Catalytic Intermolecular Amination of C−H Bonds: Method Development and Mechanistic Insights

Abstract

Reaction methodology for intermolecular C-H amination of benzylic and 3 degrees C-H bonds is described. This process uses the starting alkane as the limiting reagent, gives optically pure tetrasubstituted amines through stereospecific insertion into enantiomeric 3 degrees centers, displays high chemoselectivity for benzylic oxidation, and enables the facile preparation of isotopically enriched 15N-labeled compounds. Access to substituted amines, amino alcohols, and diamines is thereby made possible in a single transformation. Important information relevant to understanding the initial steps in the catalytic cycle, reaction chemoselectivity, the nature of the active oxidant, and pathways for catalyst inactivation has been gained through mechanistic analysis; these studies are also presented.

Capturing fleeting intermediates in a catalytic C–H amination reaction cycle

“…In our experience, the oxidation of substrate by Rh-nitrene 6 seems to correlate with competitive formation of a mixed-valent (Rh 2+ /Rh 3+ ) dimer 8 that visibly colors the reaction solution red. Previous studies show that this red species is generated when Rh 2 (esp) 2 1, sulfamate 2, and oxidant 3 are mixed in solution (e.g., 0.3 mM 1 in chlorobenzene) (4,5,11). In this report, we provide direct evidence for the formation of species 8.…”

“…mass spectrometry | transient intermediates | C-H oxidation | catalysis C atalytic methods for selective C-H oxidation rely on the exquisite choreography of a series of ligand substitution and redox events (1,2) and in some instances, the controlled generation of a hyperreactive electrophile (3)(4)(5). The Du Bois laboratory has developed an amination protocol that uses the catalyst bis [rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)], hereafter designated as Rh 2 (esp) 2 , to promote both intra-and intermolecular oxidation reactions (1,2).…”

“…+ , which appears to result from reaction of the nitrenoid oxidant (4,5,11). The fast rates of the on-and off-path steps in this catalytic process and the transient nature of the reactive Rh-nitrene have confounded direct detection of many of the proposed reaction intermediates.…”

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

“…Du Bois and colleagues have developed a bridged achiral rhodium catalyst Rh 2 (esp) 2 that has performed well at low catalyst loadings in both intra-and intermolecular C2H amination reactions (Fig. 12) [83][84][85] . Enantioselective intermolecular reactions of metal nitrenes are less developed than the parallel reactions of metal carbenes, although some significant examples have been reported 81,82,86,87 .…”

Iodobenzene Dicarboxylates as Transferrable Oxygen Sources: Synthesis of α-Oxygenated Ketones from Terminal Aryl Alkynes

“…The reaction was further explored by investigating other hypervalent iodine(III) reagents (Scheme 2). [16] It was found that the reaction of 1a with PhI(OPiv) 2 or PhI(OBz) 2 furnished the corresponding α-t-butylcarbonyloxy ketone 4 and α-benzoyloxy ketone 5 in 86% and 89% yield, respectively [Eq. (1) and (2)].…”