Esters of 2-aryl-2-isocyanato-3,3,3-trifluoropropionic acid in cyclocondensation with amines

Article abstract of DOI:10.1134/S1070363212040111

The hitherto unknown representatives of fluorinated isocyanates, esters of 2-aryl-2-isocyanato-3,3,3-trifluoropropionic acid, were prepared. The synthetic potential of these compounds for preparation of trifluoromethylated hydantoins by the reactions of c

Full text of DOI:10.1134/S1070363212040111

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 4, pp. 672–675. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.B. Sokolov, T.A. Epishina, A.Yu. Aksinenko, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 4, pp. 586–589.
Esters of 2-Aryl-2-isocyanato-3,3,3-trifluoropropionic Acid
in Cyclocondensation with Amines
V. B. Sokolov, T. A. Epishina, and A. Yu. Aksinenko
Institute of Physiologically Active Compounds of Russian Academy of Sciences,
Chernogolovka, Moscow oblast, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received February 14, 2011
Abstract—The hitherto unknown representatives of fluorinated isocyanates, esters of 2-aryl-2-isocyanato-
3,3,3-trifluoropropionic acid, were prepared. The synthetic potential of these compounds for preparation of
trifluoromethylated hydantoins by the reactions of cyclocondensation with primary amines was demonstrated.
DOI: 10.1134/S1070363212040111
The derivatives of esters of trifluoropyruvic acid,
like N-substituted imines of trifluoropyruvates, are
successfully used in the synthesis of fluorinated hetero-
cyclic compounds [1–5]. The most promising in this
respect is the use of these reagents as 1,3-bielec-
trophiles in the reactions of cyclocondensation [6–10].
The goal of the present study is the synthesis of new
bielectrophiles based on ethyl fluoropyruvate, that is,
the esters of 2-aryl-2-isocyanato-3,3,3-trifluoropro-
pionic acid, and investigation of their behavior in the
reactions of cyclocondensation.
IIа, IIb to carbamates IIIа, IIIb, whose subsequent
dealkoxylation with phosphorus pentachloride results
in isocyanates IVа, IVb.
Ethoxycarbonylimine I reacts exothermally with
arylmagnesium bromides with the formation of the
corresponding carbamates IIа, IIb isolated in 74 and
68% yield, respectively. The composition and the
structure of compounds IIIа, IIIb were proved by the
1
19
data of elemental analysis and Н and F NMR spec-
troscopy. The characteristic signal in the 19F NMR spectra
1
is the singlet at 6.4–6.7 ppm, and in the Н NMR
The procedure of preparation of ethyl esters of 2-
aryl-2-isocyanato-3,3,3-trifluoropropionic acid (IVа,
IVb) includes the arylation of ethoxycarbonylimine of
ethyltrifluoropyruvate (I) with arylmagnesium bromides
spectra, the singlet of the NH proton at 6 ppm. The
subsequent dealkoxylation of carbamates IIIа, IIIb
upon reflux with PCl5 in the POCl3 solution for 2–3 h
gives rise to isocyanates IVа, IVb in 68–71% yield.
O
C2H5O(O)C
R
+
MgBr
N−C−OC2H5
F3C
I
IIa, IIb
C(O)OC2H5
C(O)OC2H5
NCO
PCl5
R
NH−C−OC2H5
R
O
CF3
CF3
IIIa, IIIb
IVa, IVb
II, III, IV: R = H (а), F (b).
672

ESTERS OF 2-ARYL-2-ISOCYANATO-3,3,3-TRIFLUOROPROPIONIC ACID
673
Isocyanates IVа, IVb are colorless mobile high-
boiling liquids prepared in 58 and 62% yield, respec-
tively, their composition and structure are proved by
the data of elemental analysis and the 1Н and 19F NMR
spectroscopy. The characteristic signal in the 19F NMR
spectra is the singlet at 4 ppm.
mechanism of addition of the binucleophile followed
by heterocyclization. Indeed, isocyanates IVа, IVb
react exothermally with amines to form ureas; the
subsequent heating of the latter in the presence of
catalytic amounts of Et3N results in the corresponding
imidazolidine-2,4-diones VIIа–VIIe. In the case of the
reaction of isocyanate IVa with 3-aminomethyl-
pyridine, urea VI was isolated as an individual com-
pound and characterized; after heating in DMF in the
presence of catalytic amounts of Et3N it was converted
into imidazolidine-2,4-dione VIIa.
The presence in the molecules of isocyanates IVа,
IVb of two functional groups, isocyanate and alkoxy-
carbonyl, allows regarding these compounds as 1,4-
bielectrophilic reagents in the reactions of cyclo-
condensation with binucleophiles proceeding via the
C(O)OC2H5
N
C(O)OC2H5
N
R
H2NCH2
R
NCO +
NH−C−NHCH2
O
CF3
IVa
CF3
Va
VI
CF3
HN
O
Et3N
R
NH
N
CH2
O
VIIa
Imidazolidine-2,4-diones VIIа–VIIe are prepared
in 68–78% yield without isolation of the intermediate
adducts (ureas) by heating the equimolar amounts of
the reagents in DMF in the presence of catalytic
amounts of Et3N.
Compounds VIIа–VIIe are crystalline substances,
their composition and structure were proved by the
1
data of elemental analysis and the Н and 19F NMR
spectroscopy. The characteristic signal in the 19F NMR
spectra is the singlet of the trifluoromethyl group at 2–
1
3 ppm, and in the Н NMR spectra, the singlet of the
NH proton at 10–11 ppm.
C(O)OC2H5
Therefore, we have synthesized the hitherto un-
known representatives of fluorinated isocyanates:
esters of 2-aryl-2-isocyanato-3,3,3-trifluoropropionic
acid, which are promising synthons for preparation of
various fluorinated hydantoins by the reaction of
cyclocondensation.
H2N−R1
R
NCO +
CF3
IVa, IVb
Va−Ve
CF3
O
Et3N
R
EXPERIMENTAL
HN
NH
1H and 19F NMR spectra were recorded on a Bruker
DPX 200 spectrometer at 200.13 and 188.29 MHz in
CDCl3 relative to tetramethylsilane (internal reference)
and CF3COOH (external reference) respectively.
Melting points were determined in a glass capillary.
The starting ethoxycarbonylimine of ethyltri-
fluoropyruvate I was synthesized by the procedure
R1
O
VIIa−VIIe
IV: R = H (а), F (b); VII: R1 = (pyridin-3-yl)methyl (а), 5-
methylpyridi-2-yl (b), pyridin-2-yl (c), 2-(4-methoxy-
phenyl)ethyl (d), (furan-2-yl)methyl (e).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

674
SOKOLOV et al.
[11], amines VIIа–VIIe (Aldrich) were used without
additional purification.
The reaction mixture was stirred for 1 h, 50 ml of
water was added, the precipitate formed was crystal-
lized from hexane. Yield 3.1 g (81%), mp 148–150°С.
1Н NMR spectrum, δ, ppm: 1.14 t (3H, Me, J 7.4 Hz);
4.13 q (2H, CH2O, J 7.4 Hz); 4.34 m (2H, CH2N); 6.91
t (1H, NH, J 6.1 Hz); 7.29–7.56 m (7H, CHAr + NH);
7.75 d (1H, CHAr, J 9.1 Hz); 8.48 d (2H, CHAr,
J 9.3 Hz). F NMR spectrum, δ, ppm: 5.26 s. Found,
%: C 56.50; H 4.94; N 11.21. C18H18F3N3O3. Cal-
culated, %: C 56.69; H 4.76; N 11.02.
Ethyl 3,3,3-trifluoromethyl-2-phenyl-2-ethoxy-
carbonylaminopropionate (IIIа). To the solution of
0.1 mol of compound I in 100 ml of tetrahydrofuran at
0°С while stirring 0.1 mol of compound IIa in 100 ml
of tetrahydrofuran was added. The reaction mixture
was stirred for 1 h, 200 ml of water was added, the
organic layer was separated, dried over Na2SO4, and
evaporated, the residue was crystallized from hexane.
19
1
Yield 31.9 g (74%), mp 65–67°С. Н NMR spectrum,
5-Trifluoromethyl-3-(pyridin-3-yl)methyl-5-phenyl-
imidazolidine-2,4-dione (VIIа). a. To the solution of
0.005 mol of compound VI in 10 ml of DMF 0.1 g of
Et3N was added. The reaction mixture was heated for
1 h at 80°С, 50 ml of water was added, the precipitate
formed was crystallized from hexane. Yield 1.2 g
δ, ppm: 1.18–1.41 m (6H, Me); 4.17 q (2H, CH2O, J
7.1 Hz); 4.39 q (2H, CH2O, J 7.3 Hz); 5.96 s (1H,
NH); 7.42–7.60 m (5H, Ph). 19F NMR spectrum, δ,
ppm: 6.74 s. Found, %: C 52.44; H 5.26; N 4.55.
C14H16F3NO4. Calculated, %: C 52.67; H 5.05; N 4.39.
1
(72%), mp 147-149°С. Н NMR spectrum, δ, ppm:
Ethyl 3,3,3-trifluoromethyl-2-(4-fluoro-phenyl)-
4.64 s (2H, CH2N); 7.27 m (1H, CHAr); 7.42 m (3H,
CHAr); 7.61 d (1H, CHAr, J 8.6 Hz); 7.80 m (2H,
CHAr); 8.47 m (2H, CHAr); 10.28 s (1H, NH). 19F NMR
spectrum, δ, ppm: 2.58 s. Found, %: C 57.11; H 3.83;
N 12.34. C16H12F3N3O2. Calculated, %: C 57.32; H
3.61; N 12.53.
2-ethoxycarbonylaminopropionate
(IIIb)
was
prepared similarly to IIIа. Yield 68 %, mp 57–59°С.
1Н NMR spectrum, δ, ppm: 1.16 t (3H, Me, J 7.2 Hz);
1.45 t (3H, Me, J 7.3 Hz); 4.25 q (2H, CH2O, J 7.1 Hz);
4.44 q (2H, CH2O, J 7.3 Hz); 6.09 s (1H, NH); 7.46 d
(2H, CHAr); 7.78 m (2H, CHAr). 19F NMR spectrum, δ,
ppm: 6.49 s (3F, CF3); –42.70 m (1F, CFAr). Found, %:
C 50.11; H 4.59; N 4.02. C14H15F4NO4. Calculated, %:
C 49.86; H 4.48; N 4.15.
b. To the solution of 0.005 mol of compound IVa
in 10 ml of DMF 0.005 mol of compound Va was
added at 20°С while stirring. The reaction mixture was
stirred for 1 h, 50 ml of water was added, the pre-
cipitate formed was crystallized from hexane. Yield
1.3 g (78%).
Ethyl 3,3,3-trifluoro-2-isocyanato-2-phenylpro-
pionate (IVa). The mixture of 0.05 mol of compound
IIIa and 0.05 mol of PCl5 in 30 ml of POCl3 was
refluxed for 2 h, POCl3 was removed, the residue was
distilled. Yield 8.1 g (59 %), bp 106–108°С (1 mm Hg).
1Н NMR spectrum, δ, ppm: 1.22 t (3H, Me, J 7.1 Hz);
4.13 q (2H, CH2O, J 7.2 Hz); 7.32–7.53 m (5H, CHAr).
19F NMR spectrum, δ, ppm: 4.21 s. Found, %: C
52.55; H 3.91; N 5.30. C12H10F3NO3. Calculated, %: C
52.75; H 3.69; N 5.13.
3-(5-Methylpyridin-2-yl)-5-trifluoromethyl-5-
phenylimidazolidine-2,4-dione (VIIb) was prepared
similarly to VIIа (method b). Yield 73%, mp 150–
1
152°С. Н NMR spectrum, δ, ppm: 2.39 s (3H, Me);
7.20 d (1H, CHAr, J 8.5 Hz); 7.44 m (3H, CHAr); 7.59
d.d (1H, CHAr, J1 1 8.5 Hz, J2 2 2.8 Hz); 7.87 m (2H,
CHAr); 8.36 d (1H, CHAr, J 2.7 Hz); 10.40 s (1H, NH).
19F NMR spectrum, δ, ppm: 2.44 c. Found, %: C
57.14; H 3.83; N 12.32. C16H12F3N3O2. Calculated, %:
C 57.32; H 3.61; N 12.53.
Ethyl
3,3,3-trifluoro-2-isocyanato-2-(4-fluoro-
phenyl)propionate (IVb) was prepared similarly to
IVа. Yield 62%, bp 100–102°С (1 mm Hg). Н NMR
1
spectrum, δ, ppm: 1.29 t (3H, Me, J 7.2 Hz); 4.23 q
(2H, CH2O, J 7.3 Hz); 7.52 d (2H, CHAr); 7.61 m (2H,
CHAr). 19F NMR spectrum, δ, ppm: 4.11 s (3F, CF3);
–42.12 m (1F, CFAr). Found, %: C 49.68; H 3.33; N
4.63. C12H9F4NO3. Calculated, %: C 49.50; H 3.12; N
4.81.
3-Pyridin-2-yl-5-trifluoromethyl-5-(4-fluoro-
phenyl)imidazolidine-2,4-dione (VIIc) was prepared
similarly to VIIа (method b). Yield 70%, mp 182–
1
184°С. Н NMR spectrum, δ, ppm: 7.23 t (2Н CHAr,
J 8.2 Hz); 7.48 m (1H, CHAr); 7.82 m (1H, CHAr); 7.95
m (2H, CHAr); 8.58 d.d (1H, CHAr, J1 5.3 Hz, J2 2.0 Hz);
8.63 d (1H, CHAr, J 2.0 Hz); 10.66 s (1H, NH). 19F
NMR spectrum, δ, ppm: 2.69 s (3F, CF3); –42.12 m
(1F, CFAr). Found, %: C 53.33; H 2.45; N 12.21.
C15H9F4N3O2. Calculated, %: C 53.11; H 2.67; N 12.39.
Ethyl 3,3,3-trifluoromethyl-2-phenyl-2-(3-pyridin-
3-ylmethylureido)propionate (VI). To the solution of
0.01 mol of compound IVа in 20 ml of DMF at 20°С
while stirring 0.01 mol of compound Va was added.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

ESTERS OF 2-ARYL-2-ISOCYANATO-3,3,3-TRIFLUOROPROPIONIC ACID
3-[2-(4-Methoxyphenyl)ethyl]-5-trifluoromethyl- REFERENCES
675
5-(4-fluorophenyl)imidazolidine-2,4-dione (VIId) was
prepared similarly to VIIа (method b). Yield 68%, mp
143–145°С. 1Н NMR spectrum, δ, ppm: 2.81 and 3.65
t (2H, CH2, J 7.0 Hz); 3.78 s (3H, MeO); 6.62 and 6.97
d (2H, CHAr, J 8.4 Hz); 7.15 d (2H, CHAr, J 8.8 Hz);
7.77 m (2H, CHAr); 10.05 s (1H, NH). 19F NMR
spectrum, δ, ppm: 2.78 s (3F, CF3); –42.12 m (1F,
CFAr). Found, %: C 57.76; H 4.22; N 6.83. C19H16·
F4N2O3. Calculated, %: С 57.58; Н 4.07; N 7.07.
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5-Trifluoromethyl-5-(4-fluorophenyl)-3-(furan-
2-ylmethyl)imidazolidine-2,4-dione (VIIe) was
prepared similarly to VIIа (method b). Yield 76%, mp
1
111–113°С. Н NMR spectrum, δ, ppm: 4.63 s (2H,
CH2N); 6.27 d (2H, CHAr, J 8.4 Hz); 7.17 t (2H, CHAr,
J 8.8 Hz); 7.38 m (1H, CHAr); 7.87 m (2H, CHAr);
19
10.24 s (1H, NH). F NMR spectrum, δ, ppm: 2.51 s
(3F, CF3); –42.12 m (1F, CFAr). Found, %: С 52.47; Н
2.78; N 8.33. C15H10F4N2O3. Calculated, %: C 52.64;
H 2.95; N 8.19.
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ACKNOWLEDGMENTS
This work was performed with the financial support
from the Program “Biomolecular and Medicinal
Chemistry” of the Russian Academy of Sciences.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012