Fluoro-containing 4-ethylidene-2,4-dihydropyrazol-3-ones in the diels-alder reaction with cyclopentadiene and cyanamines

Article abstract of DOI:10.1134/S1070363212100155

The fluorinated 4-ethylidene-2,4-dihydropyrazol-3-ones act as heterodienes and dienophiles in the Diels-Alder reaction with amines and cyclopentadiene to give 1,4-dihydropyrazolo[4,3-e]-1,3-oxazines and spirobicyclo[2.2.1]hept-5-ene- 2,4'-pyrazolones, res

Full text of DOI:10.1134/S1070363212100155

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 10, pp. 1728–1730. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, T.A. Epishina, T.V. Goreva, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 10,
pp. 1724–1726.
Fluoro-Containing 4-Ethylidene-2,4-dihydropyrazol-3-ones
in the Diels–Alder Reaction with Cyclopentadiene
and Cyanamines
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, and T. V. Goreva
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received August 1, 2011
Abstract—The fluorinated 4-ethylidene-2,4-dihydropyrazol-3-ones act as heterodienes and dienophiles in the
Diels–Alder reaction with amines and cyclopentadiene to give 1,4-dihydropyrazolo[4,3-e]-1,3-oxazines and
spirobicyclo[2.2.1]hept-5-ene-2,4'-pyrazolones, respectively.
DOI: 10.1134/S1070363212100155
The heterodienes derived from hexafluoroacetone
and methyl trifluoropyruvate like acylimines are
known to act in the Diels–Alder reaction as the elec-
tron-excessive heterodienes in the cycloaddition with
dienophiles and as the electron deficient dienophiles in
the reactions with dienes [1–7]. So, hexafluoroacetone
acylimines and methyl trifluoropyruvate react with the
electron-releasing dienophiles, like aldehydes and
ketones [2], ketenes [8, 9], sulfoxides [10], nitriles
[11], cyanamines [3, 4, 7, 12]. They also react as the
electron-deficient dienophiles with dienes, like
cyclopentadiene [6, 7, 13] and 1,3-butadiene [5].
ylides derived from 5-methyl-2-phenyl-1,2-dihydro-
pyrazol-3-one I, hexafluoroacetone IIa and methyl
trifluoropyruvate IIb, with cyanamines and cyclo-
pentadiene resulting in six-membered heterocycles and
spirobicyclo[2.2.1]hept-5-enes containing dihydro-
pyrazolone fragment, which is a substructural cluster
of certain drug molecules. [14]
The fluorinated 4-ethylidene-2,4-dihydropyrazol-3-
ones [15] were obtained by a modified one-pot method
including the sequential addition of pyridine,
hexafluoroacetone IIa, or methyl trifluoropyruvate IIb
and SOCl2 to a suspension of 5-methyl-2-phenyl-1,2-
dihydropyrazol-3-one I in benzene.
The aim of this research is the study of the Diels–
Alder reaction of trifluoromethyl heterodienes and
CF3
CH3
CH3
HN
CF3
X
Py, SOCl2
O
+
N
N
O
N
O
X
IIа, IIb
I
IIIа, IIIb
II, III, X = CF3 (а), C(O)OCH3 (b).
Compared with hexafluoroacetone, acylimines, and
methyl trifluoropyruvate, heterodienes IIIa and IIIb
are less reactive in the [2+4]-cycloaddition reaction with
cyanamines IVa and IVb. So, to complete the reac-tion
of compounds IIIa and IIIb with IVa and IVb boiling is
required of the equimolar mixture of reagents in
benzene over 5 h. The reaction results in the corres-
ponding dihydropyrazolo[4,3-e]-1,3-oxazines Va–Vd.
1728

FLUORO-CONTAINING 4-ETHYLIDENE-2,4-DIHYDROPYRAZOL-3-ONES
1729
CF3
X
points were determined in a glass capillary. The initial
5-methyl-2-phenyl-1,2-dihydropyrazol-3-one I, hexa-
fluoroacetone IIa, methyl triftorpiruvate IIb,
cyanamines IVa and IVb, cyclopentadiene VI
(Aldrich) were used without previous purification
CH3
N
N
+
N
O
NR2
IIIа, IIIb
N
C
NR2
IVа, IVb
5-Methyl-2-phenyl-4-[2,2,2-trifluoro-1-(trifloro-
methyl)ethylidene]-2,4-dihydro-3Н-pyrazol-3-one
(IIIа). To a suspension of 0.05 mol of compound I in
50 ml of benzene were subsequently added 0.1 mol of
pyridine and 0.05 mol of compound IIa while stirring
at 20°C. The reaction mixture was stirred for 1 h till
dissolution of the precipitate. Then 0.05 mol of SOCl2
was added. The mixture was stirred for 1 h, filtered,
and concentrated. The residue was recrystallized from
Vа−Vd
IV, R = CH3 (a), СH2CH2OCH2CH2 (b); V, Х = CF3, R =
CH3 (a), СH2CH2OCH2CH2 (b); X = C(O)OCH3, R = CH3
(c), СH2CH2OCH2CH2 (d).
The fluorinated 4-ethylidene-2,4-dihydropyrazol-3-
ones IIIa and IIIb react as dienophiles with cyclo-
pentadiene at 20°C in benzene to form spirobicyclo
[2.2.1]heptenes VIIa and VIIb in 77 and 74% yields,
respectively.
1
hexane. Yield 12.3 g (76%), mp 75–77°C. Н NMR
spectrum (CDCl3), δ, ppm: 2.28 q (3Н, СH3, JHF 3.0 Hz),
7.13 t (1H, CHAr, J 7.3 Hz), 7.29 t (2H, CHAr, J 7.3 Hz),
7.69 d (2H, CHAr, J 7.3 Hz). 19F NMR spectrum
(CDCl3), δF, ppm: 18.76 q (JFF 10.3 Hz), 21.46 q.q (JFF
10.3, JFH 2.8 Hz). Found, %: С 48.26; Н 2.25; N 8.43.
C13H8F6N2O. Calculated, %: С 48.46; Н 2.50; N 8.69.
CF3
CH3
X
Methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-
1,5-dihydro-4Н-pyrazol-4-ylidene)propionate (IIIb)
was prepared similarly. Yield 12.8 g (82%), mp 110–
N
N
O
IIIа, IIIb
+
1
111°C. H NMR spectrum (CDCl3), δ, ppm: 2.30 q
VI
(3Н, СH3, JHF 1.9 Hz), 3.90 s (3H, CH3O), 7.11 t (1H,
CHAr, J 7.2 Hz), 7.29 t (2H, CHAr, J 7.2 Hz), 7.69 d
(2H, CHAr, J 7.2 Hz). 19F NMR spectrum (CDCl3), δF,
ppm: 21.54 q (JFH 1.9 Hz). Found, %: С 53.61; Н 3.76;
N 8.72. C14H11F3N2O3. Calculated, %: С 53.85; Н
3.55; N 8.97.
VIIа, VIIb
VII, Х = CF3 (а), C(O)OCH3 (b).
The synthesized dihydropyrazolo[4,3-e]-1,3-oxa-
zines Va–Vd and spirobicyclo[2.2.1]heptenes VIIa
and VIIb are crystalline solids. Their composition and
Dimethyl (3-methyl-1-phenyl-4,4-bistrifluoro-
methyl-1,4-dihydropyrazolo[4,3-e]-1,3-oxazin-6-yl)-
amine (Va). A solution of 0.01 mol of compound III
and 0.01 mol of compound IVa in 20 ml of benzene
was refluxed for 5 h. Then the solvent was evaporated,
and the residue was recrystallized from hexane. Yield
3.5 g (89%), mp 140–142°C. 1H NMR spectrum
(CDCl3), δ, ppm: 2.26 s (3Н, Me), 3.11 s (6H, MeN),
7.32 t (1H, CHAr, J 7.2 Hz), 7.48 t (2H, CHAr, J 7.2 Hz),
7.70 d (2H, CHAr, J 7.2 Hz). 19F NMR spectrum
(CDCl3): δF 2.70 ppm. Found, %: С 48.71; Н 3.88; N
14.53. C16H14F6N4O. Calculated, %: С 48.99; Н 3.60;
N 14.28.
1
structure were proved by the elemental analysis, H
NMR and 19F NMR spectroscopy. In the 19F NMR
spectra there are the characteristic singlet signals at
1.5–2.5 (Va–Vd) and 1.6 ppm (VIIb) or the quartets
of the nonequivalent trifluoromethyl groups at 18.7
and 21.5 ppm (VIIb).
Thus, we developed promising reagents for the
Diels–Alder reaction, the fluorinated 4-ethylidene-2,4-
dihydropyrazol-3-ones, which act as 1,3-heterodienes
and dienophiles in the considered transformations.
EXPERIMENTAL
5-Methyl-2-phenyl-4-[2,2,2-trifluoro-1-(methyl-
amino)-1-(trifluoromethyl)ethyl]-1,2-dihydro-3Н-
pyrazol-3-one (Vb) was prepared similarly. Yield 3.7 g
(85%), mp 138–140°С. 1H NMR spectrum (CDCl3), δ,
ppm: 2.30 s (3Н, СH3), 3.58 m (4H, CH2N), 3.70 m
The H NMR and 19F NMR spectra were recorded
on a Bruker DPX 200 spectrometer operating at 200.13
and 188.29 MHz relative to internal tetramethylsilane
and external CF3COOH, respectively. The melting
1
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1730
SOKOLOV et al.
(4H, CH2O), 7.33 t (1H, CHAr, J 7.2 Hz), 7.50 t (2H,
CHAr, J 7.2 Hz), 7.68 d (2H, CHAr, J 7.2 Hz). 19F NMR
spectrum (CDCl3): δF 0.21 ppm. Found, %: С 49.67; Н
3.92, N 12.71. C18H16F6N4O2. Calculated, %: С 49.48;
Н 3.71; N 12.90.
CHAr, J 8.4 Hz), 7.38 t (2H, CHAr, J 8.4 Hz), 7.78 d
(2H, CHAr, J 8.4 Hz). 19F NMR spectrum (CDCl3): δF
16.12 ppm. Found, %: С 60.15; Н 4.32, N 7.63.
C19H17F3N2O. Calculated, %: С 60.32; Н 4.53; N 7.40.
ACKNOWLEDGMENTS
Methyl 6-dimethylamino-3-methyl-1-phenyl-4-
trifluoromethyl-1,4-dihydropyrazolo[4,3-e]-1,3-oxa-
zine-4-carboxylate (Vc) was prepared similarly. Yield
3.0 g (76%), mp 80–81°С. 1H NMR spectrum (CDCl3),
δ, ppm: 2.21 s (3Н, Me), 3.11 s (6H, MeN), 3.73 s
(3Н, MeO), 7.29 t (1H, CHAr, J 7.2 Hz), 7.47 t (2H,
CHAr, J 7.2 Hz), 7.71 d (2H, CHAr, J 7.2 Hz). 19F NMR
spectrum (CDCl3): δF 1.73 ppm. Found, %: С 53.21; Н
4.69, N 14.41. C17H17F3N4O3. Calculated, %: С 53.40;
Н 4.48; N 14.65.
This work was supported by the Programme
“Biomolecular and Medicinal Chemistry” of the
Department of Chemistry and Materials Science of the
Russian Academy of Sciences.
REFERENCES
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3.71 m (4H, CH2O), 3.79 s (3Н, MeO), 7.30 t (1H,
CHAr, J 7.3 Hz), 7.48 t (2H, CHAr, J 7.3 Hz), 7.67 d
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5'-Methyl-2'-phenyl-3,3-bis(trifluoromethyl)-
spiro(bicyclo[2.2.1]hept-5-ene-2,4'-pyrazol)-3'(2'H)-
one (VIIа). To a solution of 0.01 mol of compound
IIIа in 20 ml of benzene was added 0.01 mol of
compound VI at 20°С. The reaction mixture was
stirred for 1 h and concentrated. The residue was
recrystallized from hexane. Yield 3.0 g (77%), mp
1
9. Gambaryan, N.P. and Zeifman, Yu.V., Izv. Akad. Nauk
100–102°С. H NMR spectrum (CDCl3), δ, ppm: 1.71
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d (1Н, J 10.4 Hz), 2.07 q (3Н, MeC, JHF 3.1 Hz), 3.12
br.s (1Н), 3.31 d (1Н, J 10.4 Hz), 3.42 br. s (1Н), 6.52
m (1Н), 6.76 m (1Н), 7.16 m (1H, CHAr, J 8.4 Hz),
7.38 t (2H, CHAr, J 8.4 Hz), 7.78 d (2H, CHAr, J
8.4 Hz). 19F NMR spectrum (CDCl3), δF, ppm: 18.70 m
(3F), 21.51 m (3F). Found, %: С 55.50; Н 3.89, N
7.43. C18H14F6N2O. Calculated, %: С 55.68; Н 3.63; N
7.21.
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5'-Methyl-2'-phenyl-3-trifluoromethyl-3-methoxy-
carbonylspiro(bicyclo[2.2.1]hept-5-ene-2,4'-pyrazol)-
3'(2'H)-one (VIIb) was prepared similarly. Yield 2.8 g
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1
(74%), mp 76–78°С. H NMR spectrum (CDCl3), δ,
Moscow: Meditsina, 1994, pt. 1.
ppm: 1.71 d (1Н, J 10.4 Hz), 2.07 s (3Н, MeC), 3.12
br.s (1Н), 3.31 d (1Н, J 10.4 Hz), 3.42 br.s (1Н), 3.68 s
(3H, MeO), 6.52 m (1Н), 6.76 m (1Н), 7.16 m (1H,
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