Chemoselective synthesis of 1,2-disubstituted benzimidazoles in lactic acid without additive

Article abstract of DOI:10.1515/chempap-2016-0056

Lactic acid is recognised as a biocompatible medium for the chemoselective synthesis of the 1,2-disubstituted benzimidazole scaffold via a direct one-pot cyclocondensation of o-phenylenediamine with aldehydes. Various 1,2-disubstituted benzimidazole deriv

Full text of DOI:10.1515/chempap-2016-0056

Chemical Papers 70 (9) 1293–1298 (2016)
DOI: 10.1515/chempap-2016-0056
ORIGINAL PAPER
Chemoselective synthesis of 1,2-disubstituted benzimidazoles
in lactic acid without additive
Zhi-Yu Yu, Jia Zhou, Qiu-Sheng Fang, Ling Chen, Zhi-Bin Song*
State Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang 330022, China
Received 27 July 2015; Revised 5 February 2016; Accepted 11 February 2016
Lactic acid is recognised as a biocompatible medium for the chemoselective synthesis of the 1,2-
disubstituted benzimidazole scaffold via a direct one-pot cyclocondensation of o-phenylenediamine
with aldehydes. Various 1,2-disubstituted benzimidazole derivatives were successfully synthesised
with high selectivity with good to excellent yields without any additional catalyst or additive. Most
products could be isolated by a simple filtration after completion of the reactions. Satisfactory
results were also obtained from multi-gram scale reactions.
c
ꢀ 2016 Institute of Chemistry, Slovak Academy of Sciences
Keywords: chemoselective, 1,2-disubstituted benzimidazoles, lactic acid, green synthesis
Introduction
by Chakraborti (Kommi et al., 2012, 2013).
However, the cyclocondensation of o-phenylenedi-
amine with aldehydes encounters a selectivity prob-
lem due to the competitive formation of the 1,2-
disubstituted, the 2-substituted benzimidazoles and
the Schiff base compounds (Fig. 1). Several meth-
ods have been reported for the selective synthesis of
1,2-disubstituted benzimidazoles using FeF3 (Kumar
et al., 2012), Me3SiCl (Wan et al., 2009), ZnO-NPs
(Sharma et al., 2015), HClO4–SiO2 (Kumar et al.,
2013) as catalyst or microwave irradiation in acetic
acid (Azarifar, 2010), ultrasonic irradiation (Kumar et
al., 2014). In addition, Chebolu et al. (2012) reported
a metal/Lewis acid-free protocol in which fluorous al-
cohols with better hydrogen bond donor (HBD) abil-
ities could efficiently promote the selective formation
of 1,2-disubstituted benzimidazoles.
The present study reports a “green” and efficient
procedure for the synthesis of 1,2-disubstituted benz-
imidazoles in lactic acid as a biocompatible solvent at
ambient temperature and with an easy set-up via a di-
rect one-pot cyclocondensation of o-phenylenediamine
with aldehydes. In addition, most of the products
could be obtained by simply adding water and recrys-
tallisation after completion of the reactions.
Benzimidazoles are regarded as favoured struc-
tures in the area of medicinal chemistry (Kallashi et
al., 2011). 1,2-Disubstituted benzimidazoles and their
derivatives as an important branch of this family ex-
hibit valuable pharmacological activities, such as an-
titumour (Boiani & González, 2005), antiviral (Miller
et al., 2010) and antifungal (Chen et al., 2009) ap-
plications. In addition, 1,2-disubstituted benzimida-
zoles are of special interest for their application in
polymers and catalysis (Plater et al., 2009; Harkal et
al., 2004; Georgiou et al., 2009). These special uses
of 1,2-disubstituted benzimidazoles highlight the im-
portance attached to their synthesis (Carvalho et al.,
2011).
Substantial effort has been invested in the con-
struction of this scaffold, such as cyclocondensation
procedures (Ozden et al., 2005; Vourloumis et al.,
2003), alkylation or arylation procedures (Porcari et
al., 1998; Ezquerra et al., 1997; Zheng & Buchwald,
2007), intramolecular cyclisation procedures (Brain &
Steer, 2003; Zhu et al., 2009; Shenvi et al., 2009). In
addition, the novel “all water” strategy for the syn-
thesis of 1,2-disubstituted benzimidazoles was devised
¨
*Corresponding author, e-mail: zbsong@jxnu.edu.cn
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Z. Y. Yu et al./Chemical Papers 70 (9) 1293–1298 (2016)
Fig. 1. Cyclocondensation of o-phenylenediamine with aldehydes.
Table 1. Formation of IVa via condensation of o-phenylenediamine with benzaldehydea
Entry
solvent
T (◦C)
t (h)
Yield of IVab (%)
1d
2
ethyl lactate
lactic acid
ethanol
80
80
80
80
60
40
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
10
8
6
4
2
4
35
85
15
25
86
84
83
84
82
85
84
70
95
3d
4d
5
furfuryl alcohol
lactic acid
lactic acid
lactic acid
lactic acid
lactic acid
lactic acid
lactic acid
lactic acid
lactic acid
6
7
8
9
10
11
12
13c
rt
rt
a) Reaction conditions: Ia (1 mmol), o-phenylenediamine (1 mmol) in solvent (2 mL); b) yield of isolated product in relation to Ia;
c) Ia (2 mmol), o-phenylenediamine (1 mmol); d) determined by GC; rt – ambient temperature.
Experimental
densation of aminothiophenol with aldehydes (Yu et
al., 2015). This result prompted investigation of the
construction of 2-substituted benzimidazoles under
the same conditions. Accordingly, o-phenylenediamine
was treated with an equivalent of benzaldehyde (Ia)
in ethyl lactate at 80◦C overnight. However, the yield
of 2-phenyl benzimidazole was not good under these
conditions, and 1,2-disubstituted benzimidazole (IVa)
was obtained with a 35 % yield (in relation to Ia). In
order to increase the yield of 2-phenyl benzimidazole,
o-phenylenediamine was treated with Ia in different
protic solvents by using a 1 : 1 mole ratio (Table 1,
entries 1–4).
The unexpected results showed that the use of
equimolar amounts of o-phenylenediamine and ben-
zaldehyde afforded IVa as the major product in lactic
acid. Hence, the reaction of o-phenylenediamine with
Ia at 1 : 1 mole ratio was adopted as the model re-
action. The effects of reaction temperature, time and
mole ratio of raw materials were assessed (Table 1,
entries 5–13). The results showed that the reaction at
ambient temperature gave a similarly high yield of IVa
as in the elevated temperature. Subsequent examina-
tion of the reaction time showed that there was almost
no change in the yield of IV, even though the reaction
time was shortened from 12 h to 4 h (Table 1, entries
7–12), but a reaction time of 2 h was not sufficient
for complete conversion as detected by TLC analysis.
Hence, the reaction time was selected as 4 h. Finally,
the yield of IVa was further increased to 95 % with
Lactic acid (AR, 85–90 % aqueous solution) and
ethyl lactate (purity ≥ 99 %) were purchased from
Aladdin (Shanghai, China). Other reagents such as
aldehydes, o-phenylenediamine and solvents were of
analytical grade and used without further purification.
Thin-layer chromatography (TLC) was used to moni-
tor the reaction progress. Melting points were recorded
in open capillaries and are uncorrected. 1H NMR spec-
tra were recorded on a BRUKER AVANCE (Ger-
many) 400 MHz spectrophotometer using CDCl3 and
DMSO-d6 as solvents and tetramethylsilane (TMS)
as the internal standard. Mass spectra analysis was
performed using GC–MS (Trace1300/ISQ, Thermo
Fisher Scientific, USA) analyser and high resolution
mass spectrometry (HRMS) spectra analysis was per-
formed by electrospray ionisation (ESI-micro TOF).
Aldehydes (2 mmol), o-phenylenediamine (1 mmol)
were dissolved in lactic acid (2 mL). The mixture was
stirred at ambient temperature for 4–6 h (TLC). Af-
ter complete consumption of the aldehydes, 15 mL
of water was added to the reaction mixture and the
solution phase was filtered. The pure products were
recrystallised from ethanol.
Results and discussion
At the outset, 2-substituted benzothiazoles could
be obtained in ethyl lactate via the aerobic con-
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Fig. 2. Multi-gram scale synthesis of 1,2-disubstituted benzimidazoles; conditions: p-substituted benzaldehydes (50 mmol), yield
for IVa (5.8 g, 82 %); IVe (7.6 g, 88 %); IVh (8.8 g, 80 %).
Fig. 3. Plausible mechanism for formation of 1,2-substituted benzimidazole derivatives in lactic acid.
Table 2. Comparison of Brønsted acids with lactic acid in syn-
Brønsted acids (Table 2). The superiority of lactic acid
was clearly established not only in its good selectiv-
ity of 1,2-disubstituted benzimidazoles but also in the
“green” and sustainable chemistry.
thesis of 1,2-disubstituted benzimidazolesa
Entry
Solvent
t (h)
Yield of IVab (%)
Subsequently, the general applicability of selec-
tive 1,2-disubstituted benzimidazoles was also ex-
plored. The reaction of o-phenylenediamine with var-
ious aromatic aldehydes was further examined (Ta-
ble 3). It was observed that all aromatic aldehydes
and the aliphatic aldehyde (i.e. n-butyl aldehyde)
could be successfully converted to the corresponding
1,2-disubstituted benzimidazoles and these products
could be readily obtained with good to excellent yields
by crystallisation. The structures of all products were
confirmed by 1H NMR and mass spectrometry and
by comparing the melting points with results in the
literature (Table 4).
In view of the simplicity of this synthetic method,
scale-up experiments were subsequently performed
so as to confirm the applicability of this proto-
col. Accordingly, the direct one-pot cyclocondensa-
tion of o-phenylenediamine and aldehydes with an
electron-withdrawing or electron-donating group was
performed on a multi-gram scale (Fig. 2). The satis-
factory results from these scale-up experiments fur-
ther confirmed the advantage of this simple and
“green” protocol for its potential in large-scale syn-
thesis.
1
HOAc
oxalic acid
H2SO4
glyoxalic acid
lactic acid
4
6
6
4
4
84
68
58
73
95
2c
3c
4c
5
a) Reaction conditions: Ia (2 mmol), o-phenylenediamine
(1 mmol, phenylenediamine is the limiting reagent) in solvent
(2 mL) at ambient temperature; b) isolated yield; c) 30 % aque-
ous solution.
the 2 : 1 mole ratio of Ia to o-phenylenediamine.
These results indicated lactic acid to have the
ability to drive increase selectivity towards the for-
mation of IVa. According to a report in the liter-
ature (Chebolu et al., 2012), the better hydrogen
bond donor (HBD) abilities of the solvent exhibit bet-
ter selectivity. In this case, lactic acid may also act
as a hydrogen-bond-driven electrophilic activator for
the selective formation of 1,2-disubstituted benzim-
idazoles. This may be attributed to the formation of
intramolecular hydrogen bond in lactic acid increasing
the HBD ability (Fig. 3). In addition, the performance
of lactic acid was compared with the results of other
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Z. Y. Yu et al./Chemical Papers 70 (9) 1293–1298 (2016)
Table 3. Lactic acid-promoted 1,2-disubstituted benzimidazoles formationa
Entry
R
Product
Yieldb (%)
m.p. (◦C)
m.p.c (◦C)
1
2
3
4
5
6
7d
8
9
Ph
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
95
85
90
85
91
92
86
85
93
136–138
256–258
125–127
165–167
128–131
148–150
125–127
133–135
146–148
130–132
254–256
129–130
170–172
130–131
142–144
129–130
139–141
146–147
4-HOC6H4
4-MeC6H4
2-O2NC6H4
4-MeOC6H4
3,4-(MeO)2C6H4
n-butyl
4-BrC6H4
thienyl
a) General conditions: o-phenylenediamine (1 mmol) and Ia (2 mmol) in lactic acid (2 mL), stirred at ambient temperature for
4–6 h; b) yield of isolated product; c) values reported in literature (Kumar et al., 2012; Chebolu et al., 2012; Ahmadian et al.,
2015); d) reaction at 80◦C and purified by silica gel column chromatography.
Table 4. Spectral data of compounds
Compound
IVa
Spectral data
1H NMR (400 MHz, CDCl3), δ: 7.90–7.92 (m, 1H), 7.70–7.71 (m, 2H), 7.46–7.50 (m, 3H), 7.31–7.35 (m, 4H), 7.22
(d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 5.48 (s, 2H); MS m/z (MH)+ calcd.: 285.4, found: 285.1
1H NMR (400 MHz, DMSO-d6), δ: 9.97 (s, 1H), 9.41 (s, 1H), 7.65 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 2H), 7.42
(d, J = 8 Hz, 1H), 7.18–7.21 (m, 2H), 6.89 (d, J = 8 Hz, 2H), 6.83 (d, J = 8 Hz, 2H), 6.65 (d, J = 8 Hz, 2H), 5.42
(s, 2H); HRMS m/z (MH)+ calcd.: 317.1285, found: 317.1305
1H NMR (400 MHz, CDCl3), δ: 7.82 (d, J = 8 Hz, 1H), 7.53–7.55 (m, 2H), 7.25–7.13 (m, 5H), 7.07–7.09 (m, 2H),
6.95–6.97 (m, 2H), 5.38 (s, 2H), 2.42 (s, 3H), 2.35 (s, 3H)
1H NMR (400 MHz, CDCl3), δ: 8.14–8.16 (m, 2H), 7.95–7.98 (m, 1H), 7.86 (d, J = 8 Hz, 1H), 7.67–7.69 (m, 2H),
7.47–7.52 (m, 2H), 7.30–7.37 (m, 2H), 7.15 (d, J = 8 Hz, 1H), 6.94–6.96 (m, 1H), 5.70 (s, 2H); HRMS m/z (MH)+
calcd.: 375.1088, found: 375.1099
IVb
IVc
IVd
IVe
IVf
1H NMR (400 MHz, CDCl3), δ: 7.96–7.98 (m, 1H), 7.80–7.83 (m, 3H), 7.69 (d, J = 8 Hz, 2H), 7.38–7.43 (m, 3H),
7.20–7.23 (m, 3H), 5.55 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H); HRMS m/z (MH)+ calcd.: 345.1598, found: 345.1576
1H NMR (400 MHz, CDCl3), δ: 7.88 (d, J = 8 Hz, 1H), 7.51–7.57 (m, 1H), 7.27−7.31 (m, 2H), 7.22–7.24 (m, 1H),
7.11–7.13 (m, 1H), 6.92 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.66 (m, 1H), 6.64 (d, J = 8 Hz, 1H), 5.41 (s,
2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H); HRMS m/z (MH)+ calcd.: 405.1809, found: 405.1813
1H NMR (400 MHz, CDCl3), δ: 7.71–7.73 (m, 1H), 7.27–7.30 (m, 1H), 7.20–7.23 (m, 2H), 4.07 (t, J = 8 Hz, 2H),
2.82 (t, J = 8 Hz, 2H), 1.90–1.96 (m, 2H), 1.74–1.78 (m, 2H), 1.37–1.41 (m, 2H), 1.07 (t, J = 8 Hz, 3H) 0.96 (t,
J = 8 Hz, 3H); HRMS m/z (MH)+ calcd.: 216.1626, found: 216.1623
IVg
IVh
IVi
1H NMR (400 MHz, CDCl3), δ: 7.82–7.83 (m, 1H), 7.54–7.56 (m, 2H), 7.48–7.50 (m, 2H), 7.41–7.43 (m, 2H),
7.25–7.28 (m, 2H), 7.15–7.17 (m, 1H), 6.93–6.96 (m, 2H), 5.42 (s, 2H); HRMS m/z (MH)+ calcd.: 440.9596, found:
440.9560
1H NMR (400 MHz, CDCl3), δ: 7.83–7.85 (m, 1H), 7.51–7.53 (m, 1H), 7.47–7.48 (m, 1H), 7.36–7.38 (m, 1H), 7.28–
7.31 (m, 2H), 7.23–7.25 (m, 1H), 7.13–7.15 (m, 1H), 6.93–6.95 (m, 1H), 6.86–6.87 (m, 1H), 5.71 (s, 2H); HRMS m/z
(MH)+ calcd.: 297.0515, found: 297.0527
From the experimental observations and literature
reports on experiments carried out under similar re-
action conditions (Chebolu et al., 2012), a plausible
reaction mechanism for the selective formation of 1,2-
substituted benzimidazoles in lactic acid was proposed
(Fig. 3). First, Schiff base bisimine E-1 is formed in
lactic acid. Subsequently, lactic acid promotes the for-
mation of immonium E-2 by the intramolecular cycli-
sation of E-1. Finally, lactic acid mediated the rear-
rangement of imminium E-2 to afford 1,2-substituted
benzimidazole derivatives.
zimidazoles in lactic acid as a biocompatible medium
under mild conditions. The α-hydroxy acid structure
of lactic acid may gain a better hydrogen bond donor
(HBD) ability in the formation of 1,2-disubstituted
benzimidazoles. The products of 1,2-disubstituted
benzimidazoles could be readily obtained by simply
adding water and recrystallisation after completion of
the reactions. More notably, the reactions were found
to be practical for scale-up synthesis by affording 1,2-
disubstituted benzimidazoles in a multi-gram scale re-
action.
Conclusions
Acknowledgements. This work received financial support
from the Department of Education of Jiangxi Province and Key
Laboratory of Functional Small Organic Molecules, Ministry of
Education (no. GJJ13214, KLFS-KF-201229).
A simple and “green” protocol was developed for
the chemoselective synthesis of 1,2-disubstituted ben-
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Z. Y. Yu et al./Chemical Papers 70 (9) 1293–1298 (2016)
1297
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