Fe(OTf)3-catalyzed practical synthesis of 2-trifluoromethylarylimidazoles from o-arylenediamines and hexafluoroacetylacetone

Article abstract of DOI:10.1016/j.tetlet.2016.06.086

An iron-catalyzed practical synthesis of 2-trifluoromethylarylimidazoles through condensation of o-arylenediamines and hexafluoroacetylacetone followed by intramolecular addition and C–C bond cleavage in one-pot has been developed. A series of title compounds were obtained with up to 99% yield. This method is quite practical and suitable for scalable preparation due to simple experimental procedure and readily available reagents.

Full text of DOI:10.1016/j.tetlet.2016.06.086

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Fe(OTf) -catalyzed practical synthesis of 2-
3
trifluoromethylarylimidazoles from o-arylenediamines and
hexafluoroacetylacetone
⇑
Yanmei Zhou, Guanshuo Shen, Yuebo Sui, Haifeng Zhou
Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An iron-catalyzed practical synthesis of 2-trifluoromethylarylimidazoles through condensation of
o-arylenediamines and hexafluoroacetylacetone followed by intramolecular addition and C–C bond
cleavage in one-pot has been developed. A series of title compounds were obtained with up to 99% yield.
This method is quite practical and suitable for scalable preparation due to simple experimental procedure
and readily available reagents.
Received 17 May 2016
Revised 17 June 2016
Accepted 20 June 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Arylimidazoles
o-Arylenediamines
Hexafluoroacetylacetone
Trifluoromethylation
Introduction
o-arylenediamines and hexafluoroacetylacetone, intramolecular
nucleophile addition, and C–C bond cleavage in the presence of
2
-Trifluoromethylarylimidazoles are widely applicable building
iron catalyst.
blocks in functional materials, agrochemicals, and pharmaceuti-
1
cals. Due to strong electronegativity and steady C–F bonds, the
Results and discussion
acidity, dipole moment, lipophilicity, metabolic stabilities, and bio-
logical properties of the compounds are prone to vary with the
introduction of trifluoromethyl group. Although some elegant
methods have been developed for trifluoromethylation of arenes
and heteroarenes, the approaches to import fluoroalkyl groups
In our initial studies, the reaction of o-phenylenediamine 1a
and hexafluoroacetylacetone 2 was chosen as a model reaction to
screen out the optimum reaction conditions. As shown in Table 1,
the desired product 2-trifluoromethylbenzimidazole 3a was
observed when 1a and 2 were treated in toluene at 80 °C for 24 h
2
3
at the 2-position of arylimidazoles are very rare. For example,
the reactions of o-phenylenediamines with fluorinated partners,
in the presence of 10 mol% iron chloride hexahydrate (FeCl
3
ꢀ6H
2
O).
4,5
6
including trifluoroacetic acid, fluorinated dichlorozine, and flu-
orinated imidolyl chloride were developed.4 Copper-catalyzed
direct C–H oxidative trifluoromethylation of arylimidazoles with
Then we tried different solvents such as 1,4-dioxane, ethanol, and
N,N-dimethylformamide (DMF). The results showed that DMF is
the best one, and gave the product 3a in 88% yield (entries 1–4).
An attempt to enhance the yield of 3a by increasing the reaction
temperature failed (entry 5). The performance of different iron cat-
h
(
trifluoromethyl)trimethylsilane was also realized.7 However,
most of the reported methods were limited to the reactions of o-
arylenediamines with excess amount of volatile and strong corro-
sive trifluoroacetic acid. To develop general and practical
approaches for preparing of 2-trifluoromethylarylimidazoles is
highly desirable. During the course of studying efficient iron-cat-
alyzed transformations,8 we found that 2-trifluoromethylarylimi-
dazoles are readily available by successive condensation of
alysts was also evaluated. Fe(OTf)
3
gave an excellent outcome by
, and provided 3a in 99%
comparing with FeCl , FeCl , Fe(OAc)
2
3
2
yield (entries 4, 6–9). In contrast, the yield of 3a was decreased
from 99% to 71% when lowering the catalyst loading to 5 mol%
(
entry 9–10). Therefore, the subsequent reactions of various
o-arylenediamines 1 with 2 were performed in the presence of
0 mol% Fe(OTf) at 80 °C in DMF for 24 h.
The applicability of this approach for the synthesis of 2-triflu-
oromethylarylimidazoles was exemplified by the reactions of
1
3
⇑
Corresponding author. Tel.: +86 (717)639 5547; fax: +86 (717)639 5580.
E-mail address: haifeng-zhou@hotmail.com (H. Zhou).
http://dx.doi.org/10.1016/j.tetlet.2016.06.086
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0
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2
Y. Zhou et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 1
a
Optimization of reaction conditions
H
N
NH2
O
O
iron catalyst
80 oC, 24 h
+
CF3
F3C
CF3
N
NH
2
1a
2
3a
Entry
Iron catalyst
Solvent
Yield (%)b
1
2
3
4
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
Fe(OAc)
Fe(OTf)
Fe(OTf)
3
3
3
3
3
3
2
ꢀ6H
ꢀ6H
ꢀ6H
ꢀ6H
ꢀ6H
2
O
2
O
2
O
2
O
2
O
Toluene
1,4-Dioxane
Ethanol
DMF
DMF
DMF
DMF
DMF
DMF
DMF
16
30
65
88
78
80
82
86
99
71
c
5
6
7
8
9
2
3
1
0d
3
a
Reaction conditions: o-phenylenediamine (1a; 0.5 mmol), hexafluoroacetylacetone (2; 0.6 mmol), iron catalyst (10 mol%),
solvent (2.0 mL), 80 °C, 24 h.
b
Isolated yield.
c
1
5
00 °C.
mol% Fe(OTf)
d
3
was used.
Table 2
Synthesis of 2-trifluoromethylarylimidazolesa
R2
N
H
N
O
O
R2
3
Fe(OTf) (10 mol%)
R1
R
1
CF
3
+
F C
CF3
3
o
N
DMF, 80 C, 24 h
NH2
1
2
3
Entry
1
Substrate 1
Product 3
Yield (%)b
99 (96)c
NH2
NH2
H
N
1a
1b
3a
3b
CF
3
N
NH2
H
N
2
3
4
CF3
CF3
93
77
87
O N
NH2
2
N
O N
2
NH2
H
N
1c
3c
F3C
NH2
N
F3C
F
F
NH2
H
N
1d
3d
CF
3
F
NH2
N
F
NH2
H
N
5
6
7
8
1e
1f
CF3
3e
3f
90
97
94
80
F
NH2
N
F
NH2
H
N
CF3
Cl
Br
NH
2
N
Cl
NH
2
H
N
1g
1h
CF3
CF3
3g
3h
NH2
N
Br
NH2
H
N
N
Me
NH
2
Me
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Y. Zhou et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2 (continued)
Entry
Substrate 1
Product 3
Yield (%)b
93
Me
NH2
H
Me
Me
N
N
9d
1i
1j
3i
3j
CF3
Me
NH2
NH2
H
N
1
0d
CF3
97 (94)c
EtO C
NH2
2
N
EtO C
2
H
N
Me
N
Me
1
1
1k
3k
61
CF3
NH2
N
H
Ph
N
N
1
1
2e
Ph
1l
3l
n.d.
73
CF3
NH2
N
NH2
NH2
H
N
3
1m
3m
CF3
N
NH2
H
N
H N
CF3
2
1 f
4
NH2
1n
1o
N
3n
3o
67
42
N
F3C
N
H N
N
H
N
2
NH2
NH2
1 f
5
CF3
N
H
N
a
b
c
d
e
f
Reaction conditions: o-arylenediamine (1; 0.5 mmol), hexafluoroacetylacetone (2; 0.6 mmol), Fe(OTf)
Isolated yield.
Gram scale reactions: o-arylenediamine (1; 5.0 mmol), hexafluoroacetylacetone (2; 6.0 mmol), Fe(OTf)
3
(10 mol%), DMF (2.0 mL), 80 °C, 24 h.
3
(10 mol%), DMF (10 mL), 80 °C, 24 h.
2
0 mol% Fe(OTf)
n.d. = not detect.
0 mol% Fe(OTf)
3
was used.
2
3
and 1.2 mmol hexafluoroacetylacetone 2 were used.
NH2
N
CF3
CF
O
O
FeCl3. 6H O (10 mol%)
2
+
o
3
F3C
CF3
toluene, 80 C, 3 h
NH2
NH2
O
1a
2
4, 43%
N
CF3
CF3
H
N
Fe(OTf)3 (10 mol%)
o
CF
3
DMF, 80 C, 24 h
NH2
N
O
4
3a, 93%
Scheme 1. Controlled experiment.
various o-arylenediamines 1 with hexafluoroacetylacetone 2, and
the results are summarized in Table 2. In addition to
o-phenylenediamine (Table 2, entry 1), the o-arylenediamines
bearing electron-withdrawing substituents, such as 4-nitro
example, the reaction of N-methyl-o-phenylenediamine 1k with
2 gave the N-methyl-2-trifluoromethylbenzimidazole 3k in 61%
yield (entry 11). In contrast, N-phenyl-2-trifluoromethylbenzimi-
dazole 3l was not observed by the reaction of N-phenyl-o-
phenylenediamine 1l and 2 (entry 12). The naphthalenediamine
1m was also applicable to this transformation, and provided
the desired product 3m in 73% yield (entry 13). Notably, the
transformation was also compatible with 3,3 ,4,4 -tetraamino-
biphenyl 1n and gave the bisbenzimidazole 3n in 67% yield
(entry 14). The 2,3-diaminopyridine 1o was attempted in this
transformation, but the corresponding 2-trifluoromethylazabeni-
mizazole 3o was isolated in a lower yield of 42% (entry 15).
To demonstrate the practicability of this approach, gram scale
(
entry 2), 4-trifluoromethyl (entry 3), 4,5-difluoro (entry 4), 4-
fluoro (entry5), 4-chloro (entry 6), and 4-bromo (entry 7), were
well tolerated under the optimized conditions and gave the cor-
responding products 3b–3f in 77–97% yields. The electron-donat-
ing methyl, ethyl ester groups substituted o-phenylenediamines
0
0
1
h, 1i, 1j also afforded the corresponding products 3h, 3i, 3j in
8
0%, 93%, 97% yield, respectively. Except for 1H-benzimidazoles,
N-alkyl benzimidazoles also can be prepared using this one-pot
procedure from the corresponding o-phenylenediamines. For
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4
Y. Zhou et al. / Tetrahedron Letters xxx (2016) xxx–xxx
NH2
NH2
O
CF3
Fe(III)
1
a
N
CF3
CF3
N
[Fe]
+
CF
3
NH2
NH2
O
O
O
F3C
CF3
4
5
2
CF3
O
CF3
OH
H
N
H
N
H
N
CF3
N
N
H
CF3
N
H
CF3
3
a
7
6
Scheme 2. A proposed reaction pathway.
syntheses of 3a and 3j were carried out, affording 96% and 94%
isolated yields, respectively (Table 2, entries 1 and 10).
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Acknowledgment
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We acknowledge the financial support from the National
Natural Science Foundation of China (21202092), Startup
Foundation from China Three Gorges University (KJ2012B080,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
0
86.
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