Copper-catalyzed tandem C-N bond formation reaction: Selective synthesis of 2-(trifluoromethyl)benzimidazoles

Article abstract of DOI:10.1055/s-0028-1088160

A highly practical method for the synthesis of fluorinated benzimidazoles was developed by CuI/TMEDA-catalyzed cross-coupling reaction of N-(2-haloaryl)trifluoroacetimidoyl chlorides with primary amines. The present double amination process tolerates the

Full text of DOI:10.1055/s-0028-1088160

PAPER
1431
Copper-Catalyzed Tandem C–N Bond Formation Reaction: Selective
Synthesis of 2-(Trifluoromethyl)benzimidazoles
Selective Synthesis of
u
2-(Trifluorom
-
ethyl)b
Wenzimidazoles ang Chen, Xing-Guo Zhang,* Ping Zhong, Mao-Lin Hu
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, P. R. of China
Fax +86(577)88368607; E-mail: zxg@wzu.edu.cn
Received 9 December 2008; revised 8 January 2009
Transition metal catalyzed C–N bond formation has been
an area of intensive research during the past decade.13 Pi-
oneering work has been reported concerning the palladi-
um-14 or copper-15 catalyzed N-arylation and alkenylation
Abstract: A highly practical method for the synthesis of fluorinated
benzimidazoles was developed by CuI/TMEDA-catalyzed cross-
coupling reaction of N-(2-haloaryl)trifluoroacetimidoyl chlorides
with primary amines. The present double amination process toler-
ates the presence of Cl, Br, or I substituent at the 2-position of the coupling reactions. In 2007, Buchwald16 developed a cop-
phenyl group.
per-catalyzed tandem C–N bond forming reaction of 1,4-
diiodo(dibromo)-1,3-dienes with tert-butyl carbamate to
prepare pyrroles and heteroarylpyrroles. Inspired by the
aforementioned work, we envisioned whether N-(2-halo-
aryl)trifluoroacetimidoyl chlorides could undergo double
amination reaction with primary amines to construct N-
substituted 2-(trifluoromethyl)benzimidazole framework
by the similar tandem amination reaction strategy.
Key words: copper, double amination, N-(2-haloaryl)trifluoroacet-
imidoyl chlorides, primary amines, benzimidazoles
Benzimidazole derivatives are known as an important
class compounds due to their wide range of biological ac-
tivities.1 Heterocycles containing a benzimidazole scaf-
fold were reported as drug leads (such as polymerase
inhibitor)2 and commercial pharmaceutical products (such
as telmisartan),3 and were also widely used in fungicides,
herbicides, and other veterinary applications.4 It is well
known that the trifluoromethyl group has a great effect on
biological activity and often confers significant changes
in chemical and physical properties.5 The introduction of
a trifluoromethyl group into benzimidazole resulted in
compounds with a broad spectrum of insecticidal and her-
bicidal activities.6 Consequently, a number of methods
have been reported for the synthesis of trifluoromethyl-
containing benzimidazole derivatives.7 The classical
methods for these compounds involve the direct trifluo-
romethylation of benzimidazoles8 and the condensation of
o-phenylenediamine9 or o-nitroaniline10 with trifluoroace-
tic acid or trifluoroacetic anhydride. Uneyama’s group,11
for example, has described the preparation of 2-(trifluo-
romethyl)benzimidazoles by electrochemical oxidative
intramolecular cyclization of N,N¢-disubstituted trifluoro-
ethanimidamides. In an attempt to expand the diversity of
the available starting materials, Ma and co-workers12 pre-
pared N-substituted 2-(trifluoromethyl)benzimidazoles
by a Cu-catalyzed cascade aryl amination/condensation
process of 2-iodo(bromo)trifluoroacetanilides with pri-
mary amines. Herein, we wish to report a new process for
the formation of N-substituted 2-(trifluoromethyl)benz-
imidazoles via tandem amination reactions of N-(2-ha-
loaryl)trifluoroacetimidoyl chlorides with primary
amines.
With this idea in mind, we examined the double amination
reaction of N-(2-iodophenyl)trifluoroacetimidoyl chloride
(1a), which can be conveniently prepared from 2-iodo-
aniline and trifluoroacetic acid.17 A variety of ligands,
bases and solvents were examined to optimize the reaction
conditions, and the results are summarized in Table 1. Ini-
tially, a suitable ligand was screened for the reaction of
substrate 1a with benzylamine (2a), CuI and Cs2CO3 in
toluene at 110 °C (entries 1–5). To our delight, N,N,N¢,N¢-
tetramethylethylenediamine (L2) gave the best results
among the four ligands L1–L4 tested, and the correspond-
ing fluorinated benzimidazole 3a was obtained in 98%
yield (entry 3). We found that the amount of L2 affected
the reaction, and the yield of 3a was reduced sharply to
46% in the presence of 10 mol% of L2. Subsequently, the
effect of base was tested (entries 3 and 7–9). The results
indicated that the choice of base also played a crucial role
in the reaction because the formation of 3a through elim-
ination of HX presumably requires the strong basicity.18
Thus, Cs2CO3 was found to provide the best results.
Switching to mild bases, such as K2CO3, K3PO4, or trieth-
ylamine, resulted in low yields (entries 7–9). Finally, a se-
ries of other solvents, including DMF, THF, dioxane, and
MeCN were evaluated and found to be less effective than
toluene (entries 10–13).
With the optimized conditions in hand, we next explored
the scope and generality of this coupling reaction. A range
of N-(2-halophenyl)trifluoroacetimidoyl chlorides and
primary amines were used to investigate the synthesis of
N-substituted 2-(trifluoromethyl)benzimidazoles. The re-
sults are summarized in Table 2. These results demon-
strated that a variety of N-(2-halophenyl)trifluoro-
acetimidoyl chlorides were compatible with these reac-
tion conditions. Interestingly, the less expensive and more
SYNTHESIS 2009, No. 9, pp 1431–1436
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088160; Art ID: F25208SS
© Georg Thieme Verlag Stuttgart · New York

1432
M.-W. Chen et al.
PAPER
Table 2 Synthesis of 2-(Trifluoromethyl)benzimidazolesa
Table 1 Optimization of Double Amination of N-(2-Iodophenyl)tri-
fluoroacetimidoyl Chloridea
R
X
N
CuI, L2
Cl
+
H2N
R
I
CF3
CuI, L1–L4
Cs2CO3
Cl
N
N
N
+
N
CF3
NH2
base, solvent
CF3
1
2
N
CF3
3
1a
2a
3a
Entry 1, X =
2, R =
Product Yield
3
(%)b
98
89
95
83
89
93
88
98
79
82
76
86
73
70
92
62
89
77
76
70
NH HN
N
N
1
2
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
Br (1b)
Br (1b)
Cl (1c)
Cl (1c)
PhCH2 (2a)
3a
3b
3c
3d
3e
3f
N
H
N
N
N
H
L1
L2
L3
L4
4-MeOC6H4CH2 (2b)
4-MeC6H4CH2 (2c)
4-ClC6H4CH2 (2d)
2-ClC6H4CH2 (2e)
4-FC6H4CH2 (2f)
2-FC6H4CH2 (2g)
PhCHMe (2h)
Entry
1
Ligand/mol% Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
Yield (%)b
3
none
Cs2CO3
19
57
98
64
76
46
trace
64
48
68
78
26
19
4
2
L1/20
L2/20
L3/20
L4/20
L2/10
L2/20
L2/20
L2/20
L2/20
L2/20
L2/20
L2/20
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
5
3
6
4
7
3g
3h
3i
5
8
6
9
MeCH2CH2CH2 (2i)
4-MeC6H4 (2j)
2-MeC6H4 (2k)
4-MeOC6H4 (2l)
3-MeOC6H4 (2m)
2-MeOC6H4 (2n)
4-ClC6H4 (2o)
7
10
11
12
13
14
15
16
17
18
19
20
3j
8
K2CO3
K3PO4
3k
3l
9
10
11c
12
13d
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3m
3n
3o
3p
3a
3j
THF
dioxane
MeCN
4-NO2C6H4 (2p)
PhCH2 (2a)
a Reactions were carried out with 1.0 mmol of 1a, 1.2 mmol of 2a, 0.1
mmol of CuI, 2.0 mmol of base, 0.1–0.2 mmol of ligand in 3 mL of
solvent in a sealed tube at 110 °C for 8 h.
4-MeC6H4 (2j)
PhCH2 (2a)
b Isolated yield.
c At 65 °C.
3a
3j
d At 80 °C.
4-MeC6H4 (2j)
available aryl chlorides can also be converted into the cor-
responding benzimidazoles. As shown in Table 2, N-(2-
chlorophenyl)-, N-(2-bromophenyl)- and N-(2-iodophe-
nyl)trifluoroacetimidoyl chlorides ran smoothly in this
procedure and afforded the corresponding benzimidazoles
in good to excellent yields. It is well known that the reac-
tivity of aryl iodides is higher than that of aryl bromides
and aryl chlorides in the coupling reaction, and the elimi-
nation of HI is easier than that of HBr and HCl in the am-
ination of haloarenes. However, less active aryl bromides
and aryl chlorides can be also transformed to the corre-
sponding benzimidazoles in this Cu-catalyzed double am-
ination reaction, albeit aryl bromides and aryl chlorides
afforded lower yields of products (entries 17–20). It is
worth noting that the strong electron-withdrawing ability
of trifluoromethyl is essential to this double amination re-
action. Without the activation of C–Cl bond by trifluoro-
methyl, the corresponding benzimidazole could not be ob-
tained. For example, the amination took place only at the
I
Cl
21
PhCH2 (2a)
–
0
N
(1d)
a Reactions were carried out with 1.0 mmol of 1, 1.2 mmol of amine,
0.1 mmol of CuI, 2.0 mmol of Cs2CO3, 0.2 mmol of TMEDA in 3 mL
of toluene in a sealed tube at 110 °C for 8 h.
b Isolated yield.
C–I bond when N-(2-iodophenyl)acetimidoyl chloride
(1d) was treated with benzylamine (2a) under the standard
conditions, without the formation of any benzimidazole
product (entries 21).
As listed in Table 2, both aromatic and aliphatic amines
were suitable substrates for this tandem amination reac-
tion. It should be noted that electronic effects of the sub-
stituent in the primary amine have significant influence on
the yields. In general, aromatic amines (Table 2, entries
Synthesis 2009, No. 9, 1431–1436 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of 2-(Trifluoromethyl)benzimidazoles
1433
N-Substituted 2-(Trifluoromethyl)benzimidazoles 3 from N-(2-
Halophenyl)acetimidoyl Chlorides 1; General Procedure
A flame-dried Schlenk tube with a magnetic stirring bar was
charged with N-(2-halophenyl)trifluoroacetimidoyl chloride 1 (1.0
mmol), primary amine 2 (1.2 mmol), CuI (19.1 mg, 0.1 mmol),
Cs2CO3 (650 mg, 2.0 mmol), N,N,N¢,N¢-tetramethylethylenedi-
amine (L2; 23.2 mg, 0.2 mmol), and toluene (3 mL). The reaction
vessel was fitted with a rubber septum and the system was evacuat-
ed and back-filled with N2. The reaction mixture was stirred for 30
min at r.t., and then heated at 110 °C for 8 h. The mixture was
cooled to r.t. and the solvent was evaporated under reduced pres-
sure. The residue was purified by flash column chromatography on
a silica gel column using EtOAc–petroleum ether (1:10) as eluent to
give the product 3.
10–16) afforded higher yields than aliphatic amines
(Table 2, entries 1–9). In comparison with aromatic
amines bearing an electron-donating group on the phenyl
ring (e.g., methyl or methoxy group), electron-deficient 4-
nitrobenzeneamine reduced the reaction yield significant-
ly (Table 2, entry 16). In addition, the yields were influ-
enced slightly by the different position of the substituent
on the phenyl ring in aromatic amines. Thus, low yields
were observed for aromatic amines bearing an ortho-sub-
stituent (Table 2, entries 11 and 14) which might be due to
the steric hindrance of the substrate. All compounds 3
were identified by 1H NMR, 13C NMR, 19F NMR and IR
spectroscopy as well as MS, and the structures were un-
ambiguously confirmed by the X-ray single-crystal dif- 1-Benzyl-2-(trifluoromethyl)-1H-benzo[d]imidazole (3a)12
fraction analysis of 3l (Figure 1).19
Yellowish solid; mp 75–76 °C.
IR (KBr): 3061, 2924, 1593, 1521, 1479, 1428, 1361, 1278, 1188,
747, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89–7.92 (m, 1 H), 7.29–7.38 (m,
6 H), 7.11 (m, 2 H), 5.52 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 48.6, 111.3, 119.3 (q, JC,F = 270.1
Hz), 121.9, 124.0, 125.7, 126.5, 128.4, 129.2, 135.0, 135.8, 141.1
(q, JC,F = 38.0 Hz), 141.4.
19F NMR (CDCl3): d = –61.53.
MS (ESI): m/z = 277 (M + H+).
HRMS (ESI): m/z calcd for C15H11F3N2 + Na ([M + Na]+):
299.0767; found: 299.0763.
1-(4-Methoxybenzyl)-2-(trifluoromethyl)-1H-benzo[d]imida-
zole (3b)
Yellowish solid; mp 80–81 °C.
IR (KBr): 3017, 2941, 1613, 1515, 1466, 1424, 1342, 1265, 1183,
1137, 825, 751 cm–1.
Figure 1 ORTEP diagram of the single crystal X-ray structure of
compound 3l
1H NMR (300 MHz, CDCl3): d = 7.88–7.91 (m, 1 H), 7.29–7.35 (m,
3 H), 7.06 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 5.45 (s, 2
In conclusion, we have successfully developed a highly
practical method to synthesize N-substituted 2-(trifluo-
romethyl)benzimidazoles by CuI/TMEDA (L2) catalyzed
H), 3.75 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 48.3, 55.4, 111.4, 114.6, 119.4 (q,
JC,F = 270.1 Hz), 121.8, 123.9, 125.7, 127.1, 128.0, 135.8, 140.9 (q,
coupling reaction of N-(2-haloaryl)trifluoroacetimidoyl JC,F = 38.0 Hz), 141.5, 159.7.
19F NMR (CDCl3): d = –61.65.
MS (ESI): m/z = 307 (M + H+).
HRMS (ESI): m/z calcd for C16H13F3N2O + Na ([M + Na]+):
chlorides with primary amines. It is worth noting that N-
(2-chlorophenyl)-, N-(2-bromophenyl)-, and N-(2-iodo-
phenyl)trifluoroacetimidoyl chlorides can participate
smoothly in the amination reaction. The tandem process
allows the assembly of a wide range of N-substituted 2-
(trifluoromethyl)benzimidazoles by changing different
aromatic primary amines or aliphatic primary amines.
329.0872; found: 329.0874.
1-(4-Methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3c)
Yellowish solid; mp 65–66 °C.
IR (KBr): 3057, 2963, 1592, 1520, 1477, 1428, 1355, 1278, 1181,
1125, 800, 748 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89–7.92 (m, 1 H), 7.28–7.36 (m,
3 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 5.49 (s, 2
H), 2.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 48.6, 111.4, 119.4 (q,
JC,F = 270.1 Hz), 121.9, 124.0, 125.7, 126.6, 129.9, 132.1, 135.9,
138.3, 141.1 (q, JC,F = 38.0 Hz), 141.5.
19F NMR (CDCl3): d = –61.57.
MS (ESI): m/z = 291 (M+ H+).
Chemicals were either purchased from commercial vendors or puri-
fied by standard techniques. Petroleum ether used refers to the frac-
1
tion boiling at 60–90 °C. H NMR and 13C NMR spectra were
recorded in CDCl3 on a Bruker Avance 300 (300 M Hz) spectro-
meter using TMS as the internal standard. 19F NMR spectra were re-
corded in CDCl3 on a Bruker Avance 300 (282.2 MHz)
spectrometer using CF3CO2H as the external standard. All chemical
shifts (d) were expressed in parts per million, and coupling con-
stants (J) were given in Hertz. All reactions were conducted under
N2 using standard Schlenk techniques. Column chromatography
was performed using EM silica gel 60 (300–400 mesh).
HRMS (ESI): m/z calcd for C16H14F3N2 ([M + H]+): 291.1104;
found: 291.1105.
Synthesis 2009, No. 9, 1431–1436 © Thieme Stuttgart · New York

1434
M.-W. Chen et al.
PAPER
1-(4-Chlorobenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
MS (ESI): m/z = 295 (M + H+).
(3d)
Yellowish oil.
HRMS (ESI): m/z calcd for C15H11F4N2 ([M + H]+): 295.0853;
found: 295.0853.
IR (neat): 2948, 1666, 1522, 1453, 1278, 1119, 1017, 806, 748 cm–1.
1-(1-Phenylethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3h)
Yellowish oil.
1H NMR (300 MHz, CDCl3): d = 7.90–7.93 (m, 1 H), 7.34–7.39 (m,
2 H), 7.24–7.31 (m, 3 H), 7.03 (d, J = 8.4 Hz, 2 H), 5.50 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 48.0, 111.1, 119.3 (q, JC,F = 270.1
Hz), 122.1, 126.0, 127.9, 128.8, 129.5, 133.6, 134.5, 138.8, 141.0
(q, JC,F = 38.0 Hz), 141.4.
19F NMR (CDCl3): d = –61.72.
MS (ESI): m/z = 311 (M + H+).
HRMS (ESI): m/z calcd for C15H11ClF3N2 ([M + H]+): 311.0557;
IR (neat): 3062, 2989, 1587, 1524, 1453, 1422, 1280, 1257, 1177,
1125, 747, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87 (d, J = 8.1 Hz, 1 H), 7.24–
7.39 (m, 6 H), 7.14 (m, 1 H), 6.97 (d, J = 8.1 Hz, 1 H), 6.03 (q,
J = 7.4 Hz, 1 H), 2.02 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 18.4, 55.0, 113.4, 119.7 (q,
JC,F = 270.1 Hz), 122.0, 123.5, 125.1, 126.6, 128.4, 129.1, 134.0,
138.4, 140.9 (q, JC,F = 38.0 Hz), 142.1.
19F NMR (CDCl3): d = –61.87.
MS (ESI): m/z = 291 (M + H+).
found: 311.0555.
1-(2-Chlorobenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3e)
Yellowish oil.
IR (neat): 3065, 2929, 1678, 1593, 1525, 1465, 1426, 1347, 1278,
1198, 1097, 909, 738 cm–1.
HRMS (ESI): m/z calcd for C16H13F3N2 + Na ([M + Na]+):
313.0923,.found: 313.0920.
1H NMR (300 MHz, CDCl3): d = 7.92–7.95 (m, 1 H), 7.43–7.47 (m,
1 H), 7.35–7.39 (m, 2 H), 7.22–7.34 (m, 2 H), 7.07–7.20 (m, 1 H),
6.44 (d, J = 7.5 Hz, 1 H), 5.63 (s, 2 H).
1-Butyl-2-(trifluoromethyl)-1H-benzo[d]imidazole (3i)20
Yellowish oil.
IR (neat): 3058, 2963, 1590, 1520, 1477, 1457, 1366, 1266, 1196,
1130, 1096, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.84–7.87 (m, 1 H), 7.30–7.43 (m,
3 H), 4.27 (t, J = 7.8 Hz, 2 H), 1.78 (tt, J = 15.6, 7.8 Hz, 2 H), 1.35–
1.45 (qt, J = 15.6, 7.3 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 20.1, 32.2, 45.2, 110.8, 119.5
(q, JC,F = 270.1 Hz), 121.8, 123.7, 125.4, 135.6, 140.7 (q, JC,F = 38.0
Hz), 141.4.
13C NMR (75 MHz, CDCl3): d = 46.0, 111.0, 119.3 (q, JC,F = 270.1
Hz), 122.0, 124.2, 126.0, 126.7, 127.6, 129.5, 129.9, 132.2, 132.7,
135.7, 141.3 (q, JC,F = 38.0 Hz), 141.5.
19F NMR (CDCl3): d = –61.83.
MS (ESI): m/z = 311 (M + H+).
HRMS (ESI): m/z calcd for C15H11ClF3N2 ([M + H]+): 311.0557;
found: 311.0557.
19F NMR (CDCl3): d = –61.92.
MS (ESI): m/z = 243 (M + H+).
1-(4-Fluorobenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3f)
Yellowish solid; mp 62–63 °C.
HRMS (ESI): m/z calcd for C12H14F3N2 ([M + H]+) 243.1104;
IR (KBr): 3070, 2949, 1606, 1514, 1467, 1423, 1388, 1193, 1128,
845, 751 cm–1.
found: 243.1102.
1-p-Tolyl-2-(trifluoromethyl)-1H-benzo[d]imidazole (3j)
Yellowish oil.
1H NMR (300 MHz, CDCl3): d = 7.88–7.91 (m, 1 H), 7.33–7.37 (m,
2 H), 7.25–7.28 (m, 1 H), 7.06–7.10 (m, 2 H), 6.95–7.01 (m, 2 H),
5.48 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 47.9, 111.1, 116.0, 116.3, 119.3 (q,
JC,F = 270.1 Hz), 121.9, 125.8, 128.3, 130.9, 135.7, 140.9 (q,
JC,F = 38.0 Hz), 141.4, 162.7 (d, JC,F = 249.9 Hz).
IR (neat): 3041, 2932, 1591, 1517, 1452, 1420, 1334, 1288, 1264,
1137, 846, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92–7.95 (m, 1 H), 7.36–7.41 (m,
4 H), 7.25–7.31 (m, 2 H), 7.14–7.17 (m, 1 H), 2.49 (s, 3 H).
19F NMR (CDCl3): d = –61.51, –113.47.
MS (ESI): m/z = 295 (M + H+).
HRMS (ESI): m/z calcd for C15H11F4N2 ([M + H]+): 295.0853;
13C NMR (75 MHz, CDCl3): d = 21.5, 111.5, 119.2 (q, JC,F = 270.1
Hz), 121.6, 126.0, 127.5, 128.7, 130.6, 132.1, 133.2, 138.9, 140.6
(q, JC,F = 38.0 Hz), 141.5.
19F NMR (CDCl3): d = –60.52.
MS (ESI): m/z = 277 (M + H+).
found: 295.0859.
1-(2-Fluorobenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3g)
Yellowish solid; mp 63–64 °C.
HRMS (ESI): m/z calcd for C15H12F3N2 ([M + H]+): 277.0947;
found: 277.0945.
IR (KBr): 3059, 2951, 1589, 1526, 1472, 1429, 1359, 1279, 1175,
1127, 841, 751 cm–1.
1-o-Tolyl-2-(trifluoromethyl)-1H-benzo[d]imidazole (3k)
Yellowish oil.
1H NMR (300 MHz, CDCl3): d = 7.89–7.92 (m, 1 H), 7.33–7.37 (m,
4 H), 7.26–7.30 (m, 1 H), 6.98–7.13 (m, 1 H), 6.73 (m, 1 H), 5.58
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 42.2 (dq, JC,F = 4.3 Hz, 7.5 Hz),
110.9, 115.7, 115.9, 119.3 (q, JC,F = 270.1 Hz), 121.9, 122.4, 124.9,
125.9, 127.8, 130.2, 135.6, 140.5 (q, JC,F = 38.0 Hz), 141.3, 159.9
(d, JC,F = 249.9 Hz).
IR (neat): 3059, 2928, 1590, 1524, 1498, 1456, 1417, 1289, 1263,
1203, 1139, 912, 721 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94–7.97 (m, 1 H), 7.29–7.52 (m,
6 H), 6.99 (d, J = 7.4 Hz, 1 H), 1.96 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 17.2, 111.3, 119.1 (q, JC,F = 270.1
Hz), 121.8, 124.2, 126.1, 127.4, 128.8, 130.6, 131.5, 133.4, 136.7,
136.9, 140.5 (q, JC,F = 38.0 Hz), 141.0.
19F NMR (CDCl3): d = –61.68, –118.22.
Synthesis 2009, No. 9, 1431–1436 © Thieme Stuttgart · New York

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Selective Synthesis of 2-(Trifluoromethyl)benzimidazoles
1435
19F NMR (CDCl3): d = –60.61.
MS (ESI): m/z = 277 (M + H+).
HRMS (ESI): m/z calcd for C15H12F3N2 ([M + H]+): 277.0947;
13C NMR (75 MHz, CDCl3): d = 111.2, 119.0 (q, JC,F = 270.1 Hz),
121.8, 124.5, 126.3, 129.0, 130.4, 133.2, 136.4, 137.3, 140.9 (q,
JC,F = 38.0 Hz), 141.2.
19F NMR (CDCl3): d = –60.71.
MS (ESI): m/z = 297 (M + H+).
found: 277.0944.
1-(4-Methoxyphenyl)-2-(trifluoromethyl)-1H-benzo[d]imida-
zole (3l)11a
Yellowish solid; mp 90–91 °C.
HRMS (ESI): m/z calcd for C14H9ClF3N2 ([M + H]+): 297.0401;
found: 297.0402.
IR (KBr): 2972, 1610, 1514, 1453, 1419, 1296, 1254, 1205, 1180,
1138, 1026, 850, 680 cm–1.
1-(4-Nitrophenyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
(3p)
Yellowish solid; mp 107–108 °C.
1H NMR (300 MHz, CDCl3): d = 7.91–7.92 (m, 1 H), 7.32–7.40 (m,
4 H), 7.14–7.16 (m, 1 H), 7.05–7.08 (m, 2 H), 3.89 (s, 3 H).
IR (KBr): 2924, 1594, 1528, 1498, 1453, 1349, 1293, 1263, 1157,
915, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.49 (m, 2 H), 7.96–7.97 (m, 1 H),
7.67 (d, J = 8.7 Hz, 2 H), 7.44–7.47 (m, 2 H), 7.15–7.18 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.8, 111.4, 115.1, 119.2 (q,
JC,F = 270.1 Hz), 121.6, 124.2, 125.9, 127.1, 128.9, 137.8, 141.1 (q,
JC,F = 38.0 Hz), 142.0, 160.7.
19F NMR (CDCl3): d = –60.45.
MS (ESI): m/z = 293 (M + H+).
HRMS (ESI): m/z calcd for C15H12F3N2O ([M + H]+): 293.0896,
13C NMR (75 MHz, CDCl3): d = 110.8, 119.0 (q, JC,F = 270.1 Hz),
122.2, 125.0, 125.6, 126.8, 128.8, 136.9, 140.2, 140.7 (q, JC,F = 38.0
Hz), 141.2, 148.8.
19F NMR (CDCl3): d = –60.74.
MS (ESI): m/z = 308 (M + H+).
found: 293.0896.
1-(3-Methoxyphenyl)-2-(trifluoromethyl)-1H-benzo[d]imida-
zole (3m)
Yellowish oil.
HRMS (ESI): m/z calcd for C14H9F3N3O2 ([M + H]+): 308.0641;
found: 308.0647.
IR (neat): 2941, 1602, 1525, 1493, 1461, 1290, 1267, 1240, 1207,
1006, 853, 695 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 7.90–7.93 (m, 1 H), 7.35–7.48 (m,
3 H), 6.93–7.10 (m, 4 H), 3.83 (s, 3 H).
This work was supported by the National Natural Science Founda-
tion of China (Grant No 20872112).
13C NMR (75 MHz, CDCl3): d = 55.8, 111.5, 113.3, 115.8, 119.1 (q,
JC,F = 270.1 Hz), 119.7, 121.6, 124.5, 126.0, 130.7, 135.6, 137.3,
140.8 (q, JC,F = 38.0 Hz), 141.2, 160.7.
References
19F NMR (CDCl3): d = –60.54.
MS (ESI): m/z = 293 (M + H+).
HRMS (ESI): m/z calcd for C15H12F3N2O ([M + H]+): 293.0896;
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1 H), 7.30–7.39 (m, 3 H), 7.04–7.13 (m, 3 H), 3.69 (s, 3 H).
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1-(4-Chlorophenyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole
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Synthesis 2009, No. 9, 1431–1436 © Thieme Stuttgart · New York