Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature.

An enantioselective organocatalytic α-trifluoromethylation of aldehydes has been accomplished using a commercially available, electrophilic trifluoromethyl source. The merging of Lewis acid and organocatalysis provides a new strategy for the enantioselective construction of trifluoromethyl stereogenicity, an important chiral synthon for pharmaceutical, material, and agrochemical applications. This mild and operationally simple protocol allows rapid access to enantioenriched α-trifluoromethylated aldehydes through a non-photolytic pathway.Within the realm of drug design, the stereospecific incorporation of polyfluorinated alkyl substituents is a powerful and widely employed tactic to enhance binding selectivity, elevate lipophilicity, and/or circumvent metabolism issues arising from in vivo C-H bond oxidation. 1 In particular, the catalytic production of CF 3 -containing stereogenicity has become a methodological goal of central importance to practitioners of chemical and pharmaceutical synthesis. 2 Recently, we reported the first highly enantioselective α-trifluoromethylation of aldehydes using photoredox organocatalysis, a protocol that employs fluorescent household lights to generate ·CF 3 radicals that can intercept stereofacially-biased enamines (eq 1). 2a In this communication we describe a new mechanistic (non-photolytic) approach to the same product class via the merger of Lewis acid and organocatalysis with an electrophilic trifluoromethyl alkylating reagent (eq 2). 3,4 Using this alternative chemical pathway, enantioenriched α-trifluoromethyl aldehydes (and α-CF 3 carbonyl building blocks) can be generated under mild reaction conditions using commercially available, 5 bench-stable 6 reagents and catalysts, and without the requirement of a light source.

The enantioselective α-arylation of aldehydes has been accomplished using diaryliodonium salts and a combination of copper and organic catalysts. These mild catalytic conditions provide a new strategy for the enantioselective construction and retention of enolizable α-formyl benzylic stereocenters, a valuable synthon for the production of medicinal agents. As one example, this new asymmetric protocol has been applied to the rapid synthesis of (S)-ketoprofen, a commercially successful oral and topical analgesic.

The first terminal rhenium phosphinidene complex, [Re(CO) 5 (η 1 -PN i Pr 2 )][AlCl 4 ], has been synthesized by chloride abstraction from [Re(CO) 5 {P(Cl)-(N i Pr 2 )}]. The electrophilic character of the terminal phosphinidene ligand is demonstrated by phosphine addition at the unsaturated phosphorus center and by novel reactions with azobenzene, PhNdNPh, which generate, via C-H activation and P-N and P-C bond formation, coordinated benzodiazaphosphole ligands. The cations [Re(CO) 5 P(PPh 3 )N i Pr 2 ] + and [Re(CO) 5 -{P(PhNNHC 6 H 4 )N i Pr 2 }] + have been crystallographically characterized as their AlCl 4salts. The corresponding late-metal terminal phosphinidene complexes [Co(CO) 3 -(PR 3 )(η 1 -PN i Pr 2 )][AlCl 4 ] (R ) Ph, Et) also afford coordinated benzodiazaphospholes via reaction with PhNd NPh.