Synthesis of 1-aryl-4-tosyl-5-(trifluoromethyl)-1H-imidazoles

Article abstract of DOI:10.1016/j.jfluchem.2014.04.013

A new synthetic protocol for the synthesis of 1,4,5-trisubstituted imidazoles containing trifluoromethyl group has been developed using van Leusen reaction, which incorporates two-component condensation reaction trifluoroacetimidoyl chlorides with tosylmethylisocyanide. This protocol provides a novel and improved method for obtaining trifluoromethyl containing 1,4,5-trisubstituted imidazoles in good yields.

Full text of DOI:10.1016/j.jfluchem.2014.04.013

Accepted Manuscript
Title: Synthesis of
1-aryl-4-tosyl-5-(trifluoromethyl)-1H-imidazoles
Author: Alexander S. Bunev Maksim A. Vasiliev Vladimir E.
Statsyuk Gennady I. Ostapenko Alexander S. Peregudov
PII:
S0022-1139(14)00104-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.04.013
FLUOR 8309
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Received date:
Revised date:
Accepted date:
3-4-2014
21-4-2014
22-4-2014
Please cite this article as: A.S. Bunev, M.A. Vasiliev, V.E. Statsyuk, G.I. Ostapenko, A.S.
Peregudov, Synthesis of 1-aryl-4-tosyl-5-(trifluoromethyl)-1H-imidazoles, Journal of
Fluorine Chemistry (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.04.013
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Synthesis of 1-aryl-4-tosyl-5-(trifluoromethyl)-1H-imidazoles
Alexander S. Bunev a*, Maksim A. Vasiliev a, Vladimir E. Statsyuk a, Gennady I. Ostapenko a,
Alexander S. Peregudov b
a Togliatti State University, 14 Belorusskaya St, Togliatti 445667, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov
St, B-334, Moscow 119991, Russian Federation
*Corresponding author. Tel.: +78482 535455 ; fax: +78482 535455. E-mail address:
a.s.bunev@gmail.com (A. S. Bunev)
Abstracts.
A new synthetic protocol for the synthesis of 1,4,5-trisubstituted imidazoles containing
trifluoromethyl group has been developed using van Leusen reaction, which incorporates two-component
condensation reaction trifluoroacetimidoyl chlorides with tosylmethylisocyanide. This protocol provides a
novel and improved method for obtaining trifluoromethyl containing 1,4,5-trisubstituted imidazoles in
good yields.
Keywords: Imidazoles, trifluoromethyl azoles, trifluoroacetimidoyl halides, isocyanides, Van Leusen
reaction.
1. Introduction
Fluorine-containing heterocycles are widely recognized as important organic molecules showing
interesting biological activities with a potential for applications in medicine and agriculture [1-7].
Inclusion of trifluoromethyl group-containing nitrogen heterocycles in drug molecules can bring about
remarkable changes in their physical, chemical and biological properties [8-11].
Imidazole and its derivatives play an important role as versatile building blocks for the synthesis of
natural products and as therapeutic agents [12,13]. In particular, substituted imidazoles occur in structures
of a number of anti-flammatory [14], anti-allergic [15], analgesic [16], antitumor [17] agents and
glucagon receptor antagonists [18].
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In recent years, numerous methods have been developed for the synthesis of highly substituted
imidazoles by using various catalytic system including InF3 [19], silica gel or Zeolite HY [20], silica
gel/NaHSO4 [21], molecular iodine [22], HClO4-silica gel [23], and L-proline [24]. In some cases, van
Leusen reaction has been utilized for synthesis of imidazoles [25,26]. Moreover, in recent years a series
of publications, focused on attractive preparation of diverse imidazole derivatives, including optically
active products, was published [27,28]. Apart from a recent work on 5-trifluoromethylimidazolones [29],
there is virtually no information about 5-trifluoromethyl-substituted imidazoles in the literature. This
work is attempt to eliminate this gap.
2. Results and discussion
N-aryltrifluoroacetimidoyl chloride can be utilized in several important synthetic transmutations
[30-32], in particular for synthesis of some trifluoromethyl-containing heterocycles [33-36].
We have shown, that N-aryltrifluoroacetimidoyl chlorides 1a-i react with tosylmethylisocyanide
(TOSMIC) and sodium hydride in THF at room temperature under argon atmosphere to produce 1,4,5-
trisubstituted imidazoles 2a-i (scheme 1).
Ts
N
N
CF3
NaH, THF
r.t., 2 h
N
Ts
N
R
F3C
C
Cl
R
1a-i
2a-i
Yield: 61-78%
a: R = H; b: R = 2-Me; c: R = 4-Me; d: R = 2,4-Me; e: R = 4-MeO;
f: R = 2-Cl; g: R = 4-Cl; h: R = 4-Br; i: R = NO2
Scheme 1.
The starting N-aryltrifluoroacetimidoyl chlorides were synthesized by the method shown in Scheme
2 [37].
NH2
CF3CO2H, Ph3P, Et3N
CCl4, 3h reflux
1a-i
R
Scheme 2.
It is possible to assume the following mechanism of this reaction (scheme 3). The TOSMIC molecule
is deprotonated under action of sodium hydride forming a stable carbanion. The interaction of the
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carbanion with N-aryltrifluoroacetimidoyl chloride and subsequent intramolecular cyclization of the
formed intermediate lead to the target imidazoles.
Ar
F3C
Cl
NaH
-H2
Ar
N
Ts
Ts
N
Ts
NC
NC
Cl
CF3
NC
Ar
N
Ar
F3C
F3C
N
C
H
Ts
-Cl
N
N
Ts
Scheme 3.
It is worth mentioning that the maximum yield (65-78 %) is reached using trifluoroacetimidoyl
halides containing electron-donating substituents. In general, the synthesis of the target compounds
proceeds with good yields (61-78 %).
The structure of obtained compounds was unambiguously identified by NMR spectroscopy. In the
1H NMR spectra there are signals with characteristic proton chemical shifts at the C2 atom of the
imidazole fragment in the range 8.2 - 8.48 ppm as well as other characteristic signals chemical shifts of
protons of substituents. 13C NMR spectra contain chemical shifts downfield C2, C4 and C5 atoms of the
imidazole moiety. 19F NMR spectra of 2a-i reveal siglet trifluoromethyl group in the range -51.81 – (-
53.64) ppm.
3. Conclusions
А simple synthetic protocol is offered for synthesis of 1,4,5-trisubstituted imidazoles based on the van
Leusen reaction with good yields. The opportunity to prepare 5-trifluoromethyl-substituted imidazoles
has distinctive features of the proposed method. This approach can be easily used for combinatorial
synthesis of imidazole derivatives. The obtained compounds are of interest for the investigation of the
potential biological activity.
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4. Experimental
4.1 General
4.1.1 Materials
Trifluoroacetimidoyl chlorides were prepared according to literature procedure [34].
For tosylmethylisocyanide syntheses see also [24]. Solvents were dried before use by
standard methods. Thin layer chromatography (TLC) was carried out on aluminium
plates coated with silica gel (Merk Kieselgel 60 F254).
4.1.2 Measurements
IR spectra were recorded on an FSM-1201 instrument for KBr pellets1H and 13C NMR
spectra were recorded on Bruker Avance TM 600 spectrometer (600.22 MHz for 1H and
150.93 MHz for 13C). Chemical shifts are given relative to the residual proton signal of
1
solvent (2.50 ppm) for H and relative to DMSO-d6 (35.9 ppm) for 13C. 19F NMR
spectra were recorded on the Bruker Avance TM 400 or 300 spectrometers, operating at
376.5 and 282.4 MHz correspondingly. 19F chemical shifts was measured relative to
CFCl3 as an external standard.
4.2 Typical procedure for synthesis of imidazoles (2a-i).
A solution of TOSMIC (0.976 g, 5 mmol) and corresponding trifluoroacetimidoyl chlorides
1a-i (5 mmol) in THF (15 ml) is added over 15 min to a suspension of sodium hydride (0.12
g, 5 mmol) in dry THF (10 ml) at room temperature under argon atmosphere. The reaction
mixture is stirred (2 h), and then poured slowly into water. The precipitate is collected and
recrystallized from toluene-hexane (9:1) as a creamy solid.
4.2.1 1-Phenyl-4-tosyl-5-(trifluoromethyl)-1H-imidazole (2a)
Yield 62 %, mp – 202-204 °C, Rf = 0.19 (hexane/EtOAc, 7:3). IR: ν-1 3106, 1584,
1
1498, 1385, 1335, 1190, 1150, 680, 593. H NMR (600 MHz, DMSO-d6): δ 2.42 (s,
3H), 7.49 (d, 2H, J = 8.1 Hz), 7.64-7.53 (m, 5H), 7.87 (d, 2H, J = 8.0 Hz), 8.28 (s, 1H).
13C NMR (151 MHz, DMSO-d6): δ 21.59, 118.65, 120.44, 121.28, 121.54, 1227.14,
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128.63, 128.77, 129.94, 130.44, 130.60, 130.83, 134.90, 137.12, 142.16, 143.42,
145.50. 19F NMR (376 MHz, DMSO-d6): δ -52.15 (s). Anal. calcd. for C17H13F3N2O2S:
C 55.73; H 3.58; N 7.65; found: C 55.62; H 3.51; N 7.68.
4.2.2 1-(o-Tolyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazole (2b)
Yield 63 %, mp – 179-180 °C, Rf = 0.21 (hexane/EtOAc, 7:3). IR: ν-1 3105, 1593,
1
1495, 1335, 1181, 1151, 771, 661, 594. H NMR (600 MHz, DMSO-d6): δ 1.97 (s,
3H), 2.42 (s, 3H), 7.41-7.35 (m, 1H), 7.46 (d, 1H, J = 7.0 Hz), 7.51 (td, 4H, J = 5.5 Hz
and 2.8 Hz), 7.88 (d, 2H, J = 8.3 Hz), 8.26 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ
16.83, 21.59, 127.46, 128.21, 128.56, 130.48, 131.18, 131.37, 134.00, 135.23, 137.12,
142.20, 143.28, 145.52. 19F NMR (282 MHz, DMSO-d6): δ -53.47 (s). Anal. calcd. for
C18H15F3N2O2S: C 56.84; H 3.97; N 7.36; found: C 56.80; H 3.91; N 7.41.
4.2.3 1-(p-Tolyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2c)
Yield 65 %, mp – 158-159 °C, Rf = 0.28 (hexane/EtOAc, 7:3). IR: ν-1 3104, 1594,
1516, 1472, 1337, 1191, 1152, 1006, 683, 593. 1H NMR (600 MHz, DMSO-d6): δ 2.37
(s, 3H), 2.41 (s, 3H), 7.36 (d, 2H, J = 8.2 Hz), 7.45 (d, 2H, J = 8.3 Hz), 7.48 (d, 2H, J =
8.2 Hz), 7.88 (d, 2H, J = 8.2 Hz), 8.24 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ
21.10, 21.55, 118.66, 120.45, 121.29, 126.84, 128.04, 128.61, 129.11, 129.75, 130.31,
19
130.86, 132.37, 137.19, 143.38, 143.40, 145.45. F NMR (376 MHz, DMSO-d6): δ -
52.25 (s). Anal. calcd. for C18H15F3N2O2S: C 56.84; H 3.97; N 7.36; found: C 56.77; H
4.01; N 7.31.
4.2.4 1-(2,4-Dimethylphenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2d)
Yield 76 %, mp – 177-176 °C, Rf = 0.21 (hexane/EtOAc, 7:3). IR: ν-1 3111, 1596,
1336, 1261, 1185, 1154, 1008, 813, 682, 594. 1H NMR (600 MHz, DMSO-d6): 2.40 (s,
3H), 2.42 (s, 3H), 2.43 (s, 3H), 7.36 (s, 1H), 7.50 (d, 2H, J = 8.1 Hz), 7.60-7.57 (m,
2H), 7.88 (d, 2H, J = 7.4 Hz), 8.29 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ 19.02,
21.59, 21.62, 127.14, 128.70, 129.94, 130.45, 130.83. 134.90, 137.12, 142.16, 145.50.
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19F NMR (282 MHz, DMSO-d6): δ -53.32 (s). Anal. calcd. for C19H17F3N2O2S: C
57.86; H 4.34; N 7.10; found: C 57.91; H 4.29; N 7.04.
4.2.5 1-(4-Methoxyphenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (3e)
Yield 78 %, mp – 202-203 °C, Rf = 0.17 (hexane/EtOAc, 7:3). IR: ν-1 3110, 1586,
1502, 1336, 1261, 1185, 1154, 1008, 682, 584. 1H NMR (600 MHz, DMSO-d6): δ 2.42
(s, 3H), 3.82 (s, 3H), 7.11-7.07 (m, 2H), 7.50 (dd, 4H, J = 8.4 and 5.8 Hz), 7.86 (d, 2H,
J = 8.3 Hz), 8.20 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ 21.59, 56.08, 114.93,
121.66, 127.44, 128.52, 128.59, 130.41, 137.22, 142.34, 143.21, 145.43, 160.83. 19F
NMR (282 MHz, DMSO-d6): δ -52.28 (s). Anal. calcd. for C18H15F3N2O3S: C 54.54; H
3.81; N 7.07; found: C 54.48; H 3.77; N 7.11.
4.2.6 1-(2-Chlorophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2f)
Yield 62 %, mp – 198-199 °C, Rf = 0.17 (hexane/EtOAc, 7:3). IR: ν-1 3107, 1593,
1
1490, 1335, 1180, 1153, 1008, 676, 594. H NMR (600 MHz, DMSO-d6): δ 2.42 (s,
3H), 7.51 (d, 2H, J = 8.1 Hz), 7.57 (td, 1H, J = 7.7 and 1.4 Hz), 7.66 (td, 1H, J = 7.7
and 1.4 Hz), 7.77 (dd, 1H, J = 8.1 and 1.4 Hz), 7.85 (dd, 1H, J = 7.9 and 1.6 Hz), 7.88
(d, 2H, J = 8.3 Hz), 8.35 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ 21.60, 118.51,
120.30, 122.07, 128.58, 128.65, 128.89, 131.25, 132.48, 133.01, 137.01, 142.39,
143.28, 145.64. 19F NMR (282 MHz, DMSO-d6): -53.64 (s). Anal. calcd. for
C17H12ClF3N2O2S: C 50.94; H 3.02; N 6.99; found: C 50.89; H 2.99; N 7.02.
4.2.7 1-(4-Chlorophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2g)
Yield 63 %, mp – 200-201 °C, Rf = 0.19 (hexane/EtOAc, 7:3). IR: ν-1 3107, 1594,
1
1499, 1336, 1190, 1151, 1022, 839, 664, 593. H NMR (600 MHz, DMSO-d6): δ 2.41
(s, 3H), 7.49 (d, 2H, J = 8.1 Hz), 7.68-7.65 (m, 4H), 7.87 (d, 2H, J = 8.2 Hz) 8.28 (s,
1H). 13C NMR (151 MHz, DMSO-d6): δ 21.57, 118.61, 121.39, 121.66, 128.63,
129.16, 129.33, 129.93, 130.43, 133.78, 135.61, 137.11, 142.18, 143.47, 145.51. 19F
NMR (376 MHz, DMSO-d6): δ -52.12 (s). Anal. calcd. for C17H12ClF3N2O2S: C 50.94;
H 3.02; N 6.99; found: C 51.01; H 3.08; N 7.02.
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4.2.8 1-(4-Bromohenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2h)
Yield 63 %, mp – 202-203 °C, Rf = 0.20 (hexane/EtOAc, 7:3). IR: ν-1 3106, 1533,
1495, 1336, 1190, 1152, 1020, 836, 662, 593. 1H NMR (600 MHz, DMSO-d6): δ 2.41
(s, 3H), 7.49 (d, 2H, J = 8.1 Hz), 7.58 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.7 Hz),
7.87 (d, 2H, J = 8.0 Hz), 8.28 (s, 1H). 13C NMR (151 MHz, DMSO-d6): δ 21.58,
118.60, 120.39, 121.33, 121.60, 124.18, 129.00, 130.44, 132.89, 134.21, 137.10,
142.13, 143.47, 145.52. 19F NMR (376 MHz, DMSO-d6): δ -52.09 (s). Anal. calcd. for
C17H12BrF3N2O2S: C 45.86; H 2.72; N 6.29; found: C 45.79; H 2.79; N 6.33.
4.2.9 1-(4-Nitrophenyl)-4-tosyl-5-(trifluoromethyl)-1H-imidazoles (2i)
Yield 61 %, mp – 261-263 °C, Rf = 0.15 (hexane/EtOAc, 7:3). IR: ν-1 3116, 1596,
1
1515, 1344, 1177, 1150, 1020, 657, 592, 534. H NMR (600 MHz, DMSO-d6): δ 2.42
(s, 3H), 7.50 (d, 2H, J = 8.0 Hz), 7.88 (d, 2H, J = 8.1 Hz), 7.94 (d, 2H, J = 8.7 Hz),
8.36 (s, 1H), 8.42 (d, 2H, J = 8.9 Hz). 13C NMR (151 MHz, DMSO-d6): δ 21.59,
118.56, 120.35, 121.42, 121.69, 125.18, 128.65, 128.90 130.48, 136.99, 139.98,
142.09, 143.79, 145.62, 148.79. 19F NMR (376 MHz, DMSO-d6): δ -51.81 (s). Anal.
calcd. for C17H12F3N3O4S: C 49.64; H 2.94; N 10.22; found: C 49.53; H 3.01; N 10.31.
Acknowledgement
The authors are grateful to the Ministry of Education and Science of the Russian Federation (State
job No. 426)
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Graphical Abstract
Ar
N
Tos
F3C
N
N
NaH, THF
r.t., 2 h
Tos
N
C
F3C
Cl
Ar
Yield: 61-78 %
9 examples
11
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Highlights
Synthesis of new series of 9 trifluoromethyl-containing imidazoles.
This method has the ability to tolerate a wide variety of substitutions.
Compounds were characterized adequately by various spectral data and CHN analysis.
Newly synthesized compounds exhibited potential biological activity.
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