Chiral dienes as "ligands" for borane-catalyzed metal-free asymmetric hydrogenation of imines

Article abstract of DOI:10.1021/ja4025808

This paper describes a highly enantioselective metal-free hydrogenation of imines using chiral dienes as "ligands" for the generation of catalysts with HB(C₆F₅)₂ by hydroboration in situ to furnish a variety of chiral amin

Full text of DOI:10.1021/ja4025808

Communication
pubs.acs.org/JACS
Chiral Dienes as “Ligands” for Borane-Catalyzed Metal-Free
Asymmetric Hydrogenation of Imines
Yongbing Liu 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
Moreover, Stephan and co-workers described a diastereose-
ABSTRACT: This paper describes a highly enantioselec-
tive metal-free hydrogenation of imines using chiral dienes
as “ligands” for the generation of catalysts with HB(C6F5)2
by hydroboration in situ to furnish a variety of chiral
amines with up to 89% ee, which provides a practical
strategy for the development of novel chiral frustrated
Lewis pairs for asymmetric hydrogenation.
lective catalytic hydrogenation of chiral imines using B-
(C6F5)3.8d Despite the aforementioned progress, highly
enantioselective metal-free hydrogenation promoted by chiral
FLPs still remains a formidable challenge, and the development
of highly efficient and readily accessible chiral FLP catalysts is
one of the most important subjects in this area.
As a recently emerging ligand class, chiral olefins have been
widely utilized as steering ligands for transition-metal-catalyzed
asymmetric reactions.9 In comparison with a variety of well-
established chiral diene ligands containing internal olefins and
rigidly bicyclic frameworks,10 several flexible acyclic diene
ligands bearing two terminal olefins have also been successfully
developed by our group11 and those of Yu12a and Trost.12b
Inspired by early work on the synthesis of intramolecular FLPs
from vinyldimesitylphosphane by Erker’s group13 and the
seminal work on asymmetric hydrogenation with chiral borane
by Klankermayer’s group,4d we envision that direct hydro-
boration of chiral dienes bearing two terminal olefins with
ince Stephan and co-workers accomplished the first metal-
S
free reversible hydrogen activation by an intramolecular
combination of strong Lewis acid and base in 2006,1 the area of
frustrated Lewis pairs (FLPs) has witnessed an extremely rapid
growth, and FLPs have become one promising catalyst class for
homogeneous hydrogenation, which has been predominated by
transition-metal catalysis.2,3 Over the past 5 years, FLP-
catalyzed metal-free hydrogenation of imines,4 N-heterocyc-
les,2e,5 nitriles,4a,c alkenes,4b,e,j,l,6 and so on7 has been
successfully realized. In particular, important progress has
been achieved in the challenging field of asymmetric hydro-
genation promoted by FLPs. In 2008, Klankermayer and co-
workers reported the first FLP-catalyzed asymmetric hydro-
genation of an imine using α-pinene-derived chiral borane 3a to
furnish the desired chiral amine with 13% ee (Scheme 1).4d
14
HB(C6F5)2 probably provides an excellent opportunity to
access simple chiral borane catalysts for metal-free hydro-
genation of imines (Scheme 2).15 In this strategy, binaphthyl-
Scheme 2. Our Strategy for the Development of Novel
Catalysts from Chiral Dienes
Scheme 1. Seminal Work on Chiral FLP-Catalyzed
Asymmetric Hydrogenation of Imines
based chiral diene 4 acts like a “ligand” in the transition-metal
catalysis to generate the borane catalyst 5 in situ without further
isolation, which ensures easy operation and rapid evaluation.
Moreover, terminal olefins will generate enantiomerically pure
boranes by hydroboration with HB(C6F5)2 instead of the
diastereoisomer mixture in the case of internal olefins. Herein,
we report our preliminary results on this subject.
The feasibility of our strategy for metal-free asymmetric
hydrogenation was initially examined using imine 1a as
substrate under H2 (10 bar) with a chiral borane catalyst
Subsequently, the same group reported the first example of
highly enantioselective hydrogenation with chiral FLP salts 3b
generated by treating (+)-camphor-derived chiral borane and
tri-tert-butylphosphine with H2 (Scheme 1).8a,b Very recently,
Repo and co-workers reported the use of chiral ansa-
ammonium borate 3c for the asymmetric hydrogenation of
imines and 2-phenylquinoline with up to 37% ee (Scheme 1).8c
Received: March 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4025808 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
generated in situ from HB(C6F5)2 (10 mol%) and chiral diene
4a (5 mol%) in toluene at 60 °C for 15 h. We were pleased to
find that this reaction went cleanly to give chiral amine 2a with
20% ee (Table 1, entry 1). Although the enantioselectivity is
Encouraged by the results obtained with chiral diene 4n, we
subsequently investigated reaction conditions including sol-
vents, temperature, and catalyst loading to further improve the
enantioselectivity. Some of the results are summarized in Table
2. Solvents were found to have a large impact on both reactivity
Table 1. Evaluation of Chiral Dienes for Asymmetric
Hydrogenation of Imine 1a
a b
,
Table 2. Optimization of Reaction Conditions for
Asymmetric Hydrogenation of Imine 1a
a
b
c
entry
solvent
temp (°C)
conv (%)
ee (%)
1
toluene
30
30
30
30
30
30
30
30
rt
100
100
100
100
14
66
61
72
55
43
−
2
benzene
mesitylene
hexane
conv
c
ee
(%)
conv
c
ee
(%)
3
d
d
entry diene
(%)
entry diene
(%)
4
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
100
100
100
100
100
100
100
100
20
16
8
9
4i
100
100
100
100
100
100
100
100
25
25
30
40
31
60
50
41
5
CH2Cl2
10
11
12
13
14
15
16
4j
6
Et2O
trace
72
tBuOMe
PhOMe
mesitylene
mesitylene
mesitylene
mesitylene
6
4k
4l
7
17
14
22
26
12
8
78
66
75
75
77
78
4m
4n
4o
4p
9
100
100
100
100
10
0
d
4g
4h
11
rt
e
12
rt
a
a
All reactions were carried out with imine 1a (0.25 mmol), HB(C6F5)2
All reactions were carried out with imine 1a (0.25 mmol), HB(C6F5)2
(10 mol%), chiral diene (5 mol%), and H2 (10 bar) in toluene (2.0
(10 mol%), chiral diene 4n (5 mol%), and H2 (20 bar) in solvent (2.0
b
b
mL) at 60 °C for 15 h. The absolute configuration of 2a was assigned
mL) for 15 h unless otherwise noted. The conversion was determined
c
c
by crude 1H NMR. The ee was determined by chiral HPLC
by comparing the optical rotation with the reported value. The
d
conversion was determined by crude 1H NMR. The ee was
d
(Chiralcel OD-H column). Imine 1a (0.5 mmol), HB(C6F5)2 (5 mol
%), and diene 4n (2.5 mol%) were used. Imine 1a (0.5 mmol),
e
determined by chiral HPLC (Chiralcel OD-H column).
HB(C6F5)2 (2.5 mol%), and diene 4n (1.25 mol%) were used.
not satisfactory, this interesting result prompted us to further
explore more effective chiral diene “ligands” by tuning the
substituents at the 3,3′-positions of binaphthyl frameworks. As
shown in Figure 1, chiral dienes 4b−o bearing a wide range of
and enantioselectivity (Table 2, entries 1−8). Mesitylene
proved to be a suitable solvent to give 72% ee (Table 2,
entry 3). Lowering the temperature from 30 to 0 °C led to only
a slightly higher ee (Table 2, entry 3 vs 10). Significantly,
reducing the diene loading from 5 to 1.25 mol% gave a better
ee without loss of any activity (Table 2, entry 9 vs 12).
With the optimal chiral diene and reaction conditions in
hand, metal-free asymmetric hydrogenations of various imines
were next studied. As shown in Table 3, a variety of imines can
be smoothly hydrogenated in good yields and high
enantioselectivities (74−89% ee). Both electron-donating and
-withdrawing substituents at the para-positon of phenyl group
were well tolerated for this reaction (Table 3, entries 2−10).
Meta-substituted imines were also suitable substrates to give
74−80% ee (Table 3, entries 11−15). However, ortho-
substituted imines still cannot give satisfactory results under
the current conditions.16 It is noteworthy that the alkyne group
was also tolerated for this asymmetric catalytic system to give
chiral amine 2p in 95% yield with 85% ee (Table 3, entry 16).
When the imine derived from 4-isopropoxyphenyl-propanone
was used as substrate, the asymmetric hydrogenation went
cleanly to afford product 2q with 78% ee (Table 3, entry 17).
The substrate scope can also been successfully extended to
imines derived from cyclic ketones (Table 3, entries 18 and 19).
Unfortunately, for the challenging diaryl or dialkyl ketimine
substrates in transition-metal-catalyzed asymmetric hydro-
genation,15 the chiral borane catalyst exhibited high activity
but poor enantioselectivity (<20% ee) (see Supporting
Information). Although further improvement is still necessary,
to the best of our knowledge, the current system gives the
highest enantioselectivity (89% ee) in the field of FLP-catalyzed
asymmetric hydrogenation to date.8
Figure 1. Representative chiral diene “ligands” for FLP-catalyzed
asymmetric hydrogenation of imines.
aryl substituents were therefore prepared and evaluated. It was
found that the steric bulkiness of the aryl substituent has a large
impact on enantioselectivity, although all these dienes can lead
a quantitative conversion of imine 1a (Table 1, entries 2−15).
Chiral diene 4n proved to be the optimal “ligand” to give the
desired amine 2a with 60% ee (Table 1, entry 15). Moreover, a
promising result (100% conversion, 41% ee) was also obtained
with chiral diene 4p developed by Yu’s group,12a which
provides additional opportunities for further improvement
(Table 1, entry 16).
B
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Journal of the American Chemical Society
Communication
a
An NMR study indicates that the desired chiral borane is
generated cleanly by mixing chiral diene 4n and HB(C6F5)2 in
C6D6 at room temperature for several minutes (see Supporting
Information). A complete racemization of chiral amines in the
presence of B(C6F5)3 was reported to occur at high
temperature;8c therefore, the impact of chiral boranes on the
enantioenriched amine 2a was investigated. As shown in
Scheme 3, the ee value of amine 2a is well maintained after its
Table 3. Asymmetric Hydrogenation of Imines
Scheme 3. Impact of Chiral Borane on Enantioenriched
Amine
treatment with chiral boranes at room or high temperature
under or without H2, which demonstrates that there is no
racemization involved in this catalytic system.
In summary, a highly enantioselective metal-free hydro-
genation of imines using simple chiral borane (1.25−5 mol%)
as catalyst, generated in situ from readily available chiral dienes
and HB(C6F5)2 under mild conditions, has been successfully
achieved to furnish a variety of chiral amines in 63−99% yield
with 74−89% ee. In this study, chiral diene is utilized like a
chiral “ligand” in the transition-metal catalysis, which provides
an alternative and practical strategy for the development of
accessible and highly efficient chiral FLP catalysts for the metal-
free asymmetric catalysis. Further understanding the asym-
metric induction of chiral borane catalysts, developing a more
effective asymmetric hydrogenation process using different
types of chiral olefins, and expanding the substrate scope are
under investigation in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedure for the metal-free catalytic asymmetric hydro-
genation of imines and chiral diene synthesis; characterization
of dienes, imines, and products; and data for the determination
of enantiomeric excesses. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
haifengdu@iccas.ac.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for generous financial support from the
National Natural Science Foundation of China (20802079,
21222207) and the National Basic Research Program of China
(973 program, 2011CB808600). We also thank Prof. Zhi-Xiang
Yu from Perking University for a gift of chiral diene 4p.
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