Computational study of the mechanism and selectivity of ruthenium-catalyzed hydroamidations of terminal alkynes

Abstract

Density functional theory calculations were performed to elucidate the mechanism of the ruthenium-catalyzed hydroamidation of terminal alkynes, a powerful and sustainable method for the stereoselective synthesis of enamides.

Solvent‐Promoted Regio‐ and Stereoselectivity in Ru‐Catalyzed Hydrocarboxylation of Terminal Alkynes: A DFT Study

“…The step involving alkyne to vinyl transformation is associated with a four‐membered cyclic transition state [2 – 3] ≠ with a lower activation barrier of 5.3 ( 3.0 ) kcal mol −1 . A similar activation barrier (8.7 kcal mol −1 ) was observed for alkyne insertion to the Ru−H bond in the hydroamidation reaction in the presence of the (P n Bu 3 ) 2 Ru(DMAP) 2 catalytic system . To achieve another regio‐isomer of 3 with respect to the vinyl group, an alternative approach of alkyne, that is, H 1 and C α are syn to each other, was considered (Figure , Figure S2 in the Supporting Information).…”

“…According to their interpretation, the mechanistic routes of such nucleophilic additions are governed by both the electronic nature and steric environment around the metal center. It is well known that in the presence of electron‐rich ruthenium in lower oxidation state (i.e., Ru 0 ), the reaction mechanism involves the following steps: oxidative addition of Nu−H, insertion of the alkyne into the Ru−H bond, nucleophilic attack, and reductive elimination to release the product . Dixneuf et al .…”

“…proposed an alternative mechanism that is initiated by the oxidative addition of the alkyne C(sp)−H bond instead of Nu−H. On the contrary, if the ruthenium center is electron deficient (that is, Ru II ), then the alkyne coordination precedes the nucleophilic attack step . It is worthwhile to mention that the active species 8 is a 16‐ e Ru II complex with square‐pyramidal geometry.…”

“…The above reaction flow will provide the regioselective Markovnikov addition product. However, to get the anti‐Markovnikov product, the reaction includes one additional step in which alkyne to vinylidene tautomerization occurs prior to the nucleophilic attack . In the subsequent sections we will first discuss the pathways involving Markovnikov addition followed by the anti‐Markovnikov addition route.…”

“…In the vinylidene intermediate, the C α represents a strong electrophilic center whereas in the Ru‐alkyne intermediate, the C β center is more electropositive. Recently, we have successfully addressed the ligand‐controlled regio‐ and stereoselectivity in hydroamidation and hydrocarboxylation of terminal alkynes (Schemes S1 and S2 in the Supporting Information). Our results further revealed that the regioselectivity is decided in the alkyne to vinylidene transformation step, whereas the stereoselectivity is controlled in the step of nucleophilic addition to vinylidene …”