Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs

Article abstract of DOI:10.1002/anie.201914568

The concept of frustrated Lewis pairs (FLPs) has been widely applied in various research areas, and metal-free hydrogenation undoubtedly belongs to the most significant and successful ones. In the past decade, great efforts have been devoted to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral Lewis base derived FLPs have rarely been disclosed for the asymmetric hydrogenation. In this work, a novel type of chiral FLP was developed by simple combination of chiral oxazoline Lewis bases with achiral boron Lewis acids, thus providing a promising new direction for the development of chiral FLPs in the future. These chiral FLPs proved to be highly effective for the asymmetric hydrogenation of ketones, enones, and chromones, giving the corresponding products in high yields with up to 95 % ee. Mechanistic studies suggest that the hydrogen transfer to simple ketones likely proceeds in a concerted manner.

Full text of DOI:10.1002/anie.201914568

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Accepted Article
Title: Asymmetric Hydrogenations of Ketones and Enones with Chiral
Lewis Base-Led Frustrated Lewis Pairs
Authors: Bochao Gao, Xiangqing Feng, Wei Meng, and Haifeng Du
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914568
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10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Hydrogenations of Ketones and Enones with Chiral
Lewis Base-Led Frustrated Lewis Pairs
Bochao Gao,[a,b] Xiangqing Feng,[a,b] Wei Meng,*[a,b] and Haifeng Du*[a,b]
Abstract: The concept of frustrated Lewis pairs (FLPs) has been
widely applied into various research areas, and the metal-free
hydrogenation undoubtedly belongs to the most significant and
successful ones. In the past decade, great efforts have been devoted
to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral
Lewis base-led FLPs have rarely been disclosed for the asymmetric
hydrogenation. In this work, a novel type of chiral FLPs was
developed by a simple combination of chiral oxazoline Lewis bases
with achiral boron Lewis acids, which might provide a promising new
direction for the development of chiral FLPs in the future. These chiral
FLPs proved to be highly effective for the asymmetric hydrogenations
of ketones, enones, and chromones, giving the corresponding
products in high yields with up to 95% ee. Mechanistic studies suggest
that the hydrogen transfer to simple ketones is likely in a concerted
manner.
knowledge, the only example was reported by Stephan and co-
workers using chiral DIOP and B(C6F5)3, giving 25% ee in the
asymmetric hydrogenation of an imine.[7b] Recently, our group
developed a chiral FLP of (R)-tert-butylsulfinamide and HB(C6F5)2
for the asymmetric transfer hydrogenation with ammonia
borane.[7c,d] The challenges for the type III FLPs-catalyzed
asymmetric hydrogenation are likely to come from two
competitions. (1) Which one acts as the Lewis base component
of the FLP, the substrate with lone-electron pair or the additional
chiral Lewis base? Once the substrate is in the pole position, a
racemic reaction will occur. (2) Which kind of hydrogen (proton or
hydride) transfer is prior? If the proton-transfer takes place first,
the Lewis base will escape from the reaction center, then its
chirality will have little impact on the asymmetric induction. A
concerted hydrogen (proton and hydride) transfer (figure 1) will be
an ideal manner to achieve high enantioselectivities, which is
similar to the well-known chiral Brønsted acid catalysis.[8]
Introduction
(I) intramolecular FLPs
(II) achiral LB + chiral LA
(III) chiral LB + achiral LA
Catalytic hydrogenation is a very useful reaction in both academic
and industrial communities, in which transition metals have been
being the predominant catalysts.[1] In 2006, the advent of
frustrated Lewis pairs (FLPs) opens a brand-new period for the
metal-free hydrogenation.[2] An extremely rapid growth for the
FLP catalysis has been achieved in the past decade.[3] However,
some challenges concerning on the asymmetric hydrogenation
still await to be solved.[4] The manner for the construction of chiral
FLPs can be categorized into three types, (I) intramolecular
FLP,[5] (II) intermolecular FLP of chiral acid and achiral base,[6] (III)
intermolecular FLP of achiral acid and chiral base (Figure 1). For
the hydrogenation with type I-II FLPs, the asymmetric induction is
highly dependent on the chirality of Lewis acids (Figure 1). But the
synthetic difficulty and the lack of suitable chiral framework for the
moisture sensitive boron Lewis acids largely restrict their broad
acceptance and application.
LA = Lewis acid LB = Lewis base
*
*
*
LB
LA
LA
LB
LB
LA
*
*
*
LB
LB
H
LA
H
LB
LA
H
LA
H
R'
R
R'
R
R'
R
HX
X
HX
successful
successful
unsuccessful
Figure 1. General Types of Chiral FLPs and Asymmetric Induction Models.
Chiral Lewis bases are very stable and ubiquitous, which have
been widely employed as chiral ligands or catalysts for the
asymmetric catalysis. Imaginably, it would be a facile strategy
toward the FLP construction by the combination of chiral Lewis
bases with achiral Lewis acids (type III, Figure 1). Strangely, very
limited intermolecular FLPs with chiral Lewis bases have been
explored so far.[7] Especially, even seldom of them could be
employed for the asymmetric hydrogenation. To the best of our
Ketones were one class of well-solved substrates for the
transition-metal catalyzed asymmetric hydrogenation.[9] However,
they were still inert substrates for the majority of FLP catalysts.[10]
The first catalytic hydrogenation of ketones 1 with FLPs was not
disclosed until 2014 by the groups of Stephan and Ashley
concurrently and independently (Scheme 1).[11,12] Diethyl ether
and 1,4-dioxane were employed as weak Lewis bases, which
could generate strong Brønsted acids after the splitting of H2 with
B(C6F5)3 (2). The proton associated with oxygen atom of diethyl
ether or 1,4-dioxane was proposed to activate the ketone
substrate via hydrogen-bonding, which facilitated the nucleophilic
attack of hydride to furnish the corresponding alcohols 3 (Scheme
1). Based on the previous work, we envision that the combination
of chiral Lewis base and achiral boron Lewis acid as chiral FLP
catalyst is likely to realize the asymmetric hydrogenation of
ketones via model III shown in Figure 1. It is noteworthy that the
FLP-catalyzed asymmetric hydrogenation of ketones and other
[a]
B. Gao, Dr. X. Feng, Dr. W. Meng, Prof. H. Du
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190 (China), E-mail: mengwei@iccas.ac.cn,
haifengdu@iccas.ac.cn
[b]
School of Chemical Sciences, University of Chinese Academy of
Sciences, Beijing 100049 (China).
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
Ph
electron-deficient unsaturated compounds has never been
reported yet. Herein, we wish to report our efforts on this subject.
O
O
O
O
Ph
Ph
Ph
Ph
N
N
N
N
Ph
5b
Ph
5c
Ph
Ph
5d
O
H
OH
R'
5e
B(C6F5)3 (2)
+
H2
R
R'
98% conv.
(72% ee)
99% conv.
(57% ee)
99% conv.
(68% ee)
97% conv.
(62% ee)
R
diethyl ether or
1,4-dioxane
1
3
O
N
O
N
O
N
O
tBu
iPr
Me
PMP
N
O
H
O
O
H
H B(C6F5)3
H
B(C6F5)3
R'
R
R'
m
Ph
O
O
Ph
Ph
PMP
R
5f
5g
5h
5i
74% conv.
(66% ee)
57% conv.
(7% ee)
59% conv.
(66% ee)
53% conv.
(72% ee)
D. W. Stephan
A. E. Ashley
Scheme 1. Catalytic Hydrogenations of Ketones with FLPs.
O
N
O
4-tol
4-tol
4-F-Ph
N
4-F-Ph
5k
Results and Discussion
5j
84% conv.
(72% ee)
99% conv.
(72% ee)
Oxazoline moieties are extensively presented in chiral ligands or
catalysts.[13] Their relatively weak Lewis basicity makes them a
suitable component of chiral FLPs for the asymmetric
hydrogenation. We set out our study by examination of the
asymmetric hydrogenation of ketone 1a using 10 mol % of chiral
bisoxazoline (BOX) 4a and B(C6F5)3 (2)[14] in toluene at 60 °C for
18 h (Scheme 2). A low conversion with a 41% ee was obtained.
When BOX 4b bearing two cis-phenyl groups was employed,
alcohol 3a was afforded in 85% conversion and 60% ee with an
inverse configuration. A 1/1 mixture of toluene and cyclohexane
as solvent gave an obviously better ee (Scheme 2). Chiral
oxazolines 5a and 5b were also tested for this reaction. In
comparison to BOX 4b, chiral oxazoline 5b exhibited a much
higher activity without loss of any enantioselectivity, except with
an inverse absolute configuration.
Figure 2. Evaluation of Chiral Oxazolines for Asymmetric Hydrogenations.
Table 1. Optimization of Reaction Conditions with Chiral Oxazoline 5b.[a]
Temp.
[°C]
Conv.
[%][b]
Ee
Entry
Borane
Solvent
[%][c]
1[d]
2[e]
3
2
2
6
7
6
6
6
6
6
6
6
6
Toluene/c-C6H12 (1/1)
Toluene/c-C6H12 (1/1)
Toluene/c-C6H12 (1/1)
Toluene/c-C6H12 (1/1)
Toluene/c-C6H12 (1/1)
n-Hexane
60
30
30
30
10
30
30
30
30
30
30
30
98
50
93
NR[f]
36
33
50
85
36
13
82
81
72
78
81
--
4
5
85
74
79
80
78
71
80
81
O
B(C6F5)3 (2) (10 mol %)
H
OH
Me
6
4 (10 mol %) or 5 (20 mol %)
Me
H2 (40 bar)
7
c-C6H12
F3C
F3C
solvent, 60 °C, 18 h
1a
3a
8
Toluene
O
O
O
O
O
O
9
C6H5F
Ph
Ph
Ph
N
N
N
N
N
N
10
11[g]
12[h]
CH2Cl2
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
5a
56% conv. 98% conv.
(59% ee)
(72% ee)
(toluene/cyclohexane = 1/1)
5b
Toluene/c-C6H12 (1/1)
Toluene/c-C6H12 (1/1)
15% conv. (41% ee) 85% conv. (-60% ee)
(toluene)
(toluene)
60% conv. (-72% ee)
(toluene/cyclohexane = 1/1)
[a] All reactions were carried out with ketone 1a (0.10 mmol), borane = B(C6F5)3
(2), B(p-HC6F4)3 (6), or B(3,5-H2C6F3)3 (7) (0.01 mmol), and chiral oxazoline 5b
(0.02 mmol) in solvent (1.0 mL) under H2 (40 bar) for 24 h unless other noted.
[b] Determined by crude 1H NMR. [c] The ee was determined by chiral HPLC.
[d] For 18 h. [e] For 48 h. [f] No reaction. [g] Chiral oxazoline 5b (0.01 mol) was
used. [h] H2 (30 bar)
Scheme 2. Initial Studies with Chiral Lewis Base-Led FLPs.
Several oxazolines were next evaluated for this asymmetric
hydrogenation (Figure 2). Oxazoline 5c with trans-phenyl groups
gave a quantitative conversion with 57% ee. Tuning the tert-butyl
group to the bulkier groups (5d and 5e) resulted in a little drop of
ee. Oxazolines 5f-h with alkyl substituents exhibited much lower
reactivities. Oxazoline 5i with p-methoxyphenyl (PMP) group
nearly gave a racemic product. In contrast, oxazolines 5j and 5k
gave similar results with oxazoline 5b.
The reaction condition was further optimized to improve the
enantioselectivity. When the temperature was lowered from 60 to
30 °C, the reactivity was diminished sharply (Table 1, entries 1 vs
2). B(p-HC6F4)3 (6)[15], a relatively weaker Lewis acid, was
subsequently examined for this reaction. To our pleasure, the
reactivity was largely improved with a promising 81% ee (Table 1,
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10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
entry 3). A probable explanation was that the weaker Lewis acidity
of B(p-HC6F4)3 (6) enhanced the nucleophilic ability of the
resulting hydride. When a much weaker Lewis acid, B(3,5-
H2C6F3)3 (7), was used, no reaction occurred at all (Table 1, entry
4). Further decreasing the temperature to 10 °C resulted in a
sharp drop of reactivity (Table 1, entry 5). Solvents were found to
have a large influence on the reactivity (Table 1, entries 6-10).
When the loading amount of oxazoline 5b was reduced to 10
mol %, 82% conversion with 80% ee were obtained (Table 1,
entries 3 vs 11). It might suggest that the excess of oxazoline 5b
is essential to diminish the racemic reaction catalyzed by the
achiral boron Lewis acid itself. Reducing the H2 pressure to 30
bar gave a lower conversion without loss of any enantioselectivity
(Table 1, entries 3 vs 12).
moieties were well tolerant for this reaction. Interestingly, the
asymmetric hydrogenation of 1,4-diacetylbenzene (1u) furnished
compound 3u as the single product in 46% yield with 74% ee
without over-reduced diol. When 1,3,5-triacetylbenzene (1v) was
utilized as the substrate, compound 3v was obtained as the major
product in 37% yield with 78% ee accompanied by ca. 7% diol
byproduct. It was noteworthy that dialkyl ketones 1w-c’ were also
suitable substrates for this asymmetric hydrogenation to furnish
the corresponding alcohols 3w-c’ in 95-97% yields with 50-75%
ee’s. Unfortunately, simple ketones bearing electron-donating
substituents at the aryl group or heteroaryl-substituted ketones
(see Supporting Information) were still not effective substrates for
the current catalytic system.
Although the result is still not satisfactory, the current work
represents the first FLP-catalyzed highly enantioselective
hydrogenation of ketones. Significantly, the combination of chiral
Lewis base and achiral boron Lewis acid as a chiral FLP catalyst
has proven to be a feasible and practical strategy for the
asymmetric hydrogenation. To broaden the application of this
novel type of chiral FLPs, the asymmetric hydrogenation of 1-
tetralone-derived enone 8a was investigated under a similar
reaction condition (Scheme 4).[16] With the use of chiral oxazoline
5a, the desired product 9a was obtained in 61% conversion with
62% ee. Chiral oxazoline 5b gave a relatively lower ee value. To
use chiral oxazoline 5l, 95% conversion with 79% ee was
obtained.
B(p-HC6F4)3 (6) (10 mol %)
O
H
OH
R'
oxazoline 5b (20 mol %)
R
R
R'
H2 (40 bar)
toluene/cyclohexane (1/1)
30 °C
1
3
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
F3C
O2N
MeO2C
F
Cl
3e
3d
78% (71% ee)[c] 93% (76% ee)[c]
3c
73% (80% ee)[b] 89% (74% ee)[b]
3b
3a
90% (81% ee)[a]
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
C6F5
Br
F
Cl
3j
3h
3i
3g
96% (80% ee)[b]
3f
94% (78% ee)[c]
54% (68% ee)[c] 94% (77% ee)[c] 94% (78% ee)[c]
B(p-HC6F4)3 (6)
(10 mol %)
oxazoline 5 (20 mol %)
O
O
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
H
OH
Me
H
H2 (40 bar)
CF3
CF3
F
Cl
CF3
NO2
3m
Br
3k
91% (77% ee)[c]
toluene, 30 °C, 24 h
3o
3l
3n
9a
8a
53% (79% ee)[b] 81% (81% ee)[b] 74% (87% ee)c
93% (80% ee)[b]
OH
Me
H
H
OH
Et
H
OH
Me
H
OH
Me
H
OH
Me
F3C
F
O
O
O
Ph
N
N
F3C
N
Br
F
F
F
CF3
3p
3q
88% (85% ee)[a]
3r
3s
3t
Ph
5a
Ph
Ph
43% (86% ee)[c]
82% (85% ee)[b] 75% (81% ee)[b] 95% (76% ee)[b]
5b
5l
H
OH
Me
Cl
H
OH
61% conv.
(62% ee)
94% conv.
(54% ee)
95% conv.
(79% ee)
Ac
Ph
Me
OH
Me
OH
Me
OH
Me
Ph
H
H
H
Ac
3v
3y
3u
3w
3x
Ac
Scheme 4. Evaluation of Chiral Oxazolines for Asymmetric Hydrogenations of
Enone 8a.
46% (74% ee)[c,d] 37% (78% ee)]c,d,e] 95% (64% ee)[c,f] 95% (50% ee)[c,f] 95% (75% ee)[c]
Me
OH
Br
Me
OH
Me
OH
Me
OH
H
H
H
H
Cl
Br
The substrate scope was studied under a slightly modified
reaction condition. As shown in Scheme 5, asymmetric
hydrogenations of enones 8a-h’ catalyzed by the FLP of chiral
oxazoline 5l and B(p-HC6F4)3 (6) went well to produce optically
active ketones 9a-h’ in 86-99% yields with 63-92% ee’s. Both
electron–withdrawing and –donating substituents on the phenyl
group (8a-n) were well tolerated for this reaction. The introduction
of substituent at the 7-position of tetralone moiety (8o-t and 8w-
h’) gave up to 92% ee. But the hydrogenation of enones 8u and
8v with bromo substituent at the 6 and 5-position only gave 68%
and 69% ee, respectively. The absolute configurations of
compounds 9 were tentatively assigned as R according to X-ray
structure of compound 9y (see Supporting Information).[17]
Cl
3c'
96% (74% ee)[b]
3z
97% (75% ee)[c]
3a'
95% (72% ee)[b]
3b'
95% (73% ee)[b]
Scheme 3. Asymmetric Hydrogenations of Ketones with FLPs: [a] 24 h; [b] 48
h; [c] 72 h; [d] 6 (20 mol %) and 5b (40 mol %); [e] Toluene/cyclohexane (9/1);
[f] At 40 °C.
A variety of aryl-alkyl ketones 1a-t were subsequently
subjected to the asymmetric hydrogenation using 20 mol % of
chiral oxazoline 5b with 10 mol % of B(p-HC6F4)3 (6) (Scheme 3).
All these reactions proceeded smoothly to furnish secondary
alcohols 3a-t in 43-96% yields with 68-87% ee’s. Electron-
withdrawing substituents at o, m or p-positions of the phenyl
This article is protected by copyright. All rights reserved.

10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
O
O
A variety of 3-substituted chromones were subjected to the
asymmetric hydrogenation under the optimal reaction conditions.
As shown in Scheme 7, 3-isopropyl substituted chromones 10a-k
containing substituents at the 6, 7, or 8 position were effective
substrates to afford the corresponding products 11a-k in 91-98%
yields with 72-95% ee’s. The asymmetric hydrogenation of
chromone 10l gave a slightly lower ee. The enantioselectivity was
very sensitive to the steric hindrance. When the isopropyl group
was changed to the less bulky ethyl or methyl group (10m,n), the
ee was found to drop dramatically from 87% to 33%. 3-
Arylchromones 10o and 10p were also effective substrates for
this asymmetric hydrogenation to give chromanones 11o and 11p
in high yields with 44% and 80% ee’s, respectively.
B(p-HC6F4)3 (6) (10 mol %)
oxazoline 5l (20 mol %)
H
R
R
H2 (40 bar)
R'
R'
mesitylene, 30 °C
9
8
R = H
9h (R' = 4-OMe): 94% (78% ee)[c]
9i (R' = 3-F): 94% (78% ee)[c]
9j (R' = 3-Cl): 86% (78% ee)[a]
9k (R' = 3-Br): 95% (77% ee)[c]
9l (R' = 2-F): 96% (63% ee)[c]
9m (R' = 2-Cl): 94% (70% ee)[c]
9n (R' = 2-Br): 91% (71% ee)[c]
9a (R' = 4-CF3): 94% (80% ee)[a]
9b (R' = 4-F): 95% (78% ee)[a]
9c (R' = 4-Cl): 91% (79% ee)[a]
9d (R' = 4-Br): 96% (79% ee)[a]
9e (R' = 4-CO2Me): 96% (77% ee)[c]
9f (R' = H): 94% (77% ee)[c]
9g (R' = 4-Me): 94% (78% ee)[c]
R' = H
9s (R = 7-(4-CF3C6H4)): 97% (85% ee)[b]
9t (R = 7-PMP): 94% (85% ee)[b]
9u (R = 6-Br): 96% (68% ee)[c]
9o (R = 7-Cl): 98% (84% ee)[a]
9p (R = 7-Br): 97% (85% ee)[a]
9q (R = 7-Me): 94% (86% ee)[b]
9r (R = 7-Ph): 94% (85% ee)[a]
9v (R = 5-Br): 94% (69% ee)[c]
O
O
borane 13 (5 mol %)
oxazoline 5l (5 mol %)
R'
H
R'
R = 7-Br
R
R
9w (R' = 4-F): 98% (86% ee)[a]
9x (R' = 4-Cl): 98% (85% ee)[a]
9y (R' = 4-Br): 98% (86% ee)[a]
9z (R' = 4-CF3): 98% (87% ee)[a]
9c' (R' = 4-OMe): 98% (86% ee)[a]
9d' (R' = 3-Me): 99% (86% ee)[a]
9e' (R' = 2-OMe): 98% (77% ee)[b]
9f' (R' = 2-CF3): 91% (77% ee)[c]
H2 (40 bar)
mesitylene (0.2 M), 30 °C
O
O
11
10
9a' (R' = 4-CO2Me): 95% (87% ee)[b] 9g' (R' = 2-Me): 98% (92% ee)[b]
9b' (R' = 4-Me): 99% (86% ee)[a]
9h' (R' = 2-Et): 99% (92% ee)[c]
O
O
O
O
MeO
iPr
iPr
Ph
iPr
H
O
O
Cl
Br
iPr
H
H
H
O
11b
O
11c
Scheme 5. Asymmetric Hydrogenations of Enones: [a] 24 h; [b] 48 h; [c] 72 h.
11d
11a
95% (95% ee)[a]
96% (95% ee)[a]
95% (92% ee)[b]
95% (92% ee)[b]
F3C
Me
O
O
O
O
O
O
borane (5 mol %)
iPr
H
iPr
Br
Br
iPr
H
Me
oxazoline 5l (10 mol %)
H
H
O
H2 (40 bar)
mesitylene (0.1 M)
O
O
O
11e
11f
98% (93% ee)[b]
11g
97% (93% ee)[c]
10a
11a
95% (92% ee)[c]
30 °C, 24 h
O
O
O
O
O
B(p-HC6F4)3 (6): 33% conv. 93% ee
iPr
H
iPr
H
iPr
H
iPr
B(3,5-H2C6F3)(p-HC6F4)2 (12): 80% conv. 94% ee
B(3,4,5-H3C6F2)(p-HC6F4)2 (13): 69% conv. 95% ee
H
Br
O
Me
O
O
Me
O
N
11h
11i
93% (92% ee)[c]
11j
11k
Br
98% conv. 95% ee
98% (90% ee)[c]
91% (72% ee)[c]
95% (89% ee)[c]
Ph
5l
[5l (5 mol %), 13 (5 mol %), 0.2 M]
O
O
O
O
O
iPr
Ph
Me
Et
H
Scheme 6. Asymmetric Hydrogenations of Chromone 10a.
H
H
H
H
Me
O
O
O
O
O
11l
11o
11m
11n
11p
96% (44% ee)[b] 98% (80% ee)[b]
92% (87% ee)[c,d] 93% (51% ee)[c,d] 93% (33% ee)[c,d]
With these results, the application of this FLP was further
explored for the asymmetric hydrogenation of 3-substituted
chromones 10. Notably, 2-substituted chromones were the most
often studied substrates in the transition-metal-catalyzed
asymmetric hydrogenations or hydrosilylations.[18] Very few
examples have been reported for the asymmetric hydrogenation
of 3-substituted chromones. With the use of chiral oxazoline 5l
(10 mol %), various borane Lewis acids were evaluated for the
asymmetric hydrogenation of 3-substituted chromone 10a with H2
(40 bar) in mesitylene (0.1 M) at 30 °C for 24 h. As shown in
Scheme 6, the desired chromanone 11a was obtained with high
levels of ee’s for these three boranes. The Lewis acidity had a
large influence of the reactivity. Borane 6 gave a 33% conversion,
while the relatively weaker Lewis acid 12 gave an 80% conversion.
Further decreasing the Lewis acidity (borane 13) would lead a
little drop of reactivity without loss of enantioselectivity. To our
pleasure, when the reaction concentration was increased from 0.1
to 0.2 M, 98% conversion with 95% ee was obtained using only 5
mol % of oxazoline 5l and borane 13.
Scheme 7. Asymmetric Hydrogenations of Chromones: [a] 24 h; [b] 48 h; [c] 72
h; [d] At 40 °C.
A DFT-calculation was conducted utilizing M06-2X method[19]
on the 6-31G(d) level[20 to understand the mechanism and the
origination of chirality in the asymmetric hydrogenation of ketones.
As shown in Figure 3a, the invasion of dihydrogen into the territory
of the frustrated Lewis pair of chiral oxazoline 5b and B(p-HC6F4)3
(6) gives rise to a thermodynamically favorable hydrogen-splitting
INT via transition state TS1 with an activation Gibbs free energy
of 13.5 kcal/mol in gas phase. In TS1, the distances of N-H, H-H
and H-B are 2.08, 0.76 and 1.84 angstrom, respectively. Then
hydrogen-splitting product INT binds with ketone 1a in the joint
effort of hydrogen bonding and π-π stacking interactions. A
sequential concerted H-transfer (proton and hydride) process
(TS2) has been located. A 5.5 kcal/mol energy difference between
TS2-(R) and TS2-(S) predicts to produce the R-isomer, which is
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10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
in compliance with the experiment results and this process has an
activation free energy of 9.1 kcal/mol in gas phase. The
underlying background reaction catalyzed by B(p-HC6F4)3 itself is
likely claimed for the dwindling enantioselectivity between
theoretical result and experimental one. For the hydrogenation of
chromone 10a, the protonation is the configuration-determining
step. As shown in Figure 3b, a 2.2 kcal/mol activation free energy
difference between TS3-(S) and TS3-(R) suggests to afford the
S-isomer favorably, which is well consistent with experimental
results too.
a) ketone 1a
b) chromone 10a
F
F
B(p-HC6F4)3
O
+
B
F
N
O
Ph
H
(S)-11a
B
H
O
N
O
N
N
B
H
Ph
H
H
5b
+
H2
ΔG (Kcal·mol-1
)
TS1
INT
TS3-(S)
13.5
0.0
-1.9
≠
ΔGact (Kcal·mol-1
)
21.6
O
O
1a
N
N
B
H
O
B
H
F
O
B
O
H
H
(R)-11a
F
N
H
F
TS2-(S)
TS2-(R)
7.2
12.7
TS3-(R)
≠
ΔGact (Kcal·mol-1
)
23.8
(S)-3a
Figure 3. DFT Calculation for Asymmetric Hydrogenation: a) Ketone 1a (borane 6 and oxazoline 5b); b) Chromone 10a (borane 13 and oxazoline 5l).
Keywords: asymmetric hydrogenation • frustrated Lewis pair •
Conclusion
chiral Lewis base • ketones • enones
A novel strategy for the construction of chiral FLPs by the
combination of readily available chiral oxazoline Lewis bases and
achiral boron Lewis acids has been successfully developed for
[1]
For leading reviews, see: a) J. G. de Vries, C. J. Elsevier, The Handbook
of Homogeneous Hydrogenation; Wiley-VCH. Weinheim, 2007; b) G. Ertl,
H. Knözinger, F. Shcüth, J. Weitkamp, Handbook of Heterogeneous
Catalysis; Wiley-VCH. Weinheim, 2008.
the asymmetric hydrogenation, which provides
a potential
[2]
[3]
G. C. Welch, R. R. San Juan, J. D. Masuda, D. W. Stephan, Science
2006, 314, 1124-1126.
direction for the design of chiral FLPs in the future. With these
chiral FLPs, asymmetric hydrogenations of ketones, enones, and
chromones were realized to furnish the corresponding products in
good to high yields with up to 95% ee. Significantly, the current
work represents the first successful example for the FLP-
catalyzed asymmetric hydrogenation of electron-deficient
unsaturated compounds.[21] DFT calculation indicates the proton
and hydride transfer to simple ketones is in a concerted manner,
which ensures the effective asymmetric induction by the chirality
of Lewis base.
For leading reviews, see: a) A. L. Kenward, W. E. Piers, Angew. Chem.
Int. Ed. 2008, 47, 38-41; Angew. Chem. 2008, 120, 38-42; b) D. W.
Stephan, G. Erker, Angew. Chem. Int. Ed. 2010, 49, 46-76; Angew.
Chem. 2010, 122, 50-81; c) T. Soós, Pure Appl. Chem. 2011, 83, 667-
675; d) G. Erker, Pure Appl. Chem. 2012, 84, 2203-2217; e) J. Paradies,
Angew. Chem. Int. Ed. 2014, 53, 3552-3557; Angew. Chem. 2014, 126,
3624-3629; f) D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2015, 54,
6400-6441; Angew. Chem. 2015, 127, 6498-6541; g) M. Oestreich, J.
Hermeke, J. Mohr, Chem. Soc. Rev. 2015, 44, 2202-2220; h) D. W.
Stephan, J. Am. Chem. Soc. 2015, 137, 10018-10032; i) D. W. Stephan,
Acc. Chem. Res. 2015, 48, 306-316; j) D. W. Stephan, Science 2016,
354, aaf7229; k) D. J. Scott, M. J. Fuchter, A. E. Ashley, Chem. Soc. Rev.
2017, 46, 5689-5700; l) Y. Ma, S. Zhang, C.-R. Chang, Z.-Q. Huang, J.
C. Ho, Y. Qu, Chem. Soc. Rev. 2018, 47, 5541-5553.
Acknowledgements
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21825108,
21871269, 91856103, and 21521002) and the Youth Innovation
Promotion Association CAS (No. 2019037, W.M.).
[4]
For leading reviews, see: a) Y. Liu, H. Du, Acta Chim. Sinica 2014, 72,
771-777; b) X. Feng, H. Du, Tetrahedron Lett. 2014, 55, 6959-6964; c) L.
Shi, Y.-G. Zhou, ChemCatChem 2015, 7, 54-56; d) L. C. Wilkins, R. L.
Melen, Coord. Chem. Rev. 2016, 324, 123-129; e) J. Paradies, Top
This article is protected by copyright. All rights reserved.

10.1002/anie.201914568
Angewandte Chemie International Edition
RESEARCH ARTICLE
Organomet. Chem. 2018, 62, 193-216; f) W. Meng, X. Feng, H. Du, Acc.
Chem. Res. 2018, 51, 191-201.
[13] For selected reviews, see: a) E. J. Corey, C. J. Helal, Angew. Chem. Int.
Ed. 1998, 37, 1986-2012; Angew. Chem. 1998, 110, 2092-2118; b) J. S.
Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325-335; c) G.
Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345; d) L.-X. Dai,
T. Tu, S.-L. You, W.-P. Deng, X.-L. Hou, Acc. Chem. Res. 2003, 36, 659-
667; e) G. Desimoni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106,
3561-3651; f) S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40,
1402-1411; g) G. C. Hargaden, P. J. Guiry, Chem. Rev. 2009, 109, 2505-
2550; h) G. Desimoni, G. Faita, K. A. Jørgensen, Chem. Rev. 2011, 111,
PR284-437; i) S.-F. Zhu, Q.-L. Zhou, Acc. Chem. Res. 2017, 50, 988-
1001; j) G. Yang, W. Zhang, Chem. Soc. Rev. 2018. 47, 1783-1810.
[14] A. G. Massey, A. J. Park, J. Organometallic Chem. 1964, 2, 245-250.
[15] M. Ullrich, A. J. Lough, D. W. Stephan, J. Am. Chem. Soc. 2009, 131,
52-53.
[5]
a) V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger, T.
Repo, Adv. Synth. Catal. 2011, 353, 2093-2110; b) G. Ghattas, D. Chen,
F. Pan, J. Klankermayer, Dalton Trans. 2012, 41, 9026-9028; c) M.
Lindqvist, K. Borre, K. Axenov, B. Kόtai, M. Nieger, M. Leskelä, I. Pápai,
T.Repo, J. Am. Chem. Soc. 2015, 137, 4038-4041; d) K.-Y. Ye, X. Wang,
C. G. Daniliuc, G. Kehr, G. Erker, Eur. J. Inorg. Chem. 2017, 368-371.
a) D. Chen, J. Klankermayer, Chem. Commun. 2008, 2130-2131; b) D.
Chen, Y. Wang, J. Klankermayer, Angew. Chem. Int. Ed. 2010, 49, 9475-
9478; Angew. Chem. 2010, 122, 9665-9668; c) Y. Liu, H. Du, J. Am.
Chem. Soc. 2013, 135, 6810-6813; d) J. Hermeke, M. Mewald, M.
Oestreich, J. Am. Chem. Soc. 2013, 135, 17537-17546; e) S. Wei, H. Du,
J. Am. Chem. Soc. 2014, 136, 12261-12264; f) Z. Zhang, H. Du, Angew.
Chem. Int. Ed. 2015, 54, 623-626; Angew. Chem. 2015, 127, 633-636;
g) X. Ren, G. Li, S. Wei, H. Du, Org. Lett. 2015, 17, 990-993; h) Z. Zhang,
H. Du, Org. Lett. 2015, 17, 2816-2819; i) Z. Zhang, H. Du, Org. Lett. 2015,
17, 6266-6269; j) J. Lam, B. A. R. Günther, J. M. Farrell, P. Eisenberger,
B. P. Bestvater, P. D. Newman, R. L. Melen, C. M. Crudden, D. W.
Stephan, Dalton Trans. 2016, 45, 15303-15316; k) X. Ren, H. Du, J. Am.
Chem. Soc. 2016, 138, 810-813; l) M. Shang, M. Cao, Q. Wang, M. Wasa,
Angew. Chem. Int. Ed. 2017, 56, 13338-13341; Angew. Chem. 2017, 129,
13523-13526; m) X.-S. Tu, N.-N. Zeng, R.-Y. Li, Y.-Q. Zhao, D.-Z. Xie,
Q. Peng, X.-C. Wang, Angew. Chem. Int. Ed. 2018, 57, 15096-15100;
Angew. Chem. 2018, 130, 15316-15320; n) X. Li, J.-J. Tian, N. Liu, X.-S.
Tu, N.-N. Zeng, X.-C. Wang, Angew. Chem. Int. Ed. 2019, 58, 4664-
4668; Angew. Chem. 2019, 131, 4712-4716.
[6]
[16] For selected examples on transition-metal catalysed asymmetric
hydrogenations of α-substituted α,β-unsaturated ketones, see: a) C.
Thorey, S. Bouquillon, A. Helimi, F. Hénin, J. Muzart, Eur. J. Org. Chem.
2002, 2151-2159; b) S.-M. Lu, C. Bolm, Angew. Chem. Int. Ed. 2008, 47,
8920-8923; Angew. Chem. 2008, 120, 9052-9055; c) W.-J. Lu, Y.-W.
Chen, X.-L. Hou, Adv. Synth. Catal. 2010, 352, 103-107; d) F. Tian, D.
Yao, Y. Liu, F. Xie, W. Zhang, Adv. Synth. Catal. 2010, 352, 1841-1845;
e) X. Liu, Z. Han, Z. Wang, K. Ding, Angew. Chem. Int. Ed. 2014, 53,
1978-1982; Angew. Chem. 2014, 126, 2009-2013.
[17] CCDC-1936726 contains the supplementary crystallographic data for
compound 9y. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
.
[7]
a) M. Shang, X. Wang, S. M. Koo, J. Youn, J. Z. Chan, W. Yao, B. T.
Hastings, M. Wasa, J. Am. Chem. Soc. 2017, 139, 95-98; b) D. W.
Stephan, S. Greenberg, T. W. Graham, P. Chase, J. J. Hastie, S. J. Geier,
J. M. Farrell, C. C. Brown, Z. M. Heiden, G. C. Welch, M. Ullrich, Inorg.
Chem. 2011, 50, 12338-12348; c) S. Li, G. Li, W. Meng, H. Du, J. Am.
Chem. Soc. 2016, 138, 12956-12962; d) S. Li, W. Meng, H. Du, Org. Lett.
2017, 19, 2604-2606.
[18] For selected examples on asymmetric reductions of chromones, see: a)
D. Zhao, B. Beiring, F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 8454-
8458; Angew. Chem. 2013, 125, 8612-8616; b) D. Xiong, W. Zhou, Z. Lu,
S. Zeng, J. J. Wang, Chem. Commun. 2017, 53, 6844-6847; c) X. Ren,
C. Han, X. Feng, H. Du, Synlett 2017, 28, 2421-2424.
[19] a) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157-167; b) Y.
Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215-241.
[8]
For selected reviews, see: a) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2006, 45, 1520-1543; Angew. Chem. 2006, 118, 1550-
1573; b) D. Kampen, C. M. Reisinger, B. List, Top Organomet. Chem.
2009, 291, 395-456; c) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011,
44, 1156-1171; d) M. Rueping, A. Kuenkel, I. Atodiresei, Chem. Soc. Rev.
2011, 40, 4539-4549; e) D. Parmar, E. Sugiono, S. Raja, M. Rueping,
Chem. Rev. 2014, 114, 9047-9153; f) C. Min, D. Seidel, Chem. Soc. Rev.
2017, 46, 5889-5902.
[20] W. J. Hehre, L. Radom, P. v. R. Schleyer, J. A. Pople, Ab Initio Molecular
Orbital Theory; Wiley: New York, 1986.
[21] For selected examples on FLP-catalyzed hydrogenations of electron-
deficient unsaturated compounds, see: a) J. S. Reddy, B.-H. Xu, T.
Mahdi, R. Fröhlich, G. Kehr, D. W. Stephan, G. Erker, Organometallics
2012, 31, 5638-5649; b) B. Inés, D. Palomas, S. Holle, S. Steinberg, J.
A. Nicasio, M. Alcarazo, Angew. Chem. Int. Ed. 2012, 51, 12367-12369;
Angew. Chem. 2012, 124, 12533-12536; c) L. Greb, C.-G. Daniliuc, K.
Bergander, J. Paradies, Angew. Chem. Int. Ed. 2013, 52, 5876-5879;
Angew. Chem. 2013, 125, 5989-5992.
[9]
For selected reviews, see: a) R. Noyori, T. Ohkuma, Angew. Chem. Int.
Ed. 2001, 40, 40-73; Angew. Chem. 2001, 113, 40-75; b) W. Tang, X.
Zhang, Chem. Rev. 2003, 103, 3029-3070; c) F. D. Klinger, Acc. Chem.
Res. 2007, 40, 1367-1376; d) C. A. Sandoval, Y. Li, K. Ding, R. Noyori,
Chem. Asian J. 2008, 3, 1801-1810; e) R. H. Morris, Chem. Soc. Rev.
2009, 38, 2282-2291; f) Z. Wang, G. Chen, K. Ding, Chem. Rev. 2009,
109, 322-359; g) A. Bartoszewicz, N. Ahlsten, B. Martín-Matute, Chem.
Eur. J. 2013, 19, 7274-7302; h) M. Yoshimura, S. Tanaka, M. Kitamura,
Tetrahedron Lett. 2014, 55, 3635-3640; i) Y.-M. He, Y. Feng, Q.-H. Fan,
Acc. Chem. Res. 2014, 47, 2894-2906; j) Y.-Y. Li, S.-L. Yu, W.-Y. Shen,
J.-X. Gao, Acc. Chem. Res. 2015, 48, 2587-2598; k) X. Xie, B. Lu, W. Li,
Z. Zhang, Coord. Chem. Rev. 2018, 355, 39-53.
[10] For early examples, see: a) J. Nyhlén, T. Privalov, Dalton Trans. 2009,
5780-5786; b) L. E. Longobardi, C. Tang, D. W. Stephan, Dalton Trans.
2014, 43, 15723-15726.
[11] a) T. Mahdi, D. W. Stephan, J. Am. Chem. Soc. 2014, 136, 15809-15812;
b) T. Mahdi, D. W. Stephan, Angew. Chem. Int. Ed. 2015, 54, 8511-8514;
Angew. Chem. 2015, 127, 8631-8634.
[12] a) D. J. Scott, M. J. Fuchter, A. E. Ashley, J. Am. Chem. Soc. 2014, 136,
15813-15816; b) Á. Gyömöre, M. Bakos, T. Földes, I. Pápai, A. Domján,
T. Soós, ACS Catal. 2015, 5, 5366-5372; c) D. J. Scott, T. R. Simmons,
E. J. Lawrence, G. G. Wildgoose, M. J. Fuchter, A. E. Ashley, ACS Catal.
2015, 5, 5540-5544
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Entry for the Table of Contents (Please choose one layout)
RESEARCH ARTICLE
A novel type of frustrated Lewis pairs
was developed by the combination of
chiral oxazoline Lewis bases and
achiral boron Lewis acids, in which
chiral Lewis bases act as the steering
component for asymmetric induction. A
highly enantioselective hydrogenation
Bochao Gao, Xiangqing Feng, Wei
Meng*, and Haifeng Du*
Page No. – Page No.
Asymmetric Hydrogenations of
Ketones and Enones with Chiral
Lewis Base-Led Frustrated Lewis
Pairs
of
ketones
and
enones
was
successfully realized, giving the
corresponding products in high yields
with up to 95% ee.
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