Copper-Catalyzed Inter/Intramolecular N-Alkenylation of Benzimidazoles via Tandem Processes Involving Selectively Mild Iodination of sp3 C-H Bond at α-Position of Ester

Article abstract of DOI:10.1021/acs.joc.6b01465

Inter/intramolecular approaches to sp² C-N bond formation of N-alkenyl benzimidazoles have been accomplished in the presence of an iodide anion associated with a copper catalyst. Both intermolecular and intramolecular reactions included tandem processes, in which selective iodination of sp³ C-H bond at the α-position of ester under mild conditions was demonstrated for the first time. Tandem reactions involving sp³ C-H activation via α-iodo ester intermediate under copper catalysis efficiently provided more than 20 novel azole compounds, and free radicals were not involved in this transformation.

Full text of DOI:10.1021/acs.joc.6b01465

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Article
Copper-Catalyzed Inter/Intramolecular N-Alkenylation of
Benzimidazoles via Tandem Processes Involving Selectively
Mild Iodination of sp3 C-H Bond at alpha-Position of Ester
Ting-Ting Lai, Dan Xie, Cheng-He Zhou, and Gui-Xin Cai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01465 • Publication Date (Web): 07 Sep 2016
Downloaded from http://pubs.acs.org on September 7, 2016
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The Journal of Organic Chemistry
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Copper-Catalyzed Inter/Intramolecular N-Alkenylation of
Benzimidazoles via Tandem Processes Involving Selectively Mild
Iodination of sp3 C-H Bond at α-Position of Ester
Ting-Ting Lai,† Dan Xie,† Cheng-He Zhou,†,* and Gui-Xin Cai†,‡,
*
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†Key Laboratory of Applied Chemistry of Chongqing Municipality, Institute of Bioorganic & Medicinal Chemistry,
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
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‡Beijing National Laboratory for Molecular Sciences, Beijing 100190, China
*Eꢀmails of corresponding author: gxcai@swu.edu.cn; zhouch@swu.edu.cn.
Keywords: sp3 CꢀH bond activation; iodination; tandem reactions; Nꢀalkenylation azoles; copper
Abstract: Inter/intramolecular approaches to sp2 CꢀN bond formation of Nꢀalkenyl benzimidazoles have been
accomplished in the presence of iodide anion associated with copper catalyst. Both intermolecular and
intramolecular reactions included tandem processes, in which selective iodination of sp3 CꢀH bond at αꢀposition
of ester under mild conditions was demonstrated for the first time. Tandem reactions involving sp3 CꢀH activation
via αꢀiodo ester intermediate under copper catalysis efficiently provided more than 20 novel azole compounds,
and free radicals were not involved in this transformation.
Introduction
Nitrogenꢀcontaining heterocycles are important motifs and versatile building blocks, as core intermediates for
medicines and other materials.1,2 Particularly, efficient approaches to sp2 CꢀN bond formation of Nꢀheterocycles3
is a topic of vital importance to the pharmaceutical industry and other related industries. Although great
achievements of Nꢀalkenylation of heterocycles had been obtained,4,5,6 current methods possessed some
limitations such as the lack of atom and step economy as well as the uncontrollable regioselectivity (Scheme 1).
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Thus the strategy concerning selective CꢀH bond activation, namely dual dehydrogenative amination involving
sp2 CꢀH bond of alkenes and NꢀH bond of Nꢀheterocycles, is desirable to construct sp2 CꢀN bond of
Nꢀheterocycles. As for dual dehydrogenative amination of Nꢀalkenyl benzimidazoles,2 there are mainly two
challenges. The first challenge is the cleavage activity of the CꢀN bond.7 The second challenge is the
polymerization of α,βꢀunsaturated esters8a and the homocoupling of benzimidazole8b in the presence of copper
catalyst. Despite significant progress in the α,βꢀdehydrogenation of carbonyl compounds (such as aldehydes,
ketones, amides and esters)9, a combination of diverse dehydrogenation of esters and benzimidazole
functionalizations for highly efficient synthesis of Nꢀalkenyl benzimidazoles in oneꢀpot is quite rare (Scheme 1).
Recently, direct CꢀH amination via a dehydrogenative pathway has bloomed as an elegant strategy to construct
various CꢀN bonds owing to obviating complicated steps associated with prefunctionalized partners.10 For
example, representative palladium(II)ꢀmediated oxidative amination of alkenes with Nꢀheterocycles had been
developed by Stahl, Miura, Su and Jang, independently.9bꢀd,11 Besides, Goldꢀcatalyzed heterogeneous oxidative
amination of α,βꢀunsaturated aldehydes and Nꢀheterocycles was also demonstrated by Mizuno.12 Moreover, Ueno
and Kuwano reported the β amination of ethyl ketones catalyzed by Nickel.13 The strategy involving copper salt
catalyzed dehydrogenative amination has been promoted by Su14 and Wu15. Especially, Wu’s work15 provided an
efficient procedure for the preparation of tetrasubstituted 1,4ꢀenedione derivatives, while the special structure of
1,4ꢀenediones limited the scope of this method. Based on the inspiration of the combination of Pd and
hypervalent iodine catalyzed the tandem Wacker oxidationꢀdehydrogenation16, we report herein iodide
anionꢀinitiated and Cuꢀcatalyzed inter/intramolecular Nꢀalkenylation of benzimidazoles through tandem processes
involving selective iodination of sp3 CꢀH bond at αꢀposition of ester under mild conditions.
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Scheme 1. NꢀAlkenylation of heterocycles.
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Results and Discussion
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Based on previous work17, we attempted to develop simple synthetic protocols for the construction of
ꢀalkenyl heterocycles through dual dehydrogenative amination. Our investigation started with the
N
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9
dehydrogenation coupling of easily available 1
reaction (Table 1). ( )ꢀButylꢀ3ꢀ(1 ꢀbenzo[ ]imidazoleꢀ1ꢀyl) acrylate (4a) was obtained in 75% isolated
yield when we submitted 1 ꢀbenzimidazoles (1a) and butyl acrylate (2a) in the presence of LiI,
Hꢀbenzimidazole (1a) and butyl acrylate (2a) as the model
E
H
d
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H
Cu(OAc)2·H2O as a catalyst, 2,2'ꢀbipyridine (BPY) as a ligand and DABCO (1,4ꢀdiaza bicycle [2.2.2]
octane) as an additive with O2 balloon in DMF at 100 °C for 48 h (Table 1, entry 1). The use of cumene,
recently reported for the dehydrogenative amination of phenols18, resulted in the formation of a trace
amount of 4a (entry 2). The mixture solvents of DMF and cumene were further screened by changing the
ratio of DMF/cumene (entries 3ꢀ4), and the best results showed that 4a was obtained in 84% isolated
yield at a DMF / cumene ratio of 9:1 (entry 4). Furthermore, various factors were evaluated regarding the
optimal condition. 4a was not isolated in the absence of LiI, while removing Cu(OAc)2·H2O led to a 30%
yield of the corresponding product 4a. Those results showed that the iodide would be critical for
dehydrogenation transformation (entries 5ꢀ6). Using LiCl in place of LiI did not afford the desired
product 4a to exclude the Lewis acid effect of lithium ion (entry 7). Moreover, replacing LiI with other
iodide salts and iodine, respectively, gave unsatisfactory results (entries 9ꢀ10). However KI was a
suitable replacement (entry 8). Especially, 4a could not been found in the presence of PhI(OAc)2, which
again verified that iodide anion might initiate this process (entry 11). Other copper catalysts such as
CuBr2, CuI and CuOAc were also suitable (entries 12ꢀ14) with the exception of Pd(OAc)2 that was found
to be inferior (entry 15). In addition, other relative factors were evaluated including the ligand, the O2
atmosphere, the additive as well as the reaction temperature and those results showed above factors
affected this transformation, to an extent (entries 16ꢀ20). Besides, 4a was obtained in 51% isolated yield
under the optimal condition of path B (entry 21). Certainly, 4a was not generated under the reaction
condition reported by Wu15 (entry 22). It may be briefly summarized that the reaction was initiated by
iodide anion and Cu(OAc)2·H2O as an important catalyst along with other factors together promoted this
transformation.
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Table 1. Optimization of path Aa.
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2
3
4
5
6
entry
catalyst
iodide/LiCl
solvent
4a(%)b
DMF
1
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
ꢀ
LiI
LiI
75
<10
55
7
8
9
cumene
DMF/cumene (5/5)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
3
LiI
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4
LiI
84
5
ꢀ
NPc
6
LiI
30
7
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuBr2
LiCl
KI
NPc
71
8
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF
9
Bu4NI
I2
<10
25
10
11
12
13
14
15
16d
17e
18f
19g
20h
21i
22j
PhI(OAc)2
LiI
NPc
80
CuI
LiI
71
CuOAc
LiI
77
Pd(OAc)2
LiI
33
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
LiI
78
LiI
50
LiI
58
LiI
37
LiI
62
LiI
51
ꢀ
NPc
DMSO
a1a (0.25 mmol), 2a (0.5 mmol), catalyst (0.025 mmol), iodide ions (2.5 mmol), 2,2'ꢀbipyridine (0.025 mmol),
o
b
DABCO (0.25 mmol) and solvent (1 mL) in a sealed tube under O2 balloon at 100 C for 48 h. isolated yields.
cNP = no desired product.dWithout 2,2'ꢀbipyridine. eUnder N2. fUnder air. gWithout DABCO. h80 oC. iThe optimal
condition of path B. j80 oC in DMSO under air (the condition of wu’s work15).
Interestingly, we found that 4a could be obtained coming from benzimidazole ester 3a. The
α,βꢀdehydrogenation of esters was regarded as an unmet challenge9c, thus we also investigated
α,βꢀdehydrogenation of 3a to optimize the protocol as shown in Table 2. The desired product 4a was obtained in
51% isolated yield via applying the optimal condition of path A (entry 1). Similarly to path A, 4a was not
generated from 3a in the absence of LiI (entry 2), which meant iodide anion also initiated this transformation
regarding α,βꢀdehydrogenation of 3a. A decrease in the amount of LiI also led to the poor performance (entry 3).
Replacing the mixed solvent with pure cumene gave the unsatisfactory result (entry 4), whereas using pure DMF
afforded the desired product 4a in 70% isolated yield (entry 5). Furthermore, the effect of 2,2'ꢀbipyridine ligand
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and Cu(OAc)2·H2O catalyst was also evaluated respectively (entries 6ꢀ7), those results showed that the catalyst
was necessary for this transformation yet the ligand was unnecessary. Both the O2 atmosphere and DABCO also
played assistant roles as shown in entries 8ꢀ9. Owing to the presence of 1Hꢀbenzimidazole coming from the CꢀN
bond cleavage of benzimidazole ester 3a, the extra addition of butyl acrylate 2a could slightly improve this
transformation in 79% isolated yield (entry 10).
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Table 2. Optimization of path Ba
entry
catalyst
iodide
solvent
4a(%)b
DMF/cumene (9/1)
DMF/cumene (9/1)
DMF/cumene (9/1)
cumene
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2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
ꢀ
LiI
ꢀ
51
NPc
36
<10
70
72
3
LiId
LiI
LiI
LiI
LiI
LiI
LiI
LiIh
4
DMF
5
6e
7e
8ef
9eg
10eh
DMF
DMF
9
DMF
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
15
DMF
22
DMF
79
a3a (0.25 mmol), catalyst (0.025 mmol), LiI (2.5 mmol), 2,2'ꢀbipyridine (0.025 mmol), DABCO (0.25
o
b
mmol) and solvent (1 mL) in a sealed tube under O2 balloon at 100 C for 48 h. isolated yields. cNP = no
d
e
f
h
desired product. LiI (1.25 mmol). Without 2,2'ꢀbipyridine. Under N2. gWithout DABCO. Extra
n
ꢀbutylacrylate 2a (0.25 mmol) was added.
The substrate scope of intermolecular Nꢀalkenylation reaction was investigated using a range of benzimidazole
derivatives 1 and acrylates 2 under the optimal condition of path A, as shown in Scheme 2. The desired product of
4a was confirmed by Xꢀray crystallographic analysis. 5,6ꢀDimethylꢀ1Hꢀbenzo[d]imidazole afforded the
corresponding product 4b in 73% isolated yield. 1HꢀNaphtho[2,3ꢀd]imidazole also underwent the transformation
to give the target product 4c in 75% isolated yield. Owing to the tautomerism, benzimidazole derivatives bearing
the single substituent on the phenyl led to a tautomeric mixture. Benzimidazole derivatives possessing various
substituents on the phenyl, such as methylꢀ, nitrylꢀ, ester and halogen groups were suitable to provide
corresponding products 4d(d’)-4h(h’) in moderate to good yields, in which each isomer of benzimidazoles (4f
and 4f’, 4g and 4g’, 4h and 4h’) was independently isolated for the first time.The above results showed that the
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intermolecular Nꢀalkenylation reaction，possessing excellent functional group tolerance, was compatible with
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electronꢀrich and electronꢀdeficient phenyl rings of benzimidazole derivatives. The 2ꢀsubstituent of
benzimidazole apparently decreased this transformation owing to the steric hindrance effect. For example, the
treatment of 2ꢀmethylbenzimidazole and 2ꢀphenylbenzimidazole led to corresponding products 4i and 4j in 25%
and 55% isolated yields, respectively. Moreover, other Nꢀcontaining heterocyclic compounds, such as imidazole,
indole and benzotriazole were screened under the suitable condition. Although the result of indole reacting with
2a was unsatisfactory, imidazole and benzotriazole smoothly transformed into corresponding products 4k and 4m
in moderate yields without isomers. Subsequently, the scope of α,βꢀunsaturated esters was explored via the
treatment of 1Hꢀbenzimidazole 1a and various acrylates. Acrylates bearing functional groups, such as ethyl,
benzyl, tertꢀbutyl, 2ꢀmethoxyethyl, trifluoroethyl, cyclohexyl and tetrahydrofurfuryl groups, provided
corresponding products (4nꢀ4t) in moderate to good yields. The steric hindrance of alkenes obviously reduced
this transformation (4uꢀ4w). Although target products were obtained in low yields, this approach compensated for
limitations of traditional methods, such as 4v and 4w, which could not be synthesized through nucleophilic
addition of Nꢀheterocycles to alkynes. Furthermore, other α,βꢀunsaturated compounds such as ethyl vinyl ketone,
acrylamide and acrylonitrile were respectively tested, and the results showed that three compounds were tolerant
and acrylonitrile performed good reactivity under suitable conditions (4x-4z).
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Scheme 2. Scope of Path Aa
4a 84%
Xꢀray structure of 4a
4b 73%
4c 75%
4d: 4d' 82%, (1:1)c
4e: 4e', 50%, (61:39)c
4f 58% + 4f' 10%
4i 25%
4g 42% + 4g' 42%
4k 39%b
4j 55%
4h 39% + 4h' 39%
4l trace
4m 54%
O
N
O
N
R5= Et,
4n 79%
4o 42%b
4p 39%
4q 56%
4r 32%b
4s 65%
4u trace
4t 55%
R5 = Bn,
O
R5 = tBu,
R5 = (CH2 )2 OMe,
R5 = CH2CF3,
R5 = Cy,
O
N
N
4w 30%b
4v 24%
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4z 42%d
4x <10%
4y <10%
a1 (0.25 mmol), 2 (0.5 mmol), Cu(OAc)2·H2O (0.025 mmol), LiI (2.5 mmol), 2,2'ꢀbipyridine (0.025 mmol),
DABCO (0.25 mmol) and solvent (1 mL) in a sealed tube at 100 oC under O2 balloon for 17 to 48 h with isolated
yields; bKI (2.5 mmol) instead of LiI (2.5 mmol); cThe ratio is determined by 1H NMR. d Acrylonitrile (1.0 mmol)
was added.
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Furthermore, the intramolecular Nꢀalkenylation reaction was selectively explored under the optimal condition
of path B, as shown in Scheme 3. Desired products of 4a and 4b were obtained in 79% and 65% isolated yields,
respectively. Each isomer of Nꢀalkenyl benzimidazole derivatives (4h and 4h’) was independently isolated in
moderate yields. Butyl 3ꢀ(2ꢀmethylꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl) propanoate afforded the corresponding product 4i
in poor yield, which meant that the steric hindrance had obvious inhibitory effect on this transformation.
Additionally, (E)ꢀethylꢀ3ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl) acrylate 4n was obtained in 61% isolated yield.
Scheme 3. Scope of Path Ba
4a 79%
4b 65%
4h 35% + 4h' 35%
O
OEt
N
N
4n 61%
4i 13%
a3 (0.25 mmol), corresponding acrylate 2 (0.25 mmol), Cu(OAc)2·H2O (0.025 mmol), LiI (2.5 mmol), DABCO
(0.25 mmol) and solvent (1 mL) in a sealed tube at 100 oC under O2 balloon for 30 to 60 h with isolated yields.
We further had insight into the mechanism besides the correlation between intermolecular reaction and
intramolecular reaction under the optimal condition of path A. The reaction progress was monitored by LC, and
overall kinetic profiles of intermolecular and intramolecular reaction were presented in Figure 1. Regarding
intermolecular reaction (Figure 1a), the rate of reaction of 1a and 2a was quite fast, in which 3a and 4a were
produced in approximate 50 % and 20% LC yields at 4 min. Subsequently, the decrease of 3a and the increase of
4a processed simultaneously after oneꢀhour reaction time. Those results illustrated that the intermolecular
reaction might mainly undergo tandem azaꢀMichael addition and α,βꢀdehydrogenation process. Moreover, the
result of the intramolecular reaction of 3a transforming to 4a also verified the α,βꢀdehydrogenation of
benzimidazole ester 3a as shown in Figure 1b.
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(a)
(b)
Figure 1. Overall kinetic profiles of intermolecular reaction and intramolecular reaction
Scheme 4. Control experimental results
In addition, various control experiments were conducted to explore the mechanism (Scheme 4). Compared with
Lei’s work19, the control experiment of using TEMPO indicated that the transformation was not involved in free
radicals (equation 1). We further investigated the α,βꢀdehydrogenation mechanism. When the reaction of 1a and
2a was dealt under standard condition at room temperature for 10 minutes, 3a, 4a and αꢀiodo benzimidazole ester
5a were obtained in 18%, 13%, 14% isolated yields, respectively (equation 2). The treatment of 1a and 2a with
LiI led to 3a, 4a and 5a in 66%, 11% and 4% isolated yields, respectively (equation 3). Dealing with 3a in the
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presence of LiI gave 4a and 5a in 3% and 7% isolated yields, respectively, accompanying with a large amount of
substrate 3a (equation 4). Owing to αꢀiodo ester20 5a isolated from both intermolecular and intramolecular
reactions, various control experiments of 5a were investigated (equation 5). The compound 5a under the optimal
condition of path A without iodide anion smoothly transferred to 4a with 92% isolated yield, which showed that
αꢀiodo benzimidazole ester 5a, as a vital intermediate participating in this transformation (equation 5, entry1).
Control experiments at R.T. and without DABCO performed inferior reactivity (equation 5, entries 2ꢀ3), while the
control experiment without Cu(OAc)2·H2O and BPY also afforded 4a with 92% isolated yield (equation 5, entry
4). Those results showed that both DABCO and heating promoted the dehydrohalogenation of αꢀiodo
benzimidazole ester 5a. Owing to the exothermic phenomenon of LiI dissolving in DMF, 4a was generated by the
dehydrohalogenation of 5a as shown in equations 3 and 4. Besides, other control experiments (equation 5, entries
5ꢀ6) illustrated the stability of αꢀiodo ester 5a without basic compounds and heating, to an extent. In short,
regarding intermolecular reaction, the process would primarily include tandem azaꢀMichael addition, selective
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iodination of CꢀH bond and dehydrohalogenation (Scheme 5, Route I) and an alternative path could not been
excluded (Scheme 5, Route III); whereas intramolecular formal α,βꢀdehydrogenation of benzimidazole esters
involved selective iodination of CꢀH bond and dehydrohalogenation (Scheme 5, Route II). Especially, as for the
effect of copper catalyst21, according to the result of screening condition (Table 2, entry 7), the absence of
Cu(OAc)2·H2O gave 4a with 9% isolated yield, which showed preliminarily that copper catalyst could promote
selective iodination of sp3 CꢀH bond at αꢀposition of benzimidazole ester. The detailed mechanism involving
copper catalyst is under investigation in our group.
Scheme 5. The process of Nꢀalkenylation of benzimidazoles.
Conclusion
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In conclusion, we have demonstrated the CꢀN bond formation of Nꢀalkenyl benzimidazoles via intermolecular
tandem azaꢀMichael addition, occurred from iodination of CꢀH bond and dehydrohalogenation as well as
intramolecular formal α,βꢀdehydrogenation of benzimidazole esters initiated by iodide anion under copper
catalysis. We believed that this protocol described here would provide a viable methodology for synthesizing a
series of potential biologically active Nꢀalkenyl azole derivatives. Further studies of functionalizing
benzimidazoles and other heterocycles are future goals of our group.
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EXPERIMENTAL SECTION
General Information
Reagents and solvents were purchased from commercial sources and were used without further purification. Butyl
3ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl)propanoate (3a), butyl 3ꢀ(5,6ꢀdimethylꢀ 1Hꢀbenzo[d]imidazolꢀ1ꢀyl)propanoate (3b),
butyl 3ꢀ(2ꢀmethylꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl)propanoate (3i) butyl 3ꢀ(5ꢀchloroꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl)
propanoate (3g) and butyl 3ꢀ(6ꢀchloroꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl)propanoate (3g’) ethyl 3ꢀ(1Hꢀbenzo[d]
imidazolꢀ1ꢀyl)propanoate (3o)17, ethyl 1Hꢀbenzimidazoleꢀ5ꢀcarboxylate22 and 1Hꢀnaphtho[2,3ꢀd]imidazole23 were
prepared according to published procedures. NMR Spectra were recorded on 400 or 600 MHz NMR
spectrometers. The chemical shift is given in dimensionless δ values and is frequency referenced relative to TMS
in 1H and 13C NMR spectroscopy. Chemical shifts are reported relative to CDCl3 (δ =7.26 ppm) for 1H NMR and
relative to CDCl3 (δ =77 ppm) for 13C NMR. Peak multiplicities were recorded as follows: s = singlet, d = doublet,
t = triplet, m = multiplet or unresolved, br = broad singlet. FTꢀIR spectra were tested by using KBr pellets in the
400ꢀ4000 cmꢀ1 range. High resolution mass spectra were obtained from QꢀTOF instrument by electrospray
ionization (ESI). A polarꢀembedded reversed phase stationary phaseꢀcolumn (250*4.6mm, analytical Column) was
prepared in HPLC analyses. (Solvent: H2O (0.1% HCOOH): MeCN (0.1% HCOOH) = 1:1, flow rate = 0.8mL/min,
λ = 205 nm, 30 oC). Unless otherwise stated, all reactions were conducted in sealed tube under an atmosphere of
oxygen balloon.
General experiments of path A for the synthesis of compounds 4
Benzimidazole derivatives (0.25 mmol), acrylates (0.5 mmol), 2,2'ꢀbipyridine (0.025 mmol, 10 mol%),
Cu(OAc)2·H2O (0.025 mmol, 10 mol%), LiI (2.5 mmol), DABCO (1,4ꢀdiazabicyclo[2.2.2]octane) (0.25 mmol),
DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube under an atmosphere
of oxygen balloon. The mixture was stirred at 100 °C for required time. After cooled to room temperature, the
mixture was added the appropriate amount of Na2S2O3, as monitored by TLC, and the resulting mixture was
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partitioned between water and ethyl acetate, and the separated aqueous layer extracted with ethyl acetate (2
mL×3). The combined organic layers were washed with brine (2 mL×3), dried over anhydrous Na2SO4, filtered,
and evaporated under reduced pressure. The residue was purified by flash column chromatography on neutral
Al2O3, eluting with EA/PE (1:15 to 1:5) to afford compounds 4.
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General experiments of path B for the synthesis of compounds 4
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3ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl)propanoates (0.25 mmol), corresponding acrylates (0.25 mmol), Cu(OAc)2·H2O
(0.025 mmol, 10 mol%), LiI (2.5 mmol) and DABCO (0.25 mmol), and DMF (1 mL) as noted were put into the
10 mL sealed tube under an atmosphere of oxygen balloon. The mixture was stirred at 100 °C for required time.
The reaction was added the right amount of Na2S2O3, as monitored by TLC, and the resulting mixture was
partitioned between water and ethyl acetate, and the separated aqueous layer extracted with ethyl acetate (2
mL×3). The combined organic layers were washed with brine (2 mL×3), dried over anhydrous Na2SO4, filtered,
and evaporated under reduced pressure. The residue was purified by flash column chromatography on neutral
Al2O3, eluting with EA/PE (1:15 to 1:5) to afford compounds 4.
Synthesis of compound butyl 3-(1H-benzo[d]imidazol-1-yl)-2-iodopropanoate 5a
1HꢀBenzimidazole (0.25 mmol), butyl acrylate (0.5 mmol), 2,2'ꢀbipyridine (0.025 mmol, 10 mol%),
Cu(OAc)2·H2O (0.025 mmol, 10 mol%), LiI (2.5 mmol), DABCO (1,4ꢀdiazabicyclo[2.2.2]octane) (0.25 mmol),
DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube under air. The reaction
mixture was stirred at room temperature for 10 minutes. The mixture was added the right amount of Na2S2O3, as
monitored by TLC, and the resulting mixture was partitioned between water and ethyl acetate, and the separated
aqueous layer extracted with ethyl acetate (2 mL×3). The combined organic layers were washed with brine (2
mL×3), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified
by flash column chromatography on neutral Al2O3, eluting with EA/PE (1:25 to 1:5) to afford intermediate 5a
(yellow oil, 13 mg, 14%). 1H NMR (600 MHz, CDCl3) δ = 8.08 (s, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.41 (d, J = 6.9
Hz, 1H), 7.38ꢀ7.28 (m, 2H), 4.93ꢀ4.83 (t, J = 12Hz, 1H), 4.80ꢀ4.50 (m, 2H), 4.20ꢀ3.95 (m, 2H), 1.54 (m, 2H),
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1.33ꢀ1.23 (m, 2H), 0.87 (t, J = 6.8 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 168.8, 142.5, 142.1, 132.1,
122.7, 122.0, 119.5, 108.3, 65.4, 48.2, 29.1, 17.9, 14.1, 12.5 ppm; HRMS (ESI/TOFꢀQ) m/z Calcd for
C14H17IN2O2 [M + H]+: 373.0407, Found 373.0411.
General experiments from intermediate 5a to compound 4a
Butyl 3ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl)ꢀ2ꢀiodopropanoate 5a (0.16 mmol), Cu(OAc)2·H2O (0.016 mmol, 10 mol%),
DABCO (0.16 mmol), DMF (0.576 mL) and cumene (0.064 mL) as mixed solvent were put into the 10 mL sealed
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tube under an atmosphere of oxygen balloon. The mixture was stirred at 100 °C for 0.5 h. The reaction was added
the right amount of Na2S2O3, as monitored by TLC, and the resulting mixture was partitioned between water and
ethyl acetate, and the separated aqueous layer extracted with ethyl acetate (2 mL×3). The combined organic layers
were washed with brine (2 mL×3), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure.
The residue was purified by flash column chromatography on neutral Al2O3, eluting with EA/PE (1:15 to 1:5) to
afford compound 4a.
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(E)-Butyl 3-(1H-benzo[d]imidazol-1-yl) acrylate (4a): The title compound could be prepared according to
general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
eluted with EA/PE (1:15 to 1:5) to afford a white solid (51 mg, 84%).
The reaction also was conducted with modifications to the general procedure B for 48 h. The crude product was
purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid
(48 mg, 79%).
The third method was butyl 3ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl)ꢀ2ꢀiodopropanoate (0.16 mmol) as reactant,
Cu(OAc)2·H2O (0.016 mmol, 10 mol%), DABCO (0.16 mmol), DMF (0.576 mL) and cumene (0.064 mL) as
mixed solvent were put into the 10 mL sealed tube under an atmosphere of oxygen balloon. The mixture was
stirred at 100 °C for 0.5 h. The reaction was added the right amount of Na2S2O3, as monitored by TLC, and the
resulting mixture was partitioned between water and ethyl acetate, and the separated aqueous layer extracted with
ethyl acetate (2 mL×3). The combined organic layers were washed with brine (2 mL×3), dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash column
chromatography on neutral Al2O3, eluting with EA/PE (1:15 to 1:5) to afford a white solid (42 mg, 92%), m.p.:
69ꢀ71 oC. 1H NMR (600 MHz, CDCl3) δ = 8.21 (s, 1H), 8.15 (d, J = 14.4 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.65
(d, J = 7.9 Hz, 1H), 7.41 (dt, J = 18.0, 7.4 Hz, 2H), 6.32 (d, J = 14.4 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 1.74ꢀ1.68
(m, 2H), 1.49ꢀ1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 166.4, 144.6, 141.6,
135.4, 132.2, 125.0, 124.3, 121.2, 111.1, 106.0, 64.9, 30.8, 19.2, 13.7 ppm; IR (KBr) υ 3088, 3058, 3030, 2956,
2871, 1711, 1649, 1461, 1402, 1269, 1195, 1164, 1111, 742 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C14H16N2O2
[M + Na]+ : 267.1104, Found: 267.1093.
(E)-Butyl 3-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl) acrylate (4b): The title compound could be prepared
according to general procedure A for 48 h. The crude product was purified by column chromatography on neutral
Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid (50 mg, 73%).
The reaction also was conducted with modifications to the general procedure B for 60 h. The crude product was
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purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid
(44 mg, 65%), m.p.: 100ꢀ102oC. 1H NMR (600 MHz, CDCl3) δ = 8.22 (s, 1H), 8.09 (d, J = 14.4 Hz, 1H), 7.65 (s,
1H), 7.40 (s, 1H), 6.30 (d, J = 14.4 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 1.75ꢀ1.68 (m, 2H),
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1.50ꢀ1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.4, 142.1, 141.5, 135.5,
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2870, 1702, 1650, 1513, 1200, 1161, 854 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C16H20N2O2 [M + Na]+:
295.1417, Found: 295.1415.
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(E)-Butyl 3-(1H-naphtho[2,3-d]imidazol-1-yl) acrylate (4c): The title compound could be prepared according
to general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
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eluted with EA/PE (1:15 to 1:5) to afford a white solid (55 mg, 75%), m.p.: 141ꢀ143 C. H NMR (600 MHz,
CDCl3) δ = 8.27 (d, J = 5.6 Hz, 2H), 8.19 (d, J = 14.3 Hz, 1H), 7.98 (dd, J = 17.9, 7.9 Hz, 3H), 7.54ꢀ7.44 (m, 2H),
6.34 (d, J = 14.3 Hz, 1H), 4.28 (t, J = 6.7 Hz, 2H), 1.78ꢀ1.69 (m, 2H), 1.53ꢀ1.43 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H)
ppm; 13C NMR (151 MHz, CDCl3) δ = 166.6, 145.3, 144.1, 135.5, 132.0, 131.4, 131.0, 128.6, 127.9, 125.7, 124.9,
118.7, 108.2, 104.8, 64.8, 30.9, 19.2, 13.8 ppm; IR (KBr) υ 3123, 3055, 2960, 2871, 1707, 1636, 1517, 1449,
1356, 1272, 1183, 1162, 1111, 985, 751 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C18H18N2O2 [M + H]+: 295.1441,
Found: 295.1438.
(E)-Butyl 3-(5-methyl-1H-benzo[d]imidazol-1-yl)acrylate (4d) and (E)-Butyl 3-(6-methyl-1H-benzo
[d]imidazol-1-yl)acrylate (4d'): The title compounds could be prepared according to general procedure A.
5ꢀMethylbenzimidazole (33 mg, 0.25 mmol), butyl acrylate (64 mg, 72 µL, 0.5 mmol), 2,2'ꢀbipyridine (4 mg,
0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), LiI (333 mg, 2.5 mmol), DABCO (28 mg,
0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube under an
atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 48 h. The crude product was
purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid
(52 mg, 81%, 4d: 4d' = 1: 1). 1H NMR (600 MHz, CDCl3) δ = 8.18 (m, 4H), 7.70 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H),
7.52 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.32ꢀ6.27 (m, 2H),
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4.28ꢀ4.22 (m, 4H), 2.53 (s, 3H), 2.50 (s, 3H), 1.75ꢀ1.68 (m, 4H), 1.50ꢀ1.41 (m, 4H), 1.01ꢀ0.92 (m, 6H) ppm; C
NMR (151 MHz, CDCl3) δ = 166.53, 166.52, 145.0, 142.7, 141.8, 141.1, 135.6, 135.5, 135.3, 134.4, 132.4, 130.2,
126.3, 125.8, 121.0, 120.6, 111.2, 110.8, 105.6, 105.5, 64.83, 64.81, 30.8, 21.9, 21.5, 19.2, 13.7 ppm; IR (KBr) υ
3105, 3051, 2963, 2870, 1708, 1647, 1504, 1354, 1267, 1183, 812 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for
C15H18N2O2 [M + Na]+: 281.1261, Found: 281.1256.
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(E)-Ethyl 1-(3-butoxy-3-oxoprop-1-en-1-yl)-1H-benzimidazole-5-carboxylate (4e) and (E)-Ethyl 1-(3-
butoxy-3-oxoprop-1-en-1-yl)-1H-benzimidazole-6-carboxylate (4e’): The title compound could be prepared
according to general procedure A. Ethyl 1Hꢀbenzimidazoleꢀ5ꢀcarboxylate (47 mg, 0.25 mmol), butyl acrylate (64
mg, 72 µL, 0.5 mmol), 2,2'ꢀbipyridine (4 mg, 0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10
mol%), LiI (333 mg, 2.5 mmol), DABCO (28 mg, 0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed
solvent were put into the 10 mL sealed tube under an atmosphere of oxygen balloon. The reaction mixture was
stirred at 100 °C for 48 h. After extraction and evaporation, the crude product was purified by column
chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid (40 mg, 50%, 4e :
4e’ = 61 : 39). 1H NMR (600 MHz, CDCl3) δ = 8.54 (s, 1H), 8.37 (d, J = 10.3 Hz, 2H), 8.31 (s, 1H), 8.23ꢀ8.07 (m,
4H), 7.90ꢀ7.60 (m, 2H), 6.40 (d, J = 14.4 Hz, 1H), 6.36 (d, J = 14.4 Hz, 1H), 4.49ꢀ4.39 (m, 4H), 4.27 (d, J = 4.0
Hz, 4H), 1.72 (d, J = 6.1 Hz, 4H), 1.51ꢀ1.40 (m, 10H), 0.99 (d, J = 1.4 Hz, 6H) ppm; 13C NMR (151 MHz, CDCl3)
δ = 166.34, 166.32, 166.10, 166.05, 147.6, 144.2, 143.7, 142.7, 135.2, 134.9, 134.8, 132.1, 127.4, 127.0, 126.4,
125.6, 123.2, 120.8, 113.0, 110.7, 107.3, 65.0, 61.4, 61.2, 30.8, 19.2, 14.41, 14.37, 13.7 ppm; IR (KBr) υ 3082,
2961, 2873, 1715, 1652, 1502, 1284, 1191, 1025, 769 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C17H20N2O4 [M +
Na]+: 339.1315, Found: 339.1305.
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(E)-Butyl 3-(5-nitro-1H-benzo[d]imidazol-1-yl) acrylate (4f): The title compound could be prepared according
to general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
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eluted with EA/PE (1:25 to 1:7) to afford a yellow solid (42 mg, 58%), m.p.: 137ꢀ139 C. H NMR (600 MHz,
CDCl3) δ = 8.74 (d, J = 1.4 Hz, 1H), 8.42 (s, 1H), 8.36 (dd, J = 8.9, 1.7 Hz, 1H), 8.16 (d, J = 14.4 Hz, 1H), 7.75 (d,
J = 9.0 Hz, 1H), 6.43 (d, J = 14.4 Hz, 1H), 4.28 (t, J = 6.7 Hz, 2H), 1.76ꢀ1.69 (m, 2H), 1.50ꢀ1.41 (m, 2H), 0.99 (t, J
= 7.4 Hz, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 165.6, 145.1, 144.1, 136.2, 134.2, 120.5, 117.6, 111.0, 108.8,
77.3, 77.1, 76.9, 65.3, 30.7, 19.2, 13.7 ppm; IR (KBr) υ 3103, 3042, 2962, 2872, 1708, 1652, 1524, 1347, 1262,
1204, 1166, 952, 736 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C14H15N3O4 [M + Na]+: 312.0955 Found: 312.0947.
(E)-Butyl 3-(6-nitro-1H-benzo[d]imidazol-1-yl) acrylate (4f'): The title compound could be prepared according
to general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
eluted with ethyl acetate/petroleum ether (1/25 to 1/5) to afford a yellow solid (7 mg, 10%), m.p.: 119ꢀ121 oC. 1H
NMR (600 MHz, CDCl3) δ = 8.61 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 14.4 Hz, 1H), 7.95
(d, J = 8.8 Hz, 1H), 6.43 (d, J = 14.4 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 1.77ꢀ1.70 (m, 2H), 1.51ꢀ1.43 (m, 2H),
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0.99 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 165.6, 148.7, 145.6, 145.2, 134.2, 131.8, 121.5,
119.9, 108.7, 107.9, 65.3, 30.7, 19.2, 13.7 ppm; HRMS (ESI/TOFꢀQ) m/z Calcd for C14H15N3O4 [M + H]+:
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290.1135, Found: 290.1139.
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Al2O3 and eluted with EA/PE (1:25 to 1:5) to afford a white solid (27 mg, 42%), m.p.: 87ꢀ89 C. H NMR (600
MHz, CDCl3) δ = 8.25 (s, 1H), 8.11 (d, J = 14.4 Hz, 1H), 7.59 (dd, J = 8.9, 4.3 Hz, 1H), 7.54 (dd, J = 8.7, 2.2 Hz,
1H), 7.18 (td, J = 9.0, 2.3 Hz, 1H), 6.32 (d, J = 14.4 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 1.74ꢀ1.68 (m, 2H),
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1.49ꢀ1.42 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.2, 160.3 (d, JCꢀF = 241.6
Hz), 145.0, 143.1, 135.1, 128.7, 113.3 (d, JCꢀF = 27.2Hz), 111.7 (d, JCꢀF = 10.6 Hz), 107.3 (d, JCꢀF =24.2 Hz), 106.7,
65.0, 30.8, 19.2, 13.7 ppm; IR (KBr) υ 3125, 3078, 3044, 2961, 2873, 1708, 1650, 1486, 1251, 1213, 1174, 956,
835 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C14H15FN2O2 [M + Na]+: 285.1010, Found:. 285.1008.
(E)-Butyl 3-(6-fluoro-1H-benzo[d]imidazol-1-yl) acrylate (4g'): The title compound could be prepared
according to general procedure A for 48 h. The crude product was purified by column chromatography on neutral
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Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid (27 mg, 42%), m.p.: 86ꢀ88 C. H NMR (600
MHz, CDCl3) δ = 8.22 (s, 1H), 8.07 (d, J = 14.4 Hz, 1H), 7.80 (dd, J = 8.6, 4.7 Hz, 1H), 7.35 (dd, J = 8.3, 1.7 Hz,
1H), 7.14 (td, J = 9.1, 2.1 Hz, 1H), 6.29 (d, J = 14.4 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 1.75ꢀ1.68 (m, 2H),
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1.49ꢀ1.42 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.1, 160.8 (d, JCꢀF = 244.6
Hz), 142.1, 140.6, 134.9, 132.5, 122.0 (d, JCꢀF = 9.1 Hz), 112.8 (d, JCꢀF = 25.7 Hz), 107.0, 98.5 (d, JCꢀF = 28.7 Hz),
65.0, 30.8, 19.2, 13.7 ppm; HRMS (ESI/TOFꢀQ) m/z Calcd for C14H15FN2O2 [M + H]+: 263.1190, Found:.
263.1197.
(E)-Butyl 3-(5-chloro-1H-benzimidazol-1-yl) acrylate (4h)23: The title compound could be prepared according
to general procedure A 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
eluted with EA/PE (1:15 to 1:5) to afford a white solid (27 mg, 39%).
The reaction also was conducted with modifications to the general procedure B. The mixture of butyl
3ꢀ(5ꢀchloroꢀ1Hꢀbenzimidazolꢀ1ꢀyl)propanoate and butyl 3ꢀ(6ꢀchloroꢀ1Hꢀbenzoimidazolꢀ1ꢀyl)propanoate (70 mg,
0.25 mmol), butyl acrylate (32 mg, 37 µL, 0.25 mmol), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), LiI (333
mg, 2.5 mmol), DABCO (28 mg, 0.25 mmol), DMF (1 mL) as solvent were put into the 10 mL sealed tube under
an atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 30 h. After extraction and
evaporation, the crude product was purified by column chromatography on neutral Al2O3 and eluted with EA/PE
(1:20 to 1:5) to afford a white solid (24 mg, 35%). m.p.: 121ꢀ123 oC. 1H NMR (600 MHz, CDCl3) δ = 8.24 (s, 1H),
8.10 (d, J = 14.4 Hz, 1H), 7.84 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.42ꢀ7.37 (m, 1H), 6.32 (d, J = 14.4 Hz, 1H), 4.26
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(t, J = 6.7 Hz, 2H), 1.74ꢀ1.68 (m, 2H), 1.50ꢀ1.40 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm;13C NMR (151 MHz, CDCl3)
δ = 166.1, 145.1, 142.8, 134.9, 130.8, 130.2, 125.5, 121.0, 111.9, 107.1, 65.0, 30.8, 19.2, 13.7 ppm; IR (KBr) υ
3135, 3089, 2959, 2872, 1706, 1650, 1502, 1467, 1399, 1360, 1204, 1167, 1063, 805, 656 cmꢀ1; HRMS
(ESI/TOFꢀQ) m/z Calcd for C14H15ClN2O2 [M + H]+: 279.0895, Found: 279.0893.
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(E)-Butyl 3-(6-chloro-1H-benzimidazol-1-yl) acrylate (4h')23: The title compound could be prepared according
to general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
eluted with EA/PE (1:15 to 1:5) to afford a white solid (27 mg, 39%).
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The reaction also was conducted with modifications to the general procedure B. The mixture of butyl
3ꢀ(5ꢀchloroꢀ1Hꢀbenzimidazolꢀ1ꢀyl)propanoate and butyl 3ꢀ(6ꢀchloroꢀ1Hꢀbenzimidazolꢀ1ꢀyl)propanoate (70 mg,
0.25 mmol), butyl acrylate (32 mg, 37 µL, 0.25 mmol), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), LiI (333
mg, 2.5 mmol), DABCO (28 mg, 0.25 mmol), DMF (1 mL) as solvent were put into the 10 mL sealed tube under
an atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 30 h. After extraction and
evaporation, the crude product was purified by column chromatography on neutral Al2O3 and eluted with EA/PE
(1:20 to 1:5) to afford a white solid (24 mg, 35%), m.p.: 90ꢀ92 oC. 1H NMR (600 MHz, CDCl3) δ = 8.22 (s, 1H),
8.08 (d, J = 14.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.38ꢀ7.34 (m, 1H), 6.31 (d, J = 14.4 Hz, 1H),
4.26 (t, J = 6.7 Hz, 2H), 1.75ꢀ1.68 (m, 2H), 1.51ꢀ1.41 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (151 MHz,
CDCl3) δ = 166.0, 142.9, 142.2, 134.8, 132.8, 131.1, 125.1, 121.9, 111.5, 107.1, 65.0, 30.8, 19.2, 13.7 ppm;
HRMS (ESI/TOFꢀQ) m/z Calcd for C14H15ClN2O2 [M + H]+: 279.0895, Found: 279.0894.
(E)ꢀButyl 3-(2-methyl-1H-benzo[d]imidazol-1-yl) acrylate (4i): The title compound could be prepared
according to general procedure A for 48 h. The crude product was purified by column chromatography on neutral
Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid (16 mg, 25%).
The reaction also was conducted with modifications to the general procedure B for 48 h. The crude product was
purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid
(9 mg, 13%), m.p.: 70ꢀ72 oC. 1H NMR (600 MHz, CDCl3) δ = 8.10 (d, J = 14.3 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J
= 6.0, 2.4 Hz, 1H), 7.36ꢀ7.30 (m, 2H), 6.35 (d, J = 14.3 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 2.75 (s, 3H), 1.76ꢀ1.68
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(m, 2H), 1.50ꢀ1.42 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.8, 152.4, 143.2,
135.9, 133.1, 124.22, 124.18, 120.0, 111.9, 107.0, 64.9, 30.8, 19.2, 14.9, 13.7 ppm; IR (KBr) υ 3061, 2959, 2873,
1715, 1649, 1611, 1553, 1459, 1380, 1276, 1152, 955, 741 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C15H18N2O2
[M + H]+: 259.1441, Found: 259.1437.
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(E)-Butyl 3-(2-phenyl-1H-benzo[d]imidazol-1-yl) acrylate (4j): The title compound could be prepared
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Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid (44 mg, 55%), m.p.: 80ꢀ82 C. H NMR (600
MHz, CDCl3) δ = 8.16 (d, J = 14.4 Hz, 1H), 7.87 (dd, J = 6.2, 2.8 Hz, 1H), 7.75 (ddd, J = 9.4, 7.5, 4.0 Hz, 3H), 7.56
(dd, J = 6.8, 3.5 Hz, 3H), 7.44ꢀ7.39 (m, 2H), 6.41 (d, J = 14.4 Hz, 1H), 4.21 (t, J = 6.6 Hz, 2H), 1.70ꢀ1.63 (m, 2H),
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1.48ꢀ1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.6, 154.3, 144.0, 137.8,
133.5, 130.6, 130.1, 129.1, 129.0, 124.6, 124.5, 120.8, 112.4, 107.8, 64.7, 30.7, 19.2, 13.7 ppm; IR (KBr) υ 3059,
2953, 2869, 1716, 1648, 1541, 1455, 1377, 1283, 1185, 1185, 820, 737, 698 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd
for C20H20N2O2 [M + Na]+: 343.1417, Found: 343.1403.
(E)-Benzyl 3-(1H-imidazol-1-yl) acrylate (4k): The title compound could be prepared according to general
procedure A. 1Hꢀimidazole (17 mg, 0.25 mmol), benzyl acrylate (81 mg, 75 µL, 0.5 mmol), 2,2'ꢀbipyridine (4 mg,
0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), KI (415 mg, 2.5 mmol), DABCO (28 mg,
0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube under an
atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 17 h. After extraction and
evaporation, the crude product was purified by column chromatography on neutral Al2O3 and eluted with ethyl
o
EA/PE (1:15 to 1:5) to afford a white solid (22 mg, 39%), m.p.: 91ꢀ93 C. H NMR (600 MHz, CDCl3) δ = 7.91
(d, J = 14.2 Hz, 1H), 7.77 (s, 1H), 7.42ꢀ7.32 (m, 5H), 7.23 (s, 1H), 7.18 (s, 1H), 6.10 (d, J = 14.2 Hz, 1H), 5.24 (s,
13
2H) ppm; C NMR(151 MHz, CDCl3) δ = 165.7, 138.1, 136.9, 135.7, 132.0, 128.7, 128.5, 128.4, 116.4, 106.8,
66.8 ppm; IR (KBr) υ 3144, 3125, 3090, 3061, 2921, 1704, 1652, 1498, 1218, 1168, 1020, 961, 878, 736 cmꢀ1;
HRMS (ESI/TOFꢀQ) m/z Calcd for C13H12N2O2 [M + Na]+: 251.0791, Found: 251.0802.
(E)-Butyl 3-(1H-benzo[d][1,2,3]triazol-1-yl) acrylate (4m): The title compound could be prepared according to
general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
eluted with EA/PE (1:15 to 1:5) to afford a white solid (33 mg, 54%), m.p.: 65ꢀ67oC. 1H NMR (600 MHz, CDCl3)
δ = 8.51 (d, J = 14.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.49 (t, J
= 7.6 Hz, 1H), 6.76 (d, J = 14.3 Hz, 1H), 4.28 (t, J = 6.7 Hz, 2H), 1.76ꢀ1.69 (m, 2H), 1.51ꢀ1.43 (m, 2H), 0.99 (t, J
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= 7.4 Hz, 3H) ppm; C NMR (151 MHz, CDCl3) δ = 166.0, 146.7, 135.2, 131.6, 129.4, 125.5, 120.9, 110.2,
108.4, 65.0, 30.8, 19.2, 13.3 ppm; IR (KBr) υ 3096, 3063, 2960, 2929, 2867, 1706, 1657, 1461, 1282, 1161, 959,
754 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C13H15N3O2 [M + Na]+: 268.1057, Found: 268.1059.
(E)-Ethyl 3-(1H-benzimidazol-1-yl) acrylate (4n)24: The title compound could be prepared according to general
procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and eluted
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with EA/PE (1:15 to 1:5) to afford a white solid (43 mg, 79%).
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The reaction also was conducted with modifications to the general procedure B for 36 h. The crude product was
purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a white solid
(33 mg, 61%). 1H NMR (600 MHz, CDCl3) δ = 8.24 (s, 1H), 8.15 (d, J = 14.3 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H),
7.64 (d, J = 6.4 Hz, 1H), 7.45ꢀ7.36 (m, 2H), 6.33 (d, J = 14.4 Hz, 1H), 4.31 (dd, J = 8.4, 5.3 Hz, 2H), 1.36 (t, J =
6.8 Hz, 3H) ppm.
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(E)-Benzyl 3-(1H-benzimidazol-1-yl) acrylate (4o): The title compound could be prepared according to general
procedure A. Benzimidazole (29 mg, 0.25 mmol), benzyl acrylate (81 mg, 75 µL, 0.5 mmol), 2,2'ꢀbipyridine (4
mg, 0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), KI (415 mg, 2.5 mmol), DABCO (28
mg, 0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube
under an atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 36 h. After extraction and
evaporation, the crude product was purified by column chromatography on neutral Al2O3 and eluted with EA/PE
(1:15 to 1:5) to afford a white solid (29 mg, 42%), m.p.: 115ꢀ117 oC. 1H NMR (600 MHz, CDCl3) δ = 8.17 (d, J =
15.0 Hz, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.45ꢀ7.34 (m, 7H), 6.35 (d, J = 14.3 Hz, 1H),
5.28 (s, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ = 166.2, 144.6, 141.6, 135.9, 135.8, 132.1, 128.7, 128.5, 128.4,
125.0, 124.4, 121.2, 111.2, 105.5, 66.8 ppm; IR (KBr) υ 3080, 3031, 2953, 1715, 1647, 1498, 1464, 1368, 1267,
1152, 998, 742 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C17H14N2O2 [M + Na]+: 301.0948, Found: 301.0944.
(E)-tert-Butyl 3-(1H-benzimidazol-1-yl) acrylate (4p): The title compound could be prepared according to
general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
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eluted with EA/PE (1:15 to 1:5) to afford a white solid (24 mg, 39%), m.p.: 125ꢀ127 C. H NMR (600 MHz,
CDCl3) δ = 8.18 (s, 1H), 8.06 (d, J = 14.3 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.40 (dt, J =
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21.1, 7.4 Hz, 2H), 6.26 (d, J = 14.4 Hz, 1H), 1.56 (s, 9H) ppm; C NMR (151 MHz, CDCl3) δ = 165.5, 144.5,
141.5, 134.6, 132.2, 124.9, 124.2, 121.1, 111.1, 108.0, 81.4, 28.3 ppm; IR (KBr) υ 3087, 3061, 3027, 2974, 2929,
2859, 1715, 1650, 1496, 1460, 1367, 1258, 1147, 955, 861, 765, 700, 554 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for
C14H16N2O2 [M + Na]+: 267.1104, Found: 267.1101.
(E)-2-Methoxyethyl 3-(1H-benzimidazol-1-yl) acrylate (4q): The title compound could be prepared according
to general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
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eluted with EA/PE (1:15 to 1:5) to afford a white solid (34 mg, 56%), m.p.: 80ꢀ82 C. H NMR (600 MHz,
CDCl3) δ = 8.18 (dd, J = 13.8, 4.5 Hz, 2H), 7.84 (d, J = 6.1 Hz, 1H), 7.64 (d, J = 6.2 Hz, 1H), 7.44ꢀ7.35 (m, 2H),
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6.37 (d, J = 14.4 Hz, 1H), 4.43ꢀ4.39 (m, 2H), 3.71ꢀ3.66 (m, 2H), 3.46ꢀ3.41 (m, 3H) ppm; C NMR (151 MHz,
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CDCl3) δ = 166.3, 144.6, 141.7, 135.9, 132.1, 125.0, 124.4, 121.2, 111.2, 105.4, 70.5, 63.9, 59.0 ppm; IR (KBr) υ
3087, 3056, 2983, 2909, 2816, 1721, 1651, 1502, 1459, 1364, 1270, 1205, 1165, 1122, 974, 766 cmꢀ1; HRMS
(ESI/TOFꢀQ) m/z Calcd for C13H14N2O3 [M + Na]+: 269.0897, Found 269.0907.
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(E)-Trifluoromethyl 3-(1H-benzimidazol-1-yl) acrylate (4r): The title compound could be prepared according to
general procedure A. Benzimidazole (29 mg, 0.25 mmol), 2,2,2ꢀtrifluoroethyl acrylate (77 mg, 63 µL, 0.5 mmol),
2,2'ꢀbipyridine (4 mg, 0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), KI (415 mg, 2.5
mmol), DABCO (28 mg, 0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10
mL sealed tube under an atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 36 h. The
crude product was purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:7 to 1:5) to
afford a white solid (22 mg, 32%), m.p.: 113ꢀ115 oC. 1H NMR (600 MHz, CDCl3) δ = 8.28ꢀ8.17 (m, 2H), 7.86 (d, J
= 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 14.3, 7.7 Hz, 2H), 6.37 (d, J = 14.3 Hz, 1H), 4.64 (q, J = 8.4
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Hz, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ = 164.7, 144.6, 141.8, 137.3, 132.1, 125.4, 124.8, 123.0 (q, JCꢀF
=
277.8 Hz), 121.4, 111.3, 103.5, 60.6 (q, JCꢀF = 37.8 Hz) ppm; IR (KBr) υ 3124, 3066, 3050, 2967, 2921, 2851,
1721, 1653, 1502, 1464, 1417, 1368, 1270, 1155, 989, 768 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C12H9F3N2O2
[M + Na]+: 293.0508, Found 293.0512.
(E)-Cyclohexyl 3-(1H-benzimidazol-1-yl) acrylate (4s): The title compound could be prepared according to
general procedure A for 48 h. The crude product was purified by column chromatography on neutral Al2O3 and
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eluted with EA/PE (1:15 to 1:5) to afford a white solid (44 mg, 65%), m.p.: 120ꢀ122 C. H NMR (600 MHz,
CDCl3) δ = 8.19 (s, 1H), 8.14 (d, J = 14.4 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.40 (dt, J =
15.1, 7.1 Hz, 2H), 6.32 (d, J = 14.3 Hz, 1H), 4.96ꢀ4.88 (m, 1H), 1.98ꢀ1.91 (m, 2H), 1.80ꢀ1.78 (m, 2H), 1.60ꢀ1.58
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(m, 1H), 1.54ꢀ1.49 (m, 2H), 1.45ꢀ1.39 (m, 2H), 1.35ꢀ1.25 (m, 1H) ppm; C NMR (151 MHz, CDCl3) δ = 165.8,
144.6, 141.6, 135.2, 132.2, 124.9, 124.3, 121.2, 111.2, 106.6, 73.4, 31.8, 25.4, 23.8 ppm; IR (KBr) υ 3117, 3051,
2939, 2858, 1774, 1643, 1495, 1464, 1360, 1269, 1162, 1018, 716 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for
C16H18N2O2 [M + Na]+: 293.1261, Found 293.1256.
(E)-(Tetrahydrofuran-2-yl) methyl 3-(1H-benzimidazol-1-yl) acrylate (4t): The title compound could be
prepared according to general procedure A for 48 h. The crude product was purified by column chromatography
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on neutral Al2O3 and eluted with EA/PE (1:15 to 1:3) to afford a white solid (38 mg, 55%), m.p.: 70ꢀ72 C. H
NMR (600 MHz, CDCl3) δ = 8.19 (t, J = 7.1 Hz, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H),
7.44ꢀ7.36 (m, 2H), 6.38 (d, J = 14.4 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.25ꢀ4.13 (m, 2H), 3.97ꢀ3.91 (m, 1H),
3.88ꢀ3.81 (m, 1H), 2.12ꢀ2.03 (m, 1H), 2.02ꢀ1.92 (m, 2H), 1.70ꢀ1.61 (m, 1H) ppm; 13C NMR (151 MHz, CDCl3) δ
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= 166.3, 144.6, 141.7, 135.9, 132.1, 125.0, 124.4, 121.2, 111.2, 105.4, 76.6, 68.5, 66.9, 28.1, 25.7 ppm; IR (KBr)
υ 3092, 2924, 2853, 1718, 1651, 1504, 1461, 1366, 1276, 1193, 1087, 1027, 742 cmꢀ1; HRMS: (ESI/TOFꢀQ) m/z
Calcd for C15H16N2O3 [M + Na]+: 295.1053, Found 295.1054.
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(E)-Ethyl 3-(1H-benzo[d]imidazol-1-yl)-2-methylacrylate (4v): The title compound could be prepared
according to general procedure A for 48 h. The crude product was purified by column chromatography on neutral
Al2O3 and eluted with ethyl EA/PE (1:10 to 1:5) to afford a white solid (14 mg, 24%), m.p.: 120ꢀ122 oC. 1H NMR
(600 MHz, CDCl3) δ = 8.30 (s, 1H), 8.02 (s, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.42ꢀ7.36 (m,
2H), 4.34 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 167.1,
142.6, 142.0, 129.6, 124.5, 124.0, 122.0, 120.6, 110.4, 100.0, 61.5, 14.3, 13.6 ppm; IR (KBr) υ 3127, 3057, 2923,
2853, 1705, 1656, 1495, 1460, 1385, 1363, 1267, 1135, 1088, 887, 774 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for
C13H14N2O2 [M + Na]+: 253.0948, Found 253.0945.
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(E)-Trifluoroethyl 3-(1H-benzimidazol-1-yl)-2-methylacrylate (4w): The title compound could be prepared
according to general procedure A. Benzimidazole (29 mg, 0.25 mmol), 2,2,2ꢀtrifluoroethyl methacrylate (84 mg,
71 µL, 0.5 mmol), 2,2'ꢀbipyridine (4 mg, 0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%),
KI (415 mg, 2.5 mmol), DABCO (28 mg, 0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent
were put into the 10 mL sealed tube under an atmosphere of oxygen balloon. The reaction mixture was stirred at
100 °C for 28 h. The crude product was purified by column chromatography on neutral Al2O3 and eluted with
EA/PE (1/10 ꢀ 1/5) to afford a white solid (21 mg, 30%), m.p.: 119ꢀ121 oC. 1H NMR (600 MHz, CDCl3) δ = 8.25
(s, 1H), 8.13 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.45ꢀ7.37 (m, 2H), 4.67 (q, J = 8.4 Hz, 2H),
2.29ꢀ2.20 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ = 165.7, 143.1, 141.3, 133.5, 131.6, 125.7, 124.6, 124.1,
123.0 (q, JCꢀF = 277.8 Hz), 117.9, 110.1, 61.1 (q, JCꢀF = 36.2 Hz) 13.6 ppm; IR (KBr) υ 3158, 3054, 1726, 1644,
1489, 1400, 1365, 1315, 1277, 1249, 1164, 957, 741 cmꢀ1; HRMS (ESI/TOFꢀQ) m/z Calcd for C13H11F3N2O2 [M +
H]+: 285.0845, Found 285.0847.
(E)-3-(1H-benzo[d]imidazol-1-yl)acrylonitrile (4z)25: The title compound could be prepared according to
general procedure A. Benzimidazole (29 mg, 0.25 mmol), acrylonitrile (53 mg, 65 µL, 1.0 mmol), 2,2'ꢀbipyridine
(4 mg, 0.025 mmol, 10 mol%), Cu(OAc)2·H2O (5 mg, 0.025 mmol, 10 mol%), LiI (333 mg, 2.5 mmol), DABCO
(28 mg, 0.25 mmol), DMF (0.9 mL) and cumene (0.1 mL) as mixed solvent were put into the 10 mL sealed tube
under an atmosphere of oxygen balloon. The reaction mixture was stirred at 100 °C for 48 h. The crude product
was purified by column chromatography on neutral Al2O3 and eluted with EA/PE (1:15 to 1:5) to afford a yellow
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solid (18 mg, 42%). H NMR (400 MHz, CDCl3) δ = 8.13 (s, 1H), 7.86 (m, 1H), 7.82 (d, J = 14.8 Hz, 1H), 7.55
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(m, 1H), 7.48ꢀ7.38 (m, 2H), 5.77 (d, J = 14.8 Hz, 1H) ppm.
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Associated Content
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Supporting Information Available: Copies of H and 13C NMR spectra for products; LCꢀMS spectra of the
9
overall kinetic profiles of intermolecular reaction and intramolecular reaction at 4 minute. Crystal data and
structure refinement, important bond lengths, bond angles for 4a. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Author Information
Notes
The authors declare no competing financial interest.
Corresponding Author: *Eꢀmail: gxcai@swu.edu.cn
Acknowledgment
This work was supported by the National Natural Science Foundation of China (21004075, 21372186), Beijing
National Laboratory of Molecular Sciences (BNLMS) (20140130), the Doctoral Fund of Southwest University
(SWU111075) and the Research Funds for the Central Universities (XDJK2013C112).
Notes and references
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