Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

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

The direct functionalization of heterocyclic compounds has emerged as one of the most important topics in the field of metal-catalyzed C–H bond activation due to the fact that products are an important synthetic motif in organic synthesis, the pharmaceutical industry, and materials science. This critical review covers the recent progresses on the regioselective dehydrogenative direct coupling reaction of heteroarenes, including arylation, olefination, alkynylation, and amination/amidation mainly utilizing transition metal catalysts (113 references).

Recent advances in the transition metal-catalyzed twofold oxidative C–H bond activation strategy for C–C and C–N bond formation

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.

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

Easy does it: Aryl boronic acids undergo smooth and selective trifluoromethylation with low-cost fluoroform-derived CuCF(3) in DMF in non-dried air. The reaction occurs under mild conditions (1 atm, room temperature), exhibits unprecedented functional-group tolerance, and affords trifluoromethylated aromatic compounds in up to 99 % yield.

Fluoroform‐Derived CuCF3 for Low‐Cost, Simple, Efficient, and Safe Trifluoromethylation of Aryl Boronic Acids in Air

In the last decade, C H bond-activation protocols have profoundly changed the landscape of organic synthesis through unconventional bond-disconnection strategies for the assembly of complex organic molecules. Ideally, directing groups that are commonly employed in C H activation processes should have a dual role by assisting chelation and subsequently promoting further functionalization. The use of benzoic acids holds great promise in this regard, as illustrated by the recent work of Yu and co-workers, and other research groups. Despite the available background knowledge, the development of catalytic methods for activating C(sp) H bonds is still in its infancy. Indeed, it is highly desirable to design new synthetic pathways based on C(sp) H activation in order to dramatically increase molecular complexity while avoiding tedious functional group manipulation. Benzolactones are a prominent structural motif of many bioactive natural products and pharmaceutically important compounds. Classical methods for the synthesis of benzolactones include the cyclization of hydroxy acids or halolactonization processes (Scheme 1, path b). Unfortunately, these methods require prefunctionalization steps, which limit the applicability because of the need for additional synthetic steps (Scheme 1, path a). The most attractive route toward benzolactones 2 would imply a direct catalytic conversion of benzoic acids 1, thus drastically reducing the overall number of synthetic steps (Scheme 1, path c). Despite encouraging precedents, particularly the pioneering and elegant work reported by Sames and co-workers when using Pt catalysts, this seemingly routine transformation is not yet efficient because of the low functional group tolerance, the high price of Pt, and the limited substitution patterns that can be accessed, thus enforcing a change in strategy. As part of our ongoing interest in the synthesis of benzoic acids by Pdcatalyzed CO2 activation, [11] it was anticipated that 1 might undergo a Pd-catalyzed activation of a proximal C(sp) H bond, followed by a virtually unexplored reductive elimination of a Pd intermediate to form a C(sp) O bond (Scheme 1, path c). This step would be rather challenging because of the large energy gap between the highest occupied molecular orbital (HOMO) of the Pd O bond and the lowest unoccupied molecular orbital (LUMO) of the Pd C bond, and the substantial ionic character of the Pd O bond. Overall, path c (Scheme 1) would constitute a direct, stepeconomical approach toward benzolactones 2. We hypothesized that the judicious choice of a supporting ligand and its appropriate fine-tuning might play an important, if not critical, role in the synthesis of 2. Herein, we demonstrate that these two mechanistically distinct Pd-catalyzed processes can be drastically accelerated by the employment of an Nprotected amino acid as the supporting ligand in the synthesis of highly functionalized benzolactones with a diverse set of substitution patterns that are beyond reach otherwise. We began our study with 1a as the model substrate. After considerable optimization, we found that the use of Pd(OAc)2, K2HPO4, and Ag2CO3 as the oxidant in chlorobenzene as the solvent afforded a remarkable level of activity (Table 1). As expected from our previous work in inert-bond activation, a minor modification in the ligand backbone had a detrimental impact on the reaction outcome. Among the ligands examined, we noticed that the use of L2 and L3 was highly beneficial (Table 1, entries 2–3). Subsequently, we found that commercially available N-protected amino acids L4–L9 could be successfully employed as ligands (Table 1, entries 4–10). The beneficial effect of using Nprotected amino acids for the activation of various C(sp) H bonds has already been demonstrated by the pioneering work of Yu and co-workers; however, the use of N-protected amino acids for the functionalization of C(sp) H bonds has received much less attention. To the best of our knowledge, N-protected amino acids have not been employed as ligands in Pd-catalyzed C(sp) O bond-forming reactions. Ligand L7 was particularly active; its use drastically reduced the yield of 3a while the yield of 2a was increased up to 95% (Table 1, Scheme 1. Synthetic approaches to benzolactones.

Synergistic Palladium‐Catalyzed C(sp3) ? H Activation/C(sp3) ? O Bond Formation: A Direct, Step‐Economical Route to Benzolactones

Rutheniumkatalysierte regioselektive direkte Alkylierungen von Arenen mit nichtaktivierten Alkylhalogeniden unter C‐H‐Bindungsspaltung

The C–X bond (X = Br, Cl) of α-haloketones is smoothly trifluoromethylated with the fluoroform-derived CuCF3 reagent recently developed in our laboratories. This is the first nucleophilic α-trifluoromethylation reaction of carbonyl compounds and a rare example of CF3–C(sp3) coupling. The transformation employs only low-cost chemicals and cleanly occurs in up to 99% yield at room temperature, thereby providing an unprecedentedly easy entry to valuable 2,2,2-trifluoroethylketones.

Petr Novák

Papers

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

Fluoroform‐Derived CuCF3 for Low‐Cost, Simple, Efficient, and Safe Trifluoromethylation of Aryl Boronic Acids in Air

Synergistic Palladium‐Catalyzed C(sp3) ? H Activation/C(sp3) ? O Bond Formation: A Direct, Step‐Economical Route to Benzolactones

Rutheniumkatalysierte regioselektive direkte Alkylierungen von Arenen mit nichtaktivierten Alkylhalogeniden unter C‐H‐Bindungsspaltung

Trifluoromethylation of α-haloketones.