Cis-selective and highly enantioselective hydrogenation of 2,3,4-trisubstituted quinolines

Article abstract of DOI:10.1021/acs.orglett.5b01240

A highly enantioselective cis-hydrogenation of 2,3,4-trisubstituted quinolines has been realized for the first time using chiral borane catalysts generated in situ from chiral dienes. A variety of tetrahydroquinoline derivatives containing three contiguous stereogenic centers were obtained in 76-99% yields with 82-99% ee's.

Full text of DOI:10.1021/acs.orglett.5b01240

Letter
pubs.acs.org/OrgLett
Cis-Selective and Highly Enantioselective Hydrogenation of 2,3,4-
Trisubstituted Quinolines
Zhenhua Zhang and Haifeng Du*
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
S
* Supporting Information
ABSTRACT: A highly enantioselective cis-hydrogenation of 2,3,4-trisubsti-
tuted quinolines has been realized for the first time using chiral borane
catalysts generated in situ from chiral dienes. A variety of tetrahydroquinoline
derivatives containing three contiguous stereogenic centers were obtained in
76−99% yields with 82−99% ee’s.
Scheme 2. Hydrogenation of 2,3,4-Trisubstituted Quinoline
1a
he catalytic asymmetric hydrogenation of quinolines
Trepresents one of the most efficient accesses to optically
active tetrahydroquinoline derivatives, which are very important
building blocks for the synthesis of natural products and
biologically active compounds.1,2 In 2003, Zhou and co-workers
reported the first asymmetric hydrogenation of 2-substituted
quinolines using a chiral iridium catalyst to give tetrahydroqui-
nolines with up to 96% ee (Scheme 1).3 Following this seminal
work, a variety of transition-metal catalytic systems have been
rapidly developed.4,5 Notably, in contrast to the intensive
studies on 2-substituted quinolines, the asymmetric hydro-
genation of 2,3-disubstituted quinolines seems to be more
challenging, and only several examples have been reported.6,7
For example, in 2009, Zhou and co-workers described an Ir-
catalyzed enantioselective hydrogenation of 2,3-disubstituted
quinolines with up to 86% ee.6a In 2011, Fan and co-workers
reported a Ru-catalyzed asymmetric reaction with up to 98%
ee.6b Despite these advances, there still are some unsolved
quinoline substrates for the asymmetric hydrogenation with H2,
such as 4-substituted quinolines.8 Glorius and co-workers
reported a two-step heterogeneous hydrogenation of chiral 2,4-
disubstituted quinolines to give decahydroquinolines, in which
the carbocyclic instead of the heterocyclic ring was hydro-
genated first.9 However, for the even more difficult 2,3,4-
trisubstituted quinolines, the asymmetric hydrogenation has not
Scheme 3. Evaluation of Chiral Dienes for Asymmetric
Hydrogenation of 2,3,4-Trisubstituted Quinoline 1a
Scheme 1. Asymmetric Hydrogenation of Quinolines with
H2
been reported yet. The challenges are likely to lie in how to
overcome the bulky steric hindrance and construct the three
Received: April 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01240
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions for
Asymmetric Hydrogenation of 2,3,4-Trisubstituted
Quinoline 1a
Table 2. Metal-Free Asymmetric Hydrogenation of
Quinolines
a
a
b
c
entry
diene 3
solvent
concn (M)
conv (%)
ee (%)
1
3i
toluene
CH2Cl2
n-hexane
Et2O
0.1
0.1
0.1
0.1
0.1
0.5
0.5
0.1
0.5
1.0
0.5
0.5
85
30
84
92
67
2
3i
3
3i
71
4
3i
trace
72
5
3i
mesitylene
toluene
CH2Cl2
toluene
toluene
toluene
CH2Cl2
toluene
83
84
80
92
90
90
90
90
6
3i
>99
>99
28
7
3i
8
3k
3k
3k
3k
3k
9
>99
82
10
11
40
d
12
15
a
All reactions were carried out with 2,3,4-trisubstituted quinoline 1a
(0.10 mmol), chiral diene 3 (0.005 mmol), HB(C6F5)2 (0.01 mmol),
b
and H2 (20 bar) at 40 °C for 20 h unless other noted. Determined by
c
d
1
crude H NMR. Determined by chiral HPLC. 5 mol % of borane
was used.
contiguous stereogenic centers with high levels of stereo- and
enantioselectivity.
The metal-free hydrogenation with molecular H2 enters a
new era due to the rapid growth of frustrated Lewis pair (FLP)
chemistry.10 A wide range of unsaturated compounds have been
hydrogenated using stoichiometric or catalytic amount of FLP
catalysts.11 Recently, some significant advances have also been
made for the catalytic asymmetric hydrogenation using chiral
substrates or chiral FLP catalysts.12−14 2-Substituted quinolines
proved to be suitable substrates for the metal-free hydro-
genation.15 In particular, in 2011, Repo and co-workers
reported an asymmetric hydrogenation of 2-phenylquinoline
using chiral ansa-ammonium borate to give the product with
37% ee.13e Our group has been exploring highly enantiose-
lective hydrogenation of unsaturated compounds, especially
some unsolved substrates. Recently, we successfully realized the
asymmetric hydrogenation of imines, silyl enol ethers, and 2,3-
disubstituted quinoxalines using in situ generated borane
catalysts by the hydroboration of chiral dienes or diynes with
Piers’ borane.16−18 On the basis of these previous works, our
catalytic system is expected to have a good chance to solve the
challenging hydrogenation of 2,3,4-trisubstituted quinolines.
Herein, we report our preliminary efforts on this subject.
Initially, an in situ generated achiral borane by hydroboration
of styrene (5 mol %) with Piers’ borane HB(C6F5)2 (5 mol %)
was subjected to the hydrogenation of 3-methyl-2,4-diphenyl-
quinoline (1a) under H2 (20 bar) in toluene at 40 °C for 20 h
(Scheme 2). We were pleased to find that this reaction
proceeded smoothly to give the desired product 2a in a
quantitative conversion. Significantly, this hydrogenation was a
highly stereoselective reaction to furnish a single cis,cis-isomer.
This interesting result indicates that it is possible to realize the
asymmetric reaction using a chiral borane catalyst.
A variety of chiral dienes 3 were therefore examined for the
asymmetric hydrogenation of 2,3,4-trisubstituted quinoline 1a.
As shown in Scheme 3, all of these chiral dienes were effective
for this reaction to give cis,cis-tetrahydroquinoline 2a. A simple
chiral diene 3a derived from (S)-BINOL gave a good
conversion with 54% ee, while 6,6′-Ph2BINOL-derived diene
3b led a converse absolute configuration. H8-BINOL-derived
a
All reactions were carried out with quinolines 1 (0.40 mmol),
HB(C6F5)2 (0.04 mmol), chiral diene 3k (0.02 mmol), and H2 (20
b
bar) in toluene (0.8 mL) at 40 °C for 20 h. Isolated yield.
c
d
Determined by chiral HPLC. Contained 9% stereoisomers
e
determined by GC−MS. Contained 15% stereoisomers determined
by GC−MS.
B
DOI: 10.1021/acs.orglett.5b01240
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Letter
helpful to solve some other challenging substrates in the field of
hydrogenation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedure for the metal-free asymmetric hydrogenation of
2,3,4-trisubstituted quinolines, characterization of quinolines
and products, a CIF file for the single crystal, and data for the
determination of enantiomeric excesses along with the NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01240.
AUTHOR INFORMATION
Corresponding Author
■
Figure 1. X-ray structure of compound (2S,3R,4R)-2o.
*E-mail: haifengdu@iccas.ac.cn.
Notes
diene 3c resulted in a low conversion and ee. It was found that
the 3,3′-substituents on the binaphthyl framework (3d−k) had
a large impact on both reactivity and enantioselectivity. Chiral
diene 3i gave 85% conversion with 84% ee. When chiral diene
3k was used, 92% ee was obtained but only with a very low
conversion.
The reaction conditions were next optimized to further
improve the reactivity and enantioselectivity. Solvents had an
obvious influence on this hydrogenation (Table 1, entries 1−6).
CH2Cl2 gave a better ee but a lower conversion (Table 1, entry
2). Increasing the concentration from 0.1 to 0.5 M resulted in a
quantitative conversion without loss of enantioselectivity
(Table 1, entry 1 vs 6). Notably, this improvement was more
significant when chiral 3k was used (Table 1, entries 8 vs 9),
and a quantitative conversion with 90% ee was obtained.
Further increasing the concentration to 1.0 M gave only 82%
conversion due to the incomplete dissolution of substrate
(Table 1, entry 10). Reducing the catalyst loading to 5 mol %
diminished the reactivity largely (Table 1, entry 12).
The metal-free asymmetric hydrogenation of a broad range
of 2,3,4-trisubstituted quinolines 1 was investigated under the
optimal reaction conditions. As shown in Table 2, all these
reactions went efficiently to afford the desired products 2a−t in
76% yields with 82−99% ee’s. Various aryl substituents at the 2-
or 4-positions of quinolines were well tolerant for this reaction
(Table 2, entries 1−11). When quinolines bearing an ethyl or
n-hexanyl group at the 3-position were used as substrates,
products 2l,m were obtained in high yields with 92−93% ee’s
(Table 2, entries 12 and 13). However, a small amount of
stereoisomers was observed in these two cases. 2,3,4,6-
Tetrasubstituted quinolines were also suitable substrates for
this reaction to furnish tetrahydroquinolines 2n−r in 81−97%
yields with 91−97% ee’s (Table 1, entries 14−18). The
hydrogenation of quinolines containing a thiophene-yl group at
the 2-position gave up to 99% ee (Table 2, entries 19 and 20).
The absolute configuration of compound 2o was determined to
be 2S,3R,4R by its X-ray structure (Figure 1).
In summary, a highly enantioselective metal-free hydro-
genation of 2,3,4-trisubstituted quinolines was successfully
realized for the first time using a chiral borane catalyst
generated in situ from chiral dienes. A wide range of
tetrahydroquinolines containing three contiguous stereogenic
centers were obtained in 76% yields with 82−99% ee’s.
Significantly, in most cases, only cis,cis-isomers were afforded.
The current work exhibits some unique advantages of FLP
catalysts on the bulky polysubstituted substrates, which may be
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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 (21222207).
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