Remarkably Facile Hexatriene Electrocyclizations as a Route to Functionalized Cyclohexenones via Ring Expansion of Cyclobutenones

Article abstract of DOI:10.1021/ja0399066

This Communication describes a cascade reaction sequence that leads to highly functionalized cyclohexenones starting from reaction of cyclobutenones with α-lithio-α,β-unsaturated sulfones and amides. The hexatriene-cyclohexadiene cyclization steps presumed to be involved in these transformations are among the most facile hexatriene electrocyclizations reported thus far. Copyright

Full text of DOI:10.1021/ja0399066

Published on Web 01/27/2004
Remarkably Facile Hexatriene Electrocyclizations as a Route to
Functionalized Cyclohexenones via Ring Expansion of Cyclobutenones
Nabi A. Magomedov,* Piero L. Ruggiero, and Yuchen Tang
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
Received December 2, 2003; E-mail: magomedov@chem.rochester.edu
Cascade electrocyclic reactions based on cyclobutene ring expan-
sion have been used for the synthesis of a variety of carbocyclic
systems.1 Transformations of cyclobutenones to the six-membered
carbocycles typically involve 6π-electrocyclic ring closure
(6π-ERC) of reactive intermediates of type 1, which incorporate
an sp carbon at the terminus of the 6π system to facilitate the ring
closure reaction.2 As a consequence, these reactions produce
products containing all sp2-hybridized ring carbons, such as phenols
and quinones. Reactions of cyclobutenones leading to the syntheti-
cally more versatile cyclohexenones by 6π-ERC of the parent 3-oxy
hexatrienes (2) have not been reported.3
with the two substituents at the adjacent stereocenters trans and
pseudoaxial was unequivocally established by X-ray crystal-
lographic analysis. Notably, reaction of 11 with â-(E)-lithiostyrene
stopped after the cyclobutene ring opening,6 indicating that the pres-
ence of an electron-withdrawing sulfonyl group in 10 was essential
for the 6π-ERC to occur. The mild conditions for the formation of
12 are noteworthy, because 6π-ERC of hexatrienes typically
requires thermal activation.7 The observed reactivity is comparable
to that of methylenepropenylidenecyclohexadienes, which undergo
fast thermal 6π-electrocyclic reactions proceeding at room tem-
perature.8
We believed that quenching the reaction between 10 and 11 at
low temperature (-78 °C) would allow for the isolation of reaction
intermediates. Indeed, this reaction produced alcohol 13 (61%) and
a ring-opened compound 14 (23%), the conjugated acids of the
two intermediates postulated in the reaction. Treatment of 13 with
LDA (1.2 equiv, -78 °C to room temperature) cleanly furnished
cyclohexenone 12 in 94% isolated yield.9 As expected, the reaction
of 10 with 4-methyl-3-phenylcyclobutenone produced the ring-
opened compound 15 as a single isomer at the double bond, indicat-
ing that the cyclobutene ring opening was conrotatory with an out-
ward rotation of the oxide group.10
In this Communication we describe a cascade reaction sequence
that leads to highly functionalized cyclohexenones starting from
reaction of cyclobutenones with R-lithio-R,â-unsaturated sulfones
and amides. The hexatriene-cyclohexadiene cyclization steps pre-
sumed to be involved in these transformations are among the most
facile hexatriene electrocyclizations reported thus far.
We imagined that reaction of enone 3 with vinyl anion 4 con-
taining an electron-withdrawing group at the anionic carbon, fol-
lowed by a charge-accelerated four-electron conrotatory ring open-
ing of the cyclobutene, would generate a hexatriene intermediate 7
(Scheme 1).4 The 6π-ERC of 7 was expected to be exceptionally
facile because bond reorganization leads to the more stable enolate
8. This cyclization can also be formally considered as an intramo-
lecular Michael addition of an extended enolate to an electron-
deficient alkene. We reasoned that R-lithiated R,â-unsaturated sul-
fones would be convenient nucleophiles for the proposed reaction.
These compounds can be generated by the reaction of readily avail-
able R,â-unsaturated sulfones with alkyllithiums or lithium amides.5
Having established proof of principle for the proposed cascade,
we next investigated the scope of the process (Table 1). Nucleo-
philes containing aromatic, heteroaromatic, and tert-alkyl substit-
uents were well tolerated (entries 1-4). Entry 4 illustrates the
potential of this reaction for the formation of cyclohexenones with
quaternary carbon centers.
Scheme 1. Proposed Transformation of Cyclobutenones into
Cyclohexenones
Interestingly, the sulfones containing allylic hydrogen atoms in
a trans relationship to the sulfonyl group displayed a different mode
of reactivity. Thus, the addition of 16 to 11 did not produce a cyclo-
hexenone but instead gave rise to the formation of an open-chain
enone 18 in 85% yield (eq 2). Apparently, this compound results
Initial experiments demonstrated that treatment of sulfone 9 with
n-BuLi at -78 °C, followed by addition of cyclobutenone 11 and
warming the reaction mixture to room temperature, produced the
desired cyclohexenone 12 in 81% yield (eq 1). The structure of 12
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10.1021/ja0399066 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Cyclohexenones from Cyclobutenonesa
also good candidates for this reaction (eq 4). Thus, reaction of 11
with 23, generated from bromide 22 by bromine/lithium exchange,
furnished the hydroisoquinoline derivative 24 in 52% isolated yield.
In summary, we demonstrated nucleophilic addition/4π-ring
opening/6π-ring closing cascade reactions between cyclobutenones
and R-lithio-R,â-unsaturated sulfones and amides leading to func-
tionalized cyclohexenones. Strategic incorporation of electron-
withdrawing groups at the C-2 of the 3-oxido hexatrienes signifi-
cantly lowers the activation energy of the 6π-eletrocyclizations,
which proceed under mild conditions.
Acknowledgment. We thank the Research Corporation and the
University of Rochester for financial support. We are grateful to
Dr. Christine Flaschenriem for the X-ray analyses.
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, and X-ray data (in CIF
format) for 12, 21, and bicyclic sulfone (Table 1, entry 6). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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a Conditions: THF, -78 °C to room temperature, 1-3 h. b Reaction
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cis isomer.
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Sigmatropic rearrangement can be circumvented by employing
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fone 19 with 11 proceeded via an 8π-ERC to produce 21 (eq 3),12
which exists in the enol form both in the solid state and in solution.
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The overall conversion outlined in Scheme 1 is not limited to
nucleophiles containing the sulfonyl activating group. Αmides are
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