Copper‐Catalysed Aminoboration of Vinylarenes with Hydroxylamine Esters—A Computational Mechanistic Study

Abstract

An in-depth computational probe of the copper-mediated formal aminoboration of β-alkylstyrenes with bis(pinacolato)diboron B pin and an archetype hydroxylamine ester by a dppbz-ligated {P^P}Cu boryl catalyst (dppbz≡{P^P}≡1,2-bis(diphenylphosphino)benzene) is presented. This first comprehensive computational study of the copper-mediated formal aminoboration utilising an electrophilic strategy has identified the most accessible pathway for productive catalysis. The mechanistic picture derived from smooth energy profiles acquired by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The high degree of regio- and stereoselectivity achieved in syn-borylcupration and Umpolung electrophilic amination is instrumental to the exclusive generation of the (syn)-β-aminoalkylborane product. On the one hand, syn-borylcupration furnishes exclusively β-borylalkylcopper nucleophile upon boryl addition onto the vinylarene β-carbon. Its subsequent approach by the hydroxylamine electrophile to deliver the product with the release of {P^P}Cu benzoate favours a stepwise stereoretentive S 2-type oxidative addition/N-C bond-forming reductive elimination sequence. The copper benzoate species represents the catalyst resting state, and its transformation into the catalytically active borylcopper species upon salt metathesis with Li(OtBu) base and transmetallation with B pin is turnover limiting. Electronically modified β-alkylstyrenes featuring a para-CF substituted phenyl ring render the borylcupration faster, and more electron-rich hydroxylamine agents decelerate the electrophilic amination.

Beyond Carbon: Enantioselective and Enantiospecific Reactions with Catalytically Generated Boryl- and Silylcopper Intermediates

“…However, quantum-chemical calculations and experimental investigations have suggested that the migratory insertion of an internal double bond into Cu–B/Si bonds likely proceeds with a syn stereochemistry, resulting in the formation of the alkylcopper species IX/X . 64 − 70 This also rationalizes the stereochemical outcome of borylative amination and arylation reactions later presented in section 4 . 70 , 130 , 131 …”

Copper-Catalyzed Carbonylative Synthesis of β-Boryl Amides via Boroamidation of Alkenes

“…CCS Chemistry with literatures [52][53][54]. Subsequently, hydroxylamine 2 reacts with CO and no R 2 NCO-OBz was detected, which excludes anhydride intermediate(Scheme 3, b).…”

Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives

“…Moreover, without any racemization, the chiral center in 5a was observed under harsh conditions [e.g., in the presence of NaOH or trifluoroacetic acid (TFA)], indicating that these types of chiral compounds might have the capacity to transfer into more complicated chiral compounds while maintaining the enantioselectivity. According to previous reports, [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]62,63 a mechanism involving a regio-and enantioselective insertion of CuH into C-C double bond in a Michael acceptor to form benzylcopper intermediate, followed by an amination process with hydroxylamine 4 to provide expected chiral β-amino carbonyls, might be possible. Other mechanisms cannot be excluded, and further studies need to be carried out to illuminate the origin of this unusual regio-and enantionselectivity.…”

“…Transition-metal-catalyzed asymmetric hydroamination of unsaturated hydrocarbons is a straightforward and powerful approach for rapid assembly of a variety of biologically active chiral amines. [36][37][38][39] In this context, asymmetric hydroamination of various alkenes and alkynes [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] with in situ generated CuH catalysts [56][57][58][59][60][61] has attracted much attention since the pioneering reports by Buchwald 62 and Hirano, and Miura in 2013. 63 Besides, an array of electronically matched CuH-catalyzed asymmetric transformations of Michael acceptors, namely undergoing the 1,4-hydrocupration process, have also been disclosed in past decades (Scheme 1b).…”