PREFACE TO VOLUME 111

We will have rings and things and fine array

William Shakespeare

The Taming of the Shrew, 1590-1592

The two chapters in this volume of Organic Reactions describe the reductive ring-opening reactions of epoxides with titanium(III) reagents and the reductive cyclization reactions of nitroaryl and nitroalkenyl derivatives. Both chapters feature the generation and synthetic utility of a specific reactive intermediate, a free radical and a nitrene, respectively. Interestingly, despite the wide variety of processes that proceed through reactive intermediates, there are only a limited number of different types of such species, i.e., carbanions, radicals, carbocations, carbenes, carbynes, and nitrenes. These are usually high energy, short-lived, and therefore have significant reactivity to permit an array of transformations. Hence, a critical component in developing a new reaction that deploys a specific type of reactive intermediate is the ability to generate it in a controlled and selective manner, thereby taming the inherent reactivity to facilitate the desired bond-forming event in the desired manner. A particularly compelling aspect of Organic Reactions chapters is the delineation of so-called Black-Swan Events that provides the insight for accessing a specific reactive intermediate with new chemical reactivity. Notably, both chapters feature different types of ring-forming reactions, albeit this is the entire focus of the latter chapter. The first chapter also delineates other things and fine array to illustrate the synthetic utility of the reductive opening of epoxides. Another contrasting feature of the chapters is that while the first is almost entirely centered around a specific method to generate a free-radical intermediate, the second compares two different ways to access the same reactive intermediate, both of which constitute named reactions. Hence, this volume of the Organic Reactions series represents another stellar contribution that outlines the seminal developments in the generation and productive reactions of reactive intermediates to construct important synthetic motifs embedded in functional molecules.

The first chapter by T. V. (Babu) RajanBabu, William A. Nugent, and Sandipan Halder provides an outstanding treatise on the ring opening of epoxides with titanium(III) reagents. The authors concisely describe the historical events that led to the discovery of the reduction of epoxides by single-electron transfer using titanocene monochloride, which is ascribed to a series of Black-Swan Events (vide supra). For instance, Davies and Gibson reported the first example of the conversion of cyclohexene oxide to cyclohexene with titanocene monochloride in 1984; however, this work was preceded by several seemingly unrelated reports. For instance, Linnemann described probably the first epoxide cleavage by an SET process in 1866 using sodium amalgam in water, followed by contributions from Percy Julian in 1954 and mechanistic studies by Kochi in the late 1960s using chromium(II) salts. The culmination of these developments paved the way for the catalytic and stoichiometric titanium(III) reactions with epoxides outlined herein.

The Mechanism and Stereochemistry section describes the critical features associated with the generation of ß-titanoxy radicals from epoxides, including the impact of the titanium complex and the mechanistic details for the carbon-oxygen bond cleavage. A particularly valuable feature of this section is the insight into the regeneration of the titanium reagent to facilitate the catalytic version. The authors also delineate the various mechanistic pathways to the ß-titanoxy radicals, essential for planning a reaction sequence, including different methods deployed to trap the radicals formed after an initial cyclization. The section then culminates with a discussion of various aspects of regio- and stereocontrol, in which the diastereoselective processes are further subdivided into inter- and intramolecular variations. For example, the cyclization reaction section is organized by the type of Baldwin process, namely, 5-exo-trig, 5-exo-dig, 6-endo-trig, 6-exo-trig, and 6-exo-dig and includes sections on tandem cyclization reactions and the reactions of ß,?-epoxy alcohols.

The Scope and Limitation section starts with a survey of suitable epoxides to provide the reader with a sense of what types of transformations are feasible, followed by an important section on functional-group compatibility and the effects of substrate structure on reactivity. Each section is critical to anyone contemplating utilizing this reaction in complex synthesis. The intramolecular addition reactions and the associated termination strategies comprise a sizable component of this section, including transannular cyclization reactions and the construction of polycyclic products via cascade-type cyclization reactions. The Applications to Synthesis section is organized by the type of transformation, which permits a strategic analysis of these reactions. Hence, each sub-section delineates how this process has been deployed in the synthesis of a target of value to illustrate its impact in useful applications. Notably, this process has been utilized to prepare nearly two hundred natural products and advanced intermediates, making it a "formidable tool" for target-directed synthesis. The Comparison with Other Methods section delineates two critical limitations of the current process that can be mitigated to some degree by using alternative protocols, which thus provides a complementary picture of how to manipulate these types of epoxy alcohols. Additionally, the chapter provides detailed Experimental Conditions, which will be particularly insightful for anyone wishing to understand the nuances of this type of process. The Tabular Survey incorporates reactions reported up to October 2021. The tables mirror the Scope and Limitations section, making identifying examples of a particular process straightforward. Overall, this is an outstanding chapter on a very interesting and powerful synthetic transformation that has been widely deployed in organic synthesis.

The second chapter by Björn C. G. Söderberg and the late William F. Berkowitz outlines the reductive cyclization of 2-nitro- and ß-nitrostyrenes, 2-nitrobiphenyls, and 1-nitro-1,3-dienes to prepare indoles, carbazoles, and pyrroles with a particular emphasis on indoles. Notably, the indole core is arguably one of the oldest and most widely studied heterocyclic motifs. For instance, early studies on the synthesis of indigo dye inspired the first chemical synthesis of indole itself by von Baeyer in 1866 by reducing oxindole with zinc dust. The importance of the indole motif in dyes, medicinal chemistry, bioactive natural products, bacterial physiology, and neurotransmitters, such as serotonin and melatonin, make it an important structural array. Thus, methods to prepare this heterocycle have inspired many innovative synthetic approaches. Ironically, the two methods reported herein utilize nitro aromatics as the nitrogen source in the heterocyclic product, which is analogous to the method employed by von Baeyer and Emmerling in 1869 for the conversion of 2-nitrocinnamic acid to indole using iron filings under basic conditions. Interestingly, this approach remained dormant for nearly a century until the development of the Cadogan-Sundberg process and then the related Watanabe-Cenini-Söderberg reaction to convert nitrostyrenes to indoles using trivalent phosphorus reagents and palladium catalysts, respectively.

The Mechanism and Stereochemistry section is organized by the named reaction and the type of product formed. For example, some general mechanistic considerations delineate the importance of forming a nitroso derivative en route to the putative nitrene in the Cadogan-Sundberg process. DFT calculations support a concerted [3+1] cycloaddition followed by a retro [2+2] cycloaddition to generate the nitrosoarene, which undergoes a second deoxygenation via an oxazaphosphiridine to afford the nitrene to initiate cyclization. The remainder of the section deals with the caveats that have evolved with this mechanistic proposal in constructing carbazoles, indoles and pyrroles. The format for the Watanabe-Cenini-Söderberg reaction is similar, albeit, in this case, the cyclization is proposed to occur through either the nitroso or the nitrene intermediate. The initiation is thought to involve the formation of a radical anion that reacts with carbon monoxide to form a series of metallacycle intermediates. The recognition that both of these processes undergo cyclization via an equivalent nitroso/nitrene intermediate provides a unifying theme for these reactions.

The Scope and Limitations section commences with the methods used to prepare the substrates for both types of reactions. The remainder of the section is then organized by the type of reaction, namely, 2-nitrostyrenes to form indoles and ß-nitrostyrenes to produce indoles in the context of the specific named reaction. Additional sections describe the conversion of 1-nitro-1,3-dienes to pyrroles and the synthesis of heterocyclic analogs of indoles and carbazoles. A particularly useful feature is the direct comparison of the two methods, which gives the...