Rational Design of an Iron‐Based Catalyst for Suzuki–Miyaura Cross‐Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles

Abstract

Suzuki–Miyaura cross‐coupling reactions between a variety of alkyl halides and unactivated aryl boronic esters using a rationally designed iron‐based catalyst supported by β‐diketiminate ligands are described. High catalyst activity resulted in a broad substrate scope that included tertiary alkyl halides and heteroaromatic boronic esters. Mechanistic experiments revealed that the iron‐based catalyst benefited from the propensity for β‐diketiminate ligands to support low‐coordinate and highly reducing iron amide intermediates, which are very efficient for effecting the transmetalation step required for the Suzuki–Miyaura cross‐coupling reaction.

Recent Advances in Nonprecious Metal Catalysis

“…Given its fundamental importance in organic chemistry, catalytic methods for the formation of carbon–carbon bonds using Fe as a catalyst are of particular interest. While examples of sp 2 –sp 3 C–C coupling of unactivated boronic ester nucleophiles with alkyl halides mediated by well-defined Fe complexes are starting to emerge, , albeit with strong bases, Kumada coupling is more frequently encountered, and examples of such couplings on a large scale in the synthesis of pharmaceuticals have been reported. − Although Grignard reagents are quite reactive, functional group tolerance can be obtained due to the mild operating conditions of Fe-catalyzed Kumada coupling, which promote the desired coupling over impurity formation. , As a large number of boronic acids or esters are prepared through the intermediacy of a Grignard reagent (or the more reactive aryl lithium), interception of these intermediates could improve throughput as well as reduce PMI (process mass intensity). Furthermore, the possibility of forming Grignard reagents in a continuous, on-demand manner would improve the overall safety of such a process …”

“…Given its fundamental importance in organic chemistry, catalytic methods for the formation of carbon−carbon bonds using Fe as a catalyst are of particular interest. While examples of sp 2 −sp 3 C−C coupling of unactivated boronic ester nucleophiles with alkyl halides mediated by well-defined Fe complexes are starting to emerge, 38,39 albeit with strong bases, Kumada coupling is more frequently encountered, and examples of such couplings on a large scale in the synthesis of pharmaceuticals have been reported. 40−43 Although Grignard reagents are quite reactive, functional group tolerance can be obtained due to the mild operating conditions of Fe-catalyzed Kumada coupling, which promote the desired coupling over impurity formation.…”

An Iron-Based Catalyst Enables The Enantioconvergent Synthesis of Chiral 1,1-Diarylalkanes Through a Suzuki-Miyaura Cross-Coupling Reaction

“…These catalysts have demonstrated remarkable reactivity, especially for cross coupling reactions involving sterically demanding substrates and heteroaromatic boronic esters. 18 Despite these rapid advancements, enantioselective cross-coupling reactions that utilize iron-based catalysts are exceedingly rare and have been greatly overshadowed by the tremendous achievements in enantioconvergent systems employing nickel-based catalysts. 19 In fact, only three enantioselective cross coupling reactions that utilize iron-based catalysts have been reported.…”