Ta-Catalyzed Hydroaminoalkylation of Alkenes: Insights into Ligand-Modified Reactivity Using DFT

Abstract

Density functional theory (DFT) calculations were performed to probe the mechanism of tantalum-catalyzed hydroaminoalkylation, a reaction that affords Csp3–Csp3 bond formation via α-alkylation of a secondary amine with an alkene. Electronic effects in catalyst design were probed to reveal key features in the energy profile of the proposed mechanism, corroborating experimental trends in which electrophilic metal centers demonstrate enhanced reactivity. Modeling of the energy profile with an N,O-chelating amidate Ta catalyst (I) revealed profound differences in relative energetics, rationalizing improvements that have been observed using sterically and electronically varied ligands. N,O-Chelating ligands electronically promote preferential reactivity in the equatorial plane. The turnover-limiting step can be completely changed depending upon the ligand; for sterically bulky monoamidate complexes, the protonolysis of an intermediate metallacycle is the turnover-limiting step rather than C–H activation, as has been found for systems lacking steric bulk. Unproductive off-cycle pathways were also modeled to compare with experimental studies. These insights contribute to a theoretical understanding of key features in ligand design for developing improved catalysts for hydroaminoalkylation.

Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines

“…In the formation of intermediate D two diastereomers can result ( D and D′ ), with the trans-orientation of the metallacyclic intermediates giving the major diastereomer . This is consistent with computational investigations of early transition-metal-catalyzed hydroaminoalkylation , which propose that polarized, activated alkenes, such as vinyl silanes, offer enhanced reactivity and modified regioselectivity due to substrate and catalyst dependent electronic control. For example, a bulky Ti complex affords the linear product with dimethylphenylvinylsilane, while Ta hydroaminoalkylation catalysts offer mixtures of regioisomers with vinylsilane substrates. , …”

Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α‐Arylated Amines and N‐Heterocycles

“…For intermediate J , both cis and trans isomers could form. Previous computational studies on early transition metal catalyzed HAA suggest that alkene insertion is under electronic control and depends on the polarization of the double bond of the alkene and the identity of the metal center in the transition state [16, 23] . This work shows that steric parameters also play a role with this zirconium catalyst.…”

“…Previous computational studies on early transition metal catalyzed HAA suggestt hat alkene insertion is under electronic control and depends on the polarization of the double bond of the alkene and the identityo ft he metal centeri nt he transition state. [16,23] This work shows that steric parameters also play ar ole with this zirconium catalyst. Literature reports on tantalum [24] and titanium [13] HAA with vinylsilane show the formation of mixture of regioisomers or exclusive formation of the linear product, respectively.T od ate, steric effectsd ominate over electronic parameters in zirconium catalyzed reactivity.…”

Exploiting Natural Complexity: Synthetic Terpenoid‐Alkaloids by Regioselective and Diastereoselective Hydroaminoalkylation Catalysis

“…Substrate electronic properties have a notable effect on reaction productivity, in which electron rich, pi‐donating substituents typically result in higher reaction conversions. This is proposed to be due to the increased amine nucleophilicity resulting in improved coordination to promote associative protonolysis of Ta−C bonds in the turnover limiting step of the catalytic cycle ( vide infra , Figure ) …”

“…The alkene insertion is a key step in defining the regiochemistry and stereochemistry of the final product. Recent computational chemistry investigations of the mechanism of hydroaminoalkylation showed that regioselectivity is affected by electronic effects consistent with the build‐up of partial positive charge on the more substituted carbon during the alkene insertion step …”