Angewandte
Chemie
DOI: 10.1002/anie.201501018
Asymmetric Hydrogenation
Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Hydrazones
and Other Ketimines**
Haiyan Xu, Peng Yang, Pratanphorn Chuanprasit, Hajime Hirao,* and Jianrong (Steve) Zhou*
Abstract: We report the use of nickel catalysts for the catalytic
transfer hydrogenation of hydrazones and other ketimines with
formic acid. Strongly donating bisphosphines must be used to
support the catalysts. As in enzymatic catalysis, attractive weak
interactions may be important for stereochemical control by
the nickel/binapine catalyst.
the research groups of Beller[12] and Morris[13] independently
developed iron catalysts for the asymmetric hydrogenation of
imines, but only N-phosphinyl ketimines were hydrogenated
with high enantioselectivity. In another line of research, chiral
phosphoric acids were successfully used as transition-metal-
free catalysts for asymmetric ketimine reduction.[14]
Nickel is much cheaper than the noble metals. Recent
prices of nickel, iridium, and rhodium were around $16,
$16000, and $40000 per kg, respectively.[15] The production of
nickel is as high as 2.1 million tons a year, as compared with
30 tons for rhodium. Discrete nickel complexes of N-hetero-
cyclic carbenes and phosphines have been examined in
nonstereoselective hydrogenation and hydrosilylation reac-
C
hiral alkyl amines are common in drugs and agrochemicals.
They are present in about 20% of blockbuster drugs. In the
past, classical resolution was often used to prepare chiral alkyl
amines.[1] In recent decades, metal-catalyzed hydrogenation
reactions of imines, enamines, and enamides have emerged as
economic alternatives for the large-scale preparation of
pharmaceuticals.[2] Today, noble-metal catalysts based on
Rh,[3] Ir,[4] and Ru[5] dominate the field of asymmetric
(transfer) hydrogenation, with the recent addition of Pd
catalysts.[6] In particular, millions of turnovers are possible
with iridium hydrogenation catalysts, and they are used in the
industrial production of the cough suppressant dextrome-
thorphan[7] and the herbicide metolachlor.[8] However, these
heavy metals are extremely expensive and highly toxic and
pollute our ecosystems if released. Furthermore, their
reserves in the Earthꢀs crusts are very limited; they are
produced in dozens of tons yearly.
tions of C C, C O, and C N bonds.[18] Furthermore, the
nickel-catalyzed asymmetric hydrogenation of a-amino-b-
ketoesters under dynamic kinetic resolution has been
reported[19] as well as the hydrosilylation of some ketones
(around 80% ee).[20] We recently disclosed a nickel/binapine
catalyst for the asymmetric transfer hydrogenation of enam-
ides.[21] Heterogeneous nickel catalysts modified with tartaric
acid derivatives have been applied in the asymmetric hydro-
genation of ketones (Orito reaction), although the success of
this approach has been quite limited.[22]
[16]
[17]
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Herein, we describe the use of nickel catalysts for the
asymmetric transfer hydrogenation of hydrazones and other
ketimines.[23] Recently, Zhang and co-workers reported an
asymmetric reductive amination via hydrazone intermediates
with an Ir/f-binaphane catalyst.[24] The hydrazine products can
be reduced to release free alkyl amines by treatment with
SmI2[23] and hydrogenation over nickel.[25]
First-row metals are much cheaper and less toxic or
nontoxic. Every year, they are produced in millions of tons.
Back in 1996, Mukaiyama and co-workers disclosed a cobalt-
catalyzed asymmetric reduction with a modified borohydride,
but the imines were limited to N-phosphinyl ketimines.[9] At
a similar time, Buchwald and co-workers successfully applied
chiral titanocene catalysts to the hydrogenation and hydro-
silylation of aryl ketimines.[10] Lipshutz and Shimizu also
reported a copper-catalyzed asymmetric hydrosilylation of
aryl ketimines.[11] In recent years, there has been renewed
interest in finding new first-row-metal catalysts. For example,
In our study of the nickel-catalyzed transfer hydrogena-
tion of a model hydrazone of acetophenone, highly electron
rich, bulky bisphosphines showed high activity (Scheme 1). In
particular, (S)-binapine, which was invented by Zhang and co-
workers, afforded the product with 97% ee and full con-
version.[26] The related bisphosphines BenzP* and QuinoxP*
also afforded good selectivity,[3f,27] and with iPr-DuPhos the
product was obtained with 80% ee.[28] Notably, one of the
josiphos ligands of Togni and co-workers gave almost perfect
stereoselectivity.[29] The less donating bisphosphine ligands
binap, segphos, and dipamp, with two or three aryl rings
attached to each phosphorus center, were completely inactive
in nickel catalysis. Iron, cobalt, and copper salts were also
tested, but no active catalyst was found with binapine.
A 2:2 molar mixture of HCO2H and Et3N was used as
a hydrogen surrogate. Sometimes partial hydrolysis of the
hydrazone was detected and dry molecular sieves were
included to prevent the unwanted side reaction.[30] In
alcoholic solvents (Table 1, entries 1–5), the reaction was
much faster than in aprotic solvents (entries 7–10).[31]
[*] H. Xu, Dr. P. Yang, P. Chuanprasit, Prof. Dr. H. Hirao,
Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: hirao@ntu.edu.sg
[**] We are grateful for a 2014 Singapore GSK-EDB Green and
Sustainable Manufacturing Award and thank Nanyang Technolog-
ical University for financial support. We thank Dr. Rakesh Ganguly
and Yongxin Li for X-ray diffraction analysis. P.C. and H.H.
performed DFT calculations.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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