FULL PAPER
DOI: 10.1002/chem.201204194
Fast Reductive Amination by Transfer Hydrogenation “on Water”
Qian Lei,[a] Yawen Wei,[a] Dinesh Talwar,[b] Chao Wang,*[a] Dong Xue,[a] and
Jianliang Xiao*[a, b]
Abstract: Reductive amination of vari-
ous ketones and aldehydes by transfer
hydrogenation under aqueous condi-
tions has been developed, by using cy-
clometallated iridium complexes as cat-
alysts and formate as hydrogen source.
The pH value of the solution is shown
with that in organic solvents, the reduc-
tive amination in an aqueous phase is
faster, and the molar ratio of the sub-
strate to the catalyst (S/C) can be set
as high as 1ꢀ105, the highest S/C value
ever reported in reductive amination
reactions. The catalyst is easy to access
and the reaction is operationally
simple, allowing a wide range of ke-
tones and aldehydes to react with vari-
ous amines in high yields. The protocol
provides a practical and environmental
friendly new method for the synthesis
of amine compounds.
Keywords: amination
· amines ·
to be critical for
a high catalytic
hydrogenation · iridium catalyst ·
water
chemoselectivity and activity, with the
ACHTUNGTRENNUNG
best pH value being 4.8. In comparison
Introduction
NaBH3CN and the inability to aminate aromatic ketones
with NaBH(OAc)3, two most widely used hydrides in
AHCTUNGTRENNUNG
Amine moieties are widely found in natural products, agro-
chemicals and pharmaceuticals.[1] Development of methods
for the efficient and economic production of amines has at-
tracted great attention.[1,2] One of the best ways for produc-
ing amines is the reduction of imino C=N bonds,[1a,c,2n,q,s]
which are most conveniently obtained from the condensa-
tion of carbonyl compounds with amines. However, imines
are not always easy to synthesise and have limited stability.
Reductive amination (RA) exploits imines in situ generated
from carbonyl compounds and amines, alleviating the prob-
lematic imine isolation. Tremendous efforts have been de-
voted to the development of efficient RA reactions; howev-
er, the progress is far from satisfactory.[1b,c,2h,p,s–u] In most of
the RA reactions developed, stoichiometric boron hydride
reduction and heterogeneous hydrogenation dominate the
scene.[1b,2t] Borane hydride reduction has been used in a
number of industrial applications,[3] for example, synthesis of
a CCR3 antagonist[4] and an antiangiogenic tyrosine kinase
inhibitor.[5] However, the use of a stoichiometric amount of
boron hydrides generates copious amounts of waste and is
associated with other problems, such as toxicity issues with
RA.[2t,6] Although heterogeneous catalysts have found many
applications in RA including industrial examples, they gen-
erally display poor chemoselectivity.[1b,7] Progress in devel-
oping homogeneous catalytic systems, including organome-
tallic hydrogenative,[8] organocatalytic[9] and enzymatic[10]
ones, has been made in recent years, even allowing for enan-
tioselective RA in a few cases.[8a,c–e,h–k,9,10c] However, there is
still much room for improvement in terms of substrate
scope and catalytic activity.
Transfer hydrogenation, which usually uses organometallic
catalysts and hydrogen sources other than hydrogen gas, is
an operationally simple and versatile method for reduction
and has been very successful in carbonyl reduction.[11] How-
ever, the development of transfer hydrogenation systems for
the reduction of C=N bonds lags behind that for carbonyl
groups.[12] Indeed, only a handful of examples of transfer hy-
drogenative RA have been reported.[13] Kitamura, Kadyrov,
Wills, Ogo and Strotman and their co-workers reported RA
using formate as hydrogen source, including asymmetric and
aqueous versions.[13a–d,f] Carbtree and co-workers attempted
RA of aldehydes with isopropanol as hydrogen source, by
using an iridium carbene catalyst.[13e] Recently, we devel-
oped a versatile and efficient transfer hydrogenation system
for RA, which exploits cyclometallated iridium complexes
as catalysts and HCOOH/Et3N as hydrogen source in alco-
holic solvents.[14]
[a] Q. Lei, Y. Wei, Prof. C. Wang, Prof. D. Xue, Prof. J. Xiao
Key Laboratory of Applied Surface and Colloid Chemistry
Ministry of Education
School of Chemistry and Chemical Engineering
Shaanxi Normal University, Xi’an, 710062 (P.R. China)
In this paper, we disclose our findings that cyclometallat-
ed iridium complexes also catalyse RA with formate under
aqueous conditions, when a suitable pH value is chosen
[Eq. (1)]. It is shown that water not only serves as a green
solvent, but also accelerates the RA reaction, affording
better activity than in organic solvents.
[b] D. Talwar, Prof. J. Xiao
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2013, 19, 4021 – 4029
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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