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.

Ruthenium(II)-Catalyzed C–H Bond Activation and Functionalization

Rhodium(III)-catalyzed direct functionalization of C-H bonds under oxidative conditions leading to C-C, C-N, and C-O bond formation is reviewed. Various arene substrates bearing nitrogen and oxygen directing groups are covered in their coupling with unsaturated partners such as alkenes and alkynes. The facile construction of C-E (E = C, N, S, or O) bonds makes Rh(III) catalysis an attractive step-economic approach to value-added molecules from readily available starting materials. Comparisons and contrasts between rhodium(III) and palladium(II)-catalyzed oxidative coupling are made. The remarkable diversity of structures accessible is demonstrated with various recent examples, with a proposed mechanism for each transformation being briefly summarized (critical review, 138 references).

C–C, C–O and C–N bond formation via rhodium(III)-catalyzed oxidative C–H activation

C-H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C-H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C-H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C-H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C-H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp(3))-H bonds by using 8-aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.

Catalytic Functionalization of C(sp2) ? H and C(sp3) ? H Bonds by Using Bidentate Directing Groups

Oxidative transition-metal-catalyzed C H bond functionalizations have attracted significant recent interest, because these methods avoid the multi-step preparation of preactivated starting materials, and hence allow for an overall streamlining of organic synthesis. Pioneering reports by the research groups of Miura and Satoh, Fagnou, and Jones revealed that particularly rhodium catalysts enabled effective dehydrogenative annulation reactions of alkynes through chelation assistance, which have set the stage for very recently developed rhodium-catalyzed isoquinolone syntheses. On the contrary, the use of less-expensive ruthenium catalysts for oxidative annulations through cleavage of C H bonds has thus far not been reported. During studies on oxidative ruthenium-catalyzed homodehydrogenative arylations, we observed unprecedented ruthenium-catalyzed direct annulations of alkynes through the chemoand site-selective functionalization of both C H and N H bonds, and we wish to disclose our results herein. At the outset of our studies, we explored the effect of different reaction parameters on the oxidative annulation of alkyne 2a by amide 1a, which included the use of representative ruthenium precursors, solvents, oxidants, and additives (Table 1, and Table S1 in the Supporting Information). Among a variety of ruthenium complexes, optimal yields of product 3a were obtained with [{RuCl2(p-cymene)}2], along with Cu(OAc)2·H2O as the terminal oxidant, and tAmOH (tAm= tert-amyl) as the solvent. On the contrary, the use of silver(I) salts as stoichiometric oxidants resulted in decreased catalytic efficacy. As to the reaction mechanism (see below), the formation of compound 4a in apolar solvents is noteworthy. With an optimized catalytic system in hand, we explored its scope in C H bond functionalizations by employing differently substituted benzamides 1 (Scheme 1). Owing to its remarkable chemoselectivity the ruthenium catalyst proved tolerant of valuable electrophilic functional groups, such as fluoro, chloro, or ester substituents. Furthermore, amides 1 bearing different groups on the nitrogen atom, such as N-alkyl, N-benzyl, or N-aryl derivatives, were efficiently reacted, with the latter being chemoselectively converted into isoquinolones 3k and 3 l, without the formation of any indole by-products. Likewise, the successful use of a heteroaromatic benzamide turned out to be viable. The catalytic system was not restricted to the use of tolane (2a), but also allowed for efficient oxidative annulations of aryl-, alkenylor alkyl-substituted alkynes 2 (Scheme 2). Importantly, the annulation process occurred with high regioselectivity even when using unsymetrically substituted aryl/alkyl or alkenyl/alkyl alkynes 2. Given the remarkable activity of the novel catalytic system, we became interested in understanding its mode of action. Thus, intramolecular competition experiments with meta-substituted substrates were largely controlled by steric interactions, thus delivering isoquinolones 3m and 3n as the sole products (Scheme 1). In contrast, the use of substrates 1b and 1c, which have electronegative heteroatoms in metaposition, gave significant amounts of products 3w and 3y, respectively, through C H bond functionalizations at the 2[*] Prof. Dr. L. Ackermann, Dr. A. V. Lygin, Dipl.-Chem. N. Hofmann Institut f r Organische und Biomolekulare Chemie Georg-August-Universit t Tammannstrasse 2, 37077 G ttingen (Germany) Fax: (+49)551-39-6777 E-mail: lutz.ackermann@chemie.uni-goettingen.de Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/

Ruthenium‐Catalyzed Oxidative Annulation by Cleavage of CH/NH Bonds

Ruthenium catalysts enabled C–H bond functionalizations on arenes with challenging secondary alkyl halides. Particularly, ruthenium(II) biscarboxylate complexes proved to be the key to success for direct alkylations with excellent levels of unusual meta-selectivity. The direct alkylations occurred under mild reaction conditions with ample scope and tolerated valuable functional groups. Detailed mechanistic studies were performed, including various competition experiments as well as reactions with isotopically labeled substrates. These studies provided strong support for an initial reversible cyclometalation. The cycloruthenation thereby activates the arene for a subsequent remote electrophilic-type substitution with the secondary alkyl halides. Independently prepared cycloruthenated complexes were found to be catalytically active provided that a carboxylate ligand was present, thereby highlighting the key importance of carboxylate assistance for effective meta-selective C–H bond alkylations.

meta-Selective C-H bond alkylation with secondary alkyl halides

Direct arylation of arenes by C H bond cleavage, which is attractive because of its ecologically and economically benign nature, is an increasingly viable alternative to conventional cross-coupling reactions with stoichiometric amounts of organometallic reagents. 2] However, while the development of stabilizing ligands allowed for the use of unactivated alkyl halides in traditional cross-coupling chemistry, generally applicable methodologies for intermolecular regioselective direct alkylations of arenes with alkyl halides by C H bond cleavage have proven elusive. Recently, we reported on the beneficial effect of carboxylic acids as additives in ruthenium-catalyzed direct arylation 11] with aryl bromides, chlorides, or tosylates. Given the significantly improved activity of the in situ generated catalytic system, we became interested in exploring its use for unprecedented ruthenium-catalyzed direct alkylations with unactivated alkyl halides 15] as electrophiles. Herein, we report our findings on the development of such C H bond functionalization reactions, which allowed for the efficient conversion of primary and secondary alkyl halides and proved applicable to neopentyl-substituted electrophiles. At the outset of our studies, we probed various additives in the ruthenium-catalyzed direct alkylation of 2-pyridyl benzene (1a), employing unactivated alkyl bromide 2 a in NMP as solvent (Table 1). Different phosphines did not significantly affect the outcome of the envisioned reaction (Table 1, entries 1–4). On the contrary, more promising results were obtained when catalytic amounts of carboxylic acids were used as additives (Table 1, entries 5–9). The alkylsubstituted, sterically hindered acid 1-AdCO2H gave the best results (Table 1, entry 9). Reactions performed in toluene as solvent proceeded less efficiently (Table 1, entry 10), and other solvents, such as THF, 1,4-dioxane, DMSO, or N,N-dimethylacetamide, gave considerably lower yields of desired product 3a. As an economically attractive alternative, RuCl3·n H2O [17] could be employed as catalyst precursor (Table 1, entry 11). Importantly, direct alkylation of pyridine derivative 1a could be performed at reaction temperatures as low as 60 8C with comparable efficiencies (Table 1, entries 13–15). Finally, the use of independently prepared carboxylic ester 1-AdCO2(nHex) clearly indicated that its formation was not relevant to the generation of the catalytically active ruthenium species (Table 1, entry 16). We then explored the scope of the optimized catalytic system in the direct alkylation of pyridine derivatives 1 (Table 2). A variety of unactivated alkyl bromides bearing bhydrogen atoms enabled regioselective direct alkylations (Table 2, entries 1–8). While an alkyl iodide also led to an acceptable yield of product 3a (Table 2, entry 9), the corresponding alkyl chloride turned out to be a more challenging substrate (Table 2, entry 10). Notably, our in situ generated catalytic system was not limited to the use of primary alkyl halides but also enabled the conversion of sterically more congested secondary alkyl halides, albeit with lower yield (Table 2, entry 11). Importantly, neopentyl bromide also served as starting material for a direct alkylation (Table 2, entry 12), which indicated that mechanisms relying on either a Table 1: Optimization of ruthenium-catalyzed direct alkylation.

Nora Hofmann

Papers

Ruthenium‐Catalyzed Oxidative Annulation by Cleavage of CH/NH Bonds

meta-Selective C-H bond alkylation with secondary alkyl halides

Ruthenium-catalyzed regioselective direct alkylation of arenes with unactivated alkyl halides through C-H bond cleavage.

Ruthenium-catalyzed oxidative synthesis of 2-pyridones through C-H/N-H bond functionalizations.

Carboxylate-assisted ruthenium-catalyzed direct alkylations of ketimines.