Communications
DOI: 10.1002/anie.201100911
Multicomponent Reactions
Benzannulated Bicycles by Three-Component Aryne Reactions**
Kevin M. Allan, Christopher D. Gilmore, and Brian M. Stoltz*
Benzyne has been an integral tool for the discovery of new
multicomponent reactions for over 70 years.[1] In particular,
the ability to function as a relay species between a nucleophile
and an electrophile makes this reactive intermediate well
suited to the rapid preparation of 1,2-disubstituted arene
scaffolds.[2] In designing an approach toward new multi-
component aryne reactions, we began by considering reac-
tivity patterns of classic transformations. In the Passerini
synthesis of a-acyloxyamides (e.g., 6),[3] an aldehyde compo-
nent (1) acts as both an electrophile and a latent nucleophile
(i.e., 1!6)[4] during the course of the reaction (Scheme 1a).
protonation at the aryl anion. In order to avoid this outcome,
we envisioned that the third component be replaced with an
ester (9), which would instead undergo nucleophilic attack.
Subsequent expulsion of the alkoxide (ꢀOR4) to generate the
benzylic ketone and recombination with the nitrilium cation
would ultimately generate o-ketobenzimidate 10. Further
access to the corresponding o-ketobenzamide (11) could then
be gained through hydrolysis.
Our initial attempt to accomplish this three-component
transformation employed ethyl acetate with 2-(trimethylsi-
lyl)phenyl triflate (12a) and tert-butyl isocyanide (2a) in the
presence of tetra-N-butylammonium difluorotriphenylsilicate
(TBAT) (Scheme 2a). Unfortunately, this ester failed to
Scheme 1. a) Passerini reaction. b) Aryne analogue of the Passerini
reaction.
We postulated that this rudimentary mechanism could be
adapted to the synthesis of o-ketobenzamides (11) by replac-
ing the aldehyde component with an aryne (Scheme 1b). In
analogy to the formation of zwitterion 3, nucleophilic
addition of the isocyanide to benzyne (7) has been shown to
form aryl nitrilium 8.[5] In the presence of a carboxylic acid,
however, this intermediate would be expected to undergo
Scheme 2. a) Attempted three-component coupling using ethyl acetate.
b) Phenoxy iminoisobenzofuran synthesis by three-component cou-
pling of benzyne, tert-butyl isocyanide, and phenyl acetate.
provide the desired o-ketobenzimidate, instead producing
trace quantities of N-tert-butylbenzamide (13) through hydra-
tion of zwitterion 8 (R1 = tBu).[5] Reasoning that a more
electrophilic ester would display greater reactivity toward the
aryl anion, we decided to employ phenyl acetate (9a).
However, under the same conditions, we were surprised to
find that instead of the expected benzimidate, phenoxy
iminoisobenzofuran 14a was isolated in 60% yield. Presum-
ably, this heterocycle is formed through intramolecular attack
of the tetrahedral alkoxide on the nitrilium cation (15) and
results in formation of a formal dipolar cycloaddition product
(Scheme 2b),[6] akin to reactivity previously observed by
Yoshida and Kunai et al. using aldehydes[7] and aldimines.[8,9]
To our knowledge, this method represents the first prepara-
tion of a stable phenoxy-substituted iminoisobenzofuran.[10,11]
Intrigued by this new three-component coupling reaction
and the unusual heterocyclic scaffold observed in the product,
we examined the scope of the reaction. By altering the
stoichiometry of the reagents involved, optimized conditions
[*] K. M. Allan, C. D. Gilmore, Prof. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Boulevard, MC 101-20, Pasadena, CA 91125
(USA)
Fax: (+1)626-395-8436
E-mail: stoltz@caltech.edu
[**] The authors thank Abbott, Amgen, Boehringer Ingelheim, Bristol-
Myers Squibb, Merck, Sigma–Aldrich, Teva, and Caltech for financial
support. Lawrence Henling and Dr. Michael Day are gratefully
acknowledged for X-ray crystallographic structural determination.
The Bruker KAPPA APEX II X-ray diffractometer was purchased
through an NSF CRIF:MU award to the California Institute of
Technology, CHE-0639094. Dr. Scott C. Virgil is acknowledged for
helpful discussions.
Supporting information for this article is available on the WWW
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Angew. Chem. Int. Ed. 2011, 50, 4488 –4491