Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines

Article abstract of DOI:10.1021/acs.orglett.5b03307

A metal-free hydrogenation of 2,4-disubstituted quinolines was realized for the first time using chiral diene derived borane catalysts to furnish the corresponding tetrahydroquinolines in 75-98% yields with 95/5-99/1 dr's and 86-98% ee's. This catalytic system was also effective for 2,3-disubstituted quinolines to give moderate to good ee's.

Full text of DOI:10.1021/acs.orglett.5b03307

Letter
pubs.acs.org/OrgLett
Enantioselective Metal-Free Hydrogenations of Disubstituted
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 metal-free hydrogenation of 2,4-disubstituted quinolines
was realized for the first time using chiral diene derived borane catalysts to
furnish the corresponding tetrahydroquinolines in 75−98% yields with 95/
5−99/1 dr’s and 86−98% ee’s. This catalytic system was also effective for
2,3-disubstituted quinolines to give moderate to good ee’s.
he asymmetric hydrogenation of heteroarenes provides an
extremely powerful and straightforward approach for the
with up to 91% ee (Figure 1).7 Notably, the asymmetric
hydrogenation of polysubstituted quinolines is of great interest
due to its ability to concurrently construct at least two
stereogenic centers. For 2,3-disubstituted quinolines, various
catalytic hydrogenation and transfer hydrogenation systems
have been developed (Figure 1).8 Glorius and co-workers
reported an interesting carbocyclic ring hydrogenation for
chiral 2,4-disubstituted quinolines in 2010 (Figure 1).9 Very
recently, our group described a highly enantioselective metal-
free hydrogenation of 2,3,4-trisubstituted quinolines (Figure
1).10 However, the asymmetric hydrogenation of 2,4- and 3,4-
disubstituted quinolines still remains as an unsolved problem.
Rapid growth has been witnessed in the metal-free
hydrogenation accompanied by the recently emerging chem-
istry of frustrated Lewis pairs (FLPs).11,12 Significantly,
promising advances have been achieved for the FLP-catalyzed
asymmetric hydrogenation.13 Quinolines were also reported to
be suitable substrates for the FLP catalysis.14 In 2011, Repo and
co-workers reported an asymmetric hydrogenation of 2-
phenylquinoline with 37% ee.15 Recently, our group accom-
plished various highly enantioselective hydrogenations utilizing
chiral borane catalysts derived in situ from chiral dienes or
diynes.16,17 In particular, a wide range of 2,3,4-trisubstituted
quinolines were smoothly hydrogenated for the first time with
high cis-selectivities and enantioselectivies.10 Herein, we report
our preliminary efforts on the metal-free asymmetric hydro-
genation of 2,4-disubstituted quinolines as well as 2,3-
disubstituted quinolines.
T
synthesis of optically active saturated heterocycles.1 Quinolines
are one class of the most often studied substrates due to the fact
that the resulting tetrahydroquinoline derivatives are very useful
building blocks for the synthesis of natural products and
biologically interesting compounds.2 Since the first example of
highly enantioselective hydrogenation of 2-subsituted quino-
lines was reported in 2003 by Zhou and co-workers (Figure 1),3
Figure 1. Asymmetric hydrogenations or transfer hydrogenations of
quinolines.
numerous chiral transition-metal catalysts and organocatalysts
have been successfully developed for this transformation.4,5 For
3- or 4-substituted quinolines, however, only very limited
examples have been reported. In 2008, Rueping and co-workers
described a chiral Brønsted acid catalyzed asymmetric transfer
hydrogenation of 3-subsitutued quinolines using Hantzsch ester
as hydrogen source to give up to 86% ee (Figure 1).6 Soon
after, the same group reported such a transformation of 4-
substituted quinolines to afford the corresponding products
We initially chose the optimal reaction conditions for the
asymmetric hydrogenation of 2,3,4-triphenylquinoline (1) to
examine the transformation of 2,4-diphenylquinoline (4a)
(Scheme 1).10 Under the catalysis of chiral borane derived in
situ from chiral diene 3a, the desired tetrahydroquinoline 5a
Received: November 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03307
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Controlled Experiments on the Hydrogenation of
Quinolines 1 and 4a
Table 1. Optimization of Reaction Conditions
b
c
c
entry
solvent
temp (°C)
conv (%)
cis/trans
ee (%)
1
2
3
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
mesitylene
Et2O
25
15
0
>99
98
97/3
97/3
98/2
97/3
97/3
97/3
97/3
96/4
85
90
92
88
90
91
73
78
37
d
4
15
15
15
15
15
15
15
>99
93
e
5
f
6
19
7
67
8
81
9
trace
75
10
n-hexane
95/5
81
a
All reactions were carried out with quinoline 4a (0.10 mmol), chiral
diene 3b (0.005 mmol), HB(C6F5)2 (0.01 mmol), and H2 (20 bar) in
b
solvent (0.2 mL) for 24 h unless otherwise noted. Determined by
c
d
crude 1H NMR. Determined by chiral HPLC. 0.1 mL of toluene was
e
f
was obtained with 90/10 dr and 80% ee. The diminished
stereoselectivities of compound 5a compared with 2 are likely
attributed to the less steric hindrance of quinoline 4a than that
of quinoline 1. Further decreasing the temperature from 40 to
25 °C gave 83% ee with an identical dr (Figure 2). Under these
used. 1.0 mL of toluene was used. 5 mol % of catalyst was used.
largely, and toluene proved to be the better one (Table 1,
entries 2 and 7−10).
2,4-Disubstituted quinolines 4a−y were next subjected to the
asymmetric hydrogenation using chiral diene 3b under the
optimal reaction conditions. It was found that all these
reactions proceeded well to give the corresponding tetrahy-
droquinolines 5a−y in 75−98% yields with 95/5−99/1 dr’s and
86−98% ee’s (Table 2, entries 1−25). Both electron-rich and
electron-poor aryl substituents at the 2- and 4-positions of
quinolines were well tolerant to give high levels of
diastereoselectivities and enantioselectivities (Table 2, entries
1−14, 18−22). Notably, furan, thiophene, and alkene
substituents were well tolerable to the hydrogenation condition
using the FLP catalysis (Table 2, entries 15−17, 23). The
asymmetric hydrogenation of quinoline 4w containing a
cyclohexenyl substituent at the 4-position furnished the desired
product 5w in 93% yield with 98/2 dr and 86% ee (Table 2,
entry 23). Moreover, quinolines 4x,y bearing substituents at the
6-position were also effective for this hydrogenation. However,
alkyl substituents at 2- or 4-position of quinolines only gave low
to moderate ee's at present. The absolute configuration of
tetrahydroquinoline 5c was determined to be 2S,4R by its X-ray
structure (Figure 3).
The current catalytic system can also be applied to the
asymmetric hydrogenation of 2,3-disubstituted quinolines. It
was found that 2,3-disubstituted quinolines were more reactive
and more sensitive to the reaction concentration than 2,4-
disubstituted quinolines. As shown in Table 3, the asymmetric
hydrogenation of various 2,3-disubstituted quinolines 6a−o in
toluene (0.1 M) at 0 °C went smoothly to give the
corresponding products 7a−o in 74−99% yields with >95/
5−99/1 dr’s and 45−80% ee’s (entries 1−15). The relatively
lower ee indicated that the substituents on the 4-positions of
quinolines were beneficial to the acquirement of high
enantioselectivities.10
Figure 2. Representative chiral dienes for asymmetric hydrogenations
of quinoline 4a.
reaction conditions, various chiral dienes 3b−f were next
studied for this hydrogenation (Figure 2). With the change of
isopropoxy group to methoxy group, chiral diene 3b gave a
much better diastereoselectivity. Chiral 3c gave comparable
results with 3b. When chiral 3d was used, a drastic drop of
reactivity and ee was observed. Chiral dienes 3e and 3f were
also effective for this transformation to afford high diaster-
eoselectivities but moderate ee’s.
To further improve the enantioselectivity, the reaction
conditions including temperature, concentration, and solvents
were subsequently optimized. Lowering the temperature to 15
°C can give a 90% ee (Table 1, entry 2). A slightly higher ee
was obtained at 0 °C but with only a 37% conversion (Table 1,
entry 3). The change of concentration had little impact on this
reaction (Table 1, entries 4 and 5). When the catalyst loading
was reduced to 5 mol %, a very low conversion was obtained
but without loss of diastereoselectivity and enantioselectivity
(Table 1, entry 6). Solvents influenced this hydrogenation
In summary, with the use of chiral borane catalysts derived in
situ from chiral dienes, a highly enantioselective hydrogenation
of 2,4-disubstituted quinolines was accomplished for the first
time to furnish a wide range of tetrahydroquinoline derivatives
in 75−98% yields with 95/5−99/1 dr’s and 86−98% ee’s.
Moreover, this catalytic system was also effective for the
asymmetric hydrogenation of 2,3-disubstituted quinolines to
afford high levels of yields and dr’s with moderate to good ee’s.
B
DOI: 10.1021/acs.orglett.5b03307
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Asymmetric Hydrogenation of 2,4-Disubstituted
a
Quinolines 4
Figure 3. X-ray structure of compound (2S,4R)-5c.
Table 3. Asymmetric Hydrogenation of 2,3-Disubstituted
a
Quinolines 6
a
All reactions were carried out with quinolines 6 (0.40 mmol),
HB(C6F5)2 (0.04 mmol), chiral diene 3b (0.02 mmol), and H2 (20
b
c
bar) in toluene (4.0 mL) at 0 °C for 24 h. Isolated yield. Determined
by chiral HPLC.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03307.
a
All reactions were carried out with quinolines 4 (0.40 mmol),
HB(C6F5)2 (0.04 mmol), chiral diene 3b (0.02 mmol), and H2 (20
b
bar) in toluene (0.8 mL) at 15 °C for 24 h. Isolated yield.
Procedure for the metal-free asymmetric hydrogenation
of disubstituted quinolines, characterization of products,
and data for the determination of enantiomeric excesses
along with the NMR spectra (PDF)
c
Determined by chiral HPLC.
Further efforts to expand the substrate scope and explore novel
metal-free hydrogenations are underway in our laboratory.
X-ray data for 5c (CIF)
C
DOI: 10.1021/acs.orglett.5b03307
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W.
Science 2006, 314, 1124.
(12) For leading reviews, see: (a) Kenward, A. L.; Piers, W. E. Angew.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: haifengdu@iccas.ac.cn.
Chem., Int. Ed. 2008, 47, 38. (b) Stephan, D. W.; Erker, G. Angew.
́
Chem., Int. Ed. 2010, 49, 46. (c) Soos, T. Pure Appl. Chem. 2011, 83,
Notes
667. (d) Paradies, J. Angew. Chem., Int. Ed. 2014, 53, 3552. (e) Liu, Y.;
Du, H. Huaxue Xuebao 2014, 72, 771. (f) Shi, L.; Zhou, Y.-G.
ChemCatChem 2015, 7, 54. (g) Stephan, D. W.; Erker, G. Angew.
Chem., Int. Ed. 2015, 54, 6400. (h) Stephan, D. W. J. Am. Chem. Soc.
2015, 137, 10018. (i) Stephan, D. W. Acc. Chem. Res. 2015, 48, 306.
(13) (a) Chen, D.; Klankermayer, J. Chem. Commun. 2008, 2130.
(b) Chen, D.; Wang, Y.; Klankermayer, J. Angew. Chem., Int. Ed. 2010,
49, 9475. (c) Heiden, Z. M.; Stephan, D. W. Chem. Commun. 2011, 47,
5729. (d) Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J. Dalton
Trans. 2012, 41, 9026. (e) Chen, D.; Leich, V.; Pan, F.; Klankermayer,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21222207 and
21572231).
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DOI: 10.1021/acs.orglett.5b03307
Org. Lett. XXXX, XXX, XXX−XXX