Angewandte
Chemie
DOI: 10.1002/anie.201409471
Asymmetric Catalysis
A Highly cis-Selective and Enantioselective Metal-Free Hydrogenation
of 2,3-Disubstituted Quinoxalines**
Zhenhua Zhang and Haifeng Du*
Abstract: A wide range of 2,3-disubstituted quinoxalines have
been successfully hydrogenated with H2 using borane catalysts
to produce the desired tetrahydroquinoxalines in 80–99%
yields with excellent cis selectivity. Significantly, the asymmet-
ric reaction employing chiral borane catalysts generated by the
in situ hydroboration of chiral dienes with HB(C6F5)2 under
mild reaction conditions has also been achieved with up to
96% ee, and represents the first catalytic asymmetric system to
Scheme 1. Reductions of 2,3-disubstituted quinoxalines. THF=tetra-
hydrofuran.
furnish optically active cis-2,3-disubstituted 1,2,3,4-tetrahydro-
quinoxalines.
T
etrahydroquinoxalines are very useful moieties and present
in a wide range of biologically and medicinally active
compounds, and a lot of methods have been developed to
access them.[1] The direct reduction of quinoxalines is one of
the most efficient approaches among these methodologies.[2]
In particular, the catalytic hydrogenation with H2 as well as its
asymmetric version has attracted attention and great advan-
ces have been made.[3] Since the first asymmetric hydro-
genation of 2-methylquinoxaline with chiral rhodium cata-
lysts reported by Murata and co-workers in 1987,[4a] a variety
of chiral transition metal catalysts have been developed for
the enantioselective hydrogenation of 2-substituted quinoxa-
lines.[4] However, in sharp contrast, the reduction of 2,3-
substituted quinoxalines has been rarely reported.[5,6] For
example, Deselms and Mosher reported a noncatalytic lith-
ium aluminium hydride reduction of 2,3-dimethylquinoxaline
to give a cis product in 1960 (Scheme 1).[5a] Gavin and co-
workers described the reduction of 2,3-dimethyl- and 2,3-
diphenylquinoxaline with borane in THF solution (Sche-
me 1).[5b] Recently, Xu, Fan, and Xiao reported an iridium-
catalyzed transfer cis-selective hydrogenation of 2,3-dime-
thylquinoxaline (Scheme 1).[5c] Glorius and co-workers de-
scribed a ruthenium/carbene-catalyzed cis-selective hydro-
genation of 2,3-diphenyl-6-methylquinoxaline. In 2011, Fan
and co-workers disclosed the first and the only asymmetric
hydrogenation of 2,3-dialkylquinoxalines with chiral cationic
ruthenium diamine catalysts to give the desired trans products
with up to 99% ee and 86:14 d.r. (Scheme 1).[5e] Therefore, the
development of highly stereoselective hydrogenations of 2,3-
disubstituted quinoxalines under mild reaction conditions
with a good substrate scope, especially the corresponding
asymmetric reactions, still remains a challenge in the field of
catalytic hydrogenation.
The recently emerging frustrated Lewis pair (FLP)
chemistry provides a breakthrough approach for metal-free
hydrogenation with molecular H2 since catalytic hydrogena-
tion has long been dominated by transition-metal catalysis.[7–9]
A wide range of unsaturated compounds have proven to be
effective substrates for the FLP-catalyzed hydrogenations.[9,10]
Significantly, some promising advances have also been made
for FLP-catalyzed asymmetric reactions,[11,12] but the asym-
metric hydrogenation of silyl enol ethers is the only example
to proceed with more than 90% ee.[11f] In 2013, Stephan and
co-workers described the hydrogenation of 2,3-dimethyl- and
2,3-diphenylquinoxaline using an equivalent of the Lewis acid
B(C6F5)3. Interestingly, decahydro- instead of tetrahedroqui-
noxaline derivatives were obtained.[10c] As part of our general
interest in exploring novel FLP catalytic systems, we recently
reported the asymmetric hydrogenation of imines[11e] and silyl
enol ethers,[11f] and the cis-selective hydrogenation of simple
pyridines,[10d] using an in situ catalyst generation strategy
involving the hydroboration of alkenes with HB(C6F5)2
(Piersꢀ borane).[13,14] Our attempts on other challenging
substrates for the hydrogenation show that 2,3-disubstituted
quinoxalines can be highly cis-selectively and enantioselec-
tively hydrogenated under FLP catalysis. Herein, we report
our preliminary efforts on this subject.
[*] Z. Zhang, Prof. Dr. H. Du
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS
Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
Initially, the metal-free hydrogenation of 2,3-dimethyl
quinoxaline (1a) under H2 (20 bar) at 1008C in toluene was
examined using 10 mol% of B(C6F5)3 (3a)[15a] or B(p-HC6F4)3
(3b).[15b] These reactions went well to give trans-2a as a major
product (Table 1, entries 1 and 2). Further lowering the
temperature can obviously improve the cis selectivities
(entries 3–6), and up to 98:2 d.r. was obtained at 608C using
3b. Reducing the catalyst loading to 5 mol% gave a similar
E-mail: haifengdu@iccas.ac.cn
[**] We are grateful for the generous financial support from the National
Basic Research Program of China (973 program, 2011CB808600),
and the National Natural Science Foundation of China (20802079,
21222207).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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