Intermolecular cyclotrimerization of haloketoalkynes and internal alkynes: facile access to arenes and phthalides

A highly chemo- and regioselective cyclo(co)trimerization between 3-halopropiolamides and symmetrical internal alkynes is reported. The reaction is catalyzed by CpRuCl(COD) and proceeds under air at ambient temperature in ethanol with no additional precautions. Iodo-, bromo-, and chloropropiolamides, esters, and ketones are viable coupling partners and, in a 2 : 1 stoichiometry relative to internal alkyne, yield fully-substituted arenes in a single step. The highest regioselectivities (96% single isomer) were observed when employing 2 degrees and 3 degrees-halopropiolamides. A mechanistic hypothesis accounting for this selectivity is proposed. Notably, by using 1,4-butynediol as the internal alkyne, in situ lactonization following [2+2+2]-cycloaddition generates therapeutically-relevant phthalide pharmacophores directly.