The N‐Methylpyrrolidone (NMP) Effect in Iron‐Catalyzed Cross‐Coupling with Simple Ferric Salts and MeMgBr

Abstract

The use of N-methylpyrrolidone (NMP) as a co-solvent in ferric salt catalyzed cross-coupling reactions is crucial for achieving the highly selective, preparative scale formation of cross-coupled product in reactions utilizing alkyl Grignard reagents. Despite the critical importance of NMP, the molecular level effect of NMP on in situ formed and reactive iron species that enables effective catalysis remains undefined. Herein, we report the isolation and characterization of a novel trimethyliron(II) ferrate species, [Mg(NMP) ][FeMe ] (1), which forms as the major iron species in situ in reactions of Fe(acac) and MeMgBr under catalytically relevant conditions where NMP is employed as a co-solvent. Importantly, combined GC analysis and Fe Mössbauer spectroscopic studies identified 1 as a highly reactive iron species for the selective formation generating cross-coupled product. These studies demonstrate that NMP does not directly interact with iron as a ligand in catalysis but, alternatively, interacts with the magnesium cations to preferentially stabilize the formation of 1 over [Fe Me ] cluster generation, which occurs in the absence of NMP.

Iron‐Catalyzed C(sp2)−C(sp3) Cross‐Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

“…At present, this catalytic system represents the catalyst of choice for the vast majority of iron‐catalyzed cross‐couplings in both academic and industrial settings . Mechanistic studies showed that NMP forms O‐coordinated catalytically active octahedral complexes of iron(II) ,. We were delighted to find that addition of NMP delivered the C4‐alkylated product in excellent 92% yield (Table , entry 1).…”

The Role of Organoferrates in Iron‐Catalyzed Cross‐Couplings

“…The isolation of structurally related yet more labile σ‐alkyl ferrates by Neidig and co‐workers constituted a milestone achievement in the mechanistic elucidation of Fe‐catalyzed cross‐couplings (Scheme , bottom). Reactions of FeX 3 (X=Cl, acac) with alkylmagnesium bromides (methyl, ethyl) in THF/ N ‐methyl‐2‐pyrrolidinone (NMP) under conditions very similar to those of cross‐couplings afforded the tridentate ferrates [Mg(nmp) 6 ][FeR 3 ] 2 (R=Me: 7 ; R=Et: 8 ) in very high spectroscopic yields . Indeed, both ferrates underwent quantitative cross‐coupling with alkenyl bromide; 8 also readily reacted with 4‐chlorobenzoate (Scheme ) .…”

Zur Rolle von Organoferraten in eisenkatalysierten Kreuzkupplungen

“…Die Isolierung von strukturell verwandten, aber labileren σ‐Alkylferraten durch Neidig und Mitarbeiter stellte einen Meilenstein in der mechanistischen Aufklärung von Fe‐katalysierten Kreuzkupplungen dar (Schema , unten). Reaktionen von FeX 3 (X=Cl, acac) mit Alkylmagnesiumbromiden (Methyl, Ethyl) in THF/ N ‐Methyl‐2‐pyrrolidinon (NMP) unter Bedingungen sehr ähnlich wie bei Kreuzkupplungen lieferten die dreizähnigen Ferrate [Mg(nmp) 6 ][FeR 3 ] 2 (R=Me: 7 ; R=Et: 8 ) in sehr hohen spektroskopischen Ausbeuten . Tatsächlich gingen beide Ferrate eine quantitative Kreuzkupplung mit Alkenylbromid ein; 8 reagierte auch bereitwillig mit 4‐Chlorbenzoat (Schema ) .…”

“…In früheren Studien fanden Cahiez et al., dass NMP die unerwünschte β‐H‐Eliminierung in Fe‐katalysierten Kreuzkupplungen mit höheren Alkyl‐Grignard‐Reagenzien unterdrückt . Diese Beobachtung kann nun als eine effektive Gegenion‐Koordination interpretiert werden, welche die Bildung katalytisch aktiver monomerer Ferrate ermöglicht . Tatsächlich waren die Ethylferrate 8 und 10 inert gegenüber β‐H‐Eliminierung, was in voller Übereinstimmung mit zahlreichen Literaturberichten über Fe‐katalysierte Alkylkupplungen steht…”