Chemically Induced Anion Radical Cycloadditions: Intramolecular Cyclobutanation of Bis(enones) via Homogeneous Electron Transfer

Article abstract of DOI:10.1021/ja030543j

The first examples of anion radical cycloaddition induced by homogeneous electron transfer from chemical agents are described. Specifically, upon exposure to chrysene anion radical, bis(enone) substrates are found to engage in stereoselective intramolecular [2 + 2] cycloaddition. These studies, along with the corresponding electrochemically initiated reactions, provide insight into this fundamentally new pattern of reactivity and support the feasibility of expanding this novel reaction type. Copyright

Full text of DOI:10.1021/ja030543j

Published on Web 01/27/2004
Chemically Induced Anion Radical Cycloadditions: Intramolecular
Cyclobutanation of Bis(enones) via Homogeneous Electron Transfer
Jingkui Yang, Greg A. N. Felton, Nathan L. Bauld,* and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received September 19, 2003; Revised Manuscript Received November 18, 2003
Scheme 1. Postulated Mechanism for Chemically Induced Anion
Radical [2 + 2] Cycloaddition of Bis(enones)
The extensive body of cation radical cycloaddition chemistry
brought forth in recent years clearly establishes this reaction type
as a preferred and efficient reaction mode for cation radicals in
their combinations with neutral molecules.1,2 The possibility that a
similarly robust body of chemistry involving anion radicals might
exist is therefore of substantial interest. Indeed, the first examples
of anion radical cycloaddition, which involve the cyclobutanation
of activated alkenes initiated by heterogeneous electron transfer
from electrodes, have recently been reported.3 We now wish to
report the first examples of anion radical cycloaddition induced
by homogeneous electron transfer from chemical agents.4,5 Specif-
ically, upon exposure to chrysene anion radical, bis(enone) sub-
strates are found to engage in stereoselective intramolecular [2 +
2] cycloaddition. These studies, along with the corresponding
electrochemically initiated reactions, provide insight into this
fundamentally new pattern of reactivity and support the feasibility
of expanding this novel reaction type.
Table 1. Cyclobutanation of Bis(enones) 1a-1f Promoted by
Chrysene Anion Radicala
Recently, an intramolecular Co-catalyzed [2 + 2] cycloaddition
of bis(enones) was discovered by one of the present authors.4
Mechanistic studies pertaining to this transformation implicate Co-
complexed anion radicals as reactive intermediates.3c,4 This finding
stimulated interest in the broader, more significant question of
whether pericyclic processes are generally amenable to promotion
via single-electron transfer. To explore this possibility, bis(enone)
1a was exposed to an assortment of aromatic anion radicals.
Gratifyingly, exposure of 1a to chrysene anion radical at -78 °C
in THF results in the formation of the [2 + 2] cycloaddition product
cis-2a and the [4 + 2] cycloaddition Diels-Alder adduct 3 as single
stereoisomers. Reductive cyclization-aldolization product 4 and
the simple reductive cyclization product 5 are also obtained.6 The
anion radicals of anthracene and naphthalene were found to induce
cycloaddition; however, the most favorable results are obtained
using chrysene anion radical. Transformations carried out at higher
temperatures were found to produce large quantities of oligomeric
and polymeric materials. The [2 + 2] cycloaddition mechanism is
believed to involve nonconcerted C-C bond formation via inter-
mediacy of a distonic anion radical, as previously proposed for the
electrochemically promoted transformation (Scheme 1).
substrate
cis-2 (yield%)b
3 (yield%)b
4 (yield%)b
5 (yield%)b
1a
1b
1c
1d
1e
1f
31.5
35.0
60.4
61.7
50.8
41.4
9.2
5.0
-
-
9.8
4.0
20.1
35.8
14.0
18.0
16.4
8.0
2.9
-
4.0
10.0
16.4
6.2
a RepresentatiVe Procedure: To a solution of 1c (50 mg, 0.109 mmol,
100 mol %) in THF (3 mL, 0.036 M) at -78 °C, was added over a period
of 15 s a solution of chrysene anion radical (0.077 mmol, 70 mol %) in
THF (0.9 mL, 0.086 M). After a reaction time of 3.5 min, the reaction
mixture was quenched with aqueous ammonium chloride solution and then
partitioned between water and dichloromethane. The organic layer was
separated, dried (Na2SO4), filtered, and evaporated to give the crude reaction
products. b Isolated yield after purification by silica gel chromatography.
Under these conditions, anion radical cycloaddition of assorted
aromatic bis(enones) was explored. It can be noted from Table 1
that the yields of cis-2 are modest in the case of substrates 1a and
1b primarily because of the competing formation of 4 and 5.
Products 4 and 5 appear to derive from dianions formed by over-
reduction of the intermediate distonic anion radical.7 That is, the
distonic anion radical can either engage in cycloaddition to afford
the cyclobutane or Diels-Alder products or accept a further electron
to give a dianion. Protonation of the latter can lead to either 4 or
5. It is noteworthy and expected that, when the benzoyl substituents
of 1a are replaced by acetyl or carboethoxy groups, neither
cyclobutane nor Diels-Alder products are formed, since the second
bond-forming step would then require placement of the anion radical
moiety in the LUMO of an acetyl or ester group, either of which
is much higher in energy than the LUMO of a benzoyl group.
The proposed stepwise nature of the cycloaddition suggests that,
if the anion radical moiety in the cyclobutane product could reside
in a still lower-energy LUMO than that of the parent benzoyl group,
the rate of the second C-C bond formation might be enhanced
such that formation of cyclobutane products would be favored over
formation of dianionic products. This hypothesis was investigated
by examining the reactions of 1c and 1d, which provide more
extensive delocalization of the anion radical moiety than does the
benzoyl moiety. In both of these cases the yield of pericyclic
products is observed to be substantially increased and that of the
dianion-type products diminished. Of special interest is the observa-
tion that the Diels-Alder products 3c and 3d were not observed.
Since neither the trans-cyclobutane nor the Diels-Alder product
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J. AM. CHEM. SOC. 2004, 126, 1634-1635
10.1021/ja030543j CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Electrochemically Promoted Cyclobutanation of
Bis(enones) 1a, 1b, 1d, and 1ea
is formed, cycloaddition in these cases is highly stereo- and
periselective.
The pronounced cis-diastereoselectivity is presumed to derive
from relatively strong electrostatic interactions between the sodium
ion and both carbonyl oxygens in the transition state for cyclization.
Although the anion radical moiety is presumed to reside primarily
upon just one of the aroyl groups in the product anion radical, it
appears plausible that in the transition state the anion radical moiety
is substantially delocalized over both benzoyl groups. The circum-
stances under which the Diels-Alder product is not formed at all
are attractive synthetically but are also of particular interest
mechanistically. The most intriguing possibility is that, as a result
of enhanced thermodynamic driving force, the cyclobutanation may
have become concerted. The more likely possibility, however, is
that the second cyclization step may have become so rapid that the
bond rotations which may be necessary in order to generate the
conformations appropriate for Diels-Alder formation may be too
slow to compete with the covalent bond formation which leads to
the cyclobutane product.
The further possibility of accelerating the rate of the second
cyclization step, and therefore increasing the yield of pericyclic
products, by installing electron-withdrawing groups on the aromatic
ring was also investigated. As demonstrated by the reaction of
substrate 1e, a 4-chloro substituent is indeed observed to signifi-
cantly enhance the yield of cyclobutane product cis-2e, but in
contrast to the results obtained for 1c and 1d, a small amount of
Diels-Alder adduct 3e is also formed. Notably, products of
dechlorination are not observed. Finally, with increased chloro
substitution, as in the case of 3,4-dichlorobenzoyl-derived bis(enone)
1f, the yield of pericyclic products is relatively modest. In this case
a large amount of polymer formation is observed, suggesting the
anion radical moiety may now be too stabilized for efficient
intramolecular cycloaddition.
In all cases, these chemically induced cycloadditions appear to
be stoichiometric, rather than catalytic radical chain processes.
Optimum yields were obtained when about 70-120 mol % of the
chrysene anion radical was used relative to the substrate. Quite
possibly, tight ion-pairing of the sodium ions with the product anion
radicals in the somewhat nonpolar solvent has the effect of retarding
the rate of intermolecular electron transfer to substrate molecules,
which would be required for chain propagation. Notably, although
four products are formed in some cases, the cyclobutane products
cis-2a-cis-2f are predominantly the major reaction products (Table
1). Finally, use of samarium iodide failed to generate any cyclo-
butane products. Instead, the previously mentioned aldol-type
products were formed in a reaction requiring 2 mol of samarium
iodide.
For selected substrates, electrochemical promotion of the cy-
cloaddition was examined. For cycloadditions conducted under
electrochemical conditions, reduction of the distonic anion radical
intermediate does not contribute as a competitive reaction pathway.
However, both cis- and trans-cyclobutane isomers are formed, as
would perhaps be expected considering the relatively more polar
solvent involved and the steric characteristics of the tetrabutylam-
monium counterion, both of which would tend to diminish ion-
pairing interactions. The total yields of pericyclic products are seen
to be quite good, and since the cis-cyclobutanes are readily
converted to the more stable trans-cyclobutanes,4 the procedure
affords a high-yielding approach to the latter. As with the chemical
procedure, no pericyclic products are formed when the COY groups
are acetyl or ester. An especially attractive feature of the electro-
chemical procedure is that it is electrocatalytic, furnishing modest
turnovers of between 3 and 5 (Table 2).
cis-2
trans-2
3
pericyclic products
(total yield%)
substrate
(yield%)b
(yield%)b
(yield%)b
1a
1bc
1d
1e
17.1
38.8
14.4
11.1
58.6
20.9
28.9
52.0
12.6
28.4
8.2
88.3
88.1
51.3
74.7
11.6
a RepresentatiVe Procedure: To a flask charged with 1a (100 mg, 0.329
mmol, 100 mol %) under a positive flow of N2(g) was added 22 mL of a
0.1 M solution Bu4NBF4 in acetonitrile. This solution was added to the
working electrode (WE) compartment, and a further 6 mL of the electrolyte
solution was placed in the counter electrode (CE) compartment. Reticulated
carbon electrodes were used for the WE and CE, alongside a silver wire
“pseudo-standard” reference electrode (RE) encased in porous Vycor glass.
The solution was subjected to electrolysis at constant voltage, with stirring
under an atmosphere of N2(g) at room temperature, between -1.5 and -2.0
V vs RE. Upon complete consumption of starting material, the reaction
mixture was partitioned by between water and benzene. The organic layer
was separated, dried (Na2SO4), filtered, and evaporated to give the crude
reaction products. b Isolated yield after purification by silica gel chroma-
tography. c For 1b, MgClO4 was used as electrolyte and electrolysis was
performed at -2.5 to -3.0 V.
further variation of the single-electron reductant. The scope of these
transformations, including intermolecular cross-cyclobutanation and
Diels-Alder cycloaddition, and their reaction mechanisms are
currently under active investigation in these laboratories.
Acknowledgment. This research was supported, in part, by the
Robert A. Welch Foundation (F-149, N.L.B.) and the NIH (RO1
GM65149-01, M.J.K.).
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). Single-crystal
X-ray crystallographic data for compounds cis-2b, trans-2b, 3b, and
4b (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Bauld, N. L. Tetrahedron 1989, 45, 5307.
(2) Bauld, N. L. In Electron Transfer in Chemistry; Balzani, V., Ed.; Wiley-
VCH: Weinheim, 2001; Vol. 2, p 133.
(3) For electrochemically induced anion radical cyclobutanation, see: (a)
Delaunay, J.; Mabon, G.; Orliac, A.; Simonet, J. Tetrahedron Lett. 1990,
31, 667. (b) Jannsen, R.; Motevalli, M.; Utley, J. H. P. J. Chem. Soc.,
Chem. Commun. 1998, 539. (c) Roh, Y.; Jang, H.-Y.; Lynch, V.; Bauld,
N. L.; Krische, M. J. Org. Lett. 2002, 4, 611.
(4) Anion radicals haVe been implicated as reactiVe intermediates in the Co-
catalyzed [2 + 2] cycloaddition of bis(enones): (a) Baik, T.-G.; Wang,
L.-C.; Luiz, A.-L.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 6716. (b)
Wang, L.-C.; Jang, H.-Y.; Lynch, V.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 9448.
(5) For other pericyclic reactions of anion radicals, see: (a) Bauld, N. L.;
Chang, C.-S.; Farr, F. R. J. Am. Chem. Soc. 1972, 94, 7164. (b) Bauld,
N. L.; Cessac, J.; Chang, C.-S. Farr, F. F.; Holloway, R. J. Am. Chem.
Soc. 1976, 98, 4561. (c) Fox, M. A.; Hurst, J. R. J. Am. Chem. Soc. 1984,
106, 7626. (d) Borhani, D. W.; Greene, F. D. J. Org. Chem. 1986, 51,
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Chem. 1989, 54, 3544.
(6) â,â-Coupling of bis(enones) with and without subsequent aldolization has
previously been observed under the conditions of electron transfer. For
selected examples, see: (a) Enholm, E. J.; Kinter, K. S. J. Am. Chem.
Soc. 1991, 113, 7784. (b) Hays, D. S.; Fu, G. C. J. Org. Chem. 1996, 61,
4.
(7) It appears unlikely that the aldol-type cyclization occurs at the stage of
distonic anion radical in view of the fact that aldol type products are not
formed in the electrochemical reactions, which also involve distonic anion
radical intermediates.
In summation, we report the first anion radical cycloadditions
mediated by chemical agents in solution. The present results clearly
suggest the feasibility of expanding this new reaction type through
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