Critical ligand and salt effects in organomagnesiate-promoted 3,3-disubstituted phthalides synthesis from 2-iodobenzoate derivatives

Touchet, Sabrina and Yeardley, Callum and O'Hara, Charles T. and Gros, Philippe C. (2021) Critical ligand and salt effects in organomagnesiate-promoted 3,3-disubstituted phthalides synthesis from 2-iodobenzoate derivatives. European Journal of Organic Chemistry, 2021 (34). pp. 4835-4845. ISSN 1434-193X

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    Abstract

    Phthalides, also called isobenzofuranones, are widespread in many biologically active compounds and natural products. To date, most of their synthetic routes are non-convergent. Herein we report a convergent route using a metal halogen exchange (MHE) strategy. Indeed MHE of easily available 2-iodobenzoate derivatives, using the bimetallic organomagnesiate complex (rac)-(BIPHEN)BuMgLi, where (rac)-BIPHEN is (rac)-5,5′,6,6′-tetramethyl-3,3′-di-t-butyl-1,1′-biphenyl-2,2′-diol, followed by addition of a ketone which lead to an intramolecular cyclisation, and the formation of a series of diverse 3,3-disubstituted isobenzofuranones in good yield. Among the several MHE agents investigated, (rac)-(BIPHEN)BuMgLi was the only one to make such a process possible with full tolerance of various reactive functional substituents useful for subsequent transformations. The synthetic pathway to access the magnesiate has been found to play a prominent role in its reactivity. Therefore, the bimetallic magnesiate complex has been characterized by solution-state 1H, 7Li and 1H DOSY NMR experiments.