The development of a catalytic, efficient and regioselective method to directly activate inert and stable C-H bonds of simple aliphatic compounds is perhaps one of the most important challenges in synthetic chemistry. In 2014, our group reported the first example of direct palladium-catalysed C(sp<sup>3</sup>)–H functionalisation of simple aliphatic secondary amines, exploiting the native coordinating ability of the nitrogen atom. Inspired by this novel approach, we wondered if the method could be expanded towards the oxidative synthesis of azetidine compounds through a five-membered-ring palladacycle. A novel cyclic hypervalent iodine species was used to oxidize the Pd(II) complex to a Pd(IV) species and exclusively promote the energetically unfavourable C–N bond formation, which is not observed using classical (diacetoxyiodo)benzene derivatives due to the selective C–O reductive elimination processes. After optimization, various azetidines could be synthesized in good yields, demonstrating the generality of the method. Perhaps most importantly, substrates containing C–H bonds adjacent to the nitrogen atom were tolerated under the reaction conditions, showing for the first time in Pd(IV) chemistry the possibility of using α-chiral substrate as starting amines. It is noteworthy that the reaction exhibited high diastereoselectivity when this class of substrates was employed. The novel methodology was used to rapidly synthesize chiral quaternary azetidine-2-carboxylic acid (Aze) derivatives, which are challenging to obtain using existing methods.

Synthesis of azetidine derivatives <i>via</i> palladium-catalysed C(sp3)–H functionalisation of aliphatic secondary amines

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Synthesis of azetidine derivatives via palladium-catalysed C(sp3)–H functionalisation of aliphatic secondary amines