Electrocatalytic reactions: anion radical cyclobutanation reactions and electrogenerated base reactions

Article abstract of DOI:10.1016/j.tetlet.2007.11.171

Intermolecular anion radical [2+2] cyclobutanation reactions have been observed between vinyl sulfones and vinyl/propenyl ketones. The products are novel and formed electrocatalytically, although yields are at best modest (11-45%). Competing mechanisms are discussed. Additionally, the electrochemical reduction of vinyl alkyl sulfones in acetonitrile leads to near quantitative formation of cyanomethylation product cyano-sulfones. The single step approach has electrocatalytic factors in excess of thirty.

Full text of DOI:10.1016/j.tetlet.2007.11.171

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 884–887
Electrocatalytic reactions: anion radical cyclobutanation reactions
and electrogenerated base reactions
Greg A. N. Felton *
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
Received 1 October 2007; revised 20 November 2007; accepted 27 November 2007
Available online 4 December 2007
Dedicated to Professor Nathan L. Bauld on the occasion of his retirement from the University of Texas at Austin
Abstract
Intermolecular anion radical [2+2] cyclobutanation reactions have been observed between vinyl sulfones and vinyl/propenyl ketones.
The products are novel and formed electrocatalytically, although yields are at best modest (11–45%). Competing mechanisms are
discussed. Additionally, the electrochemical reduction of vinyl alkyl sulfones in acetonitrile leads to near quantitative formation of
cyanomethylation product cyano-sulfones. The single step approach has electrocatalytic factors in excess of thirty.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cyclobutanation; Cyanomethylation; Phenyl vinyl sulfone; Electrocatalysis; Electrogenerated base
1. Introduction
radical chemical methods,5 the scope, limitations, and
mechanisms involved,6 and an intriguing diastereotopic
electrolyte effect.7 These systems are of special interest
because they represent rare examples of inter- or intra-
molecular anion radical cycloaddition, rather than the
Cyclobutanation reactions of the cation radicals of
alkenes with neutral alkenes have become rather common-
place and are characterized by high cycloaddition rates and
low activation barriers, especially in comparison to the
corresponding thermal reactions.1 There have been some
recent indications that this extensive body of cation radical
cyclobutanation chemistry may have a close counterpart in
the domain of anion radical chemistry. Specifically, the
reduction of phenyl vinyl sulfone under electrochemical
conditions (mercury pool cathode) has been reported
to yield trans-1,2-bis(phenylsulfonyl)cyclobutane.2 Subse-
quently, the cyclo-dimerizations of a variety vinylpyridines
and vinylquinolines under similar conditions have also been
established.3
more
common
electrohydrocyclization/dimerization
(EHC or EHD).8 This Letter intends to expand this field,
into vinyl ketone cross-cyclization with phenyl vinyl
sulfone.
The [2+2] cross-cyclobutanation is assumed to proceed
via anion radical to neutral substrate coupling, with rapid
subsequent cyclization via a distonic anion intermediate.
This is based upon an electrochemical/computational study
of phenyl vinyl sulfone cyclodimerization,9 and also the
previous ability to trap the distonic anion radical of the
analogous intramolecular enone case.6
A variety of intramolecular anion radical cyclobutana-
tions of tethered bis(enones) have been previously
described.4 This work has looked at competitive anion
The electrogenerated formation of cyanomethyl anions,
and subsequent addition reactions, was first reported thirty
years ago.10 This initial work expanded to a number of
systems where electroreduction of aromatic carbonyl
compounds lead to base formation, such that the substrates
were themselves in situ pro-bases (PB), analogous to a
previously published allyl phenyl sulfone system. The
*
Tel.: +1 609 258 3896; fax: +1 609 258 1980.
E-mail address: gfelton@princeton.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.171

G. A. N. Felton / Tetrahedron Letters 49 (2008) 884–887
885
difference lies in the lack of a readily removed proton from
the substrate, such that the substrate PB deprotonates the
acetonitrile solvent, giving a CH2CN carbanion.11 This
reactive species is then seen to undergo nucleophilic attack,
in the published case, upon the carbonyl group of the sub-
strate.12 An identical observation is made here, where alkyl
vinyl sulfones act as in situ PB’s to give simple cyano sul-
fones in a single step with near quantitative yield and high
electrocatalytic values.
particularly suggested by the more efficient cyclobutanation
of 1 alone, where a catalytic factor of around ten is quoted
for a near quantitative reaction,2,9,13 and side (charge con-
suming) reactions are minimized.
2.1. Phenyl vinyl sulfone (1) and 3-penten-2-one (2a)
The mixed-cyclobutanation of 3-penten-2-one (2a) and
phenyl vinyl sulfone (1) occurs readily, to give 3a
(Fig. 1), when a variety of substrate ratios are used. The
nominal peak mixed-cyclobutane yield occurs with a slight
2a excess, although there is no real variability (19–26%) in
yield from a 3.5-fold 2a excess to the reverse threefold 1
excess (Supplementary data). These results do not therefore
suggest an appropriate route for yield improvement, and
that a yield of around 25% may be maximal for this system.
This could be due to the electroreactivity of 2a under all
conditions, such that oligomerization limits substrate avail-
ability. The dephenylsulfonylation of trans-1,2-bis(phenyl-
sulfonyl)cyclobutane (5), to yield 6 (Fig. 2), is a clear
indication of the presence of electrogenerated bases
(EGB’s). Indeed, added pro-bases, which form EGB’s
upon reduction, have been used to produce good yields
of 6 from 5.15 EGB’s also lead to the formation of the
minor product 7a (<5% yield) via deprotonation of 2a
and subsequent addition to two moles of 1, analogous to
chemistry seen before for allyl phenyl sulfone.16
2. Cyclobutanations
The electrocyclobutanation of phenyl vinyl sulfone (1) is
well established,2,9 yet other vinyl compounds are not seen to
electrocyclobutanate (see Supplementary data). This maybe
due to polymerization or an EHD, however, reaction with 1
may prevent further reactivity, due the relative polymeric
passivity of 1. Therefore, mixed cyclobutanation products
should be feasible with vinyl compounds containing electron
withdrawing groups (see Scheme 1). While a large variety of
substrates were studied, the only class of substrates that
proved successful were ketones. The yields are generally
modest (Table 1), and appear to be depressed by a variety
of competing mechanisms (such as polymerization, and the
mechanisms highlighted below). The cross-cyclobutanes
formed are however novel, and crystal structures of several
are presented. While reactions are electrocatalytic in nature,
the true extent of catalysis is not well defined. Competing
mechanisms in solution, such as oligomerization or base
generation, also consume charge. This leads to a given
experiment apparently requiring more charge than is
strictly used by cyclobutanation. Thus, the catalytic factors
given are likely to be somewhat lower than those specifi-
cally engendered by the cross-cyclobutanation. This is
2.2. Methyl vinyl ketone (2b) and ethyl vinyl ketone (2c)
The reactions of two alkyl vinyl ketones with phenyl
vinyl sulfone were also investigated (Table 1). Unsurpris-
ingly, the methyl and ethyl vinyl ketones behaved near
identically, with cross-cyclobutane yields of around 30%.
R
R
a: R = Me, R' = Me.
+
b
: R = H, R' = Me.
: R = H, R' = Et.
e(carbon), -2.5 V
Et4NBF4, CH3CN
c
R'
PhO2S
O
PhO2S
d: R = Me, R' = Ph.
R'
2a-e
O
e
: R = Me, R' = Ph-Ph.
1
3a-e
Scheme 1. The intermolecular cyclobutanation reaction between phenyl vinyl sulfone and various vinyl ketones.
Table 1
Summary of the yields and catalytic factors of cyclobutanes (3) formed from cross-reaction of vinyl sulfones (1, 4) with ketones (2)
Sulfone
Ketone
Reaction ratio
% Yield
Catalytic factor14
1: Phenyl vinyl
1: Phenyl vinyl
1: Phenyl vinyl
1: Phenyl vinyl
1: Phenyl vinyl
4: Divinyl
2a: 3-Penten-2-one
1:2a = 1:1.7
1:2b = 1:2.9
1:2c = 1:2.9
1:2d = 1:4.0
1:2e = 1:4.0
4:2e = 4.0:1
3a: 26
3b: 28
3c: 32
3d: 45
3e: 28
3f: 11
6
5
9
2
6
2
2b: Methyl vinyl ketone
2c: Ethyl vinyl ketone
2d: Phenyl propenyl ketone
2e: Biphenyl vinyl ketone
2e: Biphenyl vinyl ketone
Experimental: 100–200 mg of two substrates, in the described mole ratio are electrolyzed at ꢀ2.5 V versus Ag wire, in 0.1 M Et4NBF4 acetonitrile, using a
reticulated vitreous carbon working electrode. Consumption of the starting materials was tracked by TLC, recording the amount of charge required. The
products are obtained by extraction and PTLC separation. See Supplementary data for more information.

886
G. A. N. Felton / Tetrahedron Letters 49 (2008) 884–887
Fig. 3. View of 3d showing the atom labeling scheme. Displacement
ellipsoids are scaled to the 50% probability level. Deposited as CCDC
659006.
promoted product. This product, 8, is formed via EGB
deprotonation of the substrate to give a carbanion, which
then adds to another mole of substrate, effectively giving
a dimer. Again, this mechanism is entirely analogous to
the self addition reaction observed for allyl phenyl
sulfone.16
Fig. 1. View of 3a showing the atom labeling scheme. Displacement
ellipsoids are scaled to the 50% probability level. Deposited as CCDC
659007.
5
7
6
8
O
S
O
O
S
S
Ph
Ph
2.4. Divinyl sulfone (4) and biphenyl propenyl ketone (2e)
Ph
O
O
O
O
The reaction between divinyl sulfone and biphenyl pro-
penyl ketone, using a 4:1 excess of 4, lead to a rather mod-
est 12% yield (Table 1) of the cross-cyclobutane 3f. While
attempts to improve upon this yield were unsuccessful, this
small yield does represent the only non-phenyl vinyl sul-
fone cyclobutanation obtained in this work, although a
vinyl sulfone moiety is still involved.
Ph
R'
O
O
PhO2S
SO2Ph
Ph
Fig. 2. Product 6 is the dephenylsulfonylation product of 5. Minor
products 7 and 8 are formed via the presence of electrogenerated base,
where R0 = Me (7a), Ph (7d) and Ph–Ph (7e).
3. Cyanomethylation
Increases in the excess of 1 boost yield, form ꢁ10% at 1:1
to ꢁ30% at 3:1 (Supplementary data). A fivefold excess
reaction actually led to no cyclobutane products, suggest-
ing a limit to this approach. The excess of phenyl vinyl sul-
fone readily dimerizes under these conditions (5), and leads
to the formation of the minor dephenylsulfonylation prod-
uct, 6, via EGB.
The reduction of two alkyl vinyl sulfones leads to effec-
tively quantitative cyanomethylation (Scheme 2), to give
the corresponding cyano sulfones, with large catalytic
factors of around 35 (Table 2). These products have been
synthesized by non-electrochemical means, in multi-step
e (carbon)
O
O
2.3. Phenyl and biphenyl propenyl ketones (2d and 2e)
S
S
Et4NBF4
CH3CN
N
R
R
O
O
The reactions of phenyl vinyl sulfone with phenyl prope-
nyl ketone represent the best cross-cyclobutanation yield
obtained, at 45% (see Fig. 3). It is thought that the reaction
proceeds via reduction of 2d/2e, and subsequent addition
to a neutral molecule of 1, due to the lower reduction
potential of 2d/2e and the observation that a 2:1 excess
of 2d over 1 gave polymeric products. However, increasing
the excess of 1, above twofold, gives only a slight increase
in cross-cyclobutane yield, from 37% to 45% at a fourfold
excess (Supplementary data).
9a-b
10a-b
Scheme 2. The cyanomethylation reaction, cyano sulfones, 10, formed via
single step where R = Me (10a) and Et (10b). Procedure is altered for
R = Ph (10c, see text).
Table 2
Yields of cyanomethylation of selected vinyl sulfones
Substrate
Yield of 10
Catalytic factor
Cyclobutanation was considered rather unlikely
between propenyl compounds, for steric reasons, so it
was not extensively studied. However, electrolysis of 2d
did give a modest 23% yield of an interesting EGB
9a: Methyl vinyl sulfone
9b: Ethyl vinyl sulfone
1: Phenyl vinyl sulfonea
a
10a: 94
10b: 96
10c: 31
38
36
5
Not directly reduced, added to reduced diphenyl sulfone solution.

G. A. N. Felton / Tetrahedron Letters 49 (2008) 884–887
887
processes, with 30% yield of 10a17 and a better 87% yield of
10b.18
(Fax: +44-1223-336033 or e-mail: deposit@ccdc.cam.ac.
uk). Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2007.11.171.
The process for cyanomethylating phenyl vinyl sulfone
(1) was necessarily different, as reduction yields the cyclo-
butane dimer, 5. Initially a pro-base, diphenyl sulfone
was co-reduced, yet this did not disrupt the anion radical
cyclobutanation process. However, by reducing this pro-
base in isolation, ex situ EGB generation, and then adding
1, appeared to give only 10c. Separation gave a rather mod-
est yield below the published value of 70%,18 although that
was via a multi-step synthesis. This pre-generation of base
may well be a way to access a variety of cyanomethylation
reactions that would not normally occur, due to the sub-
strates given electroreactivity.
References and notes
1. (a) Bauld, N. L. Tetrahedron 1989, 45, 5307–5363; (b) Bauld, N. L. In
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4. Summary
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7. Felton, G. A. N.; Bauld, N. L. Tetrahedron Lett. 2004, 46, 8465–8469.
8. (a) Fry, A. J.; Little, R. D.; Leonetti, J. J. Org. Chem. 1994, 59, 5017–
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The mixed reactant approach has lead to modest to rea-
sonable yields of novel ketone/sulfonyl cyclobutanes.
These compounds have been synthesized via an electrocata-
lytic mechanism. While this synthetic method may have
limited range, the use of more complex vinyl/propenyl
ketone compounds, with aroyl and alkyl variation may
expand the examples shown here. The presence, possibly
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is also confirmed. Indeed, electrogenerated bases are shown
to promote successful reactions in their own right.
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13. Crystallographic support for the known E-1,2-diphenylsulfonecyclo-
butane product is provided in the Supplementary data. Similar
electrocatalysis values and yields, to those published, are obtained.
14. A catalytic factor of 10 equates to a 0.1 F molꢀ1 process (10 reactions
per electron passing through the solution). Catalytic factors are found
using the moles of limiting reagent consumed, the charge consumed,
and 96,485 C molꢀ1, see: Hamman, C. H.; Hamnett, A.; Vielstich, W.
Electrochemistry; Wiley-VCH: Weinheim, 1998; pp 7–9.
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Acknowledgments
The author acknowledges the assistance of Nathan L.
Bauld and Jingkui Yang. And thanks the Robert A Welch
Foundation (F-149) for support of this research.
Supplementary data
Crystallographic data (excluding structure factors) for
3a and 3d, have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication
numbers CCDC 659007 and CCDC 659006, respectively.
Copies of the data can be obtained, free of charge, via
www.ccdc.cam.ac.uk/data_request/cif or on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
17. Truce, W. E.; Bannister, W. W.; Knopse, R. H. J. Org. Chem. 1962,
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