Cycloaddition and cyclocondensation of methyl 2-(4,4-Dimethyl-2,6- dioxocyclohexylidene)-3,3,3-trifluoropropionate

Full text of DOI:10.1134/S1070363214060310

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 6, pp. 1243–1245. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 6, pp. 1043–1045.
LETTERS
TO THE EDITOR
Cycloaddition and Cyclocondensation
of Methyl 2-(4,4-Dimethyl-2,6-dioxocyclohexylidene)-3,3,3-
trifluoropropionate
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received November 5, 2013
Keywords: methyl trifluoropyruvate, dimedone, cyanamines, primary amines, cycloaddition, cyclo-
condensation
DOI: 10.1134/S1070363214060310
The information on heterocyclization of methyl
trifluoropyruvate ylides is limited to transformations of
fluorinated 4-ethylidene-2,4-dihydro-3-ones in cyclo-
addition [1–4] and cyclocondensation [4–6], despite
the fact that methyl trifluoropyruvate imines have been
widely studied in such transformations [7–12].
reagents in benzene for 2 h to produce the correspond-
ing tetrahydrobenzoxazines VIa and VIb in a 74 and
78% yield, respectively.
The addition of the primary amines Va and Vb to
ylide III proceeded with heat evolution at the highly
electrophilic C=C bond to give compounds VIIa and
VIIb. The latter were converted under heating into
3,5,6,7-tetrahydro-1-benzofuran-2,4-diones VIIIa and
VIIIb in a 76 and 82% yield, respectively (Scheme 1).
The purpose of this work was to develop the
method for obtaining methyl triftorpiruvate ylides and
to study cyclocondensation and cycloaddition reactions
of newly prepared methyl 2-(4,4-dimethyl-2,6-
dioxocyclohexylidene)-3,3,3-trifluoropropionate with
the primary amines.
The synthesized 1,3-benzoxazines VI and 3,5,6,7-
tetrahydro-1-benzofuran-2,4-diones VIII are colorless
crystalline substances. The 19F NMR spectra of III
contained the singlet signal of CF3-group at 18.7 ppm,
whereas in the spectra of VI and VIII this signal
appears in the ranges of 0.73–0.79 and 16.01–
16.33 ppm, respectively.
Methyl 2-(4,4-dimethyl-2,6-dioxocyclohexylidene)-
3,3,3-trifluoropropionate III was synthesized in 88%
yield by condensation of 5,5-dimethylcyclohexane-1,3-
dione I with methyl trifluoropyruvate II. The reaction
was carried out by successively adding dione II and
SOCl2 to a mixture of dimedone I and pyridine in
In summary, we synthesized a new highly reactive
trifluoromethyl-containing ylide, methyl 2-(4,4-di-
methyl-2,6-dioxocyclohexylidene)-3,3,3-trifluoropro-
pionate. The latter can be successfully used as a
heterodiene in the Diels–Alder reaction, and as a bis-
electrophile in the cyclocondensation, which can be
considered as a preparative method for the synthesis of
N-substituted 3-amino-3-(trifluoromethyl)-3,5,6,7-tetra-
hydro-1-benzofuranones.
19
benzene. The F NMR spectrum of the resulting ylide
III contained the singlet signal of CF3-group at
18.68 ppm, which was characteristic of trifluoro-
methyl-containing ylides [1].
In the aza-Diels–Alder reaction with cyanamines
ylide III was less reactive than acyl imines of
hexafluoroacetone and methyl trifluoropyruvate that
reacted with cyanamines with heat evolution [7, 8].
The reaction of ylide III with cyanamines IVa and
IVb proceeded at boiling equimolar mixture of the
5,5-Dimethylcyclohexane-1,3-dione I, methyl tri-
fluoropyruvate II, dialkylcyanamines IVa and IVb,
1243

1244
SOKOLOV, AKSINENKO
Scheme 1.
O
O
O
O
C
O
C
C(O)OCH3
CF3
Py, SOCl2
+ CF3
OCH3
O
II
I
III
R1
N R1
R1
R1
O
N
CN
N
IVа, IVb
C(O)OCH3
CF3
O
VIа, VIb
O
H2NCH2R2
O
CF3
NHCH2R2
C(O)OCH3
Vа, Vb
NHCH2R2
−CH3OH
O
O
CF3
O
VIIIа, VIIIb
VIIа,VIIb
IV, VI, R1 = Me (а), Et (b), V, VII, VIII, R2 = C6H5 (a), pyrid-3-yl (b).
amines Va and Vb (Aldrich) were used without pre-
purification.
Methyl 2-(diethylamino)-7,7-dimethyl-5-oxo-4-
(trifluoromethyl)-5,6,7,8-tetrahydro-4Н-1,3-benz-
oxazine-4-carboxylate (VIb) was obtained similarly.
Yield 2.8 g (74%), mp 197–199°С. 1Н NMR spectrum
(CDCl3), δ, ppm: 1.02–1.25 m (12H, Me), 2.34 s (2H,
CH2), 2.45 s (2H, CH2), 3.23–3.45 m (4H, MeCH2),
3.79 s (3H, MeO). 19F NMR spectrum (CDCl3): δF 0.79
ppm. Found, %: C 54.06; H 6.33; N 7.25. C17H23F3N2O4.
Calculated, %: C 54.25; H 6.16; N 7.44.
Methyl 2-(4,4-dimethyl-2,6-dioxocyclohexylidene-
3,3,3-trifluoropropionate (III). To a solution of
0.1 mol of compound I and 0.2 mol of pyridine in
100 mL of benzene were successively added with
stirring at 20°С 0.1 mol of compound II, 0.1 mol of
SOCl2. After 2 h the reaction mixture was filtered and
evaporated. Yield 24.6 g (88%), colorless oil. 1Н NMR
spectrum (CDCl3), δ, ppm: 1.10 s (6H, Me), 2.71 s
(2H, CH2), 2.76 s (2H, CH2), 3.86 s (3H, MeO). 19F
NMR spectrum (CDCl3): δF 18.68 ppm. Found, %: C
51.57; H 4.49. C12H13F3O4. Calculated, %: C 51.80; H
4.71.
3-Benzylamino-6,6-dimethyl-3-(trifluoromethyl)-
3,5,6,7-tetrahydro-1-benzofuran-2,4-dione (VIIIa).
To a solution of 10 mmol of III in 10 mL of DMF was
added with stirring 10 mmol of Va. The reaction
mixture was stirred at 90°С for 2 h, then cooled and
poured into 50 mL of water. The precipitate was
separated and recrystallized from 50% ethanol. Yield
2.7 g (76%), mp 201–203°С. 1Н NMR spectrum
(DMSO-d6), δ, ppm: 0.88 s (3H, Me), 1.01 s (3H, Me),
1.63 d (1H, CH2, J 11.7 Hz), 1.88 d (1H, CH2, J
11.7 Hz), 2.24 d (1H, CH2, J 13.5 Hz), 2.64 d (1H,
CH2, J 13.5 Hz), 4.25 d (2Н, CH2, JАВ 14.4 Hz), 6.53 s
(1Н, NH), 6.82–7.06 m (5Н, Ph). 19F NMR spectrum
(DMSO-d6): δF 16.01 ppm. Found, %: C 61.43; H
5.29; N 4.11. C18H18F3NO3. Calculated, %: C 61.19; H
5.13; N 3.96.
Methyl 2-(dimethylamino)-7,7-dimethyl-5-oxo-4-
(trifluoromethyl)-5,6,7,8-tetrahydro-4Н-1,3-benz-
oxazine-4-carboxylate (VIа). A mixture of 10 mmol
of III and 10 mmol of IVа in 10 mL of benzene was
heated at 80°С for 2 h. After cooling, benzene was
removed. The residue was recrystallized from hexane.
Yield 2.7 g (78%), mp 132–134°С. 1Н NMR spectrum
(CDCl3), δ, ppm: 1.11 s (3H, Me), 1.14 s (3H, Me),
2.33 s (2H, CH2), 2.46 s (2H, CH2), 2.97 s (6H, MeN),
3.79 s (3H, MeO). 19F NMR spectrum (CDCl3): δF 0.73
ppm. Found, %: C 51.58; H 5.69; N 8.25. C15H19F3N2O4.
Calculated, %: C 51.72; H 5.50; N 8.04.
6,6-Dimethyl-3-[(pyridin-3-yl)amino]-3-(trifluo-
romethyl)-3,5,6,7-tetrahydro-1-benzofuran-2,4-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

CYCLOADDITION AND CYCLOCONDENSATION
1245
Fokin, A.V., Russ. Chem. Bull., 1993, vol. 42, no. 3,
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dione (VIIIb) was obtained similarly. Yield 2.9 g
(82%), mp 128–130°С. Н NMR spectrum (DMSO-
1
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d6), δ, ppm: 0.96 s (3H, Me), 1.07 s (3H, Me), 1.95 d
(2Н, CH2, JАВ 13.7 Hz), 2.38 d (1H, CH2, J 14.1 Hz),
2.84 d (1H, CH2, J 13.7 Hz), 4.58 d (2Н, CH2, JАВ
16.4 Hz), 7.00 s (1Н, NH), 7.31 d. d (1Н, CHAr, J 4.5,
1.6 Hz), 7.40 d (1Н, CHAr, J 7.8 Hz), 7.40 t. d (1Н,
CHAr, J 7.8, 1.6 Hz), 8.52 d (1Н, CHAr, J 4.5 Hz). 19F
NMR spectrum (DMSO-d6): δF 16.33 ppm. Found, %:
C 57.46; H 4.63; N 7.75. C17H17F3N2O3. Calculated,
%: C 57.63; H 4.84; N 7.91.
1
The H and 19F NMR spectra were registered on a
Bruker DPX 200 spectrometer operating at 200.13 and
188.29 MHz, internal reference TMS, external
reference CF3COOH, respectively. Melting points
were determined using glass capillaries.
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ACKNOWLEDGMENTS
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This work was performed within the Programs
“Development of methods for obtaining chemical
substances and new materials” and “Medical and
biomedical chemistry” of the Department of Chemistry
and Materials Science of the Russian Academy
Sciences. The work was financially supported by the
Russian Foundation for Basic Research (grant no. 11-
03-00496-a).
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