Atom-economical catalysis has emerged as a powerful and efficient tool in organic synthesis over the last years. The direct functionalization of (hetero-)aromatics seems especially attractive for these type of reactions since prefunctionalization via halogenation or borylation can potentially be avoided. Only recently, the combination of epoxide opening via single electron transfer from titanocene(III) complexes and radical arylation was merged into an atom-economical functionalization of anilines. The reaction offers complete regiocontrol over epoxide opening and proceeds catalytically in titanocene and reductant under mild conditions. Due to their abundance in natural products and pharmaceuticals, pyrroles are an attractive heteroaromatic target for this type of transformation. Initial investigations showed that substrate 1 undergoes nucleophilic opening of the epoxide upon treatment with a Lewis acid such as ZnI2 to form the tetrahydroindolizine 3 (Table 1). Reaction of the same substrate with catalytic amounts of Cp2Ti(III)Cl leads to ring opening of the epoxide to the tertiary radical which reacts in an arylation reaction to dihydropyrrolizine 2 in good yield. The substrate scope of the reaction turned out to be compatible with a variety of aromatic substitutents attached to the pyrrole core (products 4 and 5) as well as polar functional- and protecting groups. Furthermore, radical cascade reactions are possible with epoxypolyene-substituted pyrroles to form steroidal scaffolds (product 7). The reaction proved to be valuable in the concise preparation of 8, an intermediate in the synthesis of the natural product Rhazinal.

Atom-economical functionalization of pyrrole scaffolds: Synthesis of dihydropyrrolizines and tetrahydroindolizines enabled by titanocene(III) catalysis

253rd National Meeting (2017)

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