Controllable access to multi-substituted imidazoles: Via palladium(II)-catalyzed C-C coupling and C-N condensation cascade reactions

Article abstract of DOI:10.1039/c7cc05315k

A novel and efficient protocol for the synthesis of various 2,4-disubstituted, 1,2,4-trisubstituted and 1,2,4,5-tetra-substituted imidazoles via cascade palladium catalyzed C-C coupling followed by intramolecular C-N bond formation was developed. Readily accessible boronic acids and N-substituted-2-aminoacetonitriles were firstly reported as starting materials to construct di-, tri-, and tetra-substituted imidazoles in good to excellent yield.

Full text of DOI:10.1039/c7cc05315k

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Controllable access to multi‐substituted imidazoles via
palladium(II)‐catalyzed C‐C coupling and C‐N condensation
cascade reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Haihua Yu a, Li Xiao a, Xicheng Yang a, Liming Shao *ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient protocol for the synthesis of various 2, 4‐ to develop a method which can construct 2, 4‐disubstituted, 1, 2, 4‐
disubstituted, 1, 2,4‐trisubstituted and 1, 2, 4, 5‐tetra‐substituted trisubstituted and 1, 2, 4, 5‐tetrasubstituted imidazoles at will
imidazoles via cascade palladium catalyzed C‐C coupling followed without further oxidant.
by intramolecular C‐N bond formation was developed. Readily
Palladium catalyzed synthesis of arylketone through addition of
accessible boronic acids and N‐substituted‐2‐amino‐acetonitriles arylboronic acid to nitrile has been developed by Lacrock’s group9, 10
were firstly reported as starting materials to construct di‐, tri‐, and and others11. Inspired by these previous examples, we proposed a
tetra‐ substituted imidazoles in good to excellent yield.
palladium (II) catalyzed tandem reaction for the synthesis of di‐, tri‐,
and tetra‐ substituted imidazoles through the addition of
arylboronic acids to nitriles followed by an intramolecular
cyclization. As a starting point, N‐substituted‐2‐amino‐acetonitrile
and phenylboronic acid were used to test the concept. As shown in
Table 1, the reaction was carried out between N‐(cyanomethyl)‐N‐
phenylacetamide 1a (0.5 mmol) and phenylboronic acid 2a (0.75
mmol) in anhydrous toluene (2.0 mL) at 130 ˚C under microwave
irradiation for 2.5 h, in the presence of catalyst Pd(TFA)2 (10 mol %)
or Pd(OAc)2 (10 mol%) and ligand L1 (10 mol%). The desired product
3a was obtained in 43% and 17% yields, respectively (Table 1,
entries 1‐2). We chose Pd(TFA)2 as the metal source and screened
Multi‐substituted imidazoles are common motifs in many drug
molecules with interesting bioactivities.1 By introducing different
substituents to the imidazole ring, binding affinity and
characteristics of the molecule could be modified. In recent years,
various synthetic methods have been developed for di‐substituted2
and tri‐substituted3 imidazoles while the synthesis of tetra‐
substituted imidazole has received relatively less attention.4
Neuville’s group developed an efficient copper‐catalyzed synthesis
of 1, 2, 4‐trisubstituted imidazoles using amidines and terminal
alkynes (Scheme 1A).5 Chen’s group reported iron(III)‐catalyzed
synthesis of 1, 2, 4‐trisubstituted imidazoles with amidines and
aldehydes (Scheme 1B).6 Li’s group published iron(III)‐catalyzed
synthesis of 1, 2, 4, 5‐tetrasubstituted imidazoles with amidines and
chalcones (Scheme 1C).7 Maiti’s group took primary amine and 1, 2‐
diketone as the starting materials to synthesize tetra‐substituted
imidazoles with Ni catalyst (Scheme 1D).8 Reissig and co‐workers
also developed
a
four‐component multisteps reaction of
alkoxyallenes, imines, iodine, and nitriles to prepare tetra‐
4d
substituted imidazoles.4c,
In the protocols mentioned above,
researchers focused on only one specific substitution pattern,
either tri‐substituted imidazoles (Neuville and Chen) or tetra‐
substituted imidazoles (Li, Maiti and Reissig). To the best of our
knowledge, no method which is capable of synthesizing di‐, tri‐ and
tetra‐ substituted imidazoles has been developed. In addition,
further oxidant such as O2 was required in all previously published
cases. In order to complete the existing arsenal, we set out the goal
a. School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi‐tech
Park, Pudong, Shanghai 201203, P.R. China
b. State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan
Road, Shanghai 200032, P.R. China.
†Electronic Supplementary Information (ESI) available: Experimental methods,
characterization of products and NMR spectra. See DOI: 10.1039/x0xx00000x
Scheme 1 Synthetic strategies of 1, 2, 4‐trisubstituted and 1, 2,
4, 5‐tetrasubstituted imidazoles.
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a variety of bipyridyl ligands (L2‐L9, Fig. 1). The results showed
that L2 was the optimal ligand for the model reaction with
yield up to 56% (Table 1, entry 4).
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DOI: 10.1039/C7CC05315K
In order to improve the reaction conversion, additives were
employed. Trifluoroacetic acid was first considered as the
additive, with the assumption that CF3COO‐ may play an
important role in the catalytic cycle (Table 1, entry 12).
Although a promising increase on the conversion was observed,
higher ratio of hydrolyzed byproduct formed at the same time
(Table 1, ESI†). Thus, CF3CO2NH4 (1.0 equiv) was tested
alternatively. The result showed that not only the reaction
yield was increased dramatically, but also the ketimine
hydrolysis byproduct was restrained completely (Table 1, entry
13). In order to further optimize the reaction condition,
reduced Pd loading to 5 mol% was also tested. However, a
decreased yield to 52% was rendered (Table 1, entry 14).
With the optimized condition, the scope of boronic acids was then
explored (Scheme 2). In terms of electronic effect, both electron‐
rich substrates (2a‐2d) and electron‐deficient substrates (2e‐2h)
could be tolerated (yield from 64% to 90%, Scheme 2). Substitution
at the ortho position such as methyl (2i, 60%), methoxy (2j, 31%)
and isopropyl (3k, 47%) indicated that the reaction is sensitive to
steric effect. In order to further install different functional groups,
halogens containing boronic acids were screened (2l‐2n, 45%‐68%).
Heterocycle such as 6‐indole boronic acid (2o) was examined and
Fig. 1 Structures of bipyridyl ligands.
the product (3o) in 55% yield was obtained.
After investigation of boronic acids, our focus was directed to
construction of di‐, tri‐, and tetra‐ substituted imidazoles.
Aminoacetonitrile was initially investigated to prepare tri‐
substituted imidazoles (Scheme 3, 3jb‐3jo). When R1 groups
are aryl rings with electron‐donating or electron‐
withdrawing groups, the protocol was able to afford the
products with moderate to good yields (3jb
with halogenated aryl rings gave similar results (3jf, 45%; 3jg
79%). The method was robust when R1 were aliphatic
substituents, such as cyclohexyl (3ji, 70%), isopropyl (3jj, 89%),
and n‐butyl (3jk, 57%). Fused ring and hetero‐aromatic
substrates were challenging, while naphthyl (3jl, 40%), pyridyl
‐3je, 57‐80%). R1
,
(
3jm, 49%) and pyrazolyl (3jn, 71%) showed decreased
reactivity. N‐substituted alkyl group such as benzyl at R2
position (3jn, 90%) proceeded smoothly with excellent yield.
Besides, 3jn could easily be further transformed into di‐
substituted imidazole 3jo through a simple benzyl group
deprotection. Furthermore, in order to prove that the protocol
could construct disubstituted imidazole, preparation of 3jo
with R1 and R2 as hydrogens was demonstrated (45%).
Table 1 Screening of the reaction conditions for synthesis of 1, 2, 4‐
trisubstituted imidazoles.
Direct synthesis of 1, 2, 4, 5‐tetrasubstituted imidazoles with
different functional groups remained a challenge. Remarkably, our
method demonstrated that the reactions could proceed smoothly
to generate the tetra‐substituted imidazoles when R1 and R3 are
both methyl groups (3jp‐3js), or trifluoromethyl and methyl groups,
respectively (3jt‐3jv). Worth mentioning, the aminoacetonitrile with
R1 position being strong withdrawing trifluoromethyl group gave a
Entrya Pd(II)
L
Additive
Yield b (%)
1
Pd(TFA)2 L1
Pd(OAc)2 L1
Pd(OAc)2 L2
Pd(TFA)2 L2
Pd(TFA)2 L3
Pd(TFA)2 L4
Pd(TFA)2 L5
Pd(TFA)2 L6
Pd(TFA)2 L7
Pd(TFA)2 L8
Pd(TFA)2 L9
43
17
37
56
36
34
29
13
23
26
40
56
2
3
OH
N
Pd(TFA)2 / L2
O
4
B
N
HO
N
N
toluene, refluxed,
CF3COONH4, 4~6 h
5
R
R
1a
2b-2o
3b-3o
6
7
N
3e, R = 4-CF3, 80%
3f, R = 4-F, 64%
3g, R = 3, 4-difluoro, 65%
3h, R = 3-CF3, 66%
3a, R = H, 73%
3b, R = 4-MeO, 76%
3c, R = 4-Me, 82%
N
N
N
8
R
R
3d, R = 3,4-dimethoxy, 90%
9
3e-3h
3a-3d
N
R
10
11
12c
13c
14d
Cl
O
N
3i, R = methyl, 60%
3j, R = methoxy, 31%
3k, R = isopropoyl, 47%
N
N
Pd(TFA)2 L2 TFA (2.0 equiv)
3i-3k
3l, 65%
H
Pd(TFA)2 L2 CF3CO2NH4 (1.0 equiv) 73
N
N
N
N
N
Cl
N
Br
N
Pd(TFA)2 L2 CF3CO2NH4 (1.0 equiv) 52
Cl
a Standard reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol, 1.5
equiv), palladium(II) (0.05 mmol, 10 mol%), ligand (0.05 mmol, 10
mol%), toluene (2.0 mL). microwave irradiation at 130 ˚C for 2.5 h. b
Isolated yield based on 1a. Entries 12‐13 refluxed for 4 h.
Pd(TFA)2(II) (0.025 mmol, 5 mol%), L2 (0.025 mmol, 5 mol%),
3m, 68%
3n, 45%
3o, 55%
Scheme 2 Scope of boronic acid. Standard reaction conditions: 1a
(0.5 mmol), boronic acid (0.75 mmol, 1.5 equiv), Pd(TFA)2 (0.05
mmol, 10 mol%), ligand (0.05 mmol, 10 mol%), CF3CO2NH4 (0.5
mmol, 1.0 equiv), toluene (2.0 mL), refluxed for 4~6 h; Isolated yield
based on 1a.
c
d
refluxed for 4 h.
2 | J. Name., 2012, 00, 1‐3
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Scheme 4 Gram‐scale Synthesis.
Ar
Pd(CF3CO2)2
O
R3
O
N
R2
L
H
R1
H
ArB(OH)2
Ar
Pd(CF3CO2)2L
NH
O
A
R3
N
CF3COO
O2CCF3
R2
R1
L
E
Ar
Ar
Pd
NH2
O
ArPd(CF3CO2)L
N
R3
R3
O
B
N
N
R2
N
R2
R1
O
N
R2
R1
R3
F
D
R1
R3
O
Ar
N
R2
N
N
N
R1
R1
- H2O
Ar Pd
L
R3
R2
O2CCF3
G
C
Fig. 2 A plausible mechanism was proposed.
first report to prepare multi‐substituted imidazoles from
readily accessible aminoacetonitrile and boronic acid. Further
studies to explore the possibility for synthesis of various
heterocycles are currently underway.
This work was financially supported by the National Basic
Research Program of China (973 Program, 2015CB931804), the
Science and Technology Commission of Shanghai Municipality
(No.15431900100) and the National Natural Science
Foundation of China (81473076, 81673292).
Scheme 3 Scope of aminoacetonitrile. Standard Reaction conditions:
1b‐1s (0.5 mmol), boronic acid (0.75 mmol, 1.5 equiv), Pd(TFA)2
(0.05 mmol, 10 mol%), ligand (0.05 mmol, 10 mol%), CF3CO2NH4
(0.5 mmol, 1.0 equiv), toluene (2.0 mL), refluxed for 4~6 h; Isolated
yield based on 1b‐1s.
lower yield than with methyl group.
Notes and references
To substantiate the feasibility of this method, a gram scale
synthesis (Scheme 4) was performed using aminoacetonitrile 1d
(1.53 g, 5 mmol), (3,4‐difluorophenyl)boronic acid (1.2 g, 7.5 mmol),
Pd(TFA)2 (0.5 mmol), L2 (0.5 mmol) and CF3CO2NH4 (5 mmol) in
anhydrous toluene. The product (3jw) could be obtained in 60%
yield.
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