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Synthesis of 1-aryl-4-tosyl-5-(trifluoromethyl)-1H-imidazoles
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: DOI: Reference:
S0022-1139(14)00104-3 http://dx.doi.org/doi:10.1016/j.jfluchem.2014.04.013 FLUOR 8309
To appear in:
FLUOR
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 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St, B-334, Moscow 119991, Russian Federation
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b
Togliatti State University, 14 Belorusskaya St, Togliatti 445667, Russian Federation
[email protected] (A. S. Bunev)
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Abstracts.
cr
*Corresponding author. Tel.: +78482 535455 ; fax: +78482 535455. E-mail address:
A new synthetic protocol for the synthesis of 1,4,5-trisubstituted imidazoles containing
an
trifluoromethyl group has been developed using van Leusen reaction, which incorporates two-component
M
condensation reaction trifluoroacetimidoyl chlorides with tosylmethylisocyanide. This protocol provides a novel and improved method for obtaining trifluoromethyl containing 1,4,5-trisubstituted imidazoles in
te
d
good yields.
reaction.
Ac ce p
Keywords: Imidazoles, trifluoromethyl azoles, trifluoroacetimidoyl halides, isocyanides, Van Leusen
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
ip t
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],
cr
there is virtually no information about 5-trifluoromethyl-substituted imidazoles in the literature. This work is attempt to eliminate this gap.
us
2. Results and discussion
N-aryltrifluoroacetimidoyl chloride can be utilized in several important synthetic transmutations
an
[30-32], in particular for synthesis of some trifluoromethyl-containing heterocycles [33-36].
M
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-
CF3
te
N
d
trisubstituted imidazoles 2a-i (scheme 1).
Ts
R
Cl
Ac ce p
1a-i
N
Ts
N
F3 C
N
NaH, THF
C
r.t., 2 h
R 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].
NH 2
CF3CO2 H, Ph3 P, Et3 N
R
1a-i
CCl4, 3h reflux
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 2
Page 2 of 12
carbanion with N-aryltrifluoroacetimidoyl chloride and subsequent intramolecular cyclization of the formed intermediate lead to the target imidazoles.
-H 2
NC
F 3C H Ts
-Cl
Cl
Ar N N
Ar Ts
CF3
F3 C C Ts
F3 C Cl Ar N NC
Ar N N
ip t
NC
N
Ts
cr
NaH
Ts
Scheme 3.
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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
an
proceeds with good yields (61-78 %).
The structure of obtained compounds was unambiguously identified by NMR spectroscopy. In the H NMR spectra there are signals with characteristic proton chemical shifts at the C2 atom of the
M
1
imidazole fragment in the range 8.2 - 8.48 ppm as well as other characteristic signals chemical shifts of C NMR spectra contain chemical shifts downfield C2, C4 and C5 atoms of the
19
F NMR spectra of 2a-i reveal siglet trifluoromethyl group in the range -51.81 – (-
Ac ce p
53.64) ppm.
te
imidazole moiety.
13
d
protons of substituents.
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].
ip t
For tosylmethylisocyanide syntheses see also [24]. Solvents were dried before use by standard methods. Thin layer chromatography (TLC) was carried out on aluminium
cr
plates coated with silica gel (Merk Kieselgel 60 F254). 4.1.2 Measurements
us
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
an
150.93 MHz for 13C). Chemical shifts are given relative to the residual proton signal of solvent (2.50 ppm) for 1H and relative to DMSO-d6 (35.9 ppm) for
13
C.
19
F NMR
M
spectra were recorded on the Bruker Avance TM 400 or 300 spectrometers, operating at 19
F chemical shifts was measured relative to
d
376.5 and 282.4 MHz correspondingly.
te
CFCl3 as an external standard.
Ac ce p
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, 1498, 1385, 1335, 1190, 1150, 680, 593. 1H 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). 13
C NMR (151 MHz, DMSO-d6): δ 21.59, 118.65, 120.44, 121.28, 121.54, 1227.14, 4
Page 4 of 12
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)
ip t
Yield 63 %, mp – 179-180 °C, Rf = 0.21 (hexane/EtOAc, 7:3). IR: ν-1 3105, 1593, 1495, 1335, 1181, 1151, 771, 661, 594. 1H NMR (600 MHz, DMSO-d6): δ 1.97 (s,
cr
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
us
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
an
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)
M
Yield 65 %, mp – 158-159 °C, Rf = 0.28 (hexane/EtOAc, 7:3). IR: ν-1 3104, 1594,
d
1516, 1472, 1337, 1191, 1152, 1006, 683, 593. 1H NMR (600 MHz, DMSO-d6): δ 2.37
te
(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).
13
C NMR (151 MHz, DMSO-d6): δ
Ac ce p
21.10, 21.55, 118.66, 120.45, 121.29, 126.84, 128.04, 128.61, 129.11, 129.75, 130.31, 130.86, 132.37, 137.19, 143.38, 143.40, 145.45. 19F 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.
5
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19
F 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,
ip t
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, 13
C NMR (151 MHz, DMSO-d6): δ 21.59, 56.08, 114.93,
cr
J = 8.3 Hz), 8.20 (s, 1H).
121.66, 127.44, 128.52, 128.59, 130.41, 137.22, 142.34, 143.21, 145.43, 160.83.
19
F
3.81; N 7.07; found: C 54.48; H 3.77; N 7.11.
us
NMR (282 MHz, DMSO-d6): δ -52.28 (s). Anal. calcd. for C18H15F3N2O3S: C 54.54; H
an
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,
M
1490, 1335, 1180, 1153, 1008, 676, 594. 1H NMR (600 MHz, DMSO-d6): δ 2.42 (s,
d
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
te
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).
13
C NMR (151 MHz, DMSO-d6): δ 21.60, 118.51,
Ac ce p
120.30, 122.07, 128.58, 128.65, 128.89, 131.25, 132.48, 133.01, 137.01, 142.39, 143.28, 145.64.
19
F 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, 1499, 1336, 1190, 1151, 1022, 839, 664, 593. 1H 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).
13
C 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.
19
F
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. 6
Page 6 of 12
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,
ip t
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), 13
C NMR (151 MHz, DMSO-d6): δ 21.58,
cr
7.87 (d, 2H, J = 8.0 Hz), 8.28 (s, 1H).
118.60, 120.39, 121.33, 121.60, 124.18, 129.00, 130.44, 132.89, 134.21, 137.10,
us
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.
an
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,
M
1515, 1344, 1177, 1150, 1020, 657, 592, 534. 1H NMR (600 MHz, DMSO-d6): δ 2.42
d
(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),
te
8.36 (s, 1H), 8.42 (d, 2H, J = 8.9 Hz).
13
C 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,
Ac ce p
142.09, 143.79, 145.62, 148.79.
19
F 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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Ac ce p
te
d
M
an
us
cr
ip t
[35]
10
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Graphical Abstract N
Ar
NaH, THF Tos
F3C
N
Cl
C
r.t., 2 h
Tos
N
F3C
N Ar
Ac ce p
te
d
M
an
us
cr
ip t
Yield: 61-78 % 9 examples
11
Page 11 of 12
Ac ce p
te
d
M
an
us
cr
ip t
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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S0022-1139(14)00104-3 http://dx.doi.org/doi:10.1016/j.jfluchem.2014.04.013 FLUOR 8309
To appear in:
FLUOR
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 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St, B-334, Moscow 119991, Russian Federation
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b
Togliatti State University, 14 Belorusskaya St, Togliatti 445667, Russian Federation
[email protected] (A. S. Bunev)
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Abstracts.
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*Corresponding author. Tel.: +78482 535455 ; fax: +78482 535455. E-mail address:
A new synthetic protocol for the synthesis of 1,4,5-trisubstituted imidazoles containing
an
trifluoromethyl group has been developed using van Leusen reaction, which incorporates two-component
M
condensation reaction trifluoroacetimidoyl chlorides with tosylmethylisocyanide. This protocol provides a novel and improved method for obtaining trifluoromethyl containing 1,4,5-trisubstituted imidazoles in
te
d
good yields.
reaction.
Ac ce p
Keywords: Imidazoles, trifluoromethyl azoles, trifluoroacetimidoyl halides, isocyanides, Van Leusen
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
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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],
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there is virtually no information about 5-trifluoromethyl-substituted imidazoles in the literature. This work is attempt to eliminate this gap.
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2. Results and discussion
N-aryltrifluoroacetimidoyl chloride can be utilized in several important synthetic transmutations
an
[30-32], in particular for synthesis of some trifluoromethyl-containing heterocycles [33-36].
M
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-
CF3
te
N
d
trisubstituted imidazoles 2a-i (scheme 1).
Ts
R
Cl
Ac ce p
1a-i
N
Ts
N
F3 C
N
NaH, THF
C
r.t., 2 h
R 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].
NH 2
CF3CO2 H, Ph3 P, Et3 N
R
1a-i
CCl4, 3h reflux
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 2
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carbanion with N-aryltrifluoroacetimidoyl chloride and subsequent intramolecular cyclization of the formed intermediate lead to the target imidazoles.
-H 2
NC
F 3C H Ts
-Cl
Cl
Ar N N
Ar Ts
CF3
F3 C C Ts
F3 C Cl Ar N NC
Ar N N
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NC
N
Ts
cr
NaH
Ts
Scheme 3.
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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
an
proceeds with good yields (61-78 %).
The structure of obtained compounds was unambiguously identified by NMR spectroscopy. In the H NMR spectra there are signals with characteristic proton chemical shifts at the C2 atom of the
M
1
imidazole fragment in the range 8.2 - 8.48 ppm as well as other characteristic signals chemical shifts of C NMR spectra contain chemical shifts downfield C2, C4 and C5 atoms of the
19
F NMR spectra of 2a-i reveal siglet trifluoromethyl group in the range -51.81 – (-
Ac ce p
53.64) ppm.
te
imidazole moiety.
13
d
protons of substituents.
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].
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For tosylmethylisocyanide syntheses see also [24]. Solvents were dried before use by standard methods. Thin layer chromatography (TLC) was carried out on aluminium
cr
plates coated with silica gel (Merk Kieselgel 60 F254). 4.1.2 Measurements
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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
an
150.93 MHz for 13C). Chemical shifts are given relative to the residual proton signal of solvent (2.50 ppm) for 1H and relative to DMSO-d6 (35.9 ppm) for
13
C.
19
F NMR
M
spectra were recorded on the Bruker Avance TM 400 or 300 spectrometers, operating at 19
F chemical shifts was measured relative to
d
376.5 and 282.4 MHz correspondingly.
te
CFCl3 as an external standard.
Ac ce p
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, 1498, 1385, 1335, 1190, 1150, 680, 593. 1H 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). 13
C NMR (151 MHz, DMSO-d6): δ 21.59, 118.65, 120.44, 121.28, 121.54, 1227.14, 4
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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)
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Yield 63 %, mp – 179-180 °C, Rf = 0.21 (hexane/EtOAc, 7:3). IR: ν-1 3105, 1593, 1495, 1335, 1181, 1151, 771, 661, 594. 1H NMR (600 MHz, DMSO-d6): δ 1.97 (s,
cr
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
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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
an
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)
M
Yield 65 %, mp – 158-159 °C, Rf = 0.28 (hexane/EtOAc, 7:3). IR: ν-1 3104, 1594,
d
1516, 1472, 1337, 1191, 1152, 1006, 683, 593. 1H NMR (600 MHz, DMSO-d6): δ 2.37
te
(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).
13
C NMR (151 MHz, DMSO-d6): δ
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21.10, 21.55, 118.66, 120.45, 121.29, 126.84, 128.04, 128.61, 129.11, 129.75, 130.31, 130.86, 132.37, 137.19, 143.38, 143.40, 145.45. 19F 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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19
F 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,
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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, 13
C NMR (151 MHz, DMSO-d6): δ 21.59, 56.08, 114.93,
cr
J = 8.3 Hz), 8.20 (s, 1H).
121.66, 127.44, 128.52, 128.59, 130.41, 137.22, 142.34, 143.21, 145.43, 160.83.
19
F
3.81; N 7.07; found: C 54.48; H 3.77; N 7.11.
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NMR (282 MHz, DMSO-d6): δ -52.28 (s). Anal. calcd. for C18H15F3N2O3S: C 54.54; H
an
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,
M
1490, 1335, 1180, 1153, 1008, 676, 594. 1H NMR (600 MHz, DMSO-d6): δ 2.42 (s,
d
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
te
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).
13
C NMR (151 MHz, DMSO-d6): δ 21.60, 118.51,
Ac ce p
120.30, 122.07, 128.58, 128.65, 128.89, 131.25, 132.48, 133.01, 137.01, 142.39, 143.28, 145.64.
19
F 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, 1499, 1336, 1190, 1151, 1022, 839, 664, 593. 1H 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).
13
C 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.
19
F
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. 6
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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,
ip t
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), 13
C NMR (151 MHz, DMSO-d6): δ 21.58,
cr
7.87 (d, 2H, J = 8.0 Hz), 8.28 (s, 1H).
118.60, 120.39, 121.33, 121.60, 124.18, 129.00, 130.44, 132.89, 134.21, 137.10,
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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.
an
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,
M
1515, 1344, 1177, 1150, 1020, 657, 592, 534. 1H NMR (600 MHz, DMSO-d6): δ 2.42
d
(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),
te
8.36 (s, 1H), 8.42 (d, 2H, J = 8.9 Hz).
13
C 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,
Ac ce p
142.09, 143.79, 145.62, 148.79.
19
F 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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Ac ce p
te
d
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an
us
cr
ip t
[35]
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Graphical Abstract N
Ar
NaH, THF Tos
F3C
N
Cl
C
r.t., 2 h
Tos
N
F3C
N Ar
Ac ce p
te
d
M
an
us
cr
ip t
Yield: 61-78 % 9 examples
11
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Ac ce p
te
d
M
an
us
cr
ip t
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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