Benzylic acetoxylation

Benzylic Acetoxylation. The reaction of Mn(OAc)3 in AcOH with methylben-zenes when carried out in the absence of oxygen yields products of side-chain acetoxylation and hydroxylation 842 

The oxidation occurs in a one-electron process through a radical cation [Eq. (9.161)]. Bromide ions have a catalytic effect with the involvement of radical intermediates856 [Eq. (9.162)]  

Several studies have been reported about Pd(II)-cataIyzed acetoxylation. Pd(OAc)2, which catalyzes aromatic coupling and nuclear acyloxylation as well (see Section 9.4.1), is an efficient catalyst of benzylic acetoxylation in the presence of alkali acetates. Stoichiometric oxidation in the absence of oxygen857,858 and a catalytic method858 are known. A twofold rate increase was observed when a mixture of Pd(OAc)2, Sn(OAc)2, and charcoal was employed in acetoxylation.859 Xylenes are converted to the a,a -diacetyloxy compounds in high yields.860 

Oxidation with peroxydisulfate in AcOH in the presence of catalytic amounts of iron and copper salts gives benzylic acetates in good yields.785,861 The reaction of lead tetraacetate with alkylarenes in AcOH provides benzylacetates in moderate yields.693 Most of these oxidations usually involve methyl-substituted benzenes since aromatics with longer chain produce different side products. 

Early observations of benzylic acetoxylation were made in the study of arene acetoxylation and biaryl coupling when toluene was used as a substrate. In 1966, the reaction between stoichiometric Pd(OAc)2 and toluene to give benzyl acetate as the major product was disclosed [72]. Two years later, acetoxylation of toluene with catalytic Pd salts was reported by Union Carbide by using phosphines or a combination of Sn(OAc)2, charcoal, and air as oxidant to give 96TONs [73]. Additional metal acetates such as KOAc are beneficial for the reaction [74]. These acetoxylation methods were further applied to other arenes [75] (e.g., benzene, cyclohexene) and the synthesis of benzyl diacetate [76] (a precursor to benzalde-hyde). 

Characterization of in situ and ex situ synthesized catalysts on a silica support confirms the presence of tin oxides and tin hydroxyl species [80]. In the same report, the authors determined that a 1 2 Pd Sn stoichiometry is optimal and implicated PdSn2 particles as being important for effective catalysis. It was proposed that in situ catalyst formation is a two-step process that involves the formation of a Pd Sn 2(OAc)g complex followed by the decomposition of this complex to give oxygenated PdSn2 clusters. Other Pd-based catalysts have also been developed. The addition of Bi [71,81], persulfate/Sn (Phillips Petroleum Co.) [82], Sn/Sb (BP) [83], and ultrafine Au [84] have been shown to be beneficial. 

The initial discovery of the oxidative Heck reaction was reported by Fujiwara and Moritani in 1967 when they disclosed the coupling of styrene with benzene in the presence of acetic acid and PdCl2 to give traws-stilbene and a-methylbenzyl acetate (Eq. (8.20)) [92]. Attempts to achieve catalytic turnover were made by adding Cu or Ag salts, but oidy 1-2 TONs were obtained [93]. 

Aerobic oxidative Heck reactions also proceed between olefins and other aryl nucleophiles such as aryl tin and aryl boron reagents (Eq. (8.22)). This field started by utilizing aryl tin reagents and electron-deficient alkenes with stoichiometric base additives such as NaOAc [100], but has been significantly improved by 

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Benzylic acetoxylation with lead tetraacetate has preparative value as applied to acenaphthene, = and the yield is no better with preformed reagent than with that generated in situ from Pb304. The 7-acetoxy compound purified by distillation... 

As with the allylic oxidation of olefins (see above) the giant Pd-561 cluster was also found to catalyze benzylic acetoxylation under mild conditions in acetic acid [10]. 

In addition to the industrial apphcations, in Scheme 8.1, other reactions have been the focus of extensive research and development. For example. Chapter 12 surveys the research efforts directed toward Pd-catalyzed oxidative carbonylation of phenol affords the important monomer, diphenyl carbonate (Scheme 8.2a). Other reactions of potential industrial significance highlighted in this chapter include the oxidation of alcohols to aldehydes and ketones (Scheme 8.2b), oxidative coupling of arenes and carboxylic acids to afford aryl esters (Scheme 8.2c), benzylic acetoxylation (Scheme 8.2d), and oxidative Heck reactions (Scheme 8.2e). The chapter concludes by highlighting a number of newer research developments, including ligand-modulated catalytic oxidations, Pd/NO cocatalysis, and alkane oxidation. 

Benzyl acetates are important precursors to fragrances, and their hydrolyzed alcohol products are valuable synthons. Benzylic acetoxylation of toluene to benzyl acetate is seen as a potential route for commercial production. The major existing route to benzyl acetate proceeds via benzyl chlorides [71]. Pd-catalyzed aerobic acetoxylation toluene and other methyl arenes would offer an appealing alternate route to these products (Scheme 8.7). 

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]. 

A particularly significant and useful contribution of transition metals in fine organic synthesis as well at the industrial level is based on their use as catalysts. This aspect is of course particularly important with expensive transition metals (Rh, Os, Pd, etc.). Indeed, there are numerous examples of selective processes which have never been developed up to the industrial stage because of catalyst costs, especially when some (even minor) loss of the catalyst could not be avoided. This was, for example, the case for palladium-catalyzed benzylic acetoxylation reactions, and several rhodium-catalyzed reactions, such as the direct ethylene glycol production from syngas (prohibitive pressures being an additional major drawback in this latter case). 

Methyl substituted benzene derivatives are oxidized in boiling AcOH to the corresponding benzyl acetates (eq 8) with sodium, potassium, or ammonium peroxydisulfate, Cu(0Ac)2-H20, and NaOAc." The peroxydisulfate radical is responsible for the primary oxidation, whereas Cu(OAc)2 prevents dimerization of the intermediate benzylic radical by oxidizing it to benzyl acetate. The benzylic acetoxylation of alkyl aromatics can also be carried out with O2 using Pd(OAc)2 and Cu(OAc)2 as catalysts. ... 

The product from fluonnation of sodium acetate is acetyl hypofluorite [64], which IS isolated and characterized [65] The value of this reagent lies in its relative mildness, because it reacts cleanly with most olefins adding the elements of acetoxyl and fluorine [66] Tnfluoroacetyl hypofluorite adds cleanly only to benzylic or electron-rich double bonds... 

BASF has developed a direct electrochemical process based on anodic acetoxylation for the production of aromatic aldehydes on industrial scale [40,146,147]. The reaction passes smoothly through the benzyl acetate stage. 

Asymmetric epoxidation of 10a under standard conditions yields the crystalline epoxy alcohol 2a in 95% ee (91% chemical yield). Treatment of 9a with thioanisol in 0.5N NaOH, in rerf-butyl alcohol solution, gives -after protection of the hydroxyl groups as benzyl ethers- the sulfide a (60% overall yield) through an epoxide ringopening process involving a Payne rearrangement. Since the sulfide could not be hydrolysed to the aldehyde 7a without epimerisation at the a-position, it was acetoxylated in 71% yield under the conditions shown in the synthetic sequence (8a... 

Alkoxyl and acetoxyl protons in A-acetoxy-A-alkoxybenzamides give rise to sharp signals well below room temperature. In contrast, hydroxamic esters usually exhibit line broadened alkoxyl group resonances in their H NMR spectra at or even signihcantly above room temperature" . In toluene-rfg, the benzylic and acetoxyl methyl resonances of A-acetoxy-A-benzyloxybenzamide (100) showed signihcant line broadening below 250 K but remained isochronous down to 190 K. 

Neighboring-group participation by the vicinal, trans-acetoxyl group (see p. 125) serves to explain the abnormal behavior of methyl 4-0-acetyl-2,3-anhydro-6-0-benzyl- or -trityl-a-D-gulopyranoside with hydrogen chloride in acetone, or with 80% aqueous acetic acid, which give D-galactose, instead of the D-idose, derivatives.67 In the same way, 2-0-acetyl-3,4-anhydro-D-altropyranosides yield D-man-nosides, not D-idosides.9 6z(see p. 125). 

Acetoxylation of toluene using a Pd(OAc)2-Sn(OAc)2-charcoal catalyst selectively produces benzyl acetate with high turnover numbers ( 100).373,434 The active catalyst presumably contains Pd—Sn bonds. Tin ligands are known to increase the 7r-acceptor ability of palladium, and may favor the coordination of the toluene in the form of a benzylic 7r-allyl complex (141) which is nucleophilically attacked by the acetate anion.435... 

Aliphatic-Substituted Acetylated benzylic a, 0, 7 7-CH2OH 7-CH2OAc Methoxyl Acetoxyl Aromatic Aliphatic... 

Side-chain substitution of aromatics is best rationalized by an ECrECn me" chanism via a radical cation 30 in Eq. (101) as intermediate 106-226-241-243. Yet side products of typical radical origin, e.g., bibenzyl in acetoxylation of toluene, have been accounted in favor of a radical chain mechanism (Eq.(99) ) 230, 244,24 5) An ECE-mechanism however has been clearly demonstrated by cyclic voltammetry for side-chain substitution of pentamethylanisole and p-methoxy-toluene 241 Eberson has proposed a modified ECrECn mechanism to account for the formation of radical coupling products 242 (Eq. (101) ) The radical cation 30, the first intermediate, can escape from the electrode surface and loose a proton to form a benzyl radical in the bulk of the solution. This benzyl radical can couple to bibenzyl or abstract hydrogen to form starting material. 

Bryant et al.s96 found that the relative amounts of oxidative coupling and side-chain acetoxylation of toluene are determined by the molar ratio of PdCl2 and acetate present. For molar ratios of NaOAc PdCl2 equal to 5 and 20, the relative yields of bitolyl benzyl acetate were 64 2 and 1 68, respectively. Similarly, in the oxidation of toluene with Pd(OAc)2-KOAc in acetic acid, increasing the molar ratio of KOAc to Pd(OAc)2 from 5 to 20 improved the yield of benzyl acetate from 53 to 93%. 

These various intermolecular a-acetoxylation reactions have intramolecular counterparts. For example, treatment of the sulfinylbutanoic acid shown in equation (11) with acetic anhydride containing p-toluenesulfonic acid yields a sulfenylated butanolide, the carboxylic acid function having intercepted the a-thiocarbocation intermediate. Yet another demonstration of Ae intramolecular process, due to Al-lenmark, is the cyclization of o-carboxyphenyl benzyl sulfoxide with acetic anhydride to form the 1,3-benzoxathian-4-one shown in equation (12). This reaction was also conducted with one of the... 

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