Alkyl 2-chloro-3,3,3-trifluoro-2-isocyanatopropionates

Article abstract of DOI:10.1007/s11172-007-0354-z

Earlier unknown representatives of fluorine-containing α- chloroalkylisocyanates, viz., esters of 2-chloro-3,3,3-trifluoro-2- isocyanatopropionic acid, were obtained. Synthetic potentialities of these compounds in the preparation of 2-substituted derivatives of 3,3,3-trifluoroalanine were demonstrated.

Full text of DOI:10.1007/s11172-007-0354-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2255—2257, November, 2007
2255
Alkyl 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatopropionates

V. B. Sokolov, T. V. Goreva, T. A. Epishina, and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
Earlier unknown representatives of fluorineꢀcontaining αꢀchloroalkylisocyanates, viz., esꢀ
ters of 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatopropionic acid, were obtained. Synthetic potenꢀ
tialities of these compounds in the preparation of 2ꢀsubstituted derivatives of 3,3,3ꢀtriꢀ
fluoroalanine were demonstrated.
Key words: trifluoropyruvates, carbamates, isocyanates, amino acids, aminals, alcohols,
anilines, phosphorus pentachloride, organofluorine compounds.
Fluorineꢀcontaining αꢀchloroalkylisocyanates are imꢀ
portant subjects of organic chemistry.1 These compounds
can be considered as the synthetic blocks for the introꢀ
duction of fluorineꢀcontaining carbamine groups into the
molecules of acyclic and heterocyclic substances,2,3 in
addition, they are of interest as the precursors of various
fluorineꢀcontaining azomethines.4 The present work is
aimed at the synthesis of new representatives of fluorineꢀ
containing αꢀchloroalkylisocyanates, viz., esters of
2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatopropionic acid
(Scheme 1). These compounds have a specific feature
consisting in the simultaneous presence in their molecules
at the quaternary carbon atom of three fragments, interꢀ
esting from the synthetic point of view: the labile chlorine
atom, isocyanate and alkoxycarbonyl groups, the potenꢀ
tial electrophilic reaction centers. The presence in the
molecules 5a,b of pharmacophoric trifluoroalanine fragꢀ
ment, which in a number of cases defines the high bacteꢀ
riostatic activity of related compounds,5 is appreciated
from the quest for new potentially biologically active subꢀ
stances.
A synthetic protocol for the preparation of compounds
5a,b (see Scheme 1) consists in the chlorination of
hemiaminals 3a,b, which are obtained by the reaction of
urethane 1 with esters of trifluoropyruvic acid 2a,b upon
treatment with SOCl2. The subsequent dealkoxylation of
the intermediate compounds 4a,b upon reflux with PCl5
in POCl3 gives isocyanates 5a,b in 62 and 69% yield,
respectively.
Scheme 1
Isocyanates 5a,b are colorless mobile liquids with high
boiling points, their composition and structures were conꢀ
firmed by elemental analysis and 1Н and 19F NMR specꢀ
troscopy data, as well as by chemical transformations in
the reactions with nucleophilic reagents. Such reactions
enable one to realize synthetic potentialities of these new
bielectrophilic reagents, in particular, in the synthesis of
various 2ꢀsubstituted derivatives of 3,3,3ꢀtrifluoroalanine.
Isocyanates 5a,b exothermically react with isopropanol
(Scheme 2), leading to the corresponding carbamates 6a,b
in 81 and 78% yield. Their subsequent treatment with two
equivalents of primary amines results in the substitution
of the chlorine atom by the amino function to form
aminals 7a—d in 76—86% yield.
Compounds 7a—d are solid crystalline substances.
Their composition and structures were confirmed by elꢀ
emental analysis and 1Н and 19F NMR spectroscopy data.
19F NMR spectra contain a characteristic singlet in the
region δ 1—2.
R = Me (a), Et (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2179—2181, November, 2007.
1066ꢀ5285/07/5611ꢀ2255 © 2007 Springer Science+Business Media, Inc.

2256
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Sokolov et al.
Scheme 2
2 H, CH3CH2O); 6.44 (s, 1 H, NH). 19F NMR (CDCl3), δ:
1.48 (s, CF3).
Ethyl 2ꢀchloroꢀ2ꢀ(Nꢀethoxycarbonylamino)ꢀ3,3,3ꢀtrifluoroꢀ
propionate (4b) was obtained similarly to ester 4a. The yield
was 87%, b.p. 83—85 °C (2 Torr). Found (%): C, 34.45; H, 3.82;
N, 5.18. C8H11ClF3NO4. Calculated (%): C, 34.61; H, 3.99;
N, 5.05. 1H NMR (CDCl3), δ: 1.20 (t, 3 H, CH3CH2O, J =
7.2 Hz); 1.26 (t, 3 H, CH3CH2O, J = 7.4 Hz); 4.10, 4.30 (both m,
2 H each, CH3CH2O); 6.38 (s, 1 H, NH). 19F NMR (CDCl3),
δ: 1.43 (s, CF3).
Methyl 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatopropionate (5a).
A mixture of compound 4а (13.2 g, 0.05 mol) and PCl5 (10.4 g,
0.05 mol) in POCl3 (30 mL) was refluxed for 2 h. Then, POCl3
was evaporated and the residue was fractionally distilled in vacuo
to obtain 7.5 g (69%) of isocyanate 5a, b.p. 30—32 °C (18 Torr).
Found (%): C, 27.49; H, 1.22; N, 6.27. C5H3ClF3NO3. Calcuꢀ
lated (%): C, 27.61; H, 1.39; N, 6.44. 1H NMR (CDCl3), δ: 3.94
(s, MeO). 19F NMR (CDCl3), δ: 0.07 (s, CF3).
6: R = Me (a), Et (b)
7: R = Me, R´ = 5ꢀchloropyridinꢀ2ꢀyl (a); R = Et,
R´ = 3ꢀMeC6H4 (b); R = Et, R´ = 4ꢀMeC6H4 (c);
R = Et, R´ = 3ꢀF3CC6H4 (d)
Ethyl 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatopropionate (5b)
was obtained similarly to ester 5a. The yield was 62%, b.p.
35—36 °C (15 Torr). Found (%): C, 31.28; H, 2.33; N, 6.23.
C6H5ClF3NO3. Calculated (%): C, 31.12; H, 2.18; N, 6.05.
1H NMR (CDCl3), δ: 1.20 (t, 3 Н, CH3CH2O, J = 7.4 Hz); 4.28
(m, 2 H, CH3CH2O). 19F NMR (CDCl3), δ: 0.03 (s, CF3).
Methyl 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(Nꢀisopropoxycarbonylꢀ
amino)propionate (6a). Isopropanol (1.2 g, 0.02 mol) was added
to a solution of isocyanate 5а (4.4 g, 0.02 mol) in benzene
(20 mL). The reaction mixture was stirred for 2 h, benzene was
evaporated, and the residue was fractionally distilled in vacuo to
obtain 4.5 g (81%) of product 6а, b.p. 74—75 °C (1 Torr).
Found (%): C, 34.45; H, 3.82; N, 5.18. C8H11ClF3NO4. Calcuꢀ
lated (%): C, 34.61; H, 3.99; N, 5.05. 1H NMR (CDCl3), δ: 1.28
(d, 6 H, Me, J = 7.1 Hz); 3.93 (s, 3 H, MeO); 4.97 (m, 1 H,
CHO); 6.05 (s, 1 H, NH). 19F NMR (CDCl3), δ: 0.86 (s, CF3).
Ethyl 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(Nꢀisopropoxycarbonylꢀ
amino)propionate (6b) was obtained similarly to ester 6а. The
yield was 78%, b.p. 78—80 °C (1 Torr). Found (%): C, 37.21;
H, 4.62; N, 4.65. C9H13ClF3NO4. Calculated (%): C, 37.06;
H, 4.49; N, 4.80. 1H NMR (CDCl3), δ: 1.28 (d, 6 H, Me, J =
7.1 Hz); 1.38 (t, 3 H, CH3CH2O, J = 8.6 Hz); 4.41 (m, 2 H,
CH3CH2O); 4.97 (m, 1 H, CHO); 6.05 (s, 1 H, NH). 19F NMR
(CDCl3), δ: 0.92 (s, CF3).
Isocyanates 5 can be successfully used for the syntheꢀ
sis of Nꢀalkoxycarbonylimines of trifluoropyruvic acid esꢀ
ters. The sequential treatment of compound 5а with ethaꢀ
nol and pyridine in benzene affords Nꢀethoxycarbonylꢀ
imine 8 in 81% yield (Scheme 3).
Scheme 3
In conclusion, polyfunctional αꢀchloroꢀsubstituted
isocyanates, viz., 2ꢀchloroꢀ3,3,3ꢀtrifluoroꢀ2ꢀisocyanatoꢀ
propionic acid esters, synthesized by us for the first time,
are prospective synthons for the synthesis of 2ꢀsubstituted
3,3,3ꢀtrifluoroalanine derivatives, as well as Nꢀalkoxyꢀ
carbonylimines of trifluoropyruvic acid esters, potential
1,2ꢀbielectrophiles in the cyclocondensation reaction.6
Methyl 2ꢀ(5ꢀchloropyridinꢀ2ꢀyl)aminoꢀ3,3,3ꢀtrifluoroꢀ2ꢀ
(Nꢀisopropoxycarbonylamino)propionate (7a). 2ꢀAminoꢀ5ꢀ
chloropyridine (1.28 g, 0.01 mol) was added to a stirred solution
of compound 6a (1.40 g, 0.005 mol) in THF (20 mL). The
reaction mixture was stirred for 1 h, 2ꢀaminoꢀ5ꢀchloropyridine
hydrochloride was filtered off, the filtrate was concentrated, and
the residue was recrystallized from hexane to obtain 1.4 g (81%)
of compound 7а, m.p. 111—113 °C. Found (%): C, 42.38;
H, 4.25; N, 11.12. C13H15ClF3N3O4. Calculated (%): C, 42.23;
H, 4.09; N, 11.37. 1H NMR (DMSOꢀd6), δ: 1.09, 1.18 (both d,
3 Н each, Me, J = 6.3 Hz); 3.79 (s, 3 H, OMe); 4.71 (m, 1 H,
CH); 6.94 (m, 2 Н, CHAr + NH); 7.43 (dd, 1 H, CHAr, J =
9.3 Hz, J = 3.0 Hz); 7.92 (m, 2 Н, CHAr + NH). 19F NMR
(DMSOꢀd6), δ: 1.98 (s, CF3).
Experimental
1
H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in a
glass capillary tube. The starting compounds, urethane 1,
trifluoropyruvates 2a,b, anilines, and 2ꢀaminoꢀ5ꢀchloropyridine
(Aldrich) were used as purchased.
Methyl 2ꢀchloroꢀ2ꢀ(Nꢀethoxycarbonylamino)ꢀ3,3,3ꢀtriꢀ
fluoropropionate (4a). Methyl trifluoropyruvate 2а (15.6 g,
0.1 mol) was added to urethane 1 (8.9 g, 0.1 mol). After the
exothermic reaction was over, SOCl2 (11.9 g, 0.1 mol) was added
to this. The reaction mixture was heated for 2 h at 80 °C, after
which it was subjected to the fractional distillation to obtain
22.8 g (84%) of compound 4a, b.p. 80—82 °C (2 Torr).
Found (%): C, 31.75; H, 3.29; N, 5.48. C7H9ClF3NO4. Calcuꢀ
lated (%): C, 31.90; H, 3.44; N, 5.31. 1H NMR (CDCl3), δ: 1.25
(t, 3 H, CH3CH2O, J = 7.2 Hz); 3.94 (s, 3 H, MeO); 4.12 (m,
Ethyl 3,3,3ꢀtrifluoroꢀ2ꢀ(Nꢀisopropoxycarbonylamino)ꢀ2ꢀ
(3ꢀmethylphenylamino)propionate (7b) was obtained similarly to
compound 7а. The yield was 79%, m.p. 98—99 °C. Found (%):
C, 52.21; H, 5.68; N, 7.92. С16H21F3N2O4. Calculated (%):
C, 52.04; H, 5.84; N, 7.73. 1H NMR (DMSOꢀd6), δ: 0.92, 1.09

3,3,3ꢀTrifluoroꢀ2ꢀisocyanatopropionates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2257
(both d, 3 Н each, Me, J = 7.1 Hz); 1.31 (t, 3 H, CH3CH2O, J =
8.6 Hz); 2.22 (s, 3 H, MeAr); 4.38 (m, 2 H, CH3CH2O); 4.72
(m, 1 H, CHO); 7.07 (t, 1 H, CHAr, J = 6.3 Hz); 6.62—6.82 (m,
5 H, CHAr + 2 NH). 19F NMR (DMSOꢀd6), δ: 1.97 (s, CF3).
Ethyl 3,3,3ꢀtrifluoroꢀ2ꢀ(Nꢀisopropoxycarbonylamino)ꢀ2ꢀ
(4ꢀmethylphenylamino)propionate (7c) was obtained similarly to
compound 7а. The yield was 82%, m.p. 79—80 °C. Found (%):
C, 52.17; H, 5.69; N, 7.61. С16H21F3N2O4. Calculated (%):
C, 52.04; H, 5.84; N, 7.73. 1H NMR (DMSOꢀd6), δ: 0.91, 1.06
(both d, 3 Н each, Me, J = 6.4 Hz); 1.31 (t, 3 H, CH3CH2O, J =
7.1 Hz); 2.18 (s, 3 H, MeAr); 4.32 (m, 2 H, CH3CH2O); 4.61
(m, 1 H, CHO); 6.86, 6.98 (both d, 2 Н, CHAr, J = 8.3 Hz);
7.22, 7.92 (both s, 1 H each, NH). 19F NMR (DMSOꢀd6), δ:
1.91 (s, CF3).
Ethyl 3,3,3ꢀtrifluoroꢀ2ꢀ(Nꢀisopropoxycarbonylamino)ꢀ2ꢀ
(3ꢀtrifluoromethylphenylamino)propionate (7d) was obtained simiꢀ
larly to compound 7а. The yield was 86%, m.p. 75—77 °C.
Found (%): C, 46.32; H, 4.11; N, 6.88. C16H18F6N2O4. Calcuꢀ
lated (%): C, 46.16; H, 4.36; N, 6.73. 1H NMR (DMSOꢀd6), δ:
0.93, 1.08 (both d, 3 Н each, Me, J = 6.5 Hz); 1.26 (t, 3 H,
CH3CH2O, J = 8.8 Hz); 4.37 (m, 2 H, CH3CH2O); 4.64 (m,
1 H, CHO); 5.99 (s, 1 H, CHAr); 7.18 (m, 3 H, CHAr + NH);
7.34 (m, 2 H, CHAr + NH). 19F NMR (DMSOꢀd6), δ: 1.95, 15.6
(both s, 3 F each, CF3).
reaction mixture was stirred for 2 h and filtered, the filtrate was
concentrated, and the residue was distilled to obtain 9.2 g (81%)
of imine 8, b.p. 52—53 °C (3 Torr). Found (%): C, 37.21;
H, 3.72; N, 6.33. C7H8F3NO4. Calculated (%): C, 37.02;
H, 3.55; N, 6.17. 1H NMR (CDCl3), δ: 1.31 (t, 3 H, CH3CH2O,
J = 7.4 Hz); 4.05 (s, 3 H, MeO); 4.18 (m, 2 H, CH3CH2O).
19F NMR (CDCl3), δ: 7.28 (s, CF3).
References
1. V. I. Gorbatenko and L. I. Samarai, Synthesis, 1980, 85.
2. L. I. Samarai, V. I. Gorbatenko, and M. V. Vovk, Ukr. Khim.
Zh. [Ukrainian Chem. J.], 1989, 85, 966 (in Russian).
3. O. V. Korenchenko, A. Yu. Aksinenko, V. B. Sokolov, and
I. V. Martynov, J. Fluorine Chem., 1991, 54, 412.
4. O. V. Korenchenko, V. B. Sokolov, A. Yu. Aksinenko, and
I. V. Martynov, Izv. Akad. Nauk SSSR, Ser. Khim., 1990,
373 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1990, 39, 313
(Engl. Transl.)].
5. C. W. Fearon, J. A. Rodkey, and R. H. Abeles, Biochemistry,
1982, 21, 3790.
6. V. B. Sokolov and A. Yu. Aksinenko, Izv. Akad. Nauk, Ser.
Khim., 2003, 2053 [Russ. Chem. Bull., Int. Ed., 2003,
52, 2167].
Methyl 2ꢀ(Nꢀethoxycarbonylimino)ꢀ3,3,3ꢀtrifluoropropionate
(8). Ethanol (3.0 g, 0.05 mol) was added to a stirred solution of
isocyanate 5а (10.9 g, 0.05 mol) in benzene (20 mL) at 20 °C,
after 30 min, pyridine (3.6 g, 0.05 mol) was added, too. The
Received July 17, 2007