Cyclocondensation of 2-alkoxy-2-isocyanato-3,3,3-trifluoropropionates with primary amines

Article abstract of DOI:10.1007/s11172-012-0100-z

Cyclocondensation of ethyl 2-alkoxy-2-isocyanato-3,3,3-trifluoropropianates (novel 1,4-bielectrophiles) with primary amines resulted in 5-trifluoromethylimidazolidine-2,4-diones.

Full text of DOI:10.1007/s11172-012-0100-z

Russian Chemical Bulletin, International Edition, Vol. 61, No. 3, pp. 670—673, March, 2012
670
Cyclocondensation of 2ꢀalkoxyꢀ2ꢀisocyanatoꢀ3,3,3ꢀtrifluoropropionates
with primary amines
V. B. Sokolov, T. V. Goreva, T. A. Epishina, and A. Yu. Aksinenko
Institute of Physiologically Active Substances, Russian Academy of Sciences,
1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
Cyclocondensation of ethyl 2ꢀalkoxyꢀ2ꢀisocyanatoꢀ3,3,3ꢀtrifluoropropianates (novel
1,4ꢀbielectrophiles) with primary amines resulted in 5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdiones.
Key words: isocyanates, amines, imidazolidineꢀ2,4ꢀdiones, organofluorine compounds,
1,4ꢀbielectrophiles, cyclocondensation, heterocyclization.
Earlier,1 we reported on the synthesis of novel polyꢀ
Scheme 1
functional ꢀsubstituted isocyanates, esters of 2ꢀalkoxyꢀ
2ꢀisocyanatoꢀ3,3,3ꢀtrifluoropropionic acids. They are
promising intermediates for the synthesis of various acyclic
3,3,3ꢀtrifluoroalanine derivatives substituted at the posiꢀ
tion 2. The latter, taking into account the high bacterioꢀ
static activity of 3,3,3ꢀfluoroalanine, are potent biologiꢀ
cally active substances.2,3 These compounds can be reꢀ
garded as derivatives of trifluoropyruvates; some of them,
e.g., Nꢀsubstituted imines of trifluoropyruvates, are sucꢀ
cessfully used for the synthesis of fluorinated heterocyclic
compounds,4—8 also as 1,3ꢀbielectrophiles in the cycloꢀ
condensation reactions.9—13 In the present work, we studꢀ
ied chemical behavior of these novel 1,4ꢀbielectrophiles,
ethyl 2ꢀalkoxyꢀ2ꢀisocyanatoꢀ3,3,3ꢀtrifluoropropionates
1a,b, in the cyclocondensation with primary amines 2a—k
(Scheme 1).
Reaction of isocyanates 1a,b with amines 2a—k acting
in these transformations as 1,1ꢀbinucleophiles proceeded
as cyclocondensation involving (1) addition of amine to
the C=N bond to give the corresponding urea 3 and (2)
subsequent heterocyclization with removal of EtOH to
yield imidazolidineꢀ2,4ꢀdiones 4а—l. Reactions were perꢀ
formed by mixing equimolar amounts of isocyanate 1 and
amine 2 in DMF at 20 С with further heating of the
reaction mixture at 90—100 С for 2 h in the presence of
catalytic amounts of Et3N.
1: Alk = Et (a), Pr (b)
2: R = Ph (a), 3ꢀClC6H4 (b), 4ꢀMeOC6H4 (c), 4ꢀMe2CHC6H4 (d),
3ꢀCF3C6H4 (e), 4ꢀCF3C6H4 (f), 3ꢀClꢀ4ꢀFC6H3 (g),
5ꢀFꢀ2ꢀMeC6H3 (h), 5ꢀClꢀ2ꢀMeOC6H3 (i), CH2CH2Ph (j),
2ꢀPyСH2 (k)
4: Alk = Et, R = 3ꢀClC6H4 (a), 4ꢀMeOC6H4 (b), 3ꢀCF3C6H4 (c),
3ꢀClꢀ4ꢀFC6H3 (d), 2ꢀMeꢀ5ꢀFC6H3 (e)
Alk = Pr, R = Ph (f), CH2CH2Ph (g), 2ꢀPyCH2 (h), 4ꢀCF3C6H4 (i),
4ꢀMe2CHC6H4 (j), 3ꢀClC6H4 (k), 5ꢀClꢀ2ꢀMeOC6H3 (l)
In the case of isocyanate 1а and 3ꢀchloroaniline 2b, we
succeeded to isolate and characterize the individual inꢀ
termediate adducts, urea 3a. The latter was converted
into imidazolidineꢀ2,4ꢀdione 4а by heating in DMF at
90—100 С for 2 h in the presence of catalytic amounts of
Et3N (Scheme 2).
Imidazolidineꢀ2,4ꢀdiones 4a—l synthesized in 65—79%
yields are crystalline compounds. Composition and strucꢀ
ture of 4a—l were established by elemental analysis and
1Н and 19F NMR spectroscopy. 19F and NMR spectra
exhibited singlets in the range of  –(2—3) characteristic
of the trifluoromethyl group; 1Н NMR spectra contained
singlets in the range of  10—11 attributed to the protons
of the NH group.
In summary, in the present work we introduced novel
1,4ꢀbielectrophiles promising for cyclocondensation reꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 667—670, March, 2012.
1066ꢀ5285/12/6103ꢀ670 © 2012 Springer Science+Business Media, Inc.

Fluorinated hydantoins
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 3, March, 2012
671
Scheme 2
that hydantoins are widely used in medical (anticonvulꢀ
sants,14 anticancer15 agents) and agrochemical (herbiꢀ
cides16) practice.
Experimental
1
19
H and F 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 the glass
capillary and uncorrected. The starting isocyanates 1a,b were
synthesized according to the known procedure,1 amines 2a—k
(Aldrich) were used as purchased.
Ethyl 2ꢀ[3ꢀ(3ꢀchlorophenyl)ureido]ꢀ2ꢀethoxyꢀ3,3,3ꢀtrifluoꢀ
ropropionate (3a). To a solution of isocyanate 1a (0.01 mol) in
benzene (20 mL), aniline 2b (0.01 mol) was added. After comꢀ
pletion of the exothermic reaction, the mixture was stirred for
2 h, the solvent was removed in vacuo, the residue was recrystalꢀ
lized from hexane. Yield, melting points, elemental analysis data,
and spectral data for compound 3а are given in Tables 1 and 2.
3ꢀ(3ꢀChlorophenyl)ꢀ5ꢀethoxyꢀ5ꢀtrifluoromethylimidazolidineꢀ
2,4ꢀdione (4а). А. To a solution of urea 3a (0.01 mol) in DMF
(10 mL), Et3N (0.1 g) was added. The reaction mixture was
heated at 80 С for 1 h, then water (50 mL) was added, the
precipitate formed was recrystallized from hexane.
actions, esters of 2ꢀalkoxyꢀ2ꢀisocyanatoꢀ3,3,3ꢀtrifluoroꢀ
propionic acids. These compounds could be used for the
synthesis of various fluorinated hydantoins. It is of note
Tables 1. Yields, melting points, and elemental analysis data for compounds 3a and 4a—l
Comꢀ
pound
Yield (%)
M.p./С
Molecular
formula
Found
Calculated
(%)
C
H
N
3a
4a
4b
4c
4d
4e
4f
88
142—143
C14H16ClF3N2O4
C12H10ClF3N2O3
C13H13F3N2O4
C13H10F6N2O3
C12H9ClF4N2O3
C13H12F4N2O3
C13H13F3N2O3
C15H17F3N2O3
C13H14F3N3O3
C14H12F6N2O3
C16H19F3N2O3
C13H12ClF3N2O3
C14H14ClF3N2O4
46.74
45.60
44.67
44.78
46.06
46.21
43.83
43.64
42.31
42.12
48.76
78.57
51.66
51.47
54.54
54.36
49.22
49.03
45.42
45.26
55.81
55.63
46.38
46.17
45.85
45.59
4.51
4.37
3.12
3.34
4.12
4.35
2.83
2.98
2.66
2.45
3.78
3.95
4.34
4.15
5.19
5.36
4.45
4.27
3.27
3.12
5.56
5.38
3.59
3.75
3.85
3.62
7.82
7.60
8.68
8.51
8.80
8.59
7.86
7.58
8.22
8.44
8.75
8.56
9.27
9.05
8.48
8.29
13.24
13.45
7.57
7.35
8.14
8.32
8.32
8.14
7.64
7.46
81(A), 73 (B) 107—108
65
72
74
69
68
79
75
71
66
79
73
161—162
75—76
126—127
127—128
84—85
4g
4h
4i
97—98
107—108
91—92
4j
110—111
74—75
4k
4l
116—118

672
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 3, March, 2012
Sokolov et al.
Table 2. 1Н and 19F NMR spectra (DMSOꢀd6) of compounds 3a and 4a—l
Compound
1H NMR,  (J/Hz)
19F NMR, 
3a
1.26 (t, 3 H, CH3CH2O, J = 7.5); 1.32 (t, 3 H, CH3CH2O, J = 7.5);
3.72—3.94 (m, 2 H, CH3CH2O); 4.31 (m, 2 H, CH3CH2O);
6.64 (s, 1 H, CHAr); 7.12 (m, 1 H, CHAr); 7.28 (m, 2 H, CHAr);
7.56 (s, 1 H, NH); 7.68 (s, 1 H, NH)
–0.24 (s, CF3)
4a
4b
1.31 (t, 3 H, CH3CH2O, J = 7.4); 3.72—3.94 (m, 2 H, CH3CH2O);
6.64 (s, 1 H, CHAr); 7.12 (m, 1 H, CHAr); 7.28 (m, 2 H, CHAr);
9.56 (s, 1 H, NH)
–2.12 (s, CF3)
—2.16 (s, CF3)
1.42 (t, 3 H, CH3CH2O, J = 7.6); 3.69 (s, 3 H, MeO); 3.92—4.21
(m, 2 H, CH3CH2O); 6.81, 7.32 (both d, 2 H, CHAr, J = 8.6);
10.05 (s, 1 H, NH)
4c
4d
1.35 (t, 3 H, CH3CH2O, J = 7.4); 3.78—4.01 (m, 2 H, CH3CH2O);
7.15—7.26 (m, 2 H, CHAr); 7.36 (m, 2 H, CHAr); 9.88 (s, 1 H, NH)
–2.8 (s, CF3);
15.71 (s, CF3)
1.22 (t, 3 H, CH3CH2O, J = 7.5); 3.98 (m, 1 H, CH3CH2O);
4.28 (m, 1 H, CH3CH2O); 7.23 (m, 2 H, CHAr); 7.41 (m, 1 H, CHAr);
10.12 (s, 1 H, NH)
–37.02 (m, 1 F, CFAr);
–2.11 (s, 3 F, CF3)
4e
4f
1.22 (t, 3 H, CH3CH2O, J = 7.5); 2.12 (s, 3 H, Me); 3.84 (m, 2 H,
CH3CH2O); 7.12 (m, 1 H, CHAr); 7.28 (m, 2 H, CHAr); 9.98 (s, 1 H, NH)
–37.93 (m, 1 F, CFAr);
–2.24 (s, 3 F, CF3)
1.10 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.82 (m, 2 H, CH3CH2CH2O);
3.99 (m, 2 H, CH3CH2CH2O); 6.98—7.29 (m, 5 H, CHAr);
9.81 (s, 1 H, NH)
–2.35 (s, CF3)
4g
4h
1.10 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.82 (m, 2 H, CH3CH2CH2O);
2.80 (t, 2 H, PhCH2CH2, J = 8.3); 3.82 (t, 2 H, PhCH2CH2, J = 8.3);
3.99 (m, 2 H, CH3CH2CH2O); 6.98—7.29 (m, 5 H, CHAr);
9.81 (s, 1 H, NH)
–2.43 (s, CF3)
0.99 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.88 (m, 2 H, CH3CH2CH2O);
–2.14 (s, CF3)
4.02 (m, 2 H, CH3CH2CH2O); 5.06 (s, 2 H, CH2); 7.32 (t, 1 H, CHAr
J = 7.3); 7.65 (d, 1 H, CHAr, J = 7.3); 8.35—8.62 (m, 2 H, CHAr);
10.23 (s, 1 H, NH)
,
4i
4j
4k
4l
1.12 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.87 (m, 2 H, CH3CH2CH2O);
3.91 (m, 2 H, CH3CH2CH2O); 7.12, 7.26 (both m, 2 H, CHAr);
10.08 (s, 1 H, NH)
–2.71 (s, CF3);
–15.96 (s, CF3)
0.96 (d, 6 H, Me, J = 7.1); 1.08 (t, 3 H, CH3CH2CH2O, J = 7.5);
1.92 (m, 1 H, Me2CH); 1.79 (m, 2 H, CH3CH2CH2O); 3.89 (m, 2 H,
CH3CH2CH2O); 6.81, 7.13 (both d, 2 H, CHAr, J = 8.1); 10.15 (s, 1 H, NH)
–2.20 (s, CF3)
–2.18 (s, CF3)
–2.21 (s, CF3)
1.08 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.79 (m, 2 H, CH3CH2CH2O);
3.89 (m, 2 H, CH3CH2CH2O); 6.88 (s, 1 H, CHAr); 7.19 (m, 1 H, CHAr);
7.36 (m, 2 H, CHAr); 9.86 (s, 1 H, NH)
1.02 (t, 3 H, CH3CH2CH2O, J = 7.5); 1.79 (m, 2 H, CH3CH2CH2O);
3.71 (s, 3 H, MeO); 3.89 (m, 2 H, CH3CH2CH2O); 7.02 (s, 1 H, CHAr);
7.28 (d, 1 H, CHAr, J = 7.9); 7.46 (d, 1 H, CHAr, J = 7.9); 10.16 (s, 1 H, NH)
B. To a stirred solution of aniline 2a (0.01 mol) in DMF (10 mL),
lidineꢀ2,4ꢀdione (4e), 3ꢀphenylꢀ5ꢀpropoxyꢀ5ꢀtrifluoromethylimiꢀ
dazolidineꢀ2,4ꢀdione (4f), 3ꢀ(2ꢀphenylethyl)ꢀ5ꢀpropoxyꢀ5ꢀtriꢀ
fluoromethylimidazolidineꢀ2,4ꢀdione (4g), 5ꢀpropoxyꢀ3ꢀ(pyridinꢀ
2ꢀylmethyl)ꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4h), 5ꢀpropꢀ
oxyꢀ5ꢀtrifluoromethylꢀ3ꢀ(4ꢀtrifluoromethylphenyl)imidazolidineꢀ
2,4ꢀdione (4i), 3ꢀ(4ꢀisopropylphenyl)ꢀ5ꢀpropoxyꢀ5ꢀtrifluoromeꢀ
thylimidazolidineꢀ2,4ꢀdione (4j), 3ꢀ(3ꢀchlorophenyl)ꢀ5ꢀpropoxyꢀ
5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4k), and 3ꢀ(5ꢀchloroꢀ
2ꢀmetoxyphenyl)ꢀ5ꢀpropoxyꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀ
dione (4l) were synthesized similarly to the method B. Yields,
melting points, elemental analysis data, and spectral data for
compounds 4b—l are given in Tables 1 and 2.
isocyanate 1а (0.01 mol) was added at 20 С. The reaction mixꢀ
ture was stirred for 1 h, then Et3N (0.1 g) was added and the
mixture was heated at 80 С for 1 h. Water (50 mL) was added,
the precipitate formed was recrystallized from hexane. Yield,
melting point, elemental analysis data, and spectral data for comꢀ
pound 4а are given in Tables 1 and 2.
5ꢀEthoxyꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀtrifluoromethylimidazoliꢀ
dineꢀ2,4ꢀdione (4b), 5ꢀethoxyꢀ5ꢀtrifluoromethylꢀ3ꢀ(3ꢀtrifluoroꢀ
methylphenyl)imidazolidineꢀ2,4ꢀdione (4c), 3ꢀ(3ꢀchloroꢀ4ꢀfluoroꢀ
phenyl)ꢀ5ꢀethoxyꢀ5ꢀtrifluoromethylimidazolidineꢀ2,4ꢀdione (4d),
5ꢀethoxyꢀ3ꢀ(5ꢀfluoroꢀ2ꢀmethylphenyl)ꢀ5ꢀtrifluoromethylimidazoꢀ

Fluorinated hydantoins
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 3, March, 2012
673
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This work was financially supported by the Departꢀ
ment of Chemistry and Materials Science of the Russian
Academy of Sciences (program "Medicinal and Bioꢀ
medicinal Chemistry").
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Received July 7, 2011;
in revised form January 20, 2012