Regioselectivity of the Conjugate Addition of Amines to Dissymmetrical Pull‐Pull Alkenes

Abstract

The regioselectivity of the conjugate nucleophilic addition of amines to vicinal di-acceptor-substituted alkenes has been studied. A set of results obtained with standard primary and secondary amines gives some clues on the relative acceptor character of classical electron-withdrawing groups (EWG). We have shown in addition that computed inverse local nucleophilicity index can be used to predict the regioselectivity of the nucleophilic attack.

Pull‐Pull Alkenes in the Aza‐Michael Reaction

“…Indeed, the electrophilicity parameters for cyano‐ and ethoxycarbonyl groups are very close (−19.05 and −19.07 respectively) [40] . In spite of this fact, when ethyl cyanoacrylate ( Z )‐ 37 reacted with morpholine 2 b in both classical [18,41] and hyperbaric (16 kbar) [18] conditions high‐yield (up to 91%) and regioselective formation of the β ‐amino ester 38 was observed (Scheme 15). Only the same direction of nucleophilic attack observed when cyanoacrylate 37 was treated with imidazole [42]…”

“…In these reactions ethyl ( E )‐4,4,4‐trifluorobuten‐2‐onate 40 a was used as an excellent Michael acceptor: its reactions with nitrogen nucleophiles proceed regioselectively and furnish only corresponding β‐amino esters 41 . For example, aliphatic amines [18,45–47] and N,N‐ and N,O‐binucleophiles [20] were added to enoate 40 a under classical (catalytic or non‐catalytic) or hyperbaric conditions to give target β‐amino esters in high to excellent yields (Scheme 16).…”

“…The same addition direction was observed with others related compounds. For example, methyl 4‐oxopenten‐2‐oate ( E )‐ 4 a reacts with benzylamine 2 a or morpholine 2 b to give α‐amino esters 5 [18] . The reaction of 4 a with 2 b proceeds with the same regioselectivity under high or atmospheric pressure.…”

“…Moreover, the ratio of isomers depends strongly on the presence of any additives. For example, when the reaction was performed in the presence of lithium perchlorate (100 mol%), their ratio was inverted: in this case both regioisomers were formed in ratio 43:57 [18] . This phenomenon was explained by the ability of lithium cation to coordinate efficiently to the carbonyl oxygen that probably decreases the π , π ‐conjugation between the ethoxycarbonyl group and the carbon−carbon double bond.…”

Hyperbaric reactions in organic synthesis. Progress from 2006 to 2021

“…), but unfortunately, this product was not very stable and underwent a rapid retro-aza-Michael reaction upon purification. 111 At the same time, the results reported over the last two decades show that high pressure facilitates conjugate addition, even for β,β-disubstituted Michael acceptors. For example, β,β-dimethyl acrylate 188 reacted with secondary amines under 16 kbar to give the target adducts 189 in good yields (Scheme 58), whereas under classical conditions, these reactions did not occur at all.…”