Communication
trimethylsilyl-substituted, or dialkyl alkynes all resulted in com-
plex mixtures.
However, conjugated enynes 4 proved to be excellent sub-
strates for oxidative annulation[18] and provided a range of spi-
rocyclic products 5 in high yields with superstoichiometric
Cu(OAc)2 (2.1 equiv) at 658C (Scheme 2). Appreciable variation
of the alkene component of the enyne is tolerated, with p-
methylstyryl (5a–e), vinyl (5f), benzyl enoate (5g–j), and cyclo-
hexenyl groups (5j)[19] all giving excellent results with a range
of electronically diverse 2-[1-(hetero)arylvinyl]phenols. Enynes
containing simple alkyl (5f–k) and oxygenated alkyl substitu-
ents (5a–e) on the alkyne were effective, and an unprotected
alcohol (5e) was also compatible. Furthermore, Scheme 2 illus-
trates the use of 2-(1-arylalkenyl)phenols not employed in the
examples shown in Table 1, such as those containing 2-chloro
(5b), 2-allyloxyl (5e), 2-hydroxy (5i), 3-chloro (5j), and 4-bromo
substituents (5k). Thienyl-containing substrates were also com-
patible with this process, despite the potential for catalyst poi-
soning (5c and d). The spiroannulation using enynes was also
effective using catalytic Cu(OAc)2 (5 mol%) under air, albeit
with a small reduction in yield, as illustrated by the formation
of spirocycle 5g in 87% yield, compared with 95% yield using
the standard conditions with 2.1 equivalents of Cu(OAc)2.
The dearomatizing oxidative spiroannulation is not limited
to substrates containing a (hetero)aryl substituent at the 1-po-
sition of the alkene, as illustrated by the reaction of 2-alkenyl-
phenol 6, which reacted with enyne 4d to give spirocycle 7 in
82% yield [Eq. (1)].
Scheme 3. Possible catalytic cycle.
with Et3N promoted an intramolecular 1,6-conjugate addition
of the phenoxide onto the dienone to give the highly func-
tionalized tetracycle 14 in 62% yield, along with recovered
starting material in 18% yield [Eq. (2)].
In summary, we have developed a catalytic CꢀH functionali-
zation method for the dearomatizing spiroannulation of 2-alke-
nylphenols with alkynes and enynes.[20] The process exhibits
good generality, leading to highly functionalized spirocyclic
compounds in high yields and regioselectivities from relatively
simple starting materials. Compared with prior art,[12] the pres-
ence of a naphthol in the substrate is not required, and dearo-
matization occurs with more readily available phenols. The de-
velopment of enantioselective variants of this process, along
with studies into other dearomatizing oxidative annulations,
are ongoing in our laboratories.
A possible catalytic cycle for these reactions is presented in
Scheme 3. Reaction of [{Cp*RhCl2}2] with Cu(OAc)2 forms the
rhodium diacetate complex 8, which can then participate in
a phenol-directed CꢀH functionalization of the alkene of the
substrate 1 to generate rhodacycle 9.[13] Coordination and mi-
gratory insertion of the alkyne then provides the rhodacycle
10. When R1 =H, CꢀO bond-forming reductive elimination of
10 results in benzoxepine 11, as reported previously.[13] In our
reactions, in which R1 ¼H, we speculate that isomerization of
10 into rhodacycle 12 occurs to relieve an unfavorable steric
interaction between R1 and the phenoxide ring, despite this
isomerization resulting in a decrease in conjugation. A CꢀC
bond-forming reductive elimination of 12 then gives the spiro-
cyclic product 3, 5, or 7 and Cp*RhI (13), which can then un-
dergo reoxidation by Cu(OAc)2 to regenerate 8.
Acknowledgements
We thank the ERC, EPSRC, GlaxoSmithKline, and the University
of Nottingham for financial support. We are grateful to the
EPSRC for a Leadership Fellowship to H.W.L.
Finally, to demonstrate the further synthetic utility of the
products, we exploited the presence of the electrophilic dien-
one and a nucleophilic phenol in spirocycle 5i. Treatment of 5i
Keywords: alkyne · CꢀH activation · enyne · phenol · rhodium
Chem. Eur. J. 2014, 20, 8599 – 8602
8601
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