The direct acyl-alkylation of arynes

Article abstract of DOI:10.1021/ja050859m

An efficient and mild acyl-alkylation of arynes is described. The method is used to synthesize medium-sized carbocycles by the ring-expansion of cyclic β-ketoesters. Copyright

Full text of DOI:10.1021/ja050859m

Published on Web 03/26/2005
The Direct Acyl-Alkylation of Arynes
Uttam K. Tambar and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received February 9, 2005; E-mail: stoltz@caltech.edu
Table 1. Acyl-Alkylation of Benzyne
While arynes have historically received much attention from
physical organic chemists, their use as reagents in synthetic organic
chemistry has been somewhat limited.1 This is partially attributable
to the harsh conditions needed to generate arynes and the often
uncontrolled reactivity exhibited by these species. In 1983, Koba-
yashi described a mild method for the in situ preparation of benzyne
(i.e., 3) at moderate temperatures that exploits the fluoride-induced
elimination of ortho-silyl aryltriflates (e.g., 1).2 In conjunction with
our recent efforts to synthesize stereogenic quaternary carbon
centers,3 we envisioned that arynes generated by this method could
serve as a platform for the production of quaternary benzylic
stereocenters. Specifically, we anticipated that the mild conversion
of 1 to benzyne (3) in the presence of â-ketoester 2 would produce
6 (Scheme 1). To our surprise, in addition to obtaining the expected
â-ketoester 6, we observed the interesting ortho-substituted product
7 in comparable yield. The acyl-alkylation product 7 is the net result
of benzyne insertion into the R,â C-C single bond of the
â-ketoester, presumably by a formal [2 + 2] cycloaddition/
fragmentation cascade (i.e., 1 f 3 f 4 f 5 f 7). While aryne
insertions into heteroatom-hydrogen4 and heteroatom-carbon5
bonds have been reported under mild conditions, we were intrigued
by our result because it represents the first mild and direct aryne
insertion into a carbon-carbon bond.6 Herein, we describe our
explorations into the scope of this acyl-alkylation of arynes as an
efficient method for the generation of interesting ortho-disubstituted
arenes and benzannulated carbocycles.
As we began our investigation into the formation of the acyl-
alkylation product, we hypothesized that â-ketoesters lacking
R-substitution may form the putative benzocyclobutene intermediate
(i.e., 5b) more readily, thus suppressing the R-arylation product.
In support of this hypothesis, higher yields of the ortho-disubstituted
product were obtained from the treatment of non R-substituted
â-ketoesters (i.e., 8a-h) with 1 in the presence of CsF (Table 1).
The reaction tolerates substitution at the γ-position (entries 2-6),
including aliphatic and aromatic groups. Heteroatoms may also be
incorporated into the â-ketoester side chain, albeit in slightly lower
yields (entry 5). Additionally, the ester moiety can be varied while
maintaining the efficiency of the reaction. For example, â-ketoesters
of more complex alcohols such as menthol and cholesterol provide
a 1.25 equiv of 1 relative to â-ketoester 8. b Isolated yield. c 2 equiv of
1 relative to 8d.
Scheme 1
the desired acyl-alkylation products in good yield (entries 7 and
8). In general, the mild reaction conditions allow for a considerable
degree of substitution on the â-ketoester subunit.
We next examined the coupling of substituted aryne precursors
10a-c with methyl acetoacetate (Table 2). To our delight, this
simple â-ketoester reacted with arynes possessing monosubstitution
at the ortho- and meta-positions (entries 1 and 2) as well as
disubstitution (entry 3) to produce high yields of the corresponding
acyl-alkylation products (11a-c). Additionally, entries 1 and 3
demonstrate that heteroatom substituents are well-tolerated. Of
particular note is the complete regioselectivity and excellent isolated
yield observed in the coupling of methoxy substituted aryne
precursor 10a with 8a. This high selectivity points toward stepwise
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10.1021/ja050859m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Acyl-Alkylation of Substituted Arynes
occurred, presumably due to steric congestion en route to the key
benzocyclobutene. Nevertheless, we believed that these reactions
could provide efficient access to an interesting class of structures
that would otherwise be difficult to obtain. Specifically, we
envisioned that cyclic â-ketoesters would undergo ring expansion
to furnish medium-sized carbocycles, which continue to be difficult
structures to synthesize despite their prevalence in natural products
and drug substances.7 We applied our optimized conditions to a
series of cyclic â-ketoesters of varying ring size (Table 3, 12a-e).
Gratifyingly, we were able to synthesize seven-membered benzan-
nulated structures in synthetically useful yields by employing five-
membered ring â-ketoesters (entries 1-3). While the insertion into
a six-membered ring was less efficient (entry 4), the expansion of
a seven-membered ring furnished a nine-membered carbocycle in
69% yield (entry 5).
In summary, we have developed a mild, direct, and efficient
process for the acyl-alkylation of arynes to produce interesting
ortho-substituted arenes via an unusual reaction cascade. Overall,
the transformation results in the formation of two new C-C bonds
by the net insertion of an arene unit into the R,â single bond of a
â-ketoester. This facile methodology provides convergent, single-
step, high-yielding access to a variety of substituted arenes and
benzannulated structures that would otherwise be difficult to obtain.
Notably, cyclic â-ketoesters can be expanded to generate medium-
sized carbocycles. The utility of this intriguing reaction in complex
natural product synthesis is currently under investigation.
a 2 equiv of 10 relative to 8a. b Isolated yield. c 1.25 equiv of 10b relative
to 8a. d Mixture of meta- and para-regioisomers (1.2:1).
Table 3. Ring Expansion of Cyclic â-Ketoesters
Acknowledgment. This work is dedicated to our friend and
colleague Professor John D. Roberts, the father of benzyne.8 We
are grateful to the NDSEG (predoctoral fellowship to U.K.T.), the
A. P. Sloan Foundation, the Research Corporation, Pfizer, Novartis,
Merck, Amgen, Lilly, Roche, Abbott, AstraZeneka, GlaxoSmith-
Kline, and Caltech for financial support.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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a 1.25 equiv of 1 relative to â-ketoester 12. b Isolated yield. c In most
cases the R-arylated â-ketoester was isolated as the major side product.
See Supporting Information.
(8) (a) Roberts, J. D.; Semenow, D. A.; Simmons, H. E., Jr.; Carlsmith, L.
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production of the key benzocyclobutene intermediate, analogous
to the mechanism depicted in Scheme 1.
At this stage, we revisited â-ketoesters with R-substitution. We
anticipated difficulty for such reactions based on our original
observation that competitive formation of R-arylated products
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