One-Pot Ruthenium-Catalyzed Synthesis of Benzyl/Allyl-Halide Substituted (dihydro)naphthalenes via Radical Benzannulation

Herein, a selective, one-pot synthetic route to reactive benzyl- and allyl-halide-substituted naphthalenes and dihydronaphthalenes from easily accessible 2,3-aryl-1,3-butadiene substrates and simple halogenated alkanes, using [Cp*RuCl(PPh₃)₂] as the catalyst, is reported. The reaction is tolerant to various functional groups, including reactive carbonyl groups, halides, and trimethylsilyl groups. The scope of catalytic reactions can be expanded to otherwise difficult to synthesize substituted and reactive dihydronaphthalene and benzo[b]thiophene products. The resulting benzyl- and allyl-halide-substituted (dihydro-)naphthalene products are relevant synthons for drug synthesis, allowing for facile post-functionalization by making use of the reactive halide functionalities. Mechanistic studies are combined with density functional theory (DFT), which revealed a sequential catalytic atom transfer radical addition, radical benzannulation, and HCl elimination sequence. It is particularly noteworthy that the key transition state proceeds via a 6-endo-trig cyclization, in contrast to the classical 5-exo-trig cyclization as is normally observed for intramolecular radical additions. This cyclized intermediate subsequently undergoes HCl elimination to generate benzyl- and allyl-halide substituted (dihydro-)naphthalenes.

A one-pot protocol to synthesize reactive benzyl- and allyl-halide-substituted (dihydro)naphthalenes from 2,3-aryl-1,3-butadiene substrates and halogenated alkanes has been developed, using [Cp*RuCl(PPh₃)₂] as the catalyst. Mechanistic studies revealed an atom transfer radical addition and radical benzannulation sequence, followed by HCl elimination. The resulting (dihydro-)naphthalenes are relevant synthons for drugs, allowing facile post-functionalization via the reactive (benzylic or allylic) halide functionalities.