Switchable β-alkylation of secondary alcohols with primary alcohols by a well-defined cobalt catalyst

Article abstract of DOI:10.1021/acs.organomet.1c00147

β-alkylation of secondary alcohols with primary alcohols to selectively generate alcohols by a well-defined Co catalyst is presented. Remarkably, a low catalyst loading of 0.7 mol % can be employed for the reaction. More significantly, this study represents the first Co-catalyzed switchable alcohol/ketone synthesis by simply manipulating the reaction parameters. In addition, the transformation is environmentally friendly, with water as the only byproduct.

Full text of DOI:10.1021/acs.organomet.1c00147

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Switchable β‑alkylation of Secondary Alcohols with Primary
Alcohols by a Well-Defined Cobalt Catalyst
Bedraj Pandey, Shi Xu, and Keying Ding*
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ABSTRACT: β-alkylation of secondary alcohols with primary
alcohols to selectively generate alcohols by a well-defined Co
catalyst is presented. Remarkably, a low catalyst loading of 0.7 mol
% can be employed for the reaction. More significantly, this study
represents the first Co-catalyzed switchable alcohol/ketone
synthesis by simply manipulating the reaction parameters. In
addition, the transformation is environmentally friendly, with water
as the only byproduct.
#x3b2;-alkylation of secondary alcohols is one of the
alkylation of secondary alcohols with primary alcohols to form
alcohols via the BH process, reported by Kempe and co-
workers.10 In their pioneering work, a Co complex supported
by a PN5P pincer ligand was successfully employed. Never-
theless, a very high catalyst loading of 5 mol % was mandatory.
We have recently developed a new P,N mixed iPrPPPNHPyMe
tetradentate ligand.15 Its Co complex A is an efficient catalyst
for dehydrogenation of secondary alcohols to ketones,15 ADC
of primary alcohols to esters,16 and switchable alcohol amine
couplings to imines or amines.17 We recently reported the first
example of Co-catalyzed β-alkylation of secondary alcohols
with primary alcohols to selectively form ketones.18
Encouraged by the findings from our prior work, we envision
that A could also be employed to achieve selective β-alkylated
alcohol formations by manipulating the reaction parameters.
Notably, the selectivity control of the products via BH or ADC,
i.e., alcohol versus ketones, is critical but is also a challenge for
the β-alkylation of secondary alcohols with primary alcohols.
Herein, we disclose a novel homogeneous Co catalytic
system for efficient and selective β-alkylation of secondary
alcohols to alcohols utilizing a significantly reduced Co catalyst
loading of as low as 0.7 mol %. We also discovered that a
switchable alcohol and ketone synthesis can be achieved by
simply tuning the reaction parameters, such as the base
loadings, with the same Co catalyst (Scheme 1), which to the
&
prominent synthetic methods for the construction of C−
C bonds.1 In the conventional β-alkylation of secondary
alcohols to form alcohols or ketones, several drawbacks exist:
stoichiometric oxidation, alkylation with toxic and mutagenic
alkyl halides, stoichiometric reduction, and multistep pro-
cesses, which inevitably generate copious wastes.2 Therefore, it
is appealing to explore new methods that are environmentally
benign, are atom- and process-efficient, and utilize less toxic
and abundantly available starting materials: e.g., alcohols. One
such promising synthetic method is borrowing hydrogen
(BH).3,4 In a normally accepted BH process to synthesize
alcohols, primary and secondary alcohols are first dehydro-
genated to aldehydes and ketones, respectively, with the
catalyst obtaining the hydrogen atoms. Next, a base and/or the
catalyst mediates the α-C−H activation of the ketones and
forms the nucleophilic carbon anions which attack the
electrophilic aldehydes, leading to the formation of the α,β-
unsaturated ketone intermediates with loss of water. Finally,
the hydrogenated catalyst reduces the in situ formed ketones to
the alcohol products. Alternatively, hydrogen gas can be
liberated from the hydrogenated catalyst with ketones as the
final products. This process is recognized as the acceptorless
dehydrogenative coupling (ADC).3,4 Both BH and ADC have
recently received increasing attention in both academia and
industry, as they can offer significant advantages over
conventional methods in terms of sustainability.
Currently, catalysts based on precious metals such as Rh,5
Ir,6 Ru,7 and Pd8 have dominated the field. It is more desirable
to replace precious metal catalysts with inexpensive, less toxic,
and earth-abundant base-metal surrogates, e.g. Fe,9 Co,10
Mn,11 Ni,12 and Cu,13 due to increasing concerns regarding
sustainability and economic issues.14 To the best of our
knowledge, there is only a single example of Co-catalyzed β-
Received: March 10, 2021
Published: April 28, 2021
https://doi.org/10.1021/acs.organomet.1c00147
© 2021 American Chemical Society
Organometallics 2021, 40, 1207−1212
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Communication
best of our knowledge, has not been reported for base-
transition-metal catalysis using Co, Fe, or Mn.19
for the reaction (Table 1, entries 5 and 7−11). It is noteworthy
that KOtBu, NaOtBu, and KHMDS led to comparable yields
(Table 1, entries 5, 7, and 8). Toluene and a temperature of
110 °C proved to be more suitable (Table 1, entries 5 and 12−
16). It is worth mentioning that, at a higher temperature of 120
°C, a diminished yield resulted with more unidentified side
products being observed (Table 1, entry 13). Pleasingly, a very
good 75% isolated yield resulted in the 1 mmol scale reaction
(Table 1, entry 5c). A mercury test indicated a homogeneous
reaction (Table 1, entry 5d).
Scheme 1. Switchable β-Alkylation of Secondary Alcohols
with Primary Alcohols Catalyzed by a Cobalt Complex
With the optimized reaction conditions on hand, we then
investigated the reaction scope in terms of the substrates. First,
the scope of the primary alcohols was explored in the
alkylation of 1-phenylethanol. To our delight, para-substituted
benzyl alcohols with electron-donating or -withdrawing groups
reacted smoothly (Table 2, 3b−h). Notably, this method was
also applicable to some challenging substrates such as those
bearing −Br or −CF3 functional groups (Table 2, 3g,h),
furnishing moderate to good yields. Meta-substituted sub-
strates delivered the corresponding alcohol products in
moderate to very good yields (Table 2, 3i−l). It is noteworthy
that the sterically hindered ortho-substituted 2-methylbenzyl
alcohol afforded a very good 85% yield (Table 2, 3m).
However, 2-fluorobenzyl alcohol only resulted in a 19% yield,
probably due to the coordination of the −F functionality to the
catalyst, diminishing its reactivity. Aliphatic primary alcohols
were amenable to this method as well (Table 2, 3r−t). Next, a
series of secondary alcohols were examined to couple benzyl
alcohol. Pleasingly, for aromatic secondary alcohols, −OMe,
−F, −CF3, and naphthalene functional groups were well
tolerated in this method (Table 2, 3u−z). Challenging
aliphatic secondary alcohols were alkylated with benzyl
alcohols leading to satisfactory yields, albeit under relatively
harsher conditions (Table 2, 3aa−ac). This is likely due to the
difficulty in the dehydrogenation of aliphatic secondary
alcohols.15 Notably, aliphatic secondary alcohols also coupled
with aliphatic primary alcohols by this method. 2-Hexanol
reacted with 1-hexanol, affording 5-dodecanol in a good 66%
yield. (Table 2, 3ad).
Next, we carried out a preliminary mechanistic study to
understand the reaction and elucidate the selectivity switching.
In our prior work, ketone is the major product via the ADC
process.18 It is rational to surmise that the selective alcohol
formation may originate from further reduction of the in situ
formed ketone. To examine this hypothesis, we performed the
transfer hydrogenation of 3-phenylpropiophenone (4a) with 3
equiv of 1a as the hydrogen source. We found that 80 mol % of
KOtBu alone can efficiently reduce 4a to 3a to furnish a 90%
yield, supporting a base-mediated Meerwein−Ponndorf−
Verley (MPV) pathway.20,21 However, a drastically lower
KOtBu loading of 2.5 mol % also leads to a 71% yield of 3a.18
An interesting question arises: why is excess base still required in
the alcohol synthesis by the β-alkylation of secondary alcohols with
primary alcohols?We then performed the same reaction in the
presence of 5 mol % of A and 90 mol % of KOtBu.22
Interestingly, a lower 78% yield of 3a was observed in
comparison to that with 80 mol % KOtBu alone, suggesting
that the Co species may have a negative effect on the
hydrogenation of 4a in the presence of excess base. As A has
been recognized to be an efficient precatalyst for the
dehydrogenation of secondary alcohols from our prior
work,15 the alcohol products could be dehydrogenated back
to the ketones. In addition, in the β-alkylation of secondary
At the outset, 1-phenylethanol (1a) and benzyl alcohol (2a)
were selected as the model substrates. Interestingly, it was
revealed that an excess amount of base (110 mol %) was
required for the selective formation of 1,3-diphenylpropan-1-ol
(3a) (Table 1, entries 1−4), which was in stark contrast to the
a b
,
Table 1. Optimization of the Reaction Conditions
base
A
entry
base
(mol %)
(mol %)
solvent
toluene
yield (%)
1
2
3
4
5
6
7
8
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
KHMDS
KOH
K2CO3
Cs2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
0
30
80
2.5
2.5
2.5
2.5
0.7
0
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
31
53
73
110
110
110
110
110
110
110
110
110
110
110
110
110
c
d
80, 75, 79
8
80
77
26
0
9
10
11
12
13
14
15
16
0
e
67
f
71
1,4-dioxane 12
THF
benzene
5
68
a
Reaction conditions unless specified otherwise: 1-phenylethan-1-ol
(0.375 mmol), benzyl alcohol (0.25 mmol), A, base, and solvent (1.5
mL) were heated in a closed 15 mL reaction tube for 24 h under N2.
b
NMR yield using 1,3,5-trimethoxybenzene as internal standard.
c
d
Isolated yield on a 1 mmol scale. Mercury (125 mg) was added to
e
f
the reaction mixture. 100 °C. 120 °C.
ketone case, where only a catalytic amount of base (7.5 mol %)
was used.18 Both A and base are essential for this trans-
formation (Table 1, entries 1 and 6). Significantly, only 0.7
mol % of A was sufficient to mediate the alcohol-forming
reaction (Table 1, entry 5). The ketone side product 3-
phenylpropiophenone (4a) was detected with only 8% yield.
To our surprise, a slightly lower yield (73%) resulted using 2.5
mol % of A, concurrent with the generation of unknown side
products (Table 1, entry 4). Strong bases are more appropriate
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Communication
a b
,
Table 2. β-Alkylation of Secondary Alcohols with Primary Alcohols to Selectively Form Alcohols
a
Reaction conditions unless specified otherwise: secondary alcohols (0.375 mmol), primary alcohols (0.25 mmol), A (0.7 mol %), KOtBu (110 mol
b
%), and toluene (1.5 mL) were heated at 110 °C in a closed 15 mL reaction tube for 24 h under N2. NMR yield using 1,3,5-trimethoxybenzene as
c
d
e
f
internal standard. NaOtBu (110 mol %). 48 h. A (7.5 mol %), KOtBu (55 mol %), 125 °C. A (7.5 mol %), 125 °C.
alcohols to form alcohols, a higher A loading results in a lower
yield with more unidentified side products being generated
(Table 1, entries 4 and 5). To counter these competitive and
undesirable reactions mediated by the Co species, excess base
is required to enhance the MPV process. In contrast, with
regard to the selective ketone formation, a higher A loading
(2.5 mol %), a catalytic amount of base (7.5 mol %), and an
open system are more feasible to circumvent the MPV reaction
and promote the dehydrogenation of alcohols. Note that the
base is still needed for the Co precatalyst activation, the aldol
condensation of the in situ formed aldehydes and ketones, and
the reduction of the α,β-unsaturated ketone intermediates to
the ketone products.18 Very recently, we have presented a
switchable imine and amine synthesis catalyzed by A, where
the base loading also plays a critical role.17 Overall, these
results demonstrate the high versatility of our Co catalytic
system in control of the products in these transformations.
Finally, two exemplary derivatives of A were investigated
(Figure 1). Complex B, featuring a dearomatized pyridine ring,
showed activity comparable to that of A, resulting in a 76%
yield, demonstrating that B is also an efficient precatalyst. It is
noteworthy that C bearing an N−Me linker rather than the
N−H linker on A leads to a comparable yield of 74%,
suggesting that metal ligand cooperativity (MLC) that could
originate from the N−H linker on A may not play a critical role
in this reaction.
Considering our experimental findings18 and the litera-
ture,3,4 we propose a plausible mechanism for the switchable
alcohol/ketone formations (Scheme 2). Initially, primary and
secondary alcohols are dehydrogenated by the Co catalyst to
the corresponding aldehydes and ketones, respectively, which
a
Scheme 2. Proposed Mechanism
a
Figure 1. Complexes B and C examined.
Red for the ketone formation and blue for the alcohol formation.
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are further reduced, furnishing alcohols as the final products.
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unsaturated ketones could be directly reduced to the alcohols.
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underway in our laboratory.
In conclusion, we have presented a well-defined Co catalyst
for the β-alkylation of secondary alcohols with primary
alcohols to selectively form alcohols using a remarkably low
catalyst loading of 0.7 mol %. Our study provides an alternative
solution for the switchable synthesis of alcohols and ketones,
which is environmentally benign and atom- and process-
efficient. We expect this work will contribute to advanced
catalyst design with base transition metals for selective and
sustainable chemical transformations.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental details and NMR spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Keying Ding − Department of Chemistry, Middle Tennessee
State University, Murfreesboro, Tennessee 37132, United
States; Molecular Biosciences Program, Middle Tennessee
State University, Murfreesboro, Tennessee 37132, United
States; orcid.org/0000-0002-7367-129X;
Email: Keying.Ding@mtsu.edu
Authors
Bedraj Pandey − Department of Chemistry, Middle Tennessee
State University, Murfreesboro, Tennessee 37132, United
States
Shi Xu − Department of Chemistry, Middle Tennessee State
University, Murfreesboro, Tennessee 37132, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00147
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge support from the National Science
Foundation (CHE-1465051 and MRI CHE-1626549). We
also thank FRCAC, URECA, and the Clean Energy Fee Funds
of MTSU for support.
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Organometallics
pubs.acs.org/Organometallics
Communication
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