Nickel-Catalyzed Construction of 2,4-Disubstituted Imidazoles via C–C Coupling and C?N Condensation Cascade Reactions

Article abstract of DOI:10.1002/adsc.201900096

A convenient Ni(II)-catalyzed C?C and C?N cascade coupling reaction was developed to directly access various 2,4-disubstituted imidazoles. The reaction scope covers a variety of aryl and aliphatic substitutions, which demonstrate moderate-to-excellent yie

Full text of DOI:10.1002/adsc.201900096

Title: Nickel-Catalyzed construction of 2,4-disubstituted imidazoles via
C–C coupling and C–N condensation cascade reactions
Authors: Shengyang Fang, Haihua Yu, Xicheng Yang, Jianqi Li, and
Liming Shao
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10.1002/adsc.201900096
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Nickel-Catalyzed construction of 2,4-disubstituted imidazoles
via C–C coupling and C–N condensation cascade reactions
Shengyang Fang,+a Haihua Yu,+a,d Xicheng Yang,a Jianqi Li,c,* and Liming Shaoa,b,*
a
School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203,
People’s Republic of China
b
State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, People’s
Republic of China
E-mail: limingshao@fudan.edu.cn
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State
c
Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, People’s Republic of China
E-mail: lijianqb@126.com
d
Suzhou Precision Imaging Technology Co. Ltd, Jiangsu Advanced Materials Industrial Park, 18 Fuyu Road, Haiyu
Town, Changshu City, Jiangsu Province 215522, People’s Republic of China
+
These authors contributed equally to this work
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A convenient Ni(II)-catalyzed C−C and C−N
cascade coupling reaction was developed to directly
access various 2,4-disubstituted imidazoles. The reaction
scope covers a variety of aryl and aliphatic substitutions,
which demonstrate moderate-to-excellent yields. The
tolerance of halogen and N-containing heterocyclic
groups demonstrates the versatility of this method for
further synthetic explorations.
Figure 1. Selected examples of bioactive molecules
containing 2,4-disubstituted imidazoles.
Keywords: Cyano group; C−C coupling; C−N coupling;
2,4-disubstituted imidazoles; nickel catalysis
Imidazoles and their derivatives belong to an
important class of aromatic heterocycles widely
Figure 2. Methods for the synthesis of 2,4-disubstituted
imidazoles.
observed
in
numerous
natural
products,
pharmaceuticals, and agro chemicals,[1] highlighting
the importance of these chemical scaffolds. In
particular, 2,4-disubstituted imidazoles possess both
hydrogen bonding acceptors and donors, which can
enhance bioactivity properties. Numerous synthetic
bioactive molecules and drugs comprise such
modified scaffolds (Fig. 1).[2] However, synthetic
pathways to 2,4-disubstituted imidazoles have not
been extensively investigated, hitherto. Unprotected
imidazoles remain recognized as a challenging
scaffold to synthesize.[3] General routes to synthesize
2,4-disubstituted imidazoles include the Suzuki cross-
coupling of haloimidazoles[4] and [3 + 2] cyclization
in the presence of benzimidamides and vinyl azides
or bromoacetylenes.[5]
A
high-temperature/high-
pressure continuous flow strategy has also been
described (Fig. 2).[6] Although these methods are
well-established and have been developed
specifically, to further improve the applicable scope
1
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10.1002/adsc.201900096
Advanced Synthesis & Catalysis
of the methods, the bottleneck—derived from the
rigorous reaction conditions and the limited
accessibility of the starting materials—must be
circumvented.
demonstrated that the reaction barely proceeded in
the absence of any ligand (entry 18).
With optimal conditions in hand, the influence of
boronic acids to the reaction scope were studied
(Scheme 1). As illustrated in the scheme, the
electronic effect influenced, to varying degrees, the
reaction yield. Furthermore, acrylic acids bearing
electron-donating groups (3b-h) gave better yields
compared with
Over the past years, transition metal-catalyzed
nitrile insertion reactions have been demonstrated as
an important transformation to generate structurally
diverse N-containing heterocyclic compounds.[7] The
research by Larock [8] and Lu [9] first reported the C−C
addition of nitriles catalyzed by Pd and Rh. Since
their pioneering work, research by Wu, [10] Chen,[11]
and our group[12] has result in Pd-catalyzed nitrile
insertion to afford isoquinolines, benzofurans, indoles,
quinazolines, and polysubstituted imidazoles.
However, there are only a limited number of reports
detailing the use of naturally abundant nickel
catalysts.[13] As part of the current trend toward
replacing precious metal catalysts with catalysts
comprising naturally abundant metals,[14] there has
been a wealth of interdependent research in
developing Ni catalysts as alternatives to Pd
systems.[15] Herein, this work focused on developing
a novel selective synthesis method to yield 2,4-
disubstituted imidazoles using less expensive nickel
catalysts and readily accessible starting materials
under mild conditions.
Table 1. Optimization of reaction conditions. [a]
Catalyst
Ligand Desiccants Yield[b]
(%)
L1
45
Our group has focused on the development of
novel transition metal-catalyzed C−C and C−N
cascade coupling reactions using nitrile reagents.[12,
Entry
1[c]
2[d]
3[e]
Ni(acac)2
Ni(acac)2
Ni(acac)2
13d]
L1
71
As part of continuous efforts, herein, we report an
efficient and convenient nickel-catalyzed synthetic
strategy to afford 2,4-disubstituted imidazoles, which
is compatible with a wide variety of substrates.
L1
molecular 76
sieves
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
4
5
6
7
8
9
10
11
12
13
14
15
Ni(acac)2
Ni(acac)2
NiCl2
NiBr2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Ni(PPh3)2Br2
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
80
80
73
80
83
79
trace
81
57
87
78
20
71
75
< 5
At the outset, N-(cyanomethyl)acetamide 1a (0.6
mmol) and phenylboronic acid 2a (1.2 mmol) are
fixed reactant entities during the investigation of the
reaction conditions (Table 1). The reaction was
performed in the presence of Ni(acac)2 (10 mol%)
and ligand L1 (10 mol%) in toluene (3.0 mL) at
120 °C for 12 h (Table 1, entry 1). As expected, the
desired product 3a was obtained in 45% yield.
Prolonging the reaction time led to a significant
improvement in yield (71%, entry 2). Despite the
modest yield, the complete conversion of 1a was not
achieved. Inspired by the research of the Bathula
group,[16] the water produced during the
intramolecular cyclization process was proposed to
hamper the conversion rate. Therefore, molecular
sieves, or sodium sulfate, were added to remove the
water, which resulted in the yield of 3a to increase to
80% in the presence of 5.0 mmol of Na2SO4 (entries
3 and 4). A series of Ni catalysts (entries 4-8) were
then screened with Ni(PPh3)2Br2 giving the highest
yield (83%, entry 8). To further improve the yield, a
variety of ligands (L1-L8, entries 8-15) were
screened. Among all the bidentate nitrogen ligands,
5,5′-dimethyl-2,2′-bipyridine (L6) was observed to
efficiently promote the reaction—generating 3a in
87% yield (entry 13). Decreasing catalyst or
phenylboronic acid 2a amount resulted in the loss of
yield. (entries 16 and 17). Control experiments
16 [f] Ni(PPh3)2Br2
17 [g] Ni(PPh3)2Br2
18 [h] Ni(PPh3)2Br2
[a]
Reaction conditions: unless otherwise stated, all
reactions were carried out with a catalyst/ligand ratio of
1:1 (10 mol%), 1a (0.6 mmol), 2a (1.2 mmol, 2.0 equiv.),
Na2SO4 (3.0 mmol, 5.0 equiv.), and anhydrous toluene
(3.0 mL) as the solvent. The mixture was stirred at
120 °C, in air, in a sealed tube for 24 h.
[b] Isolated yield based on 1a.
[c] Reaction time was 12 h without drying agent.
[d] No drying agent.
[e] Molecular sieves as desiccants.
[f]
Ni(PPh3)2Br2 (0.03 mmol, 5.0 mol%) and L6 (0.03
mmol, 5.0 mol%).
[g] 2a (0.9 mmol, 1.5 equiv.).
[h] In the absence of any ligand.
2
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10.1002/adsc.201900096
Advanced Synthesis & Catalysis
strongly electron-withdrawing groups (3l-n).
Interestingly, arylboronic acids bearing methoxy
substituents at the 3- and, 4- positions (3g and 3h)
afforded the corresponding products in lower yields
compared with other moieties bearing other electron-
donating groups.[17] The introduction of moderately
electron-withdrawing groups, such as halogens (3i-k),
were tolerated in this reaction, achieving moderate
yields (43-48%). Introducing strongly electron-
withdrawing groups, such as diflouromethyl and
bearing an electron-donating substituent (4i),
produced a slightly higher product yield compared
with the corresponding electron-withdrawing
substituent analogues (4j and 4k). Notably, the CN
group remained intact and no nickel-catalyzed boron
addition to the group was observed (4j). The reaction
proceeded well in the presence of the halogen groups
(4l-o) with 63-80% yields, demonstrating the
potential of this method across a wide application
base after further cross-coupling reactions. Notably,
fused-aryl
Scheme 1. Scope of boronic acid. Standard reaction
conditions: 1a (0.6 mmol), boronic acid (1.2 mmol, 2.0
equiv.), Ni(PPh3)2Br2 (0.06 mmol, 10 mol%), ligand (0.06
mmol, 10 mol%), Na2SO4 (3 mmol, 5.0 equiv.), and
anhydrous toluene (3.0 mL), sealed, 120 °C for 24 h;
isolated yield based on 1a.
Scheme 2. Scope of substituted N-cyanomethyl-
acetamides. Standard reaction conditions: 1b-t (0.6 mmol),
boronic acid (1.2 mmol, 2.0 equiv.), Ni(PPh3)2Br2 (0.06
mmol, 10 mol%), ligand (0.06 mmol, 10 mol%), Na2SO4
(3.0 mmol, 5.0 equiv.), and anhydrous toluene (3.0 mL),
sealed, 120 °C for 24 h; isolated yield based on 4a-s.
triflourmethy moieties, only gave low yields (3l and
3m). The reaction barely proceeded (3n) when (4-
nitrophenyl)boronic acid, with a strong electron-
withdrawing group, was used. The steric effects also
influenced the outcome of the reaction. For example,
the yield was observed to significantly decrease with
methyl group at the ortho-position (3b). Increasing
the size of the ortho-substitution moiety further
decreased the yield (3f). Disubstituted substrates were
also incorporated. 3o and 3p were obtained in
excellent yields. Surprisingly, functional groups, such
as naphthyl (3q and 3r) and biphenyl (3s) were also
tolerated with observed yields ranging from 43% to
87%. Additionally, the 3,4-methylenedioxyphenyl
fused ring was also successfully transformed when
subjected to the reaction condition (3t).
(4p) and heteroaryl (4q) substitutions also proceeded
smoothly resulting in desired products in moderate-
to- good yields. Additionally, the reaction was also
proved suitable for various N-Boc-cycloalkanes and
gave the desired products in moderate yields (4r and
4s).
A tentative mechanism has been proposed (Scheme
3) based on previously published relevant reports.[8c,
9a, 10e]
The reaction proceeds by forming aryl nickel
species generated from the transmetalation process
derived from the Ni(II) catalyst and arylboronic acid.
Thereafter, nitrile coordination to Ni[Ar] affords the
intermediate A, which undergoes an intramolecular
Furthermore, the variation of different substituted
N-cyanomethyl-acetamides were examined (Scheme
2). Substrates bearing alkyl groups were observed to
be well tolerated with yields from 80% to 89% (4a-g).
Regarding
aryl
substitutions,
N-
cyanomethylbenzamide gave the corresponding
product in 76% yield (4h). Both electron-donating
(e.g., –Me) and electron-withdrawing (e.g., –NO2)
groups on the aromatic rings were compatible with
this reaction. In general, N-cyanomethyl-acetamide
3
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10.1002/adsc.201900096
Advanced Synthesis & Catalysis
insertion of the nitrile group to yield the
corresponding ketimine complex B. Further, the
above complex B
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Scheme 3. Proposed Mechanism.
afforded the ketimine intermediate C, and thus
regenerates the Ni(II) catalyst. The ketamine
intermediate C undergoes tautomerization to afford D,
which is followed by intramolecular condensation to
yield the corresponding desired product F.
In summary, an efficient nickel(II)-catalyzed
coupling cascade reaction has been developed to
synthesize structurally diverse 2,4-disubstituted
imidazoles. The reaction involves C−C coupling
followed by intramolecular C−N bond formation. The
method exhibits remarkable selectivity across a broad
substrate scope. Notably, halogen and N-containing
heterocyclic substituents are amenable to the reaction
to further contribute to product diversity. Further
studies are ongoing with respect to extending this
methodology for the synthesis of various heterocycles.
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Experimental Section
General procedure for the synthesis of 2,4-disubstituted
imidazoles
Anhydrous toluene (3.0 mL) was added to an over-dried 5
mL sealed tube, equipped with a stirrer bar, containing
aminoacetonitrile 1a (0.6 mmol), phenylboronic acid 2a
(1.2 mmol), Ni(PPh3)2Br2 (10 mol%), 4,4'-di-tert-butyl-
2,2'-bipyridine (10 mol%), and anhydrous Na2SO4 (3.0
mmol). The mixture was stirred at 120 °C for 24 h. After
completion of the reaction, the solvent was removed under
reduced pressure. Thereafter, the mixture was diluted with
EtOAc and washed with brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated under vacuum,
after which the residue was purified by column
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chromatography
using
2
vol.%
methanol
in
dichloromethane to give the desired product 3a.
Acknowledgements
This work was supported by the National Basic Research
Program of China (973 Program, 2015CB931804), the Science
and the National Natural Science Foundation of China
(81673292). We thank Edanz Group (www.edanzediting.com/ac)
for editing a draft of this manuscript.
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5
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10.1002/adsc.201900096
Advanced Synthesis & Catalysis
COMMUNICATION
Nickel-Catalyzed construction of 2,4-disubstituted
imidazoles via C–C coupling and C–N
condensation cascade reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Shengyang Fang, Haihua Yu, Xicheng Yang, Jianqi
Li,* and Liming Shao*
6
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