Fluorinated triazinones from hexafluoroacetone ethoxycarbonylimine

Article abstract of DOI:10.1023/B:RUCB.0000011874.67854.b1

The behavior of hexafluoroacetone ethoxycarbonylimine in cyclocondensation with different binucleophiles of the amidine type, viz., amino derivatives of N- and N,S-heterocycles, was studied. A preparative method for the synthesis of previously unknown annelated 2,2-bis(trifluoromethyl)-1,3,5-triazinones was developed.

Full text of DOI:10.1023/B:RUCB.0000011874.67854.b1

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2167—2170, October, 2003
2167
Fluorinated triazinones from hexafluoroacetone ethoxycarbonylimine
V. B. Sokolovꢀ and A. Yu. Aksinenko
Institute of Physiologically Active Substances, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 785 7024. Eꢀmail: alaks@ipac.ac.ru
The behavior of hexafluoroacetone ethoxycarbonylimine in cyclocondensation with differꢀ
ent binucleophiles of the amidine type, viz., amino derivatives of Nꢀ and N,Sꢀheterocycles,
was studied. A preparative method for the synthesis of previously unknown annelated
2,2ꢀbis(trifluoromethyl)ꢀ1,3,5ꢀtriazinones was developed.
Key words: ethoxycarbonylimine of hexafluoroacetone, 2ꢀaminopyridines, 2ꢀaminoꢀ
thiazolines, 2ꢀaminothiazoles, 2ꢀaminothiadiazoles, 2ꢀaminobenzothiazoles, substituted
annelated 2,2ꢀbis(trifluoromethyl)ꢀ1,3,5ꢀtriazinꢀ4(3H )ꢀones, cyclocondensation.
The synthesis of heterocyclic compounds containing
substituents with the fluorine atom is a promising direcꢀ
tion of the organofluorine chemistry, because the replaceꢀ
ment of the hydrogen atom in the heterocyclic system by
polyfluoroalkyl groups is known to exert a substantial efꢀ
fect on the physicochemical and biological properties of
the compounds.1 In this connection, we developed a
method for the syntheses of various fluorinated triazinones
from accessible hexafluoroacetone ethoxycarbonylimine
(1) and binucleophiles of the amidine type. The study was
prerequisited by the known published data on the cycloꢀ
condensation of binucleophiles of the amidine type
(2ꢀaminopyridines and 2ꢀaminothiadiazoles) with phenꢀ
oxycarbonyl isocyanate,2 chloroformyl isocyanate,3,4
and ethoxycarbonyl isothiocyanate5 affording triazinediꢀ
ones and thioxotriazinones and by the previously studꢀ
ied reaction of imine 1 with 2ꢀaminobenzothiazole
(xylene, 140 °C, TsOH, 6 h) to form fluorineꢀcontaining
fluorenone, whose structure was proved by Xꢀray diffracꢀ
tion analysis.6 Continuing this investigation, we studied
the transformation of imine 1 in cyclocondensation with
different heterocycles of the amidine type: substituted
2ꢀaminopyridines, 2ꢀaminothiazoline, 2ꢀaminothiadiꢀ
azole, substituted 2ꢀaminothiazoles, and 2ꢀaminobenzoꢀ
thiazoles. This allowed us to develop a convenient apꢀ
proach to the syntheses of previously unknown annelated
2,2ꢀbis(trifluoromethyl)ꢀ1,3,5ꢀtriazinꢀ4(H )ꢀones.
The transformations under study occur via the twoꢀ
step scheme: addition of the binucleophile to the C=N
bond of imine 1 followed by ring closure with elimination
of EtOH. In the case of 2ꢀaminoꢀ3ꢀmethylpyridine (2),
we isolated and identified the addition product, viz., corꢀ
responding aminal 3, which is transformed into triazinone
4a upon boiling in DMF under the acid catalysis condiꢀ
tions (TsOH).
The cyclocondensation of imine 1 with 2ꢀaminoꢀ
pyridines, 2ꢀaminothiazoline, 2ꢀaminothiadiazole, 2ꢀamiꢀ
nothiazole, and 2ꢀaminobenzothiazoles (equimolar
amounts of the reactants were mixed in DMF at 20 °C
and, after completion of the exothermic reaction, the mixꢀ
ture was refluxed for 1 h in the presence of catalytic
amounts of TsOH without isolation of intermediate addiꢀ
tion products) afforded pyridotriazinones 4b—h, tetraꢀ
hydrothiazolotriazinone 5, thiadiazolotriazinone 6, thiazoꢀ
lotriazinones 7a—d, and benzothiazolotriazinones 8a—d.
Triazinones 4—8 are solid crystalline substances obꢀ
tained in 60—80% yields, whose compositions and strucꢀ
tures were confirmed by elemental analysis and NMR
spectroscopic data. The signals of the NH proton at
10—11 ppm and signals of the geminal trifluoromethyl
1
groups at –1—–3 ppm are characteristic in the H and
19F NMR spectra.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2053—2055, October, 2003.
1066ꢀ5285/03/5210ꢀ2167 $25.00 © 2003 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Sokolov and Aksinenko
triazinones, whose accessibility is determined by the acꢀ
cessibility of the binucleophile, taking into account the
previously developed preparative method for the syntheꢀ
sis of hexafluoroacetone ethoxycarbonylimine.7
Experimental
1
H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in a
glass capillary. Hexafluoroacetone ethoxycarbonylimine was synꢀ
thesized according to a known procedure.7 The starting biꢀ
nucleophiles of the amidine type, viz., 2ꢀaminopyridine,
2ꢀaminoꢀ3ꢀmethylpyridine,
2ꢀaminoꢀ6ꢀmethylpyridine,
2ꢀaminoꢀ5ꢀmethylpyridine,
2ꢀaminoꢀ5ꢀbromopyridine,
2ꢀaminoꢀ5ꢀchloropyridine, 2ꢀaminoꢀ3ꢀchloroꢀ5ꢀtrifluoroꢀ
methylpyridine, 2ꢀaminoꢀ4,5ꢀdichloropyridine, 2ꢀaminoꢀ
thiazoline, 2ꢀaminoꢀ5ꢀmethylthiadiazole, 2ꢀaminothiazole,
2ꢀaminoꢀ5ꢀmethylthiazole, 2ꢀaminoꢀ4,5,6,7ꢀtetrahydrobenzoꢀ
thiazole, 2ꢀaminoꢀ5ꢀ(4ꢀnitrophenylsulfonylthiazole), 2ꢀaminoꢀ
6ꢀchlorobenzothiazole,
2ꢀaminoꢀ6ꢀethoxybenzothiazole,
2ꢀaminoꢀ6ꢀnitrobenzothiazole, and 2ꢀaminoꢀ6ꢀmethylsulfoꢀ
nylbenzothiazole (Aldrich), were used without purification.
Ethyl 1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀ(3ꢀmethylpyridinꢀ1ꢀyl)aminoꢀ
propꢀ2ꢀyl carbamate (3). 2ꢀAminoꢀ3ꢀmethylpyridine (2)
(0.01 mol) was added with stirring to a solution of imine 1
(0.01 mol) in benzene (20 mL). After completion of the exotherꢀ
mic reaction, benzene was evaporated, and the residue was reꢀ
crystallized from 50% EtOH. Aminal 3 (2.9 g) was obtained in
84% yield, m.p. 47—48 °C. Found (%): C, 41.62; H, 3.71;
N, 11.98. C12H13F6N3O2. Calculated (%): C, 41.75; H, 3.80;
1
N, 12.17. Н NMR (CDCl3), δ: 1.15 (t, 3 Н, СН3СН2, J =
7 Hz); 2.23 (s, Н, Me); 4.00 (q, 2 Н, СН2, J = 7 Hz); 5.88 (s,
1 Н, NH); 6.81 (t, 1 Н, J = 8 Hz); 7.45 (d, 1 Н, J = 8 Hz); 7.98
(d, 1 Н, J = 8 Hz); 9.3 (s, NH). 19F NMR (CDCl3), δ: 2.99 s.
9ꢀMethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydropyriꢀ
do[1,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (4а). A. A mixture of aminal
3 (0.01 mol) and TsOH (0.05 g) in DMF (5 mL) was refluxed for
1 h, and H2O (50 mL) was added to the mixture. A precipitate
formed was recrystallized from 50% EtOH, and compound 4a
(2.4 g) was obtained in 80.3% yield, m.p. 208—210 °C.
4: R = H (b), 7ꢀMe (c), 8ꢀMe (d), 7ꢀBr (e), 7ꢀCl (f),
9ꢀClꢀ7ꢀCF3 (g), 7,8ꢀCl2 (h)
7: R = H (a), 7ꢀMe (b), (CH2)4 (c),
(d)
8: R = 7ꢀCl (a), 7ꢀC2H5O (b), 7ꢀNO2 (c), 7ꢀMeSO2 (d)
B. Imine 1 (0.01 mol) was added to a solution of 2ꢀaminoꢀ3ꢀ
methylpyridine (2) (0.01 mol) in DMF (5 mL). After compleꢀ
tion of the exothermic reaction, TsOH (0.05 g) was added, the
reaction mixture was refluxed for 1 h, and H2O (50 mL) was
added. A precipitate formed was recrystallized from 50% EtOH.
Compound 4a was obtained in 73.5% yield (2.2 g), m.p.
208—210 °C.
4ꢀEthoxyꢀ9ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2Нꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazine (9). A mixture of aminal 3 (0.01 mol)
and PCl5 (0.01 mol) in benzene (50 mL) was refluxed until a
precipitate dissolved. Benzene and POCl3 were evaporated, and
the residue was recrystallized from hexane. Compound 9 was
obtained in 84% yield (2.9 g), m.p. 102—104 °C. Found (%):
C, 43.91; H, 3.21; N, 12.68. C12H13F6N3O2. Calculated (%):
C, 44.05; Н, 3.39; N, 12.84. 1Н NMR (CDCl3), δ: 1.40 (t, 3 Н,
СН3СН2, J = 7 Hz); 2.00 (s, Н, Me); 4.45 (q, 2 Н, СН2, J =
7 Hz); 6.10 (t, 1 Н, J = 8 Hz); 7.45 (d, 1 Н, J = 8 Hz); 7.05 (d,
1 Н, J = 8 Hz). 19F NMR (CDCl3), δ: –2.52 s.
It should be noted that the cyclocondensation step in
the transformations under study occurs through EtOH
elimination and, moreover, can be accompanied by deꢀ
hydration under certain conditions. For example, boiling
of aminal 3 in benzene with an equimolar amount of PCl5
gives pyridotriazine 9 in 84% yield.
Thus, the transformations of hexafluoroacetone
ethoxycarbonylimine in cyclocondensation with binucleoꢀ
philes of the amidine type provide various fluorinated
2,2ꢀBis(trifluoromethyl)ꢀ2,3ꢀdihydropyrido[1,2ꢀа][1,3,5]triꢀ
azinꢀ4(3H )ꢀone (4b), 7ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀ

Fluorinated triazinones
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2169
Table 1. Characteristics of compounds 4a—h, 5, 6, 7a—d, and 8a—d
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
(%)
N
(%)
N
C
H
C
H
4a
4b
4c
4d
4e
4f
73.5 208—210 40.33 2.51 14.24 С 1 0 Н 7 F 6 N 3 O
40.15 2.36 14.05
69 151—153 38.09 1.95 14.56 C 9 H 5 F 6 N 3 O
37.91 1.77 14.74
71 189—190 39.98 2.53 14.22 C 1 0 H 7 F 6 N 3 O
40.15 2.36 14.05
76 208—209 40.32 2.18 13.87 C 1 0 H 7 F 6 N 3 O
40.15 2.36 14.05
68 183—185 29.50 1.28 11.37 C9H4BrF6N3O
29.69 1.11 11.54
81 196—198 33.64 1.09 12.96 C9H4ClF6N3O
33.82 1.26 13.15
63 187—188 30.89 0.90 10.59 C7H9ClF9NO3
30.99 0.78 10.84
78 1889—191 30.72 1.03 11.59 C9H3Cl2F6N3O
30.53 0.85 11.87
6
77 186—188 27.39 1.47 18.48 C7 H4F6N4 OS
27.46 1.32 18.30
61 144—145 29.04 1.22 14.54 C7 H3F6N3 OS
28.87 1.04 14.43
70 150—151 31.60 1.53 13.58 C8 H5F6N3 OS
31.48 1.65 13.77
66 151—153 38.44 2.81 12.31 C 8 H 1 2 F 3 N O 3
38.27 2.63 12.17
64 285—287 32.89 1.09 11.59 C7H9ClF3NO3
32.78 1.27 11.76
78 232—234 35.33 1.21 11.34 C12H12F3NO3
35.17 1.07 11.19
71 221—223 40.39 2.52 11.10 C7H11F3N2O3
40.53 2.35 10.91
69 277—279 34.39 0.91 14.68 C8H11F3N2O4
34.21 1.04 14.51
7a
7b
7c
7d
8a
8b
8c
8d
4g
4h
5
71.4 181—182 28.49 1.53 14.15 C7H5 F6N3OS
28.68 1.72 14.33
79 281—283 34.21 1.49 9.85 C8H11F3N2O4
34.37 1.68 10.02
dihydropyrido[1,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (4c), 8ꢀmethylꢀ
2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydropyrido[1,2ꢀа][1,3,5]triꢀ
azinꢀ4(3H )ꢀone (4d), 7ꢀbromoꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdiꢀ
hydropyrido[1,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (4e), 7ꢀchloroꢀ2,2ꢀ
bis(trifluoromethyl)ꢀ2,3ꢀdihydropyrido[1,2ꢀа][1,3,5]triazinꢀ
4(3H )ꢀone (4f), 9ꢀchloroꢀ2,2,7ꢀtris(trifluoromethyl)ꢀ2,3ꢀdiꢀ
hydropyrido[1,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (4g), 7,8ꢀdichloroꢀ
2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydropyrido[1,2ꢀа][1,3,5]triazinꢀ
4(3H )ꢀone (4h), 2,2ꢀbis(trifluoromethyl)ꢀ2,3,6,7ꢀtetraꢀ
hydrothiazolo[3,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (5), 2ꢀmethylꢀ
7,7ꢀbis(trifluoromethyl)ꢀ6,7ꢀdihydro[1,3,4]thiadiazoꢀ
lo[3,2ꢀа][1,3,5]triazinꢀ5(6H )ꢀone (6), 2,2ꢀbis(trifluoromethyl)ꢀ
2,3ꢀdihydrothiazolo[3,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone
(7a),
7ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydrothiazoꢀ
lo[3,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀone (7b), 2,2ꢀbis(trifluoromethyl)ꢀ
2,3,5,6,7,8,9ꢀhexahydrobenzo[ f ]thiazolo[3,2ꢀa][1,3,5]triazinꢀ
Table 2. Spectroscopic characteristics of compounds 4a—h, 5, 6, 7a—d, and 8a—d (DMSOꢀd6)
Comꢀ
pound
1Н NMR
19F NMR
δ
δ (s)
4a
4b
4c
4d
4e
4f
2.40 (s, 3 Н, Me); 7.15—7.25 (m, 2 Н); 7.46 (d, 1 Н, J = 8); 10.25 (s, 1 Н, NH)
6.10 (m, 1 Н); 6.52 (d, 1 Н, J = 8); 7.10 (m, 1 Н); 7.80 (d, 1 Н, J = 8); 10.15 (s, 1 Н, NH)
2.02 (s, 3 Н, Me); 6.52, 7.10 (both d, 1 H each, J = 8); 7.63 (s, 1 H); 10.14 (s, 1 Н, NH)
2.20 (s, 3 Н, Me); 6.02 (d, 1 Н, J = 8); 6.40, 7.82 (both d, 1 H each, J = 8); 10.10 (s, 1 Н, NH)
6.22, 6.90 (both d, 1 H each, J = 8); 7.70 (s, 1 Н); 10.25 (s, 1 Н, NH)
–1.27
–2.37
–2.41
–2.01
–3.75
–3.05
6.66, 7.27 (both d, 1 H each, J = 8); 7.90 (s, 1 Н); 10.48 (s, 1 Н, NH)
4g
7.90 (s, 1 Н); 8.25 (s, 1 H); 10.90 (s, 1 Н, NH)
13.89 (3 F);
–1.90 (6 F)
–1.66
4h
5
7.49, 7.92 (both s, 1 H each); 10.66 (s, 1 Н, NH)
3.37, 4.10 (both t, 2 H each, J = 7); 9.42 (s, 1 Н, NH)
–1.74
6
2.45 (s, 3 Н); 10.10 (s, 1 Н, NH)
–1.82
7a
7b
7c
7d
8a
8b
6.62, 7.25 (both d, 1 H each, J = 8); 10.20 (s, 1 Н, NH)
2.20 (s, 3 Н); 6.95 (s, 1 Н); 9.92 (s, 1 Н, NH)
–2.01
–2.04
–1.55
–1.95
–1.28
–1.38
1.81 (br.s, 4 Н); 2.34, 2.80 (both m, 2 H each); 9.72 (s, 1 Н, NH)
8.20, 8.35 (both d, 2 H each, J = 8); 8.45 (d, 2 Н, J = 8); 10.70 (s, 1 Н, NH)
7.35 (d, 1 Н); 7.72 (s, 1 Н); 8.15 (d, 1 Н, J = 8); 10.38 (s, 1 Н, NH)
1.40 (t, 3 Н, Me, J = 7); 4.02 (q, 2 Н, СН2О, J = 7); 6.80, 7.14 (both d, 1 H each, J = 8);
8.06 (s, 1 Н); 10.10 (s, 1 Н, NH)
8c
8d
8.20, 8.40 (both d, 1 H each, J = 8); 8.68 (s, 1 Н); 10.55 (s, 1 Н, NH)
3.20 (s, 3 Н, Me); 7.92, 8.32 (both d, 1 H each, J = 8); 8.40, 10.53 (both s, 1 H each, NH)
–1.12
–1.56

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Sokolov and Aksinenko
4(3H )ꢀone (7c), 7ꢀ(4ꢀnitrophenylsulfonyl)ꢀ2,2ꢀbis(trifluoroꢀ
methyl)ꢀ2,3ꢀdihydrothiazolo[3,2ꢀа][1,3,5]triazinꢀ4(3H )ꢀ
one (7d), 8ꢀchloroꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydrobenꢀ
zo[ f ]thiazolo[3,2ꢀa][1,3,5]triazinꢀ4(3H )ꢀone (8a), 8ꢀethꢀ
oxyꢀ2,2ꢀbis(trifluoromethyl)ꢀ2,3ꢀdihydrobenzo[ f ]thiazoꢀ
lo[3,2ꢀa][1,3,5]triazinꢀ4(3H )ꢀone (8b), 2,2ꢀbis(trifluoromethyl)ꢀ
8ꢀnitroꢀ2,3ꢀdihydrobenzo[ f ]thiazolo[3,2ꢀa][1,3,5]triazinꢀ
4(3H )ꢀone (8c), and 8ꢀmethylsulfonylꢀ2,2ꢀbis(trifluoromethyl)ꢀ
2,3ꢀdihydrobenzo[ f ]thiazolo[3,2ꢀa][1,3,5]triazinꢀ4(3H )ꢀone
(8d) were synthesized similarly to triazinone 4а from imine 1
(0.1 mol) and the corresponding amidine (0.1 mol). The yields,
melting points, and spectroscopic characteristics of compounds
4a—h, 5, 6, 7a—d, and 8a—d are presented in Tables 1 and 2.
pounds: Synthesis and Application], Nauka, Novosibirsk, 2001
(in Russian).
2. M. M. ElꢀKerdawy, S. M. Bayomi, I. A. Shehata, and R. A.
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3. A. Kamal and P. B. Sattur, Synthesis, 1985, 892.
4. N. J. Leonard and S. Kumar, J. Org. Chem., 1988, 53, 3959.
5. B. Stanovnik and M. Tišler, Synthesis, 1972, 308.
6. A. N. Chekhlov, O. V. Korenchenko, A. Yu. Aksinenko, V. B.
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sintez i primenenie [Fluorineꢀcontaining Heterocyclic Comꢀ
Received June 10, 2003;
in revised form July 23, 2003