Acylimines of hexafluoroacetone and methyl trifluoropyruvate in cyclocondensation with 2-aminopyridines

Article abstract of DOI:10.1007/s11172-005-0438-6

Cyclocondensation of acylimines of hexafluoroacetone and methyl trifluoropyruvate with 2-aminopyridines afforded earlier unknown fluoro-containing 2H-pyrido[1,2-a][1,3,5]triazines.

Full text of DOI:10.1007/s11172-005-0438-6

1514
Russian Chemical Bulletin, International Edition, Vol. 54, No. 6, pp. 1514—1517, June, 2005
Acylimines of hexafluoroacetone and methyl trifluoropyruvate
in cyclocondensation with 2ꢀaminopyridines
V. B. Sokolovꢀ and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 785 7024. Eꢀmail: alaks@ipac.ac.ru
Cyclocondensation of acylimines of hexafluoroacetone and methyl trifluoropyruvate with
2ꢀaminopyridines afforded earlier unknown fluoroꢀcontaining 2Hꢀpyrido[1,2ꢀa][1,3,5]triazines.
Key words: acylimines, hexafluoroacetone, methyl trifluoropyruvate, 2ꢀaminopyridines,
2Hꢀpyrido[1,2ꢀa][1,3,5]triazines, heterocyclization, organofluorine compounds.
Scheme 1
It is known that acylimines of hexafluoroacetone
(HFA) and methyl trifluoropyruvate (MTFP) in cycloꢀ
condensation with bisnucleophiles act as 1,3ꢀ and 1,2ꢀbisꢀ
electrophilic reagents1,2 and serve as promising starting
material for the synthesis of various fluoroꢀcontaining
heterocycles. For instance, dehydration of adducts of HFA
perfluoroacylimines and perfluorocarboxamides with
oleum gives 1,3,5ꢀoxadiazines;3 reactions of HFA and
MTFP benzoylimines with 6ꢀaminouracil give4 pyrimidoꢀ
and pyrrolopyrimidines, respectively; dehydration of the
adduct of HFA ethoxycarbonylimine and 2ꢀaminopyrimiꢀ
dine with PCl5 gives pyridotriazine.5 In the present work,
we studied the cyclocondensation of HFA and MTFP
acylimines with 2ꢀaminopyridines, which yields earlier
unknown fluoroꢀcontaining 2Hꢀpyrido[1,2ꢀa][1,3,5]triꢀ
azines. The compounds obtained can be regarded as poꢀ
tential biologically active substances. Pyridotriazines are
known to exhibit high fungicidal,6 antimitotic,7 and cytoꢀ
static activities.8,9
The transformations studied follow a twoꢀstep scheme:
(1) addition of 2ꢀaminopyridine to the C=N bond of
imines 1 and 2 to give adducts 4 and 5 and (2) dehydꢀ
ration of adducts 4 and 5 with PCl5 to 2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazines 6 and 7. In the case of 2ꢀaminoꢀ
4ꢀmethylpyridine (3a), intermediate adducts 4a and 5a
(Scheme 1) were isolated in the individual state and charꢀ
acterized.
The cyclocondensation of 2ꢀaminopyridines 3b—f
with acylimines of HFA (1b—f) and MTFP (2b—e)
(equimolar amounts of the reagents were mixed in benꢀ
zene at 20 °C; after the exothermic reaction was comꢀ
pleted, PCl5 was added and the reaction mixture was
refluxed until the precipitate dissolved; intermediate adꢀ
ducts were not isolated) afforded 2,2ꢀbis(trifluoromethyl)ꢀ
2Hꢀpyrido[1,2ꢀa][1,3,5]triazines 6b—h and methyl 2ꢀtriꢀ
fluoromethylꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxyꢀ
lates 7b—f in 55 to 74% yields (Scheme 2).
Х = CF3 (1a, 4a, 6a); C(O)OMe (2a, 5a, 7a)
Pyridotriazines 6a—h and 7a—f are crystalline solids;
their compositions and structures were proved by elemenꢀ
tal analysis, NMR spectroscopy, and chemical transforꢀ
mations. Their 19F NMR spectra show characteristic sigꢀ
nals at δ –1.0 to 1.0 for geminal trifluoromethyl groups
(6a—h) and a trifluoromethyl group (7a—f).
The reaction of ester 7a with hydrazine hydrate in
MeOH gave 2Hꢀpyrido[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboꢀ
hydrazide 8 (Scheme 3).
Thus, the annelation of substituted 2ꢀaminopyridiꢀ
nes with HFA and MTFP acylimines proceeds via the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1470—1473, June, 2005.
1066ꢀ5285/05/5406ꢀ1514 © 2005 Springer Science+Business Media, Inc.

Fluoroꢀcontaining triazines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
1515
Scheme 2
Scheme 3
cyclocondensation mechanism to yield 2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazine derivatives. The compounds obꢀ
tained are promising from the viewpoint of medicinal and
combinatorial chemistry.
X = CF3 (1b—f, 6b—h); C(O)OMe (2b—e, 7b—f)
1: R = Me (b), 3ꢀMeC6H4 (c), 4ꢀFC6H4 (d),
2ꢀFC6H4 (e), 4ꢀClC6H4 (f)
Experimental
2: R = 4ꢀMeC6H4 (b), 4ꢀFC6H4 (c), 3ꢀFC6H4 (d), 2ꢀfuryl (e)
3: R´ = H (b), 3ꢀMe (c), 5ꢀMe (d), 5ꢀCl (e), 3,5ꢀCl2 (f)
6: R = Me, R´ = 7,8ꢀCl2 (b), R = 2ꢀMeC6H4, R´ = H (c);
R = 2ꢀMeC6H4, R´ = 7ꢀCl (d); R = 4ꢀFC6H4, R´ = 9ꢀMe (e);
R = 2ꢀFC6H4, R´ = 7ꢀMe (f); R = 4ꢀClC6H4, R´ = 7,9ꢀCl2 (g);
R = 4ꢀMeOC6H4, R´ = 7ꢀMe (h)
7: R = 4ꢀMeC6H4, R´ = 8ꢀMe (b); R = 4ꢀFC6H4, R´ = 9ꢀMe (c);
R = 4ꢀFC6H4, R´ = 8ꢀMe (d); R = 3ꢀFC6H4, R´ = 9ꢀMe (e);
R = 2ꢀfuryl, R´ = H (f)
1
H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in a
glass capillary. Acylimines of HFA 1a—f and MTFP 2a—e were
prepared according to known procedures.10,11 The starting subꢀ
stituted 2ꢀaminopyridines 3a—f (Aldrich Co.) were used as purꢀ
chased.
Table 1. Yields, melting points, and elemental analysis data for compounds 6b—h and 7a—f
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
6b
6c
6d
6e
6f
75
72
65
72
68
64
60
58
64
55
73
69
62
92—94
34.27
34.12
53.31
53.49
48.63
48.81
51.12
50.94
50.78
50.94
40.34
40.16
52.29
52.45
58.31
58.45
59.33
59.50
55.41
55.59
55.40
55.59
55.44
55.59
51.57
51.70
1.34
1.43
3.27
3.09
2.39
2.56
2.49
2.67
2.49
2.67
1.51
1.35
3.49
3.37
4.22
4.04
4.28
4.44
3.42
3.57
3.38
3.57
3.39
3.57
3.25
3.10
10.78
11.94
11.61
11.70
10.83
10.67
11.02
11.14
11.32
11.14
9.19
C10H5Cl2F6N3
C16H11F6N3
144—146
126—128
138—140
140—142
141—142
115—117
137—139
147—149
143—145
102—104
133—135
151—152
C16H10ClF6N3
C16H10F7N3
C16H10F7N3
6g
6h
7a
7b
7c
7d
7e
7f
C15H6Cl3F6N3
C17H13F6N3O
C17H14F3N3O2
C18H16F3N3O2
C17H13F4N3O2
C17H13F4N3O2
C17H13F4N3O2
C14H10F3N3O3
9.37
10.61
10.79
12.21
12.03
11.75
11.57
11.26
11.44
11.62
11.44
11.29
11.44
12.77
12.92

1516
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
Sokolov and Aksinenko
Nꢀ[1,1,1,3,3,3ꢀHexafluoroꢀ2ꢀ(4ꢀmethylpyridinꢀ2ꢀylamiꢀ
no)propanꢀ2ꢀyl]benzamide (4a). 2ꢀAminoꢀ4ꢀmethylpyridine (3a)
(1.08 g, 0.01 mol) was added to a solution of imine 1a (2.69 g,
0.01 mol) in benzene (20 mL). After the exothermic reaction
was completed, the solvent was removed and the residue was
recrystallized from benzene—hexane (1 : 1) to give benzamide
4a (3.25 g, 86%), m.p. 118—120 °C. Found (%): C, 50.77;
H, 3.29; N, 11.32. C16H13F6N3O. Calculated (%): C, 50.94;
C, 55.31; H, 3.22; N, 11.51. C16H11F6N3. Calculated (%):
C, 53.49; H, 3.09; N, 11.70. H NMR (DMSOꢀd6), δ: 2.13 (s,
1
3 H, Me); 5.85 (d, 1 H, H arom., J = 7.9 Hz); 6.56 (s, 1 H,
H arom.); 6.96 (d, 1 H, H arom., J = 8.0 Hz); 7.55 (m, 5 H,
H arom.). 19F NMR (DMSOꢀd6), δ: –1.04 (s).
B. 2ꢀAminoꢀ4ꢀmethylpyridine (3a) (1.08 g, 0.01 mol) was
added to a solution of imine 1a (2.69 g, 0.01 mol) in benzene
(50 mL). After the exothermic reaction was completed, PCl5
(2.09 g, 0.01 mol) was added and the reaction mixture was
refluxed to homogenization. The solvent and POCl3 were reꢀ
moved and the residue was recrystallized from hexane to give
triazine 6a (2.12 g, 56%), m.p. 121—123 °C.
1
H, 3.47; N, 11.14. H NMR (DMSOꢀd6), δ: 2.27 (s, 3 H, Me);
6.61 (d, 1 H, H arom., J = 8.0 Hz); 7.02 (s, 1 H, H arom.); 7.19
(s, 1 H, NH); 7.49, 7.92 (both m, 3 H each, H arom.); 12.68 (s,
1 H, NH). 19F NMR (DMSOꢀd6), δ: 4.68 (s).
Methyl 2ꢀbenzoylaminoꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(4ꢀmethylpyridinꢀ
2ꢀylamino)propionate (5a) was obtained analogously from imine
2a (0.01 mol) and 2ꢀaminoꢀ4ꢀmethylpyridine (3a) (0.01 mol).
The yield of compound 5a was 3.15 g (86%), m.p. 156—158 °C.
Found (%): C, 55.41; H, 4.22; N, 11.31. C17H16F3N3O3. Calcuꢀ
lated (%): C, 55.59; H, 4.39; N, 11.44. 1H NMR (DMSOꢀd6), δ:
2.17 (s, 3 H, Me); 3.79 (s, 3 H, MeO); 6.42 (d, 1 H, H arom.,
J = 7.8 Hz); 6.67 (s, 1 H, H arom.); 7.19 (s, 1 H, NH); 7.42 (m,
3 H, H arom.); 7.64 (s, 1 H, NH); 7.83 (m, 3 H, H arom.); 9.14
(s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 2.62 (s).
8ꢀMethylꢀ4ꢀphenylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazine (6a). A. A mixture of benzamide 4a
(3.77 g, 0.01 mol) and PCl5 (2.09 g, 0.01 mol) in benzene (50 mL)
was refluxed to homogenization. The solvent and POCl3 were
removed and the residue was recrystallized from hexane to give
triazine 6a (2.55 g, 71%), m.p. 121—123 °C. Found (%):
7,8ꢀDichloroꢀ4ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazine (6b), 4ꢀ(2ꢀmethylphenyl)ꢀ2,2ꢀbis(triꢀ
fluoromethyl)ꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazine (6c), 7ꢀchloroꢀ
4 ꢀ ( 2 ꢀ m e t h y l p h e n y l ) ꢀ 2 , 2 ꢀ b i s ( t r i f l u o r o m e t h y l ) ꢀ 2 H ꢀ
pyrido[1,2ꢀa][1,3,5]triazine (6d), 4ꢀ(4ꢀfluorophenyl)ꢀ9ꢀmethylꢀ
2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazine (6e),
4ꢀ(2ꢀfluorophenyl)ꢀ7ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazine (6f), 7,9ꢀdichloroꢀ4ꢀ(4ꢀchlorophenyl)ꢀ
2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazine (6g),
4ꢀ(4ꢀmethoxyphenyl)ꢀ7ꢀmethylꢀ2,2ꢀbis(trifluoromethyl)ꢀ2Hꢀ
pyrido[1,2ꢀa][1,3,5]triazine (6h), methyl 8ꢀmethylꢀ4ꢀphenylꢀ2ꢀ
trifluoromethylꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxylate
(7a), methyl 8ꢀmethylꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2ꢀtrifluoromethylꢀ
2Hꢀpyrido[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxylate (7b), methyl
4ꢀ(4ꢀfluorophenyl)ꢀ9ꢀmethylꢀ2ꢀtrifluoromethylꢀ2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxylate (7c), methyl 4ꢀ(4ꢀfluoroꢀ
Table 2. 1H and 19F NMR spectra of compounds 6b—h and 7a—f (in DMSOꢀd6)
Comꢀ
pound
δ (J/Hz)
1H
19F
6b
6c
2.48 (s, 3 Н, Ме); 7.32, 7.84 (both s, 1 H each, H arom.)
2.28 (s, 3 Н, Ме); 5.93 (t, 1 Н, H arom., J = 7.5); 6.66 (m, 2 Н, H arom.);
7.06 (m, 1 Н, H arom.); 7.28—7.41 (m, 4 Н, H arom.)
0.82 (s)
0.86 (s)
6d
6e
6f
2.29 (s, 3 Н, Ме); 6.74 (m, 2 Н, H arom..); 7.07 (d, 1 Н, H arom., J = 8.1);
7.30—7.52 (m, 4 Н, H arom.)
2.16 (s, 3 Н, Ме); 5.95 (t, 1 Н, H arom., J = 7.6); 6.97 (m, 2 Н, H arom..);
7.27 (t, 2 Н, H arom., J = 7.9); 7.59 (m, 2 Н, H arom..)
0.70 (s)
–0.67 (s, 3 F);
28.82 (m, 1 F)
–0.81 (s, 3 F);
–34.55 (m, 1 F)
0.55 (s)
1.98 (s, 3 Н, Ме); 6.62 (d, 2 Н, H arom., J = 7.9); 6.96 (d, 1 Н, H arom.,
J = 7.8); 7.37 (m, 2 Н, H arom.); 7.51, 7.78 (both m, 1 H each, H arom.)
7.23, 7.38 (both s, 1 H each, H arom.); 7.53, 7.66 (both d, 2 H each, H arom., J = 7.8)
1.96 (s, 3 Н, Ме); 3.88 (s, 3 Н, МеО); 6.64 (d, 1 Н, H arom., J = 7.7);
6.90 (s, 1 Н, H arom.); 6.93—7.07 (m, 3 Н, H arom.); 7.49 (d, 2 Н, H arom., J = 7.8)
2.13 (s, 3 Н, Ме); 3.80 (s, 3 Н, МеО); 5.78 (d, 1 Н, H arom., J = 8.1);
6.42 (s, 1 Н, H arom.); 6.91 (d, 1 Н, H arom., J = 8.0); 7.53 (m, 5 Н, H arom.)
2.17, 2.48 (both s, 3 H each, Ме); 3.84 (s, 3 Н, МеО); 5.88 (d, 1 Н, H arom., J = 7.7);
6.45 (s, 1 Н, H arom.); 6.96 (d, 1 Н, H arom., J = 7.7); 7.33, 7.47 (both d, 2 H each, H arom., J = 8.0)
2.11 (s, 3 Н, Ме); 3.82 (s, 3 Н, МеО); 5.84 (t, 1 Н, H arom., J = 7.8);
6.86 (m, 2 Н, H arom.); 7.25 (t, 2 Н, H arom., J = 7.5); 7.57 (m, 2 Н, H arom.)
2.09 (s, 3 Н, Ме); 3.81 (s, 3 Н, МеО); 5.74 (d, 1 Н, H arom., J = 7.7);
6.49 (s, 1 Н, H arom.); 6.82 (d, 1 Н, H arom., J = 7.9); 7.18 (t, 2 Н, H arom.,
J = 7.7); 7.57 (m, 2 Н, H arom..)
6g
6h
0.52 (s)
7a
7b
7c
7d
–0.26 (s)
–0.12 (s)
0.35 (s, 3 F);
–29.36 (m, 1 F)
–0.55 (s, 3 F);
29.02 (m, 1 F)
7e
7f
2.11 (s, 3 Н, Ме); 3.83 (s, 3 Н, МеО); 5.91 (t, 1 Н, H arom., J = 7.9); 6.84 (d, 2 Н,
H arom., J = 7.9); 7.27—7.36 (m, 3 Н, H arom.); 7.52 (m, 3 Н, H arom.)
3.78 (s, 3 Н, МеО); 6.05 (t, 1 Н, H arom., J = 7.7); 6.61—6.67 (m, 2 Н, H arom.);
6.98—7.09 (m, 1 Н, H arom.); 7.16, 7.44 (both d, 1 H each, H arom., J = 8.1);
7.83 (m, 1 Н, H arom.)
–0.16 (s, 3 F);
–33.44 (m, 1 F)
0.07 (s)

Fluoroꢀcontaining triazines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
1517
phenyl)ꢀ8ꢀmethylꢀ2ꢀtrifluoromethylꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triꢀ
azineꢀ2ꢀcarboxylate (7d), methyl 4ꢀ(3ꢀfluorophenyl)ꢀ9ꢀmethylꢀ
2ꢀtrifluoromethylꢀ2Hꢀpyrido[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxylate
(7e), and methyl 4ꢀ(2ꢀfuryl)ꢀ2ꢀtrifluoromethylꢀ2Hꢀpyriꢀ
do[1,2ꢀa][1,3,5]triazineꢀ2ꢀcarboxylate (7f) were obtained from
imine 1 or 2 (0.01 mol), 2ꢀaminopyridines 3 (0.01 mol), and
PCl5 (0.01 mol) as described for triazine 6a. The yields, melting
points, and spectroscopic characteristics of compounds 6b—h
and 7a—f are given in Tables 1 and 2.
3. Yu. V. Sinyakov, N. V. Vasil´ev, A. F. Kolomiets, and G. A.
Sokol´skii, Zh. Org. Khim., 1989, 24, 642 [J. Org. Chem.
USSR, 1989, 24 (Engl. Transl.)].
4. V. B. Sokolov, A. Yu. Aksinenko, and I. V. Martynov, Izv.
Akad. Nauk, Ser. Khim., 2001, 1064 [Russ. Chem. Bull., Int.
Ed., 2001, 50, 1113].
5. V. B. Sokolov and A. Yu. Aksinenko, Izv. Akad. Nauk, Ser.
Khim., 2003, 2053 [Russ. Chem. Bull., Int. Ed., 2003,
52, 2167].
8ꢀMethylꢀ4ꢀphenylꢀ2ꢀtrifluoromethylꢀ2Hꢀpyrido[1,2ꢀ
a][1,3,5]triazineꢀ2ꢀcarbohydrazide (8). Hydrazine hydrate (1.01
g, 0.02 mol) was added to a solution of triazine 7a (3.49 g, 0.01
mol) in MeOH (20 mL). The reaction mixture was kept at 20 °C
for 24 h and the precipitate that formed was filtered off and
recrystallized from 50% EtOH. The yield of hydrazide 8 was
2.75 g (79%), m.p. 168—170 °C. Found (%): C, 55.19; H, 4.21;
N, 19.88. C16H14F3N5O. Calculated (%): C, 55.02; H, 4.04; N,
20.05. 1H NMR (DMSOꢀd6), δ: 2.14 (s, 3 H, Me); 4.16 (s, 2 H,
NH2); 5.76 (d, 1 H, H arom., J = 7.6 Hz); 6.46 (s, 1 H, H
arom.); 6.92 (d, 1 H, H arom., J = 7.6 Hz); 7.54 (m, 5 H, H
arom.); 8.74 (s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: –0.94.
6. M. F. Reich, P. F. Fabio, V. J. Lee, N. A. Kuck, and R. T.
Testa, J. Med. Chem., 1989, 32, 2474.
7. C. Temple, Jr. and G. A. Rener, J. Med. Chem., 1990,
33, 3044.
8. C. Temple, Jr. and G. A. Rener, J. Med. Chem., 1989,
32, 2089.
9. C. Temple, Jr., G. A. Rener, and R. N. Comber, J. Med.
Chem., 1989, 32, 2363.
10. V. B. Sokolov and A. Yu. Aksinenko, Izv. Akad. Nauk, Ser.
Khim., 1998, 748 [Russ. Chem. Bull., 1998, 47, 727 (Engl.
Transl.)].
11. S. N. Osipov, V. B. Sokolov, A. F. Kolomiets, I. V. Martynov,
and A. V. Fokin, Izv. Akad. Nauk SSSR, Ser. Khim., 1987,
1185 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1987, 36, 1098
(Engl. Transl.)].
References
1. A. V. Fokin, A. F. Kolomiets, and N. V. Vasil´ev, Usp. Khim.,
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1992, 61, 1457 [Russ. Chem. Rev., 1992, 61 (Engl. Transl.)].
Received February 17, 2005;
in revised form April 11, 2005