C-H acetoxylation

Palladium-catalyzed aUyUc C-H acetoxylation (acyloxylation) of alkenes is one of the synthetically most established C-H functionabzation methods [57-62]. These reactions are conducted under oxidative reaction conditions. In the most commonly used approach, the reaction proceeds via a Pd(II)/Pd(0) catalytic cycle and benzoquinone (BQ) is used for reoxidation of Pd(0) and activation of the nudeophihc (acetate) attack [61, 62],... 

C-H acetoxylations using directing groups L, such as pyridine and pyrimidine. ... 

In palladium series, Ritter has described the formation of dinuclear Pd(III) intermediates 15 [61] in Pd-catalyzed aromatic C-H acetoxylation reaction of phenylpyridine previously reported by Sanford [62]. Ritter demonstrated, thanks to a thorough experimental and theoretical investigation, that bimetallic redox synergy between the two metals is responsible for the facility of the reductive elimination step involved in this kind of catalytic reaction (Scheme 14) [63]. 

Palladium-catalyzed aromatic C-H acetoxylation was first reported in 1966 [100, 101]. In 1971, Henry proposed Pd(IV) intermediates in the Pd-catalyzed acetoxylation of benzene with K2Cr207 in AcOH [102], Subsequent reports by Stock [103] and Crabtree [104] also discussed the possible intermediacy of Pd(IV) complexes in the acetoxylation of benzene (Fig. 27a). In 2004, Sanford reported the regioselec-tive ort/to-acetoxylation of 2-arylpyridines and proposed a reaction mechanism involving aromatic C-H metallation at Pd(II), oxidation of the resulting aryl Pd(II) intermediate to a Pd(IV) complex, and product-forming C-O reductive elimination (Fig. 27b) [105-108]. 

In 2009, we suggested that Pd-catalyzed aromatic C-H acetoxylation may proceed via dinuclear Pd(III) complexes instead of via mononuclear Pd(IV) intermediates [109]. On the basis of dinuclear Pd(II) complex 36, the product of cyclometallation of 2-phenylpyridine (48) with Pd(OAc)2 [110], a synthesis cycle based on dinuclear Pd(III) complexes was established (Fig. 28). Oxidation of 36 with PhI(OAc)2, a common oxidant in Pd-catalyzed aromatic acetoxylation, afforded dinuclear Pd(III) complex 50. Complex 50 was observed to undergo C-O reductive elimination under pseudocatalytic conditions to generate 49 in 91% yield. The critical dinuclear Pd(III) intermediate (50) was crystallographically characterized the Pd-Pd distance in 50 was measured to be 2.555 A (compared with 2.872 A for 36 [111]), consistent with the formation of a Pd-Pd single bond. Dinuclear Pd(III) complex 50 was found to be a kinetically competent catalyst in the acetoxylation of 2-phenylpyridine with PhI(OAc)2. 

Carbon-heteroatom reductive elimination from dinuclear transition metal complexes, as was proposed by us [96,109] as the product-forming step in Pd-catalyzed C-H acetoxylation and chlorination reactions, is rare. The two formulations of the high-valent, dinuclear Pd intermediate in arylation proposed by Sanford (60 and 61) highlight that reductive elimination from dinuclear Pd structures could, in principle, proceed with either redox chemistry at both metals (bimetallic reductive elimination reductive elimination from 60) or with redox chemistry at a single metal (monometallic redox chemistry reductive elimination from 61). While structures 60 and 61 do not differ in composition, they do differ in their respective potentials for metal-metal redox cooperation to be involved in C-C bond-forming reductive elimination. 

Electrophilic addition to quinones, eg, the reaction of 2-chloro-l,4-ben2oquinones with dia2onium salts, represents a marked contrast with acetoxylation in product distribution (58). Phenyldia2onium chloride (Ar = C H ) yields 8% 2,3-substitution [80632-59-3] 75% 2,5-substitution [39171-11-4] and 17% 2,6-substitution [80632-60-6]. Fory)-chlorophenyldia2onium chloride, the pattern is 28% 2,3-substitution [80632-61-7], 35%... 

Recently, a clean formation of 2,3-dihydro-l,4-dioxane 10 has been described in a two-step process starting from 1,4-dioxane. This approach takes advantage of the capability of lead tetraacetate to engage in the acetoxylation of C-H bonds adjacent to ethereal oxygen centers (Scheme 25) <20050S99>. 

The proposed mechanism for allyhc acetoxylation of cyclohexene is illustrated in Scheme 15. Pd -mediated activation of the allyhc C - H bond generates a Jt-allyl Pd intermediate. Coordination of BQ to the Pd center promotes nucleophilic attack by acetate on the coordinated allyl ligand, which yields cyclohexenyl acetate and a Pd -BQ complex. The latter species reacts with two equivalents of acetic acid to complete the cycle, forming Pd(OAc)2 and hydroquinone. The HQ product can be recycled to BQ if a suitable CO catalyst and/or stoichiometric oxidant are present in the reaction. This mechanism reveals that BQ is more than a reoxidant for the Pd catalyst. Mechanistic studies reveal that BQ is required to promote nucleophilic attack on the Jt-allyl fragment [25,204-206]. 

Pd(H) complexes with strongly electron-withdrawing ligands can insert into the allylic C—H bond (path c) to form directly the Jt-allyl complex via oxidative addi-tion.502,694,697 Pd(OOCCF3)2 in acetic acid, for example, ensures high yields of allylic acetoxylated products.698 The delicate balance between allylic and vinylic acetoxylation was observed to depend on substrate structure, too. For simple terminal alkenes the latter process seems to be the predominant pathway.571... 

The plane of the phenyl ring has an orientation parallel to the P-5 - 0-5 bond, and its inclination is shown in Fig. 2 (see Section 11,5). In this orientation, steric collisions with the adjacent acetoxyl group on C-l are avoided. The acetoxyl group on C-l differs considerably from the usual, syn-parallel arrangement of the C=0 bond with the C-H bond of the corresponding ring-atom. 

Pd-catalysed chelate-directed acetoxylation of meta -substituted arenes has been studied.61 Many substituted groups are tolerated by this process and the reaction shows a high degree of regioselectivity for the less sterically hindered ortfto-position. For example, 2-(3-nitrophenyl)pyridine forms 2-(2-acetoxy-3-nitrophenyl)pyridine. Finally, density functional calculations62 on the palladium acetate-promoted cyclomet-allation of dimethylbenzylamine suggest that reaction occurs via an agostic C-H complex rather than a Wheland intermediate. An intramolecular H-transfer to a coordinated acetate via a six-membered transition state follows. 

Two generally accepted reaction mechanisms for benzylic acetoxylation are shown in Scheme 8.8 [79b]. One proceeds with the rupture of a benzylic C-H bond to give surface-bound benzyl and hydride species. The Pd-benzyl species is then attacked by acetate. The other mechanism involves a concerted substitution to add an acetate ion and release of hydride to the Pd surface. This field continues to be an area of active research [85-88, 88], although high yields of benzyl acetate remain elusive [89]. 

Density functional theory (DFT) modebng studies [56] pointed out the relatively high activation energy of the oxidative addition. Since carbopaUadation of 24 is probably fast, complex 24 could not be detected. However, in the acetoxylation and the C-H borylation studies, the more strongly oxidizing iodine was used instead of 21, and detection of the Pd(IV) intermediate could be reabzed (Sections 4.4.2 and 4.4.3). 

Despite the recent progress in palladium-catalyzed diastereoselective iodin-ation, acetoxylation, and arylation reactions,Pd-catalyzed enantioselective C—H bond functionalizations are rather challenging due to lack... 

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