Scaffold-Divergent Synthesis of Ring-Fused Indoles, Quinolines, and Quinolones via Iodonium-Induced Reaction Cascades Rosliana Halim, Luigi Aurelio, Peter J. Scammells, and Bernard L. Flynn* Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia * S Supporting Information ABSTRACT: N-(2-Iodophenyl)imines A are readily formed from Schiff’s base condensation of 2-iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold- divergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring- fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed. ■ INTRODUCTION Electrophilic activation of alkynes toward intramolecular nucleophilic attack has emerged as a highly effective means of forming a variety of carbocyclic and heterocyclic ring systems. 1,2 A particularly useful reaction is the 5- and 6-endo-digonal iodocyclization of a tethered heteroatomic nucleophile Nu upon an alkyne using an iodonium source 1 → 2 → 3 (Scheme 1). The electrofuge (E f ) may either be a proton or an alkyl group that is removed using either a base or nucleophile (usually I - ), respectively. An interesting variation on the use of an electrofuge is the trapping of the initially formed cyclic cation by another nucleophile in a reaction cascade. For example, Barluenga and Larock have demonstrated that iodocyclization of o-alkynylben- zaldehydes 4 gives a benzopyranium ion 5 that undergoes subsequent nucleophilic attack to give a highly substituted 4-iodobenzopyran 6 (Scheme 2). 3,4 We rationalized that a similar cascade could be used in a cocyclization strategy to form ring- fused indoles 9 where readily accessible N-(2-alkynylphenyl)- imines 7 undergo iodocylization to an imminum ion 8 that can then be trapped by a nucleophile tethered to the alkynyl group giving 9 (Path A, Scheme 2). Herein, we report our investigations into this approach to ring-fused indoles 9. 5,6 We also describe an equivalent cocylization process for the formation of ring-fused quinolones 13 → 14 → 15. Interestingly, during our evaluation of different reaction conditions to effect cocyclizations to give indoles 9, we have identified an alternative pathway (Path B) involving iodonium activation of the imine 7 (R 2 = H, Nu = OH) such that it becomes an electrophile and undergoes a concerted cocyclization with the tethered alkynol to give a ring-fused quinolines 7 → 10 → 11 → 12 (Path B). The ring structures made available through these cocyclization strategies may provide useful scaffolds exhibiting interesting Received: January 23, 2013 Scheme 1. Iodocyclization with Electrofugal (E f ) Displacement Scheme 2. Iodocyclization with Nucleophilic Trapping Article pubs.acs.org/joc © XXXX American Chemical Society A dx.doi.org/10.1021/jo400125p | J. Org. Chem. XXXX, XXX, XXX-XXX