HFA to the carboxyl group of trifluoroalanine.23a Meanwhile
the reactions of hexafluoroacetone imine derivatives have been
less studied.24-26 On this basis, it would be important and
promising from the point of synthetic organofluorine chemistry
to prepare enamine 2 from 1 and to transform CF2 and CF3
groups of 2 selectively to a functionalized difluoromethylene
moiety and a carboxamide group, respectively, leading to
difluoroamino acid derivatives.
SCHEME 1
The Mg-promoted defluorination of trifluoromethyl imines
and ketones converting a trifluoromethyl group to a difluorom-
ethylene group has been systematically studied.27-30 Recently,
the defluorination protocol has been applied to the selective
defluorination of imine 1 to 2,31 which was transformed
as protecting and activating reagents22 or a block for a
hexafluoroisopropyl group.23 One interesting example demon-
strated a transformation of one of the trifluoromethyl groups of
(15) Synthesis of 4-fluoroproline and 4,4-difluoroproline derivatives: (a)
Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.; Sommer, J. A.;
Brown, A. D.; Chiu, P. J. S.; Moran, R.; Sybertz, E. J.; Baum, T. J. Med.
Chem. 1988, 31, 875-885. (b) Karanewsky, D. S.; Badia, M. C.; Cushman,
D. W.; DeForrest, J. M.; Dejneka, T.; Lee, V. G.; Loots, M. J.; Petrillo, E.
W. J. Med. Chem. 1990, 33, 1459-1469. (c) Kronenthal, D. R.; Mueller,
R. H.; Kuester, P. L.; Kissick, T. P.; Johnson, E. J. Tetrahedron Lett. 1990,
31, 1241-1244. (d) Hudlicky, M.; Merola, J. S. Tetrahedron Lett. 1990,
31, 7403-7406. (e) Tolman, V.; Vlasakova, V.; Nemecek, J. J. Fluorine
Chem. 1993, 60, 185-191. (f) Avent, A. G.; Bowler, A. N.; Doyle, P. M.;
Marchand, C. M.; Young, D. W. Tetrahedron Lett. 1992, 33, 1509-1512.
(g) Hudlicky, M. J. Fluorine Chem. 1993, 60, 193-210. (h) Burger, K.;
Rudolph, M.; Fehn, S.; Sewald, N. J. Fluorine Chem. 1994, 66, 87-90. (i)
Tran, T. T.; Patino, N.; Condom, R.; Frogier, T.; Guedj, R. J. Fluorine
Chem. 1997, 82, 125-130. (j) Demange, L.; Menez, A.; Dugave, C.
Tetrahedron Lett. 1998, 39, 1169-1172. (k) Konas, D. W.; Coward, J. K.
J. Org. Chem. 2001, 66, 8831-8842. (l) Doi, M.; Nishi, Y.; Kiritoshi, N.;
Iwata, T.; Nago, M.; Nakano, H.; Uchiyama, S.; Nakazawa, T.; Wakamiya,
T.; Kobayashi, Y. Tetrahedron. 2002, 58, 8453-8459. (m) O’Neil, I. A.;
Thompson, S.; Kalindjian, S. B.; Jenkins, T. C. Tetrahedron Lett. 2003,
44, 7809-7812. (n) Filosa, R.; Holder, C.; Auberson, Y. P. Tetrahedron
Lett. 2006, 47, 8929-8932. (o) Chen, L.; Kim, Y. M.; Kucera, D. J.;
Harrison, K. E.; Bahmanyar, S.; Scott, J. M.; Yazbeck, D. J. Org. Chem.
2006, 71, 5468-5473. (p) Hu, S.; Martinez, C. A.; Kline, B.; Yazbeck, D.;
Tao, J.; Kucera, D. J. Org. Process Res. DeV. 2006, 10, 650-654.
(16) Synthesis of fluoromethyl proline derivatives: (a) Chaume, G.; Van
Severen, M.-C.; Marinkovic, S.; Brigaud, T. Org. Lett. 2006, 8, 6123-
6126. (b) Zhang, X.; Qing, F.-L.; Yang, Y.; Yu, J.; Fu, X.-K. Tetrahedron
Lett. 2000, 41, 2953-2955. (c) Qiu, X.-L.; Qing, F.-L. J. Chem. Soc., Perkin
Trans. 1 2002, 2052-2057. (d) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2002,
67, 7162-7164. (e) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2003, 68, 3614.
(f) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 5201-
5206.
(21) (a) Eberhardt, E. S.; Panasik, N., Jr.; Raines, R. T. J. Am. Chem.
Soc. 1996, 118, 12261-12266. (b) Dzakula, Z.; DeRider, M. L.; Markley,
J. L. J. Am. Chem. Soc. 1996, 118, 12796-12803. (c) Bretscher, L. E.;
Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. J. Am. Chem.
Soc. 2001, 123, 777-778. (d) Renner, C.; Alefelder, S.; Bae, J. H.; Budisa,
N.; Huber, R.; Moroder, L. Angew. Chem., Int. Ed. 2001, 40, 923-925. (e)
Improta, R.; Benzi, C.; Barone, V. J. Am. Chem. Soc. 2001, 123, 12568-
12577. (f) DeRider, M. L.; Wilkens, S. J.; Waddell, M. J.; Bretscher, L. E.;
Weinhold, F.; Raines, R. T.; Markley, J. L. J. Am. Chem. Soc. 2002, 124,
2497-2505. (g) Jenkins, C. L.; Lin, G.; Duo, J.; Rapolu, D.; Guzei, I. A.;
Raines, R. T.; Krow, G. R. J. Org. Chem. 2004, 69, 8565-8573. (h) Song,
I. K.; Kang, Y. K. J. Phys. Chem. B. 2005, 109, 16982-16987. (i) Thomas,
K. M.; Naduthambi, D.; Tririya, G.; Zondlo, N. J. Org. Lett. 2005, 7, 2397-
2400. (j) Thomas, K. M.; Naduthambi, D.; Zondlo, N. J. J. Am. Chem.
Soc. 2006, 128, 2216-2217. (k) Kim, W.; Hardcastle, K. I.; Conticello, V.
P. Angew. Chem., Int. Ed. 2006, 45, 8141-8145.
(22) (a) Golubev, A.; Sewald, N.; Burger, K. Tetrahedron Lett. 1993,
34, 5879-5880. (b) Burger, K.; Windeisen, E.; Pires, R. J. Org. Chem.
1995, 60, 7641-7645. (c) Pires, P.; Burger, K. Synthesis 1996, 1277-
1279. (d) Burger, K.; Lange, T.; Pires, R. J. Fluorine Chem. 2000, 102,
317. (e) Schedel, H.; Dmowski, W.; Burger, K. Synthesis 2000, 1681. (f)
Burger, K.; Bottcher, C.; Radics, G.; Hennig, L. Tetrahedron Lett. 2001,
42, 3061-3063. (g) Spengler, J.; Schedel, H.; Sieler, J.; Quaedflieg, P. J.
L. M.; Broxterman, Q. B.; Duchateau, A. L. L.; Burger, K. Synthesis 2001,
1513-1518. (h) Bottcher, C.; Burger, K. Tetrahedron Lett. 2002, 43, 9711-
9714. (i) Radics, G.; Pires, R.; Koksch, B.; El-Kousy, S. M.; Burger, K.
Tetrahedron Lett. 2003, 44, 1059-1062. (j) Bottcher, C.; Burger, K.
Tetrahedron Lett. 2003, 44, 4223-4226.
(23) Some selected papers on the synthetic application of hexafluoro-
acetone: (a) Burger, K.; Hubl, D.; Gertischke, P. J. Fluorine Chem. 1985,
27, 327-332. (b) Iseki, K.; Nagai, T.; Kobayashi, Y. Chem. Pharm. Bull.
1992, 40, 1346-1348. (c) Ohira, Y.; Taguchi, T.; Iseki, K.; Kobayashi, Y.
Chem. Pharm. Bull. 1992, 40, 1647-1649. (d) Iseki, K.; Oishi, S.; Namba,
H.; Taguchi, T.; Kobayashi, Y. Chem. Pharm. Bull. 1995, 43, 1897-1901.
(e) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681. (f) Wu, Y.; Sabbe, K.;
De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Bioorg. Med.
Chem. Lett. 2002, 12, 1629-1632. (g) Wu, Y.; De Clercq, P.; Vandewalle,
M.; Bouillon, R.; Verstuyf, A. Bioorg. Med. Chem. Lett. 2002, 12, 1633-
1636. (h) Anderson, J. T.; Toogood, P. L.; Marsh, E. N. G. Org. Lett. 2002,
4, 4281-4283. (i) Lateef, H.; Mullins, S. T. J. Fluorine Chem. 2000, 104,
167-171. (j) Barbarich, T. J.; Nolan, B. G.; Tsujioka, S.; Miller, S. M.;
Anderson, O. P.; Strauss, S. H. J. Fluorine Chem. 2001, 112, 335-342.
(k) Nolan, B. G.; Tsujioka, S.; Strauss, S. H. J. Fluorine Chem. 2002, 118,
103-106.
(17) (a) Golbik, R.; Yu, C.; Weyher-Stingl, E.; Huber, R.; Moroder, L.;
Budisa, N.; Schiene-Fischer, C. Biochemistry 2005, 44, 16026-16034. (b)
Naduthambi, D.; Zondlo, N. J. J. Am. Chem. Soc. 2006, 128, 12430-12434.
(c) Ruzza, P.; Siligardi, G.; Donella-Deana, A.; Calderan, A.; Hussain, R.;
Rubini, C.; Cesaro, L.; Osler, A.; Guiotto, A.; Pinna, L. A.; Borin, G. J.
Pept. Sci. 2006, 12, 462-471.
(18) Staas, D. D.; Savage, K. L.; Sherman, V. L.; Shimp, H. L.; Lyle,
T. A.; Tran, L. O.; Wiscount, C. M.; McMasters, D. R.; Sanderson, P. E.
J.; Williams, P. D.; Lucas, B. J.; Krueger, J. A.; Lewis, S. D.; White, R.
B.; Yu, S.; Wong, B. K.; Kochansky, C. J.; Anari, M. R.; Yan, Y.; Vacca,
J. P. Bioorg. Med. Chem. 2006, 14, 6900-6916.
(19) (a) Holmgrem, S. K.; Taylor, K. M.; Bretscher, L. E.; Raines, R. T.
Nature 1998, 392, 666-667. (b) Malkar, N. B.; Lauer-Fields, J. L.; Borgia,
J. A.; Fields, G. B. Biochemistry 2002, 41, 6054-6064. (c) Barth, D.;
Musiol, H.-J.; Schuett, M.; Fiori, S.; Milbradt, A. G.; Renner, C.; Moroder,
L. Chem. Eur. J. 2003, 9, 3692-3702. (d) Hodges, J. A.; Raines, R. T. J.
Am. Chem. Soc. 2003, 125, 9262-9263. (e) Doi, M.; Nishi, Y.; Uchiyama,
S.; Nishiuchi, Y.; Nakazawa, T.; Ohkubo, T.; Kobayashi, Y. J. Am. Chem.
Soc. 2003, 125, 9922-9923. (f) Persikov, A. V.; Ramshaw, J. A. M.;
Kirkpatrick, A.; Brodsky, B. J. Am. Chem. Soc. 2003, 125, 11500. (g) Barth,
D.; Milbradt, A. G.; Renner, C.; Moroder, L. ChemBioChem 2004, 5, 79-
86. (h) Nishi, Y.; Uchiyama, S.; Doi, M.; Nishiuchi, Y.; Nakazawa, T.;
Ohkubo, T.; Kobayashi, Y. Biochemistry 2005, 44, 6034-6042. (i) Doi,
M.; Nishi, Y.; Uchiyama, S.; Nishiuchi, Y.; Nishio, H.; Nakazawa, T.;
Ohkubo, T.; Kobayashi, Y. J. Pept. Sci. 2005, 11, 609-616. (j) Hodges, J.
A.; Raines, R. T. J. Am. Chem. Soc. 2005, 127, 15923-15932. (k) Shoulders,
M. D.; Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2006, 128, 8112-
8113. (l) Boule`gue, C.; Milbradt, A. G.; Renner, C.; Moroder, L. J. Mol.
Biol. 2006, 358, 846-856.
(24) Middleton, W. J.; Krespan, C. G. J. Org. Chem. 1965, 30, 1398-
1402.
(25) (a) Petrov, V. A.; DesMarteau, D. D. J. Fluorine Chem. 1996, 77,
175-181. (b) Petrov, V. A.; Khasnis, D. D. Isr. J. Chem. 1999, 39, 147-
150. (c) Petrov, V. A. J. Fluorine Chem. 2000, 106, 25-34. (d) Petrov, V.
A. Tetrahedron Lett. 2000, 41, 6959. (e) Petrov, V. A. J. Fluorine Chem.
2001, 109, 123-128.
(26) (a) Roberts, J. D.; Hall, G. E.; Middleton, W. J. J. Am. Chem. Soc.
1971, 93, 4778-4781. (b) Steglich, W.; Burger, K.; Duerr, M.; Burgis, E.
Chem. Ber. 1974, 107, 1488-1498. (c) Burger, K.; Wassmuth, U.;
Penninger, S. J. Fluorine Chem. 1982, 20, 813. (d) Burger, K.; Geith, K.;
Hoess, E. Synthesis 1990, 352-356.
(27) Short accounts: (a) Uneyama, K.; Amii, H. J. Fluorine Chem. 2002,
114, 127-131. (b) Amii, H.; Uneyama, K. Mg-Promoted Selective C-F
Bond Cleavage: A General and Efficient Access to Difluoroenol Silyl Ethers
and Their Derivatives. In Fluorine-Containing Synthons; Soloshonok, V.
A., Ed.; ACS Symp. Ser. No. 911; American Chemical Society: Wash-
ington, DC, 2005; pp. 455-475.
(20) Kim, W.; McMillan, R. A.; Snyder, J. P.; Conticello, V. P. J. Am.
Chem. Soc. 2005, 127, 18121-18132.
8524 J. Org. Chem., Vol. 72, No. 22, 2007