Organocatalyzed anodic oxidation of aldehydes to thioesters

Article abstract of DOI:10.1021/ol500459x

A method has been developed for the direct conversion of aldehydes to thioesters via integration of organocatalysis and electrosynthesis. The thiazolium precatalyst was found to facilitate oxidation of thiolate anions, leading to deleterious formation of disulfide byproducts. By circumventing this competing reaction, thioesters were obtained in good-to-excellent yields for a broad range of aldehyde and thiol substrates. This approach provides an atom-efficient thioesterification that circumvents the need for stoichiometric exogenous oxidants, high cell potentials, or redox mediators.

Full text of DOI:10.1021/ol500459x

Letter
pubs.acs.org/OrgLett
Organocatalyzed Anodic Oxidation of Aldehydes to Thioesters
Kelli A. Ogawa and Andrew J. Boydston*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: A method has been developed for the direct conversion of aldehydes
to thioesters via integration of organocatalysis and electrosynthesis. The thiazolium
precatalyst was found to facilitate oxidation of thiolate anions, leading to deleterious
formation of disulfide byproducts. By circumventing this competing reaction,
thioesters were obtained in good-to-excellent yields for a broad range of aldehyde and
thiol substrates. This approach provides an atom-efficient thioesterification that
circumvents the need for stoichiometric exogenous oxidants, high cell potentials, or
redox mediators.
Scheme 1. Representative Methods for Conversion of
xidative transformations of aldehydes are excellent
Omethods for efficient functional group interconversion,
and organocatalyzed methods using N-heterocyclic carbenes
(NHCs) in particular have received considerable attention.1 In
general, NHCs facilitate aldehyde oxidations via nucleophilic
attack on the aldehyde to ultimately give an electron-rich
Breslow intermediate2 or pseudobenzylic alcohol. These
intermediates are readily oxidized to give an electrophilic acyl
azolium species capable of acyl transfer to various nucleophiles.
Although direct aldehyde-to-ester conversions have received
the greatest focus,3 access to a range of other functional groups
have also been reported.4 Among them, direct thioesterifcation
of aldehydes has received relatively little attention, which is
unfortunate considering the importance of thioesters as
synthetic intermediates and biologically active compounds.5,6
Herein, we describe the development of a direct aldehyde-to-
thioester synthesis via organocatalyzed anodic oxidation of
aldehydes that circumvents the need for stoichiometric
oxidants, high electrochemical cell potentials, or redox
mediators.
Aldehydes to Thioesters Using NHC Catalysts and
Stoichiometric Oxidants, in Comparison with the Present
Work
Despite the superficial similarities with the more familiar
NHC-catalyzed oxidative esterification of aldehydes, thioester
formation poses unique challenges due to the potentially
deleterious formation of disulfides. This not only consumes the
thiol coupling partner but also may lead to rapid irreversible
sulfenylation of NHC catalysts, as reported by Rastetter.7 While
Yadav recently reported the successful use of diaryl disulfides in
NHC-catalyzed aldehyde thioesterifications (Scheme 1); it is
unclear if moderate-to-good yields are attainable with lower
than 30 mol % catalyst loadings.5d The delicate reactivity of
thiols and thiolates signifies the importance of selecting a
compatible oxidant. This task was highlighted in the report by
Takemoto, in which phenazine emerged as an optimal
stoichiometric oxidant after screening several candidates
(Scheme 1).5c Notably, each reported general method for
NHC-catalyzed aldehyde thioesterification requires a stoichio-
metric exogenous oxidant. This reduces overall efficiency, can
limit chemoselectivity, and may give deleterious byproducts
(e.g., hydrazides are produced from hydrazobenzenes when
azobenzene is used as an oxidant).5f
We recently demonstrated a highly atom-efficient method of
NHC-catalyzed oxidative esterification via integration of
organocatalysis and electrosynthesis.8−11 This approach enables
one-pot oxidative couplings without the need for stoichiometric
oxidants, which we speculated would provide an improved
method of thioester synthesis. The catalytic cycle (Figure 1)
involves in situ deprotonation of a thiazolium precatalyst (A) to
give the active NHC catalyst B. Reaction of the NHC with
aldehyde substrates leads to an equilibrium mixture strongly
favoring the addition adduct C over the electroactive Breslow
intermediate D.12 While oxidations of (pseudo)benzylic
alcohols such as C have been demonstrated,1b the oxidation
Received: February 12, 2014
Published: March 14, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Investigation into Disulfide Formation
additive, base
MSBu ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ BuSSBu
CD3CN, rt, 2 h
b
entry
additive
MSBu
base
% BuSSBu
1
2
3
4
5
6
7
A-Mes
none
HSBu
HSBu
HSBu
NaSBu
NaSBu
HSBu
HSBu
none
0
0
DBU
DBU
none
A-Mes
none
25
0
A-Mes
none
none
15
0
DMAP
DMAP
A-Mes
4
a
Reactions conducted at rt in a screw cap NMR tube under N2 with
0.150 M A-Mes (as indicated), 0.150 M MSBu, and 0.150 M base in
b
CD3CN. Determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as the internal standard.
Figure 1. Proposed catalytic cycle for NHC-catalyzed anodic oxidation
of aldehydes to thioesters.
Table 2. Base Screen for NHC-Catalyzed Anodic Oxidation
of Aldehydes to Thioesters
a
potentials measured via cyclic voltammetry and used herein for
potentiostatic oxidation are consistent with oxidation of the
Breslow intermediate D.8,13,14 The irreversible anodic oxidation
of D provides acyl thiazolium species E, which is intercepted by
the thiol substrate to give the thioester product F and
regenerate the active catalyst B. Notably, oxidations at the
anode are balanced by the formation of H2 gas at the cathode.
We began our attempts at direct thioesterification by
applying the conditions we previously developed for
esterifications.8 Specifically, reactions were conducted in an
undivided cell using a graphite anode and Pt basket cathode,
with DBU and CH3CN as the base and solvent, respectively.
After screening a series of azolium precatalysts, we found 4-
methyl-3-(2,4,6-trimethylphenyl)thiazolium tetrafluoroborate
(A-Mes) and 4-methyl-3-(2,6-diisopropylphenyl)thiazolium
tetrafluoroborate (A-DiPP) to be most effective (see
Supporting Information). Unfortunately, these conditions
gave only a 26% yield of thioester when p-tolualdehyde and
butanethiol were used in the initial screenings.
Analysis of the reaction mixture revealed that the remainder
of the butanethiol had been oxidized to the corresponding
disulfide. We speculated that electrochemical oxidation of either
the thiol or thiolate anion was a likely cause. Notably, the
Breslow intermediates display two one-electron oxidations
clustered around −1.0 V and −0.8 V vs SCE; butanethiol and
the butanethiolate anion display oxidation potentials at +1.12
and −0.85 V vs SCE, respectively. This suggested to us that cell
potentials capable of oxidizing the Breslow intermediate would
also be capable of oxidizing thiolates, but that thiols would not
be readily oxidized.
Interestingly, our investigations also revealed results
consistent with an azolium-mediated oxidation of thiolates.
Specifically, in the absence of an applied voltage, the
combination of a thiazolium cation and thiolate anion resulted
in efficient formation of disulfides (Table 1). In the absence of
either reactant, no disulfide was observed (entries 1 and 2).
DBU was found to be a sufficiently strong base to facilitate
thiolate and thus disulfide formation (entry 3). Similarly,
sodium butanethiolate was easily oxidized in the presence of the
thiazolium salt (cf. entries 4 and 5). In an attempt to minimize
thiolate formation, we investigated DMAP and found that
disulfide was formed to a much lesser extent (entry 7).
We further investigated the influence of base strength and
concentration during the anodic oxidation to form thioesters
b
b
entry
base (M)
% thioester
% BuSSBu
1
DBU (0.15)
<1
15
21
11
3
57
15
10
4
2
K2CO3 (0.15)
DMAP (0.15)
DMAP (0.075)
DBU (0.075)
pyridine (0.075)
K2CO3 (0.075)
DIPEA (0.075)
DABCO (0.075)
NEt3 (0.075)
3
4
5
58
0
6
0
7
5
3
8
20
15
30
13
10
12
9
10
a
Reactions conducted at 45 °C in a three-neck flask under N2 with a
graphite anode, Pt basket cathode, 0.045 M Bu4NBr, 0.150 M
aldehyde, 0.300 M R′SH, and constant cell potential of +0.1 V (vs Ag/
AgNO3). Determined by GC-MS and H NMR spectroscopy using
1,3,5-trimethoxybenzene as the internal standard.
b
1
(Table 2). After 2 h, DBU (100 mol % relative to aldehyde)
gave a 57% yield of disulfide (entry 1) and only trace amounts
of thioester. Use of K2CO3 or DMAP each resulted in improved
yields of thioester (entries 2 and 3, respectively), with DMAP
giving a 21% yield of thioester while producing a 10% yield of
disulfide. To further minimize thiolate formation, we reduced
the amount of DMAP to 50 mol % (entry 4). Although the
yield of thioester dropped to only 11% in the 2-h run, the ratio
of thioester to disulfide (2.75:1) was improved in comparison
with those having higher base loadings. With the exception of
pyridine (entry 6), which was found to be completely
ineffective, we continued to observe a greater yield of thioester
than disulfide when maintaining a 50 mol % base loading
(entries 7−10).
We next explored the aldehyde and thiol substrate scope; key
results are depicted in Scheme 2. Unactivated and ortho-
substituted aldehydes gave good yields of thioester, as did
cyclohexane carboxaldehyde. In general, electron-deficient
aldehydes proceeded in good-to-excellent yields, including
heteroaromatic 2-pyridinecarboxylaldehyde. Attempts with α,β-
unsaturated aldehydes were met with limited success. In
addition to butanethiol, we found that other primary thiols such
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Scheme 2. Substrate Scope of NHC-Catalyzed Anodic
Oxidation of Aldehydes to Thioesters
ACKNOWLEDGMENTS
■
a
Financial support of this research by the University of
Washington, the Washington Technology Center, SpringStar,
Inc., and the American Chemical Society Petroleum Research
Fund (ACS PRF). We thank Candice N. Cooper (Department
of Chemistry, University of Washington) for assisting in the
synthesis of the thiazolium precatalysts.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: boydston@chem.washington.edu.
Notes
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The authors declare no competing financial interest.
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