C-H bonds, metallated

Although formally involving the reaction with a C—H bond, metal alkoxides will react with /1-diketones and / -keto esters to form six-membered chelates and alcohols. Hence the acetyl-acetonate (acac) derivatives of aluminum can be obtained (equation 63).238... 

Consequently, we were faced with the task of formulating a widely acceptable and consistent definition of bond activation . Our research, discussions, and analyses led to a conclusion that bond activation should refer to a process of increasing the reactivity of a bond in question and as such encompasses an entire spectrum of possible mechanisms. Also, we argue that activation is not equivalent to reaction or, in other words, that activation of a bond is not the same as cleavage of a bond. For the latter process we proposed the general term bond transformation . It should be emphasized that both bond activation and bond transformation are general terms and, therefore, information about the reaction and mechanism category should be specified by additional descriptors (cf. C-H bond arylation via electrophilic metalation, C-H bond metalation via concerted metal insertion). 

Cyclometallation reactions form only a part of the broad class of C-H bond metallations or C-H activation. Such reactions facilitate the synthesis of organic compounds, including pharmaceuticals, the activation of small molecules, and industrial processes. Better control of ligand electronic effects and ligand sphere geometry will enhance the development and versatility of this class of metallation reactions. 

The mechanism proposed for the formation of the complex W(PMe3)4(Ti -CH2PMc2)H from W(PMc3)6 involving a concerted C-H bond metalation via the intermediate or transition state VIII-6 has been discounted by the lack of an... 

Gorelsky, S.I., Lapointe, D., Fagnou, K., 2012. Analysis of the palladium-catalyzed (aromatic) C—H bond metalation-deprotonation mechanism spanning the entire spectrum of arenes. I. Org. Chem. 77, 658-668. 

Alternatively, a ruthenium catalyst could be applied in phthalide preparation. In 2011, Ackermann s group developed a ruthenium-catalyzed cross-dehydrogenative C-H bond alkenylation reaction. The methodology used water as a solvent, benzoic acids and terminal alkenes as substrates good yields of the desired phthalides were isolated (Scheme 2.164). The reaction sequence consisted of cross-dehydrogenative alkenylation and a subsequent intramolecular oxa-Michael reaction. Mechanistic studies provided strong evidence that the oxidative alkenylation proceeds by an irreversible C-H bond metalation via acetate assistance. 

The alkynylation of sp -C-H bonds has in general been much less developed than that of sp -C-H bonds. Metal-mediated methods have been limited to the use of alkynyl bromides [143], whereas radical approaches have been dominated by alkynyl sulfones [21, 22]. Nevertheless, Yu and Chen and co-workers recently reported that aromatic EBX reagents were highly efficient for the interception of radicals generated in a-position to heteroatoms [144]. Silyl EBX could also be used. The inherent limitations of this radical-mediated approach are the requirement for a... 

The H/D experiment studies show that the acetate-assisted C-H bond metallation is an irreversible step. A proposed mechanism is shown in Scheme 14 [145]. The cyclometallated intermediate A is expected to be formed from A-methoxybenzamide with in situ generated Ru(OAc)2(p-cymene) catalyst. The regioselective insertion of the alkene leads to the intermediate B. The alkenylated product is produced via -elimination from the intermediate B in the case of acrylate in methanol, whereas with styrene or norbomadiene in CF3CH2OH alkyl and aryl group in B favour reductive elimination. These last processes lead to the release of MeOH with the regeneration of the Ru(OAc)2(p-cymene) catalyst. 

IH-pyrazoles appeared also suitable substrates for the oxidative annulation with aryl- and alkyl- alkynes with good chemo- and regioselectivities. This reaction was carried out using 5 mol% of [RuCl2(p-cymene)]2,20 mol% of AgSbFg, 1 equiv. of Cu(0Ac)2.H20 as the oxidant The H/D experiments indicate a reversible C-H bond metallation step with the Ru(II)/AgSbF6 catalytic system in DCE/D2O (9 1) [(Eq. 90)] [179]. 

Ackermann and coworkers explored the same cyclization reactions, which were conducted with catalytic amount of KPFg and Cu(OAc)2 H2O in f-AmOH at 120 C for 16h (Eq. (7.6)) [11]. They also proposed a similar catalytic cycle involving acetate-assisted rate-determining C-H bond metalation step according to mechanistic study. 

A rate-limiting C-H bond metalation step via acetate assistance was proposed to initiate the reaction. Then after alkyne insertion and subsequent reductive elimination, the final product was formed (Scheme 7.8). 

Under conditions of C-H/N-H bond functionalization, aryl-, heteroaryl-, and alkenyl-substituted IH-pyrazoles underwent oxidative annulation with aryl and alkyl alkynes in high chemo- and regioselectivity in the presence of Ru(II)/AgSbFg catalyst (Eq. (7.28)) [36]. Aryl alkynes particularly bearing electron-donating substituents are more reactive in the present reaction system. A cationic ruthenium(II)-catalyzed reversible C-H bond metalation step was observed in the H/D exchange experiments. 

Mechanism studies suggested that the C-H bond metalation step is probably irreversible and involved in the rate-determining step. It was proposed that the reaction proceeds by an initial intermolecular carboruthenation of alkene via ratedetermining C-H bond ruthenation and subsequently (i) -hydride elimination of the potential intermediate of seven-membered ruthenacycle 13 (Pathway (a)) or (ii) C-N bond reductive elimination of the intermediate 9 for product formation (Pathway (b)) (Scheme 7.11). 

A novel route to synthesize phthahmide derivatives through ruthenium-catalyzed C-H bond functionalization of aromatic amides was developed by Ackermann and coworkers (Eq. (7.57)) [66]. This method is applicable to generate a potent COX-2 enzyme inhibitor in step-economical way. The reaction features by the insertion of a cycloruthenated species into a C—Het multiple bond of isocyanate and cleavage of pyrrolidinyl group. Electron-rich amides were found to favor the reaction, and an initial reversible C-H bond metalation step was also observed. 

A synthetic route to the quinazolin-4(3//)-ones via Pd(II)-catalyzed intramolecular aminocarbonylation of AT-arylamidines has been disclosed by Zhu et al. in 2011 [32], Reactions precede in refluxing HOAc under latm of CO with CuO as the oxidant. Sixteen examples have been given in moderate to good yields (Table 15.24). Deuterium experiments indicated that the C-H bond metalation step was reversible and deuterium-hydrogen scrambling occurred during the reaction. 

S. I. Gorelsky, D. Lapointe and K. Fagnou, Analysis of the Palladium-Catalyzed (Aromatic)C-H Bond Metalation-Deprotonation Mechanism Spanning the Entire Spectrum of Arenes,/. Org. Chem., 2012, 77(1), 658-668. 

As discussed in a recent review, there are four modes of C-H bond metalation (l) oxidative addition with eleetron-rich late transition metals (2) a-bond metathesis with early transition metals (3) electrophilic activation with electron-deficient late transition metals and (4) earboigrlate-directed metalation. The last mode has been only recently reported and proceeds via a continuum of electrophilic, ambiphilic, and nucleophilic interactions with the assistance of a bifunetional ligand bearing an additional Lewis-basic heteroatom, such as carbojgrlate. Possible mechanisms for the C-H bond palladation are shown in Seheme 2.12. 

Efficient oxidative sp C-H hydroxylations on arenes bearing weakly coordinating amides were accomplished with DIAB as the oxidant and a ruthenium(II) biscarboxylate, [Ru(02CMes)2(p-cymene)], as a catalyst. Mechanistic studies provided support for a reversible C-H bond metalation step. A 2 1 complex formed between a non-planar Mo(V)-porphyrin complex ([Mo(DPP)(0)]+, DPP = dodecaphenylporphyrin) and a ruthenium-substituted Keggin-type het-eropolyoxometalate (Ru-POM), [SiWn039Ru (DMS0)] , acts as an efficient catalyst for oxidation of benzyl alcohols with iodosobenzene as an oxidant. The kinetic... 

Simple palladium(II) salts such as chloride and acetate efficiently catalyse aerobic oxidative A-alkylation of amines and amides with alcohols. This method is suitable for a variety of sulfonamides, amides, aromatic and heteroaromatic amines as well as benzylic and heterobenzylic alcohols with a low loadings of the catalyst (0.5-1 mol%) and the alcohols. A selective carbon-carbon double bond assisted o-C-H olefination is catalysed by palladium(II) acetate. The terminal oxidant is oxygen. Addition of TFA is essential for any meaningful yield. (PdOCOCF3)+ has been proposed as the active catalyst. The observed large difference in the inter- and intra-molecular KIE values implied that the coordination of the C=C bond occurs before C-H palladation in the catalytic cycle consequently, a mechanism involving the initial coordination of allylic C=C bond to (PdOCOCF3)+ followed by selective o-C-H bond metalation has... 

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