A convenient synthesis of 4-trifluoromethylimidazol-1-ols

Article abstract of DOI:10.3987/COM-99-8729

1,1,1-Trifluoroalkane-2,3-dione 3-oximes easily obtainable from aldehyde dialkylhydrazones were reacted with aldehydes in the presence of ammonium acetate followed by treatment with 1N HCl affording 4- trifluoromethylimidazol-1-ols in good yields.

Full text of DOI:10.3987/COM-99-8729

HETEROCYCLES, Vol. 53, No. 1, 2000, pp. 107 - 113, Received, 9th August, 1999
A CONVENIENT SYNTHESIS OF 4-TRIFLUOROMETHYL-
IMIDAZOL-1-OLS
Yasuhiro Kamitori*
Department of Chemical Science and Engineering,
Faculty of Engineering, Kobe University, Kobe 657-8501, Japan
Abstract - 1,1,1-Trifluoroalkane-2,3-dione 3-oximes easily obtainable from
aldehyde dialkylhydrazones were reacted with aldehydes in the presence of
ammonium acetate followed by treatment with 1N HCl affording 4-
trifluoromethylimidazol-1-ols in good yields.
Fluorine-containing heterocycles are very fascinating targets for synthetic organic chemists because of
their potentially high biological activities applicable to agricultural and medicinal use.1-3
In the course
of our studies on the synthesis of such fluorine-containing heterocycles, we have recently reported a
successful synthesis of some trifluoromethylated heterocycles with the use of 3-hydrazono-1,1,1-
trifluoroalkan-2-ones (1) as useful synthetic intermediates.4 1,1,1-Trifluoroalkane-2,3-dione 3-oximes
(2) which have an isoelectronic structure as hydrazones (1), are also thought to be effective intermediates
to prepare several heterocycles bearing a trifluoromethyl group. Here we would like to report a
convenient synthetic method to prepare 4-trifluoromethylimidazol-1-ols (3) from oximes (2).
In general,5 trifluoroacetylation of aldehyde dialkylhydrazones and subsequent hydrolysis of 3-dialkyl-
COCF3
R
R'
R'
10 M H2SO4
TFAA
NN
NN
2,6-lutidine
R"
R"
R
COCF3
O
C
OH
NH2X
XN
R
C CF3
OH
R
1: X= NH2
2: X= OH
Scheme 1

hydrazono-1,1,1-trifluoroalkan-2-ones thus obtained afforded 1,1,1-trifluoroalkane-2,3-diones as
monohydrates. These diketones treated with hydroxylamine hydrochloride in the presence of NaOAc
gave monooximes (2) in good yields (Scheme 1).
In the presence of NH4OAc, oximes (2) and excess amounts of aldehydes were allowed to react for 18 h
at 20°C. Treatment of the reaction mixture with 1N HCl afforded 4-trifluoromethylimidazol-1-ols (3a -
h) in 60-77% yields (Scheme 2).
CF3
1) R'CHO, NH4OAc
in MeOH, 20°C, 18 h
N
R'
2
2)
1N HCl
N
R
HO
R
3
R'
Yield(%)
3a
3b
3c
3d
3e
3f
65
77
66
60
67
61
62
C6H5
p-MeC6H4
p-ClC6H4
p-MeC6H4
o-MeC6H4
Et
Et
Et
iso-Pr
iso-Pr
iso-Pr
iso-Pr
p-MeOC6H4
p-O2NC6H4
3g
3h
72
n-C6H13
iso-Pr
Scheme 2
The structure of compounds (3) is confirmed by 1H and 13C NMR, and IR spectra, and micro combustion
13
analysis. In the C NMR spectra of 3d, imidazole ring carbon atoms C2, C4, and C5 appear at 149.5,
122.5 (2JCF= 37.4 Hz), and 130.6 ppm, respectively. These values are compatible with those observed
for 1-methyl-5-(p-methylphenyl)-4-trifluoromethyl-1H-imidazole. 6,7
When the reaction mixture from 2 (R= p-MeC6H4) and propionaldehyde without subsequent treatment
with 1 N HCl was fractionated by preparative TLC, 4-trifluoromethyl-5,6-dihydro-4H-[1,2,5]oxadiazin-4-
ol (4: R= p- CH3C6H4, R’= Et) was obtained in 55 % yield together with a small amount (4 %) of
imidazole (3b). After a treatment of purified 4 with 1 N HCl under the same condition described above,
4 was completely converted to 3b. The above result clearly suggests that imidazol-1-ols (3) derived
from oxadiazines (4).
Contrary to the results from the reaction of oximes (2) with aldehydes, that of 2 with ketones in similar
conditions afforded trifluoromethylated oxadiazine derivatives. In the presence of NH4OAc, oximes (2)
dissolved in large excess amounts of acetone were stirred for 19 d at 20°C. Treatment of the reaction

Me Me
1) NH4OAc
O
N
in MeCOMe, 20°C, 19 d
2
N
R
2)
1N HCl
CF3
p-MeC6H4 5a 51%
o-MeC6H4 5b 45%
R
mixture with 1N HCl gave 4-trifluoromethyl-6H-[1,2,5]oxadiazines (5a - b).
Possible reaction pathway from oximes (2) to imidazol-1-ols (3) is illustrated in Scheme 3. Acid
catalyzed dehydration of oxadiazines (4) which are the initial products from 2 and aldehydes, should
afford 4-trifluoromethyl-6H-[1,2,5]oxadiazines (5) similarly to the case of the reactions of 2 and ketones.
Electrocyclic ring opening of 5 and subsequent intramoleculer nucleophilic attack of nitroso nitrogen
atom toward azomethine carbon atom or electrocyclic recyclization process affords nitrone type 2H-
imidazoles (6). Subsequent prototropy for aromatization on 6 gives imidazol-1-ols (3).
R'
R'
R'CHO, NH4OAc
O
N
N
5
1N HCl
O
N
NH
OH
2
CF3
CF3
R
R
4
elecrocyclic
ring opening
H
6
R'
N
R'
R'
N
N
prototropy
N
O
3
N
O
O
N
CF3
CF3
CF3
R
R
R
Scheme 3
On the basis of our 6-31G* level ab initio calculations,8 imidazol-1-ol (3: R= R’= H) is estimated 52.93
KJ/mol more stable than oxadiazine (5: R= R’= H). In contrast, 2H-imidazole (6: R= R’= H) is
calculated 37.03 KJ/mol less stable than 5 (R= R’= H). Probably there are equilibriums between
oxadiazines (5) and 2H-imidazoles (6) as is shown in Scheme 3. In the case of the reactions from
oximes (2) and ketones instead of aldehydes, there is no hydrogen on the ring carbon atom C2 of 2H-
imidazoles corresponding to 6 that is necessary for the last step in Scheme 3 and, therefore, 2H-imidazole
would return to 5 even if it was formed. These should be the reason why neither 6 type 2H-imidazoles

nor any products derived from them could be detected in the reaction products from oximes (2) and
ketones. Although we could not get a definite evidence for formation of oxadiazines (5) in the reaction
of 2 with aldehydes, the reaction pathway in Scheme 3 is thought to be the most reasonable one for
formation of imidazol-1-ols (3) from oximes (2).
In summary, we can present a convenient synthetic method accessing 4-trifluoromethylimidazol-1-ols and
4-trifluoromethyl-6H-[1,2,5]oxadiazines after few steps from various aldehydes via 1,1,1-trifluoroalkane-
2,3-dione 3-oximes. These new fluorine-containing heterocycles are not easily accessible by other
methods.
EXPERIMENTAL
Melting points were determined with a Mitamura Riken model 7-12 apparatus and uncorrected. 1H
NMR and 13C NMR spectra were recorded at 60 MHz on a JEOL PMX 60SI and at 59.5 MHz on a
Bruker AC250, respectively. Unless otherwise noted NMR spectra were measured in CDCl3 containing
TMS as an internal standard. IR spectra were taken with a Hitachi model G3
General procedure for preparation of 1,1,1-trifluoroalkane-2,3-dione 3-oximes (2).
A mixture of 1,1,1-trifluoroalkane-2,3-diones (10 mmol), hydroxylamine hydrochloride (764.4 mg, 11
mmol), and NaOAc (902.3 mg, 11 mmol) in 30 mL of dioxane / H2O (2 / 1) was stirred for 18 h under
reflux conditions. The reaction mixture was poured into CH2Cl2 (150 mL), and the whole mixture was
washed with 0.5 N aq. NaHCO3 (100 mL) and dried over Na2SO4. Removal of the solvent gave the
corresponding 1,1,1-trifluoroalkane-2,3-dione 3-oximes (2)9 quantitatively. Without farther purification
these monooximes (2) were used for the following reactions.
General procedure for preparation of 4-trifluoromethylimidazol-1-ols (3a - h).
A mixture of 2 (1 mmol), aldehyde (1.3 mmol), and NH4OAc (246.1 mg, 3 mmol) in MeOH (5 mL) was
stirred for 18 h at 20°C. The solvent was removed under reduced pressure, and the residue were
dissolved in CH2Cl2 (30 mL). After filtering off insoluble materials, the mixture was washed thoroughly
with 1 N HCl (50 mL) and subsequently, with 0.5 N aqueous Na2CO3 (50 mL), and dried over Na2SO4.
Removal of the solvent and fractionation of the residual materials by preparative TLC (CH2Cl2 / EtOAc =
95/5) afforded 4-trifluoromethylimidazol-1-ols (3a - h).
1
2-Ethyl-4-trifluoromethyl-5-phenylimidazol-1-ol (3a): syrupy oil: H NMR δ 0.98 (t, J= 7.2 Hz, 3H,
CH3), 2.40 (q, J= 7.2 Hz, 2H, CH2), 7.24 (s, 5H, C6H5), 10.50 – 11.50 (br, 1H, OH); IR (KBr): ν 2200 –
3500 (OH), 1161, 1112 (CF3) cm-1.

2-Ethyl-4-trifluoromethyl-5-(p-methylphenyl)imidazol-1-ol (3b): colorless crystals (EtOAc), mp 168-
1
169°C, H NMR (acetone-d6): δ 1.20 (t, J= 7.2 Hz, 3H, CH3CH2), 2.33 (s, 3H, p-CH3C6H4), 2.67 (q, J=
7.2 Hz, 2H, CH3CH2), 7.27 (s, 4H, p-CH3C6H4), 10.50-11.50 (br, 1H, OH); IR (KBr) ν 2100-3575 (OH),
1179, 1145 (CF3) cm-1. Anal. Calcd for C13H13N2OF3: C, 57.78; H, 4.85; N, 10.37. Found: C, 57.50; H,
4.77; N, 10.31.
2-Ethyl-4-trifluoromethyl-5-(p-chlorophenyl)imidazol-1-ol (3c): syrupy oil: 1H NMR δ 1.01 (t, J= 7.4
Hz, 3H, CH3), 2.46 (q, J= 7.4 Hz, 2H, CH2), 7.18 (s, 4H, p-ClC6H4), 10.00 - 11.00 (br, 1H, OH); IR (KBr)
ν 2100-3300 (OH), 1162, 1115 (CF3) cm-1.
2-iso-Propyl-4-trifluoromethyl-5-(p-methylphenyl)imidazol-1-ol (3d): colorless crystals (EtOAc), mp
196-197°C: 13C NMR (acetone-d6) δ 20.8 (CH3CH), 21.3 ( p-CH3C6H4), 26.2 (CH3CH), 122.5 (2JCF=
37.4 Hz, C4), 123.6 (1JCF= 266.7 Hz, CF3), 125.0, 129.5, 130.8, 139.4 ( p-CH3C6H4), 130.6 (3JCF= 2.7 Hz,
C5), 149.5 (C2); 1H NMR (acetone-d6) δ 1.24 (d, J= 7.0 Hz, 6H, CH3CH), 2.32 (s, 3H, p-CH3C6H4), 3.13
(hept, J= 7.0 Hz, 1H, CH3CH), 7.17 (s, 4H, p-CH3C6H4), 10.00 - 11.00 (br, 1H, OH); IR (KBr) ν 2080-
3100 (OH), 1160, 1109 (CF3) cm-1. Anal. Calcd for C14H15N2OF3: C, 59.15; H, 5.32; N, 9.85. Found:
C, 58.84; H, 5.22; N, 9.60.
2-iso-Propyl-4-trifluoromethyl-5-(o-methylphenyl)imidazol-1-ol (3e): colorless crystals (EtOAc), mp
198-201°C: 1H NMR (CD3OD) δ 1.35 (d, J= 7.0 Hz, 6H, CH3CH), 2.17 (s, 3H, o-CH3C6H4), 3.25 (hept,
J= 7.0 Hz, CH3CH), 7.10 - 7.45 (m, 4H, o-CH3C6H4); IR (KBr) ν 2000-3100 (OH), 1167, 1111 (CF3)
cm-1.
2-iso-Propyl-4-trifluoromethyl-5-(p-methoxyphenyl)imidazol-1-ol (3f): colorless crystals (EtOAc), mp
194-196°C: 1H NMR (CD3OD) δ 1.34 (d, J= 7.0 Hz, 6H, CH3CH), 3.25 (hept, J= 7.0 Hz, CH3CH), 3.81
(s, 3H, OCH3), 6.73 - 7.48 (q, J= 9.0 Hz, 4H, p-CH3OC6H4); IR (KBr) ν 2100-3100 (OH), 1138, 1120,
1105 (CF3) cm-1.
2-iso-Propyl-4-trifluoromethyl-5-(p-nitrophenyl)imidazol-1-ol (3g): yellow crystals (EtOAc), mp 193-
194°C, 1H NMR: δ 1.29 (d, J= 7.0 Hz, 6H, CH3), 3.14 (hept, J= 7.0 Hz, 1H, CH), 7.53, 8.15 (d, J= 8.4 Hz,
4H, p-O2NC6H4), 10.80 - 11.80 (br, 1H, OH); IR (KBr): ν 2100-3100 (OH), 1150, 1102 (CF3) cm-1.
1
2-iso-Propyl-4-trifluoromethyl-5-(n-hexyl)imidazol-1-ol (3h): syrupy oil: H NMR δ 0.60-1.90 (m,
17H, n-C5H11CH2, CH3CH), 2.40 - 2.76 (m, n-C5H11CH2), 3.15 (hept, J= 7.0 Hz, 1H, CH3CH), 10.60 -
10.95 (br, 1H, OH); IR (KBr) ν 2100-3100 (OH), 1153, 1112 (CF3) cm-1.
4-Trifluoromethyl-5,6-dihydro-4H-[1,2,5]oxadiazin-4-ol (4).
A mixture of 2 (R= p-MeC6H4, 115.6 mg, 1 mmol), propionaldehyde (75.5 mg, 1.3 mmol), and NH4OAc

(246.1 mg, 3 mmol) in MeOH (5 mL) was stirred for 18 h at 20°C. The reaction mixture was poured
into CH2Cl2 (50 mL), and the whole mixture was washed water (100 mL) and dried over Na2SO4.
Removal of the solvent and fractionation of the residual materials by preparative TLC (CH2Cl2 / EtOAc =
9/1) gave 158.5 mg (55%) of 3-(p-methylphenyl)-4-trifluoromethyl-6-ethyl-5,6-dihydro-4H-[1,2,5]-
13
oxadiazin-4-ol (4: 5/2 mixture of diastereomers) as colorless crystals, mp 117-119°C (cyclohexane): C
NMR (acetone-d6) δ 7.2 (CH3CH2), 21.5 (p-CH3C6H4), 27.2, 27.7 (CH2), 84.8, 85.8 (CH), 92.5, 92.9
(2JCF=32.9 Hz and 33.1 Hz, respectively CCF3), 123.9, 125.1 (1JCF=284.5 Hz and 288.5Hz, respectively,
CF3), 124.3 125.3 (C1’ of p-CH3C6H4), 128.5, 129.0, 129.2, (C2’, C3’, C5’, and C6’ of p-CH3C6H4),
1
134.0, 135.2 (N=C-), 141.2 (C4’ of p-CH3C6H4); H NMR (acetone-d6) δ 0.90 (t, J= 7.4 Hz, 3H,
CH3CH2), 1.20-2.15 (m, 2H, CH3CH2), 2.33 (s, 3H, p-CH3C6H4), 3.90, 4.23 (br d, J= 5.5 Hz, 1H, NH),
4.80 - 5.10 (m, 1H, CH), 6.42 - 7.42 (br, 1H, OH ), 7.16 (d, J= 8.0 Hz, 2H, p-CH3C6H4), 8.08, 8.43 (d, 1H,
J= 8.0 Hz, 2H, p-CH3C6H4); IR (KBr) ν 2050-3625 (OH), 1182, 1131 (CF3) cm-1. Anal. Calcd for
C13H15N2O2F3: C, 54.17; H, 5.24; N, 9.72. Found: C, 54.37; H, 5.22; N, 9.69.
General procedure for preparation of 4-trifluoromethyl-6H-[1,2,5]oxadiazines (5a - b).
A mixture of 2 (1 mmol), acetone (5 mL, 68.1 mmol), and NH4OAc (246.1mg, 3 mmol) was stirred for
19 d at 20°C. The subsequent workup procedures were quite similar to those described in the section for
3a - h. Fractionation of the products by preparative TLC (CH2Cl2) afforded 4-trifluoromethyl-6H-
[1,2,5]oxadiazines (5a - b).
6,6-Dimethyl-3-(p-methylphenyl)-4-trifluoromethyl-6H-[1,2,5]oxadiazine (5a): pale yellow crystals
1
(n-hexane), mp 76-77°C: H NMR δ 1.66 (s, 6H, 6-CH3), 2.35 (s, 3H, p-CH3C6H4), 7.20, 7.57 (d, J= 8.0
Hz, 4H, p-CH3C6H4); IR (KBr) ν 1208, 1138, 1118 (CF3) cm-1. Anal. Calcd for C13H13N2OF3: C, 57.78;
H, 4.85; N, 10.37; F, 21.09. Found: C, 58.01; H, 4.72; N, 10.60; F, 20.87.
6,6-Dimethyl-3-(o-methylphenyl)-4-trifluoromethyl-6H-[1,2,5]oxadiazine (5b): pale yellow crystals
(n-hexane), mp 91-92°C: 1H NMR δ 1.67 (s, 6H, 6-CH3), 2.14 (s, 3H, o-CH3C6H4), 7.07 - 7.40 (m, 4H, o-
CH3C6H4); IR (KBr) ν 1205, 1138 (CF3) cm-1.
REFERENCES AND NOTES
1. Review: R. Filler, “Organofluorine Chemicals and their Industrial Applications”, ed. by R. E. Banks,
Ellis Horwood, London, 1979, p. 123.
2. V. N. Pathak and V. Grover, Pharmazie, 1979, 34, 568 (Chem Abstr., 1980, 92, 181060n).
3. H. V. Secor and J. F. De Bardeleben, J. Med. Chem., 1971, 14, 997.

4. Y. Kamitori, M. Hojo, and T. Yoshioka, Heterocycles, 1998, 48, 2221.
5. Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, and T. Yokoyama, J. Org. Chem., 1988, 53,
129. Y. Kamitori, M. Hojo, R. Masuda, T. Yoshida, S. Ohara, K. Yamada, and T. Yokoyama, J.
Org. Chem., 1988, 53, 519.
6. Imidazole ring carbon atoms of 1-methyl-5-(p-methylphenyl)-4-trifluoromethyl-1H-imidazole appear
at 137.6 (C2), 128.8 (2JCF= 37.4 Hz, C4), and 133.0 (C5) ppm. Those of 1-methyl-4-(p-methyl-
phenyl)-5-trifluoromethyl-1H-imidazole (as a reference compound of 2-iso-propyl-4-(p-methyl-
phenyl)-5-trifluoromethylimidazol-1-ol which is the regioisomer of 3d) are observed at 140.5 (C2),
145.1 (C4), and 116.5 (2JCF= 39.1 Hz, C5) ppm.
7. Y. Kamitori, M. Hojo, R. Masuda, S. Ohara, K. Kawasaki, Y. Kawamura, and M. Tanaka, J.
Heterocycl. Chem., 1990, 27, 487.
8. Calculations were accomplished using the computer program package PC SPARTAN plus
(Wavefunction, Inc). Calculations including geometry optimizations were performed with the 6-
31G* basis set at Hartree-Fock levels.
9. For instance, 2 (R= p-MeC6H4, syn / anti= 1 / 1): mp 89-101°C: 13C NMR (CDCl3 / TMS) δ 21.4 (p-
CH3C6H4), 114.8 (1JCF=291.2 Hz, CF3), 116.7 (1JCF=291.2 Hz, CF3), 126.4, 129.2, 129.4, 130.2 (C2’,
C3’, C5’, and C6’ of p-CH3C6H4), 123.6, 125.7 (C1’ of p-CH3C6H4), 141.0, 142.3 (C4’ of p-
1
CH3C6H4), 152.7, 153.5 (C=N), 179.1 (2JCF=35.3 Hz, C=O), 186.6 (2JCF=40.6 Hz, C=O); H NMR
(CDCl3 / TMS) δ 2.32 (s, 3H, p-CH3C6H4), 7.13, 6.80 - 7.40 (s and br, 5H, p-CH3C6H4 and OH); IR
(KBr) ν 2000 - 3700 (OH), 1188, 1152 (CF3) cm-1.