Cobalt-Catalyzed Acceptorless Dehydrogenative Coupling of Primary Alcohols to Esters

Article abstract of DOI:10.1021/acs.orglett.8b01775

A novel catalytic system with a tripodal cobalt complex is developed for efficiently converting primary alcohols to esters. KO^tBu is found essential to the transformation. A preliminary mechanistic study suggests a plausible reaction route that involves an initial Co-catalyzed dehydrogenation of alcohol to aldehyde, followed by a Tishchenko-type pathway to ester mediated by KO^tBu.

Full text of DOI:10.1021/acs.orglett.8b01775

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Acceptorless Dehydrogenative Coupling of
Primary Alcohols to Esters
Keshav Paudel,†,‡,§ Bedraj Pandey,†,§ Shi Xu,†,§ Daniela K. Taylor,† David L. Tyer,†
Claudia Lopez Torres,† Sky Gallagher,† Lin Kong,† and 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
S
* Supporting Information
ABSTRACT: A novel catalytic system with a tripodal cobalt
complex is developed for efficiently converting primary
alcohols to esters. KOtBu is found essential to the trans-
formation. A preliminary mechanistic study suggests a
plausible reaction route that involves an initial Co-catalyzed
dehydrogenation of alcohol to aldehyde, followed by a Tishchenko-type pathway to ester mediated by KOtBu.
sters are a family of compounds that are common in
the pyridine ring and the phosphine moieties.11 It has been
Eorganic chemistry and have found ubiquitous applications demonstrated that the air-stable cobalt complex 1a supported
in the chemical, fragrance, and flavor industries.1,2 Conven-
tional ester production methods include esterification of
carboxylic acids with alcohols, alcoholysis of acyl chlorides
by this new ligand can mediate dehydrogenation of secondary
alcohols to ketones.11 Herein, we describe a catalytic system
involving 1a and KOtBu that can efficiently mediate accept-
orless dehydrogenative homocoupling of primary alcohols to
esters (Scheme 1). Although examples of cobalt-catalyzed
and acid anhydrides, carbonylation of alkenes with alcohols,
transesterification, etc.1,2 Despite these established methods,
acceptorless oxidant-free dehydrogenative coupling of alcohols
is an atom-economical and environmentally benign method for
the synthesis of carbonyl compounds and their derivatives with
hydrogen gas as the only byproduct.3 This method takes
advantage of inexpensive and readily available alcohols that can
be obtained from biomass resources and fermentation.
Homogeneous dehydrogenative coupling of primary alcohols
to esters have been extensively studied with rare and expensive
precious metal catalysts such as Ru,4 Os,5 and Ir.6 With
increasing concerns regarding the environment and costs,
replacing precious metal catalysts with ones based on
inexpensive, less toxic, and earth-abundant first row transition
metals is very desirable and attractive, and it represents one of
the most important directions of modern organometallic
chemistry. However, such a transformation mediated by base
metal catalysts is still a challenge, and examples are limited.
Jones, Schneider and co-workers reported highly efficient PNP
pincer ligand supported iron catalysts for dehydrogenation of
primary alcohols to esters.7 Jones and co-workers developed a
TP′Ni(QR) (Tp′ = tris(3,5-dimethylpyrazolyl)borate, Q =
quinolinate, R = CF3) catalyst for dehydrogenative coupling of
benzyl alcohol to benzyl benzoate.8 Bernskoetter, Hazari,
Holthausen, and co-workers presented methanol dehydrogen-
ation to methyl formate by a PNP pincer stabilized iron
complex.9 Recently, Gauvin demonstrated the MnPNP
complex-catalyzed dehydrogenation of primary alcohols to
esters.10
Scheme 1. 1a/KOtBu-Catalyzed Dehydrogenative Coupling
of Primary Alcohols
dehydrogenation and dehydrogenative coupling reactions are
available,12 a systematic study on homogeneous cobalt catalysts
for acceptorless dehydrogenative coupling of primary alcohols
into esters has not been reported. In addition, this work
represents the first example of base transition metal complexes
supported by a tetradentate tripodal ligand that can efficiently
catalyze such a transformation.
Dehydrogenative homocoupling of benzyl alcohol to afford
benzyl benzoate (2) is set as the model reaction for
optimization. At 105 °C, when the reaction was carried out
in a closed system under N2, a yield of 37% resulted (Table 1,
entry 1). An improved yield of 46% was observed in an open
system under argon flow (Table 1, entry 1). When the
temperature was raised to 125 °C with an open system, an
We have recently developed a novel iPrPPPNHPyMe
tetradentate tripodal ligand that featured metal−ligand
cooperativity (MLC) by introducing a N−H linker connecting
Received: June 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01775
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
disubstituted aromatic primary alcohols give 73−89% yields
(Table 2, entries 18−22). Significantly, alkyl primary alcohols
also furnished the reactions with good to excellent yields
(Table 2, entries 23−30), albeit an increased catalyst loading
or a higher reaction temperature (140 °C) was required.
Lastly, diols such as benzene-1,2-dimethanol and 1,4-
butanediol successfully afforded the desired lactones (Table
2, entries 31 and 32).
We then performed a preliminary mechanistic study to
understand the catalyst activation process and reaction
mechanism. Complex (iPrPPPNPyMe)CoCl 1b (Figure 1),
synthesized by reacting 1a with KOtBu,11 showed comparable
activity as 1a in the presence of 2 equiv of KOtBu (Table S1,
Supporting Information (SI)), indicating that 1b is likely
involved in the generation of the actual catalyst via
dehydrohalogenation of 1a by the base. To explore the
possible roles of metal−ligand cooperativity (MLC) originated
from the N−H linker in 1a, a N−Me substituted complex
[(iPrPPPNMePyMe)CoCl]OTf 1c (Figure 1) was synthesized.11
Interestingly, a 92% benzyl benzoate yield was observed using
1c as catalyst, which is close to those of 1a and 1b. These
results suggest that the N−H linker may not play a significant
role in this transformation.
Table 1. Screening of Reaction Conditions on
Dehydrogenative Coupling of Benzyl Alcohol
a
b
entry
cat.
base
solvent
temp (°C)
yield (%)
c
d
1
2
3
4
5
6
7
8
9
10
1a
1a

1a
1a
1a
1a
1a
1a
1a
KOtBu
KOtBu
KOtBu

benzene
benzene
benzene
benzene
toluene
THF
1,4-dioxane
benzene
benzene
benzene
105
125
125
125
125
125
125
125
125
125
37, 46
d
e
93, >99, 91
0
0
KOtBu
KOtBu
KOtBu
NaOtBu
KOH
61
58
42
92
44
0
K2CO3
a
Reaction conditions: alcohol (0.5 mmol), 1a (1.25 mol %), KOtBu
(3.75 mol %), and solvent (0.7 mL) were heated in a 15 mL reaction
b
tube with an argon balloon on top for 24 h. Yield was determined by
c
d
1H NMR. Reaction was run in a 100 mL pressure vessel. Reaction
was run in a 15 mL reaction tube under continuous argon flow.
e
To investigate the roles of KOtBu, reaction conditions with
various ratios of 1b and base were examined (Table S1, SI).
No ester was formed without KOtBu. Interestingly, when 1
equiv of KOtBu was used (1.25 mol %), only a 4% ester yield
was obtained. Since the amount of KOtBu is only sufficient in
activating the cobalt precatalyst,11 the generated Co active
species may not be responsible for some essential step(s)
toward ester formation. However, with further increasing
KOtBu loadings to 2.5 mol %, the ester yield was significantly
enhanced (88%), demonstrating another essential role of
KOtBu besides precatalyst activation. Small quantities of
aldehydes were detected as typical byproducts. We observed
that KOtBu alone can efficiently mediate the Tishchenko
reaction coupling aldehydes to esters at room temperature (see
SI) as also reported by Berke and co-workers.14 Interestingly,
in the presence of 1 equiv of alcohol with respect to aldehyde,
only a trace amount of ester was formed, indicating alcohol can
be detrimental to the Tishchenko reaction (see SI). This is in
contrast to the Ru alkoxide system for dehydrogenative alcohol
coupling reported by Gauvin et al., where the alcohol does not
show such adverse effects and a Tishchenko pathway is
therefore proposed.4j However, when the temperature was
raised to 125 °C, an improved 67% ester yield was obtained,
suggesting the feasibility of the Tishchenko route (see SI). On
the other hand, Beller et al. demonstrated that aldehyde (1
equiv with respect to alcohol) completely “poisons” the Ru
catalyst in the dehydrogenative coupling of ethanol to ethyl
acetate and a mechanism involving dehydrogenation of free or
deprotonated hemiacetal by the Ru complex is proposed.4e
However, for our Co/KOtBu system, a 61% yield of 2 resulted
in the presence of equal amounts of benzyl alcohol and
benzaldehyde,15 indicating less deleterious effects of aldehydes
on the Co catalyst. This is further supported by the
observations that equal amounts of 4-fluoro benzyl alcohol
and benzyldehyde led to a set of four esters from homo- and
cross-couplings, and benzyl alcohol was formed as a result of
hydrogen transfer (see SI). In light of the preceding
experimental evidence, we envision a plausible route that
involves an initial Co-catalyzed dehydrogenation of alcohol to
aldehyde, followed by a Tishchenko-type pathway mediated by
Isolated yield (1 mmol scale).
excellent yield of 93% was achieved, but tremendous solvent
loss was observed (Table 1, entry 2). Pleasingly, carrying out
the reaction in a reaction tube with an argon balloon on top
resulted in a full conversion of benzyl alcohol to benzyl
benzoate (Table 1, entry 2). Control experiments showed that,
in the absence of 1a, no benzyl benzoate was produced (Table
1, entry 3). A base is also essential for the reaction, as no ester
was generated without a base (Table 1, entry 4). With toluene,
THF, or 1,4-dioxane as solvents, diminished yields were
observed (Table 1, entries 5 to 7). KOtBu and NaOtBu are
more efficient than KOH and K2CO3 (Table 1, entries 8 to
10). It is worth mentioning that only a trace amount of benzoic
acid tert-butyl ester was formed, probably from dehydrogen-
ative coupling of benzyl alcohol and KOtBu.
With the optimized conditions in hand (Table 1, entry 2),
we explored the substrate scope of the ester formation
reaction. Aromatic primary alcohols with electron-donating
groups such as −OMe, −Me, and −iPr at the para position
reacted smoothly to afford the corresponding esters in 79−
90% isolated yields (Table 2, entries 1−3). Notably, substrates
with electron-withdrawing groups at the para positions
presented outstanding activities, with nearly full conversions
to the desired esters (Table 2, entries 4−6). In addition, most
meta-substituted substrates were transformed to corresponding
esters well (Table 2, entries 7−11). Sterically hindered
substrates such as 2-methyl benzyl alcohol and 1-naphthalene-
methanol exhibited diminished yields (Table 2, entries 12 and
13). By comparison, 2-naphthalenemethanol afforded the
desired ester in 91% yield (Table 2, entry 14). A reaction
with 2-fluorobenzyl alcohol or 2-furfuryl alcohol showed no
product at all (Table 2, entries 15 and 16). It is postulated that
an electron donor (F or O) at the ortho position might
coordinate with the cobalt complex in the reaction, thus
deactivating the catalyst. Our previous study on nickel-
catalyzed aldehyde decarbonylation showed a comparable
result that ortho substituents significantly suppressed the
Tishchenko reaction of coupling aromatic aldehydes to
esters.13 We were delighted to find that a number of
B
DOI: 10.1021/acs.orglett.8b01775
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Letter
a b
,
Table 2. Dehydrogenative Coupling of Primary Alcohols Catalyzed by Cobalt and KOtBu
a
Reaction conditions: alcohol (0.5 mmol), 1a (1.25 mol %), KOtBu (3.75 mol %), benzene (0.7 mL) were heated in 15 mL reaction tube with
b
argon balloon on top at 125 °C for 24 h. Yield was determined by 1H NMR with nitromethane as internal standard. Isolated yield is in bracket.
c
d
e
Yield was determined by GC. Reaction was run with 1a (2.5 mol %) and KOtBu (7.5 mol %) at 125 °C for 24 h. Reaction was run in toluene
f
(0.7 mL) with 1a (2.5 mol %) and KOtBu (7.5 mol %) at 140 °C for 24 h. Reaction was run in THF (0.7 mL) with 1a (2.5 mol %) and KOtBu
(7.5 mol %) at 125 °C for 24 h.
In conclusion, a novel catalytic system involving a cobalt
complex supported by a tetradentate tripodal ligand and a base
was reported to efficiently transform primary alcohols to esters
via a plausible dehydrogenation and Tishchenko-type pathway.
We expect that this study will contribute to green catalysis and
advanced catalyst design with earth-abundant transition metals.
Figure 1. 1a derivatives (1b and 1c) examined for dehydrogenative
coupling of primary alcohols.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01775.
the base. However, we cannot completely exclude a concurrent
pathway in which a base might also facilitate the generation of
hemiacetal species,4e which are then dehydrogenated by the
Co catalyst to give the final ester products. A comprehensive
mechanistic investigation is currently underway in our
laboratory.
Generation of a H2 byproduct was confirmed by GC analysis
of the headspace gas after the reaction (see Figure S1, SI). To
examine whether the catalysis is homogeneous or heteroge-
neous, we carried out a mercury test (100 equiv with respect to
1b) and noticed no detrimental effect on the reactivity (93%
yield, see SI), suggesting a homogeneous catalytic system.
Experimental details, additional figures, and other results
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: keying.ding@MTSU.edu.
ORCID
Keying Ding: 0000-0002-7367-129X
C
DOI: 10.1021/acs.orglett.8b01775
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Yield was calculated by considering both benzyl alcohol and
benzaldehyde as substrates.
Author Contributions
§K.P., B.P., and S.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by National Science Foundation (NSF-
RUI, CHE-1465051). We thank support from FRCAC,
URECA, and Clean Energy Fee Funds of MTSU.
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Org. Lett. XXXX, XXX, XXX−XXX