Hydrogen atom transfer from a metal hydride (MHAT) has emerged as a powerful, if puzzling, technique in chemical synthesis. In catalytic MHAT reactions, earth-abundant metal complexes generate stabilized and unstabilized...

Cobalt/nickel-dual catalyzed hydroarylation of terminal olefins with iodoarenes builds complexity from readily available starting materials, with a high preference for the Markovnikov (branched) product. Here, we advance a mechanistic model of this reaction through the use of reaction progress kinetic analysis (RPKA), radical clock experiments, and stoichiometric studies. Through exclusion of competing hypotheses, we conclude that the reaction proceeds through an unprecedented alkylcobalt to nickel direct transmetalation. Demonstration of catalytic alkene prefunctionalization, via spectroscopic observation of an organocobalt species, distinguishes this Csp-Csp cross-coupling method from a conventional transmetalation process, which employs a stoichiometric organometallic nucleophile, and from a bimetallic oxidative addition of an organohalide across nickel, described by radical scission and subsequent alkyl radical capture at a second nickel center. A refined understanding of the reaction leads to an optimized hydroarylation procedure that excludes exogenous oxidant, demonstrating that the transmetalation is net redox neutral. Catalytic alkene prefunctionalization by cobalt and engagement with nickel catalytic cycles through direct transmetalation provides a new platform to merge these two rich areas of chemistry in preparatively useful ways.

CONSPECTUS. Implementation of any chemical reaction in a structurally complex setting (King, S. M., J. Org. Chem., 2014, 79, 8937) confronts structurally-defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. But there are also practical barriers. Late stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions that can be relied upon at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized ‘chemoselectivity’ as a reagent’s selective reaction of one functional group or reactive site in preference to others (Trost, B. M., Science, 1983, 219, 245). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens (Collins, K. D., Nat. Chem., 2013, 5, 597). A reaction may also be characterized by its ‘chemofidelity’, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity, but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by π Lewis acids can exhibit high chemoselectivity (Trost, B. M., Science, 1983, 219, 245), but low chemofidelity: it can be highly selective for alkenes, but sensitive to substitution patterns (Larionov, E., Chem Comm., 2014, 50, 9816). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity; its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H-atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products (Crossley, S. W. M., Chem. Rev., 2016, 116, 8912). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Brønsted acid catalysis—itself a broad reactivity paradigm. This Account summarizes our group’s contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area—a stepwise hydrogenation with high chemoselectivity and high chemofidelity—has found application to many problems. More recently, we reported the first examples of a dual-catalytic cross-couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate MHAT will become a staple of chemical synthesis.

Nucleophilic terminal gold(I) amides have been prepared and their reactivity toward a variety of electrophiles has been explored. For the first time these frequently proposed intermediates were isolated and shown to be unreactive in the amination of p-bonds. The first crystallographically determined terminal group 11 metal phosphide was also synthesized. Preliminary DFT studies have been conducted to understand the structure and reactivity of these complexes.Scheme 1 Synthesis of gold(I) amides.

The gold-catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer.

The gold-catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer. Graphical AbstractChiral allylic azides and amines may be obtained by enantioselective hydroazidation and hydroamination of allenes catalyzed by acyclic diaminocarbene gold(I) catalysts derived from BINAM. The sense of enantioinduction is reversed for the two different nucleophiles, allowing easy access to both enantiomers with a single catalyst enantiomer. Keywordshydroazidation; hydroamination; enantioselective; gold catalysis; acyclic diaminocarbene Allylic amines are an important functional motif in synthetic organic chemistry and they have been utilized in the synthesis of numerous biologically active compounds. [1] Closely related allylic azides are valuable precursors for allylic amines, as well as for amino acids [2] Correspondence to: F. Dean Toste, fdtoste@berkeley.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript and amine-containing natural products. [3] Allylic azides have typically been prepared via substitution reactions from the corresponding allylic halides, (homo)allylic alcohols, and their derivatives. [4] More recently, Pd-catalyzed C-H activation, [5] and Au-catalyzed hydroazidation of allenes [6] have been employed.While reports of the synthesis of allylic azides are numerous, methods for asymmetric azidation are few. [7] Fewer still are enantioselective hydroazidation reactions, which have only been reported in a formal sense via conjugate addition to activated double bonds (Scheme 1). [8][9][10] In light of recent examples of transition-metal catalysed asymmetric additions of nitrogen nucleophiles to allenes [11] and the growing utility of organic azides, we sought to develop a gold(I)-catalyzed enantioselective hydroazidation of allenes. Cognizant of potential regioselectivity issues from the Winstein rearrangement [12] of the product allylic azides, we initiated our studies using aryl allene 3a. [13] Initial studies revealed that the use of ethereal solvents was critical to obtaining reproducible data. [14] With the choice of solvent established, the enantioinduction afforded by a number of chiral gold(I) catalysts was evaluated under conditions similar to those previously reported, with trifluoroacetic acid (TFA) and trimethylsilyl azide (TMSN 3 ) used for in situ generation of hydrazoic acid (Table 2). [6] Traditional chiral phosphine gold(I) catalysts failed to afford high levels of enantioinduction (entries 1,2) as did a previously reported [15] phosphoramidite catalyst (entry 3). Chiral NHC gold(I) catalysts [16] (entries 4-6) also were found to be unsatisfactory. However, the use of a BINAM-derived ADC gold...

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The presented transformation is one of the rare examples where the product configuration depends on the nucleophile.