First synthesis of 3,3-difluoroserine and cysteine derivatives via Mg(0)-promoted selective C-F bond cleavage of trifluoromethylimines

Article abstract of DOI:10.1016/S0040-4039(00)01350-2

3,3-Difluoroserine and cysteine derivatives were synthesized via Mg(0)-promoted defluorination of trifluoromethylimines as a key step, followed by addition of alcohols and sulfenyl chloride, respectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01350-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7893–7896
First synthesis of 3,3-difluoroserine and cysteine derivatives
via Mg(0)-promoted selective CꢀF bond cleavage of
trifluoromethylimines
Masayuki Mae, Hideki Amii and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Received 12 June 2000; revised 31 July 2000; accepted 4 August 2000
Abstract
3,3-Difluoroserine and cysteine derivatives were synthesized via Mg(0)-promoted defluorination of
trifluoromethylimines as a key step, followed by addition of alcohols and sulfenyl chloride, respectively.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids; defluorination; enamines; imines.
Among fluorinated amino acids, 3,3-difluoroamino acids are one of the most attractive
synthetic targets, because some amino acids containing gem-difluoromethylene moiety have
interesting biological activities1 such as being an irreversible inhibitor of pyridoxal phosphate
dependent enzymes.2 In spite of the promising biological activities of 3,3-difluoroamino acids,
only a few methods are available for the synthesis of these compounds.3 The development of a
systematic synthesis of the target amino acids is required.
2-N-Silylamino-3,3-difluoroacrylate would be nucleophilically or electrophilically alkoxylated,
thioalkoxylated and alkylated at the difluoromethylene carbon atom and thus would be a useful
intermediate for the synthesis of various kinds of 3,3-difluoroamino acids. Meanwhile, as for the
creation of difluoromethylene moiety from a trifluoromethyl moiety, we have already established
electroreductive methods for N-silylated difluoroenamines 2, using trifluoromethyl imines 1 as
starting materials.4 Here, we describe the first synthesis of racemic 3,3-difluoroserine and
3,3-difluorocysteine derivatives 3 and 4 using a newly developed Mg(0)-promoted selective
defluorination from trifluoromethyl imines 1 as a key step (Scheme 1). The Mg(0)-promoted
defluorination provides many advantages for a practical preparation of difluoromethylene
compounds, such as a less expensive process and the selective CꢀF bond cleavage from the
trifluoromethyl group.5
* Corresponding author. Tel: +81 86 251 8705; fax: +81 86 251 8705; e-mail: uneyamak@cc.okayama-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01350-2

7894
Scheme 1.
As shown in Table 1, the reaction of a variety of aromatic imines with either electron-with-
drawing or electron-donating substituents on the aromatic ring (1a–e) and heteroaromatic
imines (1f, 1g) provided the desired enamines in excellent yields (entries 1–7). A ten gram-scale
reaction proceeded in DMF at 0°C within 30 min using a commercially available magnesium6a
and no special activation of the magnesium such as iodine and dibromoethane or ultrasound
treatment was needed. Meanwhile, the less reducible aliphatic imine required the higher
temperature (70°C, entry 8). Moreover, the simplest 3,3-difluoroenamine 2i (R=H) could be
prepared in a reasonable yield (entry 9) and would be employed as a key starting substrate for
fluorinated polyvinylamines. It is noteworthy that reductive defluorination of ethyl 2-(N-p-ani-
syl)imino-3,3,3-trifluoropropanoate (1j) gave ethyl 2-amino-3,3-difluoroacrylate (2j) in 50% yield
in the presence of NaI and Et3N (entry 10).6b
Table 1
Mg(0)-promoted reductive defluorination of trifluoromethylimines 1a
The fluorinated acrylate 2j can be transformed into serine 3 and cysteine derivatives 4 as
shown in Scheme 2. It is particularly noteworthy that 2j reacted with both electrophiles and

7895
nucleophiles smoothly without accompanying defluorination.7,8 The difluoromethylene carbon
of 2j is highly reactive even with a weak nucleophile like alcohols, meanwhile it can accept an
electrophile such as PhSCl and PhSeF at the b-carbon of the enamine 2j. Thus, regioselective
desilylative addition of various kinds of alcohols to 2j proceeded smoothly under acidic
conditions to give the corresponding 3,3-difluoroserine derivatives 3 in good yields (Eq. 1). 2j
was allowed to react with electrophiles such as benzenesulfenyl chloride or benzeneselenenyl
fluoride,9 affording 3-thio- and 3-seleno-3,3-difluoro-2-iminopropanoates 5. Reduction of thio-
ester 5a with NaBH4 provided 3,3-difluorocysteine derivative 4a in a good yield (Eq. 2).
Scheme 2. Synthesis of 3,3-difluoroserine and cysteine derivatives
It has been clarified that the enaminoester 2j can react with both electrophiles and nucleo-
philes under conditions where no defluorination occurs from the difluoromethylene group. This
result suggests 2j is a promising precursor for a variety of difluoroamino acid derivatives.
Acknowledgements
The authors are grateful to the Ministry of Education, Science, Sports, and Culture of Japan
(grant-in-aid for scientific research No. 12450356) and Okayama University VBL for the
1
financial supports and the SC-NMR Laboratory of Okayama University for H and 19F NMR
analyses.
References
1. (a) Kukhar’, V. P.; Sholoshonok, V. A. Fluorine-containing Amino Acids; John Wiley & Sons: New York, 1995.
(b) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biochemical Frontiers of Fluorine Chemistry; ACS: Washington, 1996.
(c) Welch, J. T. Tetrahedron 1987, 43, 3123.
2. (a) Wang, E. A.; Walsh, C. Biochemistry 1981, 20, 7539. (b) Kollonitsch, J.; Perkins, L. M.; Patchett, A. A.;
Doldouras, G. A.; Marburg, S.; Duggan, D. E.; Maycock, A. L.; Aster, S. D. Nature 1978, 274, 906. (c)
Walborsky, H. M.; Baum, M.; Loncrini, D. F. J. Am. Chem. Soc. 1955, 77, 3637. (d) Walborsky, H. M.; Baum,
M. E. J. Am. Chem. Soc. 1958, 80, 187.
3. (a) Metcalf, B. W.; Bey, P.; Danzin, C.; Jung, M. J.; Casara, P.; Vevert, J. P. J. Am. Chem. Soc. 1978. 100, 2551.
(b) Hart, B. P.; Coward, J. C. Tetrahedron Lett. 1993, 34, 4917. (c) Tsushima, T.; Kawada, K. Tetrahedron Lett.
1985, 26, 2445. (d) Kollonitsch, J.; Marburg, S.; Perkins, L. M. J. Org. Chem. 1976, 41, 3107. (e) Shi, G.-Q.; Cao,
W.-L. J. Org. Chem. 1995, 60, 6289. (f) Hageman, J. M.; Wanner, M. J.; Koomen, G.-J.; Pandit, U. K. J. Med.
Chem. 1977, 20, 1677. (g) Kitagawa, O.; Hashimoto, A.; Kobayashi, Y.; Taguchi, T. Chem. Lett. 1990, 1307.
4. (a) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998, 39, 587. (b) Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T.
J. Org. Chem. 1999, 64, 6717.

7896
5. Mg(0)-promoted transformation of trifluoromethylketones to difluoroenolsilyl ethers: Amii, H.; Kobayashi, T.;
Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323.
6. A typical reaction procedure is as follows; (a) TMSCl (18.2 mL, 143 mmol) and a solution of 2-(N-p-anisyl)imino-
2-phenyl-1,1,1-trifluoroethane 1a (10.0 g, 35.8 mmol) in freshly dried DMF (43 mL) were added to a suspension
of magnesium (6.97 g, 287 mmol) in DMF (100 mL) at 0°C under an argon atmosphere. After stirring for 30 min
at 0°C, TMSCl was removed under reduced pressure (22 mmHg) at rt and a 1/9 solution of Et3N/hexane (100 mL)
was added. Magnesium was separated by filtration through Celite® under reduced pressure and the filtrate was
washed with H2O (200 mL). The aqueous layer was extracted with hexane (100 mL×2) and the organic layer was
washed with H2O (50 mL) and then dried over MgSO4. Evaporation of the solvent and bulb-to-bulb distillation
(0.3 mmHg, 120°C) provided 2a in 82% yield. (b) TMSCl (40.0 mmol) and a solution of ethyl 2-(N-p-anisyl)imino-
3,3,3-trifluoropropanoate 1j (10.0 mmol) in freshly dried DMF (10 mL) were added to a suspension of magnesium
(80.0 mmol), Et3N (42.0 mmol) and NaI (24.0 mmol) in DMF (30.0 mL) at 0°C under an argon atmosphere. After
stirring for 30 min at 0°C, magnesium was separated by filtration through Celite® under reduced pressure and the
filtrate was extracted with hexane (20 mL×3). Evaporation of solvent and bulb-to-bulb distillation (0.25 mmHg,
90°C) provided 2j in 50% yield.
7. Defluorination is usually accompanied by the addition of nucleophiles to the difluorovinyl group. For example: (a)
Huang, X.-H.; He, P.-Y.; Shi, G.-Q. J. Org. Chem. 2000, 65, 627. (b) Ichikawa, J.; Kobayashi, M.; Yokota, N.;
Noda, Y.; Minami, T. Tetrahedron 1994, 40, 11637. (c) Shi, G.-Q.; Cao, Z.-Y.; Zang, X.-B. J. Org. Chem. 1995,
60, 6608.
8. The change of reactivity (nucleophilic and electrophilic) has been dubbed ‘chemical chameleons’: Trost, B. Bull.
Chem. Soc. Jpn. 1988, 61, 107.
9. (a) Uneyama, K.; Kanai, M. Tetrahedron Lett. 1990, 31, 3583. (b) Uneyama, K.; Hiraoka, S.; Amii, H. J. Fluorine
Chem. 2000, 102, 215.
.
.