ORGANIC
LETTERS
2010
Vol. 12, No. 2
276-279
Catalytic Enantioselective Hydrogenation
of N-Alkoxycarbonyl Hydrazones: A
Practical Synthesis of Chiral Hydrazines
Naoki Yoshikawa,* Lushi Tan,* J. Christopher McWilliams, Deepa Ramasamy, and
Ruth Sheppard
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc.,
Rahway, New Jersey 07065
naoki_yoshikawa@merck.com; lushi_tan@merck.com
Received November 10, 2009
ABSTRACT
An enantioselective hydrogenation of hydrazones catalyzed by Rh complexes (Rh-Josiphos or Rh-Taniaphos) has been developed. The protocol
can be applied to hydrazones with three different protective groups (Boc, Cbz, and methoxycarbonyl), allowing for selective deprotection and
further elaboration of the hydrazine products in the presence of other functional groups.
The development of enantioselective hydrogenation of a
CdN bond has received considerable attention as it provides
a convenient access to a wide variety of compounds bearing
C-N bonds with chiral stereogenic centers,1 including
precursors to numerous natural products and other biologi-
cally important compounds. One of the key factors in the
development of enantioselective hydrogenation of imines is
the choice of substituent on the nitrogen atom, which has
proven to have critical influence on the reactivity and
selectivity. N-Benzyl and N-aryl imines are commonly used
as substrates for the enantioselective hydrogenations and offer
opportunities for selective deprotection under different condi-
tions. Cyclic imines have also been extensively studied as
substrates. On the other hand, examples of the use of
heteroatom-substituted imines2 as substrate are rather limited
except for sulfonyl and phosphinyl groups that are introduced
as the protective groups.3 In 1991, Burk et al. reported an
asymmetric hydrogenation of N-acyl hydrazones catalyzed
by Rh-Duphos complexes.4 The resulting hydrazines can
be transformed into chiral amines by reductive cleavage of
the N-N bond. The hydrazine itself also constitutes an
important class of building blocks to form various hetero-
cyclic compounds.
In connection with our program to synthesize a pharma-
ceutical intermediate, we needed to prepare a large quantity
of unprotected chiral hydrazine with an ester moiety on the
phenyl ring (1, Figure 1).
(2) Burk et al. reported the use of oximes as precursor to enamides,
which could then be hydrogenated to give chiral amines. See: Burk, M. J.;
Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084. For asymmetric
reductive acylation of ketoximes, see: Han, K.; Park, J.; Kim, M.-J. J. Org.
Chem. 2008, 73, 4302.
(3) (a) Spindler, F.; Blaser, H.-U. AdV. Synth. Catal. 2001, 343, 68. (b)
Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 12462.
(c) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 1189. (d) Yang, Q.; Shang, G.;
Gao, W.; Deng, J.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 3832. (e)
Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem.
Commun. 2006, 1766. (f) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org.
Chem. 2007, 72, 3729. (g) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang,
X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10, 2071.
(1) For recent reviews, see: (a) Tang, W.; Zhang, X. Chem. ReV. 2003,
103, 3029. (b) Spindler, F.; Blaser, H.-U. Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim,
Germany, 2007; Vol. 3, Chapter 34, pp 1193.
(4) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M. J.;
Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399.
10.1021/ol902602c 2010 American Chemical Society
Published on Web 12/17/2009