Issue 19, 2021

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

Abstract

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(sp2)–C(sp3) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-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.

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

Supplementary files

Article information

Article type
Communication
Submitted
06 7 2021
Accepted
18 8 2021
First published
18 8 2021

Green Chem., 2021,23, 7515-7521

Author version available

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

E. Bisz, M. Koston and M. Szostak, Green Chem., 2021, 23, 7515 DOI: 10.1039/D1GC02377B

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