Electrocatalytic Dehydrogenative Esterification of Aliphatic Carboxylic Acids: Access to Bioactive Lactones

Article abstract of DOI:10.1021/acs.orglett.7b03333

A scalable and efficient electrocatalytic dehydrogenative esterification is reported. With an indirect electrolysis strategy, both intra- and intermolecular-type reactions were amenable to this practical method. With n-Bu₄NI as the catalyst, un

Full text of DOI:10.1021/acs.orglett.7b03333

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrocatalytic Dehydrogenative Esterification of Aliphatic
Carboxylic Acids: Access to Bioactive Lactones
Sheng Zhang,*,† Fei Lian,†,‡ Mengyu Xue,† Tengteng Qin,† Lijun Li,† Xu Zhang,† and Kun Xu*,†
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, P. R. China
‡College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, P. R. China
S
* Supporting Information
ABSTRACT: A scalable and efficient electrocatalytic dehy-
drogenative esterification is reported. With an indirect
electrolysis strategy, both intra- and intermolecular-type
reactions were amenable to this practical method. With n-
Bu4NI as the catalyst, undesired decarboxylation and Baeyer−
Villiger oxidation were suppressed. More importantly, this
novel method provided reliable and direct access to the natural
product cytosporanone A on a gram scale.
α-Acyloxy ketones and their alcohol derivatives represent core
scaffolds that exhibit potent antifungal and antibacterial
activities and are widely distributed in natural products (Figure
1a).1 Consequently, increasing attention has been devoted to
emerged as a practical tool for organic synthesis.4 In particular,
synthetic electrochemistry has been demonstrated as a powerful
tool in cross-dehydrogenative coupling (CDC) reactions.5−9
For instance, Waldvogel has reported some impressive works
on the cross-coupling reaction of phenols and anilines (Scheme
1a).5 Recently, Xu and co-workers unveiled some prominent
research on intramolecular C−H/N−H and C−H/C−H
coupling reactions (Scheme 1b).6,7 The intermolecular
oxidative coupling reaction of electron-rich aromatic rings
and thiophenols has been elegantly resolved by Lei’s group
Scheme 1. Electrochemical Cross-Dehydrogenative
Coupling
Figure 1. γ-Keto butyrolactone in natural products and its synthetic
approach.
the synthetic approach toward these structures since the
pioneering work of Ochiai.2,3 For instance, some impressive
works on iodine- and hypervalent iodine-catalyzed lactonization
were achieved by Ishihara (Figure 1b).2b,c In 2011, Zhang and
co-workers reported an alternative method using DDQ as the
promoter (Figure 1b).2d Recently, with the explosive develop-
ment of photoredox catalysis, the photooxidative approach has
also been successfully applied to the synthesis of γ-keto lactones
starting from different substrates (Figure 1c).3 However, the
excessive use of oxidants and the relatively low efficiencies of
these methods impose restrictions on large-scale application.
Since the classical works of Faraday and Kolbe on the
electrolysis of aliphatic carboxylic acids, electrochemistry has
Received: October 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03333
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Scheme 1c).8 Moreover, extensive exploration of the
dehydrogenative coupling reactions of ketones has also been
unveiled by Wang, Zeng and other groups (Scheme 1d).9
Despite this significant progress, dehydrogenative esterification
of carboxylic acids with ketones has receive far less attention,
partly because of the undesired decarboxylation of the
carboxylic acid.10,11 Encouraged by some remarkable work in
electrochemical halide catalysis,9 we envisioned that an indirect
electrolysis with a halogenide salt as a mediator might be an
effective strategy to realize the intra- and intermolecular
dehydrogenative esterification of aliphatic acids with ketones.
Indeed, with mediation by n-Bu4NI, a scalable and highly
efficient method toward α-acyloxy ketones was achieved, and
the undesired decarboxylation and Baeyer−Villiger oxidation
were suppressed (Scheme 1e).
a
Scheme 2. Substrate Scope of γ-Keto Butanoic Acids
At the outset, γ-keto butanoic acid 1a was selected as the
model substrate to perform the electrocatalytic dehydrogen-
ative lactonization. We commenced the model reaction in an
undivided cell using n-Bu4NI as the mediator under constant-
current (10 mA) electrolysis (Table 1, entry 1). Promisingly, a
a
Table 1. Optimization of the Reaction Conditions
b
entry
x
SE
anode
J (mA/cm2)
yield (%)
a
Reaction conditions: undivided cell, platinum anode and cathode (1.5
cm × 1.5 cm), J = 6.7 mA/cm2, 1 (0.5 mmol), CH3CN (8 mL), TFE
(0.5 mL), n-Bu4NI (0.075 mmol), and n-Bu4NOAc (1 mmol) at 40 °C
1
2
3
4
5
6
7
8
9
200
200
20
−
−
Pt
4.4
13.3
6.7
6.7
6.7
6.7
6.7
6.7
6.7
16
74
81
78
76
70
81
73
69
Pt
b
n-Bu4NOAc
n-Bu4NBF4
n-Bu4NPF6
n-Bu4NClO4
n-Bu4NOAc
n-Bu4NOAc
n-Bu4NOAc
Pt
for 3 h (3.4F). A higher reaction temperature (50 °C) was required.
20
Pt
20
Pt
20
Pt
congested substrate 1o reacted smoothly in this efficient
transformation, thereby giving the product in 79% yield (2o).
Additionally, this electrochemical protocol was also compatible
with substrates bearing fused rings or a heterocycle (2p and
2q). It is particularly noteworthy that the lactone containing
alkene functionality (2r), allowing for various derivatizations,
was readily furnished in 73% yield. Because of their volatility in
the presence of oxidant, alkenyl-substituted γ-keto butanoic
acids still remain notoriously challenging substrates in oxidative
lactonization with traditional methods. Notably, benzyl γ-keto
butanoic acid 1s containing two comparable reaction sites
afforded the product 2s with excellent regioselectivity at a
higher reaction temperature. Other γ-keto butanoic acids with
complex skeletons were amenable substrates, and the
diastereoselective product 2u, six-membered-ring product 2v,
and even spiro lactones 2w and 2x were obtained in moderate
to excellent yields.
Having surveyed the intramolecular dehydrogenative reac-
tion, we were poised to apply this method to the intermolecular
dehydrogenative esterification of acetophenone (3) with acids
(Scheme 3). To overcome the lower reactivity of the
intermolecular-type reaction, a higher catalyst loading (20
mol %) and temperature (60 °C) were employed. Pleasingly, a
41% yield was observed with the assistance of the supporting
electrolyte n-Bu4NOAc. Interestingly, other supporting electro-
lytes failed to give any products. Subsequently, the esterification
of propiophenone (5) with different acids was investigated.
Both aliphatic and aromatic acids were well-tolerated, thereby
giving products 6a and 6b in 36% and 38% yield, respectively.
15
Pt
15
C
15
RVC
a
Reaction conditions: undivided cell, anode, and platinum cathode
(1.5 cm × 1.5 cm), 1a (0.5 mmol), CH3CN (8 mL), CF3CH2OH
(TFE, 0.5 mL), n-Bu4NI (x mol %), and supporting electrolyte (1
mmol) at 40 °C for 1.5−4.5 h (3.4F). Isolated yields.
b
16% yield of the product was detected. Further screening of the
parameter of current density (J) showed that 13.3 mA/cm2 was
the optimal value (Table 1, entry 2; for details, see the
Supporting Information). To demonstrate the catalytic role of
n-Bu4NI, the loading of the mediator was lowered to 20 mol %.
Varying the supporting electrolyte had little effect on the
reaction efficiency, and n-Bu4NOAc gave the highest yield
(81%; Table 1, entries 3−6). To our delight, lowering the
catalyst loading to 15% still maintained a good yield (Table 1,
entry 7). Changing the Pt anode to a graphite or reticulated
vitreous carbon (RVC) anode caused slight erosion in the yield
(Table 1, entries 8 and 9).
To test the generality of this electrocatalytic dehydrogenative
lactonization under the identified optimal conditions, various
substituted γ-keto butanoic acids were synthesized and
employed in the reaction. As shown in Scheme 2, the reaction
performance is largely independent of the electronic properties
of substitutions on the aryl ring (2b−j). Changing the
substition pattern to the meta or ortho position has little effect
on the reaction performance. Specifically, the sterically
B
DOI: 10.1021/acs.orglett.7b03333
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Organic Letters
Letter
in the reaction to identify the intermediate involved in the
reaction (eq 2). Surprisingly, monohydroxylated product 9 was
detected and isolated in 86% yield, even under an inert
atomosphere, using 2 equiv of n-Bu4NI as the electrolyte. On
the basis of a previous report,9d we speculated that α-
hydroxylated ketone 9 might be generated from an iodinated
counterpart via nucleophilic attack. Addtionally, a cyclic
voltammeric study was also performed (see the Supporting
Information for details). An obvious catalytic current was
observed, which further verified the catalytic role of n-Bu4NI.
On the basis of these results, a plausible catalytic cycle was
proposed (Figure 2b). First, reduction at the cathode gives
carboxylic ion intermediate 10, which can be directly iodinated
via keto−enol tautomerism in the presence of in situ-generated
iodine. However, there also remains another pathway that
involves acyl hypoiodite species 11 according to related
reports.10e,12 The homolytic dissociation of acyl hypoiodite
11 would induce an undesired decarboxylative process, while
the hypervalent iodine could also be intercepted by the
intramolecular keto moiety to give iodinated intermediate 12.
Because of the higher reaction rate of the iodination, the side
decarboxylation is avoided. Finally, nucleophilic cyclization of
12 affords the product 2a and regenerates iodide. In addition,
the intermolecular product may be attributed to a similar
nucleophilic attack process.
Scheme 3. Intermolecular Dehydrogenative Esterification
To probe the scalability of the electrocatalytic lactonization
of γ-keto butanoic acids, a scaled-up reaction was performed as
illustrated in Scheme 4. With graphite plates as the anode and
Scheme 4. Gram-Scale Electrocatalytic Lactonization and Its
Synthetic Application
In summary, an electrocatalytic dehydrogenative esterifica-
tion that provides a scalable and direct access to bioactive α-
acyloxy lactones is disclosed. The metal-free, oxidant-free,
highly efficient features endow it with potential practical
applications. Additionally, an unexpected intermediate 9 was
identified, and a plausible catalytic cycle was proposed. Further
investigation of the enantioselective version of this reaction is
currently in progress in our laboratory.
cathode, 10 g of substrate 1a was treated with 15 mol % n-
Bu4NI, and the lactone product 2a was obtained in 71% yield;
2a could then undergo diastereoselective reduction to afford
the natural product 7 with >99/1 dr. This preparative
experiment indicated that this electrochemical approach
opened a practical route to bioactive cytosporanone A.1e
To gain insight into the reaction mechanism, some control
experiments were carried out (Figure 2a). Initially, the
commonly used radical scavenger TEMPO and 1,1-diphenyl-
ethylene were tested to elucidate the nature of the reaction.
Treatment with 3 equiv of radical scavenger had no significant
effect on the efficiency of the reaction (eq 1), which suggested
that a radical process might not be the main pathway.
Subsequently, the methyl-protected substrate 8 was employed
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03333.
Detailed experimental procedures and spectral data
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*S. Zhang: shengzhang@nynu.edu.cn.
*K. Xu: xukun@nynu.edu.cn.
ORCID
Sheng Zhang: 0000-0002-9686-3921
Xu Zhang: 0000-0002-3588-3240
Kun Xu: 0000-0002-0419-8822
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21702113, 21602119, and U1504208) and acknowledge
the financial support from the He’nan Provincial Department of
Education (18A150041).
Figure 2. Control experiments and proposed mechanism.
C
DOI: 10.1021/acs.orglett.7b03333
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Organic Letters
Letter
(12) Perry, G. J. P.; Quibell, J. M.; Panigrahi, A.; Larrosa, I. J. Am.
Chem. Soc. 2017, 139, 11527.
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DOI: 10.1021/acs.orglett.7b03333
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