Scalable Electrochemical Dehydrogenative Lactonization of C(sp2/sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.7b03617

A practical, electrochemical method is developed for the direct dehydrogenative lactonization of C(sp²/sp³)-H bonds under external oxidant- and metal-free conditions, delivering diverse lactones, including coumarin derivatives with excellent regioselectivity. The scalable nature of this newly developed electrochemical process was demonstrated on a 40 g scale following an operationally simple protocol. The remote lactonization of C(sp³)-H bonds would constitute an important synthetic advance toward electrochemical C-O bond formation.

Full text of DOI:10.1021/acs.orglett.7b03617

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Scalable Electrochemical Dehydrogenative Lactonization of
C(sp2/sp3)−H Bonds
Sheng Zhang,*,† Lijun Li,† Huiqiao Wang,† Qian Li,† Wenmin Liu,† Kun Xu,*,†,‡
and Chengchu Zeng*,‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
‡Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of
Technology, Beijing 100124, China
S
* Supporting Information
ABSTRACT: A practical, electrochemical method is devel-
oped for the direct dehydrogenative lactonization of C(sp2/
sp3)−H bonds under external oxidant- and metal-free
conditions, delivering diverse lactones, including coumarin
derivatives with excellent regioselectivity. The scalable nature
of this newly developed electrochemical process was
demonstrated on a 40 g scale following an operationally
simple protocol. The remote lactonization of C(sp3)−H bonds
would constitute an important synthetic advance toward
electrochemical C−O bond formation.
1b).3 For instance, Martin3a and Gevorgyan3b independently
actones represent privileged structural subunits in molecules
reported the pioneering work of copper-catalyzed intramolecular
Lof pharmaceutical, biological, and medicinal interest (Figure
oxidative coupling of C(sp2)−H with aromatic carboxylic acids in
2013. Palladium-catalyzed C−H activation/C−O coupling has
also been developed by Wang’s group.3c Recently, Gonzalez-
Gomez and co-workers disclosed an efficient photocatalytic
version of C(sp2)−H lactonization.3f However, most of these
works involve the use of transition-metal catalysts, photocatalysts
or organocatalysts together with strong oxidants, which are of
high cost for large-scale industrial application. Moreover, the
existing intramolecular C−H/O−H oxidative couplings are
limited to reactions between aromatic carboxylic acids and
C(sp2)−H bonds. The direct lactonization of C(sp3)−H bonds
with carboxylic acids, especially with aliphatic carboxylic acids,
remains less explored.4
1a).1 Consequently, extensive synthetic efforts have been
devoted to this notable structure.2,3 Among developed
approaches, the direct C−H/O−H oxidative coupling reaction
has gained special attention for its high atom economy (Figure
Organic electrosynthesis obviates the use of dangerous and
toxic reagents, and the past decades have witnessed extensive
exploration in this aspect, given its environmental benignity and
operational simplicity.5,6 As carboxylic acids are normally
inexpensive and benchtop stable, the electrochemical trans-
formation of carboxylic acids into other useful motifs is of great
significance. Treatment of carboxylic acids with (external or
electrogenerated) base generates carboxylate anion, which
undergoes anodic oxidation to generate carboxylate radical.
This reactive intermediate usually proceeds via a radical
decarboxylative homocouplings, which is known as the Kolbe
reaction.7 Electrogenerated carboxylate radical could also
undergo intramolecular addition to electron-rich alkenes to
produce lactones.8 We envisioned that direct lactonization of
Figure 1. Lactones in bioactive molecules and evaluation of accessible
methods.
Received: November 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C(sp2)−H bonds could occur if C−O coupling proceeds fast
enough to outcompete the Kolbe decarboxylation. In addition, if
1,5-hydrogen-atom-transfer (HAT) makes remote C−H homo-
lytic cleavage possible, lactonization of C(sp3)−H bonds would
be achieved, though it is elusive for electrosynthesis. Herein, we
describe an electrochemical dehydrogenative lactonization of
aromatic and aliphatic carboxylic acids with C(sp2/sp3)−H
bonds (Figure 1c). This strategy exhibits broad substrate scope,
operational simplicity and high regioselectivity under additive-,
metal-, and external oxidant-free conditions. The scalability of
this method was demonstrated on a 40 g scale following an
operationally simple protocol.
Scheme 1. Substrate Scope with Respect to Biaryl Carboxylic
Acids
a
The optimized reaction conditions are demonstrated in Figure
2 (see Table S1 for details). The cyclization of 2-
Figure 2. Optimized conditions.
biphenylcarboxylic acid 1a proceeded smoothly in an undivided
cell equipped with a Pt anode and a Pt cathode using n-Bu4NBF4
in CH3CN/MeOH (7:1 v/v) as the supporting electrolyte under
constant current conditions, giving lactone 2a in 99% yield.
Pleasingly, the yield of 2a could still be obtained in 93% yield
using cheap graphite plates as the anode and cathode.
After the optimal reaction conditions were identified, the
substrate generality was investigated (Scheme 1). First, the
electronic variation in the para substitution of Ar2 ring was
investigated. The results showed that halogen (2b−d),
trifluoromethyl (2e), ester (2f), methyl (2g) and tert-butyl
(2h) groups were all well tolerated, giving lactones 2b−h in 71−
80% yields. However, when a strong electron-donating group
(OMe) was attached to the para position of Ar2 ring, the yield
decreased to 42% (2i). For substrates with two possible reactive
sites, the preferable formation of para-substituted lactones were
observed (2j−l). 2-Thienyl-substituted benzoic acid proved to
be an amenable substrate giving lactone 2m with a low yield,
which may due to the partial oxidation of electron-rich thiophene
moiety. Additionally, multisubstituted substrate was also well-
tolerated to give the corresponding product 2n in 62% yield. The
generality of this methodology was further demonstrated by
preparing substituted lactones 2o-2w in moderate to excellent
yields. To demonstrate the practicability of this method, we also
tested some substrates for lactonization using graphite as the
anode and cathode. The results showed that the lactonizations
could be carried out smoothly by employing graphite as the
electrodes, giving lactones 2a, 2g−h, 2j, 2o, 2p, 2r, and 2v in 67−
93% yields.
a
Reaction conditions: undivided cell, Pt anode, and cathode (1.5 × 1.5
cm2, J = 13.3 mA/cm2), 1 (0.5 mmol), CH3CN (7 mL), MeOH (1
b
mL), n-Bu4NBF4 (2 mmol) at room temperature for 1.5−2.5 h. n-
c
d
Bu4NClO4 was employed as the electrolyte. J = 9 mA/cm2. The ratio
of regiomers (rr) was determined by the 1H NMR spectrum.
e
Changed reaction conditions for the yields in parentheses: graphite
anode and cathode (1.5 × 1.5 cm2), 3 h.
Scheme 2. Electrochemical Lactonization of Diaryl Acrylic
Acids
C(sp3)−H bonds (Scheme 3). It is well-known that the
regioselective lactonization of a substrate with multiple reactive
sites would be more challenging.4b,c To our delight, as shown in
Scheme 3, when 2-benzylbenzoic acids 5a−e were subjected to
anodic oxidation under the standard conditions, phenyl
phthalides 6a−e were exclusively generated without observing
of the C(sp2)−H coupling products. This remarkable selectivity
might attribute to the higher stability of five-membered ring
products compared with that of seven-membered ones. For 2-
phenethyl benzoic acid 5f with two reactive benzylic C(sp3)−H
bonds, isochroman-1-one 6f was obtained as the single product.
Subsequently, a series of alkylated benzoic acids containing
tertiary carbon were examined. As expected, all of the cyclized
As shown in Scheme 1, the electrochemical cyclization of
biaryl carboxylic acids has been demonstrated as a powerful
method for lactones synthesis. It would be more valuable if the
protocol could be applied to diaryl acrylic acids, since the
resulting coumarin derivatives are important in the fragrance and
flavor industry (Scheme 2). With a minor modification of the
standard conditions, diaryl acrylic acids 3 could undergo
lactonization with C(sp2)−H bonds to give coumarins 4 in
moderate yields.
Having investigated the lactonization of C(sp2)−H bonds, we
next turned our attention to the regioselective lactonization of
B
DOI: 10.1021/acs.orglett.7b03617
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Organic Letters
Letter
a
Scheme 3. Lactonization of C(sp3)−H Bonds
Figure 3. Large-scale synthesis.
a
Reaction conditions: undivided cell, Pt anode and cathode (1.5 × 1.5
cm2, J = 13.3 mA/cm2), 5 (0.5 mmol), CH3CN/MeOH (7/1 v/v), n-
b
c
Bu4NBF4 (2 mmol) at rt for 2−3 h. J = 20 mA/cm2. J = 15.6 mA/
Figure 4. Synthetic applications.
cm2
Some control experiments were conducted in order to gain an
understanding of the reaction mechanism. At the outset, radical
scavenger TEMPO was tested to identify the reaction pathway.
As shown in Scheme 4, adding 3 equiv of TEMPO to the reaction
products 6g−k with a new quaternary carbon center were
regioselectively accessed in moderate to excellent yields. In order
to make the protocol more general and appealing, we also tested
the lactonization of aliphatic carboxylic acid (5l). The challenge
of using aliphatic carboxylic acid is that its lower oxidative
potential facilitate the decaboxylative homocoupling process. We
were delighted to find that 4-phenylbutyric acid underwent
lactonization of C(sp3)−H bond smoothly to afford five-
membered lactone 6l in 62% isolated yield under our electrolysis
conditions. The recovery of substrate 5m illustrates that benzylic
radical is formed by 1,5-HAT instead of direct benzylic oxidation.
The failure of substrates 5n and 5o indicates that a stabilized
benzylic radical intermediate is essential for this transformation.
Since an excellent yield of lactonization could be obatined by
using inexpensive graphite electrodes, undivided cell, and
constant current electrolysis (Figure 2, condition 2), which are
essential for large-scale electrosynthesis. To make this protocol
more practical, 40 g of 1a in a container was pumped to an
undivided glass cell equipped with cheap graphite anode and
cathode for lactonization. After a simple workup of the resulting
mixture, product 2a was obtained in 84% yield (33 g) with high
purity (>97%) without column chromatography (Figure 3, see
the SI for details), which indicates that the present protocol has a
potential industrial applications.
Lactone is an important class of synthon in organic synthesis.
Taking 2a and 6l as examples, their hydrolysis easily gave benzoic
acid derivatives 7 and 8 (Figure 4a).9 The present method
provides an efficient route for the remote hydroxylation of
C(sp2/sp3)−H bonds. By using product 2u as the starting
material, natural product cannabinol could be obtained in five
steps according to previous report (Figure 4b).3c Previous report
for the construction of compound 2u needed palladium catalysis
with excess amount of PhI(OAc)2 as the oxidant and excess
amount of KOAc as the base.3c
Scheme 4. Control Experiments
mixture led to the formation of radical trapping adducts 9a,b in
91−99% yields. Further kinetic isotope effect studies verified that
the aromatic C−H cleavage might not be the turnover-
determining step, suggesting a carboxylate radical initiative
mechanism.3f To determine which moiety (carboxylate or
aromatic moiety) is oxidized preferentially, the cyclic voltam-
metric study was also carried out (see Figure S10 for details). The
results showed that the carboxylate moiety has an oxidation
potential of 1.4 V vs Ag/AgCl, while the aromatic moiety has an
oxidation potential over 2.0 V vs Ag/AgCl, which indicate
carboxylate moiety is oxidized preferentially under the optimized
conditions. These results are consistence with the radical
trapping experiments. The mechanism is different from the
well-known anodic acetoxylation of aromatic coumounds
developed by Eberson and co-workers.10,11 In Eberson’s work,
anodic oxidaiton of aromatic moiety was the first step, followed
C
DOI: 10.1021/acs.orglett.7b03617
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Organic Letters
Letter
by the nucleophilic attack of acetoxyl anion to lead to the
acetoxylated products.
ACKNOWLEDGMENTS
We are grateful to the Natural Science Foundation of China
(21702113, 21602119, U1504208).
■
On the basis of these results and previously related reports,3f,4b
a plausible mechanism was proposed as shown in Figure 5. First,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03617.
Detailed experimental procedures and spectral data
(PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shengzhang@nynu.edu.cn.
*E-mail: xukun@nynu.edu.cn.
*E-mail: zengcc@bjut.edu.cn.
ORCID
Sheng Zhang: 0000-0002-9686-3921
Kun Xu: 0000-0002-0419-8822
Chengchu Zeng: 0000-0002-5659-291X
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b03617
Org. Lett. XXXX, XXX, XXX−XXX