Atom- and Step-Economical Ruthenium-Catalyzed Synthesis of Esters from Aldehydes or Ketones and Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.8b03375

We developed a ruthenium-catalyzed reductive ester synthesis from aldehydes or ketones and carboxylic acids using carbon monoxide as a deoxygenative agent. Multiple factors influencing the outcome of the reaction were investigated. Best results were obtained for commercially available and inexpensive benzene ruthenium chloride; as low as 0.5 mol % of the catalyst is sufficient for efficient reaction. Competitive studies demonstrated that the presence of even 1000 equiv of alcohol in the reaction mixture does not lead to the corresponding ester, which clearly indicates that the process is not a simple reductive esterification but a novel type of Ru-catalyzed redox process.

Full text of DOI:10.1021/acs.orglett.8b03375

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Atom- and Step-Economical Ruthenium-Catalyzed Synthesis of
Esters from Aldehydes or Ketones and Carboxylic Acids
Sofiya A. Runikhina,† Dmitry L. Usanov,‡ Alexander O. Chizhov,§ and Denis Chusov*,†
†Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, Vavilova St. 28, Moscow 119991,
Russian Federation
‡Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
§N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, Moscow 119991, Russian
Federation
S
* Supporting Information
ABSTRACT: We developed a ruthenium-catalyzed reductive ester
synthesis from aldehydes or ketones and carboxylic acids using carbon
monoxide as a deoxygenative agent. Multiple factors influencing the
outcome of the reaction were investigated. Best results were obtained
for commercially available and inexpensive benzene ruthenium
chloride; as low as 0.5 mol % of the catalyst is sufficient for efficient
reaction. Competitive studies demonstrated that the presence of even
1000 equiv of alcohol in the reaction mixture does not lead to the
corresponding ester, which clearly indicates that the process is not a
simple reductive esterification but a novel type of Ru-catalyzed redox process.
sters represent an irreplaceable class of chemicals, which
Eare widely used in natural products, pharmaceuticals,
agrochemicals, fragrances, and food additives.1 Traditional
synthesis of esters involves the reaction of alcohols with
carboxylic acids or, more frequently, with activated carboxylic
acid derivatives. The latter approach often suffers from
stoichiometric and superstoichiometric amounts of waste,
which rapidly become highly problematic with the increase of
the reaction scale. In light of the wide accessibility and
synthetic importance of aldehydes, in many cases the
alternative synthetic approach to esters from carboxylic acids
and aldehydes can be more convenient as well as step- and
atom-economical.2 Furthermore, from a sustainability point of
view, it is highly desirable to develop new methodologies that
are capable of utilizing industrial byproducts as components of
chemical synthesis. In this regard, we have been interested in
the synthetic use of the deoxygenative potential of carbon
monoxide,3 a multimillion-ton byproduct of several major
industrial processes (e.g., steel making).4 Herein, we report
expansion of this paradigm to a new type of chemistry, namely,
atom- and step-economical synthesis of esters from aldehydes
or ketones and carboxylic acids.
We studied several potential catalysts for the model reaction
of reductive ester synthesis from naphthaldehyde with acetic
acid in the presence of carbon monoxide (Figure 1 and Table
1). Ruthenium(III) complex 1 with six strong ligands led only
to trace amounts of the product (Table 1, entry 1), and the
same was observed for ruthenium(II) cyclohexadienyl complex
2 (Table 1, entry 2). However, cyclopentadienyl ruthenium(II)
complex 3 with a labile arene ligand did lead to the desired
ester with 7% yield (Table 1, entry 3). Surprisingly, one of the
Figure 1. Ruthenium precatalysts.
best catalysts in hydrogen-transfer processes (Shvo catalyst,5
4) showed similar activity (Table 1, entry 4). Complexes 1−4
were outperformed by simple ruthenium chloride, which
furnished the product with almost 3-fold higher yield (Table 1,
entry 5). The best activity was observed for ruthenium(II)
complexes with chlorides and labile ligands such as cyclo-
octadiene, benzene, and p-cymene (Table 1, entries 6−8).
The optimum temperature was found to be in the range of
140−160 °C (see the Supporting Information); however, the
reaction can be run under much milder conditions with
Received: October 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Catalyst Effect on the Reductive Ester Synthesis of
Naphthaldehyde with Acetic Acid Using Carbon Monoxide
as a Reducing Agent
a
b
entry
catalyst
temperature (°C)
pressure (bar)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
150
150
150
150
150
150
150
150
160
150
140
130
120
150
150
150
30
30
30
30
30
30
30
30
30
30
30
30
30
10
5
trace
trace
7
10
27
41
44
47
64
72
67
39
21
70
70
58
RuCl3
5
6
7
6
6
6
6
6
6
6
6
c
c
c
c
c
13
14
15
16
c
c
c
2
a
0.3 mmol scale; 10 equiv of acetic acid and 5 equiv of water were
b
c
used. Yields were determined by NMR. THF was used as a solvent.
Scheme 1. Reductive Ester Synthesis versus Classical
Esterification
Table 2. Influence of Water on the Reaction Efficiency
Figure 2. Substrate scope. The reactions were conducted under 30
atm CO at 150 °C for 22 h. Yields were determined by NMR. Isolated
a
b
yields are shown in parentheses. 180 °C. 1 mol % of 6 was used.
a
b
entry
R
pressure (bar)
water (equiv)
yield (%)
Scheme 2. Experiment with an Isotopically Labeled
Substrate
1
2
3
4
5
6
7
8
1-naphthyl
1-naphthyl
o-chloro
o-chloro
o-chloro
o-chloro
o-chloro
o-chloro
o-chloro
p-chloro
p-chloro
2,5-dimethyl
2,5-dimethyl
o-fluoro
2.6
2.6
2.6
2.6
2.6
2.6
2.6
30
30
30
30
30
7.13
0.13
10.13
7.13
5.13
3.13
2.13
7.13
0.13
7.13
0.13
7.13
0.13
7.13
0.13
58
57
76
76
62
43
38
71
73
74
85
75
16
67
27
9
10
11
12
13
14
15
increased catalyst loading or reaction time. Surprisingly, the
influence of the pressure was not critical: the reaction can
proceed even in Schlenk tubes under 2 bar pressure (see the
Supporting Information).
Interestingly, the reaction in alcoholic media did not lead to
the esterification of acetic acid with the solvent despite the
1000-fold excess thereof (Scheme 1), which clearly implies that
the process involves more advanced ruthenium catalysis than
simple water gas shift reduction6 of the aldehyde with
subsequent esterification. This was corroborated by the fact
30
30
30
o-fluoro
a
b
0.3 mmol scale; 10 equiv of acetic acid was used. Yields were
determined by NMR.
B
DOI: 10.1021/acs.orglett.8b03375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have found a new type of reaction, namely,
reductive ester synthesis from carboxylic acids and aldehydes
or ketones. The methodology takes advantage of the unique
deoxygenative potential of carbon monoxide, which renders
the methodology more atom-economical and less wasteful in
comparison to the existing synthetic alternatives. A cross-
esterification product was not observed even in the presence of
1000 equiv of competing alcohol, which indicates that the
process involves more advanced ruthenium catalysis than
simple water gas shift reduction6 of the aldehyde with
subsequent esterification. The catalytic mechanism apparently
depends not only on the catalyst and reaction conditions but
also on the substrate nature.
Scheme 3. Putative Mechanistic Scheme for the Developed
Catalytic Process
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.8b03375.
Experimental section and spectra of obtained com-
pounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chusov@ineos.ac.ru, denis.chusov@gmail.com.
ORCID
that the presence of water did not have an effect on the model
reactions of acetic acid with 1-naphthaldehyde or o-
chlorobenzaldehyde respectively (see Table 2 and the
Supporting Information). It is noteworthy, however, that at
lower pressure the reaction with o-chlorobenzaldehyde was
accelerated in the presence of water; this phenomenon was not
observed for 1-naphthaldehyde. For ortho-fluoro and 2,5-
dimethyl benzaldehydes, water increases the reaction rate even
at 30 bar pressure. We believe that the reaction mechanism
might therefore be substrate-dependent.
Denis Chusov: 0000-0001-6770-5484
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by the Russian Science
Foundation (Grant No. 16-13-10393). We thank Dr. Dmitry
Pripadchev for his help with the isotope experiment. The
contribution of the Center for Molecule Composition Studies
of INEOS RAS is gratefully acknowledged.
With the optimized conditions in hand, we proceeded to
identification of the substrate scope (Figure 2). Good yields
were observed for all the tested substrates with various
substitution patterns (1a−1p). Product 1k, a derivative of
levulinic acid, is particularly notable in light of the intense
ongoing research on the production of platform chemicals
from biomass via levulinic acid.7 We successfully used this
substrate not only in a cross-reaction but also in an
intramolecular transformation leading to γ-valerolactone 1o,
which is a highly valuable chemical intermediate8 and a “green
fuel” candidate with a demand for environmentally friendly,
step-economical, and cost-effective preparation methods. In an
interesting dichotomy for the ketone moiety, it can stay
untouched or it can react with an acid to give the product by
simply changing the reaction temperature (1o versus 1k).
We synthesized 18O-p-chlorobenzaldehyde and tried it in the
reaction with acetic acid (Scheme 2). No 18O isotope was
found in the reaction product (see the Supporting
Information). On the basis of this observation together with
the fact that 1000-fold excess of the butanol did not compete
with the main reaction (Scheme 1), we propose the putative
catalytic cycle shown in Scheme 3. The catalytic species might
insert into an activated C−OH bond of the hemiacetal or
hemiketal intermediate to provide hydroxo-complex A. Intra-
molecular hydroxylation of the Ru-bound CO then leads to
intermediate B. Its decarboxylation gives Ru-hydride species C,
which, upon reductive elimination, leads to the ester product
and regenerated catalyst.
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DOI: 10.1021/acs.orglett.8b03375
Org. Lett. XXXX, XXX, XXX−XXX