The promise and challenge of iron-catalyzed cross coupling.

Transition metal catalysts, particularly those derived from the group VIII-X metals, display remarkable efficiency for the formation of carbon-carbon and carbon-heteroatom bonds through the reactions of suitable nucleophiles with organic electrophilic partners. Within this subset of the periodic table, palladium and nickel complexes offer the broadest utility, while additionally providing the deepest mechanistic insight into thus-termed "cross-coupling reactions". The mammoth effort devoted to palladium and nickel catalysts over the past 30 years has somewhat obscured reports of alternative metal complexes in this arena. As cross-coupling reactions have evolved into a critical support for modern synthetic chemistry, the search for alternative catalysts has been taken up with renewed vigor.When the current generation of synthetic chemists reflects back to the origins of cross coupling for inspiration, the well-documented effect of iron salts on the reactivity of Grignard reagents with organic electrophiles surfaces as a fertile ground for alternative catalyst development. Iron possesses the practical benefits more befitting an alkali or alkaline earth metal, while displaying the unique reactivity of a d-block element. Therefore the search for broadly applicable iron catalysts for cross coupling is an increasingly important goal in modern synthetic organic chemistry.This Account describes the evolution of iron-catalyzed cross coupling from its inception in the work of Kochi to the present. Specific emphasis is placed on reactivity and synthetic applications, with selected examples from acyl-, alkenyl-, aryl-, and alkyl halide/pseudohalide cross coupling included. The typical reaction partners are Grignard reagents, though organomanganese, -copper, and -zinc derivatives have also been used in certain cases. Such iron-catalyzed processes occur very rapidly even at low temperature and therefore are distinguished by broad functional group compatibility. Furthermore, recent advances in carbon-heteroatom bond formation and studies relevant to the general reactivity of in situ generated and structurally defined "low-valent" iron catalysts are presented.The preparative aspects of iron-catalyzed cross coupling are encouraging, but the inclination to classify these processes within the characteristic reaction manifold is premature, as mechanistic studies have evolved at a comparatively slow pace. A typical protocol for cross coupling employs an Fe(+2) or Fe(+3) precatalyst, which is reduced in situ by the organometallic nucleophile. The nature of the resulting active component(s) is still best described, more than 30 years later, in Kochi's original terms as a "reduced form of soluble iron". Despite huge gaps in our current knowledge, three distinct mechanisms have been formulated, largely based on empirical evidence: a "canonical" cross-coupling process, a manifold wherein alkylation of an organoiron intermediate replaces transmetalation as a key step, and finally a proposal reliant on the formation of nucleophilic ate complexes. Conjecture and speculation abound, but precisely what constitutes the catalytic cycle in iron-catalyzed cross coupling remains an extremely challenging unanswered question.