4-trifluoroacetyl-2-phenyloxazol-5-one: Versatile template for syntheses of trifluoromethylsubstituted heterocycles

Article abstract of DOI:10.3987/COM-13-12838

4-Trifluoroacetyl-2-phenyloxazol-5-one (1) is a versatile template for the synthesis of various trifluoromethyl-substituted heterocycles. Cyclocondesation of 1 with hydroxylamine and hydrazine afforded isoxazole and pyrazole, respectively. Another key protocol involves nucleophilic ring opening of 1 with H₂O or MeOH to give a-amido trifluoromethyl ketones which are transformed into trifluoromethyl-substituted thiazoles, oxazoles, imidazoles, pyrazoles, and pyrimidines.

Full text of DOI:10.3987/COM-13-12838

HETEROCYCLES, Vol. 87, No. 12, 2013
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HETEROCYCLES, Vol. 87, No. 12, 2013, pp. 2533 - 2553. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 12th September, 2013, Accepted, 23rd October, 2013, Published online, 1st November, 2013
DOI: 10.3987/COM-13-12838
4-TRIFLUOROACETYL-2-PHENYLOXAZOL-5-ONE:
TEMPLATE FOR SYNTHESES OF TRIFLUOROMETHYL-
SUBSTITUTED HETEROCYCLES
VERSATILE
Ryosuke Saijo, Ken-ichi Kurihara, and Masami Kawase*
Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho,
Matsuyama, Ehime 790-8578, Japan; E-mail: kawase@cc.matsuyama-u.ac.jp
Abstract – 4-Trifluoroacetyl-2-phenyloxazol-5-one (1) is a versatile template for
the
synthesis
of
various
trifluoromethyl-substituted
heterocycles.
Cyclocondesation of 1 with hydroxylamine and hydrazine afforded isoxazole and
pyrazole, respectively. Another key protocol involves nucleophilic ring opening
of 1 with H2O or MeOH to give -amido trifluoromethyl ketones which are
transformed into trifluoromethyl-substituted thiazoles, oxazoles, imidazoles,
pyrazoles, and pyrimidines.
INTRODUCTION
We are looking for a convenient route to a series of CF3-substituted heterocycles1 and since we required
access to moderate quantities of compounds of this type for subsequent library synthesis,2 the
development of a more flexible approach to such structures was therefore investigated.
One of the key issues in organo-fluorine chemistry is the availability of suitably functionalized
fluorinated building blocks to be used of more complex fluorinated molecular structures.3
O
CO2H
CF3
H
CF3
OH
OH
CF3
TFAA
H2O
H2O
HN
Ph
CO2H
N
HN
Ph
N
(1)
O
- CO2
Ph
O
Ph
O
O
O
O
1
2
4-Trifluoroacetyl-2-phenyloxazol-5-one (4-trifluoroacetylazlactone) 1 is expected to constitute a very
promising, highly reactive, yet easy-to-handle class of fluorinated building blocks. Compound 1 can be
prepared in a one-step by the reaction of N-benzoylglycine and trifluoroacetic anhydride (TFAA) in a

2534
HETEROCYCLES, Vol. 87, No. 12, 2013
high yield (Eq. 1).4 However, the reactivity of compound 1 is nearly unexplored and 1 is involved as an
intermediate in the Dakin-West reaction of N-benzoylglycine with TFAA and undergoes hydrolysis and
subsequent decarbonylation to lead the trifluoromethyl ketone hydrate 2 (Eq. 1).5
In view of the unique biological properties displayed by many trifluoromethylated heterocyclic
compounds1 and in the course of our studies on the reactivities of mesoionic
4-trifluoroacetyl-1,3-oxazolium-5-olates 3,6 we have focused our attention on the structurally related 1 as
a novel fluorinated building block. Because 1 exists in three tautomeric forms A, B and C, in which the
last one is structurally related to mesoionic 3 (Figure 1).
O
O
O
O
CF3
CF3
OH
CF3
O-
CF3
O-
H
R
+
+
N
N
N
N
Ph
Ph
Ph
Ph
O
O
O
O
O
A
B
C
3
Figure 1
In this context, we decided to study the interaction of 1 with N- and O-nucleophiles such as NH2NH2,
PhNHNH2, NH2OH, H2O, and MeOH, in heterocyclic construction. We now report the use of 1 in the
synthesis of a wide range of trifluoromethyl-substituted pyrazoles, isoxazoles, oxazoles, thiazoles,
imidazoles and pyrimidines.
RESULTS AND DISCUSSION
The reactivity of 4-trifluoroacetylazlactone 1 is nearly unexplored, as one paper describing hydrolysis of
1 has been reported so far.4 In principle, the addition of nucleophiles to 1 can a priori be expected to
occur at three different positions (C-2, C-5, or COCF3). Therefore, we have now investigated the
reaction of 1 and N-nucleophiles such as hydroxylamine, hydrazine, and phenylhydrazine which, being
bis-nucleophilic in nature, may attack on any one of the electrophilic centers of 1.
Treatment of 1 with hydroxylamine HCl (1.5 equiv) in the presence of AcONa (3 equiv) in DMF at 80 °C
furnished 3-trifluoromethylisoxazole 4 in 82% yield (Table 1, entry 3). In the absence of a base to
liberate the hydroxylamine from their hydrochloride salt, no desired product was observed (entry 1).
Three equiv. of hydroxylamine HCl result in lower yields (entry 2).
Compound 1 reacted with hydrazine hydrate with the formation of 3-trifluoromethylpyrazole 5 (entries
4-7). At higher equiv. of hydrazine hydrate led to higher yields of product. The use of 5 equiv. of
hydrazine hydrate increased the yield to 84% (entry 6).
Condensation of 1 with phenylhydrazine afforded regioselectivity. Pyrazinone 6 was obtained as the

HETEROCYCLES, Vol. 87, No. 12, 2013
2535
major product, accompanying the formation of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole 7 (entry 8).
Acid-catalyzed dehydration of 6 yielded the corresponding 7 in 81% yield. The structures of 4, 5, 6, and
13
7 were unambiguously characterized by a careful analysis of the C-NMR spectra (Scheme 2). In the
13C-NMR spectra of 7, pyrazole ring carbon atoms C3, C4, and C5 appear at 137.1 (2J = 36 Hz), 99.1, and
149.9 ppm, respectively. These 13C-NMR data of 6 and 7 are similar to the data for the related
compounds 6x and 7x (Figure 2).7
Table 1. Reactions of 1 with bis-nucleophiles
Ph
NH CF3
NH2OH EHCl
in DMF, 80 °C
O
N
HO
O
4
O
Ph
O
NH CF3
CF3
NH2NH2 EH2O
in DMF, 80 °C
N
N
N
Ph
O
HO
O
H
1
5
Ph
O
Ph
O
CF3
OH
NH
NH
NH CF3
PhNHNH2
+
in DMF, 80 °C
N
N
O
HO
N
Ph
Ph
7
6
10% HCl/MeOH
reflux, 3 h
Entry
Bis-nucleophiles (equiv.)
NH OH HCl (3)
Base (equiv.)
Time (h)
Products (%)
4
1
2
3
4
5
6
7
8
none
3
3
3
3
3
3
3
4
(0)
·
2
AcONa (3)
AcONa (3)
none
4 (57)
4 (82)
NH OH HCl (3)
·
2
NH OH HCl (1.5)
·
2
5
NH NH H O (1.5)
(20)
·
2
2
2
none
5 (70)
5 (84)
NH NH H O (3)
·
2
2
2
NH NH H O (5)
none
·
2
2
2
5
NH NH H O (10)
none
(78)
6 (62)a
·
2
2
2
none
PhNHNH2 (1.5)
a Plus 7 (10%).
In addition, the reactions are regiospecific in the synthesis of isoxazole 4 and pyrazinone 6. The first
step of the reaction always proceeds via attack of the more nucleophilic atom (NH2) in hydroxylamine
and phenylhydrazine to the trifluoroacetyl group. The second step is the attack of hydroxyl group
(hydroxylamine) or phenyl-substituted amino group (phenylhydazine) to the lactone furnishing the
compounds 4 and 6, respectively.

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HETEROCYCLES, Vol. 87, No. 12, 2013

c 166.6

c 167.0

c 97.8

c 88.4
1
1

c 121.4 (q, JC-F = 267 Hz)
Ph
O

Ph
O
c 119.5 (q, JC-F = 270 Hz)
NH CF3
NH
CF3
2
2

c 136.9 (q, JC-F = 38 Hz)

c 153.7 (q, JC-F = 35 Hz)
N
N
N
HO
HO
c 171.1
O
H


c 150.4
4
5

c 167.3

c 55.5

Ph
c 166.9
1

c 123.6 (q, JC-F = 285 Hz)

c 99.1
1
Ph
O

c 121.1 (q, JC-F = 270 Hz)
2
CF3
OH
NH

NH
c 85.7 (q, JC-F = 30 Hz)
NH
CF3
2

c 137.1 (q, JC-F = 36 Hz)
O
N
O
HO
N
N
Ph
Ph

c 149.9

c 166.4
7
6

c 171.2
Me

c 176.2
CH3
N

c 65.0

c 115.8
1

c 122.7 (q, JC-F = 284 Hz)
1

c 120.5 (q, JC-F = 270 Hz)
Ph
O
Ph
2
N
CF3
2
CF3
OH

c 86.7 (q, JC-F = 32 Hz)

c 137.2 (q, JC-F = 39 Hz)
O
Ph
N
NH
O
O
N
N
O
Ph

c 161.6
Ph


c 161.1
c 140.2
7x (lit.7)
6x (lit.7)
Figure 2
We next investigated ring-opening of the oxazolone ring in 1 by O-nucleophiles such as H2O and MeOH
(Eq. 2). Hydrolysis of 4-trifluoroacetylazlactone 1 to afford 2-benzoylamino trifluoromethyl ketone
hydrate 2 is already reported.4
H
CF3
OH
OH
N
H2O/dioxane
y. 90%
Ph
O
O
2
CF3
N
(2)
Ph
O
O
CO2Me
CF3
OH
OH
H
1
N
MeOH/TFA
y. 95%
Ph
O
8

HETEROCYCLES, Vol. 87, No. 12, 2013
2537
We have synthesized 2 in improved yield of 90% by slight modification of the original report. Thus, the
reaction mixture was refluxed in 1,4-dioxane and H2O (3:2) for 15 min (Eq. 2). On the other hand, to
our best knowledge, reaction of 1 with alcohol was not reported. The methanolysis of 1 was performed
in MeOH in the presence of trifluoroacetic acid (TFA) and the product 8 was obtained in 95% yield.
These trifluoromethyl ketones readily form covalent hydrates 2 and 8, as observed from 13C NMR spectra.
A characteristic feature of the 13C NMR spectra of 2 and 8 in DMSO-d6 is the appearance of a quartet at
around 92 ppm (2J = 30-31 Hz) for the hydrated carbon signals.
The non-fluorinated 2-acylamino ketones constitute interesting building blocks for further
functionalization by various reactions.8 Indeed such substrates are well-known synthons in the synthesis
of azoles such as imidazoles, thiazoles, and oxazoles. Consequently, such trifluoromethylated
compounds 2 and 8 should constitute very useful building blocks as starting materials in the synthesis of
fluorinated molecules. Syntheses of 2-acylamino trifluoromethyl ketones were also reported by several
research groups9; however, no attempts were made for further synthetic application of 2 as a fluorine
building block for CF3-substituted heterocycles. Therefore, their synthetic potential has not been fully
explored. A close look at the structure of 8 reveals that the compound 8 contains a carbon substituted
with three different reactive functional groups such as COCF3, CO2Me, and NHCOPh.
Recently, Moody and co-workers reported that ethyl esters of type 8 were obtained through the
rhodium-catalyzed reaction of trifluoroacetyl diazoketoester and benzamides in low yields (32-43%),
accompanying side products.10 Several examples of subsequent cyclizations afforded CF3-substituted
oxazoles, imidazoles, and thiazoles. Obviously, our strategy provides a more simple, facile and
high-yielding route to this type of compounds 8. In our study we have chosen two compounds 2 and 8
as our readily available substrates for CF3-substituted heterocycles.
Table 2. Formation of thiazoles
R
R
H
CF3
OH
OH
N
N
LR
Ph
CF3
S
Ph
O
9
10
: R=H
: R=CO2Me
2: R=H
8: R=CO2Me
Entry
Temp (°C)
Yields (%)
Compound Solvent
LR (equiv.)
Time (h)
2
2
2
2
2
8
DME
9 (70)
9 (58)
1
2
3
4
5
6
0.6
0.6
0.6
0.6
1.2
0.6
105
158
170
170
103
105
24
12
12
24
12
12
xylene
diglyme
diglyme
DME
9
(59)
9 (69)
9 (60)
10
DME
(78)

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HETEROCYCLES, Vol. 87, No. 12, 2013
As expected, the treatment of both compounds
2
and
8
with Lawesson’s reagent
(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide; LR) gave the cyclized
5-trifluoromethylthiazoles 9 and 10, respectively (Table 2).11 Among the solvents investigated (entries
1-3), DME is found to be the solvent of choice for the transformation. 0.6 Equivalents of LR is adequate
for the conversion of 2 to 9 (entry 1). When 1.2 equiv of LR was used, the yield of 9 dropped (entry 5).
Based on these results and the previous literature,11 the reaction is likely to involve initial thionation of
the amide 2 to the corresponding thioamide which undergoes intramolecular cyclization.
Table 3. Formation of oxazoles
R
R
H
CF3
OH
OH
N
N
Ph
CF3
O
Ph
O
2
8
11
12
: R=H
: R=CO2Me
: R=H
: R=CO2Me
Entry
Temp (°C)
Yields of products (%)
Compound Solvent
Reagent
Time (h)
phosphoryl chloride
sulfuric acid
1
2
3
4
5
6
7
8
9
2
2
2
2
2
8
8
8
8
toluene
-
3
80
80
160
160
rt
11 (0)
11
3
(0)
polyphosphoric acid
phosphorus(V) oxide
6
11 (0)
toluene
toluene
DCE
6
11 (14)
PPh I Et N
11
(0)
· ·
5
3
2
3
PPh I ·Et N
4
rt
12 (20)
12 (68)
DCE
·
3
2
3
PPh I Et N
DCE
· ·
14
6
rt
3
2
3
phosphorus(V) oxide
phosphoryl chloride
12
toluene
DMF
160
rt
(27)
16
12 (14)
Historically, the cyclodehydration of 2-acylamino ketones, known as the Robinson-Gabriel reaction, is
one of the most widely used synthesis of substituted oxazoles. The conversion has been accomplished
using cyclodehydrating agents such as phosphoryl chloride, sulfuric acid, polyphosphoric acid, or
phosphorus pentoxide. We surveyed a series of conditions that could affect cyclodehydration of 2 to
yield 11 and the results are summarized in the Table 3. Thus, POCl3, H2SO4 and PPA gave completely
negative results (entries 1, 2, and 3), whereas P2O5 in toluene at 160 °C yielded the expected oxazole 11
in a low yield (14%) (entry 4). In 1993, Wipf and Miller introduced a new protocol based on the use of
triphenylphosphine/iodine in the presence of triethylamine.12 Cyclodehydration of 2 with Ph3P-I2-Et3N
under Wipf’s condition resulted in negative results (entry 5). However, treatment of 8 with
Ph3P-I2-Et3N under Wipf’s condition provided the desired oxazole 1213 in 68% yield (entry 7). These
differences indicated that an ester substituent attached to 2-posion of the ketones 8 is necessary for the

HETEROCYCLES, Vol. 87, No. 12, 2013
2539
oxazole formation using Wipf’s protocol. It has been suggested that the variation in yield of the product
is large by the difference in a substituent group.12 The cyclodehydration of 8 to 12 could also be
effected by P2O5 and POCl3 in low yields (entries 8 and 9).
Next, several examples of imidazole formation were studied: simply treating both compounds 2 and 8
with ammonia or primary amines in a solution of toluene and AcOH (5:1) gave the
5-trifluoromethylimidazoles 13a-e and 14a,b in 36-84% yields (Table 4, entries 1-8, 11, and 12). The
reactions were monitored by TLC and the optimal reaction time and temperature were determined. The
yields of the products depended on the structure of amines. The reactions of 2 with aniline gave the
enamide 15, before undergoing cyclodehydration to the 1,2-diphenylimidazole 13e (entry 9). The
Z-stereochemistry of 15 was determined by the nuclear Overhauser effect (NOE) of the amido proton
caused by irradiation of the aromatic protons (Figure 3).
Table 4. Formation of imidazoles
R1
R1
CF3
N
H
CF3
OH
OH
R2NH2
H
CF3
Ph
N
Ph
N
N
in toluene-AcOH (5:1)
135 °C
Ph
HN
O
R2
O
Ph
15
1
1
2
13a-e
: R =H
: R =H
8: R1=CO2Me
14a-b: R1=CO2Me
R1
R2
Entry Compound
Time (h) Yields of products (%)
Amine (equiv.)
NH4OAc (3)
1
2
2
2
2
2
2
2
2
2
2
2
8
8
H
H
8
8
13a (72)
13a
H
H
NH4OAc (10)
MeNH2·HCl (3)
MeNH2·HCl (10)
(68)
3
H
Me
Me
8
13b (63)
13b (84)
4
H
8
H
n-C6H13 hexylamine (3)
13c
(79)
5
8
hexylamine (10)
benzylamine (3)
benzylamine (10)
aniline (3)
6
H
n-C6H13
PhCH2
PhCH2
Ph
8
13c (75)
13d (24)
7
H
8
H
13d
(36)
8
8
9
H
2
15 (72)
10a
11
12
H
Ph
24
8
13e (45)
aniline (3)
CO2Me
CO2Me
H
NH4OAc (3)
MeNH2·HCl (3)
14a
(45)
Me
48
14b (65)
a POCl3 (2 equiv.) was used instead of AcOH.
The conversion of 15 to 13e were only moderate (up to 20%) in spite of several reactions tried.
Fortunately, 13e was directly obtained from 2 in 45% yield when the reaction was performed in the
presence of POCl3 instead of AcOH (entry 10).

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HETEROCYCLES, Vol. 87, No. 12, 2013
O
CF3
N
H
HN
H
9.6%
H
2.5%
15
Figure 3. NOE experiments in 15
The reactions of the -amido ketone 8 with ammonium acetate and methylamine also afforded the
corresponding 5-trifluoromethylimidazoles 14a and b in moderate yields, respectively (entries 11 and 12).
CF3
CF3
OH
Me
Ph
N
N
H2O/dioxane
y. 83%
NH4OAc
y. 56%
Ph
Ph
N
Me
OH
O
O
CF3
O-
+
Me
17
CO2Me
CF3
19
N
(3)
CO2Me
Ph
O
CF3
CO2Me
OH
Me
Ph
Me
Ph
N
N
N
16
MeOH/TFA
y. 91%
NH4OAc
y. 34%
O
N
Me
CF3
O
O
18A
18
20
The isomeric 4-trifluoromethylimidazoles 19 and 20 were prepared by the reactions of 17 and 18,
respectively, with ammonium acetate in moderate yields, in which both 17 and 18 were obtained by the
reactions of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olate 16 with H2O or MeOH, respectively (Eq.
3). The 13C NMR spectrum of 17 contained a hydrated carbon signal appearing at 93 ppm (quartet, 2JC-F
= 31 Hz). However, the hydrated carbon signal was not observed in 18 which was present in an enol
13
form 18A, based on a quartet at 159 ppm (2JC-F = 32 Hz) in the C NMR spectrum. Previously, the
4-trifluoromethylimidazole 19 was synthesized from the reaction of mesoionic 16 with ammonium
acetate, followed by dehydration of an intermediate.14
The 13C-NMR spectra of 5-trifluoromethylimidazoles 13b-e exhibited the carbon signals of C-4 at around
3
2
131 ppm (quartet, JC-F = 2-5 Hz) and C-5 at around 123 ppm (quartet, JC-F = 39 Hz). In isomeric
1-methyl-2-phenyl-4-trifluoromethylimidazoles (19), 1,2-diphenyl-4-trifluoromethylimidazole (21),14 and
1-benzyl-2-phenyl-4-trifluoromethylimidazole (22) ,14 the carbons of C-4 and C5 appeared at around 132
ppm (quartet, 2JC-F = 39 Hz) and 122 ppm (quartet, 3JC-F =4 Hz), respectively. Both 4-methoxycarbonyl-
13
5-trifluoromethylimidazoles (14b and 20) showed similar C-NMR spectra of 13b and 19. In the case
of the 1-methyl-5-trifluoromethylimidazoles (13b and 14b), we observed four-bond fluorine coupling to
the 1-methyl carbon (Table 5).

HETEROCYCLES, Vol. 87, No. 12, 2013
2541
Table 5. 13C NMR data of 4- and 5-trifluoromethylimidazoles
Compound
1-methyl
-
CF3
C-2
C-4
C-5
13a
122.0 (q)
(1JC-F = 266 Hz)
150.0
133.0 (q)
(2JC-F = 43 Hz)
119.3 (q)
(3JC-F = 4.3 Hz)
1-Methyl series
19
121.8 (q)
(1JC-F = 265 Hz)
149.1
151.7
121.8 (q)
(3JC-F = 3.8 Hz)
131.4 (q)
34.8
(2JC-F = 39 Hz)
13b
121.2 (q)
(1JC-F = 265 Hz)
130.6 (q)
(3JC-F = 2.3 Hz)
122.8 (q)
(2JC-F = 39 Hz)
32.7 (q)
(4JC-F = 1.4 Hz)
1-Phenyl series
21a
121.7 (q)
(1JC-F = 267 Hz)
148.0
151.0
122.2 (q)
(3JC-F = 4.0 Hz)
132.3 (q)
-
-
(2JC-F = 39 Hz)
13e
120.5 (q)
(1JC-F = 265 Hz)
130.9 (q)
(3JC-F = 4.9 Hz)
124.5 (q)
(2JC-F = 39 Hz)
1-Benzyl series
22a
121.7 (q)
(1JC-F = 267 Hz)
149.3
152.3
120.6 (q)
(3JC-F = 4.0 Hz)
131.9 (q)
-
-
-
(2JC-F = 39 Hz)
13d
14a
120.9 (q)
(1JC-F = 265 Hz)
131.4(q)
(3JC-F = 3.6 Hz)
122.8 (q)
(2JC-F = 39 Hz)
121.8 (q)
(1JC-F = 267 Hz)
148.4
121.8 (q)
(3JC-F = 2.5 Hz)
135.6(q)
(2JC-F = 39 Hz)
1-Methyl-4-methoxycarbonyl series
20
121.0 (q)
150.7
136.3(q)
122.3 (q)
(3JC-F = 2.3 Hz)
34.9
(1JC-F = 267 Hz)
(2JC-F = 39 Hz)
133.7b
14b
120.2 (q)
(1JC-F = 268 Hz)
150.7
124.4 (q)
(2JC-F = 41 Hz)
34.3 (q)
(4JC-F = 3.4 Hz)
a
The 13C NMR data of 21 and 22 were obtained from the literature.14
b 3
J
coupling was not observed.
C-F
CF3
N
CF3
N
Ph
N
Ph
N
Ph
CH2Ph
22 (lit.14)
14
21
(lit. )
These data suggested that both imidazoles 13a and 14a are predominantly present as tautomeric
4-trifluoromethylimidazoles. According to Kamitori’s work, 13a is also suggested to be predominatly
present as 4-trifluoromethylimidazole, based of ab initio calculation.15

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HETEROCYCLES, Vol. 87, No. 12, 2013
In order to explore another utility of 8 as -keto esters in the synthesis of trifluoromethyl heterocycles, we
next investigated its reaction with amidines. The cyclizations did not take place without using a base to
liberate the amidines from their hydrochloride salts (Table 6, entry 1). Thus, cyclocondensation
reactions of 8 with amidines in the presence of AcONa afforded the 6-trifluoromethylpyrimidines (23),
which was accompanied by unexpected by-product, N-benzoylglycine methyl ester (24). Several
attempts to reduce the side product 24 were performed. The reaction temperature and AcONa
equivalents have an effect on the outcome of this reaction. The reaction using 3 equiv AcONa at 100 °C
provided a 62% of 23a, accompanying by 24 (36%) (entry 3). Under similar conditions, formamidine
and acetamidine afforded the corresponding pyrimidines 23b and c in 44% and 46% yields, respectively
(entries 6 and 7).
Table 6. Reactions of 8 with amidines
NH
CO2Me
CF3
OH
CF3
HCl (1.5 eq)
H
N
O
R
Ph
NH2
H
N
N
Ph
N
H
CO2Me
O
in DMF
OH
R
N
OH
Ph
O
8
23
24
Entry
R
Base (equiv.)
Temp (°C) Time (h) Yields of products (%)
23
24
1
2
3
4
5
6
7
none
80
3
NR
Ph
Ph
Ph
Ph
Ph
H
rt
23a
MeCO2Na (3)
MeCO2Na (3)
MeCO2Na (3)
MeCO2Na (1.5)
MeCO2Na (3)
MeCO2Na (3)
24
1.5
1.5
1.5
1.5
1.5
(24)
23
36
60
51
52
48
100
120
100
100
100
23a (62)
23a (35)
23a
(48)
23b (44)
23c (46)
Me
During these reactions, we observed the formation of 24 which involves the loss of CF3CO group. The
reactions involving the loss of CF3CO moiety are rarely reported in the literature.16 The observed
de-trifluoroacetylation reaction could occur in the presence of base, because no reaction was observed
upon treating 8 with amidine at 80 °C in the absence of base and the starting material was quantitatively
recovered.
Ph
O
CO2Me
CF3
OH
OH
NH CF3
CF3
O
H
NH2NH2 EH2O
in DMF
NH2NH2 EH2O
in DMF
N
N
(4)
N
N
H
HO
Ph
O
Ph
O
O
8
5
1

HETEROCYCLES, Vol. 87, No. 12, 2013
2543
Finally, we examined a reaction of 8 with hydrazine hydrate. The product 5 was obtained in 80% yield
and identical with the product 5 obtained from 1 and hydrazine hydrate (Eq. 4).
In conclusion, we have found that hydroxylamine or hydrazine reacts with 1 mainly by the ring
opening-ring closure (RORC) sequence and furnish the pyrazoles and isoxazoles, respectively. Facile
ring opening of 1 by O-nucleophiles further prompted us to envisage efficient synthetic transformations
based on these open-chain amide adducts such as 2 and 8 providing ready access to structurally diverse
trifluoromethyl-substituted heterocycles.
EXPERIMENTAL
All melting points were determined using a Yanagimoto hot-stage melting point apparatus and are
uncorrected.
tetramethylsilane (Me4Si) as an internal reference and CDCl3 as the solvent. 13C-NMR spectra were
1H-NMR spectra were measured on Bruker AVANCE500 spectrometer with
1
13
obtained on a Bruker AVANCE500 spectrometer (at 126 MHz). Both H- and C-NMR spectral data
are reported in parts per million () relative to Me4Si. Infrared (IR) spectra were recorded on a JASCO
FT/IR-4100 spectrometer. Low- and high-resolution MS were obtained with a JEOL JMS-GC mate Ⅱ
spectrometer with a direct inlet system at 70 eV. Elemental analyses were carried out in the
microanalytical laboratory of Ehime University. Standard work-up means that the organic layers were
finally dried over Na2SO4, filtered, and concentrated in vacuo below 45 °C using a rotary evaporator.
Materials:
The following compounds were prepared by employing the reported method.
N-Benzoyl-N-methylglycine. mp 101−104 °C (lit.,14 mp 102−104 °C).
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-oxazolium-5-olate (16). Pale yellow crystals, 87% yield.
mp 161−163 °C (AcOEt–hexane) (lit.,14 mp 162−163 °C).
4-Trifluoroacetyl-5-hydroxy-2-phenyloxazole (1). To a stirred suspension of hippuric acid (2.00 g,
11.2 mmol) in acetone (20 mL) was added trifluoroacetic anhydride (4.65 mL, 33.5 mmol) at 0 °C under
atmosphere of argon, and the solution was stirred overnight. After workup with water, the precipitate
was collected and washed with water to give 1 as pink crystals, 2.56 g, 89% yield. mp 221–222 °C
(dec.) (acetone–H2O) (lit.,4 mp 227–231 °C (dec.)). IR (KBr)max: 3437, 3040, 2910, 1824, 1577, 1496,
1457, 1389, 1235, 1188, 1173, 1156, 815, 716, 697, 679 cm-1. 1H NMR (500 MHz, DMSO-d6)
7.37-7.45 (m, 3H, ArH), 7.76–7.83 (m, 2H, ArH) ppm.
N-(3,3,3-Trifluoro-2,2-dihydroxypropyl)benzamide (2). A mixture of 1 (4.90 g, 19.1 mmol),
1,4-dioxane (28.8 mL) and water (18 mL) was heated at reflux for 15 min. After evaporated and
basified with 10% sodium carbonate, the mixture was extracted with AcOEt (x 3). The combined
organic layers were washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue

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HETEROCYCLES, Vol. 87, No. 12, 2013
was purified by column chromatography (silica gel, hexane:AcOEt = 1:1) to give 2 as white crystals, 4.28
g, 90% yield. mp 107−110 °C (MeOH–H2O) (lit.,4 mp 107−109 °C). IR (KBr)max: 3368, 1627, 1604,
1567, 1436, 1415, 1343, 1320, 1294, 1249, 1201, 1172, 1141, 1105, 976, 943, 728, 715, 700, 632, 616
cm-1. 1H NMR (500 MHz, DMSO-d6) 3.62 (d, J = 6.0 Hz, 2H, NCH2), 7.24 (s, 2H, OH), 7.48–7.51 (m,
2H, ArH), 7.55–7.59 (m, 1H, ArH), 7.86–7.89 (m, 2H, ArH), 8.53 (t, J = 5.9 Hz, 1H, NH) ppm. 13C
2
1
NMR (125 MHz, DMSO-d6)  44.0, 92.3 (q, JC-F = 29.9 Hz), 123.6 (q, JC-F = 290.0 Hz, CF3), 127.4,
128.3, 131.6, 133.7, 167.9 ppm.
N-(3-Trifluoromethyl-5-hydroxyisoxazol-4-yl)benzamide (4). To a stirred mixture of hydroxylamine
hydrochloride (104 mg, 1.50 mmol) and sodium acetate (246 mg, 3.00 mmol) in DMF (5 mL) was added
1 (257 mg, 1.00 mmol) at 0 °C under atmosphere of argon, and the whole was heated at 80 °C for 3 h.
After acidified with 10% HCl, the mixture was extracted with AcOEt (x 3). The combined organic
layers were washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue was
purified by column chromatography (silica gel, hexane:AcOEt = 1:2 to 0:1) to give 4 as a pale pink hard
gum, 223 mg, 82% yield. IR (neat)max: 3281, 3066, 2923, 1651, 1515, 1485, 1192, 1152, 1004, 715,
651, 495 cm-1. 1H NMR (500 MHz, DMSO-d6)  7.50–7.53 (m, 2H, ArH), 7.57–7.60 (m, 1H, ArH),
7.90–7.96 (m, 2H, ArH), 9.55 (s, 1H, NH), 10.22 (br s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6)
1
2
 88.4, 119.5 (q, JC-F = 270.1 Hz, CF3), 127.6, 128.4, 131.8, 133.3, 153.7 (q, JC-F = 34.9 Hz), 167.0,
171.1 ppm. MS m/z: 272 (M+, 51), 105 (100). HRMS (EI) for C11H7F3N2O3 (M+): Calcd, 272.0409.
Found, 272.0405.
N-(3-Trifluoromethyl-5-hydroxy-1H-pyrazol-4-yl)benzamide (5). To a stirred solution of 1 (257 mg,
1.00 mmol) in DMF (5 mL) was added hydrazine monohydrate (250 mg, 5.00 mmol) at 0 °C under
atmosphere of argon, and the whole was heated at 80 °C for 3 h. After acidified with 10% HCl, the
mixture was extracted with AcOEt (x 3). The combined organic layers were washed with brine, dried
over anhyd sodium sulfate, and evaporated. The residue was purified by column chromatography (silica
gel, hexane:AcOEt = 2:1 to 1:2) to give 5 as white crystals, 228 mg, 84% yield. mp 188−189 °C
(AcOEt-hexane). IR (KBr)max: 3309, 3268, 3161, 3037, 2756, 2601, 1643, 1616, 1573, 1523, 1496,
1319, 1287, 1195, 1144, 1119, 1013, 1003, 717, 689 cm-1. 1H NMR (500 MHz, DMSO-d6)  7.50 (t, J =
7.3 Hz, 2H, ArH), 7.57 (t, J = 7.3 Hz, 1H, ArH), 7.94 (t, J = 7.1 Hz, 2H, ArH), 9.39 (s, 1H, CONH),
11.15 (s, 1H, NH), 12.95 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6)  97.8 (C-4), 121.4 (q,
2
1JC-F = 266.7 Hz, CF3), 127.7 (Ar), 128.2 (Ar), 131.5 (Ar), 134.0 (Ar), 136.9 (q, JC-F = 37.5 Hz, C-4),
150.4 (C-5), 166.6 (CONH) ppm. MS m/z: 271 (M+, 35), 105 (100). Anal. Calcd for C11H8F3N3O2: C,
48.72; H, 2.97; N, 15.49. Fond: C, 48.52; H, 3.27; N, 15.71.
N-(3-Trifluoromethyl-3-hydroxy-5-oxo-1-phenylpyrazolidin-4-yl)benzamide (6). To a stirred solution

HETEROCYCLES, Vol. 87, No. 12, 2013
2545
of 1 (257 mg, 1.00 mmol) in DMF (5 mL) was added phenylhydrazine (140 L, 1.50 mmol) at 0 °C under
atmosphere of argon, and the whole was heated at 80 °C for 4 h. After workup with water, the mixture
was extracted with AcOEt (x 3). The combined organic layers were washed with brine, dried over
anhyd sodium sulfate, and evaporated. The residue was purified by column chromatography (silica gel,
hexane:AcOEt = 1:2) to give 6 as white crystals, 245 mg, 67% yield. mp 130−132 °C (CHCl3–hexane).
IR (KBr)max: 3422, 3400, 3243, 3069, 3035, 2929, 1700, 1652, 1598, 1580, 1526, 1491 cm-1. 1H NMR
(500 MHz, DMSO-d6)  5.53 (d, J = 9.3 Hz, 1H, 4-CH), 7.18 (t, J = 7.5 Hz, 1H, ArH), 7.24 (s, 1H, NH),
7.42 (t, J = 7.5 Hz, 2H, ArH), 7.50 (t, J = 7.3 Hz, 2H, ArH), 7.59 (t, J = 7.3 Hz, 1H, ArH), 7.74 (s, 1H,
OH), 7.81 (dd, J = 8.7 Hz, 2H, ArH), 7.94 (d, J = 7.0 Hz, 2H, ArH), 8.80 (d, J = 9.3 Hz, 1H, CONH) ppm.
13C NMR (125 MHz, DMSO-d6)  55.5 (C-4), 85.7 (q, 2JC-F = 29.9 Hz, C-3), 118.7 (Ar), 123.6 (q, 1JC-F
=
285.4 Hz, CF3), 124.9 (Ar), 128.2 (Ar), 128.8 (Ar), 129.1 (Ar), 132.3 (Ar), 133.6 (Ar), 139.1 (Ar), 166.4
(C-5), 167.3 (s, CONH) ppm. MS m/z: 365 (M+, 4), 105 (100). Anal. Calcd for C17H14F3N3O3: C,
55.89; H, 3.86; N, 11.50. Found: C, 55.61; H, 3.73; N, 11.40.
N-(3-Trifluoromethyl-5-hydroxy-1-phenyl-1H-pyrazol-4-yl)benzamide (7). To a stirred solution of 6
(205 mg, 0.562 mmol) in MeOH (2 mL) was added 10% aq HCl (2 mL) at rt, and the mixture was stirred
for 3 h. After workup with water, the mixture was extracted with AcOEt (x 3). The combined organic
layers were washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue was
purified by column chromatography (silica gel, hexane:AcOEt = 1:1) to give 7 as pale yellow crystals,
158 mg, 81% yield. mp 108–110 °C (CHCl3–hexane). IR (KBr)max: 3305, 3077, 3035, 1623, 1551,
1524, 1479, 1342, 1311, 1178, 1148, 1125, 1008, 761, 714, 693, 642 cm-1. 1H NMR (500 MHz,
DMSO-d6)  7.42 (t, J = 7.4 Hz, 1H, ArH), 7.51–7.61 (m, 5H, ArH), 7.75 (d, 2H, J = 7.5 Hz, ArH), 7.98
(d, 2H, J = 7.5 Hz, Ar), 9.57 (s, 1H, NH), 12.48 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6) 
1
99.1 (C-4), 121.1 (q, JC-F = 269.8 Hz, CF3), 122.1, 127.3, 127.7, 128.3, 129.2, 131.6, 133.8, 137.1 (q,
2JC-F = 35.6Hz, C-3), 137.9, 149.9 (C-5), 166.9 (CONH) ppm. MS m/z: 347 (M+, 41), 105 (100). Anal.
Calcd for C17H12F3N3O2: C, 58.79; H, 3.48; N, 12.10. Fond: C, 58.56; H, 3.27; N, 12.11.
Methyl 2-(benzamido)-4,4,4-trifluoro-3,3-dihydroxybutanoate (8). To a stirred solution of 1 (1.29g,
5.00 mmol) in MeOH (15 mL) was added trifluoroacetic acid (0.37 mL, 1.00 mmol) at 0 °C under
atmosphere of argon, and the whole was stirred at rt for 5 h. After removal of the solvent, the residue
was purified by column chromatography (silica gel, hexane:AcOEt = 1:1) to give 8 as a white solid, 1.46
g, 95% yield. mp 93–95 °C (MeOH–H2O). IR (KBr)max: 3505, 3373, 3138, 2971, 1762, 1637, 1535,
1408, 1346, 1250, 1185, 1140, 1108, 1072, 973, 733, 708, 696, 624, 614 cm-1. 1H NMR (500 MHz,
DMSO-d6)  3.70 (s, 3H, OCH3), 5.02 (d, J = 9.0 Hz, 1H, CH), 7.52 (t, J = 7.5 Hz, 2H, ArH), 7.59 (t, J =
7.5 Hz, 1H, ArH), 7.67 (br s, 2H, OH), 7.88 (d, J = 7.0 Hz, 2H, ArH), 8.28 (d, J = 9.0 Hz, 1H, NH) ppm.

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HETEROCYCLES, Vol. 87, No. 12, 2013
13C NMR (125 MHz, DMSO-d6)  52.1, 55.9, 92.5 (q, 2JC-F = 30.9 Hz, CCF3), 123.0 (q, 1JC-F = 288.1 Hz,
CF3), 127.3, 128.5, 131.9, 133.2, 166.2, 168.5 ppm. MS m/z: 289 ([M–H2O]+, 2.4), 105 (100). Anal.
Calcd for C12H12F3NO5: C, 46.91; H, 3.94; N, 4.56. Found: C, 46.93; H, 3.94; N, 4.60.
5-Trifluoromethyl-2-phenylthiazole (9). A mixture of 2 (249 mg, 1.00 mmol) and Lawesson’s reagent
(243 mg, 0.600 mmol) in 1,2-dimethoxyethane (DME, 5 mL) was heated at reflux under atmosphere of
argon for 24 h. After removal of solvent, the residue was purified by column chromatography (silica gel,
hexane:AcOEt = 9:1) to give 9 as white crystals, 160 mg, 70% yield. mp 45−47 °C (MeOH-H2O). IR
(KBr)max: 3065, 1532, 1455, 1432, 1329, 1314, 1299, 1153, 1135, 1117, 1029, 763, 687, 635 cm-1. 1H
NMR (500 MHz, CDCl3)  7.46–7.51 (m, 3H, ArH), 7.96–7.97 (m, 2H, ArH), 8.12 (s, 1H, H-4) ppm.
1
2
13C NMR (125 MHz, CDCl3)  122.1 (q, JC-F = 268.9 Hz, CF3), 126.2 (q, JC-F = 38.2 Hz, C-5), 126.9
3
(Ar), 129,2 (Ar), 131.3 (Ar), 132.5 (Ar), 144.4 (q, JC-F = 3.8 Hz, C-4), 171.9 (C-2) ppm. MS m/z: 229
(M+, 100). Anal. Calcd for C10H6F3NS: C, 52.40; H, 2.64; N, 6.11. Fond: C, 52.32; H, 2.89; N, 6.16.
Methyl 5-trifluoromethyl-2-phenylthiazole-4-carboxylate (10). A mixture of 8 (308 mg, 1.00 mmol)
and Lawesson’s reagent (243 mg, 0.600 mmol) in DME (5 mL) was heated at reflux under atmosphere of
argon for 12 h. After removal of solvent, the residue was purified by column chromatography (silica gel,
hexane:AcOEt = 9:1) to give 10 as white crystals, 224 mg, 78% yield. mp 68–69 °C (MeOH–H2O).
IR (KBr)max: 3046, 2953, 1728, 1526, 1462, 1440, 1372, 1345, 1314, 1295, 1243, 1157, 1138, 1030,
1001, 972, 793, 765, 747, 687, 650 cm-1. 1H NMR (500 MHz, CDCl3)  4.02 (s, 3H, OCH3), 7.47–7.54
(m, 3H, ArH), 7.98 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125 MHz, CDCl3)  53.0, 121.1 (q, 1JC-F
=
270.7 Hz, CF3), 127.1, 129.3, 131.2 (q, 2JC-F = 40.1 Hz, C-5), 131.6, 131.8, 146.0 (q, 3JC-F = 2.5 Hz, C-4),
160.7, 169.0 (C-2) ppm. MS m/z: 287 (M+, 100). Anal. Calcd for C12H8F3NO2S: C, 50.17; H, 2.81; N,
4.88. Fond: C, 50.06; H, 3.04; N, 5.01.
5-Trifluoromethyl-2-phenyloxazole (11). A mixture of 2 (249 mg, 1.00 mmol) and phosphorus(V)
oxide (278 mg, 1.00 mmol) in toluene was heated at reflux with Dean–Stark trap under atmosphere of
argon for 7 h. After workup with 10% aq sodium carbonate, the mixture was extracted with AcOEt (x 3).
The combined organic layers were washed with brine, dried over anhyd sodium sulfate, and evaporated.
The residue was purified by column chromatography (silica gel, hexane:AcOEt = 9:1) to give 11 as a
colorless oil, 30 mg, 14% yield. IR (neat)max: 3066, 1365, 1325, 1179, 1136, 1110, 964, 926 cm-1.
1H NMR (500 MHz, CDCl3)  7.50–7.55 (m, 4H, ArH, H-4), 8.08–8.10 (m, 2H, ArH) ppm. 13C NMR
(125 MHz, CDCl3)  119.0 (q, 1JC-F = 266.3 Hz, CF3), 126.1, 127.1, 129.0, 129.4 (q, 3JC-F = 2.6 Hz, C-4),
2
131.7, 139.6 (q, JC-F = 43.9 Hz, C-5), 163.7 ppm. MS m/z: 213 (M+, 13), 105 (100). HRMS (EI) for
C10H6F3NO (M+): Calcd, 213.0402. Found, 213.0396.
Methyl 5-trifluoromethyl-2-phenyloxazole-4-carboxylate (12). To a mixture of triphenylphosphine

HETEROCYCLES, Vol. 87, No. 12, 2013
2547
(157 mg, 0.600 mmol) and iodine (152 mg, 0.600 mmol) in 1,2-dichloroethane (DCE, 20 mL) was added
a solution of 8 (92 mg, 0.300 mmol) and triethylamine (167 L, 1.20 mmol) in DCE (5 mL) at rt under
atmosphere of argon. The whole was stirred for 14 h and evaporated. The residue was purified by
column chromatography (silica gel, hexane:AcOEt = 10:1) to give 12 as a white powder, 111 mg, 68%
yield. mp 80–82 °C (MeOH–H2O) (lit.,13 mp 80.7−82.3 °C). IR (KBr)max: 2968, 1752, 1601, 1562,
1490, 1481, 1450, 1428, 1377, 1322, 1311, 1277, 1186, 1168, 1148, 1081, 1068, 1035, 1023, 951, 810,
751, 715, 691 cm-1. 1H NMR (500 MHz, CDCl3)  4.01 (s, 3H, OCH3), 7.50–7.58 (m, 3H, ArH),
1
8.13–8.15 (m, 2H. ArH) ppm. 13C NMR (125 MHz, CDCl3)  53.0, 118.3 (q, JC-F = 268.1 Hz, CF3),
3
2
125.1, 127.4, 129.1, 132.4, 133.3 (q, JC-F = 1.9 Hz, C-4), 142.1 (q, JC-F = 44.3 Hz, C-5), 159.9, 162.0
ppm. MS m/z: 271 (M+, 100). Anal. Calcd for C12H8F3NO3: C, 53.15; H, 2.97; N, 5.16. Fond: C,
53.07; H, 2.73; N, 5.40.
General procedure for the synthesis of 5-trifluoromethyl-1H-imidazoles (13a–d). A mixture of 2
(249 mg, 1.00 mmol) and amine (3 or 10 equiv) in toluene (5 mL) and acetic acid (1 mL) was heated at
135 °C for 8 h under atmosphere of argon. After evaporated and basified with 10% sodium carbonate,
the mixture was extracted with AcOEt (x 3). The combined organic layers were washed with brine,
dried over anhyd sodium sulfate, and evaporated. The residue was purified by column chromatography
(silica gel, hexane:AcOEt = 4:1) to give 13a–d.
4-Trifluoromethyl-2-phenyl-1H-imidazole (13a). White solid, 72% yield. mp 210−212 °C (MeOH–
H2O) (lit.,15 mp 212−213 °C). IR (KBr)max: 2758, 1589, 1548, 1487, 1461, 1408, 1360, 1182, 1160,
1138, 1119, 945, 808, 730, 695, 686 cm-1. 1H NMR (500 MHz, CD3OD) 7.41–7.49 (m, 3H, ArH),
7.62 (s, 1H, H-5), 7.90 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125 MHz, CD3OD)  119.3 (q, 3JC-F
=
4.3 Hz, C-5), 123.4 (q, 1JC-F = 266.0 Hz, CF3), 127.0, 130.1, 130.5, 130.7, 133.0 (q, 2JC-F = 42.8 Hz, C-4),
150.0 ppm. MS m/z: 212 (M+, 100).
5-Trifluoromethyl-1-methyl-2-phenyl-1H-imidazole (13b). White solid, 84% yield. mp 122−124 °C
(MeOH–H2O) (lit.,17 mp 118−120 °C). IR (KBr)max: 3073, 3008, 2969, 1562, 1475, 1456, 1412, 1376,
1312, 1282, 1249, 1225, 1167, 1147, 1120, 1099, 1078, 1077, 936, 850, 775, 749, 729, 717, 700, 679
cm-1. 1H NMR (500 MHz, CDCl3) 3.77 (s, 3H, Me-H), 7.49–7.50 (m, 4H, Ar-H, H-4), 7.59–7.60 (m,
2H, ArH) ppm. 13C NMR (125 MHz, CDCl3)  32.7 (q, 4JC-F = 1.4 Hz, NCH3) , 121.8 (q, 1JC-F = 265.3
Hz, CF3), 122.8 (q, 2JC-F = 38.9 Hz, C-5), 128.7, 128.9, 129.3, 129.5, 130.6 (q, 3JC-F = 2.3 Hz, C-4), 151.7
ppm. MS m/z: 226 (M+, 80), 225 (100).
5-Trifluoromethyl-1-n-hexyl-2-phenyl-1H-imidazole (13c).
Pale yellow oil, 79% yield.
IR
(neat)max: 2932, 1563, 1462, 1447, 1420, 1323, 1242, 1159, 1057, 776, 700 cm-1. 1H NMR (500 MHz,
CDCl3)  0.82 (t, J = 7.1 Hz, 3H, CH3), 1.11–1.26 (m, 6H, CH2CH2CH2), 1.63–1.69 (m, 2H, CH2), 4.08 (t,

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HETEROCYCLES, Vol. 87, No. 12, 2013
J = 8.0 Hz, 2H, NCH2), 7.48–7.52 (m, 4H, ArH and H-4), 7.55–7.58 (m, 2H, ArH) ppm. 13C NMR (125
MHz, CDCl3)  13.7, 22.2, 26.0, 30.5, 30.8, 45.9, 121.2 (q, 1JC-F = 270.6 Hz, CF3), 122.1 (q, 2JC-F = 32.9
Hz, C-5), 128.7, 129.1, 129.7, 130.1, 131.0 (q, 3JC-F = 3.6 Hz, C-4), 151.6 ppm. MS m/z: 296 (M+, 43),
252 (100). HRMS (EI) for C16H19F3N2 (M+): Calcd, 296.1500. Found, 296.1511.
1-Benzyl-5-trifluoromethyl-2-phenyl-1H-imidazole (13d). Yellow solid, 36% yield. mp 80−82 °C
(MeOH–H2O). IR (KBr)max: 3060, 1557, 1456, 1444, 1417, 1362, 1321, 1255, 1178, 1164, 1154,
1110, 1058, 983, 869, 776, 744, 724, 698, 680 cm-1. 1H NMR (500 MHz, CDCl3) 5.34 (s, 2H, ArCH2),
6.92–6.94 (m, 2H, ArH), 7.26–7.32 (m, 3H, ArH), 7.36–7.39 (m, 3H, ArH), 7.41–7.44 (m, 2H, ArH),
1
7.47–7.48 (m, 1H, H-4) ppm. 13C NMR (125 MHz, CDCl3)  49.0, 120.9 (q, JC-F = 265.4 Hz, CF3),
2
3
122.8 (q, JC-F = 39.1 Hz, C-5), 125.6, 127.8, 128.7, 128.8, 129.3, 129.6, 129.9, 136.6, 131.4 (q, JC-F
=
3.6 Hz, C-4), 152.3 ppm. MS m/z: 302 (M+, 35), 91 (100). Anal. Calcd for C17H13F3N2: C, 67.54; H,
4.33; N, 9.27. Found: C, 67.44; H, 4.16; N, 9.15.
5-Trifluoromethyl-1,2-diphenyl-1H-imidazole (13e). To a stirred solution of 2 (249 mg, 1.00 mmol)
in toluene (1 mL) was added aniline (273 L, 3.00 mmol) and phosphoryl chloride (186 L, 2.00 mmol)
at rt under atmosphere of argon, and the mixture was heated at 135 °C for 24 h. After evaporated and
acidified with 2% HCl, the mixture was extracted with AcOEt (x 3). The combined organic layers were
washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue was purified by
column chromatography (silica gel, hexane:AcOEt = 9:1) to give 13e as a white solid, 130 mg, 45%
yield. mp 115−116 °C (MeOH–H2O). IR (KBr)max: 3058, 2923, 1561, 1496, 1442, 1417, 1292, 1200,
1165, 1109, 664 cm-1. 1H NMR (500 MHz, CDCl3) 6.69–7.15 (m, 5H, ArH), 7.17–7.30 (m, 2H, ArH),
7.35–7.37 (m, 3H, ArH), 7.63 (s, 1H, NH) ppm. 13C NMR (125 MHz, CDCl3)  120.5 (q, 1JC-F = 265.4
Hz, CF3), 124.5 (q, 2JC-F = 38.8 Hz, C-5), 128.1, 128.3, 128.8, 129.0, 129.3, 129.5, 129.8, 130.9 (q, 3JC-F
=
4.9 Hz, C-4), 135.7, 151.0 ppm. MS m/z: 288 (M+, 100). Anal. Calcd for C16H11F3N2: C, 66.66; H,
3.85; N, 9.72. Found: C, 66.71; H, 3.94; N, 9.50.
General procedure for the synthesis of methyl 5-trifluoromethyl-1H-imidazole-4-carboxylates
(14a–b). A mixture of 8 (307 mg, 1.00 mmol) and amine (3 or 10 equiv) in toluene (5 mL) and acetic
acid (1 mL) was heated at 135 °C for 8 or 48 h under atmosphere of argon. After evaporated and
basified with 10% sodium carbonate, the mixture was extracted with AcOEt (x 3). The combined
organic layers were washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue
was purified by column chromatography (silica gel, hexane:AcOEt = 4:1) to give 14a–b.
Methyl 4-trifluoromethyl-2-phenyl-1H-imidazole-4-carboxylate (14a). White solid, 49% yield. mp
184−185 °C (MeOH–H2O). IR (KBr)max: 3296, 2962, 1542, 1463, 1450, 1300, 1277, 1210, 1165,
1155, 1139, 1055, 961, 785, 694 cm-1. 1H NMR (500 MHz, CDCl3) 3.98 (s, 3H, CH3), 7.48–7.50 (m,

HETEROCYCLES, Vol. 87, No. 12, 2013
2549
3H, ArH), 7.93–7.95 (m, 2H, ArH), 10.46 (s, 1H, NH) ppm. 13C NMR (125 MHz, CDCl3)  52.2, 121.8
(q, 1JC-F = 267.2 Hz, CF3), 121.8 (q, 3JC-F = 2.5 Hz, C-4), 126.8, 126.9, 128.6, 129.9, 135.6 (q, 2JC-F = 38.8
Hz, C-5), 148.4, 159.2 ppm. MS m/z: 270 (M+, 72), 238 (100). Anal. Calcd for C12H9F3N2O2: C,
53.34; H, 3.36; N, 10.37. Found: C, 53.50; H, 3.54; N, 10.43.
Methyl 5-trifluoromethyl-1-methyl-2-phenyl-1H-imidazole-4-carboxylate (14b). Pale yellow oil,
65% yield. IR (neat) max: 2954, 2847, 1563, 1408, 1458, 1438, 1402, 1336, 1289, 1213, 1186, 1161,
1121, 1086, 1056, 1030, 826, 777, 701, 448 cm-1. 1H NMR (500 MHz, CDCl3)  3.79 (s, 3H, NCH3),
3.95 (s, 3H, OCH3), 7.49–7.52 (m, 3H, ArH), 7.57–7.59 (m, 2H, ArH) ppm. 13C NMR (125 MHz,
CDCl3)  34.3 (q, 4JC-F = 3.4 Hz, NCH3), 52.4, 120.2 (q, 1JC-F = 267.7 Hz, CF3), 124.4 (q, 2JC-F = 40.5 Hz,
C-5), 128.2, 128.7, 129.7, 130.2, 133.7 (C-4), 150.7, 161.9 ppm. MS m/z: 284 (M+, 100). HRMS (EI)
for C13H11F3N2O2 (M+): Calcd, 284.0773. Found, 284.0786.
N-(3,3,3-Trifluoro-2-(phenylamino)prop-1-enyl)benzamide (15). To a stirred solution of 2 (996 mg,
4.00 mmol) in xylene (20 mL) and acetic acid (4 mL) was added aniline (1.09 mL, 12.0 mmol) at rt under
atmosphere of argon, and the whole was heated at 135 °C for 8 h. After evaporated and acidified with
10% HCl, the mixture was extracted with AcOEt (x 3). The combined organic layers were washed with
brine, dried over anhyd sodium sulfate, and evaporated. The residue was purified by column
chromatography (silica gel, hexane:AcOEt = 9:1) to give 15 as a brown oil, 955 mg, 78% yield. IR
(neat) max: 3296, 3069, 1729, 1602, 1497, 1368, 1249, 1200, 712 cm-1. 1H NMR (500 MHz, CDCl3) 
5.16 (br s, 1H, ArNH), 6.74 (d, J = 7.7 Hz, 2H, NArH-2), 6.88 (t, J = 7.4 Hz, 1H, NArH-4), 7.24 (dt, J =
7.4, 1.2 Hz, 2H, NArH-3), 7.30 (t, J = 7.6 Hz, 2H, COArH-3), 7.45 (t, J = 7.5 Hz, 1H, COArH-4), 7.49
(dd, J = 8.2, 1.2 Hz, 2H, COArH-2), 7.73 (dd, J = 11.2, 0.8 Hz, 1H, CH), 7.93 (d, J = 11.0 Hz, 1H,
CONH) ppm. 13C NMR (125 MHz, CDCl3)  111.3 (q, 2JC-F = 34.3 Hz, CF3C), 114.6 (NArC-2), 120.5
3
1
(NArC-4), 122.9 (q, JC-F = 4.5 Hz, CH), 123.0 (q, JC-F = 271.0 Hz, CF3), 127.3 (COArC-2), 128.9
(COArC-3), 129.8 (NArC-3), 132.2 (COArC-1), 132.8 (COArC-4), 142.9 (NArC-1), 164.4 (CO) ppm.
MS m/z: 306 (M+, 57), 105 (100). HRMS (EI) for C16H13F3N2O (M+): Calcd, 306.0980. Found,
306.0973.
Conversion of 15 to 13e: To a stirred solution of 15 (100 mg, 0.327 mmol) in toluene (2 mL) was
added phosphoryl chloride (61 mL, 0.654 mmol) at rt under atmosphere of argon, and the mixture was
stirred for 2 h. After evaporated and basified with 20% sodium carbonate, the mixture was extracted
with AcOEt (x 3). The combined organic layers were washed with brine, dried over anhyd sodium
sulfate, and evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt
= 9:1) to give 13e as a brown solid, 19 mg, 20% yield.
N-Methyl-N-(3,3,3-trifluoro-2,2-dihydroxypropyl)benzamide (17). To a stirred solution of 16 (3.00 g,

2550
HETEROCYCLES, Vol. 87, No. 12, 2013
10.3 mmol) in 1,4-dioxane (18 mL) was added water (9 mL) at rt, and the mixture was heated at 110 °C
for 15 min. After evaporated and basified with 10% sodium carbonate, the mixture was extracted with
AcOEt (x 3). The combined organic layers were washed with brine, dried over anhyd sodium sulfate,
and evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4:1)
to give 17 as a yellow powder, 2.25 g, 83% yield. mp 85–87 °C (CHCl3–hexane) (lit.,18 mp 90−92 °C).
IR (KBr)max: 3290, 3069, 2500, 1596, 1575, 1509, 1482, 1460, 1436, 1409, 1372, 1297, 1226, 1174,
1146, 1128, 1103, 1076, 1017, 939, 805, 792, 728, 706, 692, 572, 432 cm-1. 1H NMR (CDCl3, 500
MHz) δ 3.07 and 3.14 (s, 3H, NCH3), 3.89 and 4.66 (s. 2H, CH2), 5.70 (s, 1H, OH), 7.43-7.50 (s, 5H,
2
ArH) ppm. 13C NMR (125 MHz, DMSO-d6)  34.7, 51.1, 92.8 (q, JC-F = 30.8 Hz, CCF3), 123.5 (q,
1JC-F = 292.4 Hz, CF3), 126.9, 128.3, 129.6, 132.8, 172.0 ppm.
Methyl 2-(N-methylbenzamido)-4,4,4-trifluoro-3,3-dihydroxybutanoate (18). A solution of 16 (272
mg, 1.00 mmol) in MeOH (3 mL) was stirred at rt for 4 h. After removal of the solvent, the residue was
purified by column chromatography (silica gel, hexane: AcOEt = 1:1) to give 18 as a yellow oil, 276 mg,
91% yield. IR (neat) max: 3434, 3028, 2832, 2673, 2566, 1751, 1676, 1602, 1583, 1454, 1423, 1325,
1295, 1203, 1181, 1130, 1072, 1025, 929, 802, 701, 683, 665, 602, 547, 517 cm-1. 1H NMR (500 MHz,
DMSO-d6)  2.58 and 2.61 (s, 3H, NCH3), 3.78 and 3.99 (s, 3H, OCH3), 7.48–7.51 (m, 2H, ArH),
7.60–7.63 (m, 1H, ArH), 7.95–7.97 (m, 2H, ArH) ppm. 13C NMR (125 MHz, DMSO-d6)  32.5, 48.0,
52.5, 117.0 (q, 1JC-F = 298.6 Hz, CF3), 128.5, 129.2, 130.8, 132.7, 158.7 (q, 2JC-F = 31.7 Hz, CCF3), 167.3,
168.1 ppm. MS m/z: 303 (M+, 8), 60 (100). HRMS (EI) for C13H12F3NO4 (M+): Calcd, 303.0718.
Found, 303.0707.
4-Trifluoromethyl-1-methyl-2-phenylimidazole (19). A mixture of 17 (263 mg, 1.00 mmol) and
ammonium acetate (770 mg, 10.0 mmol) in toluene (5 mL) and acetic acid (1 mL) was heated at 135 °C
for 8 h under atmosphere of argon. After evaporated and basified with 10% sodium carbonate, the
mixture was extracted with AcOEt (x 3). The combined organic layers were washed with brine, dried
over anhyd sodium sulfate, and evaporated. The residue was purified by column chromatography (silica
gel, hexane:AcOEt = 4:1) to give 19 as a white solid, 127 mg, 56% yield. mp 56–57 °C (hexane) (lit.,14
mp 59–60 °C). IR (KBr)max: 2957, 2925, 1584, 1476, 1398, 1371, 1251, 1209, 1155, 1114, 1099, 1075,
1048, 962, 799, 776, 730, 710, 703, 681 cm-1. 1H NMR (CDCl3, 500 MHz) δ 3.77 (s, 3H, NCH3),
7.31–7.49 (m, 4H, ArH and H-4), 7.62–7.64 (m, 2H, ArH) ppm. 13C NMR (CDCl3, 125 MHz) δ 34.8,
121.8 (q, 1JC-F = 265.3 Hz, CF3), 121.8 (q, 3JC-F = 3.8 Hz, C-4), 128.7, 128.9, 129.3, 129.5, 131.4 (q, 2JC-F
= 38.5 Hz, C-5), 149.1 ppm. MS m/z: 226 (M+,100 ), 225 (M+, 100).
Methyl 4-trifluoromethyl-1-methyl-2-phenyl-1H-imidazole-5-carboxylate (20). A mixture of 18
(307 mg, 1.01 mmol) and ammonium acetate (770 mg, 10.0 mmol) in toluene (5 mL) and acetic acid (1

HETEROCYCLES, Vol. 87, No. 12, 2013
2551
mL) was heated at 135 °C for 8 h under atmosphere of argon. After evaporated and basified with 20%
sodium carbonate, the mixture was extracted with AcOEt (x 3). The combined organic layers were
washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue was purified by
column chromatography (silica gel, hexane:AcOEt = 4:1) to give 20 as a white solid, 98 mg, 34% yield.
mp 84–85 °C (MeOH–H2O). IR (KBr)max: 2959, 2703, 1725, 1692, 1642, 1542, 1442, 1410, 1367,
1349, 1293, 1259, 1213, 1162, 1136, 1051, 447 cm-1. 1H NMR (500 MHz, CDCl3)  3.94 and 3.96 (s,
3H, NCH3 and OCH3), 7.59–7.61 (m, 2H, ArH), 7.50 (m, 3H, ArH) ppm. 13C NMR (125 MHz, CDCl3)
1
3
 34.9, 52.3, 121.0 (q, JC-F = 267.2 Hz, CF3), 122.3 (q, JC-F = 2.3 Hz, C-5), 128.5, 128.8, 129.5, 130.2,
2
136.3 (q, JC-F = 38.6 Hz, C-4), 150.7, 160.0 ppm. MS m/z: 284 (M+, 100). Anal. Calcd for
C13H11F3N2O2: C, 54.93; H, 3.90; N, 9.86. Found: C, 55.06; H, 3.74; N,9.86.
N-(4-Trifluoromethyl-6-hydroxy-2-phenylpyrimidin-5-yl)benzamide
(23a)
and
Methyl
2-(benzamide)acetate (24). To a mixture of benzamidine hydrochloride (235 mg, 1.50 mmol) and
sodium acetate (246 mg, 3.00 mmol) in DMF (6 mL) was added 8 (307 mg, 1.00 mmol) at 0 °C under
atmosphere of argon, and the whole was heated at 100 °C for 1.5 h. After workup with satd aq
ammonium chloride, the mixture was extracted with AcOEt (x 3). The combined organic layers were
washed with brine, dried over anhyd sodium sulfate, and evaporated. The residue was washed with cold
tert-butyl methyl ether to give 23a as a white solid, 223 mg, 62% yield. The mother liquor was
concentrated and washed with the same solvent to give 24 as a pale yellow crystals, 64 mg, 36% yield.
23a: mp >300 °C (CHCl3–hexane). IR (KBr)max: 3223, 3068, 2975, 1685, 1655, 1604, 1558, 1507,
1486, 1405, 1315, 1289, 1202, 1185, 1139, 987, 720, 691 cm-1. 1H NMR (500 MHz, DMSO-d6) 
7.56–7.65 (m, 6H, ArH), 7.96–8.00 (m, 2H, ArH), 8.17 (s, 2H, ArH), 9.98 (s, 1H, CONH), 13.65 (s, 1H,
1
OH) ppm. 13C NMR (125 MHz, DMSO-d6)  120.9 (q, JC-F = 274.6 Hz, CF3), 123.1, 127.8, 128.0,
128.5, 128.8, 131.1, 132.0, 132.4, 133.2, 146.5, 156.2, 160.9, 162.3, 166.2 ppm. MS m/z: 359 (M+, 18)
105 (100). Anal. Calcd for C18H12F3N3O2: C, 60.17; H, 3.37; N, 11.69. Found: C, 60.36; H, 3.51; N,
11.41. 24: mp 77–80 °C (lit.,19 mp 82–83 °C). IR (KBr)max: 3223, 3068, 2975, 1685, 1655, 1604,
1558, 1507, 1486, 1405, 1315, 1289, 1202, 1185, 1139, 987, 720, 691 cm-1. 1H NMR (500 MHz,
CDCl3)  3.81 (s, 3H, COOCH3), 4.26 (d, J = 5.0 Hz, 2H, CH2), 6.68 (br s, 1H, NH), 7.44 (t, J = 7.3 Hz,
2H, ArH), 7.52 (t, J = 7.5 Hz, 1H, ArH), 7.82 (d, J = 7.1 Hz, 2H, ArH) ppm.
N-(4-Trifluoromethyl-6-hydroxypyrimidin-5-yl)benzamide (23b) and 24.
To a mixture of
formamidine hydrochloride (120 mg, 1.50 mmol) and sodium acetate (246 mg, 3.00 mmol) in DMF (6
mL) was added 8 (307 mg, 1.00 mmol) at 0 °C under atmosphere of argon, and the whole was heated at
100 °C for 1.5 h. After workup with satd aq ammonium chloride, the mixture was extracted with AcOEt
(x 3). The combined organic layers were washed with brine, dried over anhyd sodium sulfate, and

2552
HETEROCYCLES, Vol. 87, No. 12, 2013
evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 1:1) to
give 24, 93 mg, 52% yield. Further elution with tha same solvent gave 23b as a white solid, 125 mg,
44% yield. 23b: mp >300 °C (CHCl3–hexane). IR (KBr)max: 3218, 3155, 2931, 1718, 1628, 1577,
1562, 1525, 1488, 1427, 1389, 1352, 1296, 1247, 1200, 1142, 969, 819, 806, 717, 688, 640 cm-1. 1H
NMR (500 MHz, DMSO-d6)  7.53–7.64 (m, 3H, ArH), 7.94–7.96 (m, 2H, ArH), 8.37 (s, 1H, H-2), 9.92
(s, 1H, CONH), 13.44 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6)  120.9 (q, 1JC-F = 274.6 Hz,
CF3), 125.6, 127.7, 128.5, 132.1, 133.1, 146.5 (q, 2JC-F = 31.7 Hz, CCF3), 149.1, 159.1, 166.1 ppm. MS
m/z: 283 (M+, 51), 105 (100). Anal. Calcd for C12H8F3N3O2: C, 50.89; H, 2.85; N, 14.84. Found: C,
50.72; H, 2.96; N, 14.72.
N-(4-Trifluoromethyl-6-hydroxy-2-methylpyrimidin-5-yl)benzamide (23c) and 24. To a mixture of
acetamidine hydrochloride (142 mg, 1.50 mmol) and sodium acetate (246 mg, 3.00 mmol) in DMF (6
mL) was added 8 (307 mg, 1.00 mmol) at 0 °C under atmosphere of argon, and the whole was heated at
100 °C for 1.5 h. After workup with satd aq ammonium chloride, the mixture was extracted with AcOEt
(x 3). The combined organic layers were washed with brine, dried over anhyd sodium sulfate, and
evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 1:1) to
give 24, 86 mg, 48% yield. Further elution with tha same solvent gave 23c as a white solid, 137 mg,
46% yield. 23c: mp 290–295 °C (CHCl3–hexane). IR (KBr)max: 255, 3218, 1715, 1627, 1574, 1531,
1513, 1486, 1446, 1405, 1303, 1290, 1238, 1223, 1200, 1183, 1169, 1131, 1046, 721, 690 cm-1. 1H
NMR (500 MHz, DMSO-d6)  2,40 (s, 3H, CH3), 7.52–7.64 (m, 3H, ArH), 7.94–7.96 (m, 2H, ArH), 9.83
(s, 1H, CONH), 13.29 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6)  21.1, 120.9 (q, 1JC-F = 274.6
2
Hz, CF3), 122.7, 127.7, 128.4, 131.9, 133.2, 146.4 (q, JC-F = 31.4 Hz, CCF3), 158.9, 160.0, 166.1 ppm.
MS m/z: 297 (M+, 36), 105 (100). Anal. Calcd for C13H10F3N3O2: C, 52.53; H, 3.39; N, 14.14. Found:
C, 52.68; H, 3.48; N, 14.20.
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