Efficient domino synthesis of benzimidazole derivatives: Copper catalysis versus transition metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2015.01.197

An efficient and facile assembly of 2-substituted benzimidazoles and 2-benzimidazolones has been developed. Under very mild copper catalysis or transition metal-free conditions, a wide range of the 2-alkyl/alkenyl benzimidazole derivatives can be conveniently and selectively synthesized through the domino reactions of o-haloarylcarbodiimides with active methylene species. Interesting complimentary effect was discovered under the two different sets of conditions. Furthermore, a series of 1,3-disubstituted 2-benzimidazolones were facilely assembled from o-haloarylcarbodiimides and α,β-unsaturated esters.

Full text of DOI:10.1016/j.tetlet.2015.01.197

Accepted Manuscript
Efficient domino synthesis of benzimidazole derivatives: copper catalysis vs
transition metal-free conditions
Haiquan Liu, Jiaming Tang, Liu Jiang, Tingting Zheng, Xiaoxia Wang, Xin Lv
PII:
S0040-4039(15)00257-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.197
TETL 45877
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 November 2014
10 January 2015
30 January 2015
Please cite this article as: Liu, H., Tang, J., Jiang, L., Zheng, T., Wang, X., Lv, X., Efficient domino synthesis of
benzimidazole derivatives: copper catalysis vs transition metal-free conditions, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.01.197
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1
Tetrahedron Letters
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Efficient domino synthesis of benzimidazole derivatives: copper catalysis vs transition
metal-free conditions
Haiquan Liu, Jiaming Tang, Liu Jiang, Tingting Zheng, Xiaoxia Wang and Xin Lv∗
Department of Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People’s Republic of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and facile assembly of 2-substituted benzimidazoles and 2-benzimidazolones has
been developed. Under very mild copper catalysis or transition metal-free conditions, a wide
range of the 2-alkyl/alkenyl benzimidazole derivatives can be conveniently and selectively
synthesized through the domino reactions of o-haloarylcarbodiimides with active methylene
species. Interesting complimentary effect was discovered under the two different sets of
Received in revised form
Accepted
Available online
conditions. Furthermore, a series of 1,3-disubstituted 2-benzimidazolones were facilely
assembled from o-haloarylcarbodiimides and α,β-unsaturated esters.
Keywords:
Benzimidazole
Copper-catalyzed
Transition metal-free
Domino reactions
Room-temperature
2009 Elsevier Ltd. All rights reserved.
Existing in numerous biologically active molecules,
benzimidazoles are an important class of N-heterocycles. 2-
Substituted benzimidazoles show wide range of biological
activities.1 Among them, the benzimidazoles with active
methylene groups on 2-position may be useful in pharmaceutical
domino reactions at room temperature because they are low-cost,
convenient, and environmental friendly.13 It is noteworthy that
there are very limited examples on the room-temperature Cu-
catalyzed domino transformations with cross-coupling as the key
step(s).13c,f-h
chemistry.
For
examples,
the glycinamide-containing
On the other side, transformations without any transition metal
have also aroused much concern since the application of these
reactions may reduce the toxic wastes, avoid the use of expensive
catalysts and overcome the difficulties in removal of metal.14
One-pot assembly of diverse molecules under transition metal-
free conditions would benefit from the advantages such as
environmental friendliness and convenience.
benzimidazoles have valuable pharmacological properties such as
anti-CCR2 and antithrombotic activities;2 several 3-
benzimidazol-2-yl-1H-quinoxalin-2-ones coordinate with Ru or
Os to give the complexes with antiproliferative activity;3 many 4-
amino-3-benzimidazol-2-ylhydroquinolin-2-one
derivatives
exhibit attractive anti-tumor activity;4 certain coumarin-hinged
benzimidazoles inhibit hepatitis C virus and can be utilized for
the treatment of related liver diseases.5 These multifunctional
benzimidazoles may also be employed as pharmaceutical
intermediates.6 On the other hand, many 2-benzimidazolones also
possess interesting biological activities. For instance, they have
been investigated as PR antagonists,7 p38α inhibitors,8 and
inhibitors of PDGFR.9
To the best of our knowledge, there is no report illustrating
two complimentary methods for the domino assembly of the N-
heterocyles under Cu-mediated and transition metal-free
conditions. Herein, as a part of our continuing effort to synthesize
N-heterocycles using domino methods,15 we wish to develop a
facile and efficient domino synthesis of 2-substituted
benzimidazoles and 1,3-disubstituted 2-benzimidazolones under
Cu catalysis or transition metal-free conditions (Scheme 1).
Exploration of transformations that meet the requirements of
green chemistry has become one of the most important and
attractive subjects in modern chemistry.10 Domino reaction is an
efficient and facile methodology for single-step access to
molecular complexity and diversity.11 Cu-mediated domino
transformation has attracted great attention because of its
convenience, low cost, and high efficiency.12 Room-temperature
domino reactions are a class of promising synthetic methods for
their low-energy consumption and expedient procedures.
P—ar—ticu—larly, increasing interest has been drawn on Cu-mediated
∗ Corresponding author.
E-mail address: lvxin@zjnu.cn (X. Lv)
Scheme 1. The domino approaches to benzimidazole derivatives in this work

2
Tetrahedron Letters
10). Different copper sources were also screened. And CuI
Table 1 Optimization of the reaction conditionsa
performed as the most efficient ( entry 2 vs. entries 11-13). A
moderate yield of the desired product was furnished in a control
experiment without the addition of any ligand (entry 14).
Notably, another control experiment indicated that the cyclization
may also be feasible in the absence of metal catalyst, though a
higher reaction temperature was required (entry 15). The reaction
also efficiently proceeded under milder conditions (at 45 ºC)
(entry 16). Interestingly, even performed at room temperature,
the domino transformation also exhibited good efficiency (entry
17). Longer times were required for the completion of the
reactions in the cases without promoters or at lower temperatures
(entries 14-17). Considering the particularly mild conditions and
expedient procedures, we chose CuI/L2/Cs2CO3/DMSO/rt/10 h as
Entry Cat
L
Base
Sol
Temp Time Yield
(ºC)
Cs2CO3 DMSO 70
L2 Cs2CO3 DMSO 70
(h)
10
2c
2
(%)b
28
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
-
L1
2
85
80
65
30
81
trace
20
10
17
68
75
3
4
Cs2CO3 DMSO 70
Cs2CO3 DMSO 70
L3
L4
2
5
6
7
8
L2 Cs2CO3 dioxane 70
2
2
2
2
2
2
2
2
2
8
12
4
10
Cs2CO3 DMF
Cs2CO3 MeCN
70
70
the
CuI/L2/Cs2CO3/DMSO/70 ºC/2 h could also be employed as a
optimal
reaction
conditions.
In
addition,
L2
L2
L2
L2
K3PO4
K2CO3
DMSO 70
DMSO 70
group of candidate conditions for the faster speed.
9
Equipped with a set of optimized conditions, we then explored
the scope of the Cu-mediated domino transformation at room
temperature (Table 2).17 Firstly, different substituted o-
iodoarylcarbodiimides were utilized to react with diethyl
10
11
12
13
14
15
16
17
L2 Na2CO3 DMSO 70
Cs2CO3 DMSO 70
Cs2CO3 DMSO 70
Cs2CO3 DMSO 70
Cs2CO3 DMSO 70
Cs2CO3 DMSO 100
Cs2CO3 DMSO 45
Cs2CO3 DMSO rt
L2
L2
L2
-
69
malonate
(entries
1-9).
Generally,
various
o-iodo
68
-
39d
84
diarylcarbodiimides bearing electron-donating (p-Me, m-Me and
p-iPr) and deactivating (p-F) substituents on the phenyl rings
were well tolerated, giving the desired 2-alkyl benzimidazoles in
good yields at room temperature (entries 1-6).18 However, the
strong electron-withdrawing group (m-NO2) on the aromatic ring
disfavoured the formation of the benzimidazole, due probably to
the weakening of the nucleophilicity of the NH group (entry 7).
N-o-Iodoaryl-N’-alkylcarbodiimides also smoothly reacted under
CuI
CuI
L2
L2
83
a Reaction conditions: o-iodophenylcarbodiimide 1a (0.5 mmol, 1
equiv.), diethyl malonate 2a (0.55 mmol, 1.1 equiv.), Cu catalyst
(0.05 mmol, 10 mol%), ligand (0.10 mol, 20 mol%), and base
(1.0 mmol, 2 equiv.), in solvent (3 mL), under nitrogen
atmosphere.
mild conditions (entries
8 and 9). The reaction of N-
b Isolated yield.
((cyclohexylimino)methylene)-2-iodoaniline 1h required a higher
temperature (50 ºC) and afforded a relatively lower yield, which
might result from the steric hindrance of c-hexyl group (entry 8).
During the research, o-bromoarylcarbodiimide 1j was also tested,
and a higher temperature was required in this case (entry 10).
Other β-dicarbonyl compounds were also employed as the
nucleophiles (entries 11-15). The domino reaction with
diisopropyl malonate also gave 3i in a good yield (entry 11).
Ethyl acetoacetate 2c afforded a moderate of the deacetylated
product (entries 12 and 13). Only a complex mixture was
obtained when another β-keto ester bearing a phenyl ring was
used (entry 14), due possibly to its steric hindrance. The reaction
with 2,4-pentanedione 2e also gave an unsatisfactory yield of the
2-alkenyl NH-benzimidazole (entry 15), maybe because of the
special property of the β-diketone. We also representatively
repeated several reactions under 70 ºC/2 h conditions, and
slightly higher yields were obtained (entries 1, 3, 5, 11 and 22).
In these cases, the desired products could be generated more
rapidly, though much higher temperature was required. Thus 70
ºC/2 h might be utilized as an alternative group of conditions.
c
In this case, the reaction time (2 h) was based on the
consumption of the substrate and the addition intermediate
(monitored by TLC).
d Here 42% yield of the addition intermediate was isolated.
We commenced our investigation with the reaction between o-
iodophenylcarbodiimide 1a16 and diethyl malonate 2a in presence
of CuI (10 mol%), 8-hydroxyquinoline (L1, 20 mol%), Cs2CO3 (2
equiv.), in DMSO at 70 ºC (Table 1, entry 1). Only 28% yield of
desired product 3a was delivered after 8 h (entry 1). Gratifyingly,
we obtained the desired product in a good yield within 2 h when
1,10-phen (L2) was used as the ligand (entry 2). Several ligands
were tested. L-Proline L3 was found to be slightly inferior to
1,10-phen (entry 3 vs. entry 2), whereas 2-piperidinecarboxylic
acid L4 showed much lower efficiency (entry 4). An
unsatisfactory yield was obtained when the reaction was carried
out in dioxane (entry 5). DMF was slightly inferior to DMSO
(entry 6 vs. Entry 2). MeCN showed unsuitable for this reaction
(entry 7). The use of weaker bases such as K3PO4, K2CO3 and
Na2CO3 led to the formation of 3a in poor yields (entries 8, 9 and
Table 2 Cu-Catalyzed Domino Synthesis of 2-Substituted Benzimidazoles at Room Temperaturea
Entry Carbodiimide
product
Yieldb
Entry
15
Carbodiimide
product
Yieldb
30%
(33%)d
1
83%
85%c
1a
1a
3a
3b
4a
4b
2
78%
16
88%
1a
1b

3
1c
3
4
5
88%
90%c
17
18
19
91%
92%
78%
1c
4c
3c
EtO2C
N
CO2Et
N
81%
1k
4d
3d
1d
74%
78%c
1e
1e
1f
4e
3e
3f
6
7
70%
trace
20
21
70%
74%
1f
4f
-
1i
1g
4g
4h
23%
(62%)d
68%e
78%
82%c
8
9
22
23
1h
1i
1k
3g
70%
82%f
3h
1j
4b
4i
3a
1a
1j
1j
10
11
75%f
24
25
82%
75%f
1a
1a
4i
78%
85%c
3i
43%
42%
80%
68%
1a
1a
12
26
27
3j
4j
1c
1a
13
14
3k
4k
g
-
-
The isolated intermediates:
5b (in entry 8)
5c (in entry 15)
a Reaction conditions: o-haloarylcarbodiimide 1 (0.5 mmol, 1 equiv.), active methylene compound 2 (0.55 mmol, 1.1 equiv.), CuI (0.05
mmol, 10 mol%), 1,10-phen (0.10 mol, 20 mol%), and Cs2CO3 (1.0 mmol, 2 equiv.), in DMSO (3 mL), under nitrogen atmosphere, at rt
for 10 h.
b Isolated yield.
c At 70 ºC for 2 h.
d Addition intermediate 5 (5b for entry 8, and 5c for entry 15) was also isolated in accompany with the desired product. Its isolated yield
is given in the parenthesis.
e At 50 ºC for 10 h.
f At 70 ºC for 10 h.
g Ethyl 3-oxo-3-phenylpropanoate was utilzied as the reagent. A complex mixture was obtained in this case.
We also investigated the domino reactions with other active
methylene compounds such as CN-containing reagents (Table 2,
entries 16-27). A variety of substituted o-iodoarylcarbodiimides
could smoothly react with ethyl cyanoacetate, and afforded the
corresponding 2-alkenyl NH-benzimidazoles 4 in good to
excellent yields (entries 16-23). The substrates bearing electron-
withdrawing subtituents on the aromatic rings usually showed
slightly inferior to those with electron-donating substituents
(entries 19-20 vs. entries 17-18). Different cyano-containing
active methylene species were tested, delivering the
corresponding 2-alkenyl NH-benzimidazoles in moderate to good
yields (entries 16, 24, 26 and 27). The reactions of o-

4
Tetrahedron Letters
bromoarylcarbodiimide 1j also smoothly proceeded, though a
afforded 2-alkenyl NH-benzimidazoles
Noteworthy was that the o-bromo-
4
(entries 5-11).
and o-
higher temperature was required (entries 23 and 25, at 70 °C).
The structure of product 4b was ascertained unambiguously by
the X-ray crystal diffraction analysis (Figure 1).19
fluorophenylcarbodiimides, which are cheaper and easier to
access than the o-iodides, also successfully reacted with the
active methylene species, though a higher temperature was
required (entries 8, 9 and 11). However, the reaction of the o-
chlorophenylcarbodiimide only afforded the indoline derivative
in an unsatisfactory yield (entry 10).
Interestingly, exclusive regioselectivity was observed in all
the above cases. The NH group took priority over the active CH
group in the intramolecular couping process. And only the
benzimidazoles were obtained as the sole products.
We were also wondering about the mechanism of the
intramolecular N-arylation process of this transition metal-free
domino transformation, since the reactivity of different aryl
halides did not accord to the normal order (F > Cl > Br >I) for
SNAr mechanism. Additional control experiment revealed that the
reaction of m-bromoarylcarbodiimide 1j’ did not afford desired
product 3a, showing the intramolecular N-arylation may not
undergo the pathway with arylyne as the intermediate. Therefore,
we tend to hypothesize that the intramolecular cyclization
possibly undergoes the short-lived radical-intermediate
pathway,21,22 though further investigation needs to be performed
to probe the mechanism. The similar abnormal phenomenon was
also disclosed by Bolm et al, when they studied the metal-free
cyclization of o-haloaryl ureas.22
After broadening the generality of the mild Cu-mediated
domino reaction, and encouraged by the observation that the
reaction also proceeded without any Cu catalyst (Table 1, entry
15), we then studied the one-pot reaction under transition-metal-
free conditions. Our investigation found that the efficiency of the
transformation was significantly affected by the temperature.
When the mixture was stirred at 110 °C, the desired product was
obtained in 58% yield. Raising the temperature to 120 °C
provided 3a in 65% yield (Table 3, entry 1). However, when a
higher temperature (130 ºC) was applied, no obvious
improvement was observed. The scope of the transition metal-
free domino transformation was then explored under the above
modified conditions.20 As shown in Table 3, in the absence of
any transition-metal catalyst,
a
range of o-halophenyl
carbodiimides and active methylene compounds underwent the
domino process smoothly to afford desired products 3 or 4 in
moderate to good yields (entries 1-9 and 11). As expected, 2-
alkyl benzimidazoles 3 were obtained as the sole products when
malonate esters or β-keto esters were used (entries 1-4); while the
reactions with β-diketones or cyanoacetate esters exclusively
Scheme 2. The reaction of a m-bromoarylcarbodiimide with 2a
Table 3 Transition Metal-Free Domino Synthesis of Benzimidazole Derivativesa
Yieldb
65%
Entry Carbodiimide
Product
Yieldb
Carbodiimide
Product
Entry
1
7
74%
1a
1a
4i
3a
8
72%c
4b
1j
2
3
4
67%
70%
65%
75%
1e
3e
70%c
29%d
70%c
1a
1j
4i
4b
4b
9
3j
10
11
1c
1l
3k
1a
1a
1m
5
6
4a
82%
4b
a Reaction conditions: o-haloarylcarbodiimide 1 (0.5 mmol, 1 equiv.), active methylene compound 2 (0.55 mmol, 1.1 equiv.), CuI (0.05
mmol, 10 mol%), 1,10-phen (0.10 mol, 20 mol%), and Cs2CO3 (1.0 mmol, 2 equiv.), in DMSO (3 mL), under nitrogen atmosphere, at
120 ºC for 12 h.
b Isolated yield.
c At 150 ºC for 24 h.
d At 150 ºC for 48 h
Interestingly, our findings may provide two complementary
approaches to the 2-substituted benzimidazoles. And
complementary effect was found under the two different sets of
reaction conditions. As shown in Scheme 3, for the domino
reactions with malonic esters or cyanoacetate esters, the Cu-
catalyzed method afforded better results. However, when β-keto
esters or β-diketones were utilized as the C-nucleophiles, the
transition metal-free reactions showed much higher efficiency.

5
Scheme 3. The comparison of the experimental results from the two methods
To further extend the application scope of the domino
synthesis, we also attempted to use α,β-unsaturated esters as α-C
nucleophiles. Initially, o-iodophenylcarbodiimide 1a and ethyl
acrylate 6a were employed as the materials, and the reaction was
performed under the above Cu-catalyzed conditions (CuI/1,10-
phen/Cs2CO3/DMSO) at 70 °C (Scheme 4). Surprisingly, no
desired benzimidazole was observed, and an unexpected 2-
benzimidazolone derivative 7a was isolated in 41% yield.
Further investgation found that the result was significantly
improved at a higher temperature (100 °C, 70% yield) (Table 4,
entry 1). A survey of different o-iodoarylcarbodiimides and α,β-
unsaturated esters was also conducted, and 62-70% yield of the
corresponding 1,3-disubstituted 2-benzimidazolones were
isolated under these modified conditions (entries 1-5). However,
the nitro olefin seems to be incompatible with the reaction
conditions, leaving the intermediate 1-substituted 2-
benzimidazolone as the sole product (entry 6), probably due to its
special reactivity and the steric hindrance on α-position.
To gain insight into this reaction’s mechanism, additional
control experiments were also carried out (Scheme 5). The
reaction of 1a without the addition of any external reagent at 100
°C afforded unexpected monosubstituted 2-benzimidazole 8a in a
good yield (eq. 1). Under the promotion of Cs2CO3, the conjugate
addition of 8a with 6a proceeded smoothly andthe 1,3-
disubstituted 2-benzimidazolone was genarated in a moderate
yield (eq. 2).
Scheme 4. Initial attempt to synthesize a 2-benzimidazolone
Table 4. Cu-Catalyzed Domino Synthesis of 1,3-
Disubstituted 2-Benzimidazolonesa
Substr.
Reagent
Entry
1
Product 6
Yieldb
70%
1a
6a
6a
6a
Scheme 5. Two control experiments
Based on the above observations and our previous
investigation,15c a plausible pathway for the formation of the
unexpected benzimidazolone 7 is proposed in Scheme 6.
1c
1e
2
3
66%
63%
Facilitated by the base, o-iodophenylcarbodiimide
1 was
assaulted by water23 to afford (2-iodophenyl)urea II if it did not
react with the additional C-nucleophile “in time”.
1c
N
O
N
O
6b
4
65%
O
7d
1a
1a
5
6
62%
6c
-c
-
6d
aReaction conditions: o-haloarylcarbodiimide 1 (0.5 mmol, 1
equiv.), α,β-unsaturated ester 5 (1.0 mmol, 2 equiv.), CuI (0.05
mmol, 10 mol%), 1,10-phen (0.10 mol, 20 mol%), and Cs2CO3
(1.0 mmol, 2 equiv.), in DMSO (3 mL), under nitrogen
atmosphere, at 100 °C for 12 h.
Scheme 6. The proposed mechanism for the formation of
benzimidazole products
In summary, we have developed an efficient and convenient
domino assembly of 2-substituted benzimidazole derivatives. The
method provides regioselective approaches to the benzimidazoles
under mild copper catalysis or transition metal-free conditions.
Interesting complementary effect was discovered under the two
different sets of reaction conditions. Furthermore, 1,3-
disubstituted 2-benzimidazolones could be facilely assembled
from the reactions between o-haloarylcarbodiimides and α,β-
bIsolated yield.
cIntermediate 8a instead of the desired benzimidazolone was
isolated in 75% yield.

6
Tetrahedron
12. For recent reviews, see: (a) Liu, Y. Y.; Wan, J. –P. Chem. Asian J.
2012, 7, 1488-1501. (b) Liu, Y. Y.; Wan, J. –P. Org. Biomol.
Chem. 2011, 9, 6873-6894.
unsaturated esters. The complementary mild Cu-catalyzed or
transition-metal free conditions, the environmental benign
properties and the simple procedures render the method attractive
to existing routes to the relevant N-heterocyclic compounds with
biological and pharmaceutical interests.
13. For examples on Cu-mediated room-temperature domino
reactions, see: (a) Zhou, F. G.; Liu, X.; Zhang, N.; Liang, Y. J.;
Zhang, R.; Xin, X. Q.; Dong, D. W. Org. Lett. 2013, 15, 5786-
5789. (b) Nagaraj, M.; Boominathan, M.; Perumal, D.;
Muthusubramanian, S.; Bhuvanesh, N. J. Org. Chem. 2012, 77,
6319-6326. (c) Cai, Q.; Yan, J. J.; Ding, K. Org. Lett. 2012, 14,
3332-3335. (d) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2011, 13, 3076-3079. (e) Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2011, 13, 2395-2397. (f) Xu, S.; Lu, J. Y.; Fu, H. Chem.
Commun. 2011, 47, 5596-5598. (g) Xu, H.; Li, S. F.; Liu, H. X.;
Fu, H.; Jiang, Y. Y. Chem. Commun. 2010, 46, 7617-7619. (h)
Huang, H.; Jiang, H. L.; Chen, K. X.; Liu, H. J. Org. Chem. 2009,
74, 5476-5480.
Acknowledgment
This work was financially supported by the National Natural
Science Foundation of China (No. 21202152) and the Zhejiang
Provincial Natural Science Foundation (No. Y4110044).
References
14. It is noticeable that heavy metal contamination is strictly
regulated, especially in the fields of medicinal industry and
biological chemistry. For selected reviews, see: (a) Arancon, R. A.
D.; Lin, C. S. K.; Vargas, C.; Luque R. Org. Biomol. Chem. 2014,
12, 10-35. (b) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc.
Rev. 2012, 41, 3969-4009. (c) Cue, B. W.; Zhang, J. Green Chem.
Lett. Rev. 2009, 2, 193-211.
1. For selected examples, see: (a) Sharma, A.; Luxami, V.; Paul, K.
Bioorg. Med. Chem. Lett. 2013, 23, 3288-3294. (b) Singh, M.;
Tandon, V. Eur. J. Med. Chem. 2011, 46, 659-669. (c) Refaat, H.
M. Eur. J. Med. Chem. 2010, 45, 2949-2956. (d) Combs, A. P.;
Zhu, W.; Crawley, M. L.; Glass, B.; Polam, P.; Sparks, R. B.;
Modi, D.; Takvorian, A.; McLaughlin, E.; Yue, E. W.;
Wasserman, Z.; Bower, M.; Wei, M.; Rupar, M.; Ala, P. J.; Reid,
B. M.; Ellis, D.; Gonneville, L.; Emm, T.; Taylor, N.;
15. (a) Gao J. L.; Shao, Y. Y.; Zhu, J. Y.; Zhu, J. Q.; Mao, H.; Wang,
X. X.; Lv, X. J. Org. Chem. 2014, 79, 9000-9008. (b) Yuan, G.
D.; Liu, H. Q.; Gao, J. L.; Xu, H. J.; Jiang, L.; Wang, X. X.; Lv,
X. RSC Adv. 2014, 4, 21904-21908. (c) Yuan, G. D.; Liu, H. Q.;
Gao, J. L.; Yang, K. J.; Niu, Q. S.; Mao, H.; Wang, X. X.; Lv, X.
J. Org. Chem. 2014, 79, 1749-1757. (d) Niu, Q. S.; Mao, H.;
Yuan, G. D.; Gao, J. L.; Liu, H. Q.; Tu, Y. W.; Wang, X. X.; Lv,
X. Adv. Synth. Catal. 2013, 355, 1185-1192. (e) Xia, Z. M.; Wang,
K.; Zheng, J. N.; Ma, Z. Y.; Jiang, Z. G.; Wang, X. X.; Lv, X.
Org. Biomol. Chem. 2012, 10, 1602-1611.
Yeleswaram, S.; Li, Y.; Wynn, R.; Burn, T. C.; Hollis, G.; Liu, P.
C.; Metcalf, B. J. Med. Chem. 2006, 49, 3774-3789. (e) Richards,
M. L.; Lio, S. C.; Sinha, A.; Tieu, K. K.; Sircar, J. C. J. Med.
Chem. 2004, 47, 6451-6454. (f) Roth, T.; Morningstar, M. L.;
Boyer, P. L.; Hughes, S. H.; Buckheit, Jr., R. W.; Michejda, C. J.
J. Med. Chem. 1997, 40, 4199-4207.
2. (a) Cherney, R. J.; Mo, R.; Meyer, D. T.; Pechulis, A. D.;
Guaciaro, M. A.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.;
Zhao, Q.; Cvijic, M. E.; Barrish, J. C.; Decicco, C. P.; Carter, P.
H. Bioorg. Med. Chem. Lett. 2012, 22, 6181-6184. (b) Gerlach, K.;
Pfau, R.; Priepke, H.; Schuler-Metz, A.; Wienen, W.; Handschuh,
S.; Nar, H. US Patent 20050272792; Chem. Abstr. 2005, 144,
22924.
16. For selected previous reports about the one-pot synthesis of N-
heterocycles from carbodiimides, see: (a) Wang, F.; Cai, S. J.;
Liao, Q.; Xi, C. –J. J. Org. Chem. 2011, 76, 3174-3180. (b) He, H.
F.; Wang, Z. J.; Bao, W. L. Adv. Synth. Catal. 2010, 352, 2905-
2912. (c) Shen, G. D.; Bao, W. L. Adv. Synth. Catal. 2010, 352,
981-986. (d) Lv, X.; Bao, W. L. J. Org. Chem. 2009, 74, 5618-
5621. Also see ref. 15b-c.
3. Ginzinger, W.; Muhlgassner, G.; Arion, V. B.; Jakupec, M. A.;
Roller, A.; Galanski, M.; Reithofer, M.; Berger, W.; Keppler, B.
K. J Med Chem 2012, 55, 3398-3413.
17. General procedure for the room-temperature Cu-catalyzed one-
pot synthesis of benzimidazoles: An oven-dried Schlenk tube was
charged with a magnetic stir bar, CuI (0.05 mmol, 10 mol%),
1,10-phen (0.1 mmol, 20 mol%), and Cs2CO3 (1.0 mmol, 2
equiv.). The Schlenk tube was capped, and then evacuated and
backfilled with N2 (3 times). Under a positive pressure of N2, a
solution of active methylene compound 2 (0.55 mmol, 1.1 equiv.)
in DMSO (1.5 mL) was added via syringe. The mixture was
prestirred under N2 at rt for 10 min. Then a solution of o-
iodoarylcarbodiimide 1 (0.5 mmol, 1.0 equiv.) in DMSO (1.5 mL)
was added dropwise via syringe. The Schlenk tube was sealed and
the mixture was stirred at rt for 10 h. Then 30 mL of EtOAc was
added, and the mixture was washed with brine (15 mL × 3). The
organic phase was dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel (160-200 mesh) using petrol/EtOAc
(3:1, v:v) as eluent to afford the corresponding product 3 or 4.
18. Some control experiments have been performed to probe the
mechanism of the room-temperature Cu-catalyzed domino
reaction. The results indicated that copper(I) was unnecessary in
the addition step (see eq. 1 below), but it seemed to play as a
significant role in the coupling process (see eq. 2 and eq. 3).
4. Renhowe, P. A.; Pecchi, S.; Shafer, C. M.; Machajewski, T. D.;
Jazan, E. M.; Taylor, C.; Antonios-McCrea, W.; McBride, C. M.;
Frazier, K.; Wiesmann, M.; Lapointe, G. R.; Feucht, P. H.; Warne,
R. L.; Heise, C. C.; Menezes, D.; Aardalen, K.; Ye, H.; He, M.;
Le, V.; Vora, J.; Jansen, J. M.; Wernette-Hammond, M. E.; Harris,
A. L. J. Med. Chem. 2009, 52, 278-292.
5. Tsay, S.; Hwu, J. R.; Singha, R.; Huang, W.; Chang, Y. H.; Hsu,
M.; Shieh, F.; Lin, C.; Hwang, K. C.; Horng, J.; De Clercq, E.;
Vliegen, I.; Neyts, J. Eur. J. Med. Chem. 2013, 63, 290-298.
6. For examples, see: (a) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei,
D.; Ding, K. Org. Lett. 2010, 12, 1500-1503. (b) Dener, J. M.;
O’Bryan, C.; Yee, R.; Shelton, E. J.; Sperandio, D.; Mahajan, T.;
Palmer, J. T.; Spencer, J. R.; Tong, Z. Tetrahedron Lett. 2006, 47,
4591-4595. (c) Chapman, D. D.; Elwood, J. K.; Heseltine, D. W.;
Hess, H. M.; Kurtz, D. W. J. Org. Chem. 1977, 42, 2474-2480.
7. (a) Terefenko, E. A.; Kern, J.; Fensome, A.; Wrobel, J.; Zhu, Y.;
Cohen, J.; Winneker, R.; Zhang, Z. M.; Zhang, P. W. Bioorg.
Med. Chem. Lett. 2005, 15, 3600-3603. (b) Zhang, P. W.;
Terefenko, E. A.; Wrobel, J.; Zhang, Z. M.; Zhu, Y.; Cohen, J.;
Marschke, K. B.; Mais, D. Bioorg. Med. Chem. Lett. 2001, 11,
2747-2750.
8. Dombroski, M. A.; Letavic, M. A.; McClure, K. F.; Barberia, J.
T.; Carty, T. J.; Cortina, S. R.; Csiki, C.; Dipesa, A. J.; Elliott, N.
C.; Gabel, C. A.; Jordan, C. K.; Labasi, J. M.; Martin, W. H.;
Peese, K. M.; Stock, I. A.; Svensson, L.; Sweeney, F. J.; Yu, C. H.
Bioorg. Med. Chem. Lett. 2004, 14, 919-923.
9. Matsuno, K.; Ushiki, J.; Seishi, T.; Ichimura, M.; Giese, N. A.;
Yu, J. –C.; Takahashi, S.; Oda, S.; Nomoto, Y.; J. Med. Chem.
2003, 46, 4910-4925.
10. For selected recent reviews, see: (a) Lang, X. J.; Chen, X. D.;
Zhao, J. C. Chem. Soc. Rev. 2014, 43, 473-486. (b) Shirakawa, S.;
Maruoka, K. Angew. Chem. Int. Ed. 2013, 52, 4312-4348. (c)
Dunn, P. J. Chem. Soc. Rev. 2012, 41, 1452-1461. (d) Anastas, P.;
Eghbali, N. Chem. Soc. Rev. 2010, 39, 301-302.
According to the previous reports on Cu-catalyzed coupling and
our observations, we propose an addition/coupling pathway for the
Cu-mediated domino synthesis of 2-substituted benzimidazoles
(see the following scheme). Firstly, promoted by the base, the
nucleophilic addition of active methylene species 2 with o-
iodophenylcarbodiimide 1 gave corresponding intermediate A.
Then A coordinated with copper(I) to furnish Cu(I)-complex B, C
and/or D. The oxidative addition of the complex afforded
11. For selected reviews, see: (a) Pellissier, H. Chem. Rev. 2013, 113,
442-524. (b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino
Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
Germany, 2006. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115-136.

7
intermediate E. Finally, E underwent intramolecular
transmetallation and reductive elimination to give the desired
product. The coordination of the functional groups (such as N(H)
and C=O) of the intermediates with copper(I) might favour the
intramolecular C-N coupling process, therefore the reaction occurs
under the particular mild conditions.
was washed with brine (15 mL × 3). The organic phase was
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(160-200 mesh) using petrol/EtOAc (3:1, v:v) as eluent to afford
product 3 or 4.
21. For a recent review on metal-free coupling via radical-anion
intermediates, see: Sun, C. –L.; Shi, Z. –J. Chem. Rev. 2014, 114,
9219-9280. For a representative example of transition metal-free
synthesis of N-heterocycle via intramolecular C-N bond-forming
process, see: Thome, I.; Besson, C.; Kleine, T.; Bolm, C. Angew.
Chem. Int. Ed. 2013, 52, 7509-7513. Based on the relevant reports
and our observations, a possible radical-intermediate pathway for
the transition metal-free domino synthesis of benzimidazoles was
proposed in the scheme below. Firstly, intermediate A was
generated under the basic conditions; secondly, assaulted by the
base, A could be transformed into its conjugate base F; then the
internal base might undergo an intramolecular electron transfer
process to give radical-anion-form intermediate G; finally, G
furnished the product through a dehalogenation/cyclization
process.
19. The structure of product 4b was characterized by 1H NMR, 13
C
NMR, HRMS and X-ray (for its X-ray crystal structure, see the
following figure). Its CCDC reference number is 1025168.
20. General procedure for the transition metal-free one-pot synthesis
of benzimidazoles: An oven-dried Schlenk tube was charged with
a magnetic stir bar and Cs2CO3 (1.0 mmol, 2 equiv.). The Schlenk
tube was capped, and then evacuated and backfilled with N2 (3
times). Under a positive pressure of N2, a solution of active
methylene compound 2 (0.55 mmol, 1.1 equiv.) in DMSO (1.5 mL)
was added via syringe. The mixture was prestirred under N2 at rt
for 10 min. Then a solution of o-haloarylcarbodiimide 1 (0.5
mmol, 1.0 equiv.) in DMSO (1.5 mL) was added dropwise via
syringe. The Schlenk tube was sealed and allowed to prestir at rt
for 2 h. Then the mixture was stirred at 120 ºC for 12 h. After
being cooled to rt, 30 mL of EtOAc was added, and the mixture
22. Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett. 2011, 13,
2876-2879.
Since the finely-powdered base was highly hygroscopic,
absorption of moisture from air was inevitable during the
weighing process.