Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

Abstract

The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.

Ligand Effect on Iron‐Catalyzed Cross‐Coupling Reactions: Evaluation of Amides as O‐Coordinating Ligands

“…In particular, the iron‐catalyzed cross‐coupling reactions have shown tremendous promise to replace the precious metal‐based catalysts as well as to promote C(sp 2 )−C(sp 3 ) cross‐coupling reactions that are traditionally challenging to execute with palladium‐ or nickel‐based catalysts . Importantly, iron‐catalyzed C(sp 2 )−C(sp 3 ) cross‐couplings with organometallics possessing β‐hydrogens prone to β‐hydride elimination and self‐coupling have already been extensively applied in the synthesis of pharmaceuticals . However, despite the main thrust towards developing sustainable cross‐coupling technologies, the most common additive in industrial applications of sustainable, low cost iron‐catalyzed cross‐coupling chemistry is reprotoxic NMP…”

N‐Methylcaprolactam as a Dipolar Aprotic Solvent for Iron‐Catalyzed Cross‐Coupling Reactions: Matching Efficiency with Safer Reaction Media

“…Iron‐catalysis has emerged as the dominant direction in cross‐coupling methods catalyzed by sustainable metals . Following the early studies, iron‐catalysis has evolved to be among the most useful cross‐coupling methods routinely applied in large‐scale pharmaceutical manufacturing, a feat that is still elusive for other base metals, including nickel…”

“…Despite tremendous progress in the field, iron‐catalyzed cross‐coupling reactions typically employ carcinogenic NMP (NMP= N ‐methylpyrrolidinone) as a co‐solvent ,. The use of N ‐methylpyrrolidinone is especially pervasive in iron‐catalyzed C(sp 2 )−C(sp 3 ) alkylative cross‐coupling, which owing to mild conditions and broad functional group tolerance have proven indispensable in the preparation of complex architectures in the synthesis of bioactive molecules ,. The toxicity of NMP has sparked the development of new alterative solvents for organic synthesis ,.…”

“…Iron-catalysis has emerged as the dominant direction in crosscoupling methods catalyzed by sustainable metals. [1][2][3] Following the early studies, [4] iron-catalysis has evolved to be among the most useful cross-coupling methods routinely applied in large-scale pharmaceutical manufacturing, [5] a feat that is still elusive for other base metals, including nickel. [6] Despite tremendous progress in the field, iron-catalyzed crosscoupling reactions typically employ carcinogenic NMP (NMP = Nmethylpyrrolidinone) as a co-solvent.…”

Spontaneous Resolution by Crystallization of an Octanuclear Iron(III) Complex Using Only Racemic Reagents

“…[1] Enantiopure materials have also applications in magnetics and nonlinear optics. [1] Enantiopure materials have also applications in magnetics and nonlinear optics.…”