The cyclization of nitrogen‐centered radicals constitutes a powerful approach for the synthesis of a broad variety of nitrogen heterocycles. As with carbon‐centered radicals, the most common ring‐closure mode is the 5‐ exo cyclization onto an internal unsaturation, and the stereoselectivity is similar. Numerous methods for the generation of almost every type of nitrogen‐centered radical have been described. They involve the direct or indirect rupture of N–Y bonds, with Y = halogen (except fluorine), oxygen, nitrogen, sulfur, and hydrogen. Indirect methods, such as the addition of carbon radicals to imines, azides, and nitriles, have also been devised. The extended choice of methods and precursors, and the general mildness of the experimental conditions and tolerance for numerous functional groups, represent valuable synthetic advantages. Furthermore, the cyclization step can be part of a radical cascade leading to multiple bond formations and the rapid construction of complex molecular frameworks. This chapter describes the types, structures, and reactivity of nitrogen‐centered radicals, and details the mechanistic basis of the methods used to generate them. The methods include stannane‐based processes, oxidations and reductions by single‐electron transfer, thermolysis, electrolysis, photolysis, and photoredox catalysis. The factors that influence the stereoselectivity of the ring‐closures are discussed briefly. Applications to the total synthesis of natural products, as well as functional‐group compatibilities, reaction variants, and comparison to other methods for the synthesis of nitrogen heterocycles by ionic, organometallic, and uncatalyzed ring‐closures onto alkenes are also presented. The tabular surveys are organized according to the type of nitrogen‐centered radical involved in the cyclization step: aminyls, amidyls, carbamyls, iminyls, amidinyls, and other types of nitrogen‐centered radicals.

The Barton-McCombie deoxygenation is a landmark reaction in organic chemistry. Its efficiency in generating carbon radicals from alcohols is unmatched, despite the passage of more than 40 years since its discovery. Its mechanism, far from being straightforward, is in fact quite subtle and conceptually part of a much larger family of very powerful thiocarbonyl controlled radical reactions. This general mechanistic manifold encompasses the degenerate transfer of xanthates and related thiocarbonylthio congeners, a process that also subtends the now popular RAFT/MADIX polymerization technology, the remarkably versatile Barton decarboxylation via thiohydroxamate esters, the generation of nitrogen-centered radicals from oxime xanthates and thiosemicarbazones and thiosemicarbazides, and certainly other transformations that will emerge in the coming years. The present overview retraces the history of the Barton-McCombie reaction, the evolution of the mechanistic aspects and the resulting consequences in terms of new transformations and synthetic applications.

Abstract This chapter reviews in detail those reactions that form of a new pyrrole ring from vinyl, aryl, and heteroaryl azides via formal C–H insertion processes under thermal, photochemical, and metal‐catalyzed conditions. These reactions proceed via the intermediacy of vinyl or aryl nitrenes (or their metallonitrene equivalents) and generate a wide variety of pyrroles, indoles, carbazoles, and related systems. Methods for the synthesis of the starting azides are summarized, and a comprehensive survey of the cyclization processes is provided.

Abstract Deoxygenations of alcohols, i.e., processes that replace a hydroxyl group with hydrogen at a saturated carbon, find applications in both total synthesis and the systematic modifications of natural products. They may also be employed to introduce deuterium or tritium in a site‐specific manner. Reductive methods that involve ionic or highly polarized reagents or intermediates can be limited in their applicability: for example, competing reaction pathways including cationic rearrangements and anionic eliminations may be encountered in sterically hindered systems with substrates bearing heteroatoms close to the center undergoing reduction. As evidenced by developments over the last few decades, methods that involve the generation and direct quenching via hydrogen atom abstraction of the derived, carbon‐centered radical typically show the greatest tolerance for the presence of other functional groups and for variations in both the steric acid and the electronic environment in the vicinity of the center undergoing deoxygenation. Derivatization of the hydroxyl is a prerequisite, the determinant factors for efficient formation of the deoxygenated product lies in the ability of the combination of the substrate and reagents to induce homolysis of the C‐O bond coupled with the induction of homolysis to rapidly reduce a free radical by hydrogen donation, thereby propagating an efficient chain process. A high‐yielding way to realize this sequence was first described by Barton McCombie using the free‐radical chain reaction of O ‐thioacyl derivatives of secondary alcohols with tri‐ n ‐butylstannane. This chapter provides a detailed description and comparison of the combinations of substrates and reagents that will bring about these processes and provides a summary and evaluation of alternative deoxygenation methods. Mechanistic and stereochemical issues set out the scope and limitations of these processes with respect to both the thioacylation and reduction steps and exemplify some applications to both total synthesis and the modification of natural products.

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.

Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.

The CC-chemokine receptor 5 (CCR5) is the major coreceptor for macrophage-tropic (R5) HIV-1 strains. Several small molecule inhibitors of CCR5 that block chemokine binding and HIV-1 entry are being evaluated as drug candidates. Here we define how CCR5 antagonists TAK-779, AD101 (SCH-350581) and SCH-C (SCH-351125), which inhibit HIV-1 entry, interact with CCR5. Using a mutagenesis approach in combination with a viral entry assay to provide a direct functional read out, we tested predictions based on a homology model of CCR5 and analyzed the functions of more than 30 amino acid residues. We find that a key set of aromatic and aliphatic residues serves as a hydrophobic core for the ligand binding pocket, while E283 is critical for high affinity interaction, most likely by acting as the counterion for a positively charged nitrogen atom common to all three inhibitors. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands.

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.

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The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M2 subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.