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J. J. Lee, G. A. Kraus / Tetrahedron Letters 54 (2013) 2366–2368
The scope was further explored by preparing ketals from their cor-
responding ketones, which occurred in nearly quantitative yields
and could be used without additional purification. As with 4a,
the ketal 4b derived from acetophenone functions as an equivalent
of the phenylacetylene dienophile, both of which result in the same
observed regioselectivity for 5b.16 In effect, 4b provides an
alternative entry to substituted biphenyl systems with several
applications17–19 as a metal-free supplement to Suzuki cross-cou-
pling.20,21 While the examples thus far concentrate on altering
the substituents on the aromatic ring, the methodology was direc-
ted toward an annulation strategy to assemble fused bicyclic
compounds. The more highly substituted ketal 4c leads to a 1,2-
disubstituted vinyl ether intermediate to afford 5c in 81% yield.
Multiple routes22–24 have employed 5c as a target, one of which
included a Diels–Alder reaction with methyl coumalate, but it in-
volved the inconvenient preparation of a cyclohexyne dienophile.25
The aforementioned aromatic compounds installed functional-
ity with a carbon atom directly attached to the aromatic ring. How-
ever, the use of orthoesters allows the introduction of an oxygen
bond on the aromatic ring. Commercially available trimethyl ort-
hoacetate (4d) was evaluated as a dienophile to lead to anisole
5d, with numerous biological applications26,27 and potential for
deprotection to unmask its phenolic character. More importantly,
4d can be equated to the dienophiles methoxy ethyne or the corre-
sponding ketene acetal. The former is not commercially available,
and the latter has literature precedent with 2-pyrones,28,29 but is
labile. Trimethyl orthopropionate (4e) reacted with 1 to afford a
quantitative yield of 5e, cleanly establishing the trisubstituted
aromatic ring. On the contrary, an earlier Diels–Alder attempt with
4-methoxy-5-methyl pyrone and methyl propiolate resulted in a
non-selective 51:49 mixture of regioisomers.14 Orthoester 4f pro-
vided chloroester 5f, which has been experimentally purified from
a mixture of isomers30 by multi-step routes.31 The halogen would
rapidly enable the modification to advanced systems, as it has the
essential functionality for organometallic coupling. Consequently,
the relevance of our Diels–Alder approach with orthoesters is val-
idated with the ability to expeditiously generate tri-substituted
aromatic products with substantial applicability.32–34
References and notes
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In summary, we have discovered a novel methodology based on
a Diels–Alder sequence between methyl coumalate and readily
accessible vinyl ethers, ketals, or orthoesters. Advantageously, all
dienophiles are either commercially available or prepared in one
step and can be used without purification. The regioselective,
high-yielding, and single-pot experimental procedure expediently
delivers substituted aromatic systems compared to previous routes
that were either not selective for a single target, involved multi-
step syntheses, or required the use of palladium catalysts. The
methodology is a versatile and divergent platform as it can accom-
modate simplified dienophiles to generate an expansive range of
aromatic or biphenyl systems.
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Acknowledgment
We would like to thank the NSF Engineering Center for
Biorenewable Chemicals which was awarded NSF grant
EEC-0813570 for support of this research.
Supplementary data
Supplementary data associated with this article can be found, in