The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones.

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Nitrogen-Centered Radicals in Functionalization of sp2 Systems: Generation, Reactivity, and Applications in Synthesis.

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 products1–3, and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity4–6. 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 sensitive7 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. The synthesis of aziridines—three-membered nitrogen-containing heterocycles—is achieved by a new method involving the electrochemical coupling of alkenes and amines, via a dicationic intermediate.

Aziridine synthesis by coupling amines and alkenes via an electrogenerated dication.

Aliphatic azides are a versatile class of compounds found in a variety of biologically active pharmaceuticals. These compounds are also recognized as useful precursors for the synthesis of a range of nitrogen-based scaffolds of therapeutic drugs, biologically active compounds, and functional materials. In light of the growing importance of aliphatic azides in both chemical and biological sciences, a vast array of synthetic strategies for the preparation of structurally diverse aliphatic azides have been developed over the past decades. However, to date, this topic has not been the subject of a dedicated review. This review aims to provide a concise overview of modern synthetic strategies to access aliphatic azides that have emerged since 2010. The discussed azidation reactions include (a) azidation of C-C multiple bonds, (b) azidation of C-H bonds, (c) the direct transformation of vinyl azides into other aliphatic azides, and (d) miscellaneous reactions to access aliphatic azides. We critically discuss the synthetic outcomes and the generality and uniqueness of the different mechanistic rationale of each of the selected reactions. The challenges and potential opportunities of the topic are outlined.

New Strategies for the Synthesis of Aliphatic Azides.

Alkenes are versatile building blocks in modern organic synthesis. In the difunctionalization reactions of alkenes, two functional groups can be simultaneously introduced into the π system. This is an efficient strategy for the synthesis of multifunctional compounds with complex structures and has the advantages of atom and step economy. Nitrogen-containing organic compounds are widely found in natural products and synthetic compounds, such as dyes, pesticides, medicines, artificial resins, and so on. Many natural products with high biological activity and a broad range of drugs have nitrogen-containing functional groups. The research on the construction methods of C-N bonds has always been one of the most important tasks in organic synthesis, especially in drug synthesis, and the synthetic methods starting from simple and easily available raw materials have been a topic of interest to chemists. The aminative difunctionalization of alkenes can efficiently construct C-N bonds, and at the same time, prepare some compounds that usually require multiple steps of reaction. It is one of the most effective strategies for the simple and efficient synthesis of functionalized nitrogen-containing compounds. This review outlines the major developments focusing on the transition metal-catalyzed or metal-free diamination, aminohalogenation, aminocarbonation, amino-oxidation and aminoboronation reactions of alkenes from 2015-2020.

Recent advances in aminative difunctionalization of alkenes

Recent Advances in Nonprecious Metal Catalysis

Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simpl...

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Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction.

Secondary and tertiary alkylamines are privileged substance classes that are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine-derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The method has excellent functional group tolerance and a broad scope of alkenes was converted to the corresponding products, including several drug-like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, was demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.

Design and Scalable Synthesis of N-Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installation of Medicinally Relevant Amines**

Synthesis of N-Alkyl Anilines from Arenes via Iron-Promoted Aromatic C-H Amination.

Preparation of O-Pivaloyl Hydroxylamine Triflic Acid

The intramolecular carbothiolation of unsaturated hydrocarbons using a palladium–NHC catalyst (NHC = N-heterocyclic carbene) is described. Herein, a single catalyst system enables both initial activation of a C(sp2)–S bond through oxidative addition and formation of a C(sp3)–S bond through a terminal reductive elimination, unlocking a completely atom-economical transfer across alkenes. The reaction tolerates a variety of different functional groups, exhibits excellent chemoselectivity in the presence of competing thioether moieties, and can be applied to various alkenes and alkynes. Furthermore, product derivatization was demonstrated to access a broad variety of sulfur-containing compounds. 

Eric Falk

Papers

Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction.

Design and Scalable Synthesis of N-Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installation of Medicinally Relevant Amines**

Synthesis of N-Alkyl Anilines from Arenes via Iron-Promoted Aromatic C-H Amination.

Preparation of O-Pivaloyl Hydroxylamine Triflic Acid

Palladium-Catalyzed Carbothiolation of Alkenes and Alkynes for the Synthesis of Heterocycles