Modification of biologically active amides and amines with fluorine-containing heterocycles: 3*. Piracetam in the three-component reaction with methyl trifluoropyruvate and 1,3-binucleophiles

Article abstract of DOI:10.1007/s11172-010-0075-6

Three-component reaction of Piracetam, methyl trifluoropyruvate and 1,3-binucleophiles, such as 6-aminouracils, 6-aminothiouracils, 4-(4-tolylamino)pent-3-en-2-one and N-substituted ureas, has been studied. This reaction resulted in fluorinated heterocyclic derivatives of Piracetam.

Full text of DOI:10.1007/s11172-010-0075-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 288—291, January, 2010
288
Modification of biologically active amides and amines
with fluorineꢀcontaining heterocycles
3*. Piracetam in the threeꢀcomponent reaction
with methyl trifluoropyruvate and 1,3ꢀbinucleophiles
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva, and I. V. Martynov
Institute of Physiologically Active Substances, Russian Academy of Sciences,
1 Severnyi proezd, Chernogolovka, 142432 Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
Threeꢀcomponent reaction of Piracetam, methyl trifluoropyruvate and 1,3ꢀbinucleophiles,
such as 6ꢀaminouracils, 6ꢀaminothiouracils, 4ꢀ(4ꢀtolylamino)pentꢀ3ꢀenꢀ2ꢀone and Nꢀsubstiꢀ
tuted ureas, has been studied. This reaction resulted in fluorinated heterocyclic derivatives of
Piracetam.
Key words: Piracetam, methyl trifluoropyruvate, imines of methyl trifluoropyruvate, 6ꢀamiꢀ
nouracils, 6ꢀaminothiouracils, 4ꢀ(pꢀtolylamino)pentꢀ3ꢀenꢀ2ꢀone, Nꢀsubstituted ureas, fluoriꢀ
nated imidazolidines, dihydropyrroles, hexahydropyrrolopyrimidines, cyclocondensation.
Nowadays in therapy of various diseases of central nerꢀ
All attempts to synthesize the starting binucleophile,
vous system, a great importance attached to nootropic
drugs, which affect the neuron metabolism and possess
vasoactive and antihy action. The nootropics improve the
stability of the central nervous system to various injury,
information exchange in the brain, learning and memory.2
Among nootropics, the large group is represented by pharꢀ
maceuticals with metabolite action, such as cyclic derivaꢀ
tives of γꢀaminobutyric acid (Piracetam, Oxiracetam,
Aniracetam, Fenotropil and etc.). The distinctive feature
of these compounds is 2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide
fragment in the structure. The latest generation of nootroꢀ
pics represented by the compounds, which were derived
from the parent structure (Piracetam) by introduction of
different functionality at 2ꢀoxopyrrolodinꢀ1ꢀyl fragment
or at amide nitrogen.3
The aim of the present work was a modification of
the known nootropic pharmaceutical — Piracetam
(2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (1)). The functioꢀ
nalization was carried out using trifluoromethylꢀsubꢀ
stituted heterocycles under conditions of multicompoꢀ
nent reactions of 1 with methyl pyruvate (2) and 1,3ꢀN,Nꢀ
or 1,3ꢀC,Nꢀbinucleophiles. The premise of present work
were the data obtained in detailed study of the cycloꢀ
condensations of methyl trifluoropyruvate related acyꢀ
limines with 1,3ꢀN,Nꢀ or 1,3ꢀC,Nꢀbinucleophiles, which
yielded fiveꢀmembered trifluoromethylꢀsubstituted heteꢀ
rocycles.4—9
methyl 2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)ꢀacetyliminoꢀ3,3,3ꢀtrifluꢀ
oropropionate (3), in an individual state applying the
known protocols for the related Nꢀsubstituted imines4
failed. Therefore, the imine 3 was generated in situ by
successive addition of pyridine, methyl trifluoropyruvate
(2) and thionylchloride to a solution of Piracetam (1) in
DMF (Scheme 1). The formation of imine 3 was conꢀ
firmed by the data from the 19F NMR spectra of the reacꢀ
tion mixture. The 19F NMR spectra exhibited the signals
of trifluoromethyl group in the range of δ 4.1 characterisꢀ
tic of methyl trifluoropyruvate related imines.7 In the reꢀ
actions under study, Nꢀsubstituted ureas 4a,b, 4ꢀ(pꢀtoꢀ
lylamino)pentꢀ3ꢀenꢀ2ꢀone (5), 6ꢀaminouracils 6a,b
and 6ꢀaminothiouracils 7a,b were used as 1,3ꢀbinucleoꢀ
philes. The reaction of imine 3 with 1,3ꢀbinucleophiles
4—7 were carried out in DMF at 90—100 °С for 2 h in the
presence of catalytic amounts of Et3N. The cycloconꢀ
densation of imine 3 with nucleophiles 4—7 yielded
the corresponding heterocyclic derivatives of Piracetam:
2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidazolidines 8a,b, 4ꢀtriꢀ
fluorometylꢀ4,5ꢀdihydroꢀ1Нꢀpyrrole 9, 2,4,6ꢀtrioxoꢀ
5ꢀtrifluorometylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrroloꢀ
[2,3ꢀd]pyrimidines 10a—d, 4,6ꢀdioxoꢀ2ꢀthioxoꢀ5ꢀtriꢀ
fluorometylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]ꢀ
pyrimidines 11a,b.
In summary, threeꢀcomponent reaction of Piracetam,
methyl trifluoropyruvate and 1,3ꢀC,Nꢀ or 1,3ꢀN,Nꢀbinuꢀ
cleophiles are convenient synthetic approach to a variety
of trifluoromethylꢀsubstituted heterocyclic derivatives of
* For Part 1, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 281—283, January, 2010.
1066ꢀ5285/10/5901ꢀ0288 © 2010 Springer Science+Business Media, Inc.

Fluorineꢀcontaining piracetams
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
289
Scheme 1
4, 8:
R = cyclоꢀC5H9 (a); PhCH2 (b)
6, 10: R = PhCH2 (a); PhCH2CH2 (b); 3,4ꢀ(MeO)2C6H3CH2CH2 (c);
7, 11: R = Ph (a); 3ꢀMeꢀC6H4 (b)
(d)
acetamide (1) and methyl trifluoropyruvate (2) were used as purꢀ
chased (Aldrich).
Piracetam and for the introduction of heterocyclic funcꢀ
tion at the amide nitrogen.
Nꢀ[1ꢀ(Cyclopentylimidazolidinꢀ4ꢀyl)ꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromꢀ
ethyl]ꢀ2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (8a). To solution of
2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (1) (0.01 mol, 1.42 g) in DMF
(20 mL) 1.56 г (0.01 mol) pyridine (0.01 mol, 1.56 g) and methyl
trifluoropyruvate 2 (0.01 mol, 1.56 g) were successively added
with stirring. The reaction mixture was stirred for 30 min, then
SOCl2 (0.01 mol, 1.19 g) was added. After 1 h of stirring the urea
4a (0.01 mol, 1.28 g) was added and stirring was continued for
1 h at room temperature. Then Et3N (0.1 g) was added and the
resulted mixture was heated at 90—100 °C for 2 h. The reaction
mixture was cooled to room temperature, poured into 10% aqueꢀ
ous NaCl, the precipitate formed was filtered off and recrystalꢀ
Experimental
The H and 19F NMR spectra were recorded on a Bruker
1
DPX 200 instrument at 200.13 MHz and 188.29 MHz relative
to tetramethylsilane (internal standard) and CF3COOH (exterꢀ
nal standard), respectively. Melting points were determined in
open capillaries. The starting 4ꢀ(pꢀtolylamino)pentꢀ3ꢀenꢀ2ꢀone
5 was synthesized in accordance with the known method,10 6ꢀ
aminouracils 7a,b and 8 were prepared by the known proceꢀ
dure.11 NꢀSubstituted ureas 9a,b, 2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)ꢀ

290
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Sokolov et al.
lized from 50% EtOH to give acetamide 8a in 73% yield (2.74 g),
m.p. 168—170 °С. 1Н NMR (DMSOꢀd6), δ: 1.47—1.71 (m, 2 H,
CH2); 1.75—2.18 (m, 8 H, CH2); 2.20—2.38 (m, 2 H, CH2);
3.42 (m, 2 H, CH2); 3.81 and 4.11 (both d, 2 H, CH2, J = 17.2 Hz);
4.33 (m, H, CH); 9.16 (s, 1 H, NH); 9.61 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: –0.84 s. Found (%): C, 47.69; H, 5.31;
N, 14.65. C15H19F3N4O4. Calculated (%): C, 47.87; H, 5.09;
N, 14.89.
Nꢀ(1ꢀBenzylꢀ2,5ꢀdioxoꢀ4ꢀtrifluoromethylimidazolidinꢀ4ꢀyl)ꢀ
2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (8b) was synthesized in acꢀ
cordance with the procedure above in a yield of 3.06 г (77%),
m.p. 208—210 °С. 1Н NMR (DMSOꢀd6), δ: 1.93—2.14 (m, 2 H,
CH2); 2.21—2.36 (m, 2 H, CH2); 3.45 (m, 2 H, CH2); 4.02
(ABꢀsystem, 2 H, CH2, J = 19.8 Hz); 4.64 (m, 2 Н, CH2);
7.29 (s, 5 Н, CHAr); 9.38 (s, 1 H, NH); 9.75 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: –0.59 s. Found (%): C, 51.07;
H, 4.52; N, 13.85. C17H17F3N4O4. Calculated (%): C, 51.26;
H, 4.30; N, 14.06.
Found (%): C, 51.39; H, 4.21; N, 13.16. C23H24F3N5O7. Calcuꢀ
lated (%): C, 51.21; H, 4.48; N, 12.98.
Nꢀ[1ꢀ(Furanꢀ2ꢀyl)methylꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]ꢀ2ꢀ(2ꢀ
oxopyrrolidinꢀ1ꢀyl)acetamide (10d) was synthesized by the genꢀ
eral procedure in a yield of 3.87 g (85%), m.p. 190—192 °С.
1Н NMR (DMSOꢀd6), δ: 1.86—2.09 (m, 2 H, CH2); 2.26 (t, 2 Н,
CH2, J = 7.1 Hz); 3.37 (m, 2 H, CH2); 3.97 (m, 2 H, CH2); 5.06
(ABꢀsystem, 2 H, CH2, J = 15.4 Hz); 6.39 (m, 2 H, CHAr); 7,52
(m, 1 H, CHAr); 9.73 (s, 1 H, NH); 11.11 (s, 1 H, NH); 12.17
(s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 3.93 s. Found (%):
C, 47.65; H, 3.33; N, 15.61. C18H16F3N5O6. Calculated (%):
C, 51.26; H, 4.30; N, 14.06.
Nꢀ(4,6ꢀDioxoꢀ1ꢀphenylꢀ2ꢀthioxoꢀ5ꢀtrifluoromethylꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl)ꢀ2ꢀ(2ꢀ
oxopyrrolidinꢀ1ꢀyl)acetamide (11a) was synthesized in accorꢀ
dance with the general procedure in a yield of 3.83 g (82%), m.p.
221—223 °С. 1Н NMR (DMSOꢀd6), δ: 1.87—2.09 (m, 2 H,
CH2); 2.25 (t, 2 Н, CH2, J = 7.4 Hz); 3.38 (m, 2 H, CH2); 3.97
(ABꢀsystem, 2 H, CH2, J = 16.6); 7.30 (m, 2 H, CHAr); 7.52
(m, 3 H, CHAr); 9.84 (s, 1 H, NH); 11.46 (s, 1 H, NH); 12.63
(s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 4.24 s. Found (%):
C, 48.61; H, 3.23; N, 15.17. C19H16F3N5O4S. Calculated (%):
C, 48.82; H, 3.45; N, 14.98.
Nꢀ[4ꢀAcetylꢀ5ꢀmethylꢀ1ꢀ(4ꢀmethylphenyl)ꢀ2ꢀoxoꢀ3ꢀtrifluoꢀ
romethylꢀ2,3ꢀdihydroꢀ1Нꢀpyrrolꢀ3ꢀyl]ꢀ2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀ
yl)acetamide (9) was synthesized by the procedure described for
8a in a yield of 3.54 g (81%), m.p. 182—184 °С. 1Н NMR
(DMSOꢀd6), δ: 1.97—2.16 (m, 2 H, CH2); 2.17—2.37 (m, 8 H,
CH2 + Me + Me); 2.45 (s, 3 H, Me); 3.47 (m, 2 H, CH2);
4.04 (ABꢀsystem, 2 H, CH2, J = 16.6 Hz); 7.16 (d, 2 Н, CHAr
,
Nꢀ(4,6ꢀDioxoꢀ1ꢀ(3ꢀmethylphenyl)ꢀ2ꢀthioxoꢀ5ꢀtrifluoromethꢀ
ylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]ꢀpyrimidinꢀ5ꢀyl)ꢀ2ꢀ
(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (11b) was synthesized by the
general procedure in a yield of 3.85 g (80%), m.p. 232—234 °С.
1Н NMR (DMSOꢀd6), δ: 1.91—2.16 (m, 2 H, CH2); 2.18—2.36
(m, 2 H, CH2); 2.47 (s, 3 H, Me); 3.42 (m, 2 H, CH2); 4.01
(ABꢀsystem, 2 H, CH2, J = 16.8 Hz); 7.09 (m, 2 H, CHAr);
7.24—7.51 (m, 2 H, CHAr); 9.82 (s, 1 H, NH); 11.34 (s, 1 H,
NH); 12.54 (s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 4.25 s.
Found (%): C, 50.12, H, 3.52; N, 14.71. C20H18F3N5O4S. Calꢀ
culated (%): C, 49.90; H, 3.77; N, 14.55.
J = 9.3 Hz); 7.33 (d, 2 Н, CHAr, J = 9.3 Hz); 9.89 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: 4.45 s. Found (%): C, 57.45;
H, 5.24; N, 9.83. C21H22F3N3O4. Calculated (%): C, 57.66;
H, 5.07; N, 9.61.
Nꢀ(1ꢀBenzylꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl)ꢀ2ꢀ(2ꢀoxopyrroliꢀ
dinꢀ1ꢀyl)acetamide (10a) was synthesized by the general proceꢀ
dure in a yield of 4.0 g (86%), m.p. 227—229 °С. 1Н NMR
(DMSOꢀd6), δ: 1.88—2.08 (m, 2 H, CH2); 2.24 (t, 2 Н, CH2,
J = 7.7 Hz); 2.91 (t, 2 Н, CH2, J = 6.7 Hz); 3.38 (m, 2 H, CH2);
3.96 (m, 2 H, CH2); 4.06 (m, 2 H, CH2); 7.12—7.35 (m, 5 H,
CHAr); 9.70 (s, 1 H, NH); 11.00 (s, 1 H, NH); 12.21 (s, 1 H,
NH). 19F NMR (DMSOꢀd6), δ: 4.23 s. Found (%): C, 51.81;
H, 4.11; N, 15.75. C20H18F3N5O5. Calculated (%): C, 51.62;
H, 3.90; N, 15.50.
Nꢀ(1ꢀPhenylethylꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluoromethylꢀ2,3,4,5,6,7ꢀ
hexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl)ꢀ2ꢀ(2ꢀoxopyrroliꢀ
dinꢀ1ꢀyl)acetamide (10b) was synthesized in accordance with
the general procedure in a yield of 4.07 g (85%), m.p. 233—235 °С.
1Н NMR (DMSOꢀd6), δ: 1.88—2.08 (m, 2 H, CH2); 2.24 (t, 2 Н,
CH2, J = 7.7 Hz); 2.91 (t, 2 Н, CH2, J = 6.7 Hz); 3.38 (m, 2 H,
CH2); 3,96 (m, 2 H, CH2); 4,06 (m, 2 H, CH2); 7.12—7.35 (m, 5 H,
CHAr); 9.70 (s, 1 H, NH); 11.00 (s, 1 H, NH); 12.21 (s, 1 H,
NH). 19F NMR (DMSOꢀd6), δ: 4.03 s. Found (%): C, 52.84;
H, 4.39; N, 14.38. C21H20F3N5O5. Calculated (%): C, 52.61;
H, 4.20; N, 14.61.
Nꢀ{1ꢀ[2ꢀ(3,4ꢀDimethoxyphenyl)ethyl]ꢀ2,4,6ꢀtrioxoꢀ5ꢀtrifluꢀ
oromethylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ
5ꢀyl)}ꢀ2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetamide (10c) was synthesized
by the general procedure in a yield of 4.26 g (79%), m.p.
231—233 °С. 1Н NMR (DMSOꢀd6), δ: 1.86—2.15 (m, 2 H,
CH2); 2.23 (t, 2 Н, CH2, J = 9.1 Hz); 2.81 (m, 2 H, CH2); 3.34
(m, 2 H, CH2); 3.75 (s, 6 H, MeO); 3.89—4.08 (m, 4 H, CH2);
6.67—6.82 (m, 3 H, CHAr); 9.72 (s, 1 H, NH); 10.99 (s, 1 H,
NH); 12.06 (s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 4.30 s.
This work was financially supported by Russian Acadꢀ
emy of Sciences (program «Medicinal and Biomedicinal
Chemistry» of the Department of Chemistry and Material
Sciences) and the Russian Foundation for Basic Research
(Project 08ꢀ04ꢀ12074).
References
1. V. B. Sokolov, A. Yu. Aksinenko, Izv. Akad. Nauk,
Ser. Khim., 2010, 193 [Russ. Chem. Bull., Int. Ed., 2010,
58, No. 1].
2. M. A. Mashkovsky, Lekarstvennye Sredstva [Pharmaceutiꢀ
cals], Meditsina, Moscow, 1994 (in Russian).
3. S. O. Bachurin, Meditsinskaya khimia napravlennogo poiska
preparatov dlya preduprezhdeniya neyroderenerativnykh zaꢀ
bolevaniy na primere bolezni Alzgeimera v sb. Neuroꢀdeꢀ
generativnye bolezni i starenie [Medicinal chemistry of direct
search of drugs for therapy and prevention of nuerodegeneraꢀ
tive diseases on the example of Alzheimer's disease, in Neuroꢀ
degenerative disease and aging], Moscow, 2001, 399 pp.
(in Russian).
4. S. N. Osipov, A. F. Kolomiets, A. V. Fokin, Usp. Khim.,
1992, 61, 1457 [Russ. Chem. Rev. (Engl. Transl.), 1992, 61].

Fluorineꢀcontaining piracetams
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
291
5. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Gorꢀ
eva, I. V. Martynov, Izv. Akad. Nauk, Ser. Khim., 2005, 462
[Russ. Chem. Bull., Int. Ed., 2005, 54, 472].
9. V. B. Sokolov, A. Yu. Aksinenko, I. V. Martynov, Izv. Akad.
Nauk, Ser. Khim., 2007, 2171 [Russ. Chem. Bull., Int. Ed.,
2007, 56, 2247].
6. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V.
Goreva, A. N. Pushin, I. V. Martynov, Izv. Akad. Nauk,
Ser. Khim., 2005, 1619 [Russ. Chem. Bull., Int. Ed., 2005,
54, 1667].
10. O. Edafiogho, C. N. Hinko, H. Chang, J. A. Moore, D. Mulꢀ
zac, J. M. Nicholson, K. R. Scott. J. Med. Chem. 1992,
35, 2798.
11. W. Hatzenlaub, W. Pfleiderer, Lieb. Ann. Chem. 1979, 1847.
7. Yu. Aksinenko, T. V. Goreva, T. A. Epishina, A. N. Pushin,
V. B. Sokolov, Izv. Akad. Nauk, Ser. Khim., 2006, 1014 [Russ.
Chem. Bull., Int. Ed., 2006, 55, 1052].
8. V. B. Sokolov, A. Yu. Aksinenko, Izv. Akad. Nauk,
Ser. Khim., 2007, 2176 [Russ. Chem. Bull., Int. Ed., 2007,
56, 2252].
Received December 18, 2008;
in revised form April 9, 2009