N-substituted imines of methyl trif luoropyruvate in the synthesis of 5-amino-5-trifluoromethylhydantoins

Article abstract of DOI:10.1007/s11172-006-0375-z

Cyclocondensation of N-substituted imines of methyl trifluoropyruvate with monosubstituted ureas afforded novel 5-amino-5-trifluoromethylhydantoins.

Full text of DOI:10.1007/s11172-006-0375-z

Russian Chemical Bulletin, International Edition, Vol. 55, No. 6, pp. 1052—1055, June, 2006
1052
NꢀSubstituted imines of methyl trifluoropyruvate
in the synthesis of 5ꢀaminoꢀ5ꢀtrif luoromethylhydantoins
A. Yu. Aksinenko,ꢀ T. V. Goreva, T. A. Epishina, A. N. Pushin, and V. B. Sokolov
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (495) 921 2113. Eꢀmail: alaks@ipac.ac.ru
Cyclocondensation of Nꢀsubstituted imines of methyl trifluoropyruvate with monosubstiꢀ
tuted ureas afforded novel 5ꢀaminoꢀ5ꢀtrifluoromethylhydantoins.
Key words: hydantoins, imidazolidineꢀ2,4ꢀdiones, Nꢀsubstituted imines, methyl trifluoroꢀ
pyruvate, fluoroꢀcontaining ureas, cyclocondensation.
Hydantoins (imidazolidineꢀ2,4ꢀdiones) are nitrogenꢀ
containing heterocycles, which are widely used in meꢀ
dicinal (anticonvulsants1 and anticancer drugs2) and agroꢀ
chemical practice (fungicides3 and herbicides4). The bioꢀ
logical activities of many various hydantoins have been
studied to date.5
General methods for the synthesis of these compounds
involve reactions of αꢀamino acids with alkyl or aryl isoꢀ
cyanates, as well as reactions of Nꢀsubstituted ureas with
alkyl αꢀhalo carboxylates; these transformations have been
studied with a sufficiently great number of acids, ureas,
and isocyanates.6 At the same time, the problem of
the applicability of the known methods to the synthesis
of 5ꢀaminohydantoins, which are cyclic derivatives of
αꢀamino acids and are of interest as potential biologically
active substances, remains open.
cessive addition of equimolar amounts of quinoline, meꢀ
thyl trifluoropyruvate, and POCl3 to a suspension of an
appropriate amide in benzene (Scheme 1).
Imines 1a—e reacted with ureas 2a—h to give adꢀ
ducts 3 (Scheme 2), the reaction conditions being varied
with the imine nature. For instance, the reactions of imiꢀ
nes 1a—d with ureas 2a—h were exothermic, while for the
Scheme 2
Here we report on the synthesis of novel 5ꢀaminoꢀ5ꢀ
trifluoromethylhydantoins from Nꢀsubstituted imines of
methyl trifluoropyruvate 1 and monosubstituted ureas 2.
This investigation was motivated by data on the cycloꢀ
condensation of acylimines of methyl trifluoropyruvate
with C,Nꢀbinucleophiles of the enamine type7 and with
N,Nꢀbinucleophiles of the amidine type.8
The starting Nꢀsubstituted imines of methyl trifluoroꢀ
pyruvate 1a—e were prepared in 69—76% yields by sucꢀ
Scheme 1
2
a
b
R´
Me
Bu
2
c
d
R´
Ph
Bn
2
e
f
R´
2
g
h
R´
2ꢀFurfuryl
4ꢀFC6H4
4ꢀMeC6H4
cycloꢀC6H11
3, 4
a
b
c
d
R
R´
Me
Bn
Me
Bn
3, 4
R
R´
Bui
2ꢀFurfuryl
Ph
Ac
Ac
Bz
Bz
g
h
i
4ꢀClC6H4C(O)
4ꢀClC6H4C(O)
Benzothiazolyl
Benzothiazolyl
R = Ac (a), Bz (b), 4ꢀFC6H4C(O) (c), 4ꢀClC6H4C(O) (d),
(e)
j
4ꢀMeC6H4
e
f
4ꢀFC6H4C(O) 4ꢀFC6H4
4ꢀFC6H4C(O) Bn
k
l
Benzothiazolyl cycloꢀC6H11
Benzothiazolyl Bn
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1014—1017, June, 2006.
1066ꢀ5285/06/5506ꢀ1052 © 2006 Springer Science+Business Media, Inc.

5ꢀAminoꢀ5ꢀtrifluoromethylhydantoins
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1053
was 14.5 g (74%), b.p. 77—78 °C (20 Torr). Found (%): C, 36.32;
H, 3.35. C6H6F3NO3. Calculated (%): C, 36.56; H, 3.07.
1H NMR (CDCl3), δ: 2.35 (s, 3 H, Ac); 4.00 (s, 3 H, MeO).
19F NMR (CDCl3), δ: 7.60 (s).
reactions of imine 1e with ureas 2c,d,g,h to be completed,
heating at 60—80 °C for ~10—20 min was required.
Hydantoins 4a,b,e—l were obtained in 82—96% yields
without isolation of intermediate adducts 3a,b,e—l. Adꢀ
ducts 3c,d were isolated; their highꢀyielding cyclization
into hydantoins 4c,d through elimination of MeOH ocꢀ
curred in boiling benzene in the presence of catalytic
amounts of Et3N for 3—4 h or on heating in DMF at 90 °C.
Hydantoins 4 are crystalline substances; their compoꢀ
sitions and structures were confirmed by elemental analyꢀ
sis and NMR spectroscopy. The 1H NMR spectra of
hydantoins 4 show signals for the NH protons at δ 9—10,
the signal for the exocyclic NH proton is shifted downfield
by ~0.2 ppm compared to adducts 3. In the 19F NMR
spectra of hydantoins 4, the signals for the CF3 group are
shifted upfield (δ 0.5—–0.9) compared to adducts 3.
When refluxed in DMF in the presence of 1 M KOH,
adducts 3 underwent decarbomethoxylation to ureas 5a,b
(Scheme 3). Under analogous conditions, hydantoins 4c,d
were also converted into products 5a,b.
Methyl 2ꢀbenzoyliminoꢀ3,3,3ꢀtrifluoropropionate (1b) was
obtained analogously from benzamide (12.1 g, 0.1 mol). The
yield was 18.6 g (72%), b.p. 102—103 °C (2 Torr). Found (%):
C, 51.22; H, 2.85. C11H8F3NO3. Calculated (%): C, 50.98;
H, 3.11. 1H NMR (CDCl3), δ: 4.10 (s, 3 H, MeO); 7.40 (m,
3 H, CHAr); 7.90 (m, 2 H, CHAr). 19F NMR (CDCl3), δ: 7.20 (s).
Methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(4ꢀfluorobenzoylimino)propionate
(1c) was obtained analogously from 4ꢀfluorobenzamide (13.9 g,
0.1 mol). The yield was 19.1 g (69%), b.p. 111—113 °C (2 Torr).
Found (%): C, 47.01; H, 2.35. C11H7F4NO3. Calculated (%):
C, 47.67; H, 2.55. 1H NMR (CDCl3), δ: 3.90 (s, 3 H, MeO);
7.10—7.20, 8.00—8.10 (both m, 2 H each, CHAr). 19F NMR
(CDCl3), δ: 7.41 (s, 3 F, CF3); –38.20 (m, 1 F, CFAr).
Methyl 2ꢀ(4ꢀchlorobenzoylimino)ꢀ3,3,3ꢀtrifluoropropionate
(1d) was obtained analogously from 4ꢀchlorobenzamide (15.5 g,
0.1 mol). The yield was 22.4 g (76%), b.p. 138—140 °C (2 Torr).
Found (%): C, 44.72; H, 2.16. C11H7ClF3NO3. Calculated (%):
C, 45.00; H, 2.40. 1H NMR (CDCl3), δ: 4.15 (s, 3 H, MeO);
7.30, 7.85 (both d, 2 H each, CHAr, JH,H = 8.0 Hz). 19F NMR
(CDCl3), δ: 7.32 (s).
Methyl 2ꢀ(benzothiazolꢀ2ꢀylimino)ꢀ3,3,3ꢀtrifluoropropionate
(1e) was obtained analogously from 2ꢀaminobenzothiazole
(15.0 g, 0.1 mol). The yield was 22.1 g (73%), m.p. 143—145 °C.
Found (%): C, 45.56; H, 2.23. C11H7F3N2O2S. Calculated (%):
C, 45.84; H, 2.45. 1H NMR (CDCl3), δ: 3.95 (s, 3 H, MeO);
7.10, 7.25 (both m, 1 H each, CHAr); 7.60 (m, 2 H, CHAr).
19F NMR (CDCl3), δ: 6.33 (s).
Scheme 3
Methyl
2ꢀbenzoylaminoꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(3ꢀmethylꢀ
ureido)propionate (3c). Imine 1b (1.30 g, 5 mmol) was added to a
suspension of Nꢀmethylurea 2a (0.37 g, 5 mmol) in benzene
(5 mL). The reaction mixture was stirred for 1 h. The solvent
was removed and the residue was recrystallized from benꢀ
zene—hexane (1 : 1). The yield was 1.05 g (63%).
Methyl 2ꢀbenzoylaminoꢀ2ꢀ(3ꢀbenzylureido)ꢀ3,3,3ꢀtrifluoroꢀ
propionate (3d) was obtained analogously from Nꢀbenzylurea 2d
(0.75 g, 5 mmol) and imine 1b (1.30 g, 5 mmol). The yield was
1.51 g (74%).
Melting points, spectroscopic characteristics, and elemental
analysis data for compounds 3c,d are given in Tables 1 and 2.
5ꢀAcetylaminoꢀ3ꢀmethylꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀ
dione (4a). A solution of imine 1a (1.0 g, 5.1 mmol) and
Nꢀmethylurea 2a (0.38 g, 5.2 mmol) in DMF (5 mL) and Et3N
(0.05 g, 0.5 mmol) were heated at 90 °C for 3 h and then diluted
with water (100 mL). The precipitate that formed was filtered
off and recrystallized from benzene—hexane (1 : 1). The yield
was 0.99 g (82%).
5: R = Bz, R´ = Me (a); R = Bz, R´ = Bn (b)
1
In the H NMR spectra of ureas 5, the signal for the
proton of the CH—CF3 fragment appears as a characterꢀ
istic sextet at δ 6.3 (JH,H = JH,F = 7 Hz). The signals for
the CF3 group at δ ~2.5 (d, JH,F = 7 Hz) in the 19F NMR
spectra of these compounds confirmed the proposed
structure.
Thus, the cyclocondensation of Nꢀsubstituted imines
of methyl trifluoropyruvate with monosubstituted ureas
opens up broad possibilities for the synthesis of novel
5ꢀaminoꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdiones and
various aminals of trifluoroacetaldehyde.
Experimental
5ꢀBenzoylaminoꢀ3ꢀmethylꢀ5ꢀtrifluoromethylimidazolidineꢀ
2,4ꢀdione (4c). A. A solution of propionate 3c (0.5 g, 1.5 mmol)
and Et3N (0.05 g, 0.5 mmol) in benzene (5 mL) was refluxed for
3 h. The solvent was removed and the residue was recrystallized
from benzene—hexane (1 : 1). The yield was 0.35 g (77%).
B. A solution of imine 1b (1.0 g, 3.8 mmol), Nꢀmethylurea
2a (0.28 g, 3.8 mmol), and Et3N (0.05 g, 0.5 mmol) in DMF
(5 mL) was heated at 90 °C for 3 h and then diluted with
water (100 mL). The precipitate that formed was filtered off and
recrystallized from benzene—hexane (1 : 1). The yield was
0.96 g (75%).
1
H and 19F NMR spectra were recorded on a Bruker
DPX 200 spectrometer. Melting points were determined in glass
capillaries. Commercial monosubstituted ureas 2 (Aldrich,
Lancaster) were used.
Methyl 2ꢀacetyliminoꢀ3,3,3ꢀtrifluoropropionate (1a). Quinoꢀ
line (25.8 g, 0.2 mol), methyl trifluoropyruvate (15.6 g, 0.1 mol),
and POCl3 (15.4 g, 0.1 mol) were successively added to a susꢀ
pension of acetamide (5.9 g, 0.1 mol) in benzene (50 mL). The
reaction mixture was stirred for 1 h and filtered. The solvent was
removed and the residue was fractionated. The yield of imine 1a

1054
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Aksinenko et al.
Table 1. Yields, melting points, and elemental analysis data for compounds 3c,d, 4a—l, and 5a,b
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
C
H
N
3c
3d
4a
4b
4c
4d
4e
4f
63
74
82
87
177—178
119—121
245—247
110—117
176—178
143—144
195—197
128—129
158—159
153—154
227—229
213—215
205—206
142—144
255—257
239—241
46.89
46.85
55.79
55.75
35.29
35.16
49.38
49.53
47.70
47.85
57.14
57.30
51.30
51.14
54.58
54.69
47.89
47.69
47.59
47.84
52.29
52.04
53.39
53.20
51.44
51.25
53.59
53.20
48.19
48.00
58.39
58.12
4.48
4.23
4.08
4.43
3.08
3.37
3.95
3.84
3.33
3.35
3.54
3.74
2.53
2.52
3.22
3.31
3.90
4.00
2.52
2.76
2.52
2.83
3.47
3.22
4.34
4.30
3.52
3.22
4.47
4.39
4.47
4.59
12.48
12.61
10.08
10.26
17.63
17.57
13.52
13.33
13.83
13.95
11.05
11.14
10.62
10.52
10.33
10.63
11.39
11.12
10.36
10.46
14.12
14.28
13.84
13.79
14.24
14.06
13.82
13.79
15.44
15.27
11.84
11.96
C13H14F3N3O4
C19H18F3N3O4
C7H8F3N3O3
C13H12F3N3O3
C12H10F3N3O3
C18H14F3N3O3
C17H10F5N3O3
C18H13F4N3O3
77
75*
91
88*
89
90
92
93
96
93
91
88
4g
4h
4i
C15H15ClF3N3O3
C16H11ClF3N3O4
C17H11F3N4O2S
C18H13F3N4O2S
C17H17F3N4O2S
C18H13F3N4O2S
C11H12F3N3O2
C17H16F3N3O2
4j
4k
4l
5a
5b
71
78*
69
74*
* According to procedure B.
Table 2. 1H and 19F NMR spectra of compounds 3c,d, 4a—l, and 5a,b in DMSOꢀd6
Comꢀ
pound
δ (J/Hz)
1H
19F
3с
3d
2.60 (d, 3 H, MeN, JH,H = 7.0); 3.85 (s, 3 H, MeO); 6.35 (q, 1 H, NHMe,
JH,H = 7.0); 7.45 (m, 4 H, CHAr + NH); 7.90 (m, 2 H, CHAr); 8.90 (s, 1 H, NH)
3.80 (s, 3 H, MeO); 4.20 (m, 2 H, CH2N); 6.90—7.20 (m, 6 H, CHAr); 7.40 (m, 4 H,
CHAr + NH); 7.85 (m, 2 H, CHAr); 8.90 (s, 1 H, NH)
2.47 (s)
2.68 (s)
4a
4b
1.95 (s, 3 H, MeC); 2.95 (s, 3 H, MeN); 9.00, 9.37 (both s, 1 H each, NH)
1.95 (s, 3 H, MeC); 4.60 (m, 2 H, AB system, CH2N, J = 14.0); 7.10—7.25
(m, 5 H, CHAr); 9.20, 9.45 (both s, 1 H each, NH)
0.31 (s)
–0.23 (s)
4c
4d
3.00 (s, 3 H, Me); 7.45 (m, 3 H, CHAr); 7.90 (m, 2 H, CHAr); 9.15, 9.70
(both s, 1 H each, NH)
4.70 (m, 2 H, AB system, CH2); 7.20—7.60 (m, 8 H, CHAr); 7.90 (m, 2 H, CHAr);
9.20, 9.70 (both s, 1 H each, NH)
0.29 (s)
–0.16 (s)
(to be continued)

5ꢀAminoꢀ5ꢀtrifluoromethylhydantoins
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1055
Table 2 (continued)
Comꢀ
pound
δ (J/Hz)
1H
19F
4e
7.10—7.30 (m, 4 H, CHAr); 7.40—7.50, 8.00—8.10 (both m, 2 H each, CHAr);
9.60, 10.00 (both s, 1 H each, NH)
–35.10, –29.00
(both m, 1 F each);
0.53 (s, 3 F)
4f
4.70 (m, 2 H, AB system, CH2); 7.10—7.45 (m, 7 H, CHAr); 7.90—8.10
(m, 2 H, CHAr); 9.30, 9.80 (both s, 1 H each, NH)
–29.30 (m, 1 F);
0.33 (s, 3 F)
4g
0.90 (d, 6 H, Me, J = 7.0); 2.05 (m, 1 H, CH); 3.30 (d, 2 H, CH2, J = 8.0);
7.35 (d, 2 H, CHAr, J = 8.0); 7.90 (d, 2 H, CHAr, J = 7.0); 9.10, 9.70
(both s, 1 H each, NH)
0.15 (s)
4h
4.70 (m, 2 H, AB system, CH2); 6.27 (m, 2 H, CH of furan); 7.30—7.40 (m, 3 H,
CHAr + CH of furan); 7.90 (m, 2 H, CHAr); 9.25, 9.80 (both s, 1 H each, NH)
7.00—7.70 (m, 9 H, CHAr); 9.55, 9.70 (both s, 1 H each, NH)
2.45 (s, 3 H, Me); 7.05—7.40 (m, 7 H, CHAr); 7.65 (m, 1 H, CHAr); 9.40, 9.60
(both s, 1 H each, NH)
0.21 (s)
4i
4j
–0.33 (s)
–0.36 (s)
4k
1.00—1.40 (m, 3 H, CHAlk); 1.60—2.20 (m, 7 H, CHAlk); 3.90 (m, 1 H, CHN);
7.10, 7.20 (both t, 1 H each, CHAr, JH,H = 7.2); 7.40, 7.65 (both d, 1 H each, CHAr
JH,H = 7.2); 9.10, 9.45 (both s, 1 H each, NH)
4.65 (m, 2 H, CH2, JA,B = 12.0); 7.00—7.60 (m, 9 H, CHAr); 9.30, 9.50
(both s, 1 H each, NH)
–0.89 (s)
–0.57 (s)
,
4l
5a
2.65 (d, 3 H, MeN, JH,H = 7.0); 6.30 (quint, 1 H, CHCF3, JH,H = 7.0, JH,F = 7.0);
6.40 (q, 1 H, NHMe, JH,H = 7.0); 6.60 (d, 1 H, CHNH, JH,H = 7.0);
7.45 (m, 3 H, CHAr); 7.90 (m, 2 H, CHAr); 9.00 (d, 1 H, BzNH, JH,H = 7.0)
4.23 (m, 2 H, CH2); 6.25 (sext, 1 H, CHCF3, JH,F = 7.0, JH,H = 7.0);
6.72 (d, 1 H, NHCH, JH,H = 7.0); 6.90 (t, 1 H, NHCH2, JH,H = 7.0); 7.05—7.50
(m, 8 H, CHAr); 7.90 (m, 2 H, CHAr); 9.02 (d, 1 H, BzNH, JH,H = 7.0)
0.30 (d,
JH,F = 7.0)
5b
0.45 (d,
JH,F = 7.0)
5ꢀBenzoylaminoꢀ3ꢀbenzylꢀ5ꢀtrifluoromethylimidazolidineꢀ
2,4ꢀdione (4d) was obtained analogously according to proceꢀ
dures A and B.
yields, melting points, and spectroscopic characteristics of comꢀ
pounds 5a,b are given in Tables 1 and 2.
5ꢀAcetylaminoꢀ3ꢀbenzylꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀ
dione (4b), 5ꢀ(4ꢀfluorobenzoylamino)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ5ꢀ
trifluoromethylimidazolidineꢀ2,4ꢀdione (4e), 3ꢀbenzylꢀ5ꢀ(4ꢀ
fluorobenzoylamino)ꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione
(4f), 5ꢀ(4ꢀchlorobenzoylamino)ꢀ3ꢀisobutylꢀ5ꢀtrifluoromethylꢀ
imidazolidineꢀ2,4ꢀdione (4g), 5ꢀ(4ꢀchlorobenzoylamino)ꢀ3ꢀfurfuꢀ
rylꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4h), 5ꢀ(1,3ꢀbenzoꢀ
thiazolꢀ2ꢀylamino)ꢀ3ꢀphenylꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀ
dione (4i), 5ꢀ(1,3ꢀbenzothiazolꢀ2ꢀylamino)ꢀ3ꢀ(4ꢀmethylphenyl)ꢀ
5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4j), 5ꢀ(1,3ꢀbenzoꢀ
thiazolꢀ2ꢀylamino)ꢀ3ꢀcyclohexylꢀ5ꢀtrifluoromethylimidazolidineꢀ
2,4ꢀdione (4k), and 5ꢀ(1,3ꢀbenzothiazolꢀ2ꢀylamino)ꢀ3ꢀbenzylꢀ5ꢀ
trifluoromethylimidazolidineꢀ2,4ꢀdione (4l) were obtained as deꢀ
scribed for compound 4a. The yields, melting points, and specꢀ
troscopic characteristics of compounds 4a—l are given in
Tables 1 and 2.
Nꢀ[2,2,2ꢀTrifluoroꢀ1ꢀ(3ꢀmethylureido)ethyl]benzamide (5a).
A 1 M solution of KOH (1 mL) was added to a solution of
compound 3c (0.5 g, 1.5 mmol) (procedure A) or compound 4c
(0.5 g, 1.6 mmol) (procedure B) in DMF (5 mL). The reaction
mixture was refluxed for 3 h and then diluted with water (50 mL).
The precipitate that formed was filtered off and recrystallized
from 50% EtOH. The yields were 0.29 g (71%) (procedure A)
and 0.31 g (78%) (B).
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Received March 2, 2006;
in revised form April 13, 2006