Rerouting Radical Cascades: Intercepting the Homoallyl Ring Expansion in Enyne Cyclizations via C-S Scission Sayantan Mondal, Brian Gold, Rana K. Mohamed, Hoa Phan, and Igor V. Alabugin* Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States * S Supporting Information ABSTRACT: The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C-S bond provides direct mechanistic evidence for the 5-exo cyclization/ ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu 3 Sn-functionalized naphthalenes. ■ INTRODUCTION The alkyne functional group is a high-energy moiety whose versatile reactivity 1 can be harnessed for useful transformations. 2 In particular, radical cascade cyclizations 3 of alkynes 4 provide a convenient route to structures desirable in conjugated functional materials 5 such as polycyclic aromatics. 6 We recently reported that the Bu 3 Sn-mediated radical cyclization of aromatic enynes provides a facile route to Sn-substituted indenes 7 and naphthalenes. 8 The selectivity of this transformation is controlled by substitution at the alkene end (Scheme 1). Reactants with radical stabilizing groups (CO 2 R/Ph) afford indenes, while -CH 2 X (X = H, alkyl, OR, NR 2 , Ph) substitution gives six-membered products. In the cases of X = OR, NR 2 , Ph, the cyclizations afford aromatic products by the concomitant loss of the -CH 2 X group via β-scission of a C-C bond. 9 The energetic penalty for breaking a strong σ-bond is compensated by the aromaticity gained in the product and by the rational design of radical leaving groups stabilized by two-center, three-electron bonding between the radical and the lone pair of an adjacent heteroatom (or benzylic stabilization). In the latter “self-terminating” radical cyclization, alkenes serve as synthetic equivalents of alkynes, providing fully aromatized products without external oxidants. On the basis of the stereoelectronic preferences in alkyne and alkene cyclizations, 10 we were intrigued by the formation of formal 6-endo products. Radical attack at π-bonds intrinsically favors the exo path, 10 unless special factors such as steric or polar effects are used in the reaction design. 11-13 Considering the unexpected regioselectivity of the overall transformation, we set out to investigate how the nature of the substituent at the alkene controls the competition between 5-exo-trig and 6-endo-trig pathways without affecting the high chemo- and regioselectivity of the initial radical attack at the enyne. We had previously shown that the reaction selectivity stems from kinetic sorting 14 of the equilibrating “pool” of radicals via the lowest activation barrier escape route. However, the role of alkene substitution in changing the nature of the final cyclization step has so far remained unclear. In particular, we were interested in under- standing whether it involves selective stabilization of the 6-endo transition state (TS) or relative destabilization of the 5-exo TS or whether the situation is even more complex. In particular, the observed change in selectivity could rather originate from ring expansion of the initially formed 5-exo intermediate into the six-membered product and not from direct 6-endo trig cyclization, as shown in Scheme 2. Such expansion, rendered possible by the presence of an adjacent π-bond and the intrinsically low barriers of radical 3-exo cyclizations, 10d has been implicated in a variety of radical rearrangements such as Dowd-Beckwith, 15 neophyl, 27 O-neophyl, 16,17 and homoallyl 18,19 rearrangements (Scheme 2). Received: May 29, 2014 Published: July 10, 2014 Article pubs.acs.org/joc © 2014 American Chemical Society 7491 dx.doi.org/10.1021/jo5012043 | J. Org. Chem. 2014, 79, 7491-7501