Hexafluoroacetone and methyl trifluoropyruvate acylimines in the cyclocondensation with amides

Full text of DOI:10.1134/S1070363212060266

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 6, pp. 1180–1182. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, I.V. Martynov, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 6, pp. 1046–1048.
LETTERS
TO THE EDITOR
Hexafluoroacetone and Methyl Trifluoropyruvate Acylimines
in the Cyclocondensation with Amides
V. B. Sokolov, A. Yu. Aksinenko, and I. V. Martynov
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, 142432, Russia
e-mail: alaks@ipac.ac.ru
Received November 28, 2011
DOI: 10.1134/S1070363212060266
Fluorinated 1,3,5-oxadiazines comprise a promising
class of biologically active substances, including, for
example, effective insecticides and fungicides of a
general action [1]. There are two approaches to the
synthesis of these compounds. The first is based on the
Diels–Alder aza-reaction of acylimines with hexa-
fluoroacetone or methyl trifluoropyruvate with nitriles
[2, 3] or cyanamines [4–7]. The second route is de-
hydration under rigid conditions (heating in oleum) of
amidals derived from the hexafluoroacetone perfluoro-
acylimines and amides of perfluorocarboxylic acids
[8]. Thus, the availability of the 1,3,5-oxadiazines
through the cycloaddition reaction is determined
primarily by the availability of nitriles, and their
synthesis by the dehydration in rigid conditions is
applicable to a limited number of amides, in particular,
to the amides of perfluorocarboxylic acids. The aim of
this study was to expand the possibilities of cyclocon-
densation reactions of hexafluoroacetone and methyl
trifluoropyruvate acylimines with carboxylic amides to
produce a variety of 1,3,5-oxadiazines containing one
or two trifluoromethyl groups. A prerequisite for this
research were the data we obtained in the course of
systematic studies of the behavior of N-substituted
hexafluoroacetone and methyl trifluoropyruvate imines
in cyclocondensation reactions with 1,3-binucleophiles,
including the use of a system of pyridine–thionyl
chloride as a dehydrating agent [9].
The cyclocondensation of hexafluoroacetone and
methyl trifluoropyruvate acylimines Ia–Id with car-
boxylic amides IIa–IIf occurs in two stages: the
addition of amide II to the highly electrophilic C=N
bond of acylamine I followed by dehydration of the
resulting amidal to form 1,3,5-oxadiazine IV.
O
O
C
O
C
O
C
CF3
CF3
CF3
H
+
H2N
N
C
N
NH
N
N
F3C
III
IIа
Iа
CF3
N
CF3
N
NEt3, SOCl2
O
N
IVа
In the cyclocondensation of the hexafluoroacetone
benzoylimine Ia and nicotinamide IIa individual pro-
duct of amidoalkylation III was isolated and charac-
terized. Oxadiazines IVb–IVf were obtained by one-
pot process adding amide IIa–IIf, triethylamine and thio-
nyl chloride to a solution of acylimine Ib–Id in DMF.
1180

HEXAFLUOROACETONE AND METHYL TRIFLUOROPYRUVATE ACYLIMINES
1181
CF3
N
X
O
C
O
CF3
X
NEt3, SOCl2
N
R1
+
N
R
H2N C
R
R1
O
Ib−Id
IIа−IIf
IVb−IVf
I: X = CF3, R = 3-ClC6H5 (b), Furyl (c); X = C(O)OCH3, R = 4-FC6H5 (d); II: R1 = C6H5 (a), 2-CH3C6H5 (b), 3-CH3C6H5
(d), 3-CH3OC6H5 (e), Pyridin-4-yl (f); IV: X = CF3, R = 3-ClC6H5, R1 = 2-CH3C6H5 (b), Pyridin-4-yl (c); R = Furyl, R1 = 3-
CH3OC6H5 (d); X = C(O)OCH3, R = 4-FC6H5, R1 = C6H5 (e), 2-CH3C6H5 (f).
The synthesized 1,3,5-oxadiazines IVa–IVf were
obtained in yields of 66–78% as crystalline substances.
Their composition and structure were proved by
d (1H, CHAr, J1 5.1 Hz, J2 1.6 Hz), 8.99 d (1H, CHAr,
J 2.1 Hz), 9.34 s (1H, NH). 19F NMR spectrum
(DMSO-d6) δF, ppm: 3.84 s. Found, %: C 49.35; H
2.62; N 10.92. C16H11F6N3O2. Calculated, %: C 49.12;
H 2.83; N 10.74.
1
elemental analysis and H and 19F NMR spectroscopy.
The 19F NMR spectra include characteristic signals in
the range from 0 to –1 ppm for IVa–IVd and from –1
to –2 ppm for IVe and IVf.
2-Phenyl-6-pyridin-3-yl-4,4-bis(trifluoromethyl)-
4H-1,3,5-oxadiazine (IVa). a. To a solution of 3 mmol
of compound Ia and 6 mmol of triethylamine in 10 ml
of DMF while stirring at 0ºC was added 3 mmol of
SOCl2. The reaction mixture was stirred for 2 h at
20ºC, poured into 50 ml of H2O, the precipitate was
crystallized from hexane. Yield 0.8 g (71%), mp 108–
The 1,3,5-oxadiazine IVa was obtained also by
authentic synthesis from the imine Id and benzonitrile
V by heating equimolar mixture of the components at
150°C in a closed volume for 5 h.
O
1
CF3
110ºC. H NMR spectrum (DMSO-d6) δ, ppm: 7.45–
+
N
N
C
C
7.76 m (4H, CHAr); 8.22 d (2H, CHAr, J 8.6 Hz), 8.52
d (1H, CHAr, J 7.9 Hz), 8.84 d.d (1H, CHAr, J1 5.1 Hz,
J2 2.0 Hz), 9.33 d (1H, CHAr, J 2.0 Hz). 19F NMR
spectrum (DMSO-d6) δF, ppm: –0.42 s. Found, %: C
51.67; H 2.25; N 11.42. C16H9F6N3O. Calculated, %: C
51.49; H 2.43; N 11.26.
CF3
N
Id
V
CF3
CF3
N
N
b. A mixture of 3 mmol of compound Id and
3 mmol of compound V was heated in a closed vessel
for 6 h at 150ºC, then the reaction mixture was crystal-
lized from hexane. Yield 0.7 g (63.5%), mp 108–110ºC.
O
N
IVа
2-(3-Chlorophenyl)-6-o-tolyl-4,4-bis(trifluoro-
methyl)-4H-1,3,5-oxadiazine (IVb). To a solution of
5 mmol of compound Ib in 10 ml of DMF while
stirring at 20ºC was added 5 mmol of compound IIb.
The reaction mixture was stirred for 8 h at 20ºC, then
Thus, we have developed a convenient preparative
method for the synthesis of biologically active tri-
fluoromethyl-containing oxadiazines based on cyclo-
condensation of hexafluoroacetone and methyl trifluoro-
pyruvate acylimines with amides.
10 mmol of triethylamine was added, and at 0ºC,
5
mmol of SOCl2. The stirring was continued for 2 h at
20ºC, then the mixture was poured into 50 ml of H2O,
the precipitate formed was separated and crystallized
N-(Benzoylamino-2,2,2-trifluoro-1-trifluoromethyl-
ethyl)nicotinamide (III). To a solution of 5 mmol of
compound Ia in 10 ml of DMF while stirring at 20ºC
was added 5 mmol of compound IIa. The reaction
mixture was stirred for 8 h at 20ºC, poured into 50 ml
of H2O, the precipitate formed was separated and
crystallized from 50% EtOH. Yield 1.7 g (87%), mp
105–106ºC. H NMR spectrum (DMSO-d6) δ, ppm:
7.23–7.59 m (4H, CHAr); 7.61–7.85 m (3H, CHAr +
NH); 8.01 d.t (1H, CHAr, J1 7.9 Hz, J2 1.6 Hz), 8.67 g
1
from hexane. Yield 1.3 g (62%), mp 91–93ºC. H
NMR spectrum (DMSO-d6) δ, ppm: 2.69 s (3H, Me);
7.35–7.60 m (4H, CHAr); 7.65 d (1H, CHAr, J 8.2 Hz),
7.92 d ( 1H, CHAr, J 7.4 Hz), 8.8 d (1H, CHAr, J 7.5 Hz);
8.16 s (1H, CHAr). 19F NMR spectrum (DMSO-d6) δF,
ppm: –0.48 s. Found, %: C 51.21; H 2.83; N 6.87.
C18H11ClF6N2O. Calculated, %: C 51.39; H 2.64; N 6.66.
1
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1182
SOKOLOV et al.
2-(3-Chlorophenyl)-6-pyridin-4-yl-4,4-bis(trifluoro-
Found, %: C 57.62; H 3.41; N 7.33. C19H14F4N2O3.
Calculated, %: C 57.87; H 3.58; N 7.10.
methyl)-4H-1,3,5-oxadiazine (IVc) was obtained
similarly to compound IVb. Yield 1.4 g (69%), mp
1H and 19F NMR spectra were taken on a Bruker
DPX 200 spectrometer at the operating frequencies
200.13 and 188.29 MHz, relative to internal tetra-
methylsilane or external CF3COOH, respectively. Melting
points were determined in glass capillaries. Hexa-
fluoroacetone and methyl trifluoropyruvate acylamines
Ia–Id were synthesized by the method of [7]. Initial
amides IIa–IIf (Aldrich) were used without pretreatment.
1
81–82ºC. H NMR spectrum (DMSO-d6) δ, ppm: 7.55
t (1H, CHAr, J 8.1 Hz), 7.68 d (1H, CHAr, J 8.1 Hz);
7.96–8,24 m (4H, CHAr) , 8.93 d (2H, CHAr, J 6.5
Hz). 19F NMR spectrum (DMSO-d6) δF, ppm: –0.56 s.
Found, %: C 47.31; H 1.79; N 10.09. C16H8ClF6N3O.
Calculated, %: C47.14; H 1.98; N 10.31.
2-(2-Furyl)-6-(3-methoxyphenyl)-4,4-bis(trifluoro-
methyl)-4H-1,3,5-oxadiazine (IVd) was obtained
similarly to compound IVb. Yield 1.2 g (62%), mp
ACKNOWLEDGMENTS
1
This work was supported by the Program “Medical
and Biomedical Chemistry” of Russian Academy of
Sciences, Material Sciences Division.
73–75ºC. H NMR spectrum (DMSO-d6) δ, ppm: 3.88
s (3H, MeO); 7.62 m (1H, CHAr); 7.19 d.d (1H, CHAr,
J1 8.7 Hz, J2 2.2 Hz), 7.45 t (1H, CHAr, J 7.9 Hz), 7.50–
7.62 m (2H, CHAr); 7.73 d (1H, CHAr, J 7.3 Hz); 7.95
s (1H, CHAr). 19F NMR spectrum (DMSO-d6) δF,
ppm: –0.53 s. Found, %: C 48.81; H 2.36; N 7.32.
C16H10F6N2O3. Calculated, %: C48.99; H 2.57; N 7.14.
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Methyl 2-(4-fluorophenyl)-6-phenyl-4-trifluoro-
methyl)-4H-1,3,5-oxadiazine-4-carboxylate (IVe) was
obtained similarly to compound IVb. Yield 1.2 g
(63%), mp 161–162ºC. 1H NMR spectrum (DMSO-d6)
δ, ppm: 3.72 s (3H, CH3O), 7.12 t (2H, CHAr, J
8.8 Hz), 7.36–7.57 m (3H, CHAr); 7.99–8.17 m (4H,
CHAr). 19F NMR spectrum (DMSO-d6) δF, ppm: –1.19
s (3F), –27.36 m (1F). Found, %: C 56.65; H 3.32; N
7.54. C18H12F4N2O3. Calculated, %: C 56.85; H 3.18;
N 7.37.
Methyl 2-(4-fluorophenyl)-6-m-tolyl-4-trifluoro-
methyl)-4H-1,3,5-oxadiazine-4-carboxylate (IVf) was
obtained similarly to compound IVb. Yield 1.1 g
(56%), mp 102–104ºC. 1H NMR spectrum (DMSO-d6)
δ, ppm: 2.38 s (3H, Me); 3.78 s (3H, MeO); 7.01–7.22
m (2H, CHAr); 7.34 m (2H, CHAr); 7.87 m (2H,
CHAr); 8.02–8.18 m (2H, CHAr). 19F NMR spectrum
(DMSO-d6) δF, ppm: –1.21 s (3F); –27.40 m (1F).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 6 2012