Metal-free cross-dehydrogenative coupling of benzimidazoles with aldehydes to N-acylbenzimidazoles

Article abstract of DOI:10.1016/j.tet.2014.07.009

A novel and direct cross-dehydrogenative coupling (CDC) between benzimidazoles with aldehydes promoted by di-tert-butyl peroxide (DTBP) was developed. The reactions generated the corresponding N-acylbenzimidazoles in good yields under metal-free conditions. This method has broad substrate scope and high efficiency.

Full text of DOI:10.1016/j.tet.2014.07.009

Accepted Manuscript
Metal-free cross-dehydrogenative coupling of benzimidazoles with aldehydes to N-
acylbenzimidazoles
Lin Yu, Min Wang, Lei Wang
PII:
S0040-4020(14)01011-4
10.1016/j.tet.2014.07.009
TET 25803
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 March 2014
Revised Date: 25 June 2014
Accepted Date: 2 July 2014
Please cite this article as: Yu L, Wang M, Wang L, Metal-free cross-dehydrogenative coupling
of benzimidazoles with aldehydes to N-acylbenzimidazoles, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.07.009.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Metal-Free Cross-Dehydrogenative Coupling
of Benzimidazoles with Aldehydes to N-
Acylbenzimidazoles
Lin Yu,a Min Wang,*,a and Lei Wang*a,b
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P R China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P R China

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Metal-free cross-dehydrogenative coupling of benzimidazoles with aldehydes to N-
acylbenzimidazoles
Lin Yu,a Min Wang,a, and Lei Wanga,b,
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P R China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and direct cross-dehydrogenative coupling (CDC) between benzimidazoles with
aldehydes promoted by di-tert-butyl peroxide (DTBP) was developed. The reactions
generated the corresponding N-acylbenzimidazoles in good yields under metal-free
conditions. This method has broad substrate scope and high efficiency.
Available online
2014 Elsevier Ltd. All rights reserved
.
Keywords:
Metal-free, Cross-dehydrogenative coupling,
Benzimidazoles, Aldehydes,
N-Acylbenzimidazoles.
1. Introduction
synthesis of amides from aldehydes with amines via cross-
dehydrogenative coupling reaction under metal-free conditions is
a more attractive route because it can overcome the drawbacks of
the expensive, poisonous, and air-sensitive properties of metals
or organometallics.14m-u A variety of metal-free systems, such as
N-heterocyclic carbene-catalyzed redox systems,14p-r tert-butyl
hydroperoxide (TBHP),14n,o diacetoxyiodobenzene (DIB),14m,s
hydrogen peroxide (H2O2),14t and NaOCl14u have been developed.
In the above reactions, aliphatic amines are popular substrates,
but aromatic amines are less explored.14m-u To date, N–H of
aromatic heterocycles, such as pyrroles, pyrazoles, imidazoles,
benzimidazoles and indoles used for the cross-dehydrogenative
coupling reaction with aldehydes is rarely investigated.
The formation of amide bonds is one of the most significant
organic reactions, as the structural motif with amide bonds is a
ubiquitous substructure of many biologically relevant molecules,
such as proteins, natural products, pharmaceuticals, and synthetic
intermediates.1 Traditionally, amides are prepared from the
condensation of carboxylic acids with amines, which generally
relies on the use of coupling agents2 or conversion into more
reactive derivatives (acyl halides or anhydrides).3 Nevertheless,
these methods suffer from the use of hazardous or expensive
reagents, instability of activated carboxylic acid derivatives,
and/or poor atom-efficiency. In the past decade, a number of new
strategies for the construction of amide bonds have been
developed, such as the modified Staudinger reaction,4 Schmidt
reaction,5 rearrangement of oximes,6 amidation of nitriles,7
oxidative coupling between alcohols and amines,8 acylation of
amines,9 aminocarbonylation of alkenes,10 alkynes,11 and
haloarenes,12 Mn- and Fe-catalyzed C−C bond cleavage,13 and
oxidative amidation of aldehydes.14 Among the emerging amide
formation methods, the direct oxidative amidation of aldehydes
with amines is the most elegant atom economic approach, which
involves C–H activation of aldehydes and N–H activation of
amines, namely, cross-dehydrogenative coupling reaction (CDC).
The CDC reaction is one of the most attractive and atom-
economic synthetic approaches and has been widely applied in
N-Acylation of benzimidazoles are important organic
reactions, because acylation not only can provide sufficient
protection for benzimidazoles, but also N-acylbenzimidazoles are
generally considered to be mild acylation agents for kinetic
resolution.16 In the past decades, the synthesis of N-acyl aromatic
heterocyclic compounds was mainly through the reactions of
heterocycles with acyl halides in the presence of a base.
However, the methods are not environmentally friendly and atom
economical, as they require more than stoichiometric amounts of
base and generate halide and/or other wastes. To develop a more
environmentally friendly and atom economical route to N-
acylbenzimidazoles from readily available starting materials is
desirable. Herein, we present our recent results on metal-free
the C–C and C–heteroatom bond formations.15 Most recently, the
———
Corresponding author. Tel.: +86-561-380-2069; fax: +86-561-309-0518; e-mail: leiwang@chnu.edu.cn (L. Wang)
1

cross-dehydrogenative coupling of benzimidazoles with
ACCEPTED MANUSCRIPT
aldehydes to N-acylbenzimidazoles. This direct oxidative
coupling of benzimidazoles with aldehydes promoted by di-tert-
butyl peroxide (DTBP) generated the corresponding products N-
acylbenzimidazoles in good yields. The method has broad
aldehyde scope, including aryl, alkenyl and alkyl aldehydes, and
high efficiency (Scheme 1).
Entry
Oxidant
DTBP
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
Yield(%) b
1
2
3
4
5
88
84
63
50
45
TBHP
TBPB
Cumyl hydroperoxide
DIB
Cyclohexanone
peroxide
6
EtOAc
Trace
Scheme
benzimidazoles with aldehydes
1
The direct cross-dehydrogenative coupling of
7
(C6H5COO)2
H2O2
EtOAc
EtOAc
Trace
Trace c
88
8
9
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
Toluene
CH3CN
Dioxane
C6H5Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
63
2. Results and Discussion
53
58
Our initial efforts focused on the direct coupling between 5,6-
dimethyl-1H-benzo[d]imidazole (1a) and benzaldehyde (2a) to
examine suitable reaction conditions and the selected screening
results were listed in Table 1. Firstly, various oxidants were
tested for the proposed reaction using EtOAc as solvent at 110 °C
for 15 h (Table 1, entries 1−7). The oxidant plays an important
role in the reaction, and among examined oxidants, di-tert-butyl
peroxide (DTBP) exhibited the highest reactivity to the reaction,
providing 88% yield of the desired product (5,6-dimethyl-1H-
benzo[d]imidazol-1-yl)(phenyl)methanone (3a) (Table 1, entry
1). tert-Butyl hydroperoxide (TBHP) was subsequently inferior
with 84% yield of 3a (Table 1, entry 2). Moderate yield of 3a
were obtained using tert-butyl perbenzoate (TBPB), cumyl
hydroperoxide or diacetoxyiodobenzene (DIB) as oxidant (Table
1, entries 3−5). However, trace amounts of 3a were observed in
the presence of cyclohexanone peroxide, (C6H5COO)2 or H2O2
(Table 1, entries 6−8). No desired product was detected in the
absence of oxidant. We also surveyed the effect of solvent on the
model reaction and toluene was found to be equally effective as
EtOAc (Table 1, entry 9), while CH3CN, dioxane, C6H5Cl,
ClCH2CH2Cl, CH3NO2, NMP, DMSO and DMF resulted in
diminished yields, providing 23–63% yields of 3a (Table 1,
entries 10–17). When the reaction was conducted in DMA,
C2H5OH, THF or CH3OCH2CH2OCH3, no desired product was
obtained (Table 1, entries 18–21). The addition of 4 Å molecular
sieves (50 mg) slightly increased the yield of 3a up to 93%
(Table1, entry 22). For the amount of DTBP used in the reaction,
less than 2 equiv of DTBP led to the incompletion of the reaction
(Table1, entry 23). Meanwhile, up to 3 equiv of DTBP did not
increase the yield of 3a significantly (Table1, entry 24). The
effect of temperature on the reaction was also surveyed and the
results indicated that the yield of 3a was not improved when the
reaction temperature was increased to 120 °C (Table1, entry 25),
but an obviously lower yield was observed when the reaction was
performed at 100 °C (Table1, entry 26). Thus, the optimized
reaction conditions for the reaction were found to be DTBP (2
equiv), 4 Å molecular sieves (50 mg) in ethyl acetate at 110 °C
for 15 h.
ClCH2CH2Cl
CH3NO2
NMP
60
35
30
DMSO
27
DMF
23
DMA
NR
NR
NR
NR
93 d
56 e
93 f
89 g
64 h
C2H5OH
THF
CH3OCH2CH2OCH3
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
a Reaction conditions: 1a (0.50 mmol), 2a (1.0 mmol), oxidant (2.0
equiv.), solvent (3.0 mL), 110 oC, 15 h, sealed tube, under nitrogen.
Isolated yields. c 30% H2O2 aqueous solution. Addition of 4 Å
b
d
molecular sieves (50 mg).e DTBP (1.0 equiv.). f DTBP (3.0 equiv.).
g 120 oC. h 100 oC.
examined
in
the
reaction
with
5,6-dimethyl-1H-
benzo[d]imidazole (1a), and good to excellent yields of the
corresponding products were obtained. Aromatic aldehydes
bearing electron-donating groups, such as Me, MeO, N,N-
(CH3)2N, and OCH2O, or electron-withdrawing ones including F,
Cl, Br, Ph, CF3, and CO2CH3 reacted with 1a smoothly to afford
the desired corresponding products (Table 2, 3b−m). Apparently,
the reaction is sensitive to steric hindrance as the reaction with 2-
methylbenzaldehyde afforded the corresponding amide 3b in
lower yield than with 3-methylbenzaldehyde or 4-
methylbenzaldehyde (3b vs 3c and 3d). But relatively speaking,
benzaldehyde gave much improved yield of the desired product
3a than in the case of substituted benzaldehydes (Table 2, 3a vs
3b−m). The substrates 2-naphthaldehyde and cinnamaldehyde
also displayed good reactivity, affording 3n and 3o in moderate
yields. It is noteworthy that heteroaromatic aldehydes, such as
picolinaldehyde and thiophene-2-carbaldehyde could react with
1a and were converted into their corresponding amides in 32%
and 63% yields, respectively (Table 2, 3p and 3q). However,
when aliphatic aldehydes, for example 3-methylbutanal and
heptanal, were tested under the optimized reaction conditions,
only trace amount of products were detected. Gratifyingly, when
10 mol% Cu(OAc)2 was added, the yields were increased to 50%
and 48%, respectively (Table 2, 3r and 3s).
The scope of the substrates toward this direct cross-
dehydrogenative coupling of benzimidazoles with aldehydes was
further investigated under the optimized reaction conditions, and
Table 1 Optimization of the reaction conditions for the model
reaction 1a with 2a a
Table 2 Oxidative amidation of aldehydes with benzimidazolesa
2

The present reaction conditions were also suitable for the
ACCEPTED MANUSCRIPT
reactions of benzaldehyde with other benzimidazoles. Among the
methyl-substituted benzimidazoles, no matter what positions,
resulted in high yields of the corresponding products (3a and 3u
vs 3t). Especially for the reaction of 2-methyl-1H-
benzo[d]imidazole with benzaldehyde provided the desired
product in almost quantitative yield (3u). Even if bulky 2-
N
N
N
N
N
N
N
N
substituted
benzo[d]imidazole, 2-(methylthio)-1H-benzo[d]imidazole and 2-
(thiophen-2-yl)-1H-benzo[d]imidazole, reacted with
benzimidazoles,
such
as
2-phenyl-1H-
O
O
O
O
benzaldehyde, corresponding N-acyl products 3v, 3w, and 3x
were isolated in 67%, 77%, and 50% yields, respectively. Owing
to the tautomerism, when 5-methyl-1H-benzo[d]imidazole was
engaged in the system, the reactions generated the mixtures of
3a
3b
3c
3d
, 80%
, 93%
, 70%
, 85%
N
N
N
N
N
N
1
N
N
amides isomers with almost 1:1 ratio, which determined by H
NMR spectra (Table 2, 3y and 3y’, 3z and 3z’, 3aa and 3a’a’).17
However, no desired product was obtained for the reactions of 4-
hydroxybenzaldehyde or 4-formylbenzoic acid with 1a, and 1H-
benzo[d]imidazole-5-carboxylic acid with 4-methylbenzaldehyde
under the present reaction conditions.
O
O
O
O
F
H3CO
Cl
Br
3e
, 66%
3f
3g
, 71%
3h
, 70%
, 81%
N
N
N
N
N
N
N
N
To investigate the reaction mechanism, the related control
experiments were conducted, as shown in Scheme 2. No any
product was detected when the reaction of 1a and 4-
methylbenzaldehyde (2d) was carried out in the absence of
oxidant DTPB, and the starting materials were recovered in 98%
(Scheme 2, Eq. 1). When 2,2,6,6-tetramethylpiperidine N-oxide
(TEMPO, 2.0 equiv), a radical scavenger, was added to the
reaction of 1a with 2d under the optimized reaction conditions,
the coupling product of acyl radical generated from 2d with
TEMPO was confirmed by HPLC-HRMS (Scheme 2, Eq. 2, and
SI for detail). It is suggested that TEMPO acts as a radical
scavenger and the reaction involves a radical process. On the
other hand, from Eq. 3 and Eq. 4 in Scheme 2, it also verified that
the formation of the amidation product is not through the direct-
cross coupling of the acyl radical from aldehyde and the nitrogen
radical from benzimidazole in the presence of DTBP.
O
O
O
O
H3CO2C
3j
Ph
N
F3C
3i
, 52%
3k
, 77%
3l
, 52%
, 76%
N
N
N
N
N
N
N
N
O
O
O
O
Ph
O
N
,32%
O
3m
, 61%
3n
3o
, 50%
3p
, 53%
N
N
N
N
N
N
N
N
O
O
O
O
S
3q
, 63%
3r
3s
, 48%
3t
, 78%
Based on our results and literature,18 a possible mechanism
for this reaction was proposed in Scheme 3. Initially, homolysis
of DTBP gave the tert-butoxy radical. The formed tert-butoxy
radical abstracted H from aldehyde to generate the corresponding
acyl radical A, which was further oxidized by tert-butoxy radical
to afford acyl cation B.18 Finally, the desired amidation product
b
b
, 50%
was formed through
a nucleophilic reaction of amine
(benzimidazole) to intermediate B.
O
No Reaction !
N
EtOAc, 110 o
Without DTBP
C
H
+
+
Eq. 1
Eq. 2
1a and 2d were
recovered in 98%.
N
H
1a
1a
2d
O
O
DTBP (2 equiv)
TEMPO (2 equiv)
N
N
O
H
EtOAc, 110 o
C
N
H
2d
Trapping radical !
HPLC-HRMS detected !
DTBP (2 equiv)
TEMPO (2 equiv)
N
No Reaction !
Eq. 3
Eq. 4
EtOAc, 110 o
C
1a was recoveredin 97%.
N
H
1a
Trapping radical !
O
O
DTBP (2 equiv)
TEMPO (2 equiv)
N
O
H
EtOAc, 110 o
C
a
Reaction conditions: benzimidazole (1, 0.50 mmol), aldehyde (2,
2d
Trapping radical !
HPLC-HRMS detected !
1.0 mmol), DTBP (2.0 equiv), 4 Å molecular sieves (50 mg) in ethyl
b
acetate (3.0 mL) at 110 oC for 15 h, sealed tube, under nitrogen.
Scheme 2 The related control experiments
c
Addition of 10 mol% Cu(OAc)2. The ratio was determined by 1H
NMR spectra.
3

dimethyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3a, 116
ACCEPTED MANUSCRIPT
mg, 93% yield).
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone
1
(3a): Yellow solid, mp 90.4−92.9 °C. H NMR (400 MHz,
CDCl3): δ = 8.09 (s, 1H), 7.99 (s, 1H), 7.79−7.77 (m, 2H),
7.68−7.65 (m, 1H), 7.58−7.54 (m, 3H), 2.40 (s, 3H), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3): δ = 167.0, 142.4, 135.0, 134.2,
133.1, 132.9, 130.5, 129.4, 128.9, 120.5, 115.6, 20.5, 20.3. IR
(KBr, cm–1): 1700 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for
C16H15N2O: 251.1184. Found 251.1181.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(o-tolyl)methanone
1
(3b): Yellow solid, mp 83.6−84.9 °C. H NMR (400 MHz,
CDCl3): δ = 8.00 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.52−7.49
(m, 1H), 7.45−7.43 (m, 1H), 7.39−7.34 (m, 2H), 2.42 (s, 3H),
2.41 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
167.6, 142.8, 142.3, 136.6, 135.1, 134.3, 133.3, 131.4, 131.3,
127.8, 126.0, 120.6, 115.7, 20.5, 20.3, 19.4. IR (KBr, cm–1): 1706
(νC=O). HRMS (ESI) ([M+H]+): Calcd. for C17H17N2O: 265.1341.
Found 265.1338.
Scheme 3 Proposed reaction mechanism
3. Conclusions
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(m-tolyl)methanone
(3c): Yellow oil. H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1H),
In conclusion, we have developed a novel and efficient
method for the preparation of N-acylbenzimidazoles via cross-
dehydrogenative coupling of benzimidazoles with aldehydes in
the presence of di-tert-butyl peroxide under metal-free
conditions. Compared to previously known approaches, the
simplicity of this procedure and the generally satisfactory yields
make this method particularly attractive. In addition, the method
has broad aldehyde scope, including aryl, alkenyl and alkyl
aldehydes and high efficiency. The presence of a diverse range of
substituents and functional groups in benzimidazoles and
aldehydes also opens an opportunity to acquire many other
derivatives. Further studies on the mechanistic details and
expansion of the scope of the reaction are currently underway in
our laboratory.
1
8.00 (s, 1H), 7.59 (s, 1H), 7.57−7.55 (m, 2H), 7.48−7.42 (m, 2H),
2.45 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 167.2, 142.5, 139.0, 134.9, 134.2, 133.7, 133.1,
130.5, 129.9, 128.7, 126.6, 120.4, 115.6, 21.3, 20.5, 20.3. IR
(KBr, cm–1): 1696 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for
C17H17N2O: 265.1341. Found 265.1339.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(p-tolyl)methanone
1
(3d): White solid, mp 134.3−135.0 °C. H NMR (400 MHz,
CDCl3): δ = 8.10 (s, 1H), 7.97 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H),
7.56 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.39 (s, 3H),
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.0, 143.9,
142.5, 142.4, 134.8, 134.0, 130.5, 130.2, 129.7, 129.6, 120.4,
115.6, 21.6, 20.5, 20.3. IR (KBr, cm–1): 1699 (νC=O). HRMS
(ESI) ([M+H]+): Calcd. for C17H17N2O: 265.1341. Found
265.1335.
4. Experimental section
1
All reactions were carried out under N2 atmosphere. H NMR
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(4-methoxyphenyl)
methanone (3e): Yellow solid, mp 140.3−142.6 °C. H NMR
1
and 13C NMR spectra were measured on a Bruker Avance NMR
spectrometer (400 MHz or 100 MHz, respectively) with CDCl3
as solvent and recorded in ppm relative to internal
tetramethylsilane standard. The peak patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet.
The coupling constants, J, are reported in Hertz (Hz). High
resolution mass spectroscopy data of the product were collected
on an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF
LC/MS (ESI) or a Waters Micromass GCT instrument (EI).
(400 MHz, CDCl3): δ = 8.14 (s, 1H), 7.94 (s, 1H), 7.80 (d, J = 8.0
Hz, 2H), 7.58 (s, 1H), 7.05 (d, J = 7.6 Hz, 2H), 3.92 (s, 3H), 2.41
(s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 166.4,
163.6, 142.5, 142.4, 134.7, 134.0, 132.0, 130.7, 125.0, 120.4,
115.4, 114.3, 55.6, 20.5, 20.3. IR (KBr, cm–1): 1688 (νC=O).
HRMS (ESI) ([M+H]+): Calcd. for C17H17N2O2: 281.1290, Found
281.1294.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(4-fluorophenyl)
methanone (3f): White solid, mp 126.5−127.7 °C. 1H NMR (400
MHz, CDCl3): δ = 8.06 (s, 1H), 7.91 (s, 1H), 7.83−7.79 (m, 2H),
7.55 (s, 1H), 7.26−7.22 (m, 2H), 2.38 (s, 3H), 2.37 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 165.8, 165.5 (d, J = 254.1 Hz),
142.4, 142.0, 135.0, 134.3, 132.1 (d, J = 9.2 Hz), 130.4, 129.2 (d,
J = 3.3 Hz), 120.5, 116.3 (d, J = 22.1 Hz), 115.5, 20.4, 20.2. IR
(KBr, cm–1): 1702 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for
C16H14FN2O: 269.1090. Found 269.1086.
Typical procedure for the cross-dehydrogenative coupling of
benzimidazoles with aldehydes to N-acylbenzimidazoles
A sealable reaction tube equipped with a magnetic stirrer bar
was charged with 5,6-dimethyl-1H-benzo[d]imidazole (0.50
mmol, 73 mg), benzaldehyde (1.0 mmol, 106 mg), di-tert-butyl-
peroxide (1.0 mmol, 146 mg), 4 Å molecular sieves (50 mg) and
ethyl acetate (3.0 mL). The rubber septum was then replaced by a
Teflon-coated screw cap, then the reaction must be under N2 and
the reaction vessel placed in an oil bath at 110 °C. After stirring
the mixture at this temperature for 15 h, it was cooled to room
temperature and diluted with ethyl acetate then washed with 0.5
mmol/L NaOH aqueous solution (5.0 mL×3), dried over by
MgSO4. After the solvent was removed under reduced pressure,
the residue was purified by column chromatography on silica gel
(hexane/EtOAc, 4:1 to 6:1) to afford the desired product, (5,6-
(4-Chlorophenyl)(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)
1
methanone (3g): White solid, mp 165.2−166.3 °C. H NMR
(400 MHz, CDCl3): δ = 8.09 (s, 1H), 7.95 (s, 1H), 7.74 (d, J = 8.4
Hz, 2H), 7.58 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H), 2.40
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.9, 142.3, 142.0,
135.2, 134.5, 131.3, 130.9, 130.3, 129.3, 128.6, 120.5, 115.6,
20.5, 20.3. IR (KBr, cm–1): 1701 (νC=O). HRMS (ESI) ([M+H]+):
Calcd. for C16H14ClN2O: 285.0795. Found 285.0799.
4

(4-Bromophenyl)(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)
methanone (3h): White solid, mp 185.5−186.2 °C. H NMR
HRMS (ESI) ([M+H]+): Calcd. for C20H17N2O: 301.1341, Found
301.1341.
ACCEPTED MANUSCRIPT
1
(400 MHz, CDCl3): δ = 8.05 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.4
Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 2.40 (s, 3H), 2.39
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 166.0, 142.5, 141.9,
135.2, 134.5, 132.3, 131.8, 130.9, 130.3, 128.1, 120.6, 115.6,
20.5, 20.3. IR (KBr, cm–1): 1703 (νC=O). HRMS (ESI) ([M+H]+):
Calcd. for C16H14BrN2O: 329.0290. Found 329.0285.
(E)-1-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)-3-
phenylprop-2-en-1-one (3o): White solid, mp 222.7−223.9 °C.
1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1H), 8.12 (s, 1H),
8.09−8.05 (m, 1H), 7.68−7.67 (m, 2H), 7.58 (s, 1H), 7.48 (s, br,
3H), 7.23−7.19 (m, 1H), 2.43 (s, 3H), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 162.8, 148.4, 142.5, 139.9, 135.0, 134.1,
133.8, 131.3, 130.2, 129.1, 128.6, 120.5, 116.0, 115.8, 20.5, 20.2.
IR (KBr, cm–1): 1702 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for
C18H17N2O: 277.1341, Found 277.1341.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(4-(trifluoromethyl)
1
phenyl)methanone (3i): Yellow solid, mp 186.3−187.7 °C. H
NMR (400 MHz, CDCl3): δ = 7.99 (s, 1H), 7.96 (s, 1H), 7.89 (d,
J = 8.0 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 2.40 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.7,
142.5, 141.7, 136.4, 135.3, 134.7, 134.5 (q, J = 32.9 Hz), 130.2,
129.7, 126.0 (q, J = 3.7 Hz), 123.3 (q, J = 271.2 Hz), 120.6,
115.6, 20.4, 20.2. IR (KBr, cm–1): 1706 (νC=O). HRMS (EI)
([M]+): Calcd. for C17H13F3N2O: 318.0980, Found 318.0976.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(pyidin-2-yl)
methanone (3p): Yellow solid, mp 128.9−130.0 °C. H NMR
1
(400 MHz, CDCl3): δ = 9.27 (s, 1H), 8.79 (d, J = 4.4 Hz, 1H),
8.26 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 8.00−7.96 (m, 1H),
7.60−7.57 (m, 2H), 2.43 (s, 3H), 2.40 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 164.0, 150.5, 148.7, 144.0, 141.8, 137.6,
134.7, 134.2, 130.7, 127.0, 126.4, 120.4, 116.4, 20.5, 20.2. IR
(KBr, cm–1): 1685 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for
C15H14N3O: 252.1137, Found 252.1133.
Methyl
4-(5,6-dimethyl-1H-benzo[d]imidazole-1-
1
carbonyl)benzoate (3j): White solid, mp 191.4−191.5 °C. H
NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.0 Hz, 2H), 8.04 (s,
1H), 8.00 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 4.00 (s,
3H), 2.43 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
166.2, 165.7, 142.6, 141.9, 136.9, 135.3, 134.6, 134.0, 130.3,
130.1, 129.3, 120.7, 115.7, 52.6, 20.5, 20.3. IR (KBr, cm–1): 1731
(νC=O). HRMS (ESI) ([M+H]+): Calcd. for C18H17N2O3: 309.1239,
Found 309.1237.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(thiophen-2-yl)
methanone (3q): Yellow solid, mp 132.5−133.7 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.42 (s, 1H), 7.97 (s, 1H), 7.80 (d, J = 5.2
Hz, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.57 (s, 1H), 7.25−7.23 (m,
1H), 2.41 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
159.9, 142.4, 141.5, 135.9, 135.0, 134.28, 134.22, 134.0, 130.6,
128.1, 120.5, 115.5, 20.5, 20.3. IR (KBr, cm–1): 1677 (νC=O).
HRMS (ESI) ([M+H]+): Calcd. for C14H13N2OS: 257.0749,
Found 257.0748.
Biphenyl-4-yl(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)
1
methanone (3k): White solid, mp 186.9−187.0 °C. H NMR
(400 MHz, CDCl3): δ = 8.17 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 8.0
Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.60
(s, 1H), 7.53−7.49 (m, 2H), 7.46−7.42 (m, 1H), 2.43 (s, 3H), 2.41
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 166.8, 145.9, 142.6,
142.3, 139.4, 135.0, 134.2, 131.6, 130.5, 130.1, 129.0, 128.5,
127.5, 127.3, 120.5, 115.7, 20.5, 20.3. IR (KBr, cm–1): 1692
(νC=O). HRMS (ESI) ([M+H]+): Calcd. for C22H19N2O: 327.1497,
Found 327.1496.
1-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)-3-methylbutan-1-
1
one (3r): Yellow solid, mp 78.1−80.3 °C. H NMR (400 MHz,
CDCl3): δ = 8.26 (s, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 2.82−2.80
(m, 2H), 2.39−2.33 (m, 7H), 1.08 (d, J = 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3): δ = 169.7, 142.3, 140.2, 135.0, 133.8, 129.9,
120.4, 115.8, 44.5, 25.4, 22.5, 20.4, 20.1. IR (KBr, cm–1): 1724
(νC=O). HRMS (ESI) ([M+H]+): Calcd. for C14H19N2O: 231.1497,
Found 231.1493.
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(4-(dimethylamino)
phenyl)methanone (3l): Yellow solid, mp 197.1−199.3 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 7.90 (s, 1H), 7.74 (d,
J = 8.8 Hz, 2H), 7.58 (s, 1H), 6.73 (d, J = 9.2 Hz, 2H), 3.09 (s,
6H), 2.40 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
166.5, 153.6, 142.6, 142.4, 134.3, 133.4, 132.3, 131.0, 120.2,
118.6, 115.3, 111.0, 40.0, 20.5, 20.2. IR (KBr, cm–1): 1675
(νC=O). HRMS (ESI) ([M+H]+): Calcd. for C18H20N3O: 294.1606,
Found 294.1601.
1-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)heptan-1-one (3s):
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.29 (s, 1H), 8.01
(s, 1H), 7.53 (s, 1H), 2.95 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.36
(s, 3H), 1.88−1.81 (m, 2H), 1.47−1.41 (m, 2H), 1.38−1.33 (m,
4H), 0.92−0.89 (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 170.4,
142.2, 140.2, 135.1, 133.8, 129.8, 120.4, 115.8, 35.8, 31.4, 28.7,
24.3, 22.4, 20.4, 20.1, 13.9. IR (KBr, cm–1): 1698 (νC=O). HRMS
(ESI) ([M+H]+): Calcd. for C16H23N2O: 259.1810, Found
259.1810.
(1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3t):19 Yellow
solid, mp 71.7−72.8 °C. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s,
1H), 8.19−8.17 (m, 1H), 7.84−7.79 (m, 3H), 7.70−7.66 (m, 1H),
7.59−7.56 (m, 2H), 7.46−7.40 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ = 167.0, 144.0, 143.0, 133.1, 132.9, 132.1, 129.5,
129.0, 125.7, 125.2, 120.5, 115.4. IR (KBr, cm–1): 1699 (νC=O).
Benzo[d][1,3]dioxol-5-yl(5,6-dimethyl-1H-benzo[d]imidazol-
1
1-yl)methanone (3m): Yellow solid, mp 187.9−188.7 °C. H
NMR (400 MHz, CDCl3): δ = 8.13 (s, 1H), 7.92 (s, 1H), 7.56 (s,
1H), 7.35−7.33 (m, 1H), 7.28 (s, 1H), 6.95−6.93 (m, 1H), 6.10 (s,
2H), 2.40 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
166.0, 151.9, 148.3, 142.5, 142.3, 134.8, 134.1, 130.6, 126.6,
125.6, 120.4, 115.4, 109.8, 108.3, 102.2, 20.4, 20.2. IR (KBr, cm–
1): 1681 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for C17H15N2O3:
295.1083, Found 295.1082.
(2-Methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone
(3u):20 Yellow solid, mp 83.3−84.7 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.75−7.74 (m, 2H), 7.70−7.66 (m, 2H), 7.54−7.50
(m, 2H), 7.25−7.23 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.81−6.78
(m, 1H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 168.6,
153.1, 142.4, 133.9, 133.8, 133.4, 129.8, 129.0, 123.9, 123.6,
119.4, 113.3, 17.0. IR (KBr, cm–1): 1705 (νC=O).
Phenyl(2-phenyl-1H-benzo[d]imidazol-1-yl)methanone (3v):17
White solid, mp 147.3−149.8 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.89 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.62−7.60
(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)(naphthalen-2-yl)
methanone (3n): Yellow solid, mp 155.0−156.7 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.28 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H),
8.02−7.99 (m, 1H), 7.96−7.93 (m, 2H), 7.85−7.83 (m, 1H),
7.68−7.60 (m, 3H), 2.42 (s, 3H), 2.41 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 167.1, 142.6, 142.5, 135.2, 135.0, 134.2,
132.2, 130.9, 130.6, 130.2, 129.1, 129.0, 128.8, 127.9, 127.4,
125.1, 120.5, 115.7, 20.5, 20.3. IR (KBr, cm–1): 1699 (νC=O).
5

(m, 2H), 7.52−7.46 (m, 2H), 7.41−7.37 (m, 1H), 7.35−7.27 (m,
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2014.xx.xxx. These data
include MOL files and InChIKeys of the most important
compounds described in this article.
ACCEPTED MANUSCRIPT
6H); 13C NMR (100 MHz, CDCl3): δ = 169.1, 154.0, 142.9,
134.9, 134.0, 133.1, 130.5, 130.4, 129.8, 129.2, 128.7, 128.3,
124.6, 124.4, 120.2, 113.1. IR (KBr, cm–1): 1702 (νC=O).
(2-(Methylthio)-1H-benzo[d]imidazol-1-
References and notes
yl)(phenyl)methanone (3w): White solid, mp 121.0−122.7 °C.
1H NMR (400 MHz, CDCl3): δ = 7.73−7.71 (m, 2H), 7.68−7.63
(m, 2H), 7.53−7.49 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.01 (t, J =
7.6 Hz, 1H), 6.72−6.70 (m, 1H), 2.72 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 167.9, 156.0, 143.9, 134.4, 133.5, 133.0,
129.5, 128.8, 124.2, 122.8, 118.4, 113.4, 15.6. IR (KBr, cm–1):
1698 (νC=O). HRMS (ESI) ([M+H]+): Calcd. for C15H13N2OS:
269.0749, Found 269.0753.
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Phenyl(2-(thiophen-3-yl)-1H-benzo[d]imidazol-1-yl)
methanone (3x): Yellow solid, mp 124.6−124.9 °C. H NMR
1
(400 MHz, CDCl3): δ = 7.86−7.84 (m, 1H), 7.78−7.76 (m, 2H),
7.62−7.58 (m, 1H), 7.45−7.41 (m, 2H), 7.38−7.33 (m, 2H),
7.27−7.23 (m, 3H), 6.92−6.90 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ = 169.0, 147.9, 142.7, 134.9, 134.4, 132.8, 132.0,
130.6, 130.0, 129.0, 128.9, 127.5, 124.5, 124.4, 120.0, 112.7. IR
(KBr, cm–1): 1706 (νC=O). HRMS (EI) ([M]+): Calcd. for
C18H12N2OS: 304.0670, Found 304.0675.
(5-Methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone and
(6-methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3y
and 3y’) (1:1 ratio): White solid. 1H NMR (400 MHz, CDCl3): δ
= 8.16 (s, 1H), 8.12 (s, 1H), 8.05−8.03 (m, 2H), 7.79−7.77 (m,
4H), 7.70−7.65 (m, 3H), 7.61 (s, 1H), 7.58−7.54 (m, 4H),
7.26−7.23 (m, 2H), 2.51 (s, 3H), 2.50 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 167.1, 166.9, 144.3, 143.1, 142.6, 142.0,
136.0, 135.2, 133.07, 133.06, 133.03, 132.9, 132.3, 130.1, 129.5,
129.4, 128.9, 127.0, 126.6, 120.4, 119.9, 115.5, 114.9, 21.8, 21.5.
HRMS (ESI) ([M+H]+): Calcd. for C15H13N2O: 237.1028. Found
237.1032.
(5-Methyl-1H-benzo[d]imidazol-1-yl)(p-tolyl)methanone and
(6-methyl-1H-benzo[d]imidazol-1-yl)(p-tolyl)methanone (3z
and 3z’) (1:1 ratio): White solid. 1H NMR (400 MHz, CDCl3): δ
= 8.17 (s, 1H), 8.13 (s, 1H), 8.02−8.00 (m, 2H), 7.69−7.67 (m,
5H), 7.59 (s, 1H), 7.35−7.34 (m, 4H), 7.24−7.21 (m, 2H), 2.50 (s,
3H), 2.49 (s, 3H), 2.46 (s, 6H); 13C NMR (100 MHz, CDCl3): δ =
167.1, 166.9, 144.3, 144.08, 144.06, 143.1, 142.6, 142.1, 135.8,
135.0, 132.4, 130.17, 130.14, 130.0, 129.74, 129.71, 129.6,
126.8, 126.5, 120.3, 119.8, 115.4, 114.8, 21.8, 21.6, 21.5. HRMS
(ESI) ([M+H]+): Calcd. for C16H15N2O: 251.1184. Found
251.1188.
(4-Methoxyphenyl)(5-methyl-1H-benzo[d]imidazol-1-yl)
methanone
and
(4-methoxyphenyl)(6-methyl-1H-
benzo[d]imidazol-1-yl)methanone (3aa and 3a’a’) (1:1 ratio):
White solid. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 8.17
(s, 1H), 7.99−7.97 (m, 2H), 7.80−7.78 (m, 4H), 7.69 (d, J = 8.0
Hz, 1H), 7.61 (s, 1H), 7.25−7.22 (m, 2H), 7.05−7.03 (m, 4H),
3.91 (s, 6H), 2.51 (s, 3H), 2.50 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 166.5, 166.3, 163.69, 163.67, 144.3, 143.1, 142.6,
142.1, 135.7, 134.9, 132.5, 132.1, 132.0, 130.2, 126.8, 126.4,
124.95, 124.91, 120.3, 119.8, 115.2, 114.7, 114.3, 55.6, 21.8,
21.5. HRMS (ESI) ([M+H]+): Calcd. for C16H15N2O2: 267.1134.
Found 267.1135.
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Commun. 2012, 48, 145-147.
Acknowledgments
This work was financially supported by the National Science
Foundation of China (Nos. 21172092 and 21202057).
Supplementary data
6

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Supplementary Information for Tetrahedron
Metal-Free Cross-Dehydrogenative Coupling of
Benzimidazoles with Aldehydes to
N-Acylbenzimidazoles
Lin Yu,a Min Wang,*,a and Lei Wang*,a,b
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P R
China, Tel: + 86-561-3802-069 Fax: + 86-561-3090-518
E-mail: leiwang@chnu.edu.cn
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China
Table of Contents for Supporting Information
1. Effect of radical scavenger…..…………………………………………………2
2. HPLC-HRMS of TEMPO with aldehyde………………………………………2
3. 1H and 13C NMR spectra of the products.…..…….……………………………3
1

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1. Effect of radical scavenger[a]
Entry
TEMPO (mol%)
Yield (%) [b]
1
2
3
4
5
6
7
8
0
93
60
10
20
54
30
55
50
48
100
200
300
27
trace
0
[a] Reaction conditions: benzimidazole (0.50 mmol), aldehyde (1.0 mmol), DTBP (1.0
mmol), 4 Å molecular sieves (50 mg), TEMPO (amount indicated in the above Table),
sealed tube, 110 °C, under N2, 15 h.
[b] Yields of isolated products after flash chromatography.
2. HPLC-HRMS of TEMPO with aldehyde
Calculated: [M+H] = 276.1964, Found: [M+H] = 276.1957
2

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3. 1H NMR and 13C NMR spectra
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