A Green, Scalable, One-Minute Synthesis of Benzimidazoles

Article abstract of DOI:10.1055/s-0039-1690797

Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensation of 1,2-diaminoarenes and aldehydes using methanol as the reaction medium. The developed method afforded moderate to excellent yields (33-96percent) at am

Full text of DOI:10.1055/s-0039-1690797

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V. Elumalai, J. H. Hansen
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A Green, Scalable, One-Minute Synthesis of Benzimidazoles
Vijayaragavan Elumalai
Jørn H. Hansen*
UiT The Arctic University of Norway, Department of Chemistry,
Chemical Synthesis and Analysis Division, Hansine Hansens veg 54,
9037 Tromsø, Norway
jorn.h.hansen@uit.no
vijayaragavan.elumalai@uit.no
Published as part of the ISySyCat2019 Special Issue
Received: 08.10.2019
Accepted after revision: 20.12.2019
Published online: 24.01.2020
particularly utilized the condensation between aldehydes
and 1,2-diaminobenzenes under catalyst- and additive-free
conditions at ambient temperature and with very short re-
action times.
DOI: 10.1055/s-0039-1690797; Art ID: st-2019-b0536-c
Abstract Herein is reported a substantially improved synthesis of 2-
substituted benzimidazoles by condensation of 1,2-diaminoarenes and
aldehydes using methanol as the reaction medium. The developed
method afforded moderate to excellent yields (33–96%) at ambient
temperature, displays high functional group tolerance, is conducted
open to air, and requires only one minute reaction time under catalyst-
and additive-free conditions. Moreover, the efficient protocol permits
scale-up to multi-gram scale synthesis of benzimidazoles and will be-
come a method of choice when constructing such heterocyclic sys-
tems.
O
OH
H
NHR1
H
R3
N
R3
R2
R3
O
R2
N
Y
X
R3
X = OH, Cl, Br
Y = NH2, NO2, Br, I
Challenges with previous methods:
This work:
Strong acid or metal catalysis
High temperatures/microwave
irradiation
Strong oxidants/additives
Stoichiometric strong base
Poor atom-economy
No catalyst, acid or additive
Ambient temperature
Open to air
Key words benzimidazoles, green synthesis, rapid condensation, het-
erocyclization, 1,2-diaminoarenes, catalyst-free reactions
Methanol as reaction medium
Convenient one-minute reactions
Simple work-up and clean reactions
Green and atom-economical
Toxic by-products
Benzimidazole is a central heterocyclic structural motif
in numerous natural products and a crucial building block
in several drug candidates.1 Benzimidazoles display a range
of interesting biological properties such as antiviral,2 anti-
cancer,3 antibacterial,4 anti-inflammatory,5 antifungal,6
anti-ulcer,7 antihypertensive8 activities. Chemical methods
for generating benzimidazoles are numerous in the litera-
ture going back as far as 140 years (Scheme 1).9 Among
them, a classical approach involving condensation of di-
amines and aldehydes is one of the most common methods
for the synthesis of 2-substituted benzimidazoles. These re-
actions are typically conducted at high temperatures over
several hours or days at reflux,10 and in the presence of an
added Lewis or Brønsted acid catalyst,11 metal catalyst,12,13
or photocatalyst.14 Despite their efficiency, these methods
still employ expensive catalysts, additives and require rela-
tively long reaction times and harsh conditions. The devel-
opment of even more efficient, environmentally benign and
atom-economic methods is desired because of the versatile
applications of the benzimidazole heterocycle. We have
Scheme 1 Previous synthetic approaches and challenges
We were struggling to find reports of the use of milder
conditions, even though that would be desirable, and were
surprised that these mild conditions have not been report-
ed earlier. In this letter, we report on the discovery of these
extremely mild and green reaction conditions affording
benzimidazoles in medium to excellent yields.
While investigating solvent effects on the benzimidaz-
ole formation between equimolar amounts of o-phenylene-
diamine (1a) and p-nitrobenzaldehyde (2b), it was discov-
ered that high conversion was achieved already a few min-
utes after mixing the reactants in many solvents at ambient
temperature. A closer look revealed that one minute was
sufficient to achieve full conversion of the starting materi-
als. Concerning solvent effects (Table 1), no product could
be observed when using water, whereas ethanol, dioxane,
and acetonitrile gave comparably good yields (GC yields of
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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V. Elumalai, J. H. Hansen
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73, 77, and 78%, respectively). Methanol appeared to be a
superior solvent for the reaction as 99% GC yield was ob-
served (entry 1) and was therefore further utilized as the
medium for studying the generality of this approach. Add-
ing an oxidant, H2O2 (entry 4), did not change the outcome
in an observable way.
bonate in order to sequester any minute acid present in
solution afforded a diminished yield (64%) of 3b (entry 9),
which may suggest the reaction is enhanced by acid catalysis.
To study the generality of these conditions, a survey of
reactions between available substituted phenylenedi-
amines and aryl/alkyl aldehydes was conducted by using
the simple conditions found above. The short reaction time
of one minute was kept constant in order to demonstrate
the rapid reaction performance even though there may be
examples in which the conversion was not complete. In the
case of unsubstituted phenylenediamine reacting with sev-
eral p-substituted benzaldehydes, moderate to excellent
yields were achieved (Scheme 2). Particularly high yields
were obtained for p-nitro- (2b), p-cyano- (2c), and p-acet-
amido- (2e) substituted benzaldehydes (95–96% yield of 3b,
3c, and 3e). The reaction with benzaldehyde (2a) afforded
50% yield of 3a and it was shown by GC–MS that the main
remainder was the N-alkylated 1,2-disubstituted benzimid-
azole – a known by-product in this synthesis. In the case of
p-chlorobenzaldehyde (2d) a moderate 47% yield was ob-
tained of the expected benzimidazole 3d. GC–MS analysis
of the reaction mixture revealed that the N-4-chlorobenzyl-
1,2-substituted benzimidazole was formed with 45% con-
version (GC). The N-benzylated by-products likely arise
from double imine formation followed by a Cannizzaro-like
hydride transfer to saturate the benzylic carbon.15 p-Hy-
droxybenzaldehyde (2p) afforded moderate 48% yield of
benzimidazole 3p. Here, the unreacted starting material
was the majority of the remainder. The heterocyclic alde-
hyde 2h gave moderate 41% yield of the desired product 3h.
p-Phenyl benzaldehyde (2g) gave high yield of benzimidaz-
ole 3g (80%).16 Aliphatic aldehydes were also demonstrated
to work in the reaction through cyclohexyl aldehyde (2j)
which afforded the 2-cyclohexylbenzimidazole 3j in 55%
yield. In the case of linear aldehyde 2s, we obtained both
the desired 2-substituted benzimidazole 3s (52% NMR
yield) and 1,2-disubstituted benzimidazoles (in overall 78%
yield).
Next, substituted phenylenediamines were tested with
various aldehydes. A series of 4-substituted phenylenedi-
amines with bromo- (1k), chloro- (1n), and nitro- (1o) sub-
stituents were employed with various aldehydes to gener-
ate substituted 2-arylbenzimidazoles 3k, 3n, 3o, and 3r in
very good yields (71–85%). Simultaneous variations on the
aldehyde substituent revealed that the reaction is compati-
ble with both -donor (tert-butoxy) and -acceptor (cyano)
substituents in the para position of the aryl group, and even
an ortho-bromo substituent was well tolerated. The 4,5-di-
methyl-substituted phenylenediamine gave high yields of
3f (88%) and 3q (81%) and showed compatibility with the
electron-withdrawing trifluoromethyl group on the alde-
hyde. The ortho-disubstituted 2,6-dichlorobenzaldehyde
demonstrates the steric tolerance at these positions. Mark-
edly lower yields were obtained with the 4,5-dihalogenated
phenylenediamines 1i and 1l which afforded the 2-(p-nitro-
Table 1 Influence of Solvent, Equivalency, and Oxidant on the Chemi-
cal Yield of Benzimidazole Formationa
NH2
NH2
H
N
solvent (5 mL)
O
NO2
rt, 1 min
open-air
NO2
N
1a
2b
3b
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
MeOH
EtOH
99
73
0
H2O
MeOH
dioxane
MeCN
MeOH
MeOH
MeOH
99c
77
78
88d
73e
64f
a Procedure: To a stirred solution of diamine 1a (1.0 mmol) in MeOH (5
mL/mmol) was added aldehyde 2b (1.0 mmol) and stirred at rt for 1 min.
b GC yield.
c H2O2 (1 mmol) was used as oxidant.
d 2 Equivalents of aldehyde (2 mmol) were used.
e A 10 mL microwave vial was charged with diamine 1a (1 mmol) and alde-
hyde 2b (1 mmol) and the tube was sealed and flushed with N2. Degassed
MeOH (5 mL) was added and the solution stirred at rt for 1 min.
f To a stirred solution of diamine 1a (1 mmol) in MeOH (5 mL) were added
aldehyde 2b (1 mmol) and Na2CO3 (0.5 equiv) and stirred at rt for 1 min.
Doubling the equivalents of benzaldehyde led to a drop
in the yield by 11% (entry 7). These reaction conditions are
remarkably simple and convenient (stir at room tempera-
ture and open to air) with a very short reaction time of only
one minute.
The rapid rate of conversion to product observed in this
reaction prompted us to conduct some control experiments
to shed light on the chemistry. The standard reaction be-
tween 1a and 2b was conducted in a sealed tube under a
nitrogen atmosphere and with strictly degassed solvent
(entry 8). A reduction in yield from 99 to 73% (GC yield) was
observed, thus demonstrating that oxygen is important for
the performance of the reaction, likely in the oxidation of
the saturated ring-closed intermediate. Another puzzling
aspect of the reaction is the absence of an acid or metal cat-
alyst, which is very commonly employed. Activation of the
intermediate imine towards nucleophilic attack by the sec-
ond aromatic amine is usually considered necessary. It is
conceivable that small amounts of oxidized aldehydes could
be present and effect acid catalysis. Addition of sodium car-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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V. Elumalai, J. H. Hansen
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phenyl) benzimidazoles 3i and 3l in 63% and 33% yield, re-
spectively. It has been assumed that lowered yields are
mainly caused by unreacted starting materials or formation
of the benzylated benzimidazole by-product. A more thor-
ough analysis of the formation of 3l revealed that the yield
is likely low because of solubility issues with the reactants,
and longer reaction times (1–25 min) or increased tem-
perature (rt to 70°C) did not improve the yield. Finally, we
have used a more complex diamine 1t to generate 4-(N-
Boc-piperazinyl) benzimidazole 3t in 51% yield (Scheme 2).
This represents a formal synthesis of a Gonadotropin-re-
leasing hormone receptor antagonist.17 The previously re-
ported method required 48 hours under reflux, whereas
our conditions yield the target benzimidazole 3t in one
R1
R2
NH2
NH2
H
R1
R2
O
N
MeOH (5 mL)
R3
H
R3
rt, 1 min
open-air
N
R1, R2 = CH3, Cl, Br, H, NO2 R3 = aryl, heteroaryl
R1 = H, R2 = Cl, Br, NO2
cyclohexyl, alkyl
1a–t
2a–t
3a–t
H
N
H
N
H
N
NO2
CN
N
N
N
3a (50%)
3b (95%)
3c (96%)
H
N
H
N
H
N
H3C
H3C
Cl
NHAc
CF3
N
N
N
3d (47%)a
3e (95%)
3f (88%)
H
N
H
N
H
N
Cl
Cl
N
NO2
NH
N
N
N
3i (63%)
3g (80%)
3h (41%)
H
N
H
N
H
N
Br
Br
CN
NO2
N
N
N
Br
3j (55%)
3k (85%)
3l (33%)
Br
H
N
H
N
H
N
OH
O
N
N
N
Cl
O2N
3p (48%)
3o (71%)
3n (75%)
Cl
Cl
H
N
H
H3C
N
N
Cl
N
H3C
3r (61%)
3q (81%)
Boc
N
H
N
H3C
H3C
N
H
N
N
N
3s (52%)a,b
3t (51%)
Scheme 2 Synthesis of substituted benzimidazoles – scope and limitations. General procedure: To a stirred solution of diamine 1a–t (1.0 mmol) in
MeOH (5 mL) was added aldehyde 2a–t (1.0 mmol) and stirred at rt for 1 min; isolated yields are given. a In addition to the desired product N-alkyl-
substituted 1,2-disubstituted benzimidazole was observed as by-product (GC). b NMR yield.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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V. Elumalai, J. H. Hansen
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O
O
N
NH2
O
NH
MeOH (5 mL)
(i)
NH2
rt, 1 min
open-air
NO2
3m (64%a)
1m
2b
NO2
NH2
OH
OH
MeOH (5 mL)
O
(ii)
N
rt, 1 min
open-air
NO2
5 (57%a)
4
2b
NO2
Cl
H3C
H3C
NH2
NH2
MeOH (5 mL)
O
(iii)
O
NH
NH
H3C
rt, 1 min
open-air
1q
6 (2 mmol)
H3C
7 (82%a)
O
Scheme 3 (i) Formation of quinazolinone from the reaction with 2-aminobenzamide. (ii) Formation of imine in reaction with 2-aminophenol. (iii)
Formation of bis-acylation product in the reaction with benzoyl chloride. Procedures: (i) To a stirred solution of diamine 1m (1 mmol) in MeOH (5 mL)
was added aldehyde 2b (1 mmol) and stirred at rt for 1 min. (ii) To a stirred solution of aminophenol 4 (1 mmol) in MeOH (5 mL) was added aldehyde 2b
(1 mmol) and stirred at rt for 1 min. (iii) To a stirred solution of diamine 1q (1 mmol) in MeOH (5 mL) was added acid chloride 6 (1 mmol) and stirred at
rt for 1 min. a Isolated yield.
minute in good yield. Overall, the studies herein demon-
strate that the remarkably practical and mild reaction con-
ditions appear to be general for the reaction.
On the basis of the scope study, it was postulated that
the reaction conditions could also favor similar heterocy-
clizations in other dinucleophile systems reacting with al-
dehydes.
Although the yields are diminished compared to those
of the small-scale reactions, they are still high. GC–MS anal-
ysis of the reaction mixture revealed that 72% of 3b and 75%
of 3c were formed and the remainder was mainly unreacted
substrates.
On the basis of literature studies and the experimental
results, a mechanism is proposed for obtaining 2-arylben-
zimidazoles as shown in Scheme 5. The first step involves
the acid-catalyzed condensation reaction between amine
and aldehyde to form imine intermediate (C) via (B) by loss
of water. Subsequent cyclization gives intermediate D, fol-
lowed by air oxidation to obtain the observed product (E).
In summary, we have re-discovered a classical heterocy-
clization reaction between phenylenediamines and alde-
hydes to generate benzimidazoles utilizing extremely sim-
ple, practical, and green conditions without the explicit ad-
dition of any acid- or metal catalyst. The simplicity of the
Therefore, 2-aminobenzamide (1m) was employed as
the dinucleophile source with p-nitrobenzaldehyde
(Scheme 3i). The reaction afforded quinazolinone 3m in
64% isolated yield. This demonstrates that such simple reac-
tion conditions can potentially be employed more generally
or should at least be tested when similar condensations are
conducted. A reaction between 2-aminophenol and 4-ni-
trobenzaldehyde afforded the imine 5, which could be iso-
lated in 57% yield (Scheme 3 ii). This observation supports
that the first stage of the mechanism is likely imine forma-
tion. Furthermore, we tested the reaction conditions with
carboxylic acid derivatives. No reaction occurred with
phenylenediamine and benzoic acid, whereas with benzoyl
chloride 6 and diamine 1q (Scheme 3 iii), the reaction af-
forded diamide 7 in 82% yield. These compounds could be
important intermediates for various heterocyclic systems.18
In order to further probe the applicability of our reac-
tion conditions, two reactions were conducted at up to 2 g
scale. p-Nitro- (2b) and p-cyanobenzaldehyde (2c) pro-
duced the anticipated benzimidazoles 3b19 and 3c in 65 and
70% isolated yield, respectively (Scheme 4). Both products
were crystallized from the reaction mixture after work-up
and did not require further purification.
NH2
NH2
H
N
O
MeOH
R
rt, 1 min
open-air
R
N
3b, R = NO2 (65%a,b)/(72%c)
3c, R = CN (70%a,b)/(75%c)
2b, R = NO2
2c, R = CN
1a
up to 2 g
Scheme 4 Multi-gram scale synthesis of benzimidazoles. Procedure:
To a stirred solution of diamine 1a (18.5 mmol) in MeOH (50 mL) was
added aldehyde 2b or 2c (18.5 mmol) and stirred at rt for 1 min. a After
the reaction time, H2O (30 mL) was added and the mixture was diluted
with EtOAc (60 mL). The reaction solution was kept at rt for some time.
Crystals slowly formed and were finally filtered off to obtain the desired
benzimidazole derivatives 3b (dark-brown crystals) and 3c (yellow crys-
tals). b Isolated yield. c GC yield.
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V. Elumalai, J. H. Hansen
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(4) Hameed, P. S.; Raichurkar, A.; Madhavapeddi, P.; Menasinakai,
S.; Sharma, S.; Kaur, P.; Nadishaiah, R.; Panduga, V.; Reddy, J.;
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820.
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747.
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Chem. 2012, 49, 183.
H–A
O
H
H
H
A
H
H
H
N
NH2
NH2
N
H
OH
O
H
NH2
NH2
B
– H2O
H–A
N
H
N
N
air [O]
H
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N
H
N
H
NH2
E
D
C
Scheme 5 A likely reaction mechanism with general acid catalysis
conditions is remarkable and this should become a method
of choice for de novo synthesis of a range of benzimidazoles.
Funding Information
The authors gratefully acknowledge funding for this work by the Re-
search Council of Norway (Grant no. 275043 CasCat).
N
orges
F
orsk
n
i
n
gsrå
d
(2
7
5
0
4
3)
Acknowledgment
(12) For selected examples, see: (a) Kasprzak, A.; Bystrzejewski, M.;
Poplawska, M. Dalton Trans. 2018, 47, 6314. (b) Singh, M. P.;
Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthesis 2000, 1380.
(c) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org.
Lett. 2003, 5, 3713. (d) Trivedi, R.; De, S. K.; Gibbs, R. A. J. Mol.
Catal. A: Chem. 2006, 245, 8.
The advanced N-Boc piperazinyl-substituted diamine 1t was prepared
and generously provided by Mr. Eirik A. L. Rustad.
Supporting Information
(13) (a) Alibeik, M. A.; Moosavifard, M. Synth. Commun. 2009, 39,
2339. (b) Jacob, R. G.; Dutra, L. G.; Radatz, C. S. Tetrahedron Lett.
2009, 50, 1495. (c) Khan, A. T.; Parvin, T.; Choudhury, L. H.
Synth. Commun. 2009, 39, 2339. (d) Narsaiah, V.; Reddy, A. R.;
Yadav, J. S. Synth. Commun. 2011, 41, 262.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690797. Included are detailed pro-
cedures, characterization data, and NMR spectra.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(14) (a) Park, S.; Jung, J.; Cho, E. J. Eur. J. Org. Chem. 2014, 4148. (b) Li,
Z.; Song, H.; Guo, R.; Hou, C.; Sun, S.; He, X.; Sun, Z.; Chu, W.
Green Chem. 2019, 21, 3602.
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(16) 2-([1,1'-Biphenyl]-4-yl)-1H-benzo[d]imidazole (3g); Typical
Procedure
In a 25 mL round-bottomed flask, diamine 1g (100 mg, 0.93
mmol) was dissolved in MeOH (5 mL). To the stirred solution
was added aldehyde 2g (169 mg, 0.925 mmol) and it was stirred
for 1 min at rt. Then, the reaction was quenched with water (10
mL), diluted with EtOAc (50 mL), and washed with water (30
mL). The water layer was extracted with EtOAc (2 × 30 mL). The
organic layers were combined and dried with anhydrous
Na2SO4. The drying agent was removed by filtration and the
solvent was evaporated under reduced pressure. The crude
product was further isolated by using flash chromatography
(EtOAc/n-pentane, 20:80) to obtain compound 3g as a yellow
solid. Yield: 200 mg (80%); Rf = 0.48 (EtOAc/n-pentane, 30:70).
1H NMR (400 MHz, acetone-d6):  = 8.58 (s, 1 H), 7.99–7.92 (m,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
V. Elumalai, J. H. Hansen
Cluster
Synlett
2 H), 7.70–7.64 (m, 2 H), 7.64–7.57 (m, 2 H), 7.36 (dd, J = 8.4, 6.9
Hz, 2 H), 7.31–7.22 (m, 1 H), 7.02 (dd, J = 7.8, 1.4 Hz, 1 H), 6.87
(td, J = 7.6, 1.4 Hz, 1 H), 6.66 (dd, J = 8.0, 1.4 Hz, 1 H), 6.50 (td, J =
7.5, 1.4 Hz, 1 H). 13C NMR (101 MHz, acetone-d6):  = 156.6,
144.7, 129.8, 129.7, 128.5, 128.3, 127.8, 127.6, 117.6, 117.5,
115.6. HRMS: m/z [M + H]+ calcd for C19H15N2+: 271.1230;
found: 271.1232.
(2.00 g, 18.5 mmol) was dissolved in MeOH (50 mL). To the
stirred solution was added 4-nitrobenzaldehyde 2b (2.80 g, 18.5
mmol) and it was stirred for 1 min at rt. Then, the reaction was
quenched with water (40 mL) and diluted with EtOAc (50 mL).
After a while, crystals were formed in the reaction mixture at rt.
The crystals were filtered off and dried to obtain compound 3b
as dark-brown crystals. Yield: 2.85 g (65%). 1H NMR (400 MHz,
DMSO-d6):  = 8.83 (s, 1 H), 8.40–8.30 (m, 2 H), 8.34–8.22 (m, 2
H), 7.24 (dd, J = 8.0, 1.5 Hz, 1 H), 7.03 (ddd, J = 8.3, 7.2, 1.4 Hz, 1
H), 6.76 (dd, J = 8.1, 1.4 Hz, 1 H), 6.63–6.53 (m, 1 H). 13C NMR
(101 MHz, DMSO-d6):  = 153.5, 148.3, 144.9, 142.4, 133.9,
129.4, 128.8, 123.9, 117.0, 116.0, 115.1. HRMS: m/z [M – H]–
calcd for C13H8N3O2–: 238.0622; found: 238.0623.
(17) Fjellaksel, R.; Boomgaren, M.; Sundset, R.; Haraldsen, I. H.;
Hansen, J. H.; Riss, P. J. MedChemComm 2017, 8, 1965.
(18) Huang, R.; Chen, X.; Mou, C.; Luo, G.; Li, Y.; Li, X.; Xue, W.; Jin,
Z.; Chi, Y. R. Org. Lett. 2019, 21, 4340.
(19) Gram-Scale
benzo[d]imidazole (3b)
In a 250 mL round-bottomed flask, benzene-1,2-diamine 1b
Synthesis
of
2-(4-Nitrophenyl)-1H-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F