The site-selective formation of carbon-carbon bonds through direct functionalizations of otherwise unreactive carbon-hydrogen bonds constitutes an economically attractive strategy for an overall streamlining of sustainable syntheses. In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C-H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool. For instance, the use of inter alia palladium, ruthenium, rhodium, copper, or iron complexes set the stage for chemo-, site-, diastereo-, and/or enantioselective C-H bond functionalizations. Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. Traditionally, three different modes of action were primarily considered for CH bond metalations, namely, (i) oxidative addition with electronrich late transition metals, (ii) σ-bond metathesis with early transition metals, and (iii) electrophilic activation with electrondeficient late transition metals (Scheme 1). However, more recent mechanistic studies indicated the existence of a continuum of electrophilic, ambiphilic, and nucleophilic interactions. Within this continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalationmechanisms relying on the assistance of a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates (Scheme 1, iv). This novel insight into the nature of stoichiometric metalations has served as stimulus for the development of novel transformations based on cocatalytic amounts of carboxylates, which significantly broadened the scope of C-H bond functionalizations in recent years, with most remarkable progress being made in palladiumor ruthenium-catalyzed direct arylations and direct alkylations. These carboxylate-assisted C-H bond transformations were mostly proposed to proceed via a mechanism in which metalation takes place via a concerted base-assisted deprotonation. To mechanistically differentiate these intramolecular metalations new acronyms have recently been introduced into the literature, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms and will be used below where appropriate. This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Moreover, experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes are discussed as well. Mechanistically related C-H bond cleavage reactions with ruthenium or iridium complexes bearing monodentate ligands are, however, only covered with respect to their working mode, and transformations with stoichiometric amounts of simple acetate bases are solely included when their mechanism was suggested to proceed by acetate-assisted metalation.

Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: mechanism and scope.

No copper needed: In recent years, a large number of metal-free click reactions have been reported based on thiol-ene radical additions, Diels–Alder reactions, and Michael additions. In this Minireview, special attention is given to the advantages and limitations of the different methods to evaluate whether they have the potential to surpass the overwhelming success of the copper(I)-catalyzed azide-alkyne cycloaddition.

The overwhelming success of click chemistry encouraged researchers to develop alternative “spring-loaded” chemical reactions for use in different fields of chemistry. Initially, the copper(I)-catalyzed azide-alkyne cycloaddition was the only click reaction. In recent years, metal-free [3+2] cycloaddition reactions, Diels–Alder reactions, and thiol-alkene radical addition reactions have come to the fore as click reactions because of their simple synthetic procedures and high yields. Furthermore, these metal-free reactions have wide applicability and are physiologically compatible. These and other alternative click reactions expand the opportunities for synthesizing small organic compounds as well as tailor-made macromolecules and bioconjugates. This Minireview discusses the success and applicability of new, in particular metal-free, click reactions.

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Click Chemistry beyond Metal-Catalyzed Cycloaddition

Transition-metal-catalyzed C–H bond arylation has recently emerged as a powerful tool for the functionalization of organic molecules that may complement or even replace traditional catalytic cross-couplings. While many efforts have focused on the arylation of arenes and heteroarenes in the past two decades, less studies have been devoted to the arylation of nonacidic C–H bonds of alkyl groups. This tutorial review highlights recent work in this active area.

Transition metal-catalyzed arylation of unactivated C(sp3)–H bonds

Synthesis of heterocycles via electrophilic cyclization of alkynes containing heteroatom.

Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the “click reaction”, serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)...

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry

Benzyne click chemistry: synthesis of benzotriazoles from benzynes and azides.

The [3+2] cycloaddition of a variety of diazo compounds with o-(trimethylsilyl)aryl triflates in the presence of CsF or TBAF at room temperature provides a very direct, efficient approach to a wide range of potentially biologically and pharmaceutically interesting substituted indazoles in good to excellent yields under mild reaction conditions. Simple diazomethane derivatives afford N-unsubstituted indazoles or 1-arylated indazoles, depending upon the stoichiometry of the reagents and the reaction conditions, while dicarbonyl-containing diazo compounds undergo carbonyl migration to afford 1-acyl or 1-alkoxycarbonyl indazoles selectively.

Synthesis of indazoles by the [3+2] cycloaddition of diazo compounds with arynes and subsequent acyl migration.

Synthesis of 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones.

The catalytic activation of a C–H bond is a fundamentally important organic transformation. There are now numerous reports of palladium-mediated C–H activation by the through-space interaction of a palladium center with a neighboring C–H bond. This type of C–H activation can lead to a net “palladium migration” from the carbon atom where the palladium is first introduced to a remote carbon atom where C–H activation occurs. This process provides a novel method to introduce a palladium moiety into a position where direct palladium introduction may not be straightforward. This process is accompanied by concurrent migration of a hydrogen atom in the direction opposite to that of the palladium migration. Analogous rhodium migrations have also been reported. In this account, different types of palladium and rhodium migrations are reviewed and the reaction mechanism is discussed.

Remote C-H activation via through-space palladium and rhodium migrations.

3-Sulfenyl- and 3-selenylindoles are readily synthesized by a two-step process involving the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-ortho-iodoanilines and terminal alkynes and subsequent electrophilic cyclization of the resulting N,N-dialkyl-ortho-(1-alkynyl)anilines with arylsulfenyl chlorides or arylselenyl chlorides. The presence of a stoichiometric amount of n-Bu4NI is crucial to the success of the electrophilic cyclization. A variety of 3-sulfenyl- and 3-selenylindole derivatives bearing alkyl, vinylic, aryl, and heteroaryl substituents have been prepared in good to excellent yields (up to 99%). By employing N,N-dibenzyl-ortho-iodoanilines, a 3-sulfenyl-N-H-indole has been successfully prepared. In addition, 3-sulfonyl- and 3-sulfinylindoles have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles.

Synthesis of 3-Sulfenyl- and 3-Selenylindoles by the Pd/Cu-Catalyzed Coupling of N,N-Dialkyl-2-iodoanilines and Terminal Alkynes, Followed by n-Bu4NI-Induced Electrophilic Cyclization

Feng Shi

Papers

Benzyne click chemistry: synthesis of benzotriazoles from benzynes and azides.

Synthesis of indazoles by the [3+2] cycloaddition of diazo compounds with arynes and subsequent acyl migration.

Synthesis of 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones.

Remote C-H activation via through-space palladium and rhodium migrations.

Synthesis of 3-Sulfenyl- and 3-Selenylindoles by the Pd/Cu-Catalyzed Coupling of N,N-Dialkyl-2-iodoanilines and Terminal Alkynes, Followed by n-Bu4NI-Induced Electrophilic Cyclization