Convenient synthesis of 4-trifluoromethyl-substituted imidazole derivatives

Article abstract of DOI:10.1248/cpb.49.461

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines (2) with trifluoroacetic anhydride, react with ammonia to give 4-trifluoromethyl-3,4-dihydroimidazoles (3) in high yields. Dehydration of 3 gives

Full text of DOI:10.1248/cpb.49.461

April 2001
Chem. Pharm. Bull. 49(4) 461—464 (2001)
461
Convenient Synthesis of 4-Trifluoromethyl-Substituted Imidazole
Derivatives
b
Masami KAWASE, ,a Setsuo SAITO,a and Teruo KURIHARA
*
Faculty of Pharmaceutical Sciences, Josai University,a 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan and Faculty of
Science, Josai University,b 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan.
Received November 29, 2000; accepted February 3, 2001
Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines
(2) with trifluoroacetic anhydride, react with ammonia to give 4-trifluoromethyl-3,4-dihydroimidazoles (3) in
high yields. Dehydration of 3 gives 4-trifluoromethylimidazoles (4) in high yields. The novel ring transformation
of 1 into 3 occurs via a regioselective attack of ammonia on the C-2 position of the ring.
Key words imidazole; trifluoromethyl; 1,3-oxazolium-5-olate; ring transformation; trifluoroacetic anhydride
roacetylimidazoles by Hamper et al.13) Thus, munchnone
chemistries are suitable to develop new synthesis in combi-
natorial chemistry.
We now present a full account of the reactions of 1 with
ammonia7b) and a new synthesis of 4-trifluoromethylimida-
zoles (4).
The synthesis of trifluoromethyl (CF3)-substituted het-
eroaromatic compounds has received considerable interest
since many of them sometimes exhibit unique chemical,
physiological or physical properties.1) The search for a sim-
ple and efficient access to heteroaromatic compounds with a
CF3 group at a specific position is an important goal in this
area.2)
Results and Discussion
Imidazole and its derivatives are an important class of het-
erocycles and many naturally occurring imidazoles are
known to possess biological activity.3) The imidazole nucleus
is also a major component of a variety of drugs such as an-
giotensin II receptor antagonists, oral antiinflammatory
agents, protein kinase inhibitors and fungisides.4) Further-
more, CF3-substituted imidazoles have found applications in
the medicinal and agrochemical fields.5)
In the course of our studies on the reactivities of
mesoionic 1,3-oxazolium-5-olates,6) we have focused on 4-
trifluoroacetyl-1,3-oxazolium-5-olates (1) as useful synthons
for CF3-substituted heterocycles.7)
Compound 1 could easily be prepared from N-acyl-N-
alkylglycines 2 with trifluoroacetic anhydride (TFAA).8) In
general, the mesoionic 1,3-oxazolium-5-olates are too unsta-
ble to be isolated and are utilized in situ.6) However, com-
pound 1 with a 4-trifluoroacetyl group can be isolated and
stored for several months. It is reported that compound 1
showed high reactivity towards nucleophilic reagents such as
H2O, EtOH, and AcOH, bringing about ring-opening reac-
tions.8) These reactions occur via an initial attack of a nucle-
ophile on the C-5 position of the ring.7d) We have examined
the reactions of 1 with N-nucleophiles such as amidines,7a)
ammonia,7b) hydrazines,7c) and aminomalonate.7e) In princi-
ple, nucleophilic reagents can be expected to be added to one
of the three electrophilic centers at C-2, C-5, and COCF3 in
1.
The 4-trifluoroacetyl-1,3-oxazolium-5-olates (1a—d) re-
quired for this study were prepared by the reaction of N-acyl-
N-alkylglycines (2a—d) with TFAA. The derivatives em-
ployed in this study, along with the products (3a—i and 4a—
i), are summarized in Chart 1. Table 1 shows the results
when 4-trifluoroacetyl-1,3-oxazolium-5-olate (1a) was al-
lowed to react with ammonium acetate under various condi-
tions. The best result was obtained by the reaction of 1a (1
mmol) with ammonium acetate (1.5 mmol) in N,N-dimethyl-
formamide (DMF) (5 ml) at 70 °C for 2 h: 4-trifluo-
romethyldihydroimidazole (3a) was isolated in 92% yield
(Table 1, run 1). Various substituted 4-trifluoroacetyl-1,3-ox-
azolium-5-olates (1a, b, d, e) were subjected to a reaction
under the optimum conditions, and the results are listed in
Table 2. In all reactions examined, 4,5-dihydroimidazoles
(3a—i) were obtained in high yields.
A one-pot conversion of 2 to 3 also proceeded success-
fully. Thus, 2a reacted with TFAA in CH2Cl2 to give 1a,
which was directly subjected to the ring transformation reac-
tion to yield 3a in 94% yield (Table 2, run 2). The one-pot
procedure gave slightly higher yield. Pentafluoropropionic
and heptafluorobutyric anhydride also reacted readily with N-
benzoyl-N-methylglycine (2a) to yield 4-pentafluoroethyl-
(3h) and 4-heptafluoropropyldihydroimidazole (3i) by the
one-pot procedure in high yields, respectively (Chart 1 and
Table 2, runs 10 and 11).
The structures of 3a—f are supported by spectral and ana-
lytical data. In the 13C-NMR spectra of 3a, dihydroimidazole
ring carbon atoms C2, C4 and C5 appear at 169.1, 94.01
(quartet, 2JC–Fϭ31 Hz) and 59.73 ppm, respectively. The car-
bon of the CF3 group in 3a—f appears at around d 124 ppm
(quartet, 1JC–Fϭ285—290 Hz).
Combinatorial chemistry has emerged as a powerful tool
for accelerating the synthesis and screening of diverse collec-
tions of molecules.9,10) The 1,3-dipolar cycloaddition of poly-
mer-bound munchnones with a variety of alkynes has been
developed to produce a library of up to 108 different
pyrroles.11) The solid-phase synthesis of non-fluorinated imi-
dazoles is reported to utilize a munchnone cycloaddition
to aryltosylimines.12) Recently, the reaction of 1 with
amidines7a) has also been applied to a combinatorial solid-
phase synthesis to prepare a library of two hundred 5-trifluo-
Dehydration of 3a with POCl3 and pyridine14) gave the
known15) 4-trifluoromethyl-1-methyl-2-phenylimidazole (4a)
in 88% yield. As shown in Table 2, various dihydroimida-
zoles (3a—i) were transformed to the 4-trifluoromethylimi-
To whom correspondence should be addressed. e-mail: kawasema@josai.ac.jp
© 2001 Pharmaceutical Society of Japan

462
Vol. 49, No. 4
Chart 1
Table 1. Reactions of 1a with Ammonium Acetate in DMFa)
the C-2 position of the ring is reported to be explained in
terms of the HSAB principle.7d) The possible mechanism has
been described in ref. 7b.
Run
NH4OAc (eq)b) Base (eq)b)
Conditions Yield of 3a (%)
In summary, we devised an easy method of accessing 4-tri-
fluoromethylimidazole derivatives which are otherwise diffi-
cult to obtain. The principal advantage of using mesoionic
oxazoles 1 is the great variety of substituents available for R1
and R2. This flexibility in the type of substituents in the
mesoionic ring (1) will be reflected in the corresponding sub-
stitution of the resulting imidazole (4). Furthermore, the sim-
plicity of the method and the ready availability of the starting
1
2
3
1.5
1.5
1.5
3
None
None
70 °C, 2 h
25 °C, 3 h
92
45
92
91
94
K2CO3 (1.5) 70 °C, 2 h
None
None
4
70 °C, 2 h
70 °C, 2 h
5c)
1.5
a) The reactions were carried out on a 1 mmol scale. b) Eq refers to molar equiva-
lents with respect to 1a. c) Yield refers to the one-pot procedure using 2a.
Table 2. Yields of 4-Trifluoromethyl-3,4-dihydroimidazoles (3) and 4-Tri- material make this a practical approach. In addition, 4-perflu-
fluoromethylimidazoles (4)
oroalkyl-substituted imidazoles could be prepared conve-
niently by employing perfluorocarboxylic anhydride.
Yields of products (%)
Run
Starting materials
Experimental
3
4
General Methods All melting points were determined using a Yanagi-
moto hot-stage melting point apparatus and are uncorrected. 1H-NMR spec-
tra were measured on either a JEOL JNM-PMX60SI or JNM-GSX500 spec-
trometer with tetramethylsilane (Me4Si) as an internal reference and CDCl3
as the solvent. 13C-NMR spectra were obtained on a JEOL JNM-GSX500
spectrometer (at 127 MHz). Both 1H- and 13C-NMR spectral data are re-
ported in parts per million (d) relative to Me4Si. Infrared (IR) spectra were
recorded on a JASCO IR810 spectrometer. Low- and high-resolution MS
were obtained with a JEOL JMS-DX300 spectrometer with a direct inlet
system at 70 eV. Elemental analyses were carried out in the microanalytical
laboratory of this university. Standard workup means that the organic layers
were finally dried over Na2SO4, filtered, and concentrated in vacuo below 45
°C using a rotary evaporator.
1
2
3
4
5
6
7
8
9
1a
3a (92)
3a (94)
3b (78)
3c (98)
3d (91)
3e (84)
3e (91)
3f (89)
3g (85)
3h (93)
3i (87)
4a (88)
—
2aa)
1b
4b (88)
4c (91)
4d (96)
4e (93)
—
4f (99)
4g (94)
4h (99)
4i (93)
2ca)
1d
1e
2ea)
2fa)
2ga)
2aa)
2aa)
10b)
11c)
Materials The following compounds were prepared by reported proce-
dures: N-Benzoyl-N-methylglycine (2a): mp 101—104 °C (mp16) 102—104
°C). N-Methyl-N-pivaloylglycine (2b): mp 75—76 °C (mp7f ) 75—76 °C). N-
Acetyl-N-phenylglycine (2d): mp 196—198 °C (mp16) 193—195 °C). N-
Benzoyl-N-phenylglycine (2e): mp 190—193 °C (mp16) 193—195 °C). Ben-
zyl N-phenylacetyl-N-methylglycinate (5a): Yield 89%. bp5 228—230 °C.
1H-NMR (60 MHz) d: 3.00ϩ3.03 (s, 3H), 3.67ϩ3.77 (s, 2H), 4.03ϩ4.20 (s,
2H), 5.10ϩ5.17 (s, 2H), 7.27ϩ7.33 (s, 10H). IR (Nujol) cmϪ1: 1650, 1740.
MS m/z: 297 (Mϩ, 11%), 91 (100%). High-resolution MS: Calcd for
C18H19NO3: 297.1365. Found: 297.1367. Ethyl N-benzoyl-N-benzylglycinate
(5b): Yield 94%. Oil. IR (Nujol) cmϪ1: 1635, 1740. 1H-NMR (500 MHz) d:
1.21—1.24ϩ1.25—1.30 (m, 3H), 3.85ϩ4.15 (s, 2H), 4.00—4.17ϩ4.20—
4.24 (m, 2H), 4.62ϩ4.82 (s, 2H), 7.20—7.53 (m, 10H). MS m/z: 297 (Mϩ,
a) Yields refer to the one-pot procedure. b) Pentafluoropropionic anhydride was
used instead of TFAA in a one-pot procedure. c) Heptafluorobutyric anhydride was
used instead of TFAA in a one-pot procedure.
dazole derivatives (4a—i) under the same conditions14) in
high yields. In the 13C-NMR spectra of 4a, imidazole ring
carbon atoms C2, C4 and C5 appear at 149.06, 131.56 (quar-
2
3
tet, JC–Fϭ39 Hz) and 121.4 (quartet, JC–Fϭ4.1 Hz) ppm, re-
spectively.
The novel ring transformation of 1 into imidazoles 3 may
proceed through an initial attack of ammonia on the C-2 po-
sition of the ring. The regioselective attack of ammonia on 3%), 192 (100%). High-resolution MS: Calcd for C18H19NO3: 297.1365.

April 2001
463
2
Found: 297.1360. Ethyl N-acetyl-N-benzylglycinate (5c): Yield 91%. Oil. IR
(Nujol) cmϪ1: 1650, 1740. 1H-NMR (500 MHz) d: 1.22—1.28 (m, 3H),
2.13ϩ2.22 (s, 3H), 3.91ϩ4.05 (s, 2H), 4.14—4.20 (m, 2H), 4.63—4.65 (s,
2H), 7.19—7.38 (m, 5H). MS m/z: 235 (Mϩ, 4%), 192 (100%). High-resolu-
tion MS: Calcd for C13H17NO3: 235.1209. Found: 235.1225.
MHz) d: 32.43 (CH2), 33.73 (CH2), 59.22 (CH3), 93.66 (C, JC–Fϭ32 Hz),
124.42 (CF3, 1JC–Fϭ285 Hz), 127.08 (CH), 128.27 (CH), 128.84 (CH),
134.23 (C), 168.44 (C). MS m/z: 258 (Mϩ, 8%), 91 (100%). Anal. Calcd for
C12H13F3N2O: C, 55.81; H, 5.07; N, 10.85. Found: C, 55.83; H, 5.10; N,
10.90.
N-Phenylacetyl-N-methylglycine (2c) A mixture of benzyl N-phenyl-
acetyl-N-methylglycinate (5a) (7.5 g, 25 mol) and 10% Pd-C (300 mg) in
AcOEt (70 ml) was stirred under a H2 atmosphere at room temperature for
0.5 h. The mixture was filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography on silica gel with
1-Benzyl-4-trifluoromethyl-4-hydroxy-2-phenyl-4,5-dihydroimidazole
(3f): 3f; mp 175—177 °C (CH2Cl2–hexane). IR (Nujol) cmϪ1: 2550—3600
(br), 1575. 1H-NMR (500 MHz) d: 3.50 (d, 1H, Jϭ11.8 Hz), 3.67 (d, 1H,
Jϭ11.8 Hz), 4.41 (d, 1H, Jϭ16.0 Hz), 4.46 (d, 1H, Jϭ16.0 Hz), 7.02—7.15
(br, 1H), 7.18 (d, 2H, Jϭ7.9 Hz), 7.30 (t, 1H, Jϭ7.3 Hz), 7.36 (t, 2H, Jϭ7.3
Hz), 7.43 (t, 2H, Jϭ7.9 Hz), 7.48 (t, 1H, Jϭ7.3 Hz), 7.61 (d, 2H, Jϭ7.3 Hz).
13C-NMR (127 MHz) d: 50.32 (CH2), 56.14 (CH2), 93.49 (C, 2JC–Fϭ31 Hz),
123.51 (CF3, 1JC–Fϭ284 Hz), 125.94 (CH), 126.84 (CH), 127.51 (CH),
127.78 (CH), 128.02 (CH), 128.54 (C), 129.99 (CH), 135.53 (C), 168.41
(C). MS m/z: 320 (Mϩ, 1%), 91 (100%). Anal. Calcd for C17H15F3N2O: C,
63.75; H, 4.72; N, 8.75. Found: C, 63.40; H, 4.57; N, 8.69.
1
CH2Cl2–MeOH (10 : 1) to give 2c (4.9 g, 94%) as a colorless oil. H-NMR
(60 MHz) d: 2.97ϩ3.00 (s, 3H), 3.63ϩ3.77 (s, 2H), 3.97ϩ4.10 (s, 2H), 7.20
(br s, 5H). 10.00 (s, 1H). IR (Nujol) cmϪ1 : 1640, 1740, 2200—3600 (br).
MS m/z: 207 (Mϩ, 12%), 91 (100%). High-resolution MS: Calcd for
C11H13NO3: 207.0895. Found: 207.0874.
Hydrolysis of Ethyl N-Benzoyl-N-benzylglycinate (5b) and Ethyl N-
Acetyl-N-benzylglycinate (5c) A mixture of ethyl ester (5b, c) (14 mmol)
and 2 N NaOH (9.3 ml, 18 mmol) in dioxane (9.3 ml) was stirred at 65 °C for
3 h. The reaction mixture was diluted with Et2O (100 ml) and H2O (100 ml).
The aqueous layer was acidified with conc. HCl and extracted with AcOEt
(100 mlϫ2) followed by standard workup to give the desired acids (2f and g)
in high yields.
N-Benzoyl-N-benzylglycine (2f): mp 106—107 °C (AcOEt–hexane). IR
(Nujol) cmϪ1: 1610, 1740, 2500—3300 (br). 1H-NMR (500 MHz) d:
3.86ϩ4.19 (s, 2H), 4.63ϩ4.81 (s, 2H), 6.62—6.92 (br, 1H), 7.20—7.54 (m,
10H). MS m/z: 269 (Mϩ, 24%), 105 (100%). Anal. Calcd for C16H15NO3: C,
71.36; H, 5.61; N, 5.20. Found: C, 71.23; H, 5.78; N, 5.03.
1-Benzyl-4-trifluoromethyl-4-hydroxy-2-methyl-4,5-dihydroimidazole
(3g): 3g; mp 155—156 °C (CH2Cl2–hexane). IR (Nujol) cmϪ1: 2500—3600
1
(br), 1585. H-NMR (500 MHz) d: 2.00 (s, 3H), 3.33 (d, 1H, Jϭ10.8 Hz),
3.53 (d, 1H, Jϭ10.8 Hz), 4.34 (d, 1H, Jϭ16.0 Hz), 4.42 (d, 1H, Jϭ16.0 Hz),
7.09 (d, 2H, Jϭ7.6 Hz), 7.24 (t, 1H, Jϭ7.6 Hz), 7.31 (t, 2H, Jϭ7.6 Hz). 13C-
NMR (127 MHz) d: 13.39 (CH3), 49.10 (CH2), 56.48 (CH2), 93.50 (C, 2JC–Fϭ
31 Hz), 124.39 (CF3, 1JC–Fϭ284 Hz), 126.52 (CH), 127.83 (CH), 129.03
(CH), 135.76 (C), 167.14 (C). MS m/z: 258 (Mϩ, 5%), 91 (100%). Anal.
Calcd for C12H13F3N2O: C, 55.81; H, 5.07; N, 10.85. Found: C, 55.85; H,
5.02; N, 10.72.
1
The following products were identified by comparison of the IR and H-
NMR spectral data with those of authentic samples7f ): 4-Pentafluoroethyl-4-
hydroxy-1-methyl-2-phenyl-4,5-dihydroimidazole (3h) mp 183—186 °C
(Et2O). 4-Heptafluoropropyl-4-hydroxy-1-methyl-2-phenyl-4,5-dihydroimi-
dazole (3i): mp 188—189 °C (Et2O).
N-Acetyl-N-benzylglycine (2g): mp 118—119 °C (AcOEt–hexane). IR
1
(Nujol) cmϪ1: 1610, 1725, 2200—3200 (br). H-NMR (500 MHz) d: 2.16ϩ
2.24 (s, 3H), 3.94ϩ4.08 (s, 2H), 4.63ϩ4.66 (s, 2H), 7.18—7.40 (m, 5H),
7.48—7.64 (br, 1H). MS m/z: 207 (Mϩ, 13%), 164 (100%). Anal. Calcd for
C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.60; H, 6.32; N, 6.60.
General Procedure for the Preparation of 4-Trifluoroacetyl-1,3-oxa-
zolium-5-olates (1) TFAA (11 ml, 78 mmol) was added to a stirred solu-
tion of N-acyl-N-alkylglycine (26 mmol) in CH2Cl2 (50 ml) at 0 °C for 10
min. The mixture was stirred at 25 °C for 3 h and then extracted with CH2Cl2
(80 mlϫ2). The combined extracts were washed successively with 3% HCl,
H2O, 1% Na2CO3, and H2O. After the standard workup, the residue was re-
crystallized from CH2Cl2–hexane to give the 4-trifluoroacetyl-1,3-oxa-
zolium-5-olates (1).
General Procedure for the Dehydration of 3,4-Dihydroimidazoles (3)
to Afford Imidazoles (4) POCl3 (0.23 ml, 2.5 mmol) was added to a
stirred solution of 3 (1.0 mmol) in pyridine (0.73 ml, 9.0 mmol) at 0 °C and
the mixture was heated at 90 °C for 2 h. The solvent was evaporated to dry-
ness and the residue was extracted with AcOEt (40 mlϫ2). After the stan-
dard workup, the residue was purified by column chromatography on silica
gel with EtOAc–hexane (1 : 2) to give the product 4.
4-Trifluoromethyl-1-methyl-2-phenylimidazole (4a): mp 59—60 °C
1
(hexane) (mp15) 61.5—62.5 °C). H-NMR (500 MHz) d: 3.76 (3H, s), 7.31
(1H, s), 7.45—7.48 (3H, m), 7.61—7.63 (2H, m). 13C-NMR (127 MHz) d:
34.82 (CH3), 121.74 (CH, 3JC–Fϭ4.1 Hz), 121.77 (CF3, 1JC–Fϭ267 Hz),
3-Methyl-2-phenyl-4-trifluoroacetyl-1,3-oxazolium-5-olate (1a): Yield
92%. mp 161—163 °C (mp8b) 162—163 °C). 2-tert-Butyl-3-methyl-4-triflu-
oroacetyl-1,3-oxazolium-5-olate (1b): Yield 94%. mp 120—121 °C (mp7f )
120—121 °C). 2-Methyl-3-phenyl-4-trifluoroacetyl-1,3-oxazolium-5-olate
(1d): Yield 78%. mp 200—203 °C (mp8b) 211—212 °C). 2,3-Diphenyl-4-tri-
fluoroacetyl-1,3-oxazolium-5-olate (1e): Yield 81%. mp 194—196 °C (mp8b)
194—196 °C).
2
128.69 (CH), 128.95 (CH), 129.27 (C), 129.54 (CH), 131.56 (C, JC–Fϭ39
Hz), 149.06 (s). MS m/z: 226 (Mϩ, 100%).
2-tert-Butyl-4-trifluoromethyl-1-methylimidazole (4b): 4b; mp 46—47 °C
(hexane). 1H-NMR (500 MHz) d: 1.44 (s, 9H), 3.78 (s, 3H), 7.09 (q, 1H,
Jϭ1.2 Hz). 13C-NMR (127 MHz) d: 29.08 (CH3), 33.50 (C), 35.77 (CH3),
122.01 (CF3, 1JC–Fϭ267 Hz), 122.58 (CH, 3JC–Fϭ4 Hz), 128.95 (C, 2JC–Fϭ38
Hz), 155.65 (C). MS m/z: 206 (Mϩ, 27%), 191 (100%). Anal. Calcd for
C9H13F3N2: C, 52.42; H, 6.35; N, 13.58. Found: C, 52.70; H, 6.16; N, 13.44.
2-Benzyl-4-trifluoromethyl-1-methylimidazole (4c): 4c; bp1 145 °C (bath
temperature). 1H-NMR (500 MHz) d: 3.43 (s, 3H), 4.12 (s, 2H), 7.14 (d, 2H,
Jϭ7.9 Hz), 7.17 (br s, 1H), 7.23 (t, 1H, Jϭ7.6 Hz), 7.29 (t, 2H, Jϭ7.6 Hz).
13C-NMR (127 MHz) d: 33.38 (CH2), 33.61 (CH3), 121.08 (CH, 3JC–Fϭ4
General Procedure for the Reactions of 4-Trifluoroacetyl-1,3-oxa-
zolium-5-olates (1) with Ammonium Acetate A solution of 1 (1.5 mmol)
and ammonium acetate (2.2 mmol) in dry DMF (5 ml) was stirred at 70 °C
for 2 h. The mixture was diluted with AcOEt (40 ml) and H2O (30 ml). After
the standard workup, the residue was recrystallized from EtOAc–hexane to
give the product (3).
1
The following products were identified by comparison of the IR and H-
NMR spectral data with those of authentic samples.7f ) 4-Trifluoromethyl-4-
hydroxy-1-methyl-2-phenyl-4,5-dihydroimidazole (3a): mp 196—198 °C
(Et2O). 2-tert-Butyl-4-trifluoromethyl-4-hydroxy-1-methyl-4,5-dihydroimi-
dazole (3b): mp 155—157 °C (Et2O). 4-Trifluoromethyl-4-hydroxy-2-
methyl-1-phenyl-4,5-dihydroimidazole (3d): mp 201—202 °C (Et2O). 4-Tri-
fluoromethyl-4-hydroxy-1,2-diphenyl-4,5-dihydroimidazole (3e): mp 174—
175 °C (Et2O).
1
Hz), 121.85 (CF3, JC–Fϭ267 Hz), 127.01 (CH), 128.25 (CH), 128.88 (CH),
2
130.41 (C, JC–Fϭ39 Hz), 135.99 (C), 148.17 (C). MS m/z: 240 (Mϩ, 87%),
91 (100%). Anal. Calcd for C12H11F3N2: C, 60.00; H, 4.62; N, 11.66. Found:
C, 60.19; H, 4.63; N, 11.84.
4-Trifluoromethyl-2-methyl-1-phenylimidazole (4d): 4d; mp 68—69 °C
1
(Et2O–hexane). H-NMR (500 MHz) d: 2.37 (s, 3H), 7.31 (dd, 2H, Jϭ1.5,
7.9 Hz), 7.34 (q, 1H, Jϭ1.2 Hz), 7.49—7.55 (m, 3H). 13C-NMR (127 MHz)
d: 13.67 (CH3), 120.47 (CH, 3JC–Fϭ4 Hz), 121.75 (CF3, 1JC–Fϭ267 Hz),
One-Pot Procedure for the Conversion of N-Acyl-N-alkylglycine (2) to
Dihydroimidazolines (3) TFAA (0.64 ml, 4.5 mmol) was added to a
stirred solution of N-acyl-N-alkylglycine (2) (1.5 mmol) in dry CH2Cl2 (4
ml) at 0 °C. The mixture was stirred at 25 °C for 3 h and the solvents were
evaporated to dryness. The residue was dissolved in dry DMF (6 ml) and
ammonium acetate (182 mg, 2.2 mmol) was added to the DMF solution at 0
°C. The mixture was stirred at 70 °C for 2 h. After the standard workup, the
residue was recrystallized from EtOAc–hexane to give the product (3).
2-Benzyl-4-trifluoromethyl-4-hydroxy-1-methyl-4,5-dihydroimidazole
(3c): 3c; mp 176—177 °C (Et2O). IR (Nujol) cmϪ1: 2500—3600 (br), 1575.
1H-NMR (500 MHz) d: 2.75 (s, 3H), 3.46 (d, 1H, Jϭ11.0 Hz), 3.61 (d, 1H,
Jϭ15.3 Hz), 3.62 (d, 1H, Jϭ11.0 Hz), 3.82 (d, 1H, Jϭ15.3 Hz), 7.24 (t, 1H,
Jϭ7.3 Hz), 7.25 (d, 2H, Jϭ7.3 Hz), 7.30 (t, 2H, Jϭ7.3 Hz). 13C-NMR (127
2
125.64 (CH), 129.18 (CH), 129.83 (CH), 131.13 (C, JC–Fϭ38 Hz), 136.80
(C), 146.35 (C). MS m/z: 226 (Mϩ, 100%). Anal. Calcd for C11H9F3N2: C,
58.41; H, 4.01; N, 12.38. Found: C, 58.22; H, 4.05; N, 12.34.
4-Trifluoromethyl-1,2-diphenylimidazole (4e): 4e; mp 122—123 °C
(Et2O–hexane). 1H-NMR (500 MHz) d: 7.21—7.25 (m, 3H), 7.26 (br s, 1H),
7.29—7.33 (m, 1H), 7.37—7.41 (m, 2H), 7.42—7.45 (m, 3H), 7.47—7.49
(m, 1H). 13C-NMR (127 MHz) d: 121.73 (CF3, 1JC–Fϭ267 Hz), 122.24 (CH,
3JC–Fϭ4 Hz), 125.86 (CH), 128.32 (CH), 128.89 (CHϫ2), 129.03 (CH),
2
129.22 (C), 129.77 (CH), 132.28 (C, JC–Fϭ39 Hz), 137.47 (C), 147.95 (C).
MS m/z: 288 (Mϩ, 100%). Anal. Calcd for C16H11F3N2: C, 66.67; H, 3.85; N,
9.72. Found: C, 66.87; H, 4.08; N, 9.62.
1-Benzyl-4-trifluoromethyl-2-phenylimidazole (4f): 4f; mp 83—84 °C

464
Vol. 49, No. 4
(Et2O–hexane). 1H-NMR (500 MHz) d: 5.20 (s, 2H), 7.09 (d, 2H, Jϭ7.5
K. T., Pergamon, Oxford, 1984, pp. 345—498.
4) Jouneau S., Bazureau J. P., Tetrahedron Lett., 40, 8097—8098 (1999)
and references cited therein.
Hz), 7.27 (br s, 1H), 7.32—7.39 (m, 3H), 7.40—7.46 (m, 3H), 7.56 (dd, 2H,
3
Jϭ2.1, 7.3 Hz). 13C-NMR (127 MHz) d: 50.81 (CH2), 120.60 (CH, JC–Fϭ4
Hz), 121.67 (CF3, 1JC–Fϭ267 Hz), 126.81 (CHϫ2), 128.39 (CH). 128.68
(CH), 129.04 (CH), 129.16 (CH), 129.66 (C), 131.93 (C, 2JC–Fϭ39 Hz),
135.58 (C), 149.34 (C). MS m/z: 302 (Mϩ, 17%), 91 (100%). Anal. Calcd
for C17H13F3N2: C, 67.75; H, 4.33; N, 9.27. Found: C, 67.59; H, 4.47; N,
9.30.
5) Baldwin J. J., Kasinger P. A., Novello F. C., Sprague J. M., J. Med.
Chem., 18, 895—900 (1975); Scriabine A., Ludden C. T., Morgan G.,
Baldwin J. J., Experientia, 35, 1634—1637 (1979); Scriabine A., Lud-
den C. T., Watson L. S., Stavorski J. M., Morgan G., Baldwin J. J.,
ibid., 35, 653—655 (1979); Moazzam M., Parrick J., Indian J. Chem.,
27B, 1051—1053 (1988); Carini D. J., Chiu A. T., Wong P. C., John-
son A. L., Wexler R. R., Timmermans P. B. M. W. M., Bioorg. Med.
Chem. Lett., 3, 895—898 (1993); Brackeen M., Stafford J. A., Feld-
man P. L., Karanewsky D. S., Tetrahedron Lett., 35, 1635—1638
(1994); Elguero J., Fruchier A., Jagerovic N., Werner A., Org. Prep.
Proced. Int., 27, 33—74 (1995); Li H.-Y., DeLucca I., Drummond S.,
Boswell G. A., J. Org. Chem., 62, 2550—2554 (1997); Hayakawa Y.,
Kimoto H., Cohen L. A., Kirk K. L., J. Org. Chem., 63, 9448—9454
(1998); Kamitori Y., Heterocycles, 53, 107—113 (2000).
6) Kawase M., Miyamae H., Kurihara T., Chem. Pharm. Bull., 46, 749—
756 (1998); Kawase M., Hirabayashi M., Saito S., “Recent Research
Developments in Organic Chemistry,” Vol. 4, Transworld Research
Network, India, 2000, pp. 283—293.
7) a) Kawase M., J. Chem. Soc., Chem. Commun., 1994, 2101—2102; b)
Kawase M., Saito S., Kurihara T., Heterocycles, 41, 1617—1620
(1995); c) Kawase M., Koiwai H., Yamano A., Miyamae H., Tetrahe-
dron Lett., 39, 663—666 (1998); d) Kawase M., Koiwai H., Saito S.,
Kurihara T,. ibid., 39, 6189—6190 (1998); e) Kawase M., Miyamae
H., Saito S., Heterocycles, 50, 71—74 (1999); f ) Kawase M., Saito S.,
Chem. Pharm. Bull., 48, 410—414 (2000).
8) a) Singh G., Singh S., Tetrahedron Lett., 1964, 3789—3792; b) Greco
C. V., Gray R. P., Grosso V. G., J. Org. Chem., 32, 4101—4103 (1967).
9) Thompson L. A., Ellman J. A., Chem. Rev., 96, 555—600 (1996);
Armstrong R. W., Combs A. P., Tempest P. A., Brown S. D., Keating T.
A., Acc. Chem. Rev., 29, 123—131 (1996); Kobayashi S., Chem. Soc.
Rev., 28, 1—15 (1999).
10) Booth R. J., Hodges J. C., Acc. Chem. Res., 32, 18—26 (1999); Guil-
lier F., Orain D., Bradley M., Chem. Rev., 100, 2091—2157 (2000).
11) a) Mjalli A. M. M., Sarshar S., Baiga T. J., Tetrahedron Lett., 37,
2943—2946 (1996); b) Strocker A. M., Keating T. A., Tempest P. A.,
Armstrong R. W., ibid., 37, 1149—1152 (1996).
1-Benzyl-4-trifluoromethyl-2-methylimidazole (4g): 4g; mp 79—80 °C
1
(Et2O–hexane). H-NMR (500 MHz) d: 2.33 (s, 3H), 5.02 (s, 2H), 7.06 (d,
2H, Jϭ7.8 Hz), 7.13 (d, 1H, Jϭ1.2 Hz), 7.29—7.36 (m, 3H). 13C-NMR (127
3
MHz) d: 13.05 (CH3), 50.15 (CH2), 119.67 (C, JC–Fϭ4 Hz), 121.69 (CF3,
1JC–Fϭ267 Hz), 126.84 (CH), 128.40 (CH), 129.13 (CH), 130.46 (C,
2JC–Fϭ38 Hz), 134.88 (C), 146.39 (C). MS m/z: 240 (Mϩ, 32%), 91 (100%).
Anal. Calcd for C12H11F3N2: C, 60.00; H, 4.62; N, 11.66. Found: C, 60.02;
H, 4.53; N, 11.50.
1-Methyl-4-pentafluoroethyl-2-phenylimidazole (4h): 4h; mp 56—57 °C
1
(hexane). H-NMR (500 MHz) d: 3.76 (s, 3H), 7.32 (br s, 1H), 7.44—7.46
(m, 3H), 7.58—7.64 (m, 2H). 13C-NMR (127 MHz) d: 34.85 (CH3), 111.00
(CF2, 1JC–Fϭ249 Hz, 2JC–Fϭ39 Hz), 119.12 (CF3, 1JC–Fϭ286 Hz, 2JC–Fϭ39
Hz), 123.15 (CH), 128.70 (CH), 129.04 (CH), 129.27 (C), 129.56 (CH),
130.00 (C, 2JC–Fϭ39 Hz), 149.36 (C). MS m/z: 276 (Mϩ, 100%). Anal. Calcd
for C12H9F5N2: C, 52.18; H, 3.28; N, 10.14. Found: C, 52.33; H, 3.32; N,
10.25.
4-Heptafluoropropyl-1-methyl-2-phenylimidazole (4i): 4i; mp 49—50 °C
1
(hexane). H-NMR (500 MHz) d: 3.77 (s, 3H), 7.32 (br s, 1H), 7.44—7.49
(m, 3H), 7.59—7.63 (m, 2H). 13C-NMR (127 MHz) d: 34.89 (CH3), 101—
121 (CF2CF2CF3), 123.41 (CH), 128.70 (CH), 129.05 (CH), 129.28 (C),
129.56 (CH), 130.11 (C, 2JC–Fϭ39 Hz), 149.34 (C). MS m/z: 326 (Mϩ,
78%), 207 (100%). Anal. Calcd for C13H9F7N2: C, 47.86; H, 2.78; N, 8.59.
Found: C, 47.65; H, 2.87; N, 8.68.
References and Notes
1) Resnati G., Tetrahedron, 49, 9385—9445 (1993); Banks R. E., Smart
B. E., Tatlow J. C. (ed.), “Organofluorine Chemistry: Principles and
Commercial Applications,” Plenum, New York, 1994; Filler R.,
Kobayashi Y., Yagupolskii L. M. (ed.), “Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications,” Elsevier, Amster-
dam, 1993; Hudlicky M., Pavlath A. E. (ed.), “Chemistry of Organic
Fluorine Compounds II,” ACS Monograph 187, American Chemical
Society, Washington D.C., 1995; Ojima I., McCarthy J. R., Welch J. T.
(ed.), “Biomedical Frontiers of Fluorine Chemistry,” ACS Symposium
Series 639, American Chemical Society, Washington D.C., 1996.
2) McClinton M. A., McClinton D. A., Tetrahedron, 48, 6555—6666
(1992); Kiselyov A. S., Strekowski L., Org. Prep. Proced. Int., 28,
289—318 (1996).
12) Bilodeau M. T., Cunningham A. M., J. Org. Chem., 63, 2800—2801
(1998).
13) Hamper B. C., Jerome K. D., Yalamanchili G., Walker D. M., Chott R.
C., Mischke D. A., Biotech. Bioeng., 71, 28—37 (2000).
14) Kamitori Y., Hojo M., Masuda R., Wada M., Takahashi T., Heterocy-
cles, 37, 153—156 (1994).
15) Baldwin J. J., Novello F. C., U.S. Pat., 4125530; [Chem. Abstr., 90,
P121593n (1979)].
3) Grimmett M. R., “Advances in Heterocyclic Chemistry,” Vol. 27, ed.
by Katritzky A. R., Academic Press, New York, 1970, pp. 241—326;
idem, “Comprehensive Heterocyclic Chemistry,” Vol. 5, ed. by Potts
16) Deruiter J., Swearingen B. E., Wandreker V., Mayfield C. A., J. Med.
Chem., 34, 2120—2126 (1991).