Communications
DOI: 10.1002/anie.200805058
Asymmetric Catalysis
Efficient Synthesis of Chiral b-Arylisopropylamines by Using Catalytic
Asymmetric Hydrogenation**
Jian Chen, Weicheng Zhang, Huiling Geng, Wei Li, Guohua Hou, Aiwen Lei,* and
Xumu Zhang*
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Transition-metal-catalyzed asymmetric hydrogenation of
enamides[1] is a powerful method for the preparation of
chiral amines, which are important building blocks in organic
synthesis.[2] With the development of many effective chiral
ligands,[1] a variety of prochiral enamides such as 1,[3] 2,[3a-c,e,g]
3,[4] and 4,[5] have been hydrogenated with excellent enantio-
selectivities (Figure 1). However, the asymmetric hydrogena-
A number of methods for the preparation of enamides
have been reported, including rearrangement reactions,[6,7]
the reduction of nitro alkenes[8] or ketoximes,[9] the acylation
of imines,[10] and the direct condensation of a ketone and an
amide.[11] Recently, a Merck group developed an efficient
palladium-catalyzed amidation reaction leading to a diverse
array of enamides.[12] Under the optimized reaction condi-
tions, good selectivity for Z enamides such as 6 was achieved
(Scheme 1). To gain quick access to the desired substrates 5a–
Figure 1. Prochiral enamide substrates for asymmetric hydrogenation.
tion of 5 has received less attention. To our knowledge, the
only result reported for the hydrogenation of 5 employed an
Rh/dipamp (dipamp = 1,2-ethanediylbis[(2-methoxyphenyl)-
phenylphosphine]) complex to give moderate enantioselec-
tivity (50% ee).[6] Herein, we prepared a series of enamides,
(Z)-5 and (E)-5, and tested them in a rhodium-catalyzed
asymmetric hydrogenation using several chiral ligands. Excel-
lent ee values (up to 99% ee) were achieved for the Z-config-
ured enamides by using the Rh/tangphos (tangphos = 1,1’-di-
tert-butyl-[2,2’]-diphospholanyl) catalytic system.
Scheme 1. Palladium-catalyzed amidation for the synthesis of Z-enam-
ide 6.[12]
5i, we chose the direct condensation method because of its
operational simplicity. As shown in Table 1, each isomer of 5
can be isolated by using flash column chromatography; in
most cases, more of the Z enamide was obtained than the
corresponding E isomer. Although the moderate yields
remain to be optimized, we found the present method to be
suitable for the quick syntheses of both (Z)-5 and (E)-5 from
inexpensive starting materials. Additionally, diaryl enamide
5i was prepared in acceptable yield (Table 1, entry 9), which
complements the palladium-catalyzed amidation for this
bulky substrate.[12b]
Having synthesized a set of enamides 5, we tested the
rhodium-catalyzed asymmetric hydrogenation of (Z)-5a and
(E)-5a by using four widely used chiral ligands, including
(1S,1S’,2R,2R’)-tangphos (L1),[13a] (SC,RP)-duanphos (L2),[13b]
(R,R)-Et-duphos (L3),[13c] and (S)-binapine (L4).[13d] Notably,
under the same reaction conditions each ligand showed a
striking difference in enantioselectiviy toward the two
isomers (Table 2). For (Z)-5a, excellent ee values were
obtained by the use of all ligands except L4,with tangphos
giving the best results. A change in the solvent used had little
effect on the enantioselectivity. In contrast, much lower
ee values were observed for (E)-5a in EtOAc, albeit with the
same sense of product chirality as that obtained from (Z)-5a.
A change in the solvent used gave no improvement in
[*] J. Chen, Prof. A. Lei, Prof. X. Zhang
College of Chemistry and Molecular Sciences
Wuhan University (PR China)
E-mail: aiwenlei@whu.edu.cn
J. Chen, W. Zhang, H. Geng, W. Li, G. Hou, Prof. X. Zhang
Department of Chemistry and Chemical Biology & Department of
Pharmaceutical Chemistry, Rutgers, The State University of New
Jersey, Piscataway, New Jersey 08854 (USA)
Fax: (+1)732-445-6312
E-mail: xumu@rci.rutgers.edu
H. Geng
Northwest Agriculture and Forestry University
Yangling, Shanxi (PR China)
[**] This work was supported by the National Institutes of Health
(GM58832) and the China Scholarship Council. Mass spectrometry
was provided by the Washington University Mass Spectrometry
Resource, an NIH Research Resource (Grant P41RR0954).
Supporting information for this article is available on the WWW
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 800 –802