Mechanistic Exploration of Intramolecular Aminodiene Hydroamination/Cyclisation Mediated by Constrained Geometry Organoactinide Complexes: A DFT Study

The present computational mechanistic study explores comprehensively the organoactinide‐mediated intramolecular hydroamination/cyclisation (IHC) of aminodienes by employing a reliable DFT method. All the steps of a plausible catalytic reaction course have been scrutinised for the IHC of (4E,6)‐heptadienylamine 1 t by [(CGC)Th(NMe₂)₂] precatalyst 2 (CGC=[Me₂Si(η⁵‐Me₄C₅)(tBuN)]^2?). For each of the relevant elementary steps the most accessible pathway has been identified from a multitude of mechanistic possibilities. The operative mechanism involves rapid substrate association/dissociation equilibria for the 3 t ‐S resting state and also for azacyclic intermediates 4 a , 4 s , easily accessible and reversible exocyclic ring closure, supposedly facile isomerisation of the azacycle’s butenyl tether prior to turnover‐limiting protonolysis. The following aspects are in support of this scenario: 1) the derived rate law is consistent with the experimentally obtained empirical rate law; 2) the accessed barrier for turnover‐limiting protonolysis does agree remarkably well with observed performance data; 3) the ring‐tether double‐bond selectivity is consistently elucidated, which led to predict the product distribution correctly. This study provides a computationally substantiated rationale for observed activity and selectivity data. Steric demands at the CGC framework appear to be an efficient means for modulating both performance and ring‐tether double‐bond selectivity. The careful comparison of (CGC)4f‐element and (CGC)5f‐element catalysts revealed that aminodiene IHC mediated by organoactinides and organolanthanides proceeds through a similar mechanistic scenario. However, cyclisation and protonolysis steps, in particular, feature a markedly different reactivity pattern for the two catalyst classes, owing to enhanced bond covalency of early actinides when compared to lanthanides.     

Anti-Markovnikov Radical Hydro- and Deuteroamidation of Unactivated Alkenes

Radical anti-Markovnikov hydro- and deuteroamidation of unactivated alkenes was achieved by merging photoredox and thiol catalysis. Reactions proceed by addition of the electrophilic CbzHN-radical (Cbz=carbobenzyloxy), readily generated by single-electron-transfer (SET) oxidation of an α-Cbz-amino-oxy acid to an alkene. The adduct radical is reduced by thiophenol added as an organic polarity reversal cocatalyst, which mediates the H transfer from H₂O to the alkyl radical intermediate. Accordingly, deuteroamidation of alkenes was realized with excellent D incorporation by using D₂O as the stoichiometric formal radical-reducing reagent. The reaction features low redox catalyst loading, excellent anti-Markovnikov selectivity, and the use of a large alkene excess is not required. Diverse Cbz-protected primary amines, including β-deuterated amines, can be obtained by applying this method.     

CuH‐Catalysed Hydroamination of Styrene with Hydroxylamine Esters: A Coupled Cluster Scrutiny of Mechanistic Pathways

A detailed computational exploration of mechanistic intricacies of the copper(I) hydride (CuH)‐catalysed hydroamination of styrene with a prototype hydroxylamine ester by a recently reported [(dppbz)CuH] catalyst (dppbz≡{P^P}≡1,2‐bis(diphenylphosphino)‐benzene) is presented. A variety of plausible mechanistic avenues have been pursued by means of a sophisticated computational methodology, from which a general understanding of the factors controlling hydroamination catalysis emerged. The catalytically competent {P^P}Cu^I hydride, which is predominantly present as its dimer, involves in irreversible hydrocupration proceeding with complete 2,1 regioselectivity to form a secondary {P^P}Cu^I benzyl intermediate. Its interception with benzylamine ester produces the branched tertiary amine product and {P^P}Cu^I benzoate upon intramolecular S_N2 disruption of the amine electrophile′s N?O linkage, to precede a highly rapid, strongly exergonic C?N bond‐forming reductive elimination. The {P^P}Cu^I benzoate corresponds to the catalyst resting state and its conversion back into the {P^P}Cu^I hydride upon transmetalation with a hydrosilane is turnover limiting. The effect of electronic perturbations at the amine electrophile upon the reaction rate for productive hydroamination catalysis and also non‐productive reduction of the hydroxylamine ester has been gauged, which unveiled a more fundamental insight into catalytic structure‐performance relationships.     

Gold‐Catalyzed Tandem Hydroamination/Formal Aza‐Diels–Alder Reaction of Homopropargyl Amino Esters: A Combined Computational and Experimental Mechanistic Study

A tandem gold‐catalyzed hydroamination/formal aza‐Diels–Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold‐catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the asymmetric version of the tandem reaction was also evaluated.     

Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes

Over the past few years, CuH‐catalyzed hydroamination has been discovered and developed as a robust and conceptually novel approach for the synthesis of enantioenriched secondary and tertiary amines. The success in this area of research was made possible through the large body of precedent in copper(I) hydride catalysis and the well‐explored use of hydroxylamine esters as electrophilic amine sources in related copper‐catalyzed processes. This Minireview details the background, advances, and mechanistic investigations in CuH‐catalyzed hydroamination.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.