CuH-catalysed hydroamination of arylalkynes with hydroxylamine esters – a computational scrutiny of rival mechanistic pathways

Abstract

An in-depth computational mechanistic probe of the CuH-mediated hydroamination of internal arylalkynes with amine electrophile and hydrosilane defines the most accessible pathways for rival avenues of direct and reductive hydroamination, from which a general understanding of the factors controlling formal hydroamination catalysis emerges.

On the Superior Activity of In(I) versus In(III) Cations Toward ortho-C-Alkylation of Anilines and Intramolecular Hydroamination of Alkenes

“…Thus, in agreement with previous reports, the computed catalytic cycle contains four main steps as follows: ( i ) ligand exchange between the precatalysts and substrate, ( ii ) the nucleophilic attack of the amine on the bound alkene forming a free rotating alkyl-In­(I) intermediate for facilitating the transfer of protons, ( iii ) migration of a proton from the nitrogen atom to the ß-carbon to provide the secondary amine product, and ( iv ) displacement of the secondary amine to complete the catalytic cycle. These computations support the catalytic role of naked In­(I) + ions, which reversibly bind to primary amines.…”

Enantioselective Copper-Catalyzed Hydroamination of Vinylarenes with Anthranils

“…This alkylcopper species is then intercepted by an electrophilic aminating reagent such as dialkylaminobenzoate, leading to formal anti-Markovnikov hydroamination of the olefin (Scheme a). This system has been successfully extended to alkynes and internal olefins . Other unsaturated substrates including vinylsilanes, boron-substituted alkenes, enals, and enones all proved applicable.…”

“…Other unsaturated substrates including vinylsilanes, boron-substituted alkenes, enals, and enones all proved applicable. However, the products are mostly limited to chiral tertiary alkyl amines due to the dominating applicability of dialkylamino benzoate reagents. − Recently, Buchwald realized asymmetric synthesis of chiral secondary alkylamines and tertiary arylamines using meticulously designed amino benzoates with PPh 3 as a secondary ligand (Scheme b,c). , However, a satisfactory protocol that utilizes related electrophilic aminating agents to deliver secondary arylamines still has not been realized, probably due to the challenge of the undesired direct reduction of the hydroxylamine ester by CuH. On the other hand, the atom economy of using hydroxylamine O -benzoates as aminating reagents is unsatisfactory.…”

Regio- and Enantioselective Synthesis of 1,2-Diamine Derivatives by Copper-Catalyzed Hydroamination

“…The mechanism proposed for the CuH-catalyzed hydroamination process is shown in Figure . − First, the allylic amine undergoes hydrocupration to form a chiral alkylcopper species, II , which is then trapped by hydroxylamine benzoate, IV , to generate the corresponding chiral amine product, V , and copper­(I) benzoate, III . The active catalyst, I , can be regenerated after σ-bond metathesis with a hydrosilane.…”

“…In the presence of Cu­(OAc) 2 /( R )-DTBM-SEGPHOS/PPh 3 (a mixture known as CuCatMix*), (MeO) 2 MeSiH, and 2a as the electrophilic amine source, the reactions of substrates bearing tert -butoxycarbonyl (Boc, entry 1), tosyl (entry 2), and p -methoxy benzyl (PMB, entry 3) groups afforded neither the desired product 3 nor the side product 4 . The low reactivity of these substrates is consistent with the previous experimental , and computational studies, showing that hydrocupration is typically challenging for internal alkenes. When the protecting group was switched to an acetyl group (Ac, entry 4), no desired product was seen, but the formation of a moderate amount of side product 4 was observed (41%).…”