Benzamidines in cyclocondensation with hexafluoroacetone and methyl trifluoropyruvate acyl- and ethoxycarbonylimines

Article abstract of DOI:10.1007/s11172-005-0281-9

The reactions of hexafluoroacetone and methyl trifluoropyruvate acyl- and ethoxycarbonylimines with benzamidines afford fluoro containing heterocycles of four structural types: dihydrotriazines, dihydrotriazinones, imidazoles, and imidazooxazoles.

Full text of DOI:10.1007/s11172-005-0281-9

472
Russian Chemical Bulletin, International Edition, Vol. 54, No. 2, pp. 472—475, February, 2005
Benzamidines in cyclocondensation with hexafluoroacetone
and methyl trifluoropyruvate acylꢀ and ethoxycarbonylimines
V. B. Sokolov, A. Yu. Aksinenko,ꢀ T. A. Epishina, T. V. Goreva, and I. V. Martynov
Institute of Physiologically Active Compounds,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 785 7024. Eꢀmail: alaks@ipac.ac.ru
The reactions of hexafluoroacetone and methyl trifluoropyruvate acylꢀ and ethoxycarbonylꢀ
imines with benzamidines afford fluoroꢀcontaining heterocycles of four structural types:
dihydrotriazines, dihydrotriazinones, imidazoles, and imidazooxazoles.
Key words: benzamidines, acylimines, ethoxycarbonylimines, hexafluoroacetone, methyl
trifluoropyruvate, dihydrotriazines, dihydrotriazinones, imidazolines, imidazooxazole,
cyclocondensation, heterocyclization.
Benzamidines are successfully used as 1,3ꢀbisꢀnucleoꢀ
acylꢀ and ethoxycarbonylimines 3, which serve as bisꢀ
electrophilic agents, as we have shown previously.6,7
Benzamidines 1, similarly to other aminoꢀcontaining
compounds, react exothermically with imines 2 and 3 to
form five different reaction products, depending on the
nature of compounds 1, 2, and 3. For example, the reacꢀ
tions of benzamidines 1a,b with imines 2a—d in benzene
at 20 °С afford stable acyclic adducts of the iminic N
atom of benzamidines 1a,b at the azomethine bond of
compounds 2a—d in 72—85% yields (Scheme 1). This is
philes in syntheses of nitrogenꢀcontaining heterocycles,
including fluoroꢀcontaining heterocycles, by cycloconꢀ
densation with various bisꢀelectrophilic agents, for inꢀ
stance, 3ꢀoxocarboxylates,1,2 1,3ꢀdicarbonyl compounds,3
unsaturated carbonyl compounds,4 and ethyl pentafluoroꢀ
butyrate.5
In this work, we present data on the cyclocondensation
of benzamidines 1 with hexafluoroacetone acylꢀ and
ethoxycarbonylimines 2 and methyl trifluoropyruvate
Scheme 1
Reagents and conditions: i. PhH, 20 °C, 1 h; ii. Et3N, DMF, ∆, 1 h.
1: R = H (a), Me (b)
2: R´ = Me (a), Ph (b), 4ꢀClC6H4 (c), EtO (d), PhCH2 (e), PhOCH2 (f)
4: R = H, R´ = Me (a); R = H, R´ = Ph (b); R = Me, R´ = 4ꢀClC6H4 (c); R = H, R´ = EtO (d)
5: R = H, R´ = Me (a); R = H, R´ = Ph (b); R = Me, R´ = 4ꢀClC6H4 (c); R = H, R´ = PhCH2 (d); R = H, R´ = PhOCH2 (e)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 462—465, February, 2005.
1066ꢀ5285/05/5402ꢀ0472 © 2005 Springer Science+Business Media, Inc.

Amidines: cyclocondensation with fluoroimines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
473
confirmed by the signal from the NH2 group (a singlet
with the 2 H intensity at δ 5.75—6.80) in the H NMR
spectra of products 4a—d.
signals of the geminal CF3 groups at δ –1.8 to –0.5 for
triazines 5a—e and triazinones 6a,b and the signal of the
CF3 group at δ 0.5—1.7 for imidazolinones 7a—e. The
structure of compound 7a was confirmed by the chemical
transformation. Its refluxing in DMF in the presence of
catalytic amounts of Et3N produces imidazooxazole 8 in
82% yield. The latter was also obtained directly from an
equimolar mixture of compounds 1a and 3a by its refluxꢀ
ing in DMF (Scheme 4).
1
Refluxing of compounds 4a—d in DMF (1 h) in the
presence of catalytic amounts of Et3N produces the corꢀ
responding dihydrotriazines 5a—c or dihydrotriazinone
6a (in the case of 4d) in 61—77% yields.
We detected no acyclic products like compound 4 upon
the reaction of phenylꢀ and phenoxyacetylimines 2e,f with
benzamidines, because dihydrotriazines 5d,e are formed
immediately (see Scheme 1).
Scheme 4
No acyclic products were either detected upon the
reaction of Nꢀbenzylbenzamidine (1c) with imine 2d, and
dihydrotriazinone 6b was obtained (Scheme 2).
Scheme 2
Reagents and conditions: i. DMF, Et3N, ∆, 2 h.
Thus, the studied transformations of benzamidines in
the reactions with hexafluoroacetone and methyl trifluoroꢀ
pyruvate acylꢀ and ethoxycarbonylimines made it posꢀ
sible to propose preparative methods for the syntheses of
earlier unknown fluoroꢀcontaining heterocycles of four
structural types: dihydrotriazines, dihydrotriazinones,
dihydroimidazoles, and imidazooxazoles. The synthesis
of the latter is the first example of cascade cyclocondenꢀ
sation of polyfluoroketone acylimines in reactions with
bisꢀnucleophiles.
Unlike imines 2, imines 3 serve as 1,2ꢀbisꢀelectrophiles
in the reaction with benzamidines 1a,b to form dihydroꢀ
imidazoles 7a—e (Scheme 3) in 65—79% yields (despite
two acyl groups in molecule 3, which does not exclude a
possibility of formation of both fiveꢀ and sixꢀmembered
cycles in the reactions).
Scheme 3
Experimental
1
H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in a
glass capillary. Acylꢀ and ethoxycarbonylimines 2a—d and 3a—e
were synthesized according to known procedures.8,9
Amides 4a—d (general procedure). Acylimine 2a—d
(10 mmol) was added to a solution of benzamidine 1 (10 mmol)
in benzene (20 mL), and the mixture was stirred for 1 h. Benꢀ
zene was evaporated, and the residue was crystallized from a
benzene—hexane (1 : 1) mixture. The yields, melting points,
and spectral characteristics of compounds 4a—d are presented
in Tables 1 and 2.
Reagents and conditions: i. PhH, 20 °C, 1 h.
R = H (a—c, e), Me (d);
Triazines 5a—c (general procedure). Amides 4a—c (5 mmol)
and Et3N (0.1 mL) were refluxed in DMF (10 mL) for 2 h. The
reaction mixture was poured into water (50 mL), and the preꢀ
cipitate that formed was filtered off and crystallized from 50%
EtOH. The yields, melting points, and spectral characteristics of
compounds 5a—c are presented in Tables 1 and 2.
R´ = Me (a), Et (b), 4ꢀClC6H4 (c), 2ꢀFC6H4 (d), EtO (e)
Dihydrotriazines 5a—e, dihydrotriazinones 6a,b, and
dihydroimidazoles 7a—e are crystalline solids, whose comꢀ
positions and structures were confirmed by elemental
analysis and NMR spectroscopy. The 19F NMR spectra
of these compounds contain characteristic signals: the
Triazines 5d,e (general procedure). Acylimine 2e or 2f
(10 mmol) was added to a solution of benzamidine 1a (10 mmol)

474
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Sokolov et al.
Table 1. Yields, melting points, and elemental analysis data for compounds 4a—d, 5a—e, 6a,b, 7a—e, and 8
Compound
Yield
(%)
M.p./°С
Found
Calculated
Molecular
formula
(%)
C
H
N
Nꢀ[1ꢀ(Benzimidoylamino)ꢀ2,2,2ꢀtrifluoroꢀ
1ꢀtrifluoromethylethyl]acetamide (4a)
85
72
75
81
77
64
61
77
72
68
79
77
65
68
78
71
82
157—158
121—122
165—166
136—138
167—168
175—177
200—201
95—97
44.19
44.05
52.62
52.45
49.55
49.39
43.89
43.71
46.80
46.61
55.17
54.99
51.67
51.51
56.28
56.11
53.99
53.87
42.59
42.46
53.98
53.87
50.69
50.53
52.29
52.18
53.60
53.43
57.16
57.00
49.69
49.53
53.77
53.94
3.24
3.39
3.19
3.37
3.06
3.22
3.88
3.67
2.79
2.93
2.89
2.99
2.97
2.88
3.57
3.40
3.11
3.27
2.42
2.27
3.09
3.27
3.35
3.53
4.22
4.04
2.79
2.90
3.26
3.45
3.89
3.84
3.18
3.02
12.99
12.84
10.92
10.79
9.79
C12H11F6N3O
C17H13F6N3O
C18H14ClF6N3O
C13H13F6N3O2
C12H9F6N3
Nꢀ[1ꢀ(Benzimidoylamino)ꢀ2,2,2ꢀtrifluoroꢀ
1ꢀtrifluoromethylethyl]benzamide (4b)
Nꢀ[1ꢀ(Benzimidoylamino)ꢀ4ꢀchloroꢀ2,2,2ꢀtrifluoroꢀ
1ꢀtrifluoromethylethyl]benzamide (4c)
Nꢀ[1ꢀ(Benzimidoylamino)ꢀ2,2,2ꢀtrifluoroꢀ
1ꢀtrifluoromethylethyl] ethyl carbamate (4d)
2ꢀMethylꢀ4,4ꢀbis(trifluoromethyl)ꢀ6ꢀphenylꢀ
1,4ꢀdihydro[1,3,5]triazine (5a)
4,4ꢀBis(trifluoromethyl)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀ
6ꢀphenylꢀ1,4ꢀdihydro[1,3,5]triazine (5b)
4,4ꢀBis(trifluoromethyl)ꢀ2,6ꢀdiphenylꢀ
1,4ꢀdihydro[1,3,5]triazine (5c)
2ꢀBenzylꢀ4,4ꢀbis(trifluoromethyl)ꢀ6ꢀphenylꢀ
1,4ꢀdihydro[1,3,5]triazine (5d)
4,4ꢀBis(trifluoromethyl)ꢀ2ꢀphenoxyꢀ6ꢀphenylꢀ
1,4ꢀdihydro[1,3,5]triazine (5e)
4,4ꢀBis(trifluoromethyl)ꢀ6ꢀphenylꢀ1,4ꢀdihydroꢀ
1Hꢀ[1,3,5]triazinꢀ2ꢀone (6a)
1ꢀBenzylꢀ4,4ꢀbis(trifluoromethyl)ꢀ6ꢀphenylꢀ
1,4ꢀdihydroꢀ1Hꢀ[1,3,5]triazinꢀ2ꢀone (6b)
Nꢀ(5ꢀOxoꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ
1Hꢀimidazolꢀ4ꢀyl)acetamide (7a)
9.60
11.89
11.76
13.75
13.59
11.49
11.32
10.19
10.01
11.09
10.91
10.59
10.47
13.69
13.50
10.59
10.47
14.89
14.73
14.21
14.04
11.19
11.01
11.19
11.08
13.48
13.33
15.91
15.73
C17H11F6N3
C18H12ClF6N3
C18H13F6N3
112—113
155—157
143—144
183—184
238—240
183—184
212—214
212—213
222—224
C18H13F6N3
C11H7F6N3O
C18H13F6N3O
C12H10F3N3O2
C13H12F3N3O2
C17H11ClF3N3O
C18H13F4N3O2
C13H12F3N3O3
C12H8F3N3O
Nꢀ(5ꢀOxoꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ
1Hꢀimidazolꢀ4ꢀyl)propionamide (7b)
4ꢀChloroꢀNꢀ(5ꢀoxoꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ
4,5ꢀdihydroꢀ1Hꢀimidazolꢀ4ꢀyl)benzamide (7c)
2ꢀFluoroꢀNꢀ[2ꢀ(4ꢀmethylphenyl)ꢀ5ꢀoxoꢀ4ꢀtrifluoroꢀ
methylꢀ4,5ꢀdihydroꢀ1Hꢀimidazolꢀ4ꢀyl]benzamide (7d)
Nꢀ(5ꢀOxoꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ
1Hꢀimidazolꢀ4ꢀyl) ethyl carbamate (7e)
2ꢀMethylꢀ5ꢀphenylꢀ3aꢀtrifluoromethylꢀ
3aHꢀimidazo[4,5ꢀd]oxazole (8)
1
Table 2. Н and 19F NMR spectra of the synthesized compounds in DMSOꢀd6
Comꢀ
pound
δ
(J/Hz)
δ
(s)
H
F
4a
4b
4c
4d
2.12 (s, 3 H, Me); 6.71 (br.s, 2 H, NH2); 7.46 (m, 3 H, H arom.);
7.81 (d, 2 H, H arom., J = 8.2); 8.42 (s, 1 H, NH)
6.80 (br.s, 2 H, NH2); 7.42 (m, 2 H, H arom.); 7.48 (m, 3 H, H arom.);
7.55 (t, 1 H, H arom., J = 7.5); 7.84 (m, 4 H, H arom.); 8.74 (s, 1 H, NH)
2.38 (s, 3 H, Me); 6.67 (br.s, 2 H, NH2); 7.11, 7.32, 7.70, 7.83
(all d, 2 H each, H arom., J = 8.0); 8.65 (s, 1 H, NH)
5.26
3.05
5.81
1.31 (t, 3 H, Me, J = 6.9); 4.19 (q, 2 H, CH2, J = 6.9); 5.43 (s, 1 H, NH); 5.75 (br.s, 2 H, NH2);
7.45 (m, 3 H, H arom.); 7.83 (d, 2 H, H arom., J = 8.0)
1.86
5a
5b
5c
2.20 (s, 3 H, Me); 7.52 (m, 3 H, H arom.); 7.95 (d, 2 H, H arom., J = 8.0); 10.58 (s, 1 H, NH)
7.35, 7.52 (both m, 3 H each, H arom.); 7.82, 8.03 (both d, 2 H each, H arom., J = 8.0); 11.09 (s, 1 H, NH) –1.0
2.45 (s, 3 H, Me); 7.30, 7.52, 7.92, 8.13 (all d, 2 H each, H arom., J = 8.2); 11.09 (s, 1 H, NH)
–1.51
–1.0
(to be continued)

Amidines: cyclocondensation with fluoroimines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
475
Table 2 (continued)
Comꢀ
pound
δ
(J/Hz)
δ
F
(s)
H
5d
5e
2.12 (s, 2 H, CH2); 7.12—7.52 (m, 8 H, H arom.); 7.86 (d, 2 H, H arom., J = 8.0); 10.68 (s, 1 H, NH)
4.76 (s, 2 H, CH2); 6.82—7.06 (m, 3 H, H arom.); 7.24 (m, 2 H, H arom.);
7.44 (m, 3 H, H arom.); 7.96 (d, 2 H, H arom., J = 8.0); 11.02 (s, 1 H, NH)
7.45 (m, 3 H, H arom.); 8.03 (d, 2 H, H arom., J = 8.0); 9.18, 10.84 (both s, 1 H each, NH)
4.85 (s, 2 H, CH2); 6.89, 7.18 (both d, 2 H each, H arom., J = 8.1);
7.39 (m, 6 Н, H arom.); 9.82 (s, 1 H, NH)
–1.13
–0.51
6a
6b
–1.80
–1.24
7a
7b
7c
7d
7e
1.97 (s, 3 H, Me); 7.53 (m, 3 H, H arom.); 8.05 (d, 2 H, H arom., J = 8.0);
9.38, 12.0 (both s, 1 H each, NH)
1.31 (t, 3 H, Me, J = 6.8); 2.24 (q, 2 H, CH2, J = 6.8); 7.45 (m, 3 H, H arom.);
8.04 (d, 2 H, H arom., J = 8.0); 9.10, 11.86 (both s, 1 H each, NH)
7.36 (m, 3 H, H arom.); 7.52 (m, 2 H, H arom.); 7.93, 8.13 (both d, 2 H each, H arom., J = 8.2);
9.73, 12.11 (both s, 1 H each, NH)
2.38 (s, 3 H, Me); 7.11—7.39 (m, 4 H, H arom.); 7.53 (m, 1 H, H arom.); 7.75 (t, 1 H,
H arom., J = 8.0); 8.00 (d, 2 H, H arom., J = 8.0); 9.32, 12.07 (both s, 1 H each, NH)
1.25 (t, 3 H, Me, J = 7.0); 4.06 (q, 2 H, CH2, J = 7.0); 7.52 (m, 3 H, H arom.);
8.11 (d, 2 H, H arom., J = 8.2); 8.76, 12.05 (both s, 1 H each, NH)
1.94 (s, 3 H, Me); 7.52 (m, 3 H, H arom.); 8.08 (d, 2 H, H arom., J = 8.2)
0.47
0.49
1.73
0.88,
–32.94*
0.58
8
1.01
* M (1 F).
in benzene (20 mL), and the mixture was stirred for 1 h. Benꢀ
zene was evaporated, and the residue was crystallized from a
benzene—hexane (1 : 1) mixture. The yields, melting points,
and spectral characteristics of compounds 5d,e are presented in
Tables 1 and 2.
Triazinone 6a was synthesized by the ring closure of comꢀ
pound 4d under the conditions for the synthesis of compounds
5a—c (see Tables 1 and 2).
Triazinone 6b was synthesized by the reaction of Nꢀbenzylꢀ
amidine 1c and imine 2d under the conditions for the synthesis
of compounds 5d,e (see Tables 1 and 2).
Imidazolones 7a—e (general procedure). Acylimine 3
(10 mmol) was added to a solution of amidine 1 (10 mmol) in
benzene (20 mL), and the mixture was stirred for 1 h. Benzene
was evaporated, and the residue was crystallized from benꢀ
zene—hexane (1 : 1) mixture. The yields, melting points, and
spectral characteristics of compounds 7a—e are presented in
Tables 1 and 2.
References
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Compound 8. Imidazolone 7a (1.43 g, 5 mmol) and Et3N
(0.1 mL) were refluxed in DMF (10 mL) for 2 h. The reaction
mixture was poured into water (50 mL), and the precipitate that
formed was filtered off and recrystallized from 50% EtOH. The
yield was 1.1 g (82%). The physicochemical characteristics of
compound 8 are presented in Tables 1 and 2.
Received September 16, 2004;
in revised form December 1, 2004