Anion radical chain cycloaddition of tethered enones: Intramolecular cyclobutanation and Diels-Alder cycloaddition

Article abstract of DOI:10.1021/ol0172065

(formula presented) The anion radicals of certain bis(enones), generated by cethodic reduction, are observed to participate in intramolecular cyclobutanation, yielding bicyclo[3.2.0]heptane derivatives through an anion radical chain mechanism. Evidence fo

Full text of DOI:10.1021/ol0172065

ORGANIC
LETTERS
2
002
Vol. 4, No. 4
11-613
Anion Radical Chain Cycloaddition of
Tethered Enones: Intramolecular
Cyclobutanation and Diels−Alder
Cycloaddition
6
,†
Yeonsuk Roh, Hye-Young Jang, Vincent Lynch, Nathan L. Bauld,* and
Michael J. Krische*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received December 10, 2001
ABSTRACT
The anion radicals of certain bis(enones), generated by cathodic reduction, are observed to participate in intramolecular cyclobutanation,
yielding bicyclo[3.2.0]heptane derivatives through an anion radical chain mechanism. Evidence for stepwise cycloaddition involving distonic
anion radical intermediates is presented. In addition to the novel anion radical cyclobutanations, an unprecedented intramolecular anion
radical Diels−Alder product is observed. Parallel trends in substrate scope vis- a` -vis the Co-catalyzed bis(enone) cyclobutanation are discussed.
Recently, one of the present authors reported an intra-
substrates, some parallel trends in the metal-catalyzed and
electrochemically promoted processes are revealed.
molecular cobalt-catalyzed [2 + 2]cycloaddition of tethered
1
enones. Given the requirement of aroyl-substituted enone
Anion radical chain cycloadditions are of intrinsic interest.
Whereas cation radical chain cycloadditions, including
cyclobutanation, Diels-Alder cycloaddition, and cyclopro-
partners, the ease of reduction of the bis(enone) substrates
and structural analogy to previously reported anion radical
3
2
panation, are now well-known, only two reports of anion
cyclobutanations, it appeared reasonable to consider mech-
radical chain cycloadditions are reported in the literature.2
These studies describe the cyclobutanation of vinyl sulfone,
vinylarene, and vinylheteroarene precursors. In both in-
stances, cyclodimerization is proposed to occur through a
chain mechanism involving the cycloaddition of a substrate
anion radical to a neutral substrate molecule. Subsequent
intermolecular electron transfer from the anion radical of the
cyclized product to a neutral reactant molecule regenerates
the substrate anion radical to propagate the chain. Here, we
anisms invoking the intermediacy of anion radicals. To
evaluate the plausibility of metal-catalyzed anion radical
pathways and potentially expand the scope of these little
known anion radical chain cycloadditions, the electrochemi-
cally promoted anion radical cycloadditions of several bis-
(enones) were investigated. Upon examination of a range of
†
E-mail: bauld@mail.utexas.edu.
(
1) Baik, T.-G.; Wang, L.-C.; Luiz, A.-L.; Krische, M. J. J. Am. Chem.
Soc. 2001, 123, 6716.
2) (a) Delaunay, J.; Mabon, G.; Orliac, A.; Simonet, J. Tetrahedron
(
(3) Bauld, N. L. Tetrahedron 1989 47, 5307. Bauld, N. L. In Electron
Transfer in Chemistry; Balzani, V., Ed.; Wiley-VCH: Weinheim, 2001;
Vol. 2, p 133.
Lett. 1990, 31, 667. (b) Jannsen, R.; Motevalli, M.; Utley, J. H. P. J. Chem.
Soc., Chem. Commun. 1998, 539.
1
0.1021/ol0172065 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/18/2002

present evidence for a stepwise cycloaddition mechanism
involving anion radical intermediates. In addition to products
of cyclobutanation, an unprecedented intramolecular anion
radical mediated Diels-Alder product is observed.
required for the complete conversion of 1a. However, the
amount of dimeric and polymeric products increased to 52%.
The formation of both cis- and trans-2a, along with the
monocyclic product 4a (also a 2:1 mixture of cis/trans
isomers), suggests a stepwise cycloaddition process involving
the intermediacy of the distonic anion radical of 4a formed
via â-â coupling of the monoenone monoanion radical of
1a. The distonic anion radical of 4a contains both enolate
anion and enolyl radical moieties and is subject to R-R
coupling to yield the anion radical of 2a. This coupling is
presumably made energetically feasible by the presence of
the benzoyl moiety owing to delocalization of the incipient
anion radical onto both the carbonyl and phenyl moieties.
Chain propagation is achieved by an exergonic electron
transfer from the anion radical of 2a to neutral 1a. For the
anion radical of 4a, coupling between the enolate oxygen
and the R-carbon of the enolyl radical is also possible and
gives rise to the formal hetero-Diels-Alder type adduct 3a.
Once again, a benzoyl group serves to stabilize the anion
radical derived upon six-membered ring formation and
exergonic electron transfer to starting material propagates
the chain mechanism (Scheme 2).
The substrate initially chosen for study was phenyl-
substituted bis(enone) 1a. Cyclic voltammetry revealed the
peak reduction potential of 1a to be -1.20 V versus SCE.
Reduction was irreversible. To promote a chain process,
reduction was carried out at a voltage (-0.90 V) well below
that of the peak reduction potential using reticulated vitreous
carbon working electrodes. It was subsequently verified that
for reductions carried out at -1.50 V, essentially only
dimerization and oligomerization result. Presumably, reduc-
tion at the lower voltage results in lower current densities
and lower steady-state concentrations of the anion radical.
Under these conditions, generation of bis(anion radical)
intermediates is attenuated.
Given these considerations, a 0.02 M solution of 1a in
electrolyte solution (0.1 M LiClO in acetonitrile) at ambient
4
temperature was subjected to electrochemical reduction. The
reduction was found to be essentially complete when only
30% of the theoretically required electrical charge had been
passed, i.e., the starting material was completely consumed
and the current had dropped to near zero. The overall yield
of isolated products was 76%, with polymeric products
accounting for the remaining mass balance. The products
formed include the same bicyclic isomer cis-2a formed in
the cobalt-catalyzed reaction, the corresponding stereoisomer
trans-2a, and the unprecedented Diels-Alder cycloaddition
product 3. The total yield of these three bicyclic products is
Scheme 2. Postulated Stepwise Mechanism for Anion Radical
Cyclobutanation
45%, and the ratio of cis-2:trans-2:3 is 2:2.4:1. In addition
to these bicyclic products, the monocyclic product 4a and
the corresponding aldol product 5a were formed in 21% and
1
0% yields, respectively. The structural assignment of 5a
was corroborated by X-ray crystallographic analysis (Scheme
).
1
Scheme 1. Cathodic Reduction of 1a
In addition to bicyclic products 2a and 3a, monocyclic
product 4a and related aldol product 5a also are observed.
These compounds are presumed to arise via protonation of
the distonic anion radical of 4a, followed by reduction of
the remaining radical to an enolate anion and protonation of
the latter. A portion of cis-4 is then converted to the
corresponding aldol addition product 5a. The formation of
both cis- and trans-2a, coupled with the formation of 4a,
provides evidence that the cycloadditions occur through a
stepwise mechanism involving the anion radical of 4a.
With regard to the mechanism of the cobalt-catalyzed
cyclobutanation, parallel trends in substrate scope with
respect to the electrochemically promoted reaction would
lend support for a mechanism involving anion radical
intermediates. In sharp contrast to the dibenzoyl enone 1a,
the corresponding bis(4-methoxybenzoyl) derivative 1b does
Since chain propagation requires an intermolecular electron
transfer to neutral substrate, it appeared possible that
increasing the initial concentration of 1a would facilitate the
chain process. Indeed, when the initial concentration of
substrate was doubled (to 0.04 M), only 17% of the
stoichiometrically required amount of electrical charge was
2
not undergo cyclobutanation in the presence of the Co(dpm) /
silane catalysts system, instead favoring the Michael cyclo-
4
reduction pathway. In terms of a possible anion radical
mechanism, the bis-anisoyl derivative 1b should be more
612
Org. Lett., Vol. 4, No. 4, 2002

difficult to reduce than the parent benzoyl derivative 1a.
Under electrochemical conditions, generation of the anion
radical of the bis(anisoyl) derivative 1b should be possible,
although a more negative potential should be required. The
CV study of 1b revealed a peak reduction potential at -1.30
V. Again, reduction was irreversible. The peak reduction
potential of 1b is ca. 0.1 V more negative than that of 1a.
Consequently, the reduction of 1b was carried out at -1.0
V. Reduction occurred under these conditions, and starting
material was consumed, but no bicyclic products were
formed. Instead, dimers and oligomers of unknown structure
and monocyclic products analogous to 4a were observed.
This suggests a likely explanation for the failure of 1b to
undergo cycloaddition: the formation of the second bond
would require the anion radical moiety to reside upon an
anisoyl moiety, which is less capable of stabilizing negative
charge than a simple benzoyl group.
of 1f at -1.0V at an initial concentration of 0.02 M, a 21%
yield of bicyclic cyclobutanated products were obtained.
Additionally, the tricyclic aldol-cyclodehydration product
6f, characterized by single-crystal X-ray diffraction, was
isolated in 10% yield. At lower concentration (0.003 M),
the yield of 1f is increased to 35% and tricycle 6f is not
observed. Interestingly, irrespective of concentration, no
monocyclic products analogous to 4a are detected. For 1f,
the observation of cycloaddition products under cathodic
reduction parallels the result obtained in the cobalt-catalyzed
reaction of 1f, where the cis-exo-bicyclic product is formed
exclusively in 63% yield (Scheme 3).
Scheme 3. Cathodic Reduction of 1f
The CV study of the mixed anisoyl 4-nitrobenzoyl bis-
(enone) 1c revealed a reduction potential of -1.00 versus
SCE. Here, reduction was found to be reversible. Reversible
reduction is attributed to the formation of a relatively long-
lived anion radical, which is stabilized by the 4-nitrobenzoyl
moiety. The reaction of this substrate was carried out at -0.8
V and failed to yield any bicyclic or monocyclic products,
instead providing dimers and oligomers. Presumably, this
relatively stable anion radical is unable to effect even the
first bond formation. Reaction of this substrate in the
The present results provide new examples of a relatively
uncommon reaction type, anion radical chain cyclobutana-
tion. Furthermore, an example of a previously unprecedented
anion radical chain Diels-Alder cycloaddition has been
brought to light. As such, these studies provide a starting
point from which the scope of these new reaction types may
continue to broaden, as has proved to be the case for cation
radical chain cycloadditions. With regard to the mechanism
of the related cobalt-catalyzed reactions, substantial differ-
ences in stereoselectivity and the formation of products 3-6
render somewhat uncertain the assignment of a pure anion
radical mechanism. However, these differences may arise
from substantial changes in solvent polarity (acetonitrile vs
2
presence of the Co(dpm) /silane catalysts system exclusively
favors the cycloreduction pathway over cycloaddition.
Finally, substrates 1d and 1e each fail to undergo intra-
molecular cycloaddition under cathodic reduction conditions
or via cobalt catalysis (Figure 1).
1,2-dichloroethane) and, most significantly, ion-pairing state
in the two reaction types. Given the parallel trends in
substrate scope, in particular the requirement of benzoyl-
substituted enone partners, anion radical character of the
cobalt-catalyzed reactions, which is significantly modulated
by the presence of tightly ion-paired organocobalt species,
cannot be excluded.
Figure 1. Additional bis(enone) substrates.
Acknowledgment. The authors thank the Robert A.
Welch Foundation (F-149 and F-1466), the NSF-CAREER
program, the donors of the Petroleum Research Fund,
administered by the American Chemical Society, and the
CMC of UT Austin for partial support of this research.
The key role of the benzoyl group in stabilizing the anion
radical moiety of the product is evident from the mechanism
depicted in Scheme 2. However, this mechanism does not
require the presence of two benzoyl groups, suggesting that
the mixed benzoyl/acetyl-substituted bis(enone) 1f (peak
reduction potential of -1.14 V) might be a suitable substrate
for anion radical cyclobutanation. Upon cathodic reduction
1
13
Supporting Information Available: H NMR, C NMR,
and HRMS data for all new compounds. X-ray crystal-
lographic data for 5a and 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
(4) Wang, L. C.; Jang, H.-Y.; Luiz, A. L.; Baik, T.-G.; Krische, M. J.
Submitted.
OL0172065
Org. Lett., Vol. 4, No. 4, 2002
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