Facile one-pot synthesis of N-alkylated benzimidazole and benzotriazole from carbonyl compounds

Article abstract of DOI:10.1002/jhet.1616

An efficient one-pot N-alkylation of benzimidazole and benzotriazole from carbonyl compounds and tosylhydrazide has been accomplished via copper powder-catalyzed N - H bond insertion affording N-alkylated products in good yields. The reaction can tolerate a wide range of carbonyl compounds, such as aryl, alkyl, heterocyclic and α,β-unsaturated ketones, and aldehydes.

Full text of DOI:10.1002/jhet.1616

March 2014 Facile One-Pot Synthesis of N-Alkylated Benzimidazole and Benzotriazole
349
from Carbonyl Compounds
Xu Meng,a Xiaolong Li,a Wenlin Chen,a Yuanqing Zhang,a Wen Wang,a Jinying Chen,a Jinli Song,a
b
a
*
Huijie Feng, and Baohua Chen
aKey Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, State Key Laboratory
of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
bPharmaceutical Department, China Pharmaceutical University, Nanjing 210038, People’s Republic of China
*
E-mail: chbh@lzu.edu.cn
Additional Supporting Information may be found in the online version of this article.
Received November 27, 2011
DOI 10.1002/jhet.1616
Published online 12 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
(i) TsNHNH2
dioxane
60 oC, 2h
O
N
N
N
R1
R1
X
X
+
C
R2
R3
(ii) Cu powder (2 mol %)
KOtBu, DMSO
N
CH
R2
R3
H
60 oC, 6h
R2= Aryl, Alkyl, Het
R3= Alkyl, H
X = CH, N
R1= H, Me, Cl, NO2
one-pot fashion
32 examples
up to 93% yield
An efficient one-pot N-alkylation of benzimidazole and benzotriazole from carbonyl compounds and
tosylhydrazide has been accomplished via copper powder-catalyzed N—H bond insertion affording
N-alkylated products in good yields. The reaction can tolerate a wide range of carbonyl compounds, such
as aryl, alkyl, heterocyclic and a,b-unsaturated ketones, and aldehydes.
J. Heterocyclic Chem., 51, 349 (2014).
INTRODUCTION
readily available coupling reagents in carbon—carbon
and carbon—heteroatom bond-forming reactions through
transition-metal-catalyzed and metal-free processes
(Scheme 1) [6–9]. In the few past years, Barluenga [6],
Wang [7], Alami [8], Cuevas-Yañez, and others [9] had
illustrated that the utility of N-tosylhydrazones represented a
very convenient method for the unconventional modification
of carbonyl compounds. Especially, Cuevas-Yañez reported
Cu(acac)2-catalyzed N-alkylation of imidazoles using
p-toluenesulfonylhydrazones as alkylated reagents [9f]. How-
ever, drawbacks of this reaction include the following: (1) the
reaction must be performed by two steps, which means require-
ment of long reaction time (37 h) and more experimental
operations; (2) the use of additive (n-Bn4N+BrÀ) and
exclusion of air; (3) only N-alkylation of benzimidazole
and poor functional-group tolerance; and (4) the requirement
of relatively expensive and toxic transition metal catalyst.
For these reasons, the development of the simple, general,
and ecofriendly methods of N-alkylation of azoles is one of
the valuable goals for the preparation of various nitrogen-
containing compounds. Therefore, we want to investigate
whether the N—H insertion of azoles could be performed
in a simple one-pot fashion directly from the carbonyl
compound without the isolation of the intermediate N-
tosylhydrazone because N-tosylhydrazones can be easily
prepared by mixing tosylhydrazide with the corresponding
ketone or aldehyde [5]. Herein, we describe an efficient
Benzimidazoles and benzotriazoles are important reagents
in organic synthesis [1] and can serve as ligands to transition
metals for modeling biological systems [2]. More impor-
tantly, their derivatives are common structure motifs in
natural products and have various pharmacological proper-
ties, such as antiulcers, antihypertensives, antivirals, anti-
fungals, anticancers, and antihistamines [3]. Consequently,
the development of highly efficient methods for the
synthesis of functional benzimidazoles and benzotriazoles
is very important. It is clear that N-alkylation of azoles plays
a pivotal role in the synthesis of their derivatives. Tradition-
ally, the N-alkylation of azoles requires deprotonation
followed by a nucleophilic substitution with an electrophile
(RX= aryl or alkyl halide, X = halide, OTs = tosylate,
OTf = triflate, etc.) [4]. As a matter of fact, several draw-
backs of these reactions exist, such as requiring strong bases,
generating stoichiometric amount of wasteful (in)organic
salts, and low secondary/tertiary amine product selectivity
[4]. Therefore, it is necessary to develop improved synthetic
methodologies for the N-alkylation of azoles by employing
new alkylation reagents and catalysts.
In recent years, N-tosylhydrazones have been proven to
be versatile synthetic intermediates and used as in situ
source of diazo compounds in various reactions [5].
In this context, we focused on N-tosylhydrazones as
© 2013 HeteroCorporation

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X. Meng, X. Li, W. Chen, Y. Zhang, W. Wang, J. Chen, J. Song, H. Feng, and B. Chen
Vol 51
Scheme 1. Recent applications of tosylhydrazones for the unconventional elaboration of carbonyl compounds.
R3
OR3
S-Ar
R2
R2
R2
R1
R1
R1
R3-OH
R3-B(OH)2
base
metal-free
Ar-SH
base
metal-free
base
metal-free
R2
O
NNHTs
R2
N
TsNHNH2
base
CuI cat.
R2
R1
R1
azole
R1
X
X= S, O
base
R3
Ar-X Pd0 cat.
base
[Cu] or [Fe] cat.
base
[Cu] cat., ligand
Ts
Ar
R2
R1
R3
R2
R2
R1
R1
and convenient one-pot protocol for the synthesis of N-
alkylated benzimidazoles and benzotriazoles using
carbonyl compounds and tosylhydrazide as the starting
substrates and inexpensive element copper as the catalyst.
provide the product in moderate yields, but Cu(OAc)2 was
not efficient in the reaction (Table 1, entries 5–9). Fortu-
nately, the cheap and low-toxic copper powder showed the
best ability of catalysis and afforded the product 3a in 88%
yield (Table 1, entry 7). After that, it was observed that the
solvent significantly affected the C—N bond formation.
The tested solvents, such as dioxane, THF, benzene,
CH2Cl2, and DMF, were all inefficient for the reaction, but
DMSO could render C—N bond formation successful
(Table 1, entries 10–15). After a screening of reaction
conditions, the optimum conditions for N-alkylation were
identified as follows: the carbonyl compound (1.0 equiv) and
TsNHNH2 (1.0 equiv) in dioxane at 60ꢀC for 2h, then add
benzimidazole (1.2 equiv), Cu powder (2 mol%) as the cata-
lyst, KOtBu (2.0 equiv) as the base and DMSO as the solvent
to the aforementioned mixture at 60ꢀC for another 6h (more
optimized experiments, see the Supporting Information).
With the optimized reaction conditions established, the
scope of the reaction was studied using various benzimida-
zoles (1a–d) and a range of carbonyl compounds 2a–p.
As presented in Table 2, the N-alkylation is general and
functional-group tolerant. The reaction can be performed
with various ketones and aldehydes affording the corres-
ponding products 3a–3o in good yields (Table 2, entries
1–15). Other substituted benzimidazoles could be employed
as efficient substrates in the reaction to provide expected
products in good yields (Table 2, entries 17–21). It is
remarkable that electron-withdrawing groups Cl-substituted
and NO2-substituted benzimidazoles give rise to exclusive
regioisomer in good yields (Table 2, entries 20, and 21).
Overall, the reaction was not significantly affected by the
substrates on the aromatic ring of carbonyl compounds
RESULTS AND DISCUSSION
In our initial experiments, 4-methylacetophenone (2a),
TsNHNH2, and benzimidazole (1a) were mixed in one
pot with the catalyst of CuBr and the base of K2CO3
together in DMSO at 60ꢀC for 6h, we only obtained trace
amount of the desired product 3a. After that, we decided
to employ a one-pot, two-step sequence reaction to carry
out our following experiments. In the latter experiments,
the carbonyl compound 2a and tosylhydrazide were added
in dioxane, and the solution was stirred at 60ꢀC for 2h
firstly. After that, benzimidazole (1a), CuBr, K2CO3, and
DMSO were added to the aforementioned solution, and this
mixture was stirred at 60ꢀC for another 6h. To our delight,
the corresponding N-alkylated product was isolated although
the yield was only 20% (Table 1, entry 1). Subsequently, we
used this two-step sequence reaction to optimize the reaction
conditions (Table 1). Not surprisingly, the reaction could not
perform in the absence of either copper salt or base. After
some initial experiments, we found that in the presence of
KOtBu, the reaction that was catalyzed by low amount of
CuBr (2 mol%) could afford N-alkylated benzimidazole in
45% yield (Table 1, entries 1–4). Encouraged by these initial
results, various copper catalysts were used to better the
yield. Overall, some simple copper halide salts with different
oxidation state (I or II) could make the reaction work and
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A New Route to N-Alkylation of Benzimidazole and Benzotriazole
351
Table 1
Optimization of reaction conditions.a
Entry
Catalyst
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
Cu powder
CuCl2
Cu(OAc)2
Cu powder
Cu powder
Cu powder
Cu powder
Cu powder
Cu powder
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
KOtBu
K3PO4
Cs2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Dioxane
THF
20
45
21
0
40
35
88
65
Trace
0
9
10
11
12
13
14
15
0
0
0
0
Benzene
CH2Cl2
CH3CN
DMF
0
1a is benzimidazole, 2a is acetophenone, 3a is N-alkylated benzimidazole (1-(1-Phenylethyl)-1H-benzo[d]imidazole)
aReaction conditions: 2a (0.3 mmol), TsNHNH2 (0.3 mmol), dioxane, 60ꢀC, 2h; then 1a (0.4 mmol), catalyst (2 mol%), base (2.0 equiv), solvent (1.0 mL),
60ꢀC, 6h.
bIsolated yield based on 2a.
(Table 2, entries 1–13). Both electron-donating and electron-
withdrawing groups were tolerated under the reaction
conditions. Particularly, halogen substitutions in aromatic
rings were tolerated (Table 2, entries 5–7, 13), enabling
further derivatizations through metal-catalyzed cross-
coupling techniques [11]. Moreover, the carbonyl compounds
2h and 2i were tolerated under the reaction conditions
(Table 2, entries 8, and 9), which could carry out further
direct functionalization of sp3 C—H bond adjacent to
heteroatoms (such as O or N) to provide other useful
products.[12] In terms of steric hindrance, the reaction
was also not noticeably affected, even though obtaining the
corresponding products in slightly diminished yields by
using sterically hindered ketones and aldehydes (Table 2,
entries 7, 10–11, 13). To our delight, the C—N coupling
could proceed smoothly in the case of heteroaromatic
2-furaldehyde, providing the expected product in 90% yield
(Table 2, entry 14). We also tried to apply this reaction
system to the direct allylation. Consequently, cyclohex-2-
enone as the substrate gave rise to allylation product 3o
in 88% yield (Table 2, entry 15). Unfortunately, the coupling
reaction with monosubstituted acyclic a,b-unsaturated
ketone, such as chalcone, generated 3,5-diphenyl-1H-
pyrazole instead of the expected product 3p. This outcome
is attributed to the decomposition of the hydrazone followed
by electrocyclic ring closure [6d].
Encouraged by the results obtained with benzimidazoles,
we proceeded to apply this catalytic system to other nitrogen
nucleophiles. However, the results were disappointing (see
the Supporting Information). To our delight, it was found
that benzotriazole could be employed in the N-alkylation
without changing the reaction conditions (Scheme 2).
Obviously, the transformation seemed to be general and
successful, as ketones or aldehydes were converted into
corresponding products 5a–i in good to excellent yields by
using the aforementioned conditions (Scheme 2). Specifi-
cally, no significant difference in reactivity was observed
for the examined reactants with varied electronic properties,
although the reaction of the carbonyl compound 2m with
benzotriazole afforded a slightly diminished yield (Scheme 2,
5g). Furthermore, the steric hindrance did not significantly
affect the reaction as well, because the sterically hindered
2g, 2j, and 2m generated the desired product 5e, 5g, and
5h in good yields (Scheme 2). Finally, it was found that
cyclohex-2-enone could also work and give rise to allylation
product 5i in 84% yield (Scheme 2, 5i).
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Vol 51
Table 2
One-pot N-alkylation of benzimidazoles with a wide range of carbonyl compounds.a
Entry
Product
Yieldb (%)
Entry
12
Product
Yieldb (%)
1
2
88
80
78
3a
3l
86
13
3b
3c
3m
3
4
85
86
14
15
90
88
3n
3d
3o
5
86
16c
0
3e
3p
(Continued)
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A New Route to N-Alkylation of Benzimidazole and Benzotriazole
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Table 2
(Continued)
Entry
Product
Yieldb (%)
Entry
Product
Yieldb (%)
80 (1:1)
6
85
17d
3f
3q
7
81
18d
85 (1:1)
3g
3r
8
83
19d
82 (1:0.9)
3h
3s
9
78
20
82
3i
3t
10
81
21
83
3j
3u
11
83
3k
aReaction conditions: 2 (0.3 mmol), TsNHNH2 (0.3 mmol), dioxane, 60ꢀC, 2h; then 1 (0.4 mmol), Cu powder (2 mol%), KOtBu (2.0 equiv), DMSO
(1.0 mL), 60ꢀC, 6h.
bIsolated yield.
cNo expected product obtained.
1
dTwo chromatographically inseparable regioisomers combined; the ratios of two isomers are determined on the basis of H-NMR spectroscope and
reported in the parentheses.
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Scheme 2. One-pot N-alkylation of benzotriazole with a wide range of carbonyl compounds. aReaction conditions: 2 (0.3 mmol), TsNHNH2 (0.3 mmol),
dioxane, 60ꢀC, 2h; then benzotriazole (0.4 mmol), Cu powder (2 mol%), KOtBu (2.0 equiv), DMSO (1.0 mL), 60ꢀC, 6h. bIsolated yields.
(i) TsNHNH2
dioxane, 60 oC, 2h
N
O
N
N
N
R2
R3
(ii)
Cu powder, KOtBu
DMSO, 60 oC, 6h
R3
5a-i
R2
N
N
H
2a-c, e-g, m, j, o
NNHTs
R3
benzotriazole
TsNHNH2
R2
N
N
N
N
N
N
N
N
N
Cl
5a (93%)a, b
5b (90%)
5c (92%)
N
N
N
N
N
N
N
N
N
Br
Br
5d (88%)
5e (80%)
5f (85%)
N
N
N
N
N
N
N
N
N
MeO
F
5g (75%)
5h (88 %)
5i (84%)
Scheme 3. One-pot N-alkylation of benzimidazole with cyclopentanone and cyclohexanone.
N
(i) TsNHNH2
O
N
dioxane, 60 oC, 2h
N
+
N
H
Cu powder, KOtBu
(ii)
n
DMSO, 60 oC, 6h
n
1a
2q-r
6a-b
n = 1, 6a 87%
n = 2, 6b 80%
Surprisingly, when employing cyclopentanone and
cyclohexanone as the substrates, the different products
1-cyclopentenyl-1H-benzo[d]imidazole (6a) and 1-cyclo-
hexenyl-1H-benzo[d]imidazole (6b) were obtained (Scheme 3).
In terms of mechanism, it might be derived from the process of
1,2 hydrogen shift of the Cu carbene intermediate [7,6].
On the basis of Barluenga [6], Wang [7], and Cuevas-
Yañez’s [9f] understanding of the metal-catalyzed cross-
coupling reactions of N-tosylhydrazones, we proposed a
plausible mechanism of this N-alkylation. First of all, the
carbonyl compound transforms into the N-tosylhydrazone
with TsNHNH2 [5]. Then, the N-tosylhydrazone decomposes
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A New Route to N-Alkylation of Benzimidazole and Benzotriazole
355
61.7, 27.8, 11.2 ppm. ESI HRMS: Calcd for C16H16N2 [M+ H]+:
237.1386, found: 237.1378.
under thermal condition in the presence of base through
the formation of the diazo compound [6a]. Subsequently,
the diazo compound releases the nitrogen and forms the
Cu carbene complex in the presence of copper [8a,7a].
Finally, the insertion reaction of the copper carbene into
N—H bond of benzimidazole happens [5,10,13,14,15],
which gives rise to the corresponding N-alkylated product.
Acknowledgments. We are grateful to the project sponsored
by the Scientific Research Foundation for the State Education
Ministry (No. 107108) and the Project of National Science
Foundation of People’s Republic of China (No. J0730425).
We sincerely thank Miss Nan Nan for helping prepare the
manuscript.
CONCLUSION
In conclusion, the one-pot, two-step sequence reaction
of benzimidazole and benzotriazole with the carbonyl
compounds represents a general, functional-group tolerate,
operationally simple, and efficient access to N-alkylation.
This transformation, catalyzed by low amount of copper
powder (2 mol%), provides the corresponding N-alkylated
products in good to excellent yields, which render the
potential industrial application possible because of the
cheap and low-toxic catalyst. It is believable that the
reaction system could be a better alternative to existing
methodologies [4,10] for the N-alkylation of benzimidazoles
and benzotriazoles.
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General procedure for Cu powder-catalyzed one-pot
fashion N-alkylation of benzimidazole with various carbonyl
compounds.
Firstly, a solution of corresponding carbonyl
compound (1.0 mmol) and tosylhydrazide (1.0 mmol) in 3 mL
dioxane was stirred at 60ꢀC for 2h. After that, benzimidazole
(1.3 mmol), Cu powder (2.0 mol%), KOtBu (2.0 equiv), and
DMSO (3 mL) were added to the aforementioned solution. The
mixture was stirred at 60ꢀC for another 6h. When the reaction
was completed, the crude reaction mixture was allowed to reach
RT, and then the mixture was diluted with ethyl acetate and
filtered. The filtrate was extracted twice with water. After that,
the combined organic layer was washed with brine, then dried
over Na2SO4, and filtered. Finally, the solvent was removed
under reduced pressure to obtain the crude product, which was
further purified by silica gel chromatography (petroleum/ethyl
acetate = 1/1 as eluent) to yield corresponding product. The
1
identity and purity of the products was confirmed by H-NMR
and 13C-NMR spectroscopic analysis.
1-(1-Phenylethyl)-1H-benzo[d]imidazole (3a).
1H-NMR
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(400 MHz, CDCl3): d 8.10 (s, 1H), 7.83–7.81 (d, J = 8 Hz, 1H),
7.35–7.18 (m, 8H), 5.65–5.59 (q, J = 7.2 Hz, 1H), 2.01–1.99
(d, J = 7.2 Hz, 3H) ppm. 13C-NMR (100 MHz, CDCl3): 140.6,
128.9, 128.0, 125.9, 122.8, 122.2, 120.3, 110.6, 55.2, 21.5 ppm.
MS: m/z (%) = 223 (M+, 100), 119 (3). IR 2932, 1611, 1513,
1248, 1030, 834, 746 cmÀ1. ESI HRMS: Calcd for C15H14N2
[M + H]+: 223.1230, found: 223.1226.
1-(1-Phenylpropyl)-1H-benzo[d]imidazole (3b).
1H-NMR
(300 MHz, CDCl3): d 8.15 (s, 1H), 7.83–7.80 (d, J = 7.5 Hz,
1H), 7.36–7.18 (m, 8H), 5.33–5.28 (t, J = 7.5 Hz, 1H), 2.48–2.35
(m, 2H), 1.02–0.97 (t, J = 7.2 Hz, 3H) ppm. 13C-NMR (75 MHz,
CDCl3): 139.4, 128.8, 128.0, 126.4, 122.8, 122.2, 120.2, 110.5,
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X. Meng, X. Li, W. Chen, Y. Zhang, W. Wang, J. Chen, J. Song, H. Feng, and B. Chen
Vol 51
[10] Literatures on N-H functionalization by carbene insertion from
diazo compounds: (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C.
J. J Chem Soc, Perkin Trans 1 1998, 3, 591; (b) Moody, C. J.; Bagley, M.
C. J Chem Soc, Perkin Trans 1 1998, 3, 601; (c) Bagley, M. C.; Bashford,
K. E.; Hesketh, C. L.; Moody, C. J. J Am Chem Soc 2000, 122, 3301;
(d) Wang, J.; Hou, Y.; Wu, P. J Chem Soc, Perkin Trans 1 1999, 16, 2277.
[11] Review on transition-metal-catalyzed cross-coupling
reaction: (a) Monnier, F.; Taillefer, M. Angew Chem Int Ed 2009,
48, 6954; (b) Ley, S. V.; Thomas, A. W. Angew Chem Int Ed
2003, 42, 5400.
[12] Selected recent literature on direct functionalization of sp3 C-H
bond adjacent to heteroatoms: (a) Li, Z.; Yu, R.; Li, H. Angew Chem Int
Ed 2008, 47, 7497; (b) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org
Chem 2008, 73, 3961; (c) Liu, X.; Zhang, Y.; Wang, L.; Fu, H.; Jiang, Y.;
Zhao, Y. J. Org Chem 2008, 73, 6207; (d) Li, Z.; Li, C. J. Am Chem Soc
2005, 127, 3672.
[13] Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 471.
[14] Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577.
[15] Katritzky, A. R.; Puschmann, I. B.; Stevens, C. V.; Wells, A.
P. J Chem Soc, Perkin Trans 2 1995, 8, 1645.
Journal of Heterocyclic Chemistry
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