New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines.

Transition-metal catalyzed reactions that are able to construct complex aliphatic amines from simple, readily available feedstocks have become a cornerstone of modern synthetic organic chemistry. In light of the ever-increasing importance of aliphatic amines across the range of chemical sciences, this review aims to provide a concise overview of modern transition-metal catalyzed approaches to alkylamine synthesis and their functionalization. Selected examples of amine bond forming reactions include: (a) hydroamination and hydroaminoalkylation, (b) transition-metal catalyzed C(sp3)-H functionalization, and (c) transition-metal catalyzed visible-light-mediated light photoredox catalysis.

Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis.

We report a general visible-light-mediated strategy that enables the construction of complex C(sp3)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.

Synthesis of a Protected keto-Lysidine Analogue via Improved Preparation of Arabino-isoCytosine Nucleosides.

Anhydrouridines react with aliphatic amines to give N-alkyl isocytosines, but reported procedures often demand very long reaction times and can be low yielding, with narrow scope. A modified procedure for such reactions has been developed, using microwave irradiation, significantly reducing reaction time and allowing facile access to a diverse range of novel nucleosides on the gram scale. The method has been used to prepare a precursor to a novel analogue of lysidine, a naturally occurring iminonucleoside found in tRNA.

Catalytic sp3 -sp3 Functionalisation of Sulfonamides: Late-Stage Modification of Drug-Like Molecules.

A new application of Pd-catalysed allylation is reported that enables the synthesis of a range of branched sp3 -functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and base at room temperature, direct allylation was efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction was performed under mild conditions and could be applied to nanomolar sigma-receptor binders, thus enabling a late-stage functionalisation and efficient expansion of drug-like chemical space.