Chiral phosphoric acid catalyzed asymmetric transfer hydrogenation of bulky aryl ketones with ammonia borane

Article abstract of DOI:10.1016/j.tetlet.2019.151394

An asymmetric transfer hydrogenation of bulky aryl ketones with ammonia borane was successfully realized with chiral phosphoric acid (CPA) as catalyst and water as additive. A variety of optically active secondary alcohols were obtained in good to high yi

Full text of DOI:10.1016/j.tetlet.2019.151394

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Chiral Phosphoric Acid Catalyzed Asymmetric Transfer Hydrogenation of Bul-
ky Aryl Ketones with Ammonia Borane
Qiwen Zhou, Wei Meng, Xiangqing Feng, Haifeng Du, Jing Yang
PII:
S0040-4039(19)31185-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151394
TETL 151394
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
18 October 2019
9 November 2019
12 November 2019
Please cite this article as: Zhou, Q., Meng, W., Feng, X., Du, H., Yang, J., Chiral Phosphoric Acid Catalyzed
Asymmetric Transfer Hydrogenation of Bulky Aryl Ketones with Ammonia Borane, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.151394
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Graphical Abstract
A chiral phosphoric acid catalyzed transfer hydrogenation of bulky aryl ketones was realized with ammonia borane with up
to 77% ee.
Chiral Phosphoric Acid Catalyzed
Asymmetric Transfer Hydrogenation of
Bulky Aryl Ketones with Ammonia Borane
Qiwen Zhoua,b, Wei Mengb,c, Xiangqing Fengb,c,*, Haifeng Dub,c,* and Jing Yanga,*

1
Tetrahedron Letters
Chiral Phosphoric Acid Catalyzed Asymmetric Transfer Hydrogenation of Bulky
Aryl Ketones with Ammonia Borane
Qiwen Zhoua,b, Wei Mengb,c , Xiangqing Fengb,c,*, Haifeng Dub,c,* and Jing Yanga,*
aState Key Laboratory of Chemical Resource, Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical
Technology, Beijing 100029, China.
bBeijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China.
cUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An asymmetric transfer hydrogenation of bulky aryl ketones with ammonia borane was
successfully realized with chiral phosphoric acid (CPA) as catalyst and water as additive. A
variety of optically active secondary alcohols were obtained in good to high yields with up to
77% ee. The reaction likely proceeded through a Brønsted acid-promoted double-hydrogen
transfer between ketones and ammonia borane via a six-membered concerted transition state.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Chiral phosphoric acid
Asymmetric transfer hydrogenation
Bulky aryl ketones
Ammonia borane
Chiral secondary alcohols are universal building blocks and
usually have biological activity, and exist widely in the natural
products and synthetic chemistry.1 The catalytic asymmetric
reduction of ketones such as hydrogenation,2 transfer
hydrogenation,3 and Corey-Bakshi-Shibata (CBS) reduction,4
provides the most straightforward way for preparing optically
pure secondary alcohols. Great success has been achieved in this
field. However, only a few reports on the asymmetric reduction
of bulky ketones have been reported.5 For example, in 2005,
Noyori and co-workers reported a BINAP/PICA-Ru complex
catalyzed asymmetric hydrogenation of tert-alkyl ketones with
excellent yields and enantioselectivities.5a Clarke group
developed a variety of chiral ruthenium catalysts for the
hydrogenation and transfer hydrogenation of bulky ketones.5b-e
been reported (Figure 1).8 In 1984, Williams and co-workers
described an asymmetric reduction of aromatic ketones with
ammonia-borane complexes of chiral tetraphenyl-18-crown-6
derivatives to give 67% ee.8a Recently, our group developed a
frustrated Lewis pair (FLP) of (R)-tert-butylsulfamide and Piers’
borane for the asymmetric transfer hydrogenation with ammonia
borane.8d-g Very recently, we designed a renewable chiral
ammonia borane derived from chiral phosphoric acid (CPA) and
ammonia borane, which was a reactive species for asymmetric
transfer hydrogenation of imines, β-enamino esters, and enamine
cyanides.8h,i Herein, we wish to report our efforts on the chiral
phosphoric acid9 catalyzed asymmetric transfer hydrogenation of
bulky ketones with ammonia borane.
Very recently, Clarke and co-workers also developed
a
manganese catalyst based chiral P,N,N ligand for bulky ketones
to give up to 97% ee.5f Despite these advances, to the best of our
knowledge, the metal-free asymmetric reduction of bulky ketones
has seldom been reported.
Ammonia borane (AB) is an ideal hydrogen storage material
as well as a good hydrogen source for transfer hydrogenations.6,7
However, only a very few examples on the asymmetric transfer
hydrogenation with ammonia borane as hydrogen source have
Figure 1. Representative examples on asymmetric reductions with
ammonia borane.
The asymmetric transfer hydrogenation of ketones 1a-e was
initially carried out in dichloromethane at 30 °C for 4 h by using
———
*
Corresponding author at: Beijing University of Chemical Technology, Beijing 100029, China (J. Yang), and Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China (X. Feng, and H. Du).
E-mail addresses: yangj@mail.buct.edu.cn (J. Yang), fxq@iccas.ac.cn (X. Feng), haifengdu@iccas.ac.cn (H. Du).

2
Tetrahedron
bThe ee was determined by chiral HPLC.
10 mol % of CPA 2a as catalyst with NH3·BH3 (3a) as
hydrogen source. As shown in Scheme 1, all these reactions went
smoothly to afford the corresponding secondary alcohol 4a-e in
quantitative conversions. It was found that increasing steric
hindrance of ketones could lead an improvement of ee’s. Less
bulky acetophenone (1a) and propiophenone (1b) gave racemic
products. While ketones 1d and 1e containing a tert-butyl group
could give 17% and 19% ee, respectively.
With the optimal catalyst, solvent, and additive in hand (Table
1, entry 11), the reaction conditions were further optimized. The
reaction temperature had
a
slight impact on the
enantioselectivities (Table 2, entries 1-3). Decreasing the loading
of CPA 2a from 10 mol % to 0.5 mol % resulted in a little higher
ee’s without loss of reactivities (Table 2, entries 4-7). When 0.1
mol % of CPA 2a was used, the ee was dropped sharply from
73% to 59% (Table 2, entry 8). Various ammonia boranes 3b-d
were subsequently studied for the asymmetric transfer
hydrogenation of ketone 1e. Unfortunately, these ammonia
boranes bearing methyl groups on the nitrogen atom were not
suitable hydrogen sources (Table 2, entries 9-11).
Table 2. Optimization of reaction conditionsa
Scheme 1. CPA catalyzed asymmetric transfer hydrogenation
of ketones.
2a (mol
%)
Time
(h)
Conv
(%)b
Ee
Entry
AB
(%)c
To further improve the enantioselectivity, the CPA catalysts,
additives and the reaction conditions were next investigated.
Solvents had an obvious influence on the enantioselectivity, and
benzene could give 47% ee (Table 1, entries 1-3). When H2O was
used as an additive, the ee could be improved up to 55% (Table
1, entries 4-6). CPAs 2b-e were then evaluated for this reaction,
and CPA 2a proved to be a better catalyst (Table 1, entries 5 vs
7-10). We were pleased to find that 67% ee was obtained when
CS2 was used as a solvent (Table 1, entry 11). When MeOH was
used as an additive, a similar result was afforded (Table 1, entry
12).
1
10
10
10
5
3a
4
99
99
99
99
99
99
99
91
75
43
nrf
67
61
66
70
70
73
73
59
rac
rac
--
2d
3e
4
3a
7
3a
4
3a
7
5
2
3a
7
6
1
3a
9
7
0.5
0.1
0.5
0.5
0.5
3a
12
12
12
12
12
8
3a
Table 1. Evaluation of CPA catalysts and optimization of
9
MeNH2·BH3 (3b)
Me2NH·BH3 (3c)
Me3N·BH3 (3d)
reaction conditionsa
10
11
aAll reactions were carried out with ketone 1e (0.1 mmol), 2a, H2O (1.1
equiv) and AB (3) (1.1 equiv) in CS2 (0.5 mL) at room temperature.
bThe conversion was determined by crude 1H NMR.
cThe ee was determined by chiral HPLC.
dAt 0 °C.
eAt 40 °C.
fNo reaction.
Entry CPA 2 Additive (x equiv) Solvent
Ee (%)b
19
1
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
--
CH2Cl2
toluene
2
--
40
3
--
benzene 47
benzene 50
benzene 55
benzene 55
benzene 48
benzene rac
benzene 56
4
H2O (0.5)
H2O (1.1)
H2O (1.5)
H2O (1.1)
H2O (1.1)
H2O (1.1)
H2O (1.1)
H2O (1.1)
MeOH (1.1)
5
6
7
8
9
10
11
12
benzene
CS2
5
67
65
CS2
aAll reactions were carried out with ketone 1e (0.1 mmol), CPA 2 (10 mol
%), and NH3·BH3 3a (1.1 equiv) in solvent (0.5 mL) for 4 h at room
temperature.

3
TS-(R)
TS-(S)
¹
¹
G
= 1.2 Kcal/mol
G
= 0 Kcal/mol
Figure 3. DFT calculation for the hydrogen transfer process.
In order to have a better insight into the asymmetric transfer
hydrogenation of bulky ketones, 31P NMR studies were carried
out. As shown in Figure 2b, treating CPA 2a with ammonia
borane (3a) (1.0 equiv) in CS2 for 0.5 h, besides the generation of
chiral ammonia borane 5, some CPA 2a were still unchanged. In
contrast, all the CPA could be converted into chiral ammonia
borane 5 within 10 min in toluene (Figure 2d). Distinct our
previous work,8h,i chiral ammonia borane 5 might not be a
reactive species in the current reaction due to the slow reaction of
CPA 2a and ammonia borane (3a).
Scheme 2. CPA-catalyzed asymmetric transfer hydrogenation
of ketones.
A variety of bulky ketones 1e-v were subjected the asymmetric
transfer hydrogenation under the optimal conditions. As shown in
Scheme 2, all these reactions proceeded smoothly to give the
corresponding secondary alcohols 4e-v in 71-97% yields with 43-
77% ee’s. It was found that the ortho-substituted groups,
especially the alkoxy groups gave a little better ee’s. While the
meta- and para-substituents generally gave relatively lower ee’s.
The reduction of ketones 1t-v containing other bulky groups
instead of tert-butyl groups afforded the desired products 4t-v in
high yields with 44-73% ee’s.
Chiral ammonia borane
5 was prepared in toluene
conveniently (Scheme 4). When treating ketone 1e with chiral
ammonia borane 5 (1.0 equiv) in CS2 at room temperature for 10
h, no reduction occurred. Chiral ammonia borane 5 as the
reactive species could therefore be precluded. According to the
reported work,7 as well the free CPA existing in the current
catalytic system, an asymmetric induction model was proposed,
in which the CPA promoted the double hydrogen transfer
between ketones and ammonia borane via six-membered
transition state (Scheme 4). Theoretical investigations on M06-
2X/6-31G(d) level provides a further support for this assumption.
As shown in Figure 3, two concert transition states were located
with a 1.2 kcal/mol energy difference in gas phase, indicating a
preference for (S)-stereoselectivity, which is in consistent with
the experiment results.
In summary, a chiral phosphoric acid catalyzed asymmetric
transfer hydrogenation of bulky aryl ketones was realized using
ammonia borane as hydrogen source and water as an additive.
With as low as 0.5 mol % of catalyst, a variety of bulky ketones
were effective substrates to furnish the corresponding optically
active secondary alcohols in 71-97% yields with 43-77% ee’s.
Notably, distinct from our previous work, the current reaction
was likely though a chiral Brønsted acid catalysis with a double
hydrogen transfer between ketones and ammonia borane via a
six-membered concerted transition state. Further efforts on
searching for more effective catalysts and exploring more
detailed mechanism are underway in our laboratory.
Figure 2. 31P NMR studies on preparation of 3e.
Acknowledgements
We are grateful for generous financial support from the
National Natural Science Foundation of China (91856103,
21871269 and 21521002).
Scheme 4. Control experiment with chiral ammonia borane.

4
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Supplementary Material
Supplementary data (the procedures for the transfer
hydrogenation, characterization and data for the determination of
ee’s along with NMR spectra) associated with this article can be
found in the online version.
Click here to remove instruction text...

5
1. Asymmetric transfer hydrogenations with
ammonia borane were realized.
2. Optically active secondary alcohols were
obtained in good to high yields with up to
77% ee.
3. A chiral phosphoric acid was used as an
effective chiral catalyst.