I2-Catalyzed diamination of acetyl-compounds for the synthesis of multi-substituted imidazoles

Article abstract of DOI:10.1039/c5nj00910c

An expedient and straightforward synthetic route to substituted imidazole derivatives from amidines and ketones catalyzed by I₂ has been reported. The reaction proceeded smoothly, and a series of imidazole scaffolds were produced in good to exc

Full text of DOI:10.1039/c5nj00910c

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I2-Catalyzed diamination of acetyl-compounds for
the synthesis of multi-substituted imidazoles†
Cite this:DOI: 10.1039/c5nj00910c
Jinpeng Qu,ab Ping Wu,ab Dong Tang,ab Xu Meng,c Yongxin Chen,d Shuaibo Guoab
and Baohua Chen*ab
Received (in Montpellier, France)
13th April 2015,
Accepted 21st April 2015
DOI: 10.1039/c5nj00910c
www.rsc.org/njc
An expedient and straightforward synthetic route to substituted C–H/N–H have been reported.14 However, effective as they are,
imidazole derivatives from amidines and ketones catalyzed by I2 has most of these methods suffer from one or more limitations,
been reported. The reaction proceeded smoothly, and a series of such as the requirement of non-ideal solvents, poor functional
imidazole scaffolds were produced in good to excellent yields and group tolerance and the formation of hazardous by-products.15
100% regioselectivity.
Our group is dedicated to the efficient synthesis of multi-
substituted imidazoles via metal-catalyzed oxidative processes.16
Over the past years, C–H/N–H functionalization and C–N bond In recent times, we have reported the copper and zinc co-catalyzed
formation have been intensely studied,1 owing to the versatility synthesis of imidazoles via the activation of sp3 C–H and N–H
of the C–N bond in numerous N-containing natural products2 bonds. However, the reactions required expensive ligands and
and therapeutically important drug molecules.3 This process is high temperature.17 Thus, we are interested in investigating a
also prevalent and productive in the synthesis of a broad variety direct synthesis of multi-substituted imidazoles in the absence of
of N-containing organic materials, which was often promoted ligands under mild conditions. To achieve a green procedure
by transition metal catalysts such as palladium,4 iron5 and which is environmentally friendly and atom economical, we first
copper.6
reported a novel and efficient I2-catalyzed synthesis of tri-
Imidazole is an important fragment found in numerous substituted imidazoles via the oxidative activation of C–H and
compounds among diverse heterocyclic molecules,7 which is N–H bonds from amidines and ketones. It showed several
widely adopted in natural products, and biological and pharma- advantages compared to our previous methods, such as the
ceutical industries. As a privileged structural motif, its pharma- use of an inexpensive and environmentally friendly catalyst,
cological properties, including antitumoral,8 antimicrobial9 and ligand-free conditions, and ease of operation, and did not need
antiinflammatory,10 are widely exploited and utilized. In addi- a specific atmosphere.
tion, its photophysical properties have potential applications in
Hence, a simple and economical method for the synthesis of
material chemistry, such as, in organic electroluminescent multi-substituted imidazoles is expected in terms of opera-
devices (OLED).11 It is worth noting that imidazole derivatives tional simplicity and readily available starting materials. In
have been exploited as precursors of ligands or final ligands in this procedure, the reactivity and feasibility of a regioselective
synthetic organic chemistry.12,13
diamination of acetyl with I2 as a catalyst were investigated.
Initially, we commenced our study by investigating the
Given the importance as they are, diverse transition metal
catalyzed direct C–N formation reactions via the cleavage of reaction of N-phenylbenzamidine (1a) and acetophenone (2a)
as the model reaction with I2 (10%) as a catalyst in toluene at
80 1C for 5 h. To our delight, the desired 1,2,4-triphenyl
imidazole (3a) was obtained in 48% yield (Table 1, entry 1).
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou,
Gansu, 730000, P. R. China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Lanzhou, 730000, P. R. China. E-mail: chbh@lzu.edu.cn;
Fax: + 86(931)8912582
c State Key Laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China
d Key Laboratory of Petroleum Resources Research, Institute of Geology and
Geophysics, Lanzhou 730000, China
In screening of the solvents, toluene was the best solvent
among CH3CN, N-methyl-2-pyrrolidone (NMP), dimethyl sulph-
oxide (DMSO), PhCl and EtOH (Table 1, entries 2–7). Continuous
increase of temperature failed to enhance the product yield
substantially when the temperature reached 100 1C (Table 1,
entries 9–11). Fortunately, 3a was isolated in 63% yield (Table 1,
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nj00910c entry 9) in the presence of the Lewis acid ZnI2 (10%).
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope of amidinea
I2
Lewis acid Additive
(1.0 equiv.) Solvent T (1C) Yieldb (%)
Entry
R1, R2
Product
Yieldb (%)
Entry (%) (%)
1
2
3
4
5
6
7
8
9
2-Me, H, 1b
3-Ethyl, H, 1c
4-Me, 4-Me, 1d
4-Me, 4-Cl, 1e
4-Cl, H, 1f
3-Cl, H, 1g
H, 2-Cl, 1h
3b
3c
3d
3e
3f
3g
3h
3i
88
81
92
95
94
83
82
62
87
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
—
10
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Ph–Me
NMP
DMSO
Ph–Cl
DMF
EtOH
CH3CN
Ph–Me
80
80
80
80
80
80
80
80
48
Trace
Trace
41
31
38
22
56
H, 4-CF3, 1i
4-Me, 4-OMe, 1j
ZnI2 (0.1)
ZnI2 (0.1)
ZnI2 (0.1)
ZnI2 (0.1)
FeCl3 (0.1)
AlCl3 (0.1)
ZnCl2 (0.1)
PivOH (0.1)
ZnI2 (0.1)
ZnI2 (0.1)
ZnI2 (0.1)
3j
9
Ph–Me 100
Ph–Me 60
63
49
65
36
42
55
28
10
11
12
13
14
15
16
17
18
Ph–Me 120
Ph–Me 100
Ph–Me 100
Ph–Me 100
Ph–Me 100
Ph–Me 100
Ph–Me 100
Ph–Me 100
10
3k
—
52
Nr
11
4 Å M.S.
4 Å M.S.
4 Å M.S.
51c, 85d, 87e
Nr
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), I2 (10%), 4 Å M.S.
25 f, 84g
b
(1.0 equiv.), ZnI2 (10%), PhMe (2.0 mL), 100 1C, 5 h. Isolated yields.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), I2 (10%), Lewis acid,
b
c
d
e
f
additive, solvent (2.0 mL), 5 h. Isolated yield. 2 h. 5 h. 8 h. Reaction
was carried out under the nitrogen atmosphere. g Reaction was carried out
under the oxygen atmosphere. Nr = No reaction.
or some electron-donating groups including phenyl, methoxyl
and methyl reacted smoothly with 1a, and good yields ranged
from 69% to 96% (Table 3, entries 1–15). In particular, the
Furthermore, the addition of 4 Å molecular sieves (M.S.) substrates with trifluoromethyl (2h) were also well tolerated
(1.0 equiv.) could improve the yield to 85% (Table 1, entry 16). giving a 50% yield (Table 3, entry 7). Moreover, the substrate
Further control experiments indicated that reducing the reaction with a methoxy group at the ortho-position afforded the corre-
time would decrease the yield, and an increase in the reaction sponding product 3q in 79% yield (Table 3, entry 6), which
time did not show a better result (Table 1, entry 16). When the indicated that the reaction may be insensitive to steric hin-
reaction was carried out under nitrogen and oxygen atmospheres, drance. Additionally, the catalytic system was also applicable
the yield of the reaction under the nitrogen atmosphere was for 2-acetonaphthone and 6-methoxy-2-acetonaphthone under
apparently lower, which proved that O2 in the air played a vital optimized conditions offering 88% and 86% yields, respectively
role in the process (Table 1, entry 18).
(Table 3, entries 11 and 12).
With the optimized conditions in hand, we set out to
Notably, the reactions of 2-butanone and methyl isobutyl
investigate the reactivities of amidines and ketones, as shown ketone with amidine successfully proceeded to generate the
in Table 2. A variety of 1,2,4-trisubstituted imidazoles (3b–k) desired products, and the yields were 93% and 95%, respec-
could be obtained by employing various amidines (1b–l) and tively (Table 3, entries 13 and 14). Unfortunately, the reactions
acetophenone (2a) giving 52–95% yields (Table 2, entries 1–11). failed to give ideal results when substrates with 2-nitro,
Generally, halogen substituents as well as some electron- 4-amino or 4-dimethylamino were applied to this cycloaddition
donating groups such as methoxy-, methyl-, and ethyl- provided reaction, as well as 1-(pyridin-2-yl)ethanone (Table 3, entries 8–10
good to excellent yields (Table 2, entries 1–7). Nevertheless, the and 15), which might be because the nitrogen atom effected the
electron-deficient group trifluoromethyl reduced the yields formation of reaction intermediates.
apparently to only 62% (Table 2, entry 8), which might be
To gain a further insight into the reaction, 2,2,6,6-
attributed to the electronic effects. The substrate N-phenyl- tetramethyl-1-piperidinyloxy (TEMPO, 2.0 equiv.) was added to
nicotinimidamide with the pyridine ring can also be applied the system, and the reaction provided an excellent yield of 84%,
to this strategy, even with a relatively low yield (Table 2, which eliminated radical processes (Scheme 1).
entry 10). Disappointingly, we failed to find the target product
when N-phenylpivalimidamide was applied to the system above results, a proposed mechanism for this I2-catalyzed
(Table 2, entry 11). C–H/N–H oxidative cyclization is illustrated in Scheme 2. The
On the basis of the aforementioned information18 and the
On the other hand, different ketones of either electron-poor or Ortoleva–King reaction promoted by the Lewis acid was the key
electron-rich groups resulted in the targets in good yields. All the step for this reaction. Initially, acetophenone 1a was converted
ketones containing halogen substituents (fluoro-, chloro- and bromo-) into a-iodoketone 1aa in the presence of I2, with release of
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Table 3 Substrate scope of ketonesa
Table 3 (continued)
Entry
1
R3
Product
Yieldb (%)
Entry
11
R3
Product
Yieldb (%)
69
88
2
3
4
84
96
77
12
86
93
13
14
95
Nr
15
—
a
5
89
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), I2 (10%), 4 Å M.S.
b
(1.0 equiv.), ZnI2 (10%), PhMe (2.0 mL), 100 1C, 5 h. Isolated yields.
6
7
79
50
Scheme 1 Reaction carried out under optimized conditions and TEMPO.
molecular HI. Then, intermediate 2aa, which could be tauto-
merized from amidine 2a, reacted with a-iodoketone 1aa to
form the intermediate A. Simultaneously, with release of mole-
cular H2O, the subsequent intramolecular cyclization of the
intermediate A afforded the desired product 3a.
In summary, we have illustrated a convenient and direct
synthetic route to contribute imidazole derivatives from the
amidines and ketones in the presence of air, using I2 as the
catalyst and ZnI2 as the Lewis acid. The regioselective diamina-
tion reaction was carried out through sp3 C–H bond oxidation,
tolerating a wide range of functional groups such as fluoro-,
chloro-, bromo-, methoxyl-, phenyl- and alkyl-, which afforded
the corresponding imidazole scaffolds in good to excellent
yields.
8
—
—
—
Nr
Nr
Nr
9
10
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All reagents were commercially available and used as is without
1
further purification. H NMR spectra were recorded at 300 or
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General procedure for the synthesis of 1,2,4-triphenyl-
imidazole (3a)
All the reactions were carried out in a reaction vessel (10 mL),
N-phenylbenzamidine (1a, 0.2 mmol), acetophenone (2a, 0.2 mmol),
I2 (10 mol%), ZnI2 (10 mol%), 4 Å M.S. (1.0 equiv.), and PhMe
(2.0 mL) were successfully mixed in the flask using a magnetic
stir bar and reacted at 100 1C for 5 h in the presence of air. Then
the mixture was removed from the oil bath and cooled to room
temperature. The mixture was filtered and washed with ethyl
acetate (3 Â 50 mL) and the crude product was obtained by
concentrating under reduced pressure. Finally, product 3a was
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