Communications
Electrosynthesis
Economical, Green, and Safe Route Towards Substituted Lactones by
Anodic Generation of Oxycarbonyl Radicals
Abstract: A new electrochemical methodology has been
developed for the generation of oxycarbonyl radicals under
mild and green conditions from readily available hemioxalate
salts. Mono- and multi-functionalised g-butyrolactones were
synthesised through exo-cyclisation of these oxycarbonyl
radicals with an alkene, followed by the sp3–sp3 capture of
the newly formed carbon-centred radical. The synthesis of
functionalised valerolactone derivatives was also achieved,
demonstrating the versatility of the newly developed method-
ology. This represents a viable synthetic route towards
pharmaceutically important fragments and further demon-
strates the practicality of electrosynthesis as a green and
economical method to activate small organic molecules.
The use of photochemical methods to generate acyl
radicals is well established, with a wide variety of photo-
catalysts and substrates utilised.[27,31–33] In contrast, the gen-
eration of acyl radicals using electrochemical methods
remains scarcely explored.[34,35] This is perhaps surprising
considering that the latter is significantly cheaper (1 mol of
electrons costs ꢀ £0.83/E0.93 vs £60–140/E67–156 per 100 mg
of commercially available iridium-based photocatalysts),[36,37]
less toxic, greener, and easier to scale-up to industrial scale.[9]
With this in mind, we have previously employed aroyloxy
radicals, formed via anodic oxidation of aromatic carboxylic
acids, to synthesise a library of functionalised phthalides
under mild and green conditions.[38]
While the photochemical synthesis of g-butyrolactones
has recently been reported, this methodology relies on highly
toxic and expensive solvent mixtures and metal catalysts.
Moreover, it is currently limited to sp2–sp3 coupling cascades
and requires the use of a caesium salt.[27] Through an
adaptation of our previously reported electrochemical meth-
odology, we seek to complement this study and hereby report
the synthesis of various substituted g-butyrolactones from
alcohol-derived hemioxalates using an unusual free radical
sp3–sp3 cross-coupling.
Initial studies utilised the hemioxalate ammonium salt 1.
While attempts to electrolyse the precursors, under their
acidic hemioxalate form, afforded the desired outcome, their
inherent instability precluded reproducibility. While other
reports propose the use of caesium salts,[27] the synthetic
routes can be long and non-trivial, whereas the corresponding
ammonium salts are significantly cheaper, faster and easier to
prepare, and lead to CO2 and NH3 as the volatile by-products
of the reaction. Furthermore, cyclic voltammetry studies have
shown the expected chemically and electrochemically irre-
versible oxidation and suggested that these salts can be
oxidised at reasonably low potentials compared to usual
aliphatic acids ( ꢀ 0.9 V vs Fc).[39]
E
lectrochemistry has long been a useful synthetic tool in
organic chemistry, with examples as early as 1832.[1,2] With the
introduction of more readily available electrosynthesis equip-
ment,[3,4] electrosynthesis has experienced a resurgence in
interest,[5–12] and has proven to possess diverse applications
such as the allylic oxidation of alkenes,[9] fluorination of sp3
carbon centres,[11] cathodic radical deoxygenation,[12] electro-
chemical methoxymethylation,[6] and oxidative decarboxyla-
tion.[8] Furthermore, these electrochemical transformations
have been successfully transposed to an industrial scale.[9,13]
Compounds containing g-butyrolactone fragments exhibit
varied uses, for example as fungicidal,[14] antibiotic,[15,16] and
anticancer agents,[17,18] and therefore are of particular interest
in the pharmaceutical industry.[19–21] As a result, numerous
synthetic strategies have been developed to assemble sub-
stituted lactones rapidly and in good yields.[20] Generally,
these procedures rely on the use of expensive and toxic metal
catalysts at high loadings (ca. 5 mol% to multiple equiva-
lents) based on copper,[22,23] ruthenium,[15,24] palladium,[25] or
iridium[26,27] in order to increase yields, and with the exception
of halolactonisation,[28] examples of metal-free reactions
remain rare.[29,30] Unfortunately, these approaches are not
ideal due to their reliance on expensive and potentially toxic
metal catalysts and undesirable solvents, especially within
a pharmaceutical environment.
Aliphatic carboxylic co-acids were chosen as coupling
partners since they are known to undergo anodic decarbox-
ylation. Furthermore, they provide a cheap and readily
available source of alkyl radicals which undergo an unusual
metal-free sp3–sp3 cross-coupling at the surface of the
electrode (Table 1).[38] After optimisation,[40] it was found
that the substituted lactone 2 was formed in higher yields
(30%) when 1 was added to a methanolic solution of co-acid
and potassium hydroxide, with no lactone formation observed
in DMF or acetonitrile. Alcohols, water, as well as mixtures of
both are known to favour the mono-electronic anodic
oxidation of carboxylic acids while other solvents tend to
favour a bi-electronic oxidation.[13] Platinum has shown to be
[*] A. Petti, Dr. M. C. Leech, A. D. Garcia, Dr. I. C. A. Goodall,
Prof. Dr. A. P. Dobbs, Dr. K. Lam
Department of Pharmaceutical, Chemical and Environmental Scien-
ces, Faculty of Engineering and Science, University of Greenwich
Chatham Maritime, Chatham, Kent, ME4 4TB (UK)
E-mail: k.lam@greenwich.ac.uk
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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