Visible light promoted tandem dehydrogenation-deaminative cyclocondensation under aerobic conditions for the synthesis of 2-aryl benzimidazoles/quinoxalines fromortho-phenylenediamines and arylmethyl/ethyl amines

Article abstract of DOI:10.1039/d0nj03002c

Visible light promoted domino synthesis of 2-aryl benzimidazoles is reported through the reaction ofortho-phenylenediamines and arylmethyl amines under aerobic conditions. The methodology has wide substrate scope and tolerates a wide range of functional groups affording the products in high yields. The use of arylethyl amines instead of arylmethyl amines gives 2-aryl quinoxalines.

Full text of DOI:10.1039/d0nj03002c

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Visible light promoted tandem dehydrogenation-
deaminative cyclocondensation under aerobic
conditions for the synthesis of 2-aryl
Cite this: New J. Chem., 2021,
45, 4569
benzimidazoles/quinoxalines from ortho-
phenylenediamines and arylmethyl/ethyl amines†
Received 14th June 2020,
Accepted 1st February 2021
DOI: 10.1039/d0nj03002c
Firdoos Ahmad Sofi, Rohit Sharma,‡ Ravi Rawat,
Prasad V. Bharatam
Asit K. Chakraborti *§ and
rsc.li/njc
*
Visible light promoted domino synthesis of 2-aryl benzimidazoles is
The use of arylmethyl amines as the aldehyde surrogates has
reported through the reaction of ortho-phenylenediamines and emerged as a new strategy for the synthesis of 2-substituted
arylmethyl amines under aerobic conditions. The methodology benzimidazoles6 leading to several methods under transition
has wide substrate scope and tolerates a wide range of functional metal-catalysed and metal free reaction conditions.
groups affording the products in high yields. The use of arylethyl
amines instead of arylmethyl amines gives 2-aryl quinoxalines.
However, there is a need to develop new synthetic methods to
enrich medicinal chemists’ tool box in compliance with green
chemistry.2 In the last few decades, visible light promoted synthesis
The strong preponderance of nitrogen containing heterocycles in of N-heterocycles has emerged as an important green chemistry tool.
drug candidate molecules1 has encouraged medicinal chemists to In this context, the limited reports for the synthesis of
consider these heterocycles as a privileged structure for new drug 2-arylbenzimidazoles include the reaction of o-phenylenediamine
design. Among the N-heterocycles, the benzimidazole scaffold has a with aldehydes in atmospheric oxygen,7 and in the presence of a
high occurrence2 and is in the top five most commonly used five- photocatalyst such as 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz),8
membered N-heterocyclic containing pharmaceuticals approved by Rose Bengal,9 and PDI-SN.10
the U.S. FDA. Various benzimidazole derivatives are known to
Herein, we report visible light promoted tandem dehydro-
exhibit a wide range of biological activities, such as antimalarial, genation-deaminative cyclocondensation of o-phenylenediamines
anti-microbial, anti-inflammatory, anti-tubercular, anti-diabetic, (1) with arylmethyl amines (2), used as the aldehyde surrogate, for
anti-convulsant, anti-protozoal, antihypertensive, and anticancer.3 a transition metal and photocatalyst free synthesis of 2-aryl benzi-
This triggered interest from synthetic organic/medicinal chemists midazoles (3) under aerobic conditions and extension of the
toward developing effective synthetic methodologies for the protocol for the synthesis of 2-aryl quinoxalines (5) by replacing
construction of a benzimidazole ring system. The cyclo- 2 with arylethyl amines (4) as the reacting partner of 1 (Fig. 1).
condensation of an aldehyde with o-phenylenediamines appears
This study began with the model reaction of o-phenylenediamine
to be the simplest approach for this purpose but often encounters (1a) with phenylmethyl amine (2a) so as to form the 2-phenyl-
the problem of the formation of 2-substituted and 1,2-disubstituted benzimidazole (3a) (Scheme 1).
benzimidazoles.4 This selectivity issue is compounded during the
use of unsymmetrically substituted o-phenylenediamines as the
reacting partner and would require an alternative multistep strategy
to control the regioselectivity.5
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), S. A. S. Nagar, Punjab-160062, India.
E-mail: pvbharatam@niper.ac.in, akchakraborti@niper.ac.in,
chakrabortiak@iitrpr.ac.in
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral data, and scanned spectra. See DOI: 10.1039/d0nj03002c
‡ Present address: Department of Forest Product, College of Forestry, Dr Y. S. Parmar
University of Horticulture and Forestry, Nauni, Solan, India.
§ Present address: Department of Chemistry, Indian Institute of Technology-Ropar,
Rupnagar, Punjab-140001, India.
Fig. 1 Visible light promoted synthesis of 2-aryl benzimidazoles/quinoxalines.
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improved a bit (81%) (Table 1, entry 27). Herein also no
formation of 3a took place in the absence of conc. HCl
(Table 1, entry 28).
Thus, the findings (Table 1) in the present work that
the reaction does not require any photocatalyst and instead
24 mol% of aq. HCl can be used has a distinct advantage.
Hence, we planned to explore further the general synthetic
applicability of this newly developed methodology.
Scheme 1 Visible light promoted reaction of 1a with 2a to form 3a.
During initial attempts, the reaction of 1a with 2a under
visible light did not result in the formation of 3a (Table 1,
entries 1–3). However, 3a was produced in 70% yield after 40 h
in the presence of conc. HCl (12 mol%: 10 mL of aq. 12 N)
(Table 1, entry 4). Increase of the amount of conc. HCl to
24 mol% (20 ml of aq. 12 N) increased the yield of 3a to 78% in
30 h (Table 1, entry 5). The reaction either did not proceed to
form 3a or produced 3a in a trace amount when DMSO was
However, though the use of blue LED light afforded com-
parable results for the model reaction (Table 1, entry 27),
inferior product yields were obtained with other substrate
combinations (either taking any substituted arylmethyl amine
or any substituted o-phenylenediamine). Hence, the white
compact fluorescent lamp (CFL) was considered for subsequent
studies to evaluate the substrate scope of the reaction adopting
the reaction conditions of Table 1, entry 5 as the optimized
reaction conditions.
For this purpose, arylmethyl amines bearing different substitu-
tions on the aryl ring and substituted o-phenylenediamines were
considered as coupling partners. With respect to the diversity
of the arylmethyl amines, the reaction proceeded well with
arylmethyl amines bearing electron withdrawing and electron
releasing groups in the aryl moiety. In the case of arylmethyl
amines bearing electron withdrawing groups (Fig. 2, entries 3c,
and 3h) the yields were slightly higher in comparison to those
obtained for the reactions involving the arylmethyl amines con-
taining electron releasing groups in the aryl moiety (Fig. 2, entries
3b, 3d, 3e, and 3f).
i
replaced by other organic solvents (e.g., MeOH, PrOH, MeCN,
dioxane, DMF, EtOAc, THF, toulene, hexane, DCE) or water
(Table 1, entries 8–18). The use of other protic acids such as
HOAc, p-TsOH, TFA, and MsOH or metal salts as a Lewis acid
like CuCl2 and Cu(OTf)2 in place of conc. HCl as the additive
resulted in either no formation of 3a or a substantial decrease
in the yield of 3a (Table 1, entries 19–25). No formation of 3a
was observed in performing the reaction using a photocatalyst
such as Eosin dye (5 mol%) in place of aq. HCl (Table 1, entry
26). The formation of 3a also did not take place in using H2O2
as the additive replacing conc. HCl (Table 1, entry 7). When the
light source was changed to a blue LED, the yield of 3a
Table 1 The reaction of 1a with 2a under different conditions to form 3aa
The scope with respect to various substituted o-phenyle-
nediamines bearing electron withdrawing and electron releasing
groups was also explored. With respect to the o-phenylene-
diamine, substrates bearing electron withdrawing groups (Fig. 2,
entries 3g, 3h, 3i, 3k, and 3l) gave slightly higher yields in
comparison to those having an electron releasing group (Fig. 2,
entry 3n). The reaction worked well with disubstituted o-phenyle-
nediamines as well (Fig. 2, entries 3i, 3j, 3k, and 3l).
Entry Light source Additive
Time (h) Solvent Yieldb (%)
1
2
No light
No light
No additive
HCl (12 mol%)
24
24
24
40
30
24
30
30
30
30
30
30
30
30
30
30
30
30
DMSO Nil
DMSO Nil
DMSO Nil
DMSO 70
DMSO 78
DMSO Nil
MeOH Trace
MeCN Nil
Dioxane Nil
iPrOH Trace
3
4
5
7
White CFL Without HCl
White CFL HCl (12 mol%)
White CFL HCl (24 mol%)
White CFL H2O2
8
9
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL HCl (24 mol%)
White CFL AcOH (35 mol%)
To gain mechanistic insights into the reaction, several
control experiments were designed for the model reaction of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
DMF
EtOAc Nil
THF Nil
Nil
Toluene Nil
Hexane Nil
DCE
H2O
Trace
Nil
DMSO 25
DMSO 40
DMSO 35
DMSO 20
MeCN Nil
DMSO Nil
DMSO Nil
DMSO Nil
DMSO 81
DMSO Nil
White CFL p-TsOH (10 mol%) 30
White CFL TFA (26 mol%)
White CFL MsOH (20 mol%)
White CFL CuCl2 (10 mol%)
White CFL CuCl2 (10 mol%)
30
30
30
30
White CFL Cu(OTf)2 (20 mol%) 30
White CFL Eosin dye (5 mol%) 30
Blue LEDc
Blue LEDc
HCl (24 mol%)
Without HCl
30
30
a
The mixture of 1a (1 mmol) and 2a (1.2 mmol, 1.2 equiv.) in DMSO
(4 mL) in an open vessel was treated under light (a 32 W capacity
difference light source was used except for entries 1, 2, 27, and 28) in
the presence of various additives (wherever applicable the HCl used was
aq. 12 N) at room temperature. Isolated yield of 3a. 18 W capacity
light source was used. nil = no formation of 3a.
Fig. 2 Substrate scope with respect to arylmethyl amines and
o-phenylenediamines for the synthesis of 2-aryl benzimidazoles.a a Reac-
tion conditions: 1 (1 mmol) was reacted with 2 (1.2 mmol, 1.2 equiv.) in
DMSO (4 mL) in the presence of conc. HCl (24 mol%; 20 mL of 12 N aq. HCl)
under visible light (32 W White CFL) for 30 h at r.t.
b
c
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1a with 2a (Fig. 3). The radical pathway of the reaction was
established by performing the reaction in the presence of
TEMPO (2 equiv.) used as the radical scavenger,11 which did
not result in the formation of 3a (Fig. 3, entry a). When the
reaction was carried out under a nitrogen atmosphere, 3a was
not formed suggesting the necessity of molecular oxygen as the
oxidant (Fig. 3, entry c).
As singlet oxygen is far more reactive than triplet oxygen
toward organic compounds and is responsible for the photo-
degradation of many materials,12 it was felt that the singlet
oxygen is involved/responsible in each of the relevant stages of
the mechanistic pathways. To establish the involvement of
singlet oxygen, the model reaction involving 1a and 2a as the
coupling partners was performed in the presence of singlet
oxygen quencher DABCO13 (Fig. 3, entry b). The lack of for-
mation of 3a in the presence of DABCO suggested the involve-
ment of singlet oxygen species during the oxidative
transformations. In the absence of visible light only a trace
amount of 3a was formed indicating the crucial role of visible
light in promoting the transformation (Fig. 3, entry d).
Scheme 2 Plausible mechanism for the visible light promoted reaction of
1a with 2a to form 3a.
intermediate C0 which on oxidation by singlet oxygen may give
Based on the results of these control experiments and rise to the desired product 3a. However, when the reaction of 1a
previous literature reports,7,9,14 a plausible mechanism has with 2a was performed under thermal conditions (at 40 1C) in
been proposed (Scheme 2). Arylmethyl amine 2a undergoes place of using visible light, no significant amount of 3a was
oxidation with singlet oxygen leading to the formation of formed thus ruling out the probability of this alternate path-
phenylmethanimine A. The intermediate A upon subsequent way. The visible light mediated activation of C to D* probably
coupling with another molecule of 2a leads to the formation of makes the oxidative cyclisation to E faster.
(E)-N-benzyl-1-phenylmethanimine B,14 which undergoes trans-
We next thought to test the versatility of this methodology
imination reaction with o-phenylenediamine 1a in the presence with respect to the scope of constructing diverse N-heterocyclic
of HCl and produces the intermediate imine C. The imine C is system and realised that the increase of the alkyl carbon chain
activated under visible light irradiation7 to the species D* of aryl methylamine by one carbon (i.e., use of arylethyl amine)
which reduces O2 to superoxide (O2ꢀ) and becomes the radical would generate 2-aryl quinoxalines. The diverse bioactivities15
cation E. Radical cation E upon deprotonation by superoxide of compounds containing the quinoxaline moiety have gener-
generates radical F, and subsequent hydrogen radical abstrac- ated interest to develop greener synthetic methodologies16 of
tion by a hydroperoxyl radical (HOOꢁ)7 produces the product this heterocyclic system. Thus, in a model reaction, phenethyl
2-phenyl benzimidazole 3a. Through an alternative pathway the amine 4a was treated with 1a under the optimised reaction
imine may undergo intramolecular nucleophilic attack by the conditions and to our delight, the 2-phenyl quinoxaline 5a
NH2 nitrogen atom to form the 2-substituted imidazoline was obtained in 75% yield. This encouraged us to assess
the substrate scope for the reaction of various substituted
o-phenylenediamines 1 with substitute aryl ethyl amines 4.
The reactions proceeded well. Arylethyl amines bearing elec-
tron withdrawing groups (Fig. 4, entries 5b, 5d, 5h, 5j and 5k)
gave higher yields in comparison to those bearing electron
releasing groups (Fig. 4, entries 5c, 5g and 5l). Similarly,
o-phenylenediamine bearing electron withdrawing groups
(Fig. 4, entries 5e, 5f, 5g and 5h) afforded higher yields in
comparson to those containing electron releasing groups
(Fig. 4, entries 5i, 5j, 5k and 5l). In general, unsymmetrical
o-phenylenediamines resulted in the formation of two regioi-
someric products (Fig. 2, entries 5m and 5n) but the nitro
substituted o-phenylenediamine gave only one of the two
possible regioisomeric products (Fig. 4, entry 5e).17
For reactions involving unsymmetrical o-phenylenediamines
the two-regioisomeric products formed could be easily separated
by column chromatography. The pure regioisomers were char-
acterized by NMR analysis and comparison with the literature
Fig. 3 Control experiments relevant to the understanding of the mecha-
nistic course of the reaction of 1a (1 mmol) with 2a (1.2 mmol).
reports.16a,18 The regioisomers 5n and 5nI, were separated by
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outlined in Scheme 2, a plausible mechanism for the genera-
tion of quinoxalines is depicted in Scheme 3. The reaction is
triggered by initial oxidation of the phenethylamines 4 in the
presence of oxygen leading to the formation of the intermediate
G (Scheme 3). The HCl-promoted trans-imination of G with 1a
form the imine H under visible light induced oxidation by
molecular oxygen is converted to the radical cation I. The
radical cation I undergoes 1,3-H shift to J which undergoes
cyclisation via intramolecular nucleophilic attack by the NH2
nitrogen atom on the enaminic b-carbon followed by oxidation
with molecular oxygen to form the intermediate K. Following a
similar course of oxidation by molecular oxygen, K is converted
to the quinoxaline 5.
Conclusions
In summary, in this study an efficient visible light promoted
tandem dehydrogenation-deaminative cyclocondensation of
arylmethyl amines with ortho-phenylenediamines has been
achieved for the synthesis of 2-aryl benzimidazoles. Room
temperature operation, transition metal and photocatalyst free
reaction conditions, and use of air as the oxidant are the
distinct green advantages. Furthermore, the reaction has wide
substrate scope and functional group tolerability affording
good to excellent product yields and is extendable for the
synthesis of 2-aryl quinoxalines.
Fig. 4 Evaluation of substrate scope for the visible light promoted reaction
of o-phenylenediamines with arylethyl amines to form diverse 2-aryl quinox-
alines.a aReaction conditions: 1 (1 mmol) was treated with 4 (1.2 mmol,
1.2 equiv.) in DMSO (4 mL) under visible light (32 W White CFL) in the presence
of conc. HCl (24 mol%; 20 mL of 12 N aq., HCl) for 30 h at r.t.
Conflicts of interest
column chromatography and identified by comparison with the
spectral data of the reported authentic compounds formed via an
unambiguous synthetic route.16a Similarly the regioisomers 5m
and 5mI, were separated using column chromatography and
characterized by the spectral data of 5m with an authentic
compound synthesized via an unambiguous route.18
There are no conflicts to declare.
Acknowledgements
RS thanks DST-SERB, New Delhi for the award of a postdoctoral
research fellowship (file no. PDF/2017/000232). PVB thanks
Council of Scientific and Industrial Research (CSIR), New Delhi
for the research grant.
In view of the chemistry involved for the visible light-
promoted oxidative transformations of aryl alkyl amines
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