6084
J . Org. Chem. 1998, 63, 6084-6085
Below we generically depict the method for enamide
synthesis, which involves transformation of a ketone into
an oxime of type 4 followed by subsequent reduction with
iron metal in the presence of acetic anhydride.6
A Th r ee-Step P r oced u r e for Asym m etr ic
Ca ta lytic Red u ctive Am id a tion of Keton es
Mark J . Burk,* Guy Casy, and Nicholas B. J ohnson
Chirotech Technology Ltd. and Chiroscience R&D Ltd.,
Cambridge Science Park, Milton Road,
Cambridge CB4 4WE, U.K.
Received May 20, 1998
The value of optically active amines as resolving agents,
as chiral auxiliaries, and as components of many important
biologically active compounds is well documented. Accord-
ingly, the development of practical methods for the produc-
tion of enantiomerically pure amines is of cardinal interest.
We recently have described the effectiveness of cationic Me-
DuPHOS-Rh and Me-BPE-Rh catalysts for highly enanti-
oselective hydrogenation of N-Ac-R-arylenamides to the
corresponding N-Ac-R-arylalkylamines.1 Despite the osten-
sible utility of this hydrogenation procedure, the dearth of
efficient methods for synthesis of the enamide substrates2,3
essentially has rendered this process unavailing, particularly
for industrial manufacture of enantiomerically pure amines.
In addition to the demonstrated use of enamides in
asymmetric hydrogenation reactions,1,4 they have found
application in numerous other areas of organic synthesis.5
In an effort to provide practical access to prochiral enamides
of type 2, we now have developed an efficacious two-step
route from simple ketones. We disclose preliminary results
that indicate that a range of new enamides may be prepared
readily and hydrogenated with high enantioselectivities
using the Me-DuPHOS-Rh and/or Me-BPE-Rh catalyst
systems. Conceptually, the combined three-step procedure
offers a novel method for asymmetric catalytic reductive
amidation of ketones (1 f 3).
We have identified several reaction parameters that
appear vital for success in the oxime reduction step. For
instance, performing the reaction at moderate temperatures
(e75 °C) attenuates otherwise problematic product decom-
position. Also, the introduction of acetic acid (3 equiv/mol
of oxime) leads to definite enhancement of the oxime
reduction rates. Finally, the use of a cosolvent (e.g., toluene)
is an important factor that, under these conditions, greatly
facilitates product isolation. The initial reduction mixture
generally consists of both monoacetyl and diacetyl products
that, through a simple 2 M NaOH wash, are converged into
the desired monoacetyl enamides 2 in moderate to good
yields (40-85%, unoptimized) and importantly in a high
state of purity.
Figure 1 shows representative examples of varied enam-
ides that have been produced using this method. Both
acyclic and cyclic ketones may be cleanly converted to
enamides via this method. When R′ is a non-hydrogen atom,
the enamides are formed as E/ Z mixtures. With regard to
use of the latter enamides in asymmetric hydrogenation
reactions, the DuPHOS-Rh and BPE-Rh catalysts have been
found to be uniquely capable of reducing mixtures of E and
Z enamides with high enantioselectivities.1 Preliminary
studies indicate that when both R and R′ groups of oxime 4
possess enolizable protons, regioisomeric enamides are
formed. It is important to note that in most cases crude
enamides 2 isolated via this procedure were crystalline solids
of suitable purity to be employed directly in asymmetric
catalytic hydrogenation reactions (vide infra).
(1) Burk, M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996, 118,
5142. DuPHOS refers to 1,2-bis(trans-2,5-disubstituted phospholano)-
benzene ligands, whereas BPE indicates 1,2-bis(trans-2,5-disubstituted
phospholano)ethane ligands. See ref 7 below for further information on these
ligands.
(2) (a) Boar, R. B.; McGhie, J . F.; Robinson, M.; Barton, D. H. R.; Horwell,
D. C.; Stick, R. V. J . Chem. Soc., Perkin Trans. 1 1975, 1237. (b) Heng-
Suen, Y.; Kagan, H. B. Bull. Soc. Chem. Fr. 1965, 1460. (c) Lenz, G. R.
Synthesis 1978, 489 and references therein. (d) Brettle, R.; Mosedale, A. J .
J . Chem. Soc., Perkin Trans. 1 1988, 2185.
(3) (a) Heng-Suen, Y.; Horeau, A.; Kagan, H. B. Bull. Soc. Chem. Fr. 1965,
1454. (b) Kagan, H. B.; Langlois, N.; Dang, T. P. J . Organomet. Chem. 1975,
90, 353.
(4) (a) Koenig, K. E. In Asymmetric Synthesis; Morrison, J . D, Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 3. (b) Noyori, R.; Ohta,
M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J . Am. Chem. Soc. 1986,
108, 7117. (c) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.;
Takaya, H.; Noyori, R. J . Org. Chem. 1994, 59, 297. (d) Tschaen, D. M.;
Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-H.; Frey, L.; Karady, S.;
Shi, Y.-J .; Verhoeven, T. R. J . Org. Chem. 1995, 60, 4324.
(5) (a) J utz, C. Adv. Org. Chem. 1976, 9, 225. (b) Meth-Cohn, O.;
Westwood, K. T. J . Chem. Soc., Perkin Trans. 1 1984, 1173. (c) Muller, H.-
R.; Seefelder, M. J ustus Leibigs Ann. Chem. 1969, 728, 88. (d) Boar, R. B.;
McGhie, J . F.; Robinson, M.; Barton, D. H. R. J . Chem. Soc., Perkin Trans.
1 1975, 1242. (e) Sano, T.; Tsuda, Y. Heterocycles 1976, 4, 1361. (f) Sano,
T.; Toda, J .; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem. Pharm. Bull.
1987, 35, 479. (g) Cook, A. G. In Enamines, 2nd ed.; Cook, A. G., Ed.; Marcel
Dekker: New York, 1988; p 388. (h) Vilsmaier, E. In The Chemistry of the
Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New York, 1987; Part 2, p
1356. (i) Mpango, G. B.; Mahalanabis, K. K.; Mahdavi-Damghani, Z.;
Sniekus, V. Tetrahedron Lett. 1980, 21, 4823. (j) Baldwin, J . E.; DuPont,
W. A. Tetrahedron Lett. 1980, 21, 1881. (k) J urczak, J .; Golebioski, A. Chem.
Rev. 1989, 89, 149.
F igu r e 1. Representative enamides produced through reduction
of ketone oximes.
(6) The use of iron metal for reduction of a specific steroidal oxime has
been reported; see: Barton, D. H. R.; Zard, S. Z. J . Chem. Soc., Perkin Trans.
1 1985, 2191. For reduction of nitroolefins using iron powder in acetic
anhydride, see: Laso, N. M.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett.
1996, 37, 1605.
(7) (a) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M. J .;
Feaster, J . E. J . Am. Chem. Soc. 1992, 114, 6266. (c) Burk, M. J .; Feaster,
J . E.; Nugent, W.A.; Harlow, R. L. J . Am. Chem. Soc. 1993, 115, 10125. (d)
Burk, M. J .; Martinez, J . P.; Feaster, J . E.; Cosford, N. Tetrahedron 1994,
50, 4399. (e) Burk, M. J .; M. F. Gross, M. F.; Martinez, J . P. J . Am. Chem.
Soc. 1995, 117, 9375. (f) Burk, M. J .; Harper, T. G. P.; Kalberg, C. S. J .
Am. Chem. Soc. 1995, 117, 4423. (g) Burk, M. J .; Gross, M. F.; Harper, T.
G. P.; Kalberg, C. S.; Lee, J . R. Martinez, J . P. Pure Appl. Chem. 1996, 68,
37. (h) Burk, M. J .; Allen, J . G.; Kiesman, W. F. J . Am. Chem. Soc. 1998,
120, 657.
S0022-3263(98)00933-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/20/1998