Development and Evolution of Mechanistic Understanding in Iron-Catalyzed Cross-Coupling

Abstract

Since the pioneering work of Kochi in the 1970s, iron has attracted great interest for crosscoupling catalysis due to its low cost and toxicity as well as its potential for novel reactivity compared to analogous reactions with precious metals like palladium. Today there are numerous iron-based cross-coupling methodologies available, including challenging alkyl-alkyl and enantioselective methods. Furthermore, cross-couplings with simple ferric salts and additives like NMP and TMEDA (N-methylpyrrolidone and tetramethylethylenediamine) continue to attract interest in pharmaceutical applications. Despite the tremendous advances in iron cross-coupling methodologies, in situ formed and reactive iron species and the underlying mechanisms of catalysis remain poorly understood in many cases, inhibiting mechanism-driven methodology development in this field. This lack of mechanism-driven development has been due, in part, to the challenges of applying traditional characterization methods such as nuclear magnetic resonance (NMR) spectroscopy to iron chemistry due to the multitude of paramagnetic species that can form in situ. The application of a broad array of inorganic spectroscopic methods (e.g., electron paramagnetic resonance, 57 Fe Mössbauer, and magnetic circular dichroism) removes this barrier and has revolutionized our ability to evaluate iron speciation. In conjunction with inorganic syntheses of unstable organoiron intermediates and combined inorganic spectroscopy/gas chromatography studies to evaluate in situ iron reactivity, this approach has dramatically evolved our understanding of in situ iron speciation, reactivity, and mechanisms in iron-catalyzed cross-coupling over the past 5 years. This Account focuses on the key advances made in obtaining mechanistic insight in iron-catalyzed carboncarbon cross-couplings using simple ferric salts, iron-bisphosphines, and iron-N-heterocyclic carbenes (NHCs). Our studies of ferric salt catalysis have resulted in the isolation of an unprecedented iron-methyl cluster, allowing us to identify a novel reaction pathway and solve a decades-old mystery in iron chemistry. NMP has also been identified as a key to accessing more stable intermediates in reactions containing nucleophiles with and without β-hydrogens. In ironbisphosphine chemistry, we have identified several series of transmetalated iron(II)-bisphosphine complexes containing mesityl, phenyl, and alkynyl nucleophile-derived ligands, where mesityl systems were found to be unreliable analogues to phenyls. Finally, in iron-NHC cross-coupling, unique chelation effects were observed in cases where nucleophile-derived ligands contained *

Iron‐Catalyzed Reactions of 2‐Pyridone Derivatives: 1,6‐Addition and Formal Ring Opening/Cross Coupling

“…It is, however, exceedingly difficult to establish the nature of the active species generated in situ, not least because low valent organometallic iron complexes are highly sensitive, often paramagnetic, and tend to "age" rapidly;moreover,the exact speciation is strongly dependento nt he chosen conditions and the presence/absence of polar additives in the mixture. [39] The mechanistic complexity of the current system is reflected in a number of control experiments, which showed that several well-defined but structurally quite distinct iron species are competent (pre)catalysts (see Table 1): thus, the intricate Fe(+ 2)-ate complex [(Me 4 Fe)·(MeLi)][Li·(OEt 2 )] 2 (entry 10), [33] two different Fe 0 olefin complexes (entries 14, 15), [37,40] and even catalytic amounts of Fe(CO) 5 (entry 11)o rt he derived pyridone complex (entry 12) workedw ell. In contrastt ot he oxophilicity of Fe(+ 2) and Fe(+ 3) salts, many low-valent iron species are inherently carbophilic;1,3-dienesa re amongst the privileged ligands which get activated towarda ttack by certain nucleophiles, for example, upon coordinationt ot he [Fe(CO) 3 ]f ragment.…”

Zur Rolle von Organoferraten in eisenkatalysierten Kreuzkupplungen

“…Die Auswirkungen dieser bahnbrechenden Synthesen bis dato unbekannter metallorganischer Komplexe erstrecken sich auch auf die kritische Bewertung des Repertoires an Analysemethoden. Neidig und Mitarbeiter haben mit großer Sorgfalt aufgezeigt, dass paramagnetische, redoxaktive und/oder thermisch empfindliche Katalysatorzwischenstufen unter katalytischen Reaktionsbedingungen mithilfe von Operando‐Spektroskopien wie EPR, magnetischem Zirkulardichroismus und Mößbauer untersucht werden können (Schema ) …”

“…[1] Angewandte Chemie Sorgfalt aufgezeigt, dass paramagnetische,r edoxaktive und/ oder thermisch empfindliche Katalysatorzwischenstufen unter katalytischen Reaktionsbedingungen mithilfe von Operando-Spektroskopien wie EPR, magnetischem Zirkulardichroismus und Mçßbauer untersucht werden kçnnen (Schema 5). [19] Diese Untersuchungen metallkatalysierter Reaktionen haben auch die Mçglichkeit der Feinabstimmung von Katalysatoren über die Art des Gegenions aufgezeigt. Die cokatalytische Unterstützung durch Gegenionen kann verschiedene Arten der Substrat-oder Katalysatoraktivierung beinhalten.…”

Regioselective Iron‐Catalysed Cross‐Coupling Reaction of Aryl Propargylic Bromides and Aryl Grignard Reagents

“…Multiple articles deal with the mechanism of Fecatalysed cross-coupling reactions and the oxidation state of the active species. [21] Thus, Fe(I), [18b,22] Fe (II), [19,23] or even Fe(-II) [18a,24] complexes have been proposed, detected or isolated. In the present case, the experimental evidence suggests the formation of radical iron species, which is compatible with an Fe(I/ III) catalytic cycle (Scheme 8).…”