Cyclocondensation reaction of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5- olates with hydroxylamine affording 6-trifluoromethyl-5,6-dihydro-4h-1,2,4- oxadiazin-6-ols

Article abstract of DOI:10.3987/COM-12-12627

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) undergo tandem addition of hydroxylamine to afford 6-trifluoromethyl-1,2,4-oxadiazin-6-ols (3) in high yields.

Full text of DOI:10.3987/COM-12-12627

HETEROCYCLES, Vol. 87, No. 1, 2013
115
HETEROCYCLES, Vol. 87, No. 1, 2013, pp. 115 - 123. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 13th November, 2012, Accepted, 28th November, 2012, Published online, 6th December, 2012
DOI: 10.3987/COM-12-12627
CYCLOCONDENSATION REACTION OF MESOIONIC
4-TRIFLUOROACETYL-1,3-OXAZOLIUM-5-OLATES WITH
HYDROXYLAMINE AFFORDING
6-TRIFLUOROMETHYL-5,6-DIHYDRO-4H-1,2,4-OXADIAZIN-6-OLS
Ryosuke Saijo, Ken-ichi Kurihara, Kazuki Akira, 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 – Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) undergo
tandem addition of hydroxylamine to afford 6-trifluoromethyl-1,2,4-
oxadiazin-6-ols (3) in high yields.
INTRODUCTION
Trifluoromethyl-substituted heterocyclic compounds continue to receive much attention since many of
them sometimes exhibit unique chemical, physiological or physical properties.1 Therefore, development
of new efficient methodologies for the preparation of fluorinated heterocycles is strongly required. One
of the most attractive methods for the construction of these heterocyles is based on the use of easily
available fluorine-containing building blocks.2
Recently, we have focused on mesoionic
4-trifluoroacetyl-1,3-oxazolium-5-olates (1) which were easily prepared from N-acyl-N-alkylglycines (2)
in a one step through the cyclodehydration by trifluoroacetic anhydride followed by trifluoroacetylation at
C-4 position of an intermediary mesoionic 1,3-oxazolium-5-olate (Eq. 1).3
O
O
CF3
R1
3
+
4
(CF3CO)2O
N
-
R2
N
R1
CO2H
O
(1)
5
O
R2
2
1
2
1

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HETEROCYCLES, Vol. 87, No. 1, 2013
These trifluoroacetylated mesoionic oxazoles (1) represent a very reactive system owing to the presence
of the electrophilic carbon atoms at C-2, C-5 and trifluoroacetyl group. Therefore, the rich reactivity of
1 can be expected to enable a wide variety of transformation, which makes 1 extremely useful synthons
for trifluoromethyl-substituted heterocycles such as imidazoles, pyrazoles, triazines, and pyrroles.3 In
line with this continuing interest, we report the reaction of the mesoionic oxazoles (1) with
hydroxylamine leading to the formation of 6-trifluoromethyl-1,2,4-oxadiazines in excellent yields. Thus,
with the nucleophile, the tandem addition to the C-2 position of the mesoionic ring and to the
trifluoromethyl ketone yielded 6-trifluoromethyl-1,2,4-oxadiazines (3).
RESULTS AND DISCUSSION
Table 1 shows the results when 4-trifluoroacetyl-1,3-oxazolium-5-olate (1a) was allowed to react with
hydroxylamine under various conditions. The best result was obtained by the reaction of 1a (1 mmol)
with hydroxylamine hydrochloride (1.5 mmol) in DMF (5 mL) in the presence of sodium acetate (3
mmol) at 80 °C for 3 h: 6-trifluoromethyl-1,2,4-oxadiazine 3a was isolated in 95% yield (entry 1). The
effect of the base on the yield of 3a was briefly investigated (entries 1, 4, and 7).
Table 1. Condensation of 4-trifluoroacetyl-1,3-oxazolium-5-olate (1a) with hydroxylamine under
various conditions
O
NH2OH·HCl (1.5 eq)
OH
Me
CF3
Me
Ph
CF3
OH
Me
base (3.0 eq)
N
N
N
CF3
+
N
O
solvent, 80 °C
O
Ph
O
Ph
N
O
4
1a
3a
Yields of products (%)
Entry
Base
Solvent
Time (h)
3a
4
1
2
3
4
5
6
7
8
MeCO2Na
MeCO2Na
MeCO2Na
K2CO3
DMF
3
95
−
toluene
3.5
24
3.5
1.5
24
2
complex mixture
1,2-dichloroethane
DMF
4.5
74
24
8
44a
3b
6
−
K2CO3
toluene
−
K2CO3
1,2-dichloroethane
DMF
8
CF3CO2Na
22a
7b
CF3CO2Na
1,2-dichloroethane
10
a The yield was determined by 1H NMR. b Crude yield.

HETEROCYCLES, Vol. 87, No. 1, 2013
117
Sodium acetate gave the best yield of 3a in DMF as a solvent (entry 1). The reaction of 1a with
hydroxylamine could proceed in other solvents, such as toluene and 1,2-dichloroethane, but the
conversion was very low. Sometimes, the side product oxime (4) was isolated in low yields.
The
oxime (4) was identical with an authentic sample prepared in 74% yield by the reaction of
N-methyl-N-(3,3,3-trifluoro-2,2-dihydroxypropyl)benzamide (5),4 which was obtained by the hydrolysis
of 1a, with hydroxylamine in pyridine-EtOH (Eq. 2).
O
NH2OH·HCl (1.5 eq)
pyridine (3.0 eq)
OH
CF3
OH
Me
Ph
CF3
OH
Me
CF3
Me
Ph
N
H2O
N
N
(2)
N
EtOH, 90 °C
O
O
Ph
O
O
1a
5
4
With the optimized conditions in hand, the scope of the reaction substrates was investigated. The results
are summarized in Table 2. The reaction is efficient in both 3-alkyl- and 3-aryl-substituted mesoionic
compounds (entries 1, 2, 4, and 5). However, 2-methyl-substituted mesoionic compounds (1b and 1d)
gave slightly lower yields compared to 2-aryl-substituted compounds (1a and 1e).
2-tert-Butyl-substituted mesoionic compounds (1c and 1f) also gave the desired 1,2,4-oxadiazines (entries
3 and 6).
Table 2. Condensation of 4-trifluoroacetyl-1,3-oxazolium-5-olate (1) with hydroxylamine
O
NH2OH·HCl (1.5 eq)
MeCO2Na (3.0 eq)
OH
CF3
R1
R2
R1
CF3
N
N
O
in DMF, 80 °C
R2
N
O
O
3
1
Entry
1
R1
Me
Bn
Ph
R2
Ph
Time (h)
Yields of 3 (%)
1
2
3
4
5
6
a
b
c
d
e
f
3
4
3
5
4
3
3a (95)
3b (68)
3c (97)
3d (54)
3e (88)
3f (74)
Me
t-Bu
Me
Ph
Ph
Ph
Me
t-Bu

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HETEROCYCLES, Vol. 87, No. 1, 2013
The structures of 3a-f are supported by spectral and analytical data. The presence of the CF3 group in
13
3a-f was determined on the basis of long-range C-19F coupling. Thus, the carbons of the CF3 group
1
2
and C-6 appear at around  122.5 ppm (quartet, JC-F = 287 Hz) and  90.6 ppm (quartet, JC-F = 32 Hz),
respectively. The 1H-NMR spectrum of 3a exhibited the methylene signal of C-5 at  3.25 ppm (d, 1H,
J = 12 Hz) and 3.37 ppm (d, 1H, J = 12 Hz). These 1H- and 13C-NMR data are similar to the data for the
6-trifluoromethyl-1,4,5,6-tetrahydro-4-methyl-1,3-diphenyl-1,2,4-triazin-6-ol
(6),3a
5,5-dimethyl-3-
phenyl-1,2,4-oxadiazin-6-ol (7)5 and 6-methyl-3-phenyl-1,2,4-oxadiazine (8)6 as shown in Scheme 1.
3.25 (d, 1H, J = 12 Hz)
3.37 (d, 1H, J = 12 Hz)
3.48 (dq, 1H, J = 2, 13 Hz)
3.73 (d, 1H, J = 13 Hz)
c 48.4
c 39.9
c 52.4
c 40.5
H H
H H
OH
CF3
c 123.5 (q, 1JC-F = 291 Hz)
c 79.3 (q, 2JC-F = 30 Hz)
c 122.5 (q, 1JC-F = 287 Hz)
OH
Me
Ph
Me
Ph
N
N
CF3
Ph
N
O
N
N
c 90.6 (q, 2JC-F = 32 Hz)
c 154.7
c 147.1
6 (lit.,3a)
3a
3.27 (ddd, 1H)
3.52 (ddd, 1H)
c 46.4
c 51.5
Me Me
H H
OH
H
HN
Ph
HN
Ph
H
Me
O
O
N
N
c 93.7
c 67.6
c 151.2
7 (lit.,5)
c 152.3
8 (lit.,6)
Scheme 1
A plausible mechanism is described in Scheme 2. Thus, nucleophilic attack of the nitrogen of
hydroxylamine on C-2 of 1 gives rise to an adduct (9). The scission of the bond of C-2 and O-1 in 10
gives an open-chain intermediate (11), which extrudes carbon dioxide to provide the ketone (12).
Finally, intramolecular cyclization of 12 affords 3.

HETEROCYCLES, Vol. 87, No. 1, 2013
119
O
O
O
H+
R1
R1
R1
H
O
CF3
CF3
CF3
N
N
N
+
NH2OH
R2
O
R2
R2
O
O
O
O
NHOH
9
NHOH
1
10
O
O
R1
OH
CF3
O
R1
R2
H
R1
CF3
O
N
N
N
CF3
R2
–CO2
N
R2
O
NOH
NOH
H
11
12
3
Scheme 2
The 1,2,4-oxadiazine compounds possess interesting pharmacological properties such as diuretic,
antiphlogistic, peripheral vasodilative, coronary flow increasing, and hypotensive effects.7 However, the
1,2,4-oxadiazine core belongs to an underutilized class of heterocycles and there are only a handful of
methods for the synthesis of 5,6-dihydro-4H -1,2,4-oxadiazines: (a) condensation of arylamidoximes and
glyoxal,8 chloroacetyl chloride,9 ethyl -bromoacetoacetate,10 or 1,2-diaza-1,3-butadienes,11 (b) reaction
of oxazolines and hydroxylamine,5 and (c) acid-catalyzed isomerization of aziridin-1-yl oximes.6,12 In
spite of the importance of fluorine molecules, 1,2,4-oxadiazines containing trifluoromethyl substituent
have not yet been described.
In summary, we developed the first efficient and regiospecific preparation of
6-trifluoromethyl-5,6-dihydro-4H-1,2,4-oxadiazines. The method appears to be useful and convenient
in terms of the ready accessibility of the starting materials, cheap reagents, operational simplicity, and
high overall yields.
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

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HETEROCYCLES, Vol. 87, No. 1, 2013
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.,13 mp 102−104 °C). N-Acetyl-N-benzylglycine.
mp 118−119 °C (lit.,14 mp 118−119 °C). N-Phenyl-N-pivaloylglycine. mp 123−124 °C. 1H NMR
(500 MHz, CDCl3)  1.05 (s, 9H, CCH3), 4.27 (s, 2H, NCH2), 7.36-7.40 (m, 5H, ArH). 13C NMR (126
MHz, CDCl3)  29.2, 40.7, 55.1, 128.6, 129.3, 129.5, 143.8, 174.1, 178.7. N-Acetyl-N-phenylglycine.
mp 196−198 °C (mp15 193−195 °C). N-Benzoyl-N-phenylglycine. mp 126−128 °C (lit.,13 mp
127−129 °C). N-Methyl-N-pivaloylglycine. mp 75−76 °C (lit.,4 mp 75−76 °C).
General Procedure for Preparation of 4-Trifluoroacetyl-1,3-oxazolium-5-olates (1): To a stirred
suspension of N-acyl-N-alkylglycine (5.2 mmol) in AcOEt (10 mL) was added TFAA (2.2 mL, 15.6
mmol) at 0 °C, and the solution was stirred at rt for 3 h. To the mixture was added hexane, and the
precipitate was collected and recrystallized from hexane/AcOEt to give the product 1.
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-oxazolium-5-olate (1a). Pale yellow crystals, 87% yield.
mp 161−163 °C (lit.,16 mp 162−163 °C).
3-Benzyl-4-trifluoroacetyl-2-methyl-1,3-oxazolium-5-olate (1b).3a White crystals, 67% yield. mp
143−144 °C. HRMS (EI) for C13H10F3NO3 (M+): Calcd, 285.0613. Found, 258.0626.
2-tert-Butyl-4-trifluoroacetyl-3-phenyl-1,3-oxazolium-5-olate (1c). Yellow crystals, 60% yield. mp
174−175 °C. IR (KBr) max: 2985, 1880, 1639, 1551, 1357, 1259, 1201, 1148, 831, 779, 734, 705 cm-1.
1H NMR (500 MHz, CDCl3)  1.23 (s, 9H, CCH3), 7.35–7.37 (m, 2H, ArH), 7.53–7.62 (m, 3H, ArH).
13C NMR (126 MHz, CDCl3)  28.5 (CCH3), 36.8 (CCH3), 97.4, 116.6 (q, 1JC-F = 289.4 Hz, CF3), 126.9,
2
129.5, 131.1, 134.3, 157.5, 163.3, 166.1 (q, JC-F = 37.3 Hz, CCF3). MS m/z: 313 (M+, 66), 58 (100).
Anal. Calcd for C15H14F3NO3: C, 57.51; H, 4.50; N, 4.47. Found: C, 57.23; H, 4.62; N, 4.46.
4-Trifluoroacetyl-2-methyl-3-phenyl-1,3-oxazolium-5-olate (1d). White crystals, 90% yield. mp
200−203 °C (lit.,16 mp 211−212 °C).
4-Trifluoroacetyl-2,3-diphenyl-1,3-oxazolium-5-olate (1e).
194−196 °C (lit.,16 mp 194−196 °C).
Yellow crystals, 81% yield.
mp
2-tert-Butyl-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-olate (1f). White crystals, 67% yield. mp
120−121 °C (lit.,4 mp 120−121 °C).
General Procedure for Synthesis of 6-Trifluoromethyl-1,2,4-oxadiazin-6-ols (3): A mixture of
hydroxylamine hydrochloride (104 mg, 1.50 mmol) and sodium acetate (246 mg, 3.00 mmol) in DMF (5
mL) was stirred at 0 °C for 10 min under atmosphere of argon. To the mixture was added

HETEROCYCLES, Vol. 87, No. 1, 2013
121
4-trifluoroacetyl-1,3-oxazolium-5-olate 1 (1.00 mmol), and the whole was stirred at 80 °C for an
additional several hours. After workup with 10% aqueous Na2CO3, the mixture was extracted with
AcOEt (x 3). The combined organic layers were washed with brine, dried over anhyd Na2SO4, and
evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 2:1) to
give the product 3.
6-Trifluoromethyl-5,6-dihydro-4-methyl-3-phenyl-4H-1,2,4-oxadiazin-6-ol (3a).
White crystals,
95% yield. mp 163−164 °C (CHCl3-hexane). IR (KBr)max: 3032, 1602, 1577, 1413, 1368, 1335,
1272, 1200, 1051, 1024, 979, 770, 704 cm-1. 1H NMR (500 MHz, CDCl3)  2.86 (s, 3H, NCH3), 3.37 (d,
J = 11.8 Hz, 1H, NCH), 3.52 (d, J = 11.7 Hz, 1H, NCH), 4.85 (br s, 1H, OH), 7.41-7.48 (m, 5H, ArH)
2
ppm. 13C NMR (126 MHz, DMSO-d6)  39.9 (NCH3), 48.4 (NCH2), 90.6 (q, JC-F = 31.7 Hz, CF3C),
1
122.5 (q, JC-F = 287.3 Hz, CF3), 128.4, 128.7, 129.8, 131.5, 154.7 (CN) ppm. MS m/z: 260 (M+, 100).
Anal. Calcd for C11H11F3N2O2: C, 50.77; H, 4.26; N, 10.77. Found: C, 50.63; H, 4.01; N, 10.70.
4-Benzyl-6-trifluoromethyl-5,6-dihydro-3-methyl-4H-1,2,4-oxadiazin-6-ol (3b). White crystals, 68%
yield. mp 187−189 °C (CHCl3-hexane). IR (KBr)max: 3040, 1614, 1207, 1190 cm-1. 1H NMR (500
MHz, CDCl3)  2.08 (s, 3H, CH3), 3.20 (d, J = 11.4 Hz, 1H, NCH), 3.39 (d, J = 11.5 Hz, 1H, NCH), 4.37
(d, J = 16.5 Hz, 1H, PhCH), 4.62 (d, J = 16.6 Hz, 1H, PhCH), 6.04 (br s, 1H, OH), 7.26-7.27 (m, 2H,
ArH), 7.32-7.34 (m, 1H, ArH), 7.38-7.41 (m, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3)  16.6 (CH3),
2
1
47.0, 54.4, 90.9 (q, JC-F = 32.7 Hz, CCF3), 122.1 (q, JC-F = 284.9 Hz, CF3), 126.6, 128.0, 129.2, 135.5,
152.4 (CN) ppm. MS m/z: 274 (M+, 100). Anal. Calcd for C12H13F3N2O2: C, 52.56; H, 4.78; N, 10.21.
Found: C, 52.22; H, 4.52; N, 10.05.
3-tert-Butyl-6-trifluoromethyl-5,6-dihydro-4-phenyl-4H-1,2,4-oxadiazin-6-ol (3c). White crystals,
97% yield. mp 156−158 °C (CHCl3-hexane). IR (KBr)max: 3161, 2993, 2962, 1562, 1214, 1181,
1145 cm-1. 1H NMR (500 MHz, CDCl3)  1.12 (s, 9H, CCH3), 3.33 (br s, 1H, OH), 3.54 (d, J = 12.5 Hz,
1H, NCH), 3.58 (d, J = 12.4 Hz, 1H, NCH), 7.27-7.30 (m, 3H, ArH), 7.35-7.38 (m, 2H, ArH) ppm. 13C
2
NMR (126 MHz, CDCl3)  30.2 (CCH3), 38.7 (CCH3), 51.6 (NCH3), 92.2 (q, JC-F = 32.8 Hz, CCF3),
1
121.8 (q, JC-F = 286.4 Hz, CF3), 127.5, 128.8, 129.2, 146.2, 160.3 (CN) ppm. MS m/z: 302 (M+, 12),
252 (100). Anal. Calcd for C14H17F3N2O2: C, 55.62; H, 5.67; N, 9.27. Found: C, 55.32; H, 5.74; N,
9.26.
6-Trifluoromethyl-5,6-dihydro-3-methyl-4-phenyl-4H-1,2,4-oxadiazin-6-ol (3d).
White crystals,
54% yield. mp 169−170 °C (CHCl3-hexane). IR (KBr)max: 3071, 3043, 3025, 1616, 1593, 1200,
1179, 1158 cm-1. 1H NMR (500 MHz, CDCl3)  1.81 (s, 3H, CH3), 3.58 (d, J =11.6 Hz, 1H, NCH) ,
3.76 (d, J = 11.6 Hz, 1H, NCH), 6.25 (br s, 1H, OH), 7.26-7.29 (m, 2H, ArH), 7.35 (m, 1H, ArH),
7.41-7.43 (m, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3)  17.5 (CH3), 50.8 (NCH2), 90.6 (q, 2JC-F
=

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HETEROCYCLES, Vol. 87, No. 1, 2013
32.7 Hz, CCF3), 122.2 (q, 1JC-F = 286.2 Hz, CF3), 127.9, 128.2, 129.9, 142.2, 151.7 (CN) ppm. MS m/z:
260 (M+, 100). Anal. Calcd for C11H11F3N2O2: C, 50.77; H, 4.26; N, 10.77. Found: C, 50.61; H, 4.18;
N, 10.74.
6-Trifluoromethyl-5,6-dihydro-3,4-diphenyl-4H-1,2,4-oxadiazin-6-ol (3e). White crystals, 88% yield.
mp 186−187 °C (CHCl3-hexane). IR (KBr)max: 3054, 1590, 1552, 1494, 1359, 1304, 1233, 1203, 1189,
1146, 1088, 1065, 985, 768, 694 cm-1. 1H NMR (500 MHz, CDCl3) 3.88 (d, J = 12.0 Hz, 1H, NCH),
3.96 (d, J = 12.0 Hz, 1H, NCH), 4.09 (br s, 1H, OH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 7.06 (t, J = 7.4 Hz,
1H, ArH), 7.15-7.29 (m, 5H, ArH), 7.38 (d, J = 8.5 Hz, 2H, ArH) ppm. 13C NMR (126 MHz, CDCl3) 
49.8 (NCH2), 92.4 (q, 2JC-F = 33.0 Hz, CF3C), 121.8 (q, 1JC-F = 286.5 Hz, CF3), 125.5, 128.2, 129.1, 129.9,
131.1, 144.8, 153.6 (CN) ppm. MS m/z: 322 (M+, 100). Anal. Calcd for C16H13F3N2O2: C, 59.63; H,
4.07; N, 8.69. Found: C, 59.59; H, 3.84; N, 8.72.
3-tert-Butyl-6-trifluoromethyl-5,6-tetrahydro-4-methyl-4H-1,2,4-oxadiazin-6-ol (3f). White crystals,
74% yield. mp 99−101 °C (CHCl3-hexane). IR (KBr)max: 3088, 2996, 1583, 1323, 1185, 1162, 1126,
991 cm-1. 1H NMR (500 MHz, CDCl3)  1.32 (s, 9H, CCH3), 3.16 (s, 3H, NCH3), 3.19 (d, J = 11.9 Hz,
1H, NCH), 3.36 (d, J = 11.9 Hz, 1H, NCH), 3.79 (br s, 1H, OH) ppm. 13C NMR (126 MHz, CDCl3) 
2
1
28.8 (CCH3), 36.8 (CCH3), 41.5 (NCH3), 50.7 (NCH2), 90.9 (q, JC-F = 32.7 Hz, CCF3), 122.1 (q, JC-F
=
286.3 Hz, CF3), 160.2 (CN) ppm. MS m/z: 313 (M+, 66), 58 (100). Anal. Calcd for C9H15F3N2O2: C,
45.00; H, 6.29; N, 11.66. Found: C, 44.71; H, 6.19; N, 11.79.
N-[3,3,3-Trifluoro-2-(hydroxyimino)propyl]-N-methylbenzamide (4). Pale yellow crystals. mp
139−141 °C (CHCl3-hexane). IR (KBr)max: 2878, 2806, 1598, 1569, 1486, 1409, 1357, 1278, 1189,
1132, 1075, 1007, 736, 708 cm-1. 1H NMR (500 MHz, DMSO-d6)  2.86 (s, 3H, CH3), 4.40 (br s, 1H,
NCH), 4.60 (br s, 1H, NCH), 7.43-7.46 (m, 5H, ArH), 12.89 (br s, 1H, OH) ppm. 13C NMR (126 MHz,
CDCl3)  37.5 (NCH3), 121.1 (q, 1JC-F = 273.3 Hz, CF3), 126.6, 128.4, 129.6, 135.6, 143.5 (q, 2JC-F = 29.8
Hz, CCF3), 170.3 (CO) ppm. MS m/z: 260 (M+, 32), 105 (100). Anal. Calcd for C11H11F3N2O2: C,
55.62; H, 5.67; N, 9.27. Found: C, 55.32; H, 5.74; N, 9.26.
The
authentic
4
was
prepared
by
the
following
method:
A
mixture
of
N-methyl-N-(3,3,3-trifluoro-2,2-dihydroxypropyl)benzamide4 (263 mg, 1 mmol), hydroxylamine
hydrochloride (104 mg, 1.50 mmol) and pyridine (0.25 mL) in EtOH (5 mL) was stirred at 0 °C for 10
min under atmosphere of argon. Then, the whole was stirred at 90 °C for 3 h. After workup with 10%
aqueous Na2CO3, the mixture was extracted with AcOEt (x 3). The combined organic layers were
washed with brine, dried over anhyd Na2SO4, and evaporated. The residue was purified by column
chromatography (silica gel, hexane:AcOEt=1:2) to give N-methyl-N-(3,3,3-trifluoro-2-(hydroxyimino)-
propyl)benzamide (4) (195.0 mg, 74%).

HETEROCYCLES, Vol. 87, No. 1, 2013
123
REFERENCES
1. V. A. Petrov, ‘Fluorinated Heterocyclic Compounds-Synthesis, Chemistry, and Applications,’ John
Wiley & Sons, Inc., Hoboken, New Jersey, 2009.
2. T. Hiyama, ‘Organofluorine Building Blocks. In Organofluorine Compounds: Chemistry and
Applications,’ Springer-Verlag, Berlin, 2000, pp. 77-118; M. Schlosser, Angew. Chem. Int. Ed.,
2006, 45, 2; J.-P. Begue and D. Bonnet-Delpon, ‘Bioorganic and Medicinal Chemistry of Fluorine,’
John Wiley & Sons, Inc., Hoboken, New Jersey, 2008.
3. (a) M. Kawase and H. Koiwai, Chem. Pharm. Bull., 2008, 56, 433; (b) R. Saijo, Y. Hagimoto, and M.
Kawase, Org. Lett., 2010, 12, 4776; (c) R. Saijo and M. Kawase, Tetrahedron Lett., 2012, 53, 2782.
4. M. Kawase and S. Saito, Chem. Pharm. Bull., 2000, 48, 410.
5. A. Bigot, J. Blythe, C. Pandya, T. Wagner, and O. Loiseleur, Org. Lett., 2011, 13, 192.
6. S. Y. Cho, S. K. Kang, J. H. Ahn, J. D. Ha, and J.-K. Choi, Tetrahedron Lett., 2006, 47, 9029.
7. J. Mezei, S. Kuttel, L. Szemere, and I. Racz, Pharmazie, 1984, 39, 399; J. Mezei, S. Kuttel, and I.
Racz, Polish J. Pharmacol. Pharm., 1984, 36, 397; K. Takacs and K. Harsanyi, Chem. Ber., 1970,
103, 2330; K. Takacs, K. Harsanyi, P. Kolonits, and K. I. Ajzert, Chem. Ber., 1975, 108, 1911; A. J.
Crovetti, A. M. VonEsch, and R. J. Thill, J. Heterocycl. Chem., 1972, 9, 435.
8. R. M. Srivastava, L. P. F. Morais, S. C. Melo Souto, G. B. Carpenter, and L. T. Carvalho,
Tetrahedron Lett., 2006, 47, 3173.
9. A. Q. Hussein, Heterocycles, 1987, 26, 163.
10. K. Tabei, E. Kawashima, T. Takada, and T. Kato, Chem. Pharm. Bull., 1982, 30, 3987.
11. O. A. Attanasi, L. Cotarca, G. Favi, P. Filippone, F. R. Perrulli, and S. Santeusanio, Synlett, 2009, 10,
1583.
12. P. Rajagopalan and C. N. Talaty, J. Am. Chem. Soc., 1966, 88, 5048.
13. J. Deruiter, B. E. Swearingen, V. Wandreker, and C. A. Mayfield, J. Med. Chem., 1991, 34, 2120.
14. M. Kawase, S. Saito, and T. Kurihara, Chem. Pharm. Bull., 2001, 49, 461.
15. J. DeRuiter, B. E. Swearingen, V. Wandrekar, and C. A. Mayfield, J. Med. Chem., 1989, 32, 1033.
16. C. V. Greco, R. P. Gray, and V. G. Grosso, J. Org. Chem., 1967, 32, 4101.