The selective synthesis ofN-arylbenzene-1,2-diamines or 1-arylbenzimidazoles by irradiating 4-methoxy-4′-substituted-azobenzenes in different solvents

Article abstract of DOI:10.1039/d0ra10068d

The solvent-controllable photoreaction of 4-methoxyazobenzenes to afford 1-aryl-1H-benzimidazoles orN-arylbenzene-1,2-diamines has been studied. The irradiation of 4-methoxyazobenzenes in DMF containing 0.5 M hydrochloric acid providedN²-aryl-4-methoxybenzene-1,2-diamines as the major product, while irradiation in acetal containing 0.16 M hydrochloric acid led to 1-aryl-6-methoxy-2-methyl-1H-benzimidazoles as the major product. A possible reaction mechanism explaining the selectivity was also discussed.

Full text of DOI:10.1039/d0ra10068d

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The selective synthesis of N-arylbenzene-1,2-
diamines or 1-arylbenzimidazoles by irradiating 4-
methoxy-40-substituted-azobenzenes in different
solvents†
Cite this: RSC Adv., 2021, 11, 6662
b
ac
b
Tong-Ing Ho‡a and Jinn-Hsuan Ho
*
*
Po-Yi Chen, Chi-Wei Hsu,
The solvent-controllable photoreaction of 4-methoxyazobenzenes to afford 1-aryl-1H-benzimidazoles or
N-arylbenzene-1,2-diamines has been studied. The irradiation of 4-methoxyazobenzenes in DMF
containing 0.5 M hydrochloric acid provided N2-aryl-4-methoxybenzene-1,2-diamines as the major
product, while irradiation in acetal containing 0.16 M hydrochloric acid led to 1-aryl-6-methoxy-2-
Received 28th November 2020
Accepted 21st January 2021
DOI: 10.1039/d0ra10068d
methyl-1H-benzimidazoles as the major product.
A possible reaction mechanism explaining the
rsc.li/rsc-advances
selectivity was also discussed.
Compounds with 1-phenyl-1H-benzimidazole skeleton1 have of 1-phenyl-1H-benzimidazoles but they still present some
gained attention for a long time and been studied for the difficulties, such as the use of transition metal catalysts and
applications of platelet-derived growth factor receptor unsymmetrical starting materials.
(PDGFR),2 cyclooxygenase (COX),3 and phosphodiesterase 10A4
Using azobenzenes as reactants to afford 1-phenyl-1H-benz-
inhibitors, as well as for many optoelectronic materials.5 N-Aryl- imidazoles16 and N-phenylbenzene-1,2-diamines17 was reported
1,2-phenylenediamines are also important for synthesizing three decades ago. Compared to the above-mentioned synthetic
various benzimidazole derivatives, and 1,3,5-tris(N-phenyl- methods, synthesis from azobenzenes showed the benets of
benzimidazol-2-yl)benzene (TBPI) is an important electronic a simple preparation procedure and the good stability of
material for OLED applications that is still widely used symmetrical azobenzenes as starting materials (Scheme 1). The
nowadays.6
synthesis of a 1-phenyl-1H-benzimidazole16 from an azobenzene
The synthesis of 1-aryl-1H-benzimidazoles can be achieved started from a-metallation with ruthenium trichloride, trig-
via many synthetic strategies, including single and multiple gering the o-semidine rearrangement to produce the interme-
molecular reactions. Single-molecule synthetic methods diate; this was then further transformed to a 1-phenyl-1H-
include the intramolecular cyclization of arylamino and oxime benzimidazole upon reacting with an aldehyde that was
groups,7 the coupling of amidine and halogen (or hydrogen) produced via oxidizing an alcohol with ruthenium trichloride.
groups,8 and the condensation of amide and amino groups.9 However, the reaction needs high temperature, high pressure,
Methods involving bimolecular reactions include intermolec- transition-metal catalysts, and dangerous carbon monoxide,
ular coupling reactions of benzimidazoles,10 the cyclo- making it risky and environmentally unfriendly. Moreover, N-
condensation of o-diaminoarenes and aldehydes obtained from phenylbenzene-1,2-diamines17 could be obtained via the o-
the oxidation of alcohols,11 and the catalytic cyclization of aryl semidine rearrangement of hydrazobenzenes, which are the
halides/amidines12 or anilines/oxime acetates.13 Methods reductive products of azobenzenes. However, tributyltin
involving trimolecular reactions include one-pot reactions of hydride, which is used for the reduction of azobenzenes, is
arenediazonium salts, anilines, and nitriles,14 and the catalytic toxic, and the hydrazobenzenes were unstable in the presence of
cascade cyclization of aryl halides, anilines, and amides.15 air because they were easily oxidized back to azobenzenes.
These synthetic methods provide solutions for the preparation Considering the previously discovered reactions involving azo-
benzenes and hydrazobenzenes, it would be worth developing
a modied synthetic method that could be used to synthesize N-
phenylbenzene-1,2-diamines and 1-phenyl-1H-benzimidazoles
aDepartment of Chemistry, National Taiwan University, Taiwan. E-mail:
Vincenthsu631230@gmail.com
bDepartment of Chemical Engineering, National Taiwan University of Science and from azobenzenes more safely and easily.
Technology, Taiwan. E-mail: jhho@mail.ntust.edu.tw
cEdBrother Biotechnology Ltd, Taiwan
Inspired by research reporting the photoreduction of imine-
containing compounds to amines in the presence of alcohols,18
a possible idea was suggested: the photoreduction of azo-
benzenes to hydrazobenzenes with ethanol followed by the
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra10068d
‡ This paper is dedicated to the memory of the late Prof. Tong-Ing Ho.
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Scheme 3 The irradiation of 4-methoxyazobenzene (2a).
azobenzene (1a–1g) with a yield of 89–93%. The second step20
was the methylation of the hydroxyl group of 1a–1g using
potassium carbonate and dimethyl sulfate, with yields of 94–
99%. The total yields from these two steps are ca. 85–92%.
In order to investigate suitable reaction conditions for the
formation of N-arylbenzene-1,2-diamines and 1-aryl-1H-benz-
imidazoles, a series of test reactions involving 4-methoxy-
azobenzene (2a) under different reaction conditions was per-
formed (Scheme 3). The detailed experimental procedure for
entry 10 in Table 1 is described as follows. A solution containing
20 mg of compound 2a, 0.45 mL of concentrated HCl aqueous
solution (12 M) and 10.55 mL of DMF was sealed in a quartz
tube with a septum. The prepared solution was bubbled with
nitrogen gas for 15 min and irradiated with a 365 nm UV lamp.
Aer 2.5 h, the reaction solution was neutralized and extracted
using water and ethyl acetate several times. The organic layers
were collected, and the crude sample was obtained aer
removing the organic solvent under vacuum. The 1H-NMR
spectrum of the crude sample was obtained and the trans/cis-
2a : 3a : 4a ratio was calculated based on the integration of the
feature peaks of the compound (Table 1).
Scheme 1 The synthesis of 1-phenyl-1H-benzimidazoles and N-
phenylbenzene-1,2-diamines from azobenzenes and hydrazo-
benzenes.
instant
transformation
of
hydrazobenzenes
to
N-
phenylbenzene-1,2-diamines in acidic media. To investigate
this synthetic idea, the irradiation of 4-methoxyazobenzene in
ethanol containing 0.5 M hydrochloric acid with UV light at
365 nm was performed (Scheme 1). Surprisingly, this irradiation
afforded both 4-methoxy-N2-phenylbenzene-1,2-diamine and 6-
methoxy-2-methyl-1-phenyl-1H-benzimidazole as the two major
products. This synthetic method seemed to have many advantages,
including the use of stable and symmetrical azobenzenes as
starting materials, the transition-metal-free synthesis, and the
obtaining of two products in a one-pot synthesis process. There-
fore, we report the study of the irradiation of 4-methoxy-40-sub-
Table 1 The reaction conditions and results for the irradiation of 4-
methoxyazobenzene (2a)
En. WL (nm) Solvent Acid (conc.)
t (h) Ratio: t/c-2a : 3a : 4a
stitutedazobenzenes
(2a–2g)
to
afford
4-methoxy-N2-
1
2
3
4
5
6
7
8
9
365
365
365
365
365
365
365
365
365
CH3CN HCO2H (1.26 M)
CH3CN AcOH (1.59 M)
5
3
1
1
1
1
1
1
1
1 : 0 : 0
1 : 0 : 0
1 : 0 : 0
1 : 0 : 0
49 : 1 : 0
16 : 1 : 0
0.33 : 1 : 0
0.38 : 1 : 0
0.47 : 1 : 0
(substitutedphenyl)benzene-1,2-diamines (3a–3g) and 6-methoxy-
2-methyl-1-(4-substitutedphenyl)-1H-benzimidazoles (4a–4g).
A series of 4-methoxy-40-substituted azobenzenes (2a–2g) was
synthesized via a two-step synthesis process (Scheme 2). The
rst step19 was an azo coupling reaction between phenol and the
corresponding aryl diazonizum salt, which was prepared via
a diazotization reaction between 40-substituted aniline and
sodium nitrite, to afford the 4-hydroxy-40-substituted
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
None
HCl (0.05 M)
HCl (0.1 M)
HCl (0.3 M)
HCl (0.5 M)
HCl (0.7 M)
HCl (0.9 M)
HCl (0.5 M)
10 365
11 365
12 365
13 419
14 419
15 419
16 419
17 419
18 419
19 419
20 419
2.5 0.25 : 1 : 0
CH3CN HCl (0.5 M)
3
4
0.49 : 1 : 0.02
EtOH
EtOH
EtOH
EtOH
HCl (0.5 M)
HCl (0.47 M)
HCl (0.77 M)
HCl (0.91 M)
0.26 : 1 : 1.23a
0.33 2.6 : 1 : 0.35a
0.33 0.76 : 1 : 2.71a
0.33 0.74 : 1 : 1.96a
Acetal HCl (0.77 M)
Acetal HCl (0.48 M)
Acetal HCl (0.16 M)
Acetal HCl (0.16 M)
Acetal HCl (0.16 M)
2
2
2
0 : 0 : 1a
0 : 0:1b
0 : 0 : 1b
0.66 0.08 : 0 : 1c
0.33 0.98 : 0 : 1c
Aniline is observed in an amount of 20–30%. b Aniline is present in an
a
Scheme
2
The synthesis of the 4-methoxy-40-substituted azo-
amount of ca. 10%. c Aniline is present within an amount of 2%.
benzenes 2a–2g.
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Scheme 4 The synthesis of 3a–3g via the irradiation of 2a–2g.
Scheme 5 The synthesis of 4a–4g via the irradiation of 2a–2g.
Based on the experimental results (Table 1), this photore-
action could not progress effectively without strong acid (entries
1–3) or at a low concentration of hydrochloric acid (entries 4–6).
When the reaction solution was DMF containing hydrochloric
acid with a strength of at least 0.5 M, the photoreaction effec-
tively afforded 4-methoxy-N2-phenyl-benzene-1,2-diamine (3a)
as the major product (entries 7–10), and the best conditions led
to a trans/cis-2a : 3a ratio of 0.25 : 1, as shown in entry 10, Table
1. Subsequently, using acetonitrile and ethanol as the reaction
solution could produce a mixed product containing 3a, 4a, and
anilines (decomposed side products) (entries 11–15), and
conditions for obtaining a higher amount of 6-methoxy-2-
methyl-1-phenyl-1H-benzimidazole (4a) involved the use of
ethanol as the solvent with 0.77 M hydrochloric acid under
419 nm irradiation (entry 14). Finally, using acetal as the solvent
could produce 4a as the major product with some aniline as an
impurity (entries 16–20). It could be observed that the amount
of impurities (anilines) increased as the concentration of
hydrochloric acid increased; therefore, the best conditions for
the formation of 4a in acetal solution involved 0.16 M HCl
under 419 nm irradiation for 40 min.
Table 3 Results of the synthesis of 4a–4g via the irradiation of 2a–2g
in HCl/acetal at 419 nm
Yield (%) based
En. Starting Conv. (%) on conversion Yield of 4 (%) 3-Step yield (%)
1
2
3
4
5
6
7
2a: H
93
96
86
86
73
91
91
90
89.28
65.36
64.50
52.56
60.97
60.06
69.30
81.37
57.69
55.68
45.45
52.09
53.56
63.80
2b: Me 76
2c: Et 75
2d: i-Pr 72
2e: F
2f: Cl
67
66
2g: Br 77
The selective synthesis of the 1-aryl-2-methyl-6-methoxy-1H-
benzimidazoles 4a–4g could be achieved via the 419 nm irra-
diation of the 4-methoxyazobenzenes 2a–2g in acetal containing
0.16 M hydrochloric acid under ambient nitrogen conditions in
a quartz tube for 40 min (Scheme 5). The reaction results are
listed in Table 3, and the conversions and yields are determined
based on the weights of crude samples and the molar ratios of
compounds (trans-2:cis-2:4) from 1H-NMR spectrum integra-
tion. The irradiation of 2a–2g to afford 4a–4g had conversions of
66–93% and yields of 60–89%. No substitution effects were
observed in this photoreaction either. The 3-step reaction yields
for the synthesis of 4a–4g (including the preparation of
compounds 1 and 2) were 45–81%.
The proposed mechanism includes three main steps: (1)
a photoredox reaction between a protonated azobenzene and
the solvent to produce the hydrazobenzene; (2) an o-semidine
rearrangement of the hydrazobenzene to afford the N2-
arylbenzene-1,2-diamine; and (3) a condensation reaction
between the N2-arylbenzene-1,2-diamine and acetaldehyde to
produce the 1-arylbenzimidazole via oxidative aromatization
The selective synthesis of the 4-methoxy-N2-arylbenzene-1,2-
diamines 3a–3g could be achieved through the 365 nm irradi-
ation of the 4-methoxyazobenzenes 2a–2g in DMF containing
0.5 M hydrochloric acid under ambient nitrogen conditions in
a quartz tube for 2.5 h (Scheme 4 and Table 2). To avoid the
dramatic loss of amine products due to silica gel column
chromatography, conversions and yields were determined
based on the weights of crude samples and the molar ratios of
compounds (trans-2:cis-2:3) from 1H-NMR spectrum integra-
tion. The reaction conversions of irradiated 2a–2g were 61–82%,
and the yields of 3a–3g were 58–79%. No substitution effects
were observed during this photoreaction. Considering the
overall synthesis from the starting materials of phenol and
substituted anilines, the total yields of 3a–3g via this 3-step
synthesis were 51–72%.
Table 2 The results of synthesizing 3a–3g via the irradiation of 2a–2g
in HCl/DMF at 365 nm
Yield (%) based
En. Starting Conv. (%) on conversion Yield of 3 (%) 3-Step yield (%)
1
2
3
4
5
6
7
2a: H
82
97
95
98
98
98
97
96
79.54
57.95
63.7
72.52
70.56
73.72
73.92
72.47
51.15
54.99
62.72
60.29
65.74
68.06
2b: Me 61
2c: Et 65
2d: i-Pr 74
2e: F
2f: Cl
72
76
Scheme 6 The proposed mechanism for the transformation of 2a to
3a and 4a.
2g: Br 77
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with DMF and acetonitrile as the reaction solvent (entries 7–11,
Table 1); it is because DMF and acetonitrile were barely oxidized
to aldehyde.
In summary, we have successfully developed a solvent-
controllable photoreaction involving 4-methoxyazobenzenes
that could be used to synthesize 1-aryl-1H-benzimidazoles or N-
arylbenzene-1,2-diamines in moderate to good yields.
Scheme 7 The o-semidine rearrangement of 5c in acidic DMF without
irradiation.
(Scheme 6), and these are described below. 4-Methox-
yazobenzene (2a) is protonated by hydrochloric acid in acidic
media, and then protonated 2a is irradiated and undergoes
a photoredox reaction with DMF or EtOH to produce 4-methoxy-
hydrazobenzene (5a) as the photoreduction product. Aer-
wards, an o-semidine rearrangement17,21 immediately takes
place to transform 5a into 4-methoxy-N2-phenylbenzene-1,2-
diamine (3a), which is the major product when using DMF as
the reaction solvent. However, when EtOH is the reaction
solvent, acetaldehyde may be produced during the photoredox
reaction; this can consequently react with the di-amino groups
of 3a to afford the intermediate 4a-H, and then 6-methoxy-2-
methyl-1-phenyl-1H-benzimidazole (4a) can be quickly formed
via aromatization with an appropriate oxidative reagent.22 In
addition, when irradiation occurs in acidic acetal, the hydro-
lysis of acetal23 results in the production of a large amount of
acetaldehyde in the reaction system, which leads to the
formation of 4a in high yields.
In order to conrm the possibility of the existence of 4-
methoxyhydrazobenzene, the derivative 2c was reduced to
hydrazobenzene (5c)24 with tributyltin hydride. When 5c reacted
with hydrochloric acid in DMF without irradiation, the product
3c could be obtained as the major product (62.8%) with the
oxidative product 2c (26.4%) as the side product (Scheme 7).
The formation of 3c is consistent with the results from the
irradiation of 2c in DMF containing hydrochloric acid, which
may explain the existence of hydrazobenzenes.
To understand the possible source of acetaldehyde, the o-
semidine rearrangement (without irradiation) of 4-methoxyhy-
drazobenzene (5a) was performed in acidic EtOH, and
compound 3a was formed as the major product with a trace
amount of 4a (Scheme 8). However, when 2a was irradiated in
acidic EtOH, both 3a and 4a could be obtained as major prod-
ucts (entries 13–15, Table 1). The difference between the reac-
tions with and without irradiation could be used to deduce the
fact that acetaldehyde, which reacted with 3a to afford 4a, may
come from the photoredox reaction between 4-methox-
yazobenzene (2a) and ethanol. This is also the reason why
benzimidazoles are barely obtained when irradiation occurred
Conflicts of interest
We have no conicts of interest to declare.
Acknowledgements
We thank the Ministry of Science and Technology (MOST) of
Taiwan (R.O.C.) for nancial support. We also thank Ms S.-L.
Huang and Dr Iren Wang of MOST (National Taiwan Univer-
sity) for assistance with NMR experiments.
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