Simple synthesis of mono- and difluoroalanines

Article abstract of DOI:10.1016/S0022-1139(00)00258-X

Highly basic tris(diethylamino)-N-methylphosphazene was used for mono- and difluoromethylation of diethyl N-acetylaminomalonate by CH₂BrF or CHClF₂ in dichloromethane at -40°C. Acidic hydrolysis of fluoromethylated products afforded

Full text of DOI:10.1016/S0022-1139(00)00258-X

Journal of Fluorine Chemistry 105 (2000) 31±33
Simple synthesis of mono- and di¯uoroalanines
a,*
I.I. Gerus , A.A. Kolomeitsev , M.I. Kolycheva , V.P. Kukhar
Institute of Bioorganic and Petrochemistry, Ukrainian National Academy of Sciences, 1, Murmanskaya Str., Kiev-94, 253660, Ukraine
b
Institute of Organic Chemistry, Ukrainian National Academy of Sciences, 5, Murmanskaya Str., Kiev-94, 253660, Ukraine
b
a
a
a
Received 4 November 1999; accepted 10 March 2000
Abstract
Highly basic tris(diethylamino)-N-methylphosphazene was used for mono- and di¯uoromethylation of diethyl N-acetylaminomalonate by
CH BrF or CHClF
2
2
in dichloromethane at � 408C. Acidic hydrolysis of ¯uoromethylated products afforded ¯uoro- and di¯uoroalanine,
respectively. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Fluorinated amino acids; Di¯uoromethylation; Fluoromethylation; Tris(diethylamino)-N-methylphosphazene
1
. Introduction
solution of commercially available diethyl N-acetylamino-
malonate 1 and three equivalents of tris(diethylamino)-N-
methylphosphazene in methylene chloride at � 408C
(Scheme 2). The reaction demands no special protection
from moisture which causes many problems under usually
used bases, such as LDA, NaN(SiMe ) and NaH [3]. The
yield of malonate 2a was much higher than the yield of
di¯uoromethylation products obtained under conditions pre-
viously described [4]. A similar reaction with ¯uorobromo-
methane resulted in a yield of 51% of diethyl a-
¯uoromethyl-N-acetylaminomalonate 2b.
The reaction presumably proceeds via formation of
¯uoro- and di¯uorocarbenes, but no special investigation
of the reaction mechanism was carried out. Attempted
di¯uoromethylation of the methyl esters of N-Boc-pheny-
lalanine and N-Boc-phenylglycine in the presence of tris(-
diethylamino)-N-methylphosphazene did not give the
desired products. This failure may be due to the reduced
CH-acidity of the starting amino acid derivatives, which bear
only one ester group in the a-position.
The acidic hydrolysis of ¯uoro- and di¯uoromethyl acet-
ylaminomalonates 2a,b was performed by re¯uxing
with a mixture of 98% formic and 36% hydrochloric acids
to afford hydrochlorides of 3,3-di¯uoroalanine 3a and
During the past years, ¯uorinated amino acids have
attracted remarkable interest due to their potent biological
activity [1,2]. One of the most broadly used procedures for
the synthesis of a-¯uoromethylated amino acids includes
di¯uoromethylation of carbanions generated by various
bases from the Schiff base of amino acids [3] (Scheme 1).
The Schiff base or N-trichloroethoxycarbonyl derivative
of diethyl aminomalonate was shown to react with CHClF2
in THF as a solvent by treatment with three equivalents of
sodium bis(trimethylsilyl)amide or sodium hydride at
3
2
� 308C to give the di¯uoromethylated derivatives in 50%
and 41% yields, respectively [4].
In connection with our studies on the synthesis of ¯uori-
nated amino acids via di¯uoromethylation [5,6] and the
application of aminophosphorus derivatives in synthesis
of ¯uoroorganics [7], we wish to report here that the strongly
basic non-nucleophile, tris(diethylamino)-N-methylpho-
sphazene [8], can be used for mono- and di¯uoromethylation
of diethyl N-acetylaminomalonate under mild and simple
reaction conditions.
2
. Results and discussion
Diethyl a-di¯uoromethyl-N-acetylaminomalonate 2a has
been obtained in 69% yield upon passing CHClF through a
2
*
Corresponding author. Tel.: ‡38-044-573-2598;
fax: ‡38-044-573-2552.
E-mail address: gerus@ibpcg.kiev.ua (I.I. Gerus).
Scheme 1
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 5 8 - X

3
2
I.I. Gerus et al. / Journal of Fluorine Chemistry 105 (2000) 31±33
Scheme 2
3
-¯uoroalanine 3b. The titled amino acids were obtained
3.2. Diethyl 2-(acetylamino)-2-(difluoromethyl)malonate
(2b)
in free state by propylene oxide treatment in about 30±40%
overall yield, based on starting diethyl N-acetylaminoma-
lonate.
Diethyl
2-(acetylamino)-2-(di¯uoromethyl)malonate
In conclusion, we have realized a simple procedure for
uoro- and di¯uoromethylation of diethyl N-acetylamino-
(2b) was prepared from 1.92 g (8.9 mmol) of 1, 9.7 g
(35.1 mmol) of tris(diethylamino)-N-methylphosphazene
and 1 g (8.9 mmol) of ¯uorobromomethane under the same
reaction conditions as 2a and puri®ed by column chromato-
¯
malonate under mild conditions. Application of this method
for ¯uoro- and di¯uoroalanine synthesis starting from com-
mercially available diethyl N-acetylaminomalonates gives
results superior to utilization of sodium hydride or bis(tri-
methylsilyl)amide.
graphy on silica gel 60 (CHCl /hexane, 3:2 ). Colorless oil
3
1
crystallizing on cooling to 58C; 1.1 g (49.9%); H NMR
2
(CDCl ) d: 6.9 (br.s, 1H, NH), 5.08 (d, 2H, CH F, JH� F
3
2
3
47.0 Hz), 4.3 (q, 4H, OCH , J
COCH ), 1.28 (t, 6H, CH , J
7.2 Hz), 2.09 (s, 3H,
2
3
H� H
H� H
7.2 Hz).
3
3
3
. Experimental details
3
.3. 3,3-Difluoroalanine (3a)
A mixture of 3 g (11.3 mmol) of 2a, 7.5 ml of 97%
1
19
H and F NMR spectra were recorded on Variant
Gemini-200 instrument (200 and 188.28 MHz) using
TMS and CCl F as internal standards, respectively. The
starting materials tris(diethylamino)-N-methylphosphazene
8], ¯uorobromomethane [9] were prepared according to
literature procedures.
3
HCOOH and 7.5 ml of 36% aq. HCl was re¯uxed for 5 h.
The solvent was evaporated under reduced pressure. The
residue was dissolved in 15 ml of ethanol and 5 ml of
propene oxide [10] were added at 08C to precipitate 0.9 g
[
Compounds 3a,b were identi®ed by HPLC and compar-
(
64%) of di¯uoroalanine 3a.
.4. 3-Fluoroalanine (3b)
-Fluoroalanine (3b) was prepared from 0.75 g (3 mmol)
1
ison of H NMR data with data obtained for authentic
samples [4,10,11].
3
3
3
.1. Diethyl 2-(acetylamino)-2-(difluoromethyl)malonate
2a)
of 2b under the same reaction conditions as 3a. Yield of 3b
was 0.2 g (61%).
(
A mixture of 4.0 g (18.5 mmol) of 1 and 20 g (72.4 mmol)
of tris(diethylamino)-N-methylphosphazene in 25 ml of
CH Cl was cooled to � 408C, and 43.3 g (501 mmol) of
Acknowledgements
2
2
di¯uorochloromethane was passed through the stirred solu-
tion at such a rate to keep the mixture at � 358C. The reaction
mixture was warmed to room temperature, and thoroughly
washed with diluted HCl (10%, 3Â25 ml) and water
We wish to thank the International Association (INTAS
project N 95-00095) for ®nancial support of this research.
(
3Â50 ml). The organic layer was dried over MgSO and
4
References
the solvent was evaporated in vacuo. Puri®cation by column
chromatography on silica gel 60 (CHCl /hexane, 3:1)
1
afforded 2a as a colorless oil: 3.4 g (69%); H NMR (CDCl )
d: 6.74 (bs, 1H, NH), 6.47 (t, 1H, CHF , JH� F 54.8 Hz),
4
3
[
[
1] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991.
3
2
2
2] V.P. Kukhar, V.A. Soloshonok, Fluorine-containing Amino Acids.
Synthesis and Properties, Wiley, New York, 1995.
3
.34 (q, 4H, OCH , JH� H 7.0 Hz), 2.1 (s, 3H, COCH ), 1.3
2
3
3
19
(
(
t, 6H, CH , JH� H 7.0 Hz); F NMR (CDCl ) d : � 128.5
3
3
F
[3] P. Bey, J.-P. Vevert, V. Van Dorsselaer, M. Kolb, J. Org. Chem. 44
(1979) 2732.
2
d, JH� F 54.8 Hz).

I.I. Gerus et al. / Journal of Fluorine Chemistry 105 (2000) 31±33
33
[
[
4] T. Tshushima, K. Kawada, Tetrahedron Lett. 46 (1985) 2445.
5] M.T. Kolycheva, I.I. Gerus, Yu.L. Yagupolskii, S.V. Galushko, V.P.
Kukhar, Zh. Org. Khim. 27 (1991) 788.
[8] V.A. Kovenja, A.P. Marchenko, A.M. Pinchuk, Zh. Obsch. Khim. 51
(1981) 2678.
[9] R.N. Haszeldine, R.N., J. Chem. Soc. (1952) 4259.
[10] I.I. Gerus, Yu.L. Yagupolskii, V.P. Kukhar, L.S. Boguslavskaya, N.N.
Chuvatkin, A.V. Kartashov, Yu.V. Mitin, Zh. Org. Khim. 27 (1991) 537.
[11] S.V. Galushko, I.P. Shishkina, I.I. Gerus, M.T. Kolycheva, J.
Chromatogr. 600 (1992) 83.
[
[
6] M.T. Kolycheva, I.I. Gerus, V.P. Kukhar, Amino Acids (1993)
9
9.
7] A.A. Kolomeitsev, G.N. Kojdan, A.P. Marchenko, A.M. Pinchuk,
Yu.L. Yagulpolskii, Zh. Org. Khim. 26 (1990) 1143.