A convenient synthesis of 3,3,3-trifluoroalanine derivatives

Article abstract of DOI:10.1023/A:1021692717142

A one-pot synthesis of N-substituted 3,3,3-trifluoroalanine esters from alkyl trifluoropyruvates and carboxamides or substituted ureas was developed.

Full text of DOI:10.1023/A:1021692717142

2136
Russian Chemical Bulletin, International Edition, Vol. 51, No. 11, pp. 2136—2138, November, 2002
A convenient synthesis of 3,3,3ꢀtrifluoroalanine derivatives*
ꢀ
A. Yu. Aksinenko, A. N. Pushin, and V. B. Sokolov
Institute of Physiologically Active Substances, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 913 2113. Eꢀmail: alaks@ipac.ac.ru
A oneꢀpot synthesis of Nꢀsubstituted 3,3,3ꢀtrifluoroalanine esters from alkyl trifluoroꢀ
pyruvates and carboxamides or substituted ureas was developed.
Key words: Nꢀacylꢀ3,3,3ꢀtrifluoroalanine esters, reduction.
Scheme 1
Fluorineꢀcontaining amino acids and their derivatives
known to date have been obtained by syntheses: no such
amino acids occur in nature. Biological activity of these
compounds was studied. It was shown that 3,3,3ꢀtrifluoroꢀ
alanine examined to the greatest extent possesses bacteriꢀ
cidal activity owing to the inhibition of alanine racemase
and γꢀcystathionase of bacterial cells.1 The known methꢀ
ods for the synthesis of 3,3,3ꢀtrifluoroalanine and its deꢀ
rivatives are based on the reduction of hexafluoroacetone
or trifluoropyruvate Nꢀacylimines by tin dichloride, soꢀ
dium borohydride, cyclohexadiene, or trimethyl phosꢀ
phite2—5; in several cases, the syntheses involve laborꢀ
consuming intermediate stages. It is also of note that the
starting Nꢀacylamines are not easily accessible comꢀ
pounds.
We developed a convenient oneꢀpot method for the
synthesis of 3,3,3ꢀtrifluoroalanine derivatives, namely,
various Nꢀsubstituted trifluoroalanine esters from alkyl
trifluoropyruvates 1 and urethane, carboxamides, and
Nꢀsubstituted ureas 2a—k. The procedure does not reꢀ
quire sophisticated equipment and consists in successive
oneꢀpot treatment of amides 2 with equimolar amounts of
ethyl or methyl trifluoropyruvate 1a,b, SOCl2, Ph3P, and
H2O. In the case of urethane (2a), we isolated and identiꢀ
fied intermediate products of these reactions, viz., adꢀ
duct 3 (R = R´ = Et) and the corresponding chlorinated
derivative 4 (Scheme 1).
NꢀSubstituted 3,3,3ꢀtrifluoroalanine esters 5a—k are
solid substances, whose compositions and structures were
established by elemental analysis, 1H and 19F NMR specꢀ
troscopy, and chemical transformations. Heating of ester
5a with PCl5 affords isocyanate 6 in 60% yield. The latter
reacts with aniline to yield urea 5k (Scheme 2). It is noteꢀ
worthy that isocyanate 6 has previously been obtained by
the Leuckart reaction from ester 1a and formamide in a
rather low yield (36%).6
R = Et (1a, 3—5a,e—k), Me (1b, 5b—d); R´ = OEt (3, 4)
2, 5
R´
a
b
c
d
e
f
OEt 3ꢀMeC6H4 4ꢀMeOC6H4 4ꢀFC6H4
Me
Et
2, 5
R´
g
h
i
j
k
CH2Cl
Ph
MeNH
AcNH
PhNH
Scheme 2
* Dedicated to the memory of A. F. Kolomiets.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1979—1981, November, 2002.
1066ꢀ5285/02/5111ꢀ2136 $27.00 © 2002 Plenum Publishing Corporation

Synthesis of 3,3,3ꢀtrifluoroalanine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2137
Table 1. Yields, melting points, and elemental analysis data for
compounds 5a—k
Thus, the method proposed provides wide possibilities
for syntheses of various Nꢀsubstituted 3,3,3ꢀtrifluoroꢀ
alanine derivatives.
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
(%)
N
Experimental
C
H
1
H and 19F NMR spectra were recorded on a Bruker
5a
5b
5c
5d
5e
5f
68 48—50 39.79 5.08
39.53 4.98
57 88—89 52.25 4.67
52.37 4.39
69 100—102 49.40 4.33
49.49 4.15
73 107—109 47.14 3.34
47.32 3.25
70 80—81 39.60 4.53
39.44 4.73
82 93—94 42.58 5.22
42.30 5.32
5.63 C8H12F3NO4
5.76
5.23 C12H12F3NO3
5.09
4.83 C12H12F3NO4
4.81
5.05 C11H9F4NO3
5.02
6.62 C7H10F3NO3
6.57
6.03 C8H12F3NO3
6.17
DPXꢀ200 spectrometer. Melting points were determined in a
glass capillary.
Ethyl 2ꢀethoxycarbonylaminoꢀ3,3,3ꢀtrifluoroꢀ2ꢀhydroxyꢀ
propionate (3). Urethane (2a) (8.9 g, 0.1 mmol) was mixed with
ester 1a (17.0 g, 0.1 mol). After the end of the exothermic
reaction, the resulting mixture was recrystallized from hexane to
give adduct 3 (23.5 g, 91%), m.p. 41—43 °C. Found (%):
C, 37.15; H, 4.77; N, 5.25. C8H12F3NO5. Calculated (%):
1
C, 37.07; H, 4.67; N, 5.40. Н NMR (CDCl3), δ: 1.20 (t, 3 Н,
MeСН2ОСN, J = 7 Hz); 1.26 (t, 3 Н, MeСН2ОСС, J = 7 Hz);
4.10 (q, 2 Н, СН2ОСN, J = 7 Hz); 4.30 (q, 2 Н, СН2ОСС,
J = 7 Hz); 5.60 (br.s, 1 Н, ОН); 6.20 (s, 1 Н, NH). 19F NMR
(CDCl3), δ: 2.99 (s).
5g
5h
5i
64 76—78 33.89 3.90
33.96 3.66
78 109—110 52.59 4.52
52.37 4.39
71 130—131 36.59 4.52 12.12 C7H11F3N2O3
36.85 4.86 12.28
5.59 C7H9ClF3NO3
5.66
5.36 C12H12F3NO3
5.09
Ethyl 2ꢀchloroꢀ2ꢀethoxycarbonylaminoꢀ3,3,3ꢀtrifluoroproꢀ
pionate (4). Compound 3 (25.9 g, 0.1 mol) was mixed with SOCl2
(11.9 g, 0.1 mol). The reaction mixture was heated at 60 °С until
a constant weight was established (∼2 h) and fractionated to
obtain compound 4 (33.2 g, 84%), b.p. 110—112 °С (3 Torr).
Found (%): C, 34.55; H, 4.09; N, 5.11. C8H11ClF3NO4. Calcuꢀ
lated (%): C, 34.61; H, 3.99; N, 5.05. 1Н NMR (CDCl3), δ: 1.20
(t, 3 Н, MeСН2ОСN, J = 7 Hz); 1.26 (t, 3 Н, MeСН2ОСС,
J = 7 Hz); 4.10 (q, 2 Н, СН2ОСN, J = 7 Hz); 4.30 (q, 2 Н,
СН2ОСС, J = 7 Hz); 6.38 (s, 1 Н, NH). 19F NMR (CDCl3),
δ: 1.43 (s).
Ethyl 2ꢀethoxycarbonylaminoꢀ3,3,3ꢀtrifluoropropionate (5а).
A. Triphenylphosphine (13.1 g, 0.05 mol) was added with stirꢀ
ring to a solution of compound 4 (13.9 g, 0.05 mol) in diethyl
ether (100 mL). After 10 min, H2O (50 mL) was added. The
mixture was stirred for 20 min, the ethereal layer was separated
and dried with MgSO4. The solvent was evaporated, and the
residue was fractionated to obtain compound 5a (9.8 g, 81%),
b.p. 88 °C (3 Torr).
5j
85 79—80 37.39 4.47 10.84 C8H11F3N2O4
37.51 4.33 10.94
5k
79 140—142 49.44 4.34
49.66 4.51
9.54 C8H11F3N2O4
9.65
and dried with MgSO4. The solvent was evaporated, and the
residue was fractionated to obtain compound 5a (16.4 g, 68%),
b.p. 88 °C (3 Torr).
Methyl 2ꢀ(3ꢀtoluylamino)ꢀ (5b), methyl 2ꢀ(4ꢀanisoylꢀ
amino)ꢀ (5c), methyl 2ꢀ(4ꢀfluorobenzoylamino)ꢀ (5d), ethyl
2ꢀacetamidoꢀ (5e), ethyl 2ꢀpropionamidoꢀ (5f), ethyl 2ꢀchloroꢀ
acetamidoꢀ (5g), ethyl 2ꢀbenzamidoꢀ (5h), ethyl 2ꢀ(3ꢀmethylꢀ
ureido)ꢀ (5i), ethyl 2ꢀ(3ꢀacetylureido)ꢀ (5j), and ethyl 2ꢀ(3ꢀphenylꢀ
ureido)ꢀ3,3,3ꢀtrifluoropropionate (5k) were synthesized simiꢀ
larly (procedure B). The yields, melting points, and spectroꢀ
scopic characteristics for compounds 5a—k are presented in
Tables 1 and 2.
Ethyl 2ꢀisocyanatoꢀ3,3,3ꢀtrifluoropropionate (6). Propiꢀ
onate 5a (24.3 g, 0.1 mol) was mixed with PCl5 (21.0 g, 0.1 mol).
The reaction mixture was heated to 100 °С and stored for 30 min
at this temperature, and POCl3 was distilled off. The residue was
B. Urethane (2a) (8.9 g, 0.1 mol) was mixed with ester 1a
(17.0 g, 0.1 mol). After the exothermic reaction completed,
SOCl2 (11.9 g, 0.1 mol) was added, and the reaction mixture
was heated at 60 °С until a constant weight was established
(∼2 h). Then diethyl ether (200 mL) and Ph3P (26.2 g, 0.1 mol)
were added, and after 10 min H2O (100 mL) was added. The
mixture was stirred for 20 min, the ethereal layer was separated
Table 2. 1H and 19F spectra of compounds 5a—k*
Comꢀ
NMR, δ (J/Hz)
pound
1H
19F (d, 3 F)
5a
5b
5c
1.30 (t, 3 Н, MeСН2ОСN); 4.32 (q, 2 Н, СН2ОСС); 5.36 (dq, 1 Н, CH, JH,H = 8,
JH,F = 9); 6.76 (d, 1 Н, NH, JH,H = 8); 6.95—7.60 (m, 5 Н, Ph)
2.40 (s, 3 H, MeAr); 3.80 (s, 3 H, MeO); 5.52 (quint, 1 H, CH, JH,H = 8, JH,F = 8);
7.30, 7.80 (both m, 2 H each, H arom.); 9.20 (d, 1 H, NH, JH,H = 8)
3.80, 3.86 (both s, 3 H each, MeO); 5.50 (quint, 1 H, CH, JH,H = 8, JH,F = 8);
6.90, 7.90 (both d, 2 H each, H arom.); 9.05 (d, 1 H, NH, JH,H = 8)
5.39 (JH,F = 9)
7.18 (JH,F = 8.0)
7.20 (JH,F = 8.8)
(to be continued)

2138
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Aksinenko et al.
Table 2 (continued)
Comꢀ
pound
NMR, δ (J/Hz)
1H
19F (d, 3 F)
5d
5e
5f
3.85 (s, 3 H, MeO); 5.50 (quint, 1 H, CH, JH,H = 8, JH,F = 8); 7.05—7.25, 7.95—8.10
(both m, 2 H each, H arom.); 9.30 (d, 1 H, NH, JH,H = 8)
1.30 (t, 3 H, MeCH2); 1.97 (s, 3 H, MeC(O)); 3.86 (q, 2 H, CH2O); 5.52 (quint, 1 H, CH,
JH,H = 8, JH,F = 8); 8.95 (d, 1 H, NH, JH,H = 8)
1.08 (t, 3 H, MeCH2C); 1.30 (t, 3 H, MeCH2O); 2.23 (q, 2 H, CH2C(O)); 4.25 (q, 2 H,
CH2O); 5.25 (quint, 1 H, CH, JH,H = 8, JH,F = 8); 8.87 (d, 1 H, NH, JH,H = 8)
1.30 (t, 3 H, MeCH2O, J = 7); 4.13 (s, 2 H, CH2Cl); 4.25 (q, 2 H, CH2O, J = 7); 5.28
(quint, 1 H, CH, JH,H = 8, JH,F = 8); 9.25 (d, 1 H, NH, JH,H = 8)
1.30 (t, 3 H, MeCH2O, J = 7); 4.30 (q, 2 H, CH2O, J = 7); 5.52 (dq, 1 H, CH, JH,H = 7,
JH,F = 8); 7.40—7.60 (m, 3 H, H arom.); 7.95 (m, 2 H, H arom.); 9.35 (d, 1 H, NH,
JH,H = 7)
7.20 (JH,F = 8.2);
–30.03**
7.14 (JH,F = 8.4)
7.10 (JH,F = 8.2)
7.16 (JH,F = 8.2)
7.08 (JH,F = 8.1)
5g
5h
5i
1.30 (t, 3 H, MeCH2O, J = 7); 2.62 (s, 3 H, MeN); 4.25 (q, 2 H, CH2O, J = 7); 4.25
(quint, 1 H, CH, JH,H = 8, JH,F = 8); 6.03 (s, 1 H, NH); 6.90 (d, 1 H, NHCH, JH,H = 8)
1.30 (t, 3 H, MeCH2O, J = 7); 2.09 (s, 2 H, MeC(O)); 4.30 (q, 2 H, CH2O, J = 7); 5.23
(quint, 1 H, CH, JH,H = 8, JH,F = 8); 9.21 (d, 1 H, NH, JH,H = 8); 10.72 (s, 1 H, NH)
1.35 (t, 3 H, Me, J = 7); 4.30 (q, 2 H, CH2O, J = 7); 5.30 (quint, 1 H, CH, JH,H = 8,
JH,F = 8); 6.30 (d, 1 H, NH, JH,H = 8); 7.08 (t, 1 H, pꢀH arom., J = 6); 7.34 (t, 2 H,
mꢀH arom., J = 6); 7.56 (d, 2 H, oꢀH arom., J = 6); 7.70 (s, 1 H, NH)
7.18 (JH,F = 8.0)
7.24 (JH,F = 8.3)
5.46 (JH,F = 8.2)
5j
5k
* The 1H and 19F NMR spectra of compounds 5b—j were recorded in DMSOꢀd6, and those for 5a,k were recorded in
acetoneꢀd6.
** (m, 1 F).
fractionated to yield isocyanate 6 (11.2 g, 57%), b.p. 148—150 °С
(cf. Ref. 6: 56 °С (20 Torr)). Н NMR (acetoneꢀd6), δ: 1.26 (t,
2. K. Burger, K. Geith, and D. Hubl, Synthesis, 1988, 194.
3. K. Burger, E. Hoss, K. Gaa, N. Sewald, and C. Schierlinger,
Z. Naturforsch., Teil B, 1991, 46, 361.
4. O. V. Korenchenko, V. B. Sokolov, A. Yu. Aksinenko, A. N.
Pushin, and I. V. Martynov, Izv. Akad. Nauk SSSR, Ser.
Khim., 1990, 2879 [Bull. Acad. Sci. USSR, Div. Chem. Sci.,
1990, 39, 2615 (Engl. Transl.)].
5. S. N. Osipov, V. B. Sokolov, A. F. Kolomiets, I. V. Martynov,
and A. V. Fokin, Izv. Akad. Nauk SSSR, Ser. Khim., 1987,
1185 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1987, 36, 1098
(Engl. Transl.)].
1
3 Н, MeСН2ОСС, J = 7 Hz); 4.30 (q, 2 Н, СН2ОСС, J = 7 Hz);
5.10 (dq, 1 Н, CH, JH,H = 8 Hz, JH,F = 9 Hz). 19F NMR
(acetoneꢀd6), δ: 2.45 (d, JH,F = 9 Hz).
Ethyl 2ꢀ(3ꢀphenylureido)ꢀ3,3,3ꢀtrifluoropropionate (5k) (inꢀ
dependent synthesis). Isocyanate 6 (1.97 g, 0.01 mol) was added
to a solution of aniline (0.93 g, 0.01 mol) in hexane (20 mL).
The reaction mixture was stirred for 30 min, and the precipitate
that formed was filtered off to obtain compound 5k (2.6 g,
89.6%), m.p. 141—143 °С.
6. D. Matthies and S. Siewers, Liebigs Ann. Chem., 1992, 159.
References
1. C. W. Fearon, J. A. Rodkey, and R. H. Abeles, Biochemistry,
1982, 21, 3790.
Received June 6, 2002