Modification of biologically active amides and amines with fluorine-containing heterocycles 4. Trifluoromethyl-containing heterocyclic pyracetam derivatives

Article abstract of DOI:10.1007/s11172-010-0176-2

A one-pot method for the synthesis of trifluoromethyl-containing heterocyclic pyracetam derivatives has been suggested by the reaction of pyracetam, hexafluoroacetone, and 1,3-binucleophiles, viz., 3- aminocrotononitrile, 6-aminouracyls, 6-aminothiouracyl, N-benzyl-3- aminocyclohexenone, and 2-aminothiazoline.

Full text of DOI:10.1007/s11172-010-0176-2

Russian Chemical Bulletin, International Edition, Vol. 59, No. 4, pp. 864—866, April, 2010
864
Modification of biologically active amides and amines
with fluorineꢀcontaining heterocycles
4.* Trifluoromethylꢀcontaining heterocyclic pyracetam derivatives
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, and T. V. Goreva
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation
Fax: +7 (496) 524 9508. Eꢀmail:alaks@ipac.ac.ru
A oneꢀpot method for the synthesis of trifluoromethylꢀcontaining heterocyclic pyraceꢀ
tam derivatives has been suggested by the reaction of pyracetam, hexafluoroacetone, and
1,3ꢀbinucleophiles, viz., 3ꢀaminocrotononitrile, 6ꢀaminouracyls, 6ꢀaminothiouracyl, Nꢀbenꢀ
zylꢀ3ꢀaminocyclohexenone, and 2ꢀaminothiazoline.
Key words: pyracetam, hexafluoroacetone, 3ꢀaminocrotononitrile, 6ꢀaminouracyls, 6ꢀamiꢀ
noꢀ1ꢀphenylthiouracyl, Nꢀbenzylꢀ3ꢀaminocyclohexenone, 2ꢀaminothiazoline, fluorineꢀconꢀ
taining compounds, 1,4ꢀdihydropyrimidine, dihydropyrimido[4,5ꢀd]pyrimidines, tetrahydroꢀ
1Hꢀquinazoline, thiazolo[3,2ꢀa][1,3,5]triazine, cyclocondensation.
Pyracetam is a nootropic drug of metabolite action
chloride to a solution of compound 1 in DMF with subseꢀ
and is widely used for treatment of various diseases of the
nervous system.1 A distinguishing feature of the pyraceꢀ
tam structure, as well as of other cyclic derivatives of
γꢀaminobutyric acid (oxyracetam, anyracetam, phenonꢀ
tropyl, etc.), is the presence of the 2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀ
yl)acetamide fragment on the molecule. It should be
noted that the last generation of nootrops is representꢀ
ed by different versions of the basic structure (pyracetam)
modifications by introduction of various substituents
onto the 2ꢀoxopyrrolidinꢀ1ꢀyl fragment and the amide
nitrogen atom.2 The purpose of our study was modiꢀ
fication of pyracetam (2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetꢀ
amide (1)) by incorporation of its structural fragment
into a fluorineꢀcontaining heterocyclic system. The preꢀ
sent work was prompted by the data obtained during the
study of behavior of hexafluoroacetone Nꢀacylimines (2)
in the cyclocondensation reactions with 1,3ꢀN,Nꢀ
and 1,3ꢀC,Nꢀbinucleophiles, which lead to the formaꢀ
tion of sixꢀmembered trifluoromethylꢀcontaining heteroꢀ
cycles.3—5
quent involvement of imine 3, without isolation in the
individual state, into the cyclocondensation with 1,3ꢀC,Nꢀ
and N,Nꢀbinucleophiles (Scheme 1). The formation of
imine 3 was confirmed by the 19F NMR spectra of the
reaction mixtures, which exhibited a signal for the trifluoꢀ
romethyl group in the region δ 4.1 characteristic of the
hexafluoroacetone imines6, as well as by subsequent chemꢀ
ical transformations.
Such 1,3ꢀbinucleophiles as 3ꢀaminocrotononitrile 4,
6ꢀaminouracyls 6a—c, 6ꢀaminoꢀ1ꢀphenylthiouracyl 8,
Nꢀbenzylꢀ3ꢀaminocyclohexenone 10, and 2ꢀaminothiaꢀ
zoline 12 were used in the cyclocondensation with imine
3. The reaction of imine 3 with 1,3ꢀbinucleophiles was
performed upon heating a mixture of reagents in DMF at
90—100 °C for 2 h in the presence of Et3N in catalytic
amount. Cyclocondensation of imine 3 with compounds
4, 6a—c, 8, 10, and 12 leads to the corresponding heteroꢀ
cyclic pyracetam derivatives 5, 7a—c, 9, 11, and 13 in
70—76% yields.
Their structures were confirmed by the NMR spectroꢀ
scopic and elemental analysis data. The 19F NMR spectra
of compounds 5, 7a—c, 9, and 11 exhibit characteristic
singlet signals for the trifluoromethyl group in the region
δ 2—6, for 13 at δ 1.14.
In conclusion, a oneꢀpot method for the synthesis
of trifluoromethylꢀcontaining sixꢀmembered heterocyꢀ
clic pyracetam derivatives suggested by us and consistꢀ
ing in the reaction of pyracetam, hexafluoroacetone, and
1,3ꢀbinucleophiles, allows one to accomplish modifiꢀ
cation of this nootropic drug by incorporation of its strucꢀ
We failed to obtain the starting bielectrophilic reagent,
hexafluoroacetone 2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀyl)acetylimine
(3), in the individual state using known3 methods for the
synthesis of hexafluoroacetone Nꢀsubstituted imines.
Therefore, imine 3 was generated in situ by sequential
addition of pyridine, hexafluoroacetone 2, and thionyl
* For Part 3, see V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishiꢀ
na, T. V. Goreva, I. V. Martynov, Izv. Akad. Nauk, Ser. Khim.,
2010, 281 [Russ. Chem. Bull., Int. Ed., 2010, 59, 288].
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 845—847, April, 2010.
1066ꢀ5285/10/5904ꢀ0864 © 2010 Springer Science+Business Media, Inc.

Fluoroꢀcontaining pyracetams
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 4, April, 2010
865
Scheme 1
Experimental
1
H and 19F NMR spectra were recorded on a Bruker DPX
200 spectrometer (200.13 and 188.29 MHz, respectively) relaꢀ
tive to Me4Si (internal standard) and CF3COOH (external stanꢀ
dard), respectively. Melting points were determined in a glass
capillary tube. The starting 6ꢀaminouracyls 6a—c and 8,7
Nꢀbenzylꢀ3ꢀaminocyclohexenone 10 (see Ref. 8) were obtained
according to the procedures described earlier. 2ꢀ(2ꢀOxopyrrolidinꢀ
1ꢀyl)acetamide 1, hexafluoroacetone 2, 2ꢀaminocrotononitrile
4, and 2ꢀaminothiazoline 12 (Aldrich) were used as purchased.
6ꢀMethylꢀ2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀylmethyl)ꢀ4,4ꢀbis(trifluoroꢀ
methyl)ꢀ1,4ꢀdihydropyrimidineꢀ5ꢀcarbonitrile (5). Pyridine (1.56 g,
0.01 mol) was added to a solution of compound 1 (1.42 g,
0.01 mol) in DMF (20 mL) with stirring, followed by bubbling
hexafluoroacetone 2 (1.66 g, 0.01 mol), then the following reꢀ
agents were sequentially added: after stirring for 30 min, SOCl2
(1.19 g, 0.01 mol); after stirring for 1 h, nitrile 4 (0.82 g, 0.01 mol);
after stirring for 1 h at 20 °C, Et3N (0.1 g). The reaction mixture
was heated for 2 h at 90—100 °C and cooled, poured into 10%
aqueous sodium chloride (50 mL), a precipitate formed was filꢀ
tered off and recrystallized from 50% aq. EtOH. The yield was
2.7 g (76%). M.p. 168—170 °C. Found (%): C, 44.27; H, 3.22;
N, 25.59. C13H12F6N4O. Calculated (%): C, 44.08; H, 3.41;
1
N, 25.82. H NMR, δ: 2.00 (m, 2 H, CH2); 2.19 (s, 3 H, Me);
2.29 (t, 2 H, CH2, J = 8.3 Hz); 3.39 (t, 2 H, CH2, J = 6.7 Hz);
4.05 (s, 2 H, CH2); 10.98 (s, 1 H, NH). 19F NMR, δ: 2.49 (s).
7ꢀ(2ꢀOxopyrrolidinꢀ1ꢀylmethyl)ꢀ1ꢀphenylꢀ5,5ꢀbis(trifluoroꢀ
methyl)ꢀ5,8ꢀdihydroꢀ1Hꢀpyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdione
(7a) was obtained similarly to compound 5. The yield was 3.5 g
(74%). M.p. 261—262 °C. Found (%): C, 48.25; H, 3.37;
N, 14.94. C19H15F6N5O3. Calculated (%): C, 48.01; H, 3.18;
1
N, 14.73. H NMR, δ: 1.63 (m, 2 H, CH2); 1.89 (t, 2 H, CH2,
J = 8.3 Hz); 3.04 (t, 2 H, CH2, J = 6.7 Hz); 4.13 (s, 2 H, CH2);
7.31 (d, 2 H, CHAr, J = 6.7 Hz); 7.57 (m, 3 H, CHAr, J = 7.1 Hz);
10.07, 11.46 (both s, 1 H, NH). 19F NMR, δ: 4.73 (s).
1ꢀBenzylꢀ7ꢀ(2ꢀoxopyrrolidinꢀ1ꢀylmethyl)ꢀ5,5ꢀbis(trifluoꢀ
romethyl)ꢀ5,8ꢀdihydroꢀ1Hꢀpyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdione
(7b) was obtained similarly to compound 5. The yield was 3.4 g
(70%). M.p. 204—206 °C. Found (%): C, 49.31; H, 3.68;
N, 14.49. C20H17F6N5O3. Calculated (%): C, 49.09; H, 3.50;
1
N, 14.31. H NMR, δ: 1.83 (m, 2 H, CH2); 2.16 (t, 2 H, CH2,
J = 8.3 Hz); 3.28 (t, 2 H, CH2, J = 6.7 Hz); 4.33, 5.29 (both s, 2 H,
CH2); 7.28 (d, 2 H, CHAr, J = 6.7 Hz); 7.40 (t, 3 H, CHAr
,
J = 6.7 Hz); 10.37, 11.55 (both s, 2 H, NH). 19F NMR, δ: 4.99 (s).
7ꢀ(2ꢀOxopyrrolidinꢀ1ꢀylmethyl)ꢀ1ꢀphenethylꢀ5,5ꢀbis(trifluoꢀ
romethyl)ꢀ5,8ꢀdihydroꢀ1Hꢀpyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdione
(7c) was obtained similarly to compound 5. The yield was 3.4 g
(70%). M.p. 238—240 °C. Found (%): C, 50.29; H, 3.62; N, 13.63.
C21H19F6N5O3. Calculated (%): C, 50.11; H, 3.80; N, 13.91.
1H NMR, δ: 1.96 (m, 2 H, CH2); 2.23 (t, 2 H, CH2, J = 7.2 Hz);
2.88 (t, 2 H, CH2, J = 8.0 Hz); 3.48 (t, 2 H, CH2, J = 7.2 Hz);
4.21 (t, 2 H, CH2, J = 7.2 Hz); 4.29 (s, 2 H, CH2); 7.26 (m, 5 H,
CHAr); 10.04, 11.22 (both s, 1 H, NH). 19F NMR, δ: 4.42 (s).
7ꢀ(2ꢀOxopyrrolidinꢀ1ꢀylmethyl)ꢀ1ꢀphenylꢀ2ꢀthioxoꢀ5,5ꢀbisꢀ
(trifluoromethyl)ꢀ2,3,5,8ꢀtetrahydroꢀ1Hꢀpyrimido[4,5ꢀd]pyriꢀ
midinꢀ4ꢀone (9) was obtained similarly to compound 5. The yield
was 3.7 g (75%). M.p. 271—273 °C. Found (%): C, 46.63; H, 3.22;
N, 14.01. C19H15F6N5O2S. Calculated (%): C, 46.44; H, 3.08;
6, 7: R = Ph (a), PhCH2 (b), PhCH2CH2 (c)
1
tural fragment into the trifluoromethylꢀcontaining hetꢀ
erocyclic system.
N, 14.25. H NMR, δ: 1.45 (m, 2 H, CH2); 1.74 (t, 2 H, CH2,
J = 8.3 Hz); 2.78 (t, 2 H, CH2, J = 6.7 Hz); 4.04 (s, 2 H, CH2);

866
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 4, April, 2010
Sokolov et al.
7.13 (d, 2 H, CHAr, J =6.7 Hz); 7.44 (m, 3 H, CHAr, J = 7.5 Hz);
10.31, 12.75 (both s, 1 H, NH). 19F NMR, δ: 5.25 (s).
2. S. O. Bachurin, in Neirodegenerativnye bolezni i starenie
[Neurodegenerative Diseases and Aging], Eds I. A. Zavalishin,
N. N. Yakhno, S. I. Gavrilov, El´f IPR, Moscow, 2001, p. 399
(in Russian).
1ꢀBenzylꢀ7,7ꢀdimethylꢀ2ꢀ(2ꢀoxopyrrolidinꢀ1ꢀylmethyl)ꢀ4,4ꢀ
bis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1Hꢀquinazolinꢀ5ꢀone
(11) was obtained similarly to compound 5. The yield was 3.9 g
(74%). M.p. 235—237 °C. Found (%): C, 57.52; H, 4.81; N, 8.19.
C24H25F6N3O2. Calculated (%): C, 57.28; H, 5.03; N, 8.38.
1H NMR, δ: 0.98 (s, 6 H, Me); 1.78 (m, 2 H, CH2); 2.03 (t, 2 H,
CH2, J = 7.2 Hz); 2.26, 2.52 (both s, 2 H, CH2); 3.31 (t, 2 H,
CH2, J = 6.7 Hz); 4.25, 5.05 (both s, 2 H, CH2); 7.13 (d, 2 H,
CHAr, J = 7.7 Hz); 7.37 (m, 3 H, CHAr). 19F NMR, δ: 6.21 (s).
1ꢀ{2,2ꢀBis(trifluoromethyl)ꢀ6,7ꢀdihydroꢀ2Hꢀthiazolo[3,2ꢀa]ꢀ
[1,3,5]triazinꢀ4ꢀylmethyl}pyrrolidinꢀ2ꢀone (13) was obtained simiꢀ
larly to compound 5. The yield was 2.6 g (70%). M.p. 208—210 °C.
Found (%): C, 38.32; H, 3.44; N, 15.16. C12H12F6N4OS. Calcuꢀ
lated (%): C, 38.51; H, 3.23; N, 14.97. 1H NMR, δ: 2.06 (m, 2 H,
CH2); 2.32 (t, 2 H, CH2, J = 8.3 Hz); 3.34 (t, 2 H, CH2, J = 7.0 Hz);
3.43 (t, 2 H, CH2, J = 7.0 Hz); 4.17 (t, 2 H, CH2, J = 6.5 Hz);
4.25 (s, 2 H, CH2). 19F NMR, δ: –1.14 (s).
3. S. N. Osipov, A. F. Kolomiets, A. V. Fokin, Usp. Khim., 1992,
61, 1457 [Russ. Chem. Rev. (Engl. Transl.), 1992, 61].
4. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreꢀ
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2005, 1619 [Russ. Chem. Bull., Int. Ed., 2005, 54, 1667].
5. V. B. Sokolov, A. Yu. Aksinenko, Izv. Akad. Nauk, Ser. Khim.,
2006, 706 [Russ. Chem. Bull., Int. Ed., 2006, 55, 731].
6. O. V. Korenchenko, A. Yu. Aksinenko, V. B. Sokolov, A. N.
Pushin, I. V. Martynov, Izv. Akad. Nauk, Ser. Khim., 1995,
1809 [Russ. Chem. Bull. (Engl. Transl.), 1995, 44, 1740].
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8. O. Edafiogho, C. N. Hinko, H. Chang, J. A. Moore, D. Mulꢀ
zac, J. M. Nicholson, K. R. Scott, J. Med. Chem., 1992,
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Received July 29, 2009;
itsina, Moscow, 1994, Part 1, p. 132 (in Russian).
in revised form December 24, 2009