Computational Mechanistic Elucidation of the Intramolecular Aminoalkene Hydroamination Catalysed by Iminoanilide Alkaline‐Earth Compounds

A comprehensive computational exploration of plausible alternative mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes by a recently reported class of kinetically stabilised iminoanilide alkaline‐earth silylamido compounds [{N^N}Ae{N(SiMe₃)₂} ? (thf)_n] ({N^N}=iminoanilide; Ae=Ca, Sr, Ba) is presented. On the one hand, a proton‐assisted concerted N?C/C?H bond‐forming pathway to afford the cycloamine in a single step can be invoked and on the other hand, a stepwise σ‐insertive pathway that involves a fast, reversible migratory olefin 1,2‐insertion step linked to a less rapid, irreversible metal?C azacycle tether σ‐bond aminolysis. Notably, these alternative mechanistic avenues are equally consistent with reported key experimental features. The present study, which employs a thoroughly benchmarked and reliable DFT methodology, supports the prevailing mechanism to be a stepwise σ‐insertive pathway that sees an initial conversion of the {N^N}Ae silylamido into the catalytically competent {N^N}Ae amidoalkene compound and involves thereafter facile and reversible insertive N?C bond‐forming ring closure, linked to irreversible intramolecular Ae?C tether σ‐bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnover‐limiting protonolysis accounts for the substantial primary kinetic isotope effect observed; its DFT‐derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca>Sr>Ba correctly. Non‐competitive kinetic demands militate against the operation of the concerted proton‐assisted pathway, which describes N?C bond‐forming ring closure triggered by concomitant amino proton delivery at the C?C linkage evolving through a multi‐centre TS structure. Valuable insights into the catalytic structure–activity relationships are unveiled by a detailed comparison of [{N^N}Ae(NHR)] catalysts. Moreover, the intriguingly opposite trends in reactivity observed in intramolecular (Ca>Sr>Ba) and intermolecular (Ca<Sr<Ba) HA catalysis for the studied family of iminoanilide alkaline‐earth amido catalysts are rationalised.     

A novel base-mediated intramolecular hydroamination to build fused heteroaryl pyrazinones

Functionalized fused heteroaryl pyrazinones were built up through a novel DBU-catalyzed intramolecular hydroamination reaction of aryl(prop-2-yn-1-yl)-1H-heteroaryl-2-carboxamides. The nucleophilic addition afforded three isomers; two with an exo-cyclic double bond [cis (Z), trans (E)], and a third one with an endo-cyclic double bond. After the carboxamide deprotection, isomerization of the mixture under acidic conditions resulted in a unique isomer.     

Mechanistic investigation of organolanthanide-mediated hydroamination of conjugated aminodienes: a comprehensive computational assessment of various routes for diene activation

The present computational mechanistic study comprehensively explores alternative scenarios for activation of the amine-linked diene C=C linkage toward C-N ring closure in intramolecular hydroamination of a prototypical aminodiene by a well-characterised lanthanocene-amido catalyst. Firstly, the non-insertive mechanism by Scott featuring ring closure with concomitant amino proton delivery onto the diene unit has been explored and key features have been defined. This scenario has been compared with the classical stepwise insertion mechanism that involves rapid substrate association/dissociation equilibria for the 3t-S1 resting state and also for azacycle intermediates 4s, 4a, facile and reversible exocyclic migratory diene insertion into the La-N(amido) σ-bond, linked to turnover-limiting La-C azacycle aminolysis. The Ln-N σ-bond insertive mechanism prevails for the examined intramolecular hydroamination of (4E,6)-heptadienylamine 1t by [Cp*(2)La-CH(TMS)(2)] starting material 2.The following aspects are in support of this mechanism: 1) the derived rate law is consistent with the observed empirical rate law; 2) the assessed effective barrier for turnover-limiting aminolysis does agree remarkably well with empirically determined Eyring parameters; 3) the ring-ether double-bond selectivity is consistently elucidated. This study reveals that the non-insertive mechanism is not achievable for the particular lanthanocene-amido catalyst and furthermore cannot account for the observed product spectrum. Notwithstanding of these findings, the non-insertive mechanism cannot be discarded a priori for intramolecular aminodiene hydroamination. Spatial demands around the lanthanide centre influence the two mechanisms differently. The Ln-N σ-bond insertive mechanism critically relies on a sufficiently accessible lanthanide and enhanced encumbrance renders cyclisation and aminolysis steps less accessible kinetically. It contrasts with the non-insertive mechanism, where greater lanthanide protection has a rather modest influence. The present study indicates that the non-insertive mechanism would prevail if the lanthanide centre were to be protected effectively against C=C bond approach. Notably, a different product spectrum would be expected for aminodiene hydroamination following the insertive or non-insertive route.     

Intramolecular hydroamination/cyclisation of aminoallenes mediated by a neutral zirconocene catalyst: a computational mechanistic study

The complete catalytic cycle for the intramolecular hydroamination/cyclisation (IHC) of 4,5-hexadien-1-ylamine (1) by a prototypical [ZrCp(2)Me(2)] precatalyst (2) has been scrutinized by employing a reliable DFT method. The present study conducted by means of a detailed computational characterisation of structural and energetic aspects of alternative pathways for all of the relevant elementary steps complements the mechanistic insights revealed from experimental results. The operative mechanism entails an initial transformation of precatalyst 2 into the thermodynamically prevalent, but dormant, bis(amido)-Zr compound in the presence of aminoallene 1. This complex undergoes a reversible, rate-determining alpha-elimination of 1 to form the imidoallene-Zr complex. The substrate-free form, which contains a chelating imidoallene functionality, is the catalytically active species and is rapidly transformed into azazirconacyclobutane intermediates through a [2+2] cycloaddition reaction. This highly facile process does not proceed regioselectively because the alternative pathways for the formation of five- and six-membered azacycles have comparable probabilities. Degradation of cyclobutane intermediates by following the most feasible pathway occurs through protonolysis of the metallacycle moiety and subsequent proton transfer from the Zr-NHR moiety onto the azacycle. The five-membered allylamine is generated through protonation at carbon atom C(6) followed by alpha-hydrogen elimination, whereas protonolysis of the cyclobutane moiety at the Zr-N bond followed by proton transfer onto carbon atom C(5) is the dominant route for the six-membered product. Of the two consecutive proton transfer steps, the second one determines the overall kinetics of the entire protonation sequence. This process is predicted to be substantially slower than the cycloaddition reaction. The factors that regulate the composition of the cycloamine products have been elucidated.     

Copper-Catalyzed Cope-Type Hydroamination of Nonactivated Olefins toward Cyclic Nitrones: Scope,Mechanism, and Enantioselective Process Development

The catalytic synthesis of cyclic nitrones, an important type of functional molecules for both synthetic chemistry and related fields, remains underdeveloped. Herein we report the copper-catalyzed Cope-type hydroamination of oximes with pendant nonactivated olefins, which enables facile access to a series of five- and six-membered cyclic nitrones under mild conditions. In this study, heterocycle-tethered oximes were employed in the Cope-type hydroamination reaction for the first time. High enantioselectivity was achieved for carbon-tethered γ,δ-vinyl oximes to afford enantioenriched five-membered cyclic nitrones. The results of preliminary mechanistic studies indicate a mononuclear catalytic species and a unified catalytic pathway over a large temperature range.