A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones and Aldehydes

Article abstract of DOI:10.1016/j.chempr.2019.03.010

Homogeneous catalytic hydrogenation of carbonyl groups is a synthetically useful and widely applied organic transformation. Sustainable chemistry goals require replacing conventional noble transition metal catalysts for hydrogenation by earth-abundant base metals. Herein, we report how a practical in situ catalytic system generated by easily available pincer NHC precursors, CoCl₂, and a base enabled efficient and high-yielding hydrogenation of a broad range of ketones and aldehydes (over 50 examples and a maximum turnover number [TON] of 2,610). This is the first example of NHC-Co-catalyzed hydrogenation of C=O bonds using flexible pincer NHC ligands consisting of a N-H substructure. Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized by fine-tuning of the steric bulk of pincer NHC ligands. Additionally, a bis(NHCs)-Co complex was successfully isolated and fully characterized, and it exhibits excellent catalytic activity that equals that of the in-situ-formed catalytic system. Catalytic hydrogenation is a powerful tool for the reduction of organic compounds in both fine and bulk chemical industries. To improve sustainability, more ecofriendly, inexpensive, and earth-abundant base metals should be employed to replace the precious metals that currently dominate the development of hydrogenation catalysts. However, the majority of the base-metal catalysts that have been reported involve expensive, complex, and often air- and moisture-sensitive phosphine ligands, impeding their widespread application. From a mixture of the stable CoCl₂, imidazole salts, and a base, our newly developed catalytic system that formed easily in situ enables efficient and stereoselective hydrogenation of C=O bonds. We anticipate that this easily accessible catalytic system will create opportunities for the design of practical base-metal hydrogenation catalysts. A practical in situ catalytic system generated by a mixture of easily available pincer NHC precursors, CoCl₂, and a base enabled highly efficient hydrogenation of a broad range of ketones and aldehydes (over 50 examples and up to a turnover number [TON] of 2,610). Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized in high selectivities. Moreover, the preparation of a well-defined bis(NHCs)-Co complex via this pincer NHC ligand consisting of a N-H substructure was successful, and it exhibits equally excellent catalytic activity for the hydrogenation of C=O bonds.

Full text of DOI:10.1016/j.chempr.2019.03.010

Article
A Practical and Stereoselective In Situ NHC-
Cobalt Catalytic System for Hydrogenation of
Ketones and Aldehydes
Rui Zhong, Zeyuan Wei, Wei
Zhang, Shun Liu, Qiang Liu
qiang_liu@mail.tsinghua.edu.cn
HIGHLIGHTS
A practical and easily accessible
in-situ NHC-Co hydrogenation
catalyst for C=O bonds
Diastereodivergent Co-catalyzed
hydrogenation of cyclohexanone
derivatives
Isolation of a catalytically active
NHC-Co complex with a non-rigid
pincer NHC ligand
A practical in situ catalytic system generated by a mixture of easily available pincer
NHC precursors, CoCl2, and a base enabled highly efficient hydrogenation of a
broad range of ketones and aldehydes (over 50 examples and up to a turnover
number [TON] of 2,610). Diastereodivergent hydrogenation of substituted
cyclohexanone derivatives was also realized in high selectivities. Moreover, the
preparation of a well-defined bis(NHCs)-Co complex via this pincer NHC ligand
consisting of a N-H substructure was successful, and it exhibits equally excellent
catalytic activity for the hydrogenation of C=O bonds.
Zhong et al., Chem 5, 1–15
June 13, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.03.010

Please cite this article in press as: Zhong et al., A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones
and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
Article
A Practical and Stereoselective In Situ
NHC-Cobalt Catalytic System for
Hydrogenation of Ketones and Aldehydes
Rui Zhong,1,3 Zeyuan Wei,1,3 Wei Zhang,1 Shun Liu,2 and Qiang Liu1,4,
*
SUMMARY
The Bigger Picture
Catalytic hydrogenation is a
powerful tool for the reduction of
organic compounds in both fine
and bulk chemical industries. To
improve sustainability, more
ecofriendly, inexpensive, and
earth-abundant base metals
should be employed to replace
the precious metals that currently
dominate the development of
hydrogenation catalysts.
Homogeneous catalytic hydrogenation of carbonyl groups is a synthetically use-
ful and widely applied organic transformation. Sustainable chemistry goals
require replacing conventional noble transition metal catalysts for hydrogena-
tion by earth-abundant base metals. Herein, we report how a practical in situ
catalytic system generated by easily available pincer NHC precursors, CoCl2,
and a base enabled efficient and high-yielding hydrogenation of a broad range
of ketones and aldehydes (over 50 examples and a maximum turnover number
[TON] of 2,610). This is the first example of NHC-Co-catalyzed hydrogenation of
C=O bonds using flexible pincer NHC ligands consisting of a N-H substructure.
Diastereodivergent hydrogenation of substituted cyclohexanone derivatives
was also realized by fine-tuning of the steric bulk of pincer NHC ligands.
Additionally, a bis(NHCs)-Co complex was successfully isolated and fully
characterized, and it exhibits excellent catalytic activity that equals that of the
in-situ-formed catalytic system.
However, the majority of the base-
metal catalysts that have been
reported involve expensive,
complex, and often air- and
moisture-sensitive phosphine
ligands, impeding their
INTRODUCTION
Homogeneous catalytic hydrogenation of carbonyl compounds is a pivotal organic
transformation for the synthesis of alcohols in synthetic chemistry.1,2 In this area, no-
ble transition metal catalysts, such as Ru, Rh, and Ir, play a leading role.3–5 Given the
need to pursue more sustainable chemistry, the development of potential economic
and environmental benefits of catalysts based on earth-abundant metals is highly
desirable.6–13 The use of cobalt, the 3d metal congener of rhodium and iridium,
has attracted increasing interest in the development of hydrogenation cata-
lysts.12,14,15 Its unique electronic and structural properties provide many opportu-
nities to uncover new reactivities.16–20 Using a rational ligand design, significant
progress has been made in recent years, demonstrating the potential of cobalt-
based hydrogenation catalysts.21–35 Regarding the hydrogenation of ketones and
aldehydes, the groups of Hanson,36,37 Kempe,38 and Li39 have each reported a
well-defined pincer cobalt catalyst (Scheme 1A). All of these novel cobalt catalysts
possess amino-phosphine ligands, which are usually expensive, air sensitive, and
difficult to synthesize at a large scale, thus impeding their widespread application.
To the best of our knowledge, only one phosphorus-free cobalt catalyst for the hy-
drogenation of ketones has been reported.40 This arene-cobalt-ate catalyst is active
for the hydrogenation of alkenes, ketones, and imines. However, it has narrow ligand
diversification, shows limited scope for ketones substrates, and does not facilitate
reactions with aldehydes. Therefore, further development of practical catalytic hy-
drogenation of carbonyl compounds calls for the use of earth-abundant metal cata-
lysts supported by ligands that are easily prepared, stable, and highly tunable.
widespread application. From a
mixture of the stable CoCl2,
imidazole salts, and a base, our
newly developed catalytic system
that formed easily in situ enables
efficient and stereoselective
hydrogenation of C=O bonds. We
anticipate that this easily
accessible catalytic system will
create opportunities for the
design of practical base-metal
hydrogenation catalysts.
Chem 5, 1–15, June 13, 2019 ª 2019 Elsevier Inc.
1

Please cite this article in press as: Zhong et al., A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones
and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
A
B
Scheme 1. Cobalt Catalysts for Catalytic Hydrogenation of Ketones and Aldehydes
Because the cost of the ligand ultimately dictates the total cost of the catalytic sys-
tem, it should be taken into account to develop a new ligand in non-noble-metal
catalysis.
N-Heterocyclic carbenes (NHCs) are promising alternatives to phosphine ligands
because of their strong s-donating ability and high tunability.41–43 Moreover,
NHC precursors, such as imidazole salts, are air-stable, cost-effective and easily
accessible from simple starting materials. Notably, well-defined NHC-Co com-
plexes44,45 containing a rigid pincer NHC ligand have been developed as effective
catalysts for the hydrogenation of alkenes, alkynes, and nitriles.46–49 In contrast, no
1Center of Basic Molecular Science (CBMS),
NHC-Co catalytic system has yet been reported for the hydrogenation of C=O
bonds. Noting that employing the ‘‘N-H effect’’ markedly enhances the activity of
phosphine-based hydrogenation catalysts via metal-ligand cooperation,50,51 we en-
visioned that an NHC-Co hydrogenation catalyst containing the N-H moiety might
efficiently catalyze the hydrogenation of carbonyl groups. Herein, we report the first
example of NHC-Co-catalyzed hydrogenation of ketones and aldehydes by employ-
ing non-rigid pincer NHC ligands containing a N-H substructure (Scheme 1B).
Remarkably, a combination of CoCl2, imidazole salts, and a base generated robust
cobalt catalysts forming in situ, enabling the efficient discovery of practical
Department of Chemistry, Tsinghua University,
Beijing 100084, China
2School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen, Guangdong Province
529090, China
3These authors contributed equally
4Lead Contact
*Correspondence:
qiang_liu@mail.tsinghua.edu.cn
https://doi.org/10.1016/j.chempr.2019.03.010
2
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and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
Table 1. Ligand Effect on the Hydrogenation of Acetophenone 1a
O
OH
2a
CoCl2 (2 mol%), LNHC (2 mol%)
tBuOK (20 mol%)
H2 (30 bar)
+
THF, 16 h, 60 °C
1a
LNHC
:
Z
N
N
N
N
N
N
N
N
N
2Cl-
2Br-
2Br-
N
N
N
R
N
R
N
R
N
R
Dipp
Dipp
L1a-e
L2a-b
L3a
H
N
N
N
H
N
N
R2P
PR2
Cl-
N
2Cl-
L3b
N
N
Mes
Mes
Mes
L4
L5a-b
Entry
LNHC
Yield (%)a
Entry
7
LNHC
Yield (%)a
24
1
2
3
4
5
6
L1a (R = Me, Z = H)
L1b (R = Ph, Z = H)
1
L2b (R = Mes)
L3a
3
8
42
L1c (R = Mes, Z = H)
L1d (R = Dipp, Z = H)
L1e (R = Mes, Z = Me)
L2a (R = Me)
95
88
n.p.
55
9
L3b
8
10
11
12
L4
n.p.
n.p.
n.p.
L5a (R = iPr)
L5b (R = Ph)
Reaction conditions: 1 mmol scale, 2 mol % [Cat.] (LNHC:CoCl2 = 1:1), and 20 mol % tBuOK in 0.5 mL of THF under 30 bar H2 at 60ꢀC for 16 h. n.p., no product.
aYield was determined by GC analysis with biphenyl as the internal standard.
hydrogenation catalytic systems via facile screening of metal precursors and ligands.
More than 50 ketones and aldehydes were successfully hydrogenated into the cor-
responding alcohols with excellent functional group tolerance and high turnover
numbers (TONs), the highest being 2,610. Interestingly, this catalytic system also al-
lows for effective stereocontrol of the diastereodivergent hydrogenation of
substituted cyclohexanones via fine-tuning of the bulkiness of the wing-tip substitu-
ents on the NHC ligands.
RESULTS AND DISCUSSION
We initially prepared two types of pincer NHC ligands on the basis of amino- (L1)52,53
and lutidine-derived (L2) pincer motifs that involve metal-ligand cooperation function-
ality (Table 1, lower part). Both series of ligands can be simply prepared in good yields
in one or two steps that start from widely available materials (see Supplemental Infor-
mation for more details). Tuning the steric hindrance of these flexible NHC ligands was
facile to achieve by changing the N-substituted groups on the imidazole motifs. With
these pincer NHC ligands, we performed hydrogenation of acetophenone 1a via the
catalytic systems formed in situ, which were derived from a mixture of the pincer
t
NHC ligand, CoCl2, and BuOK in tetrahydrofuran (THF). The reactions were carried
out in the presence of 2 mol % cobalt catalyst under 30 bar H2 and 60ꢀC. The amino
pincer NHC ligand L1c bearing mesityl substituents performed the best with a 95%
yield (Table 1, entry 3). L1d, with 2,6-diisopropylphenyl (Dipp) substituents, showed
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Table 2. Impact of Type and Concentration of Base Employed on Hydrogenation of 1a with L1c/
CoCl2
O
OH
L1c/CoCl2 (1 mol%)
base (2.5 - 5 mol%)
+
H2 (30 bar)
THF, 16 h, 60 °C
1a
2a
Entry
Base (mol %)
5 (K2CO3)
5 (K3PO4)
5 (KOAc)
Yield (%)a
Entry
Base (mol %)
Yield (%)a
1
2
3
4
n.p.
n.p.
n.p.
80
5
6
7
8
2.5 (KOH)
5 (tBuOK)
2.5 (tBuOK)
1 (tBuOK)
8
95
39
5 (KOH)
trace
Reaction conditions: 1 mmol scale, 1 mol % [Co] (L1c:CoCl2 = 1:1), and 2.5–5 mol % base in 0.5 mL THF
under 30 bar H2 at 60ꢀC for 16 h. n.p., no product.
aYield was determined by GC analysis with biphenyl as the internal standard.
a slightly lower reactivity than that of L1c (Table 1, entry 4), and experiments with the
other amino pincer ligands with methyl and phenyl substituents resulted in very low
yields (Table 1, entries 1 and 2). Regarding the lutidine-derived pincer NHC ligands
L2a and L2b, only low to moderate yields of the desired alcohol products were ob-
tained (Table 1, entries 6 and 7). Experiments with the N-methyl substituted pincer
NHC ligand L1e exhibited no reactivity (Table 1, entry 5). This showed that an outer-
sphere hydride transfer process that took the advantage of the ‘‘N-H effect’’ might
be involved in the amino NHC-Co catalyzed hydrogenation of C=O bonds. In addition,
the corresponding rigid pincer NHC ligands L3a and L3b gave only low to moderate
yields (Table 1, entries 8 and 9). The bidentate ligand L4, which had the same mesityl
substituent as L1c, displayed no reactivity, suggesting a tridentate coordination is
necessary to generate catalytically active species. There was no reaction with either
the related PNP-pincer phosphine ligand L5a or L5b (Table 1, entries 11 and 12),
revealing the key role of NHC ligands.
Using the most active ligand L1c, we further evaluated optimal reaction conditions
including bases, solvents, and metal precursors (Tables S1–S5). THF was the best
performing solvent, and CoCl2 and CoBr2 were the most effective metal precursors
for this transformation. Other metal salts, such as FeCl2, MnCl2, NiCl2, and CuCl2,
did not yield systems that were catalytically active. Strong bases, such as KOH
and tBuOK, exhibited good reactivity with high yields for the hydrogenation product
2a (Table 2, entries 4–6). Weak bases, such as K2CO3, K3PO4, and KOAc, were
completely inactive (Table 2, entries 1–3). This observation suggested that strong
bases were required to deprotonate L1c to generate free NHCs that were capable
of coordinating with the metal center. The amounts of the base also notably
influenced the system’s reactivity: for example, decreasing the concentration of
tBuOK away from 5 mol % resulted in a dramatic drop in reaction yields (Table 2, en-
tries 6–8).
To gain further insights into the base’s role during the activation of catalyst precur-
sors, we employed electrospray ionization high-resolution mass spectrometry (ESI-
HRMS) to determine the cobalt complexes generated from the mixture of L1c,
t
t
CoCl2, and BuOK in THF. As depicted in Figure 1, the amount of BuOK markedly
influenced the cobalt species formed during the precatalyst activation process (for
t
more details, see Figures S1–S5). With 0.5 equiv of BuOK added to the L1c and
CoCl2 (1:1) mixture, two high-intensity signals at m/z values of 535.19 and 571.17
4
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H
N
N
N
tBuOK
2Cl-
CoCl2
?
+
N
RT, THF
N
H
N
Mes
Mes
L1c
N
N
1 equiv.
1 equiv.
H
N
Co
N
N
N
N
Cl
N
Mes
Mes
Co
I-2
N
N
N
N
0.5 equiv. tBuOK
Cl
Cl
Co
Mes
Mes
N
N
I-1
Mes
Mes
I-3
m/z
m/z
1.0 equiv. tBuOK
2.0 equiv. tBuOK
m/z
m/z
5.0 equiv. tBuOK
Figure 1. ESI-MS Spectra of the Reaction Mixture of L1c-CoCl2 with Variated Amount of tBuOK
were observed. These were attributed to the bis-NHC cation species I-2 and the
mono-NHC cation species I-1, respectively. A low-intensity signal observed at m/z
of 499.21 was assigned to the ion peak of an amido-cation species I-3. A gradual in-
crease in the concentration of tBuOK from 0.5 to 2.0 equiv resulted in a decreased
intensity of the I-1 signal at m/z of 571.17, but the I-2 signal (m/z of 535.19) remained
the highest peak observed. These results indicated that a high amount of base facil-
itated the formation of bis-NHC coordination species. Interestingly, an excess of
tBuOK (5.0 equiv) resulted in a high-intensity I-3 signal at m/z of 499.21 and a notable
decrease in the intensity of the m/z signal at 535.19. In combination with the afore-
mentioned base effect (Table 2), this observation suggested that tBuOK assisted the
formation of a catalytically active amido bis-NHC cobalt species in this catalytic
system.
We therefore considered varying the amount of tBuOK could lead to the formation of
different NHC-Co species, as shown in Scheme 2. More specifically, the addition of
1.0 equiv of tBuOK could permit the formation of the mono-NHC Co complex Co-1,
whereas adding 2.0 equiv of tBuOK could give rise to the bis(NHCs)-Co complexes
t
Co-2a or Co-2b. Furthermore, an excess of BuOK could generate the amido com-
plex Co-3 by further eliminating one equiv of HCl from Co-2.
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H
N
Cl
1 equiv. tBuOK
THF, RT
N
N
N
Co
N
Cl
Cl
Co-1
Mes
Mes
H
N
H
N
H
N
Cl
N
N
2 equiv. tBuOK
THF, RT
N
N
N
N
N
N
Co
Co
Cl
or
CoCl2
+
2Cl-
N
N
N
N
Cl
Cl
Mes
Mes
Mes
Mes
Mes
Mes
Co-2a
Co-2b
L1c
1 equiv.
1 equiv.
N
>3 equiv. tBuOK
THF, RT
N
N
Co
N
N
Cl
Mes
Mes
Co-3
Scheme 2. Expected NHC-Co Complexes Formed by Adding Various Amounts of Base
Intrigued by the mass-spectroscopy results, we attempted to isolate the NHC-Co
complexes formed in situ in the catalytic system and identify their structures. How-
ever, we were unable to crystallize the cobalt complexes from the mixture formed
between CoCl2 and L1c (1:1) in THF with 2 equiv tBuOK added at room temperature.
As an alternative strategy, 2 equiv tBuOK in THF was slowly added into the L1c and
CoCl2 suspension in THF at ꢁ78ꢀC, resulting in a blue suspension that was further
purified to afford a blue powder. The ESI-HRMS analysis of this blue powder dis-
played a strong signal at an m/z value of 535.19, representing the ion peak of I-2.
Its X-ray crystal structure showed the tetra-coordinated ionic bis(NHC) complex
Co-2a with a chloride as the counter anion rather than the penta-coordinated struc-
ture Co-2b (Figure 2). The coordination environment around the Co center exhibited
a distorted tetrahedron geometry with a CNHCꢁCoꢁCNHC angle of 129.9(1)ꢀ. The
effective magnetic moment of Co-2a was determined to be 4.2 mB, in line with a
high spin state consisting of three unpaired electrons. This is in accordance with
the geometry of this complex. Fortunately, the single crystal of Co-1 was also ob-
tained during the recrystallization of Co-2a, revealing a mono-NHC-coordinated
Co(II) complex. The isolation of Co-1 could support the observation I-1 ion peak
at m/z of 571.17 by ESI-MS.
After the bis(NHC)-Co complex Co-2a was isolated, we investigated its catalytic ac-
tivity for the hydrogenation of acetophenone 1a by using 1 mol % catalyst loading in
THF under 30 bar hydrogen pressure and 60ꢀC. Surprisingly, weak bases such as
K3PO4, K2CO3, and KOAc, which were inactive for the in situ catalytic systems (Table
2, entries 1–3), were effective for Co-2a-catalyzed hydrogenation reactions (Table 3,
t
entries 1–3). 2.5 mol % BuOK in combination with 1 mol % Co-2a afforded a 98%
t
yield of 2a (Table 3, entry 4), but the same amount of BuOK was insufficient when
used in the in situ catalytic system with the same ligand (Table 2, entry 7). KOH
was the most active base; a loading of just 0.5 mol % effectively promoted a high-
yielding transformation (Table 3, entry 6). Notably, the use of 1 mol % Co-2a also
6
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Figure 2. Molecular Structures of Co-1 and Co-2a with 50% Probability of Thermal Ellipsoids
ꢀ
˚
H atoms are omitted for clarity. Selected bond lengths (A) and angles ( ): (Co-1) Co1ꢁC12 2.011; Co1ꢁN3 2.091; Co1ꢁCl1 2.275; Co1ꢁCl2 2.250;
C12ꢁCo1ꢁN3 96.70; C12ꢁCo1ꢁCl1 109.92; C12ꢁCo1ꢁCl2 118.13; N3ꢁCo1ꢁCl1 103.25; N3ꢁCo1ꢁCl2 113.78; (Co-2a) Co1ꢁC1 2.020(3); Co1ꢁC4
2.045(3); Co1ꢁCl1 2.2544(8); Co1ꢁN5 2.094(2); C1ꢁCo1ꢁC4 129.88(11); C1ꢁCo1ꢁCl1 110.61(8); C4ꢁCo1ꢁCl1 111.14(8); N5ꢁCo1ꢁCl1 106.14(7);
N5ꢁCo1ꢁC1 97.02(10); N5ꢁCo1ꢁC1 96.88(10).
catalyzed this reaction under 5 bar H2 at room temperature to give a 90% yield
t
(Table 2, entry 8). We therefore employed KOH and BuOK as the bases for the
well-defined (Co-2a) and in situ (L1c-CoCl2) catalytic systems, respectively.
We further evaluated catalyst activity for gram-scale hydrogenation of acetophe-
none 1a by using a catalyst loading of 0.01 mol % (Scheme 3). Impressively, the hy-
drogenated product 2a was acquired at a yield of 87% with a high turnover number
(TON) of 2,610 at room temperature, illustrating the high stability and efficiency of
this NHC-Co catalyst.
We next explored the scope of substrates for the NHC-Co catalyzed ketone hydro-
genation reaction by using the in situ catalytic system and the well-defined complex
Co-2a (Figure 3). A series of acetophenone derivatives (1b–1j and 1n–1p) bearing a
range of electron-donating and electron-withdrawing substituents on phenyl rings
were converted to their corresponding alcohol products in high isolated yields.
Table 3. Hydrogenation of Acetophenone 1a with Co-2a
O
OH
[Co-2a] (1 mol%), base (0.25-10 mol%)
THF, 16 h, 60 °C
+
H2 (30 bar)
1a
2a
Entry
Base (mol %)
10 (K2CO3)
5 (K3PO4)
Yield (%)a
Entry
Base (mol %)
2.5 (KOH)
0.5 (KOH)
0.25 (KOH)
10 (KOH)
Yield (%)a
>99
1
2
3
4
>99
95
5
6
7
8
93
5 (KOAc)
91
84
2.5 (tBuOK)
98
90b
Reaction conditions: 1 mmol scale, 1 mol % Co-2a, and 0.25–10 mol % base in 0.5 mL THF under 30 bar H2
at 60ꢀC for 16 h.
aYield was determined by GC analysis with biphenyl as the internal standard.
bUnder 5 bar H2 at room temperature for 2 h.
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OH
O
L1c (0.01 mol%), CoCl2 (0.01 mol%)
tBuOK (0.1 mol%)
+
H2 (60 bar)
THF (50 mL), 16 h, RT
2a
1a
30 mmol
yield: 87%
TON: 2610
Scheme 3. An Example of the Efficiency of the NHC-Cobalt Catalyst
Functional groups, such as methoxyl, methylthio, fluoro, bromo, chloro, iodo, tri-
fluoromethyl, ester, heterocycles (2w–2z and 2aa and 2ab), and alkenyl groups (2t
and 2v), were all well tolerated, whereas nitro and phenolic hydroxyl groups
were incompatible (2k and 2l). With respect to the aliphatic ketones, both cyclic
(1ac–1af) and linear (1ag–1ai and 1ak) ketones were successfully reduced with
good yields. Diketone substrate 1aj was also effectively converted to the corre-
sponding diol product with a quantitative yield. To further demonstrate the
synthetic potential of this protocol, the hydrogenation of three pharmaceutical
molecules—pentoxifylline 1ak, progesterone 1am, and testosterone 1an—were
performed. Pentoxifylline is a pain-alleviating medication, whereas testosterone
and progesterone are both medications and naturally occurring steroid hormones.
All three molecules were successfully hydrogenated to their corresponding alcohol
products with excellent yields. Remarkably, by simply controlling the reaction tem-
perature, progesterone—which bears two carbonyl groups—was selectively
reduced to give (at room temperature) the mono-hydrogenated product 2al or (at
60ꢀC) the di-hydrogenated product 2am. The hydrogenation of testosterone and
progesterone led to two stereoisomers of the alcohol products, the structures of
which were confirmed by X-ray single-crystal analysis (Table S6). Finally, we also
tested aldehyde substrates and found that benzaldehyde derivatives with elec-
tron-donating or electron-withdrawing substituents could be reduced with excellent
yields (2ao–2ar). The linear and cyclic aliphatic aldehydes 2as and 2at were also both
hydrogenated with good yields.
The stereoselective reduction of substituted cyclohexanones is a valuable transfor-
mation for the synthesis of stereo-defined cyclohexanols, which are key intermedi-
ates in the fragrance and pharmaceutical industries.54–56 In classic organic synthesis,
the stereoselectivity of such reactions can be well controlled by using stoichiometric
amounts of hydride reagents with different degrees of steric hindrance.57,58 Hence,
we envisioned that diastereodivergent hydrogenation of cyclohexanones could be
also realized by fine-tuning the steric bulk of the pincer NHC ligands used in the
Co-NHC catalytic system. To test the feasibility of the proposed approach, 4-tert-
butyl-cyclohexanone 1au was selected as a model substrate along with pincer
NHC ligands L1a–L1d, which bear increasingly bulky substituents. As expected,
the use of the bulkiest ligand L1d led to the formation of the kinetically favored prod-
uct cis-4-tert-butyl-cyclohexanol 2au in a cis/trans ratio of >99:1 (Table 4, entry 4).
Conversely, the thermodynamically favored trans-isomer was obtained in a trans/
cis ratio of 8:1 via the NHC precursor L1a, which bore a small substituted group
(Table 4, entry 1). As shown in Figure 4A, the bulky Co-H species preferred to
encounter less steric hindrance from the equatorial C=O face and avoid the repul-
sion from the axial substituents (hydrogens in this case) at the 3-positions. However,
the attack of the cobalt hydride species from the equatorial C=O face had to over-
come the ‘‘torsional effect’’ that arose from an eclipsing interaction in the transition
state. Therefore, less sterically hindered cobalt hydride species tended to attack
from the axial C=O face to deliver the trans-isomer, for which torsional rather than
8
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A
B
C
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and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
Figure 3. Hydrogenation of Ketones and Aldehydes with L1c-CoCl2 or Co-2a
Reaction conditions: (aromatic ketones) 1 mmol scale, 1 mol % [Co] (L1c:CoCl2 = 1:1), and 5 mol % tBuOK in 0.5 mL THF under 30 bar H2 at 60ꢀC for 16 h;
isolated yield. (Aliphatic ketones) 1 mmol scale, 1 mol % [Co] (Co-2a), and 5 mol % KOH in 0.5 mL THF under 30 bar H2 at 60ꢀC for 16 h. Isolated yields are
shown in parentheses.
a0.5 mmol scale.
b10 bar H2 at room temperature.
c15 bar H2 at room temperature.
d50 bar H2 at room temperature.
e50 bar H2 at 60ꢀC.
f3 mol % [Co], base 15 mol %.
g4 mol % [Co], base 20 mol %.
h7.5 mol % [Co], base 37.5 mol %.
i10 mol % [Co], base 50 mol %.
jRatio of cis/trans was determined by 1H NMR.
kYield was determined by gas chromatography (GC) analysis with biphenyl as the internal standard.
steric effects dominated. Similar results were also observed for the hydrogenation of
4-phenyl-cyclohexanone 1av with good stereoselectivity (Table 4, entries 5 and 8).
When C3- or C2-substituted cyclohexanones were employed as the substrates,
equally excellent selectivities were achieved in the presence of the bulky ligand
L1d according to the same steric control model (Table 4, entries 12 and 17). Notably,
an inverse configuration was obtained for the reaction of C3-substituted cyclohexa-
nones compared with that of C4- or C2-substituted cyclohexanones, despite both
undergoing the same equatorial attack (Table 4, entries 4, 12, and 17). However,
the products from the reactions with 3-tert-butyl-cyclohexanone 1aw and
2-phenyl–cyclohexanone 1ay displayed notably decreased stereoselectivity when
the less-hindered L1a was used (Table 4, entries 9 and 14). This might be attributed
to increased steric repulsion from the axial C=O face for C2- or C3-substituted cyclo-
hexanones than for C4-substituted cyclohexanones. For example, a hydrogen atom
of the tert-butyl group at C3-position stays along the direction of two axial hydrogen
Table 4. Stereoselective Hydrogenation of Substituted Cyclohexanones
O
OH
OH
[Co] (2-16 mol%), base (10-90 mol%)
THF, 16 h, 60 °C
+
H2 (50 atm)
+
R
R
R
R-CYC
(1au-1aaa)
cis-
(2au-2aaa)
trans-
(2au-2aaa)
Entry
R-CYC
LNHC
L1a
L1b
L1c
L1d
L1a
L1b
L1c
L1d
L1a
L1b
Yield (%)
95
cis:trans
1:8
Entry
11
12
13
14
15
16
17
18
19
–
R-CYC
LNHC
Yield (%)
cis:trans
1:99
1:99
5:1
1
2
R = 4-tBu(1au)
–
L1c
L1d
L1a
L1a
L1b
L1c
L1d
L1a
L1a
–
95a
93a
98b
95b
93
–
90
1:1
–
3
–
99b
98
3:1
R = 3-Me(1ax)
4
–
99:1
1:8
R = 2-Ph(1ay)
1:1
5
R = 4-Ph(1av)
99
–
3:1
6
–
82
1:1
–
99
99:1
99:1
1:2
7
–
98b
93
2:1
–
99
8
–
99:1
3:1
R = 2-Me(1az)
R = 2-tBu(1aaa)
–
94b
n.p.a
–
9
R = 3-tBu(1aw)
–
90a,b
93a
–
10
1:1
–
Reaction conditions: 0.5–1 mmol scale, 2–4 mol % [Co] (LNHC: CoCl2 = 1:1), and 10–20 mol % tBuOK in 2–4 mL THF under 50 bar H2 at 60ꢀC for 16 h. Total yield of
cis- and trans-products was determined by GC analysis with biphenyl as the internal standard. n.p., no product.
a16 mol % [Co], 90 mol % tBuOK.
bTotal isolated yield of cis- and trans-products.
10
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A
B
Figure 4. Stereocontrol Models for the Hydrogenation of Cyclohexanones
(A) C4-substituted cyclohexanones.
(B) C3- and C2-substituted cyclohexanones.
atoms at the C3-positions, which increases the steric hindrance of the axial C=O
face, thus inhibiting the axial attack that would deliver the cis-isomer (Figure 4B,
left). Therefore, the cis/trans ratio increased from 3:1 to 5:1 when the less sterically
hindered methyl group was introduced at the 3-position of cyclohexanone instead of
the tert-butyl group (Table 4, entry 13). With respect to the 2-phenylcyclohexanone
1ay (Figure 4B, right), the bulky phenyl group remained in the equatorial position,
resulting in extra hindrance to the axial C=O face. This increase of the steric bulk
of the substituted group at the 2-position decreased the trans/cis ratio of the hydro-
genated products—from 2:1 for 2-methyl-cyclohexanol 2az (Table 4, entry 18) to 1:1
for 2-phenylcyclohexanol 2ay (Table 4, entry 14). Surprisingly, further increasing
the bulkiness at cyclohexanone’s 2-position by introducing a tert-butyl group
completely prevented the transformation (Table 4, entry 19). These results revealed
the notable influence of the steric hindrance of ligands and substrates on the stereo-
selectivity of the hydrogenation of substituted cyclohexanones.
The utility of this developed methodology was further showcased by the synthesis of
cis-4-tertbutylcyclohexyl acetate (woody acetate) 3au, which is a valuable perfume
used in cosmetics (Scheme 4A). This two-step facile synthesis of woody acetate start-
ing with the hydrogenation of 4-tert-butylcyclohexanone 1au was highly efficient and
eventually produced the target cis product in an almost-quantitative yield. Moreover,
this reaction was also employed to prepare a key synthetic intermediate for mole-
cules of pharmaceutical and biological interest, cis-4-hydroxycyclohexanecarboxylic
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11

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and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
A
B
Scheme 4. Synthetic Applications
(A) Synthesis of woody acetate 3au.
(B) Synthesis of cis-4-hydroxycyclohexanecarboxylic acid 3aab.
acid 3aab59,60 More specifically, the stereoselective cobalt-catalyzed hydrogenation
of 4-cyclohexanonecarboxylic acid ethyl ester 1aab followed by the hydrolysis of the
ester group afforded the cis-product with a high efficiency (Scheme 4B).
Conclusions
We have demonstrated an accessible in situ NHC-Co catalytic system for the high-
efficiency hydrogenation of ketones and aldehydes. This catalytic system displays
a broad substrate scope, as shown by results with more than 50 ketones and alde-
hydes bearing a variety of functional groups and high yields obtained in most
cases. Notably, a high TON of 2,610 was achieved at room temperature with a
low catalyst loading of 0.01 mol %. Moreover, the catalytic system permits effec-
tive stereocontrol of the hydrogenation of cyclohexanone derivatives via fine-tun-
ing of the steric bulk of the NHC pincer ligands. This diastereodivergent hydroge-
nation protocol was successfully applied to the straightforward syntheses of
molecules that are valuable to the fragrance and pharmaceutical industries. In
addition, a well-defined and catalytically active bis(NHC)-Co complex (Co-2a)
and a mono-NHC-Co complex (Co-1) were successfully isolated from the precata-
lyst activation process, providing insights into the Co-catalyzed hydrogenation re-
action. In combination with the base and the N–H effects, the tridentate coordina-
tion model of the catalytically active species and the metal ligand cooperation
function are crucial to high catalytic performance of the in-situ-formed NHC-Co
catalytic system.
EXPERIMENTAL PROCEDURES
Full experimental procedures and characterization data are provided in the Supple-
mental Information (for single crystal structures, see Figures S6–S9; for characteriza-
tion data of ligands and products, see Figures S10–S32 and Figures S33–S154,
respectively; for determination of the stereoselectivity of substituted cyclohexanols,
see Figures S155–S172).
12
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and Aldehydes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.03.010
DATA AND SOFTWARE AVAILABILITY
Crystallographic data of complexes Co-1, Co-2a, 2am-cis, and 2am-trans have been
deposited in the Cambridge Crystallographic Data Center. Their CCDC numbers
are CCDC: 1875857, CCDC: 1875853, CCDC: 1898605, and CCDC: 1875856,
respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.03.010.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Program for the National
Natural Science Foundation of China (21822106), the China Postdoctoral Science
Foundation (2018M630138), the Foundation of the Department of Education of
Guangdong Province (2017KZDXM085), and the 111 project. We also thank Dr.
Xin He for helpful discussions on crystallographic data.
AUTHOR CONTRIBUTIONS
R.Z. and Z.W. contributed equally to this work. They discovered the reaction
together. R.Z. performed the optimization and mechanistic study. Z.W., W.Z., and
S.L. investigated the scope of the substrate. Q.L. directed the project and wrote
the manuscript with input from all authors. All authors analyzed the results and com-
mented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 25, 2018
Revised: January 28, 2019
Accepted: March 18, 2019
Published: April 11, 2019
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