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.

The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations

Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage.

The potential of palladacycles: more than just precatalysts

ion and completion of the cyclometalation reaction are feasible and produce the cyclometalated complex 205. Notably, addition of a strong acid reverts the cyclometalation and regenerates the agostic species 204. Small changes in the rhodium precursor significantly modify the product outcome and lead at fast rates to the cyclometalated complex 203, that is, the final oxidative addition product S. Similarly, alkene C-H bond activation has been observed to occur readily in a PCP ligand setting.348 Milstein and co-workers developed a procedure for preparing the cyclometalated PCP, PCN, or PCO pincer complexes 209 by rhodium-mediated cleavage of a strong Caryl-Calkyl bond (Scheme 87).32,349,350 Kinetically, Calkyl-H bond activation is competitive and complex 208 is formed as a second product at essentially similar rates. However, C-C bond cleavage appears to be the thermodynamically more favored process. Obviously, the higher energy required for Caryl-Calkyl bond activation (bond dissociation energy 427 kJ mol-1) compared to C-H bond breaking (368 kJ mol-1) is compensated by the stronger Rh-Caryl bond and the formation of two fiverather than six-membered metallacycles. Because rhodium-mediated Caryl-Calkyl and Calkyl-H bond activations in 206 are thermodynamically and kinetically very similar processes,351 subtle changes in the ligand parameters strongly affect the reaction outcome. For example, PPh2 donors induce C-H bond cleavage to afford 208d exclusively at ambient temperatures. C-C activation and formation of 209d is only induced upon heating under H2 atmosphere,352 presumably because these conditions allow the product selectivity to be controlled thermodynamically. In contrast, bulky PtBu2 donors as in 206a promote C-C bond activation already at room temperature, and the aryl complex 209a is the only product observed. Similarly, replacing one phosphine donor by a harder NEt2 group or the use of less basic phosphinite donors results in selective C-C bond cleavage at room temperature. These preferences suggest steric factors to play a more dominant role than electronic differences in determining the C-C vs C-H selectivity. Steric congestion induced by the donor substituents has been proposed to arrange the orbitals of the metal center to be directed toward the C-C bond rather than toward the C-H bond.353 Kinetic investigations have identified the coordination compound 207 as a common intermediate of Calkyl-H and the Caryl-Calkyl bond activation. On the basis of the similar rates for both cleavage processes and because of the absence of any detectable intermediate, formation of 207 and not C-H or C-C bond activation appears to be rate-limiting. While displacement of a weakly bound olefin ligand in the metal precursor may be fast, formation of the 8-membered metallacycle in 207 may be less favored, especially due to the potential for forming diand polymeric coordination compounds. It is worth noting that, upon substituting the PCP pincer ligand to a PCN donor array, the coordination complex 207c becomes stable at low temperature and has been spectroscopically characterized.354 As a consequence, the rate-determining step is shifted to a later stage on the reaction coordinate. Notably, slight modifications in the metal precursor, that is, utilization of [Rh(C2H4)(CO)(solv)2]BF4 instead of [RhCl(C2H4)2]2, alters the stability of the intermediates and produces complex 210 (Scheme 88).355 This complex may be represented by an agostic interaction of the C-C bond with the rhodium center, or alternatively by an arenium structure including an sp3-hybridized ipso carbon. Because of only weak Cipso-Rh interactions in solution (e.g., the absence of any 103Rh coupling), the agostic description is favored. The different product outcome has been presumed to originate from the reduced electron density at the cationic rhodium(I) center due to the strongly withdrawing CO ligand and the relatively weak Rh-N bond. This configuration Scheme 87 Scheme 86 Cyclometalation Using d-Block Transition Metals Chemical Reviews, 2010, Vol. 110, No. 2 603

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Cyclometalation Using d-Block Transition Metals: Fundamental Aspects and Recent Trends

The development of new methods for the direct functionalization of unactivated C–H bonds is ushering in a paradigm shift in the field of retrosynthetic analysis. In particular, the catalytic enantioselective functionalization of C–H bonds represents a highly atom- and step-economic approach toward the generation of structural complexity. However, as a result of their ubiquity and low reactivity, controlling both the chemo- and stereoselectivity of such processes constitutes a significant challenge. Herein we comprehensively review all asymmetric transition-metal-catalyzed methodologies that are believed to proceed via an inner-sphere-type mechanism, with an emphasis on the nature of stereochemistry generation. Our analysis serves to document the considerable and rapid progress within in the field, while also highlighting limitations of current methods.

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O. A. Reutov

Papers

Asymmetric cyclopalladation of dimethylaminomethylferrocene

Asymmetric induction in the course of internal palladation of enantiomeric 1-dimethylaminoethylferrocene

Reaction of the low-valent transition metal complexes with non-transition organometallic compounds☆

Reactivity of ambident anions : Hardness of alkyl groups and symbiotic effect in alkylation of ambident anions

Formation of a chiral carbon centre by direct metallation into a methylene group