The Golden Age of Transfer Hydrogenation

Transition-metal-catalyzed carbene transformations and cross-couplings represent two major reaction types in organometallic chemistry and organic synthesis. However, for a long period of time, these two important areas have evolved separately, with essentially no overlap or integration. Thus, an intriguing question has emerged: can cross-coupling and metal carbene transformations be merged into a single reaction cycle? Such a combination could facilitate the development of novel carbon–carbon bond-forming methodologies.Although this concept was first explored about 10 years ago, rapid developments inthis area have been achieved recently. Palladium catalysts can be used to couple diazo compounds with a wide variety of organic halides. Under oxidative coupling conditions, diazo compounds can also react with arylboronic acids and terminal alkynes. Both of these coupling reactions form carbon–carbon double bonds. As the key step in these catalytic processes, Pd carbene migratory insertion plays a vital role i...

Diazo compounds and N-tosylhydrazones: novel cross-coupling partners in transition-metal-catalyzed reactions.

Transition-metal-catalyzed cross-coupling reactions have been well-established as indispensable tools in modern organic synthesis. One of the major research goals in cross-coupling area is expanding the scope of the coupling partners. In the past decade, diazo compounds (or their precursors N-tosylhydrazones) have emerged as nucleophilic cross-coupling partners in C–C single bond or C═C double bond formations in transition-metal-catalyzed reactions. This type of coupling reaction involves the following general steps. First, the organometallic species is generated by various processes, including oxidative addition, transmetalation, cyclization, C–C bond cleavage, and C–H bond activation. Subsequently, the organometallic species reacts with the diazo substrate to generate metal carbene intermediate, which undergoes rapid migratory insertion to form a C–C bond. The new organometallic species generated from migratory insertion may undergo various transformations. This type of carbene-based coupling has proven...

Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion

This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

Cofactor-mimetic aerobic oxidation has conceptually merged with catalysis of syngas reactions to form a wide range of Markovnikov-selective olefin radical hydrofunctionalizations. We cover the development of the field and review contributions to reaction invention, mechanism, and application to complex molecule synthesis. We also provide a mechanistic framework for understanding this compendium of radical reactions.

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Mn-, Fe-, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins

Copper-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes leads to the formation of C(sp)–C(sp3) bonds. Cu carbene migratory insertion is proposed to play the key role in this transformation.

C(sp)–C(sp3) Bond Formation through Cu-Catalyzed Cross-Coupling of N-Tosylhydrazones and Trialkylsilylethynes

A general method for the hydropyridylation of unactivated alkenes is described. The transformation connects metal-mediated hydrogen atom transfer to alkenes and Minisci addition reactions. The reaction proceeds under mild conditions with high site-selectivities and allows for the construction of tertiary and quaternary centers from simple alkene starting materials.

Intermolecular Hydropyridylation of Unactivated Alkenes.

A general method for the selective hydrogenation of alkenyl halides to alkyl halides is described. Fluoro, chloro, bromo, iodo, and gem-dihaloalkenes are viable substrates for the transformation. The selectivity of the hydrogenation is consistent with reduction by a hydrogen atom transfer pathway.

A Method for the Selective Hydrogenation of Alkenyl Halides to Alkyl Halides

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1–2 steps from the commercial arenes or arene N-oxides (25–99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50–85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertia...

Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts.

Classical methods for alkene hydrogenation typically reduce less-substituted or more-strained alkenes, or those in proximity to a directing group, most rapidly. Here we describe a cobalt-mediated hydrogenation protocol that provides complementary selectivities in the reduction of several classes of olefins and alkynes. The selectivity of this reduction derives from a hydrogen atom transfer mechanism, which favors the generation of the more stable alkylradical intermediate. We also report the first alkene hydrobromination, hydroiodination, and hydroselenylation by a hydrogen atom transfer process.

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Xiaoshen Ma

Papers

C(sp)–C(sp3) Bond Formation through Cu-Catalyzed Cross-Coupling of N-Tosylhydrazones and Trialkylsilylethynes

Intermolecular Hydropyridylation of Unactivated Alkenes.

A Method for the Selective Hydrogenation of Alkenyl Halides to Alkyl Halides

Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts.

Non-classical selectivities in the reduction of alkenes by cobalt-mediated hydrogen atom transfer.