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Synthetic chemistry aims to build up molecular complexity from simple feedstocks . However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space . Here we report a reaction that 'deletes' nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon-carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon-carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon-carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.

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.

The introduction of a trifluoromethyl (CF ) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp )-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp )-CF products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF ' species is formed during this process and the critical C(sp )-CF bond-forming step involves the copper catalyst.

Methods for the synthesis and functionalization of amines are intrinsically important to a variety of chemical applications. We present a general carbon-hydrogen bond activation process that combines readily available aliphatic amines and the feedstock gas carbon monoxide to form synthetically versatile value-added amide products. The operationally straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium anhydride to transform aliphatic amines into β-lactams. The reaction is successful with a wide range of secondary amines and can be used as a late-stage functionalization tactic to deliver advanced, highly functionalized amine products of utility for pharmaceutical research and other areas.

Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.

Aziridines-three-membered nitrogen-containing cyclic molecules-are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products , and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity . Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach.

Deconstructive functionalization involves carbon-carbon (C-C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis and olefin metathesis have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp )-C(sp ) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp )-N and C(sp )-C(sp ) single-bond cleavage followed by C(sp )-halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.

Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, the development of methods to functionalize the α-methylene C-H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (-)-sparteine followed by Pd(0) catalysed cross-coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalysed enantioselective α-C-H coupling of a wide range of amines, which include ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C-H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.

The manipulation of traditionally unreactive functional groups is of paramount importance in modern chemical synthesis. We have developed an iron-dipyrrinato catalyst that leverages the reactivity of iron-borne metal-ligand multiple bonds to promote the direct amination of aliphatic C-H bonds. Exposure of organic azides to the iron dipyrrinato catalyst furnishes saturated, cyclic amine products (N-heterocycles) bearing complex core-substitution patterns. This study highlights the development of C-H bond functionalization chemistry for the formation of saturated, cyclic amine products and should find broad application in the context of both Pharmaceuticals and natural product synthesis.

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.