Pd-Catalyzed Non-Directed C–H Functionalization with Fluoroalkenyl Linchpins

ChemRxiv

Abstract

Non-directed palladium-catalyzed C–H olefination has emerged as a powerful strategy for the direct diversification of arenes but has relied almost exclusively on olefin coupling partners activated through classical mesomeric effects. Herein, we demonstrate that short perfluoroalkyl-substituted olefins, whose reactivity is governed predominantly by inductive electron withdrawal, constitute a complementary class of electronically activated coupling partners for ligand-enabled non-directed C–H olefination. The reaction provides efficient access to a broad range of fluoroalkenylated arenes and heteroarenes with excellent functional-group tolerance and enables the late-stage functionalization of pharmaceuticals and natural products. Mechanistic investigations combining kinetic isotope effect measurements and DFT calculations reveal a distinct reactivity profile compared with classically mesomerically activated olefins, highlighting the influence of olefin electronics on the elementary steps of the catalytic cycle. Furthermore, the resulting fluoroalkenylated products serve as versatile fluorinated linchpins that can be readily diversified into structurally complex fluorinated molecules, establishing inductively activated olefins as a complementary design principle for non-directed C–H olefination.

Authors 5

1. Deepak Sharma

   Martin Luther University Halle-Wittenberg

   Affiliation as printed

   Institute of Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle (Saale), Germany, 06120

2. Namrata Kotwal

   Martin Luther University Halle-Wittenberg

   Affiliation as printed

   Institute of Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle (Saale), Germany, 06120

3. Levin Stockmann Aachen Institute of Organic Chemistry

   RWTH Aachen University

   Affiliation as printed

   Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, Aachen, Germany, 52074

4. Jo Pitzen Aachen Institute of Organic Chemistry

   RWTH Aachen University

   Affiliation as printed

   Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, Aachen, Germany, 52074

5. Claire Empel

   University of Bayreuth · Martin Luther University Halle-Wittenberg

   Affiliation as printed

   Institute of Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, Halle (Saale), Germany, 06120

   Organic Chemistry II, University of Bayreuth, Universitätsstr. 30, Bayreuth, Germany, 95447