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.

There is evidence to suggest that increasing the level of saturation (that is, the number of sp-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines. In particular, processes that transform accessible feedstocks into sp-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp)-C(sp) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.

We report a general visible-light-mediated strategy that enables the construction of complex C(sp 3)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(sp 3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.

Over half of new therapeutic approaches fail in clinical trials due to a lack of target validation. As such, the development of new methods to improve and accelerate the identification of cellular targets, broadly known as target ID, remains a fundamental goal in drug discovery. While advances in sequencing and mass spectrometry technologies have revolutionized drug target ID in recent decades, the corresponding chemical-based approaches have not changed in over 50 y. Consigned to outdated stoichiometric activation modes, modern target ID campaigns are regularly confounded by poor signal-to-noise resulting from limited receptor occupancy and low crosslinking yields, especially when targeting low abundance membrane proteins or multiple protein target engagement. Here, we describe a broadly general platform for photocatalytic small molecule target ID, which is founded upon the catalytic amplification of target-tag crosslinking through the continuous generation of high-energy carbene intermediates via visible light-mediated Dexter energy transfer. By decoupling the reactive warhead tag from the small molecule ligand, catalytic signal amplification results in unprecedented levels of target enrichment, enabling the quantitative target and off target ID of several drugs including (+)-JQ1, paclitaxel (Taxol), dasatinib (Sprycel), as well as two G-protein-coupled receptors—ADORA2A and GPR40.

Palladium(II)-catalyzed C-H carbonylation reactions of methylene C-H bonds in secondary aliphatic amines lead to the formation of trans-disubstituted β-lactams in excellent yields and selectivities. The generality of the C-H carbonylation process is aided by the action of xantphos-based ligands and is important in securing good yields for the β-lactam products.