Modification of biologically active amides and amines with fluorine-containing heterocycles 6. Methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1- phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)propionate in cyclocondensation with 1,3-binucleophiles

Article abstract of DOI:10.1007/s11172-012-0272-6

A reaction of methyl 3,3,3-trifluoro-2-(3-methyl-5-oxo-1-phenyl-1,5- dihydro-4H-pyrazol-4-ylidene)propionate with 1,3-binucleophiles (N-benzylurea, N-substituted 3-aminocrotonates, N-substituted 3-aminocyclohexenones, and 6-aminouracyls), leading to the formation of fluorine-containing heterocyclic 3-methyl-1-phenylpyrazol-5-one derivatives, was studied.

Full text of DOI:10.1007/s11172-012-0272-6

Russian Chemical Bulletin, International Edition, Vol. 61, No. 10, pp. 1965—1968, October, 2012
1965
Modification of biologically active amides and amines
with fluorineꢀcontaining heterocycles
6.* Methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀ
ylidene)propionate in cyclocondensation with 1,3ꢀbinucleophiles
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi prꢀd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
A reaction of methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ
4ꢀylidene)propionate with 1,3ꢀbinucleophiles (Nꢀbenzylurea, Nꢀsubstituted 3ꢀaminocrotonates,
Nꢀsubstituted 3ꢀaminocyclohexenones, and 6ꢀaminouracyls), leading to the formation of fluorꢀ
ineꢀcontaining heterocyclic 3ꢀmethylꢀ1ꢀphenylpyrazolꢀ5ꢀone derivatives, was studied.
Key words: 3ꢀmethylꢀ1ꢀphenylpyrazolꢀ5ꢀone, methyl trifluoropyruvate, Nꢀbenzylurea,
3ꢀaminocrotonates, 3ꢀaminocyclohexenones, 6ꢀaminouracyls, fluorineꢀcontaining imidazolidineꢀ
2,4ꢀdiones, dihydroꢀ1Hꢀpyrroles, tetrahydroꢀ1Hꢀindoleꢀ2,4ꢀdiones, dihydroꢀ1Hꢀpyrroloꢀ
[2,3ꢀd]pyrimidineꢀ2,4,6ꢀtriones.
Dihydroꢀ4Hꢀpyrazolꢀ3ꢀone derivatives belong to an
important class of physiologically active substances.
Among them were found nonꢀnarcotic analgesics and antiꢀ
pyrenes,2 antineoplastics,3—5 substances possessing antiꢀ
microbal,6—8 parasiticide,9 and antiviral10 activity. Many of
these compounds are successfully used in medical practice,
for example, aminophenazone, phenylbutazone, analgene.11
A general approach to the molecular design of dihydroꢀ
4Hꢀpyrazolꢀ3ꢀones consists in the introduction of substitꢀ
uents at position 4 of the heterocycle. The purpose of the
present studies is to modify 3ꢀmethylꢀ1ꢀphenylpyrazolꢀ5ꢀ
one with trifluoromethylꢀcontaining fiveꢀmembered heteroꢀ
cycles by means of the reactions of the condensation prodꢀ
uct of pyrazolone and methyl trifluoropyruvate, i.e., meꢀ
thyl 3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ1,5ꢀdiꢀ
hydroꢀ4Hꢀpyrazolꢀ4ꢀylidene)propionate (1), with 1,3ꢀbiꢀ
nucleophiles: Nꢀbenzylurea, Nꢀsubstituted 3ꢀaminoꢀ
crotonates, Nꢀsubstituted 3ꢀaminocyclohexenones, and
6ꢀaminouracyls. The present work was prompted by the
data obtained during the systematic studies of the behavꢀ
ior of imines of methyl trifluoropyruvate in the cycloconꢀ
densation reactions with 1,3ꢀbinucleophiles, leading to the
formation of fiveꢀmembered trifluoromethylꢀcontaining
heterocycles.12—18
1,3ꢀbinucleophile at the highly electrophilic C=C bond
with the formation of methyl ester of 2ꢀ(3ꢀbenzylureido)ꢀ
3,3,3ꢀtrifluoroꢀ2ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionic acid (3), which was isoꢀ
lated and characterized in the individual state, and the
cyclization of the latter in the presence of catalytic amounts
of Et3N to 3ꢀbenzylꢀ5ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀtrifluoromethylimidazolidineꢀ
2,4ꢀdione (4) (Scheme 1).
The reactions of methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ
1ꢀphenylꢀ1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀylidene)propionate
(1) with Nꢀsubstituted 3ꢀaminocrotonates 5a,b, Nꢀsubstiꢀ
tuted 3ꢀaminocyclohexenones 6a—c, and 6ꢀaminouracyls
7a,b were carried out without isolation of the intermediate
products upon heating of a mixture of reagents in DMF at
80 C during 2 h, in the presence of catalytic amounts of
Et3N in the case of 6a—c and 7a,b. The cyclocondensaꢀ
tion of 1 with 5a,b, 6a—c, and 7a,b resulted in the formaꢀ
tion of the corresponding heterocyclic derivatives of
3ꢀmethylꢀ1ꢀphenylpyrazolꢀ5ꢀone: 2ꢀmethylꢀ4ꢀ(5ꢀmethylꢀ
3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4ꢀ
trifluoromethylꢀ4,5ꢀdihydroꢀ1Hꢀpyrroles 8a,b, 6,6ꢀdiꢀ
methylꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)ꢀ1ꢀphenylꢀ3ꢀtrifluoromethylꢀ3,5,6,7ꢀtetraꢀ
hydroꢀ1Hꢀindoleꢀ2,4ꢀdiones 9a—c, 5ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ
2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀtrifluoromethꢀ
ylꢀ5,7ꢀdihydroꢀ1Hꢀpyrrolo[2,3ꢀd]pyrimidineꢀ2,4,6ꢀtriꢀ
ones 10a,b (Scheme 2).
Methyl 3,3,3ꢀtrifluoroꢀ2(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ
1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀylidene)propionate (1) exoꢀ
thermically reacted with Nꢀbenzylurea (2) according to
the scheme of cyclocondensation reaction: the addition of
The thus obtained fluorineꢀcontaining heterocyclic
derivatives of 3ꢀmethylꢀ1ꢀphenylpyrazolꢀ5ꢀone, viz., comꢀ
* For Part 5, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1949—1952, October, 2012.
1066ꢀ5285/12/6110ꢀ1965 © 2012 Springer Science+Business Media, Inc.

1966
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
Sokolov and Aksinenko
Scheme 1
Scheme 2
C(O)OMe
Me
Me
MeO(O)C
HN
R
C
F3
N
Me
5a,b
R
HN
O
N
Ph
8a,b
O
O
Me
Me
HN
R
O
6a—c
C
F3
N
1
Me
R
O
HN
N
O
Ph
9a—c
O
O
NH
NH
H2N
N
R
O
N
R
O
7a,b
C
F3
NH
Me
pounds 4, 8a,b, 9a—c, and 10a,b, are solid crystalline subꢀ
stances, their composition and structure were confirmed
by the elemental analysis data and 1H and 19F NMR specꢀ
troscopy. The 19F NMR spectra are characterized by the
signals in the region of  2.8 for the 4 and  11—12 for the
8a,b, 9a—c and 10a,b.
O
HN
N
O
Ph
10a,b
5, 8: R = H (a), Pri (b)
The suggested cyclocondensation reaction of methyl
ester of 3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ1,5ꢀ
dihydroꢀ4Hꢀpyrazolꢀ4ꢀylidene)propionic acid with 1,3ꢀbiꢀ
nucleophiles is one of the promising synthetic approaches
to the modification of biologically active dihydroꢀ4Hꢀpyrꢀ
azolꢀ3ꢀones with various trifluoromethylꢀcontaining fiveꢀ
membered heterocycles.
6, 9: R = Ph (a), 4ꢀMeOC6H4 (b), 3ꢀCF3C6H4 (c)
7, 10: R = CH2Ph (a), CH2CH2Ph (b)
(1.5 g, 10 mmol) was added to a solution of compound 1 (3.12 g,
10 mmol) in DMF (20 mL). The reaction mixture was stirred for
2 h at 20 C, poured into water, a precipitate formed was filtered
off and recrystallized from 50% aqueous EtOH to obtain comꢀ
pound 3 (4.3 g, 93%), m.p. 115—117 C. Found (%): C, 57.32;
H, 4.41; N, 12.29. C22H21F3N4O4. Calculated (%): C, 57.14;
Experimental
1
H, 4.58; N, 12.12. H NMR (DMSOꢀd6), : 2.10 (s, 3 H, Me);
1
H and 19F NMR spectra were recorded on a Bruker DPX
3.71 (s, 3 H, MeO); 4.20 (s, 2 H, CH2); 7.09—7.31 (m, 7 H,
CHAr + NH); 7.42 (t, 2 H, CHAr, J = 7.9 Hz); 7.72 (d, 2 H,
CHAr, J = 7.9 Hz); 7.89 (s, 1 H. NH); 9.01 (s, 1 H, NH).
19F NMR (DMSOꢀd6), : 2.01 s.
3ꢀBenzylꢀ5ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrꢀ
azolꢀ4ꢀyl)ꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4). Triethylꢀ
amine (0.1 g) was added to a solution of compound 3 (2.3 g,
5 mmol) in DMF (10 mL). The reaction mixture was heated for
2 h at 80 C, poured into water, a precipitate formed was filtered
off and recrystallized from 50% aq. EtOH to obtain compound 4
(1.7 g, 79%), m.p. 211—213 C. Found (%): C, 58.82; H, 4.15;
N, 13.21. C21H17F3N4O3. Calculated (%): C, 58.61; H, 3.98;
N, 13.02. 1H NMR (DMSOꢀd6), : 2.32 (s, 3 H, Me); 4.63
200 spectrometer (200.13 and 188.29 MHz, respectively) relaꢀ
tive to tetramethylsilane (internal standard) and CF3COOH (exꢀ
ternal standard), respectively. Melting points were determined
using a glass capillary tube. The starting reagents were obtained
according to the known procedures:19—21 methyl 3,3,3ꢀtrifluoꢀ
roꢀ2ꢀ(3ꢀmethylꢀ5ꢀoxoꢀ1ꢀphenylꢀ1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀ
ylidene)propionate (1) (see Ref. 19), 3ꢀaminocyclohexenones
6a—c (see Ref. 20), 6ꢀaminouracyls 7a,b (see Ref. 21). Nꢀbenzylꢀ
urea (2) and 3ꢀaminocrotonates 5a,b (Aldrich) were used withꢀ
out additional purification.
Methyl 2ꢀ(3ꢀbenzylureido)ꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(5ꢀmethylꢀ3ꢀ
oxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionate (3). Urea 2

Fluorinated pyrazolones in cyclocondesation
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 10, October, 2012
1967
(s, 2 H, CH2); 7.13—7.36 (m, 7 H, CHAr + NH); 7.45 (t, 2 H,
CHAr, J = 7.9 Hz); 7.48 (d, 2 H, CHAr, J = 7.9 Hz); 9.33 (s, 1 H,
NH). 19F NMR (DMSOꢀd6), : 2.82 s.
m.p. 252—254 C. Found (%): C, 59.89; H, 4.33; N, 7.62.
C28H23F6N3O3. Calculated (%): C, 59.68; H, 4.11; N, 7.46.
1H NMR (DMSOꢀd6), : 1.01 and 1.12 (both s, 6 H, Me);
Methyl 2ꢀmethylꢀ4ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ
1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ1Hꢀpyrꢀ
roleꢀ3ꢀcarboxylate (8a). Methyl 3ꢀaminocrotonate 5a (0.58 g,
5 mmol) was added to a solution of compound 1 (1.56 g, 5 mmol)
in DMF (20 mL). The reaction mixture was stirred for 2 h at
20 C, then heated for 2 h at 80 C, poured into water, a precipiꢀ
tate formed was filtered off and recrystallized from 50% aq. EtOH
to obtain compound 8a (1.6 g, 81%), m.p. 248—250 C.
Found (%): C, 54.87; H, 4.22; N, 10.44. C18H16F3N3O4. Calcuꢀ
2.07—2.38 (m, 4 H, CH2); 2.42 (s, 3 H, Me); 7.10 (t, 1 H, CHAr
,
,
J = 7.7 Hz); 7.32—7.62 (m, 6 H, CHAr); 7.75 (d, 2 H, CHAr
J = 8.1 Hz); 11.44 (s, 1 H, NH). 19F NMR (DMSOꢀd6), :
11.73 s; 11.92 s.
1ꢀBenzylꢀ5ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrꢀ
azolꢀ4ꢀyl)ꢀ5ꢀtrifluoromethylꢀ5,7ꢀdihydroꢀ1Hꢀpyrrolo[2,3ꢀd]ꢀ
pyrimidineꢀ2,4,6ꢀtrione (10a) was obtained similarly to comꢀ
pound 9a from compound 1 (1.56 g, 5 mmol) and compound 7a
(1.09 g, 5 mmol). The yield was 1.9 g (76%), m.p. 261—263 C.
Found (%): C, 57.74; H, 3.79; N, 14.22. C24H18F3N5O4. Calcuꢀ
lated (%): C, 57.95; H, 3.65; N, 14.08. 1H NMR (DMSOꢀd6), :
1
lated (%): C, 54.69; H, 4.08; N, 10.63. H NMR (DMSOꢀd6),
: 2.30 (s, 3 H, Me); 2.38 (s, 3 H, Me); 3.61 (s, 3 H, MeO); 7.12
(t, 1 H, CHAr, J = 8.1 Hz); 7.36 (t, 2 H, CHAr, J = 8.1 Hz); 7.72
(d, 2 H, CHAr, J = 8.1 Hz); 10.75 (s, 1 H, NH); 11.16 (s, 1 H,
NH). 19F NMR (DMSOꢀd6), : 11.12 s.
2.41 (s, 3 H, Me); 5.10 (m, 2 H, CH2); 7.17 (t, 1 H, CHAr
,
J = 7.0 Hz); 7.25—7.48 (m, 7 H, CHAr); 7.77 (d, 2 H, CHAr,
J = 8.1 Hz); 10.96 (s, 1 H, NH); 11.41 (s, 1 H, NH); 12.12
(s, 1 H, NH). 19F NMR (DMSOꢀd6), : 10.91 s.
Methyl 1ꢀisopropylꢀ2ꢀmethylꢀ4ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ
2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4ꢀtrifluoromethylꢀ4,5ꢀdiꢀ
hydroꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (8b) was obtained similarly
to compound 8a from compound 1 (1.56 g, 5 mmol) and
compound 5b (0.78 g, 5 mmol). The yield was 1.7 g (78%),
m.p. 189—191 C. Found (%): C, 57.87; H, 5.18; N, 9.78.
C21H22F3N3O4. Calculated (%): C, 57.66; H, 5.07; N, 9.61.
1H NMR (DMSOꢀd6), : 1.40 (dd, 6 H, Me, J = 7.2 Hz); 2.28
(s, 3 H, Me); 2.55 (s, 3 H, Me); 3.61 (s, 3 H, MeO); 4.19 (septet,
1 H, CH, J = 7.1 Hz); 7.17 (t, 1 H, CHAr, J = 7.4 Hz); 7.41
(t, 2 H, CHAr, J = 7.4 Hz); 7.69 (d, 2 H, CHAr, J = 7.4 Hz);
11.33 (s, 1 H, NH). 19F NMR (DMSOꢀd6), : 11.01 s.
6,6ꢀDimethylꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)ꢀ1ꢀphenylꢀ3ꢀtrifluoromethylꢀ3,5,6,7ꢀtetrahydroꢀ
1Hꢀindoleꢀ2,4ꢀdione (9a). 3ꢀAminocyclohexenone 6a (1.08 g,
5 mmol) was added to a solution of compound 1 (1.56 g, 5 mmol)
in DMF (20 mL). The reaction mixture was stirred for 2 h at 20
C, followed by the addition of Et3N (0.1 g), then heated for 2 h
at 80 C, poured into water, a precipitate formed was filtered off
and recrystallized from 50% aq. EtOH to obtain compound 8a
(2 g, 80%), m.p. 269—271 C. Found (%): C, 65.66; H, 4.71;
N, 8.31. C27H24F3N3O3. Calculated (%): C, 65.45; H, 4.88;
N, 8.48. 1H NMR (DMSOꢀd6), : 1.03 and 1.11 (both s, 6 H, Me);
2.06—2.64 (m, 7 H, CH2 + Me); 7.14 (t, 1 H, CHAr, J = 8.1 Hz);
7.39 (t, 2 H, CHAr, J = 8.2 Hz); 7.45—7.56 (m, 2 H, CHAr);
7.66—7.86 (m, 5 H, CHAr); 11.45 (s, 1 H, NH). 19F NMR
(DMSOꢀd6), : 11.61 s.
1ꢀ(4ꢀMethoxyphenyl)ꢀ6,6ꢀdimethylꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀ
phenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀtrifluoromethylꢀ3,5,6,7ꢀ
tetrahydroꢀ1Hꢀindoleꢀ2,4ꢀdione (9b) was obtained similarly
to compound 9a from compound 1 (1.56 g, 5 mmol) and
compound 6b (1.23 g, 5 mmol). The yield was 2.1 g (79%),
m.p. 253—255 C. Found (%): C, 63.80; H, 5.18; N, 8.17.
C28H26F3N3O4. Calculated (%): C, 63.99; H, 4.99; N, 8.00.
1H NMR (DMSOꢀd6), : 1.02 and 1.10 (both s, 6 H, Me);
2.07—2.47 (m, 4 H, CH2); 2.41 (s, 3 H, Me); 3.84 (s, 3 H,
MeO); 7.03 (d, 2 H, CHAr, J = 9.1 Hz); 7.16 (t, 1 H, CHAr,
J = 7.6 Hz); 7.28—7.47 (m, 4 H, CHAr); 7.74 (d, 2 H, CHAr,
J = 9.1 Hz); 11.40 (s, 1 H, NH). 19F NMR (DMSOꢀd6), : 11.64 s.
6,6ꢀDimethylꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)ꢀ3ꢀtrifluoromethylꢀ1ꢀ(3ꢀ(trifluoromethyl)phenyl)ꢀ
3,5,6,7ꢀtetrahydroꢀ1Hꢀindoleꢀ2,4ꢀdione (9c) was obtained simiꢀ
larly to compound 9a from compound 1 (1.56 g, 5 mmol) and
compound 6a (1.42 g, 5 mmol). The yield was 2.2 g (78%),
5ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
1ꢀ(2ꢀphenylethyl)ꢀ5ꢀtrifluoromethylꢀ5,7ꢀdihydroꢀ1Hꢀpyrroloꢀ
[2,3ꢀd]pyrimidineꢀ2,4,6ꢀtrione (10b) was obtained similarly to
compound 9a from compound 1 (1.56 g, 5 mmol) and comꢀ
pound 7b (1.16 g, 5 mmol). The yield was 1.9 g (74%),
m.p. 251—253 C. Found (%): C, 58.89; H, 4.12; N, 13.87.
C25H20F3N5O4. Calculated (%): C, 58.71; H, 3.94; N, 13.69.
1H NMR (DMSOꢀd6), : 2.30 (s, 3 H, Me); 2.90 (t, 2 H, CH2,
J = 7.2 Hz); 4.04 (t, 2 H, CH2, J = 7.2 Hz); 7.08—7.31 (m, 6 H,
CHAr); 7.41 (t, 2 H, CHAr, J = 7.9 Hz); 7.70 (d, 2 H, CHAr
J = 7.9 Hz); 10.93 (s, 1 H, NH); 11.51 (s, 1 H, NH); 12.07
(s, 1 H, NH). 19F NMR (DMSOꢀd6), : 11.09 s.
,
This work was financially supported by the Russian
Academy of Sciences (Program of the Division of Chemꢀ
istry and Material Sciences "Medical Chemistry: Molecuꢀ
lar Design of Physiologically Active Compounds and
Pharmaceutical Agents").
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1968
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Received March 16, 2012;
in revised form September 27, 2012