Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on enantioselectivity

Article abstract of DOI:10.1016/j.cclet.2020.09.011

A chiral cobalt pincer complex, when combined with an achiral electron-rich mono-phosphine ligand, catalyzes efficient asymmetric hydrogenation of a wide range of aryl ketones, affording chiral alcohols with high yields and moderate to excellent enantioselectivities (29 examples, up to 93% ee). Notably, the achiral mono-phosphine ligand shows a remarkable effect on the enantioselectivity of the reaction.

Full text of DOI:10.1016/j.cclet.2020.09.011

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CCLET 5840 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable
additive effect on enantioselectivity
Tian Dua, Biwen Wanga, Chao Wanga, Jianliang Xiaob, Weijun Tanga,
*
a
Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Chemistry & Chemical Engineering, Shaanxi Normal University,
Xi’an 710062, China
b
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 31 July 2020
Received in revised form 22 August 2020
Accepted 8 September 2020
Available online xxx
A chiral cobalt pincer complex, when combined with an achiral electron-rich mono-phosphine ligand,
catalyzes efficient asymmetric hydrogenation of a wide range of aryl ketones, affording chiral alcohols
with high yields and moderate to excellent enantioselectivities (29 examples, up to 93% ee). Notably, the
achiral mono-phosphine ligand shows a remarkable effect on the enantioselectivity of the reaction.
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Cobalt
Asymmetric hydrogenation
Ketones
Additive effect
Pincer complex
Asymmetric hydrogenation of unsaturated compounds with
molecular hydrogen is one of the most important chemical
processes, which have been applied to producing important chiral
intermediates for pharmaceuticals, fragrances and agrochemicals
[1]. Generally, expensive noble metal catalysts, containing Ru, Rh,
Pd and Ir metals, are employed in order to obtain high activity and
enantioselectivity for asymmetric hydrogenation. Different from
those noble-metal catalysts, some chiral catalysts containing
earth-abundant metals, such as iron, cobalt, nickel and manganese,
have attracted much attention for asymmetric hydrogenation and
transfer hydrogenation, due to their economic and environmental
benefits [2,[3]]. Amongst these catalysts, cobalt catalysts are
promising candidates for the hydrogenation of unsaturated
substrates. In fact, some cobalt complexes were used as catalysts
for hydrogenation reactions earlier [4]. However, harsh conditions,
such as high temperature and high pressure, are generally
required, limiting their practical usefulness. Recently, some
well-defined cobalt catalysts have been reported for successful
metal catalysts. However, the cobalt-catalyzed hydrogenation of
the polar C O bonds is less developed. To the best of our
knowledge, there are only five examples of cobalt-catalyzed
homogenous hydrogenation of ketones under mild conditions, and
only one of them is enantioselective (Scheme 1). In 2012, Hanson
and co-workers reported an example cobalt-catalytic hydrogena-
¼
tion of C
¼
C, C
¼
O, C N bonds using a PNP-cobalt(II)-alkyl catalyst
¼
1, with a substrate to catalyst ratio of 50:1 [6h]. In 2014, Wolf, von
Wangelin and co-workers developed an arenecobalt catalyst 2; a
high catalyst loading (5%) was required to obtain high yields [6e].
In 2015, Kempe and co-workers found that a triazine-based cobalt-
PNP catalyst 3 can affect the hydrogenation of ketones at a lower
catalyst loading (down to 0.25%), affording excellent yields [6d].
More recently, Liu and co-workers reported a highly active
phosphine-free NHC-Co(II) catalyst 4 for the hydrogenation of
ketones, affording excellent yields with only 0.01% catalyst loading
[6a]. Despite the efforts, the cobalt-catalyzed asymmetric hydro-
genation of ketones remains rare. A breakthrough was reported by
Li and co-workers in 2016 [3f]. Using the chiral PNNP-cobalt
catalyst 5 (2 mol%), moderate to good enantioselectivities for
asymmetric hydrogenation of ketones were obtained. Herein, we
report a new catalytic system for asymmetric hydrogenation of
ketones with a chiral PNN-Co catalyst [8] 6 in combination with an
achiral mono-phosphine ligand. Notably, the achiral mono-
phosphine ligand plays an important role for the stereoselectivity,
improving the enantioselectivity from 3% ee to 85% ee for the model
reaction.
hydrogenation of unsaturated substrates containing C
[3f,[6]] and C N [3e,7] bonds under mild conditions. The cobalt-
catalyzed asymmetric hydrogenation of unsaturated C C double
¼
C [5], C O
¼
¼
¼
bonds is particularly impressive, giving highly enantioselectivities
and conversions, sometimes better than those achieved with noble
* Corresponding author.
E-mail address: tangwj@snnu.edu.cn (W. Tang).
https://doi.org/10.1016/j.cclet.2020.09.011
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: T. Du, et al., Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on
enantioselectivity, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.09.011

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Table 1
Optimization of reaction conditions for cobalt-catalyzed hydrogenation of
acetophenone 1aa.a
Entry
Solvent
Base (%)
Cat.
L (%)
Conv. (%)
ee (%)
Scheme 1. Cobalt catalysts for the hydrogenation of C O bonds.
¼
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
NaOCH3 (5)
NaOCH3 (5)
NaOCH3 (5)
NaOCH3 (5)
NaOCH3 (5)
NaOCH3 (20)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
6a
6a
6a
6a
6a
6a
6a
6b
6c
–
ND
100
84
72
60
–
3
L1 (2)
L1 (3)
L1 (4)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L1 (3)
L2 (3)
L3 (3)
L4 (3)
L5 (3)
L6 (3)
L7 (3)
L8 (3)
21
30
30
5
A series of chiral PNN ligands [9] with varying electronic and
steric properties were designed and synthesized (Scheme 2).
Treatment of the ligands La-Lg with CoCl2 in THF led to the cobalt
complexes 6a-6g in good yields. The structure of 6g was confirmed
by X-ray crystallographic analysis (CCDC: 1997410).
The spectra of the electron paramagnetic resonance indicate
that 6g is a pentacoordinated low-spin cobalt(II) complex (details
in Supporting information).
100
100
30
100
100
50
100
100
100
100
100
100
100
100
3
39
24
33
37
37
38
43
50
64
68
72
74
85
ND
64
6d
6e
6f
6 g
6 g
6 g
6 g
6 g
6 g
6 g
6 g
6 g
Having obtained these cobalt catalysts, we turned our attention
to examining the hydrogenation of acetophenone with 6a as the
catalyst firstly. The reduction was carried out under similar
reaction conditions as reported by Kempe [6d]. As showed in
Table 1, no reaction was observed with the cobalt(II) catalyst under
such conditions (entry 1). Activating the catalyst with two
equivalents of NaHBEt3 led to a full conversion for the hydrogena-
tion reaction, but unfortunately, almost a racemic product was
obtained (entry 2). Considering the activated, 16eꢀ catalyst can
coordinate a solvent molecule or another 2-electron donor easily
on its vacant site, it would be possible to coordinate an electron-
rich phosphine ligand, which may alter the chiral environment.
With this hypothesis, tributylphosphane was chosen as an additive
firstly. The catalytic result demonstrated that the addition of
tributylphosphane indeed affected the enantioselectivity (entry 3).
And increasing the amount of additive led to improvement of
enantioselectivities, although the catalytic activities eroded
slightly (entries 3–5). Increasing the amount of base to 20% led
to a full conversion but decreasing its enantioselectivity from 30%
to 5% (Table 1, entry 6). Following these results, we then examined
some kinds of stronger or weaker base under the optimized
conditions (Table S1 in Supporting information), and found that
Cs2CO3 gave the best results with full conversion and 39%
60
ND: not detected.
a
Reaction conditions: Acetophenone (0.25 mmol), 6 (0.005 mmol), NaBHEt3
(0.01 mmol), base (0.0125 mmol), solvent (0.5 mL), 25 ꢁC, H2 (40 bar), 12 h; The
conversions and ee values were determined by GC analysis.
b
No NaBHEt3.
enantioselectivity (entry 7). Next, other cobalt catalysts containing
different substitutions were examined (entries 9–14).
The best one is the catalyst 6 g, affording full conversion and
43% enantioselectivity (entry 14). After the evaluation of several
solvents (Table S2 in Supporting information), Et2O was chosen as
the solvent, which gave the product with full conversion and 50%
enantioselectivity (entry 14). Decreasing hydrogen pressure or
temperature resulted in a similar enantioselectivity but lower
conversion (Table S2). Since the phosphine ligand as the additive
was found to exert a significant effect on the enantioselectivity
(Table 1, entries 2 vs. 4, 3% vs. 30%), a series of phosphines were
then subjected to the model reaction and some notable examples
are summarized in Table 1 (see Fig S1 in Supporting information
for more details). As expected, the phosphine additives signifi-
cantly influenced the stereochemical outcome of the reaction,
giving products with enantioselectivities ranging from 38% to 85%
and good to excellent conversions. As can be seen from Table 1,
the additives based on tri(2-furyl) phosphine (L2) and its
derivatives (L3-L8) afforded much better enantioselectivities than
others. Particularly, the bulky electron-donating ethyl substitute
on the furyl group (L6) gave the best results in terms of both
conversion and enantioselectivity. In contrast, the electron-
withdrawing substituent on the furyl group (L7) or fused aromatic
ring (L8) led to
a remarkable decrease in conversion and
Scheme 2. The synthesis of cobalt catalysts.
enantioselectivity.
Please cite this article in press as: T. Du, et al., Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on
enantioselectivity, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.09.011

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3
Scheme 4. Proposal mechanism.
ionization high-resolution mass spectrometry (ESI-HRMS) was
employed to determine possible intermediates. The results are
summarized in Fig. S2 (Supporting information). Firstly, a high-
intensity signal of the Co(II) complex 6g at the m/z value of
520.0885 corresponding to [M-Cl]+ was observed (Fig. S2). With
the addition of two equivalents of NaBHEt3, a high-intensity signal
of an Co(I)-H hydride intermediate A at the m/z value of 485.1193
for [M-hydride]+ was observed (Fig. S2). Following this, three
equivalents of phosphine L6 was added. As can be seen from the
mass spectra, one signal at the m/z value of 803.2564 assigned to
[M+L6+H]+ was observed. This might be due to the coordination of
L6 to the Co-hydride to form B. Considering these HRMS results, the
asymmetric hydrogenation reaction of ketones may proceed as
follows (Scheme 4).
Scheme 3. Scope of substrates. Reaction conditions: Acetophenone (0.25 mmol),
6 g (0.005 mmol), NaBHEt3 (0.01 mmol), Cs2CO3 (0.0125 mmol), L6 (0.0075 mmol),
Et2O (0.500 mL), 25 ꢁC, H2 (40 bar), 12 h. The conversions and ee values were
determined by GC analysis. aThe reaction time was 20 h.
The Co(II) complex 6 g is reduced to Co(I) with NaBHEt3 [5h],
affording a 16eꢀ Co-hydride species A. The phosphine ligand L6
coordinates to A giving an 18eꢀ Co(I)-hydride-L6 species B. With
the addition of a substrate ketone, the reduction proceeds via an
outer-sphere proton-hydride transfer mechanism as in Noyori’s
DEPN-Ru system, involving the assistance of the NH functional
group on the ligand to hydrogen-bond with the substrate [10]. The
chiral alcohol is produced along with the 16eꢀ species C. The
dihydrogen complex D can be generated from C under H2. Finally,
the active species B is regenerated via dihydrogen activation under
the assistance of the amido nitrogen.
Having established workable conditions for the cobalt catalytic
asymmetric hydrogenation of acetophenone, we subsequently
turned to exploring the scope of aryl ketones. The results are listed
in Scheme 3. As can be seen, all the substrates could undergo
smooth hydrogenation under the identical reaction conditions,
giving excellent isolated yields with moderate to good enantio-
selectivities. The enantioselectivity was relatively insensitive to
the substitution on the phenyl ring (from 2aa to 2aw). Regardless
of whether the substrate contains an electron-donating group or
electron-withdrawing group (1aa-1av), the enantioselectivity was
not very significantly affected, with the enantiomer excesses
varying between 66% and 92%. Interestingly, for the substrate with
a para-CF3 group (1av), a higher enantioselectivity 92% was
achieved. Furthermore, the substrate with a sulfide group or 1-
naphanthyl ketone could proceed smoothly with 60% ee (1am) and
62% ee (1aw). Changing the R2 substitution on the substrate led to a
remarkable effect on the enantioselectivity (1ax-1az). Increasing
the chain length of R2 alkyl group led to the improvement of
enantioselectivity (2aa, 2ax-2by); for example, the substrate 1ay
could be hydrogenated to 2ay with 93% enantioselectivity.
However, in contrast to the linear alkyl groups, bulkier substitutes
did not benefit the eantioselectivities (2az-2bb). Finally, the meta-
acetyl pyridine could also be hydrogenated fully with 51%
enantioselectivity (2bc).
In conclusion, we have found a PNN-Co complex to catalyze the
hydrogenation of ketones. Upon addition of
a free mono-
phosphine ligand, the complex turns into highly efficient
enantioselective catalyst, allowing a broad scope of ketones to
be reduced to chiral alcohols with up to 93% enantioselectivity.
Whilst the role of the mono-phosphine remains to be elucidated,
its remarkable effect in this PNN-Co catalytic system may afford a
useful clue to the design of more effective chiral cobalt catalysts in
the future.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
In order to gain some understanding of the catalytic mechanism
and particularly the role of the phosphine additive, electrospray
Please cite this article in press as: T. Du, et al., Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on
enantioselectivity, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.09.011

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Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound,inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2020.09.011.
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Please cite this article in press as: T. Du, et al., Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on
enantioselectivity, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.09.011