Peroxide- And transition metal-free electrochemical synthesis of α,β-epoxy ketones

Article abstract of DOI:10.1039/d0ob02444a

A novel electrochemical method for the synthesis of α,β-epoxy ketones is reported. With KI as the redox mediator, methyl ketones reacted with aldehydes under peroxide- and transition metal-free electrolytic conditions and afforded α,β-epoxy ketones in one pot (36 examples, 52-90% yield). This safe and environmental-friendly method has a broad substrate scope and can readily provide a variety of α,β-epoxy ketones in gram-scales for evaluation of their anti-cancer activities.

Full text of DOI:10.1039/d0ob02444a

Organic &
Biomolecular Chemistry
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Peroxide- and transition metal-free
electrochemical synthesis of α,β-epoxy ketones†
Cite this: Org. Biomol. Chem., 2021,
19, 2481
Mengxun Zhang,a,b Tie Chen,a Shisong Fang,c Weihua Wu,c Xin Wang,c
Haiqiang Wu,a Yongai Xiong,a Jun Song, b Chenyang Li,*a Zhendan He*a,d and
e
Chi-Sing Lee
*
A novel electrochemical method for the synthesis of α,β-epoxy ketones is reported. With KI as the redox
mediator, methyl ketones reacted with aldehydes under peroxide- and transition metal-free electrolytic
conditions and afforded α,β-epoxy ketones in one pot (36 examples, 52–90% yield). This safe and
environmental-friendly method has a broad substrate scope and can readily provide a variety of α,β-epoxy
ketones in gram-scales for evaluation of their anti-cancer activities.
Received 7th December 2020,
Accepted 25th February 2021
DOI: 10.1039/d0ob02444a
rsc.li/obc
improved safe and versatile method for efficient synthesis of
α,β-epoxy ketones.
Introduction
Epoxides are very important synthetic intermediates in organic
As an environmental-friendly method, electrochemistry is a
chemistry,1,2 and they are also a broad family of monomers for promising alternative to conventional synthesis involving
construction of polymeric material, such as polyether3 and dangerous and toxic reagents because it has the ability to
epoxy resin.4 A large array of bioactive molecules also contain access highly reactive intermediates under mild conditions.18
epoxide motifs, such as inhibitor of serine and cysteine pro- Although a number of electrochemical syntheses of epoxides
tease E-64,5 anticancer natural product Epothilone A,6 anti- have been reported,19 their strategies generally involve usage of
cancer chalcone derivative,7 and antibiotic Nisamycin8 (Fig. 1). stoichiometric or excessive oxidant or toxic heavy metal cata-
Due to the significance of this class of compounds, syn- lysts, which limited the utilities of these methods. Inspired by
thetic methods using various oxidants have been widely the pioneering work and the strategy of α-functionalization of
explored. For the synthesis of α,β-epoxy ketones, oxidation of carbonyl compounds via anodic oxidation of ionic halides,20
the electron-deficient double bond by a peroxide under basic we anticipate that simple methyl ketones and aldehydes could
conditions is a long-established method (Scheme 1a).9 Mandal react in the presence of an ionic halide as the redox mediator
and Loeker’s groups independently reported aerobic oxidation and afford α,β-epoxy ketones under electrolysis in one-pot
of olefins with metal catalysts,10,11 and Luo’s group recently (Scheme 1d). This strategy could provide a simple, safe, and
reported
a
visible light-induced aerobic epoxidation atom-economic method for scale-up synthesis of α,β-epoxy
(Scheme 1b).12 Starting from ketone and aldehyde substrates, ketones under peroxide- and transition metal-free conditions.
syntheses of α,β-epoxy ketone via a “condensation-epoxi-
dation” domino sequence in one pot (Scheme 1c) were
reported by several groups.13–17 Despite of the advances in this
area, hazards associated with high concentration of peroxides
and oxidants have always been a serious concern in labora-
tories and the industry, and there is still a demand for an
aDepartment of Pharmacy, School of Medicine, Health Science Center, Shenzhen
University, Shenzhen 518060, China. E-mail: hezhendan@szu.edu.cn
bCollege of physics and optoelectronic engineering, Shenzhen University, Shenzhen
518060, China
cShenzhen Center for Disease Control and Prevention, Shenzhen 518100, China
dCollege of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
eDepartment of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong
SAR, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02444a
Fig. 1 Bioactive epoxide-containing compounds.
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different solvents (entries 2–7). The optimal combination is
found to be using KI in a 1 : 1 THF/H2O mixture, which
afforded 56% yield of the α,β-epoxy ketone product with the
same trans/cis ratio (entry 5). Unfortunately, increasing the
equivalents of KI led to a decrease in yields (entry 7). In a
survey of the effects of different additives, addition of a base
generally improved the yields of the products (entries 11–15).
The optimal results were obtained using KOH, which provided
76% yield of α,β-epoxy ketone (trans/cis = 1.4 : 1) (entry 15).
This electrochemical reaction required only non-hazard
reagents, KI and KOH, in a 1 : 1 THF/H2O solution and can
provide the α,β-epoxy ketone products in good yields under a
peroxide- and transition metal-free condition in one-pot.
With the optimal condition in hand, we studied the sub-
strate scope of the electrochemical reaction.24 As shown in
Scheme 2, a variety of functional groups with different substi-
tution patterns of aryl methyl ketone substrates (2a–17a) are
generally tolerated, and their reactions with benzaldehyde
afforded the expected α,β-epoxy ketone products in 52–90%
yields with moderate to excellent trans-selectivity. Surprisingly,
reaction of 5a with benzaldehyde afforded the cis-product
(52% yield) exclusively. The trans-selectivity was also observed
in the reactions between acetophenone with a variety of aryl
aldehydes (18b–33b), which gave 67–86% yields of the
expected product. This unpredictable trans- and cis-selectivity
was also observed in the reaction between 34a and 34b, as well
as the reaction between 35a and 35b. These reactions gave only
the trans-products in 62–75% yield, while the reaction between
36a and 36b afforded only the cis-product in 72% yield.
Interestingly, substrates bearing an extended π-system tend to
give the diaryl α,β-epoxy ketone products with either poor
trans-selectivity (4 and 21) or high cis-selectivity (5 and 36),
indicating the extended π-systems of the substrates may play a
role for the formation of the cis-products. Although the trans-
and cis-selectivity in this electrochemical reaction is not clear
at this point, we have demonstrated that this reaction is robust
and can prepare a variety of diaryl α,β-epoxy ketones efficiently
with a broad scope of functional groups.
Scheme 1 Methods for constructing α,β-epoxy ketones.
Results and discussion
The electrochemical reaction was carried out in an undivided
cell with graphite anode and cathode under constant current
conditions (10 mA).21 To determine the optimal conditions,
the electrochemical reaction between acetophenone (1a) and
benzaldehyde (1b) was studied. As shown in Table 1, using
NaBr as the redox mediator in ethanol22 gave a 1 : 1 trans/cis-
product (1c and 1d) in 16% yield (entry 1). Unfortunately, pro-
longed reaction time led to polymerization of the substrates.
The trans- and cis-products are separable, and their structures
were fully characterized by NMR experiments.23 This result
prompted us to study the effects of a variety of iodides in
Table 1 Electrochemical synthesis of α,β-expoxy ketonesa
In the mechanistic studies, we found that the electro-
chemical reaction can proceed smoothly using a catalytic
amount of KI (Scheme 3a) with tetrabutylammonium per-
chlorate as the electrolyte. Without KI, no product formation
was observed and the aldol product, β-hydroxy ketone 37, was
isolated as the major side-product (Scheme 3b). These results
indicated that KI is essential for the reaction and can be regen-
erated in the reaction system. Interestingly, when β-hydroxy
ketone 37 was submitted to the optimal reaction condition,
the α,β-epoxy ketone product was formed in good yields
(Scheme 3c), suggesting the β-hydroxy ketone would be an
intermediate in the reaction. To determine other possible
intermediates in the reaction, acetophenone alone was sub-
mitted to the optimal reaction condition. However, formation
of α-iodo acetophenone (38 or 39) was not observed
(Scheme 3d). Reaction between α-iodo acetophenone 38 and
benzaldehyde did not provide the desired product.25
α,β-Unsaturated ketone 40 was also submitted to the optimal
Entry Redox mediator Solvent
Additivesb Yield (trans : cis)
1
2
3
4
NaBr
NH4I
KI
EtOH
—
—
16% (1 : 1)
0%
EtOH/H2O
EtOH/H2O
MeOH
—
—
—
—
16% (1 : 1)
36% (1.6 : 1)
56% (1 : 1)
54% (1 : 2)
40% (1 : 1)
0%
48% (1 : 1)
53% (1 : 1.4)
48% (2 : 1)
60% (3 : 1)
74% (2 : 1)
66% (1 : 1.2)
76% (1.4 : 1)
KI
5
6
7
8
KI
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
NaI
KIc
KI
KI
KI
KI
KI
KI
KI
—
H2SO4
NMO
TEMPO
TEA
DBU
DABCO
K2CO3
KOH
9
10
11
12
13
14
15
KI
a General condition: the electrochemical reaction was carried out in an
undivided cell equipped with graphite anode and cathode under con-
stant current conditions (10 mA) at rt with 1a (3 mmol), 1b (3 mmol)
and a redox mediator (6 mmol) in THF or EtOH (15 mL) and H2O
(15 mL). b Additives (0.6 mmol). c KI (12 mmol).
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Scheme 2 The scope of substrates.
condition, which did not lead to the desired product product,25 indicating the importance of the electrolytic con-
(Scheme 3e). These results indicated that α-iodo acetophenone dition for this transformation.
38 and α,β-unsaturated ketone 40 may not be the intermediate
The cyclic voltammogram (CV) of KI showed two reversible
of the reaction. Since Dietz’s group reported that molecular oxidation peaks (peak potentials at +0.52 and +0.86 V vs.
oxygen could be transformed into superoxide ions under elec- HgCl/Hg2Cl2/Cl− as reference electrode), indicating the oxi-
trolytic conditions,26 the electrochemical reaction was con- dation of iodide ions to triiodine ions and further to iodine
ducted in degassed solvents under an argon atmosphere. The (red curve in Fig. 2).27 While the CV of acetophenone and
electrochemical reaction proceed smoothly (Scheme 3f), indi- benzaldehyde did not show any obvious peaks, suggesting no
cating that molecular oxygen in air did not have influence in oxidation or reduction of these substrates on the electrodes.
this electrochemical process. Addition of TEMPO also has no
In considering the results of the mechanistic studies and
influence in the yields and selectivity,25 suggesting no radical cyclic voltammetry, a mechanism for the formation of the
intermediate is involved in the reaction mechanism. More trans-product was proposed (Fig. 3). Under basic conditions
importantly, switching to conventional conditions by replacing (KOH and the base generated by cathodic reduction), acetophe-
KI with I2 with no electrolysis did not result in any of the none was transformed into enolate A, which could undergo
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Scheme 3 Mechanistic studies: (a) KI (0.2 equiv.), KOH (0.2 equiv.), Bu4NClO4 (1.8 equiv.); (b) KOH (0.2 equiv.), Bu4NClO4 (2.0 equiv.); (c) KI (2.0
equiv.), KOH (0.2 equiv.); (d) KI (2.0 equiv.), KOH (0.2 equiv.); (e) KI (2.0 equiv.), KOH (0.2 equiv.); (f) KI (2.0 equiv.), KOH (0.2 equiv.), reaction per-
formed under Ar.
Fig. 2 Cyclic voltammograms of: red, KI (5 mM); black, acetophenone
(5 mM); blue, benzaldehyde (5 mM), in THF and H2O (5%), Bu4NClO4 (0.2
M) as supporting electrolyte vs. HgCl/Hg2Cl2/Cl− reference electrode.
Fig. 3 A proposed mechanism for the formation of the trans-product.
Claisen–Schmidt condensation with benzaldehyde and provide
β-hydroxy ketone intermediate B. The β-hydroxyl enolate C gen-
erated under basic conditions could chelate to a metal ion.
Addition of the iodine (generated by anodic oxidation) from
the less hindered face (anti to the phenyl group) should lead to
the anti-product D, which could undergo intramolecular SN2
reaction and establish trans-product 1c and regenerated an
iodide for completion of the catalytic cycle.
The utility of the electrochemical reaction was demon-
strated by a gram-scale synthesis. The amounts of substrates
were increased by 10 times of that used in the standard con-
dition. To make the reaction more economical, 0.4 equivalent
of KI was used (no electrolyte is required), and 30 mmol sub-
strates were dissolved in 60 mL of the solvent. The reaction
proceeds smoothly and provide product 1c,d in 70% yield
(4.07 g).
Epoxides are well known for their biological activity.
Fig. 4 In vitro cytotoxicity of synthesized epoxides against different
Moreover, the α,β-epoxy ketones contain the chalcone-type cancer cell lines.
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framework, which have been reported to possess various bio-
logical activities, such as anticancer, antiviral, and anti-inflam-
Acknowledgements
mation.28 Thus, the anticancer activities of all the synthetic This work was financially supported by the National Key R & D
α,β-epoxy ketones were investigated using CCK8 with three Program of China 2017YFA0503900, the National Natural
gastric cancer cell lines GT0603, GT112,29 and HGC27. Ten Science Foundation of China (31670360, 81973293, U1702286
compounds exhibited moderate to good inhibitory activities in and 81871631), the Shenzhen Science and Technology
cancer cell proliferation (see SI for detailed information). Innovation Committee Grant (ZDSYS201506031617582 and
α,β-epoxide 6c was identified as the most active compound JCYJ20190808122213241) and the Natural Science Foundation
with IC50 values equal 9.3 μM in cell line HGC27, 14.5 μM in of Guangdong Province, China (2019B1515120029 and
cell line GT112 and 9.9 μM in cell line GT0603 (Fig. 4).
2017B030301016). A special acknowledgement is made to
Instrumental Analysis Center of Shenzhen University for their
instruments and service.
Conclusions
In summary, a peroxide- and transition metal-free electro-
chemical method for the synthesis of α,β-epoxy ketones was
developed. With KI as the non-hazard redox mediator, a variety
of ketones and aldehydes can be readily converted into
α,β-epoxy ketones with good yields in one pot without using
peroxide or transition metal. This electrochemical reaction can
be conducted in a simple undivided cell with cheap carbon
electrodes at room temperature, and the reaction is insensitive
to moisture and air, which provide a robust and safe method
for synthesis of α,β-epoxy ketones. This environmental-friendly
and good atom-economic reaction is safe for scale-up and has
good toleration of a wide range of functional groups. A mecha-
nism via the β-hydroxy ketone intermediate was proposed
based on the results of the mechanistic studies and the cyclic
voltammetry. Moreover, a number of α,β-epoxy ketones showed
good in vitro inhibitory activities against gastric cancer cell pro-
liferation. The in vivo and toxicity studies of these compounds
are on-going.
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There are no conflicts to declare.
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