PREFACE TO VOLUME 113

They say opposites attract, but like meets like, too.

Ruth Downie, 2015

A Year of Ravens

The construction of functional molecules in a predictable manner is predicated on the ability to design and implement a specific synthetic strategy. Consequently, translating a retrosynthetic analysis into practice requires the identification of successful tactics and thus constitutes the most time-consuming and tedious aspect of such an endeavor. One of the overarching strengths of the Organic Reactions series is the collation of reaction conditions in curated tables that enable the reader to a priori select the appropriate tactics to expedite the implementation of a proposed synthetic sequence. The two chapters in this particular volume focus on transition-metal-catalyzed alkyl-alkyl cross-coupling reactions that form challenging carbon-carbon bonds and on the hydrozirconation of alkynes to generate reactive carbon nucleophiles for electrophilic functionalization and cross-coupling reactions. Hence, the two chapters provide important reactions that align with the notion that "opposites attract, but like meets like, too" since they both feature cross- and homo-coupling reactions. In contrast to conventional cross-coupling reactions that primarily proceed through a heterolytic-type process, homolytic processes now permit both cross- and homo-coupling reactions. Although the homolytic pathway has often been derided because of the challenges associated with controlling chemo-, regio-, and stereoselectivity, the ability to promote selective cross-coupling reactions through radical intermediates has significantly broadened the scope of these types of transformations.

The first chapter by Takanori Iwasaki and Nobuaki Kambe provides a definitive treatise on transition-metal-catalyzed alkyl-alkyl cross-coupling reactions, the development of which has proven particularly challenging. The coupling of unsaturated partners (i.e., forming bonds between sp and sp2 components) has been extensively studied and was the subject of the 2010 Nobel Prize in Chemistry. Ironically, the reactions between sp3-hybridized carbon atoms predate the former and can be traced to the seminal studies of Kharash in the 1940s. Independent studies by several groups in the 1970s illuminated the problems associated with controlling efficiency and selectivity in alkyl-alkyl coupling, stemming from undesirable side reactions. Hence, progress was limited until the 1990s when alkyl halides were identified as promising coupling partners, thereby inspiring the remarkable progress in the 2000s that led to the development of a series of important reactions, including enantioselective variants.

The Mechanism and Stereochemistry section defines the two catalytic cycles that have been used to rationalize these reactions. For instance, Type A proceeds by a more conventional process, triggered by oxidative addition with the alkyl halide, which is supported by the isolation of the oxidative addition adduct and kinetic studies. In contrast, Type B is initiated by a transmetallation or complexation of the organometallic reagent, which differs significantly based on the metal complex and the type of ligand. For example, the Kumada-Tamao-Corriu cross-coupling reaction catalyzed by nickel or palladium utilizes 1,3-butadiene as a ligand that dimerizes to form a high-oxidation state bis-p-allyl metal complex that reacts directly with the Grignard reagent. This section also addresses the stereochemical aspects of the reaction in the context of the electrophile (alkyl halide or pseudohalide) and nucleophile (organometallic reagent). In the former case, the process can be either stereospecific or stereoselective, which is relevant to developing the enantioselective variations. The catalyst impacts the stereochemical outcome for the alkyl electrophiles, which is ascribed to the switch from a heterolytic to a homolytic pathway (vide supra). Hence, tailoring the metal complex has far-reaching implications that expand the scope and permit the construction of challenging carbon-carbon bonds in a predictable manner. In contrast, the stereochemistry of the alkylmetal reagents is rarely examined because of problems with their stereochemical lability, albeit a few seminal studies are described to provide insight into the current challenges. The section on the relative reactivity of various electrophiles and nucleophiles offers further insight into designing optimal combinations for a specific coupling reaction.

The Scope and Limitations section commences with a chart summarizing the current scope and limitations for the metal catalysts and coupling partners to define the remaining knowledge gaps in this area. This section is organized by the type of metal catalyst (e.g., Cu, Ni, Pd, Ag, Fe, and Co), which is important given the differences in the reaction mechanisms. The sections are further subdivided into the kind of organometallic reagent (Mg, Li, Mn, Zn, Sm, and B), the degree of alkyl substitution and the nature of the leaving group, e.g., the copper-catalyzed cross-coupling of primary alkyl halides and pseudohalides with an array of alkyl Grignard reagents (primary, secondary, and tertiary). The nickel and palladium sections also include the merits of different ligands (e.g., phosphine, nitrogen-based, N-heterocyclic carbene, and p-carbon ligands) that have been employed. The section on asymmetric variants of the alkyl-alkyl cross-coupling reaction is important and timely because it clearly illustrates that this process is very much in its infancy and has immense synthetic possibilities. Notably, the enantioconvergent reactions generally require a nickel complex with chiral diamine and triamine ligands to access the requisite alkyl radical intermediate for the enantioconvergent process (e.g., Suzuki-Miyaura, Negishi, and Kumada-Tamao-Corriu cross-coupling reactions).

The Applications to Synthesis section highlights several adaptations of the reaction in natural-product synthesis that involve forming racemic and achiral carbon-carbon bonds. The Comparison with Other Methods section critically assesses homocoupling reactions of alkyl halides and alkylmetal reagents, including reductive cross-electrophile coupling, cross-coupling of alkyl transition-metal reagents, and cross-coupling reactions with unsaturated partners followed by reduction. The Tabular Survey is organized by the type of substitution of the electrophile and alkylmetal reagent (e.g., primary alkyl halides with primary alkylmetals) and then further subdivided by the kind of organometallic reagent (e.g., Mg, Zn, B, etc.), to permit the identification of a specific reaction combination of interest. This outstanding chapter on an important class of cross-coupling reactions complements the extensive studies with unsaturated variants. Hence, the chapter should interest anyone wishing to develop new variants or employ this type of transformation in target-directed synthesis.

The second chapter by John A. Milligan, Courtney V. Hammill, Desirae L. Crocker, and Peter Wipf describes the hydrozirconation of alkynes, which has been the subject of intensive investigation. Although hydrometallation can be accomplished with early- and late-transition metals, the former permits the stoichiometric conversion of unactivated alkenes and alkynes into various organic compounds by functionalizing the isolable s-bonded organometallic intermediate. The chapter primarily focuses on the synthetic utility of zirconocene hydrochloride (Cp2Zr(H)Cl, Schwartz Reagent), which can be accessed directly or prepared in situ from either zirconocene dichloride or dihydride. The reagent was first prepared and utilized for hydrozirconation alkenes and alkynes in the late 1960s and early 1970s by Wailes and coworkers. This chapter delineates the evolution of the hydrozirconation reaction with this reagent and the reactions of the zirconium-carbon s-bond with a range of electrophiles, which has proven to be a versatile and general methodology.

The Mechanism and Stereochemistry section outlines the challenges with the hydrozirconation of alkenes and alkynes, which are formally equilibrium processes initiated by forming a transient p-complex en route to the thermodynamically more favorable s-complex. Hydrozirconation is analogous to hydroboration since it proceeds through a four-centered, concerted asynchronous transition state. Although zirconocene hydrochloride is commonly employed, these species can also be accessed from ß-hydride elimination, albeit the mechanistic details of this process have not been reported. This section highlights the limitations of the current theoretical studies that focus entirely on ethylene and acetylene, which suggest the chlorine and hydrogen ligands are at opposing ends during the addition and that the hydrozirconation process is fully reversible at room temperature. The authors outline important stereochemical aspects through key experimental observations and the impact of solvent on kinetic and thermodynamic control. In addition, the implication of steric and electronic factors in both the reagent and the substrate on regio- and stereoselectivity provides the reader with a comprehensive summary of the factors that control reactivity and selectivity in this process.

The Scope and Limitations section begins...