N-Butylpyrrolidone (NBP) as a non-toxic substitute for NMP in iron-catalyzed C(sp2)-C(sp3) cross-coupling of aryl chlorides

Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N-methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N-butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp(2))-C(sp(3)) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing beta-hydrogens with efficiency superseding or matching that of NMP with ample scope and broad functional group tolerance. Appealing applications are demonstrated in the cross-coupling in the presence of sensitive functional groups and the synthesis of several pharmaceutical intermediates, including a dual NK1/serotonin inhibitor, a fibrinolysis inhibitor and an antifungal agent. Considering that the iron/NMP system has emerged as one of the most powerful iron cross-coupling technologies available in both academic and industrial research, we anticipate that this method will be of broad interest.

Automated summary

A new study reported the use of non-toxic and sustainable N-butylpyrrolidone (NBP) as a substitute for reprotoxic N-methylpyrrolidone (NMP) in iron-catalyzed cross-coupling reactions, achieving successful alkylations with high efficiency and broad functional group tolerance. The efficiency of NBP in these reactions surpassed or matched that of NMP, demonstrating potential applications in the synthesis of pharmaceutical intermediates.