FROM DOMINO TO MULTICOMPONENT: Pd-ASSISTED SYNTHESIS OF DIHYDROISOBENZOFURANS

Multicomponent reactions (MCRs) are a powerful tool for the synthesis of complex molecules starting from ready available building blocks in a “well-contrived” one-pot sequential procedure.1 The dihydroisobenzofuran nucleus is the core of some important biologically active molecules.2 We recently reported3 a selective synthesis of the dihydroisobenzofuran skeleton through a microwave promoted domino addition/annulation reaction of 2-alkynylbenzaldehydes with methanol in the presence of a suitable base (Scheme 1, pathway A). The approach involves two different steps with a few common requirements: the presence of a base and the needing of an energy source. We were intrigued to simplify and improve the procedure. We found that a variety of substituted dihydroisobenzofuran derivatives can be easily synthesized in high yield by a microwave-assisted three-component approach4 starting from o-bromoarylaldehydes, methanol and terminal alkynes (Scheme 1, pathway B). The reaction occurs through an unprecedented cooperative palladium/base promoted coupling/addition/cyclization sequence.