF in the presence of HMDS
8
% (Table 1, entry 6). Subsequently, under the same condi-
tions, the amount of HMDS was increased to 2 and 3 mmol
therefore, the yield of the product increased to 90 and 91%
b
entry
subs
Solvent
product
yield
Ref
(
Table 1, entries 7, 8). The best reaction conditions for the
synthesis of benzimidazole were obtained in the presence
of HMDS at 120 °C for 12 h and the yield of the product
increased to 97% (Table 1, entry 9). Increasing tempera-
ture up to 130 °C reduced the yield of the reaction to 90%
1
DMF
97
(Gao et al., 2016)
2
3
DMF
DMF
87
68
(Gao et al., 2016)
(Gao et al., 2016)
(
Table 1, entry 10). The reaction time was increased to 15 h,
but no signiꢀcant change was observed in the reaction eꢃ-
ciency (Table 1, entry 11). Finally, the number of reactants
was increased to 3 mmol and the product was obtained in
9
6% yield (Table 1, entry 12).
On the basis of optimized reaction conditions, we carried
out the reactions of o-phenylenediamine derivatives with DMF
and DEF in the presence of HMDS, and the results are pre-
sented in Table 2. To evaluate the scope of application of this
reagent, it was also used to prepare 3H-imidazo[4,5-c]pyridine,
benzothiazole, 1H-perimidine, and benzofuran. The reaction
was successful for preparing of 3H-imidazo[4,5-c]pyridine,
benzothiazole and 1H-perimidine but benzoxazole was not
formed (Table 2, entries 4–7). Benzothiazole was formed in
the reaction of o-aminothiophenol with DMF and DEF in the
optimized reaction conditions with 90 and 80% yields, respec-
tively (Table 2, entries 7, 13). The reaction of DMF and DEF
with 1,8-diaminonaphthalene was successful and 1H-Perimi-
dine was formed in 50 and 38% yields, respectively (Table 2,
entries 5, 12). When 3,4-pyridinediamine was used instead of
o-phenylenediamine, 1H-imidazo[4,5-c]pyridine was obtained
in 45 and 40% yields, respectively (Table 2, entries 4, 11).
A reasonable mechanism for the mentioned reaction is
depicted in Scheme 2. Initially, the carbonyl group of DMF
4
5
DMF
DMF
45
50
(
Gao et al., 2016)
(Nale & Bhanage, 2015)
6
7
8
DMF
DMF
DEF
0
(Nale & Bhanage, 2015)
(Nale & Bhanage, 2015)
(Gao et al., 2016)
90
77
9
DEF
DEF
76
62
(Gao et al., 2016)
1
0
(Gao et al., 2016)
is activated by the HMDS and then the –NH group of
2
o-phenylenediamine attacks to the activated carbonyl group
and intermediate (I) is formed. Then a proton exchange takes
place between the two amine groups followed by remov-
1
1
1
2
DEF
DEF
40
38
(Gao et al., 2016)
ing ammonium salt. Then the second NH group attacks to
2
the carbon having Si–O group and the intermediate (II), a
(Nale & Bhanage, 2015)
two-ring heterocyclic compound, is formed. Aromatization
of new ring was performed by removing of Me SiOH and
3
benzimidazole is formed as a ꢀnal product (Scheme 2).
To highlight the importance of this research, a number
of reagents and catalysts which was used to synthesize of
benzimidazole from the reaction of DMF with o-phenylen-
ediamine have been studied. As shown in Table 3, Zhu et al.
presented an eꢃcient way to synthesize benzimidazole using
1
3
DEF
80
(Nale & Bhanage, 2015)
Reaction condition: 1,2-arylenediamine 1 mmol, HMDS 2 mmol,
DMF or DEF 3 ml, temp. 120 °C
a
Isolated yield
PhSiH (Zhu et al. 2017). Although the practical approach
3
presented in this article is very similar to the Zhu method
and there is not much diꢂerence in the eꢃciency of two
reactions but phenylsilane is very expensive so that, the price
than the Zhu method and is preferable to other methods due
to the lack of use a toxic solvent and strong acids.
In conclusion, we used HMDS as a reagent for the syn-
thesis of benzimidazole, benzothiazole, 3H-imidazo[4,5-
c]pyridine and 1H-perimidine from DMF or DEF and
of 30 g of PhSiH is approximately equal to the price of 1 l
3
of HMDS. Therefore, this protocol is economically better
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3

Chemical Papers
Scheme 2 A plausible mechanism for the synthesis of benzimidazole from o-phenylenediamine and DMF in the presence of HMDS
Table 3 Comparison of the reaction of DMF and o-phenylenediamine in the presence HMDS and some previously reported works
Reagent or catalyst
Equivalent
of reagent or
catalyst
Temp. °C Time (h) Other condition
Yield % References
Zn (OAc) ·H O, PMHS 0.1
120
120
18
12
Reactions run in autoclave reactor
93
Nale and Bhanage (2015)
Zhu et al. (2017)
2
2
PhSiH3
4
Reactions were carried out in a heavy wall 95
pressure tube
HCl
>200
150
1
Reactions were heated in a round bottom
ask
Reactions were heated in a round bottom
ask
82
Kattimani et al. (2015)
The present work
ꢁ
HMDS
3
120
12
97
ꢁ
Bold indicates the conditions in which our synthesis is carried out
o-phenylenediamine, 2-aminothiophenol, 3,4-pyridinedi-
amine and 1,8-naphthalene diamine. The yield of the products
was moderate to excellent and this reaction can take place in
the category of green chemistry reactions because the reac-
tion does not contain strong acids, toxic metal catalyst, and
an organic solvent.
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of Kerman for the ꢀnancial of this research.
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