Waste-minimized C(sp3)-H activation for the preparation of fused N-heterocycles

Abstract

By exploiting the combined use of a heterogeneous recyclable palladium(II)-bis(N-heterocyclic carbene) catalyst and cyclopentyl methyl ether (CPME) as a convenient recoverable safer reaction medium, an effective waste-minimized approach has been developed for the intramolecular Pd-catalyzed C(sp3)-H activation of methyl pyrrole derivatives. This synthetic tools has allowed to access condensed N-heterocycles generally endowed with biological activities and representatively are the core motif of complex molecules such as Mitomycines and Tylophorines. The heterogeneous catalytic system could be recovered and reused up to representative five runs without any loss in efficiency. The target products (19 examples) have been obtained selectively and with excellent isolated yields up to 93%. The approach leads to the definition of a protocol with a very good E-factor (21) which is much lower (up to 98%) than those of comparable literature examples. Other green metrics have been calculated and the data collected demonstrate that our newly developed protocol is very promising in terms of its environmental impact profile.

Keywords

• C–H functionalization
• C–H activation
• Sustainable chemistry
• Waste-minimization
• Heterogeneous catalysis
• Safe reaction medium