New Insights into the Mechanism of Palladium-Catalyzed Allylic Amination

Abstract

A comparative investigation into palladium-catalyzed allylic amination of unsubstituted aziridines and secondary amines has been carried out. The use of NH aziridines as nucleophiles favors formation of valuable branched products in the case of aliphatic allyl acetates. The regioselectivity of this reaction is opposite to that observed when other amines are used as nucleophiles. Our study provides evidence for the palladium-catalyzed isomerization of the branched (kinetic) product formed with common secondary amines into the thermodynamic (linear) product. In contrast, the branched allyl products obtained from unsubstituted aziridines do not undergo the isomerization process. Crossover experiments indicate that the isomerization of branched allylamines is bimolecular and is catalyzed by Pd(0). The reaction has significant solvent effect, giving the highest branched-to-linear ratios in THF. This finding can be explained by invoking the intermediacy of sigma-complexes, which is consistent with NMR data. The apparent stability of branched allyl aziridines towards palladium-catalyzed isomerization is attributed to a combination of factors that stem from a higher degree of s-character of the aziridine nitrogen compared to other amines. The reaction allows for regio- and enantioselective incorporation of aziridine rings into appropriately functionalized building blocks. The resulting methodology addresses an important issue of forming quaternary carbon centers next to nitrogen. The new insights into the mechanism of palladium-catalyzed allylic amination obtained in this study should facilitate synthesis of complex heterocycles, design of new ligands to control branched-to-linear ratio, as well as absolute stereochemistry of allylamines.

Primary tert‐ and sec‐Allylamines via Palladium‐Catalyzed Hydroamination and Allylic Substitution with Hydrazine and Hydroxylamine Derivatives

“…Like the published reactions of aziridines, the regioselectivities of the reactions in Table 3 were independent of the reaction time. [4] By comparison, these reactions with morpholine formed the opposite regioisomeric products that result from substitution at the less hindered position of the allyl intermediate, just as reported with related bisphosphine ligands. [4] Reactions with cinnamyl carbonate catalyzed by [{Pd(h 3 -allyl)Cl} 2 ] and xantphos in dichloromethane also formed the linear product.…”

“…[3,4] During studies to develop the scope of the hydroamination of dienes, [5][6][7] we found that the reactions of hydrazine and hydroxylamine derivatives occur irreversibly at the more substituted position of both prenyl and crotyl palladium intermediates. We explored this transformation further because, unlike the products from additions of aziridines, [3,4] the products from addition of hydrazine and hydroxylamine derivatives could be readily transformed into primary tertalkylamines or sec-alkylamines. The synthesis of primary amines containing tertiary alkyl groups is challenging because many of the conventional methods, such as nucleophilic substitution and additions to imines, are difficult to conduct at tertiary electrophiles and at ketimines, [8,9] and few catalytic reactions have been developed that form tert-alkyl-substituted amines.…”

Primary tert‐ and sec‐Allylamines via Palladium‐Catalyzed Hydroamination and Allylic Substitution with Hydrazine and Hydroxylamine Derivatives

“…Like the published reactions of aziridines, the regioselectivities of the reactions in Table 3 were independent of the reaction time. [4] By comparison, these reactions with morpholine formed the opposite regioisomeric products that result from substitution at the less hindered position of the allyl intermediate, just as reported with related bisphosphine ligands. [4] Reactions with cinnamyl carbonate catalyzed by [{Pd(η 3 -allyl)Cl} 2 ] and xantphos in dichloromethane also formed the linear product.…”

“…[3,4] During studies to develop the scope of the hydroamination of dienes, [5][6][7] we found that the reactions of hydrazine and hydroxylamine derivatives occur irreversibly at the more substituted position of both prenyl and crotyl palladium intermediates. We explored this transformation further because, unlike the products from additions of aziridines, [3,4] the products from addition of hydrazine and hydroxylamine derivatives could be readily transformed into primary tert-alkylamines or sec-alkylamines. The synthesis of primary amines containing tertiary alkyl groups is challenging because many of the conventional methods, such as nucleophilic substitution and additions to imines, are difficult to conduct at tertiary electrophiles and at ketimines, [8,9] and few catalytic reactions have been developed that form tert-alkylsubstituted amines.…”

Novel Palladium‐Catalysed Hydroamination of Myrcene and Catalyst Separation by Thermomorphic Solvent Systems

“…The same amines can be obtained via the allylic amination of the corresponding acetates. [35][36][37][38] Nevertheless, the direct hydroamination of myrcene is proven to be the better route because the acetates are rarely available. If the pathway is telomerisation, the so-called tail-to-tail telomer (tttelomer, 3) is mainly generated.…”