Oxidation of Benzylic C-H Bonds

Vinod and coworkers were the first to develop a selective procedure for the oxidation of benzylic C-H bonds to the corresponding carbonyl functionalities using a catalytic amount of 2-iodobenzoic acid and Oxone as a stoichiometric oxidant in aqueous acetonitrile under reflux conditions (Scheme 4.52) [83]. The authors hypothesized that the active hypervalent iodine oxidant generated in situ might not be IBX (90) (Scheme 4.47) but, instead, a soluble derivative of IBX (108) that incorporates a peroxysulfate ligand. This intermediate is believed to oxidize a benzylic C-H bond via a single-electron transfer (SET) mechanism [83]. 

Zhang and coworkers have further improved the procedure for catalytic oxidation of benzylic C-H bonds using IBS as a catalyst, which is generated in situ by the oxidation of sodium 2-iodobenzenesulfonate... 

In 1994, Jacobsen and co-workers demonstrated that stereoseleetive oxidation of benzylic C—H bonds is possible utilizing readily available chiral Mn(salen) complexes.They studied the kinetic resolution of 1,2-dihy-dronaphthalene oxide via an asymmetric C—H bond hydroxylation reaction (Scheme 1.59). During the course of experiments on the asymmetric epoxidation of 1,2-dihydronaphthalene with C24, it was observed that the... 

Alkyl ethers are an important subclass of compounds in natural products. The direct constmction of alkyl ethers from C(sp )-H bonds is a challenging but promising access and thus is being actively pursued. Chen et al. first addressed this unsolved difficulty. They developed a Pd(ll)-catalyzed, picolinamide-assisted functionalization of y-C(sp )-H bond with primary, secondary, and even bulky tertiary alcohols (Scheme 1.29) [73]. The perfect compatibility of simple alcohols was one of the most striking features. Furthermore, under the optimized reaction conditions, functionalization of unreactive primary C(sp )-H bond ispreferential even in the presence of secondary C(sp )-H bond. Besides C-O bond coupling, picolinamide-assisted Pd(II)-catalyzed tandem arylation and oxidation of benzylic C-H bond can dexterously construct unsymmetric diaryl ketones [74]. 

The tra x-[Ru (0)2(por)] complexes are active stoichiometric oxidants of alkenes and alkylaro-matics under ambient conditions. Unlike cationic macrocyclic dioxoruthenium I) complexes that give substantial C=C bond cleavage products, the oxidation of alkenes by [Ru (0)2(por)] affords epoxides in good yields.Stereoretentive epoxidation of trans- and cw-stilbenes by [Ru (0)2(L)1 (L = TPP and sterically bulky porphyrins) has been observed, whereas the reaction between [Ru (0)2(OEP)] and cix-stilbene gives a mixture of cis- and trani-stilbene oxides. Adamantane and methylcyclohexane are hydroxylated at the tertiary C—H positions. Using [Ru (0)2(i)4-por)], enantioselective epoxidation of alkenes can be achieved with ee up to 77%. In the oxidation of aromatic hydrocarbons such as ethylbenzenes, 2-ethylnaphthalene, indane, and tetrahydronaphthalene by [Ru (0)2(Z>4-por )], enantioselective hydroxylation of benzylic C—H bonds occurs resulting in enantioenriched alcohols with ee up to 76%. ... 

The ET mechanism is proposed on the basis of the high value of p = —2.4 obtained from the Hammett plot, as well as the observation of benzyl chloride and chlorotoluene as the main products when the oxidation is carried out in the presence of high concentrations of LiCl [41]. Similarly, activation of benzylic C-H bonds by other strong oxidants such as Mnm or PbIV has been suggested to occur through an initial electron transfer, especially in the case of aromatic substrates with low ionization potentials [42]. However, there have been no reports of complex formation between the metal and the arene prior to ET, and no such reactive complex has been isolated and characterized by X-ray crystallography. 

Iron-containing cytochrome P-450 constitutes the most famous example of a selective C-H bond oxidizer. Although the exact nature of the mechanism remains controversial, the reaction most likely proceeds through radical intermediates [2]. The hydroxylation of activated C-H bonds has also been carried out in the presence of synthetic porphyrin complexes. In these biomimetic processes, ruthenium plays a relatively minor role when compared with iron. Zhang et al. [50], however, recently reported the enantioselective hydroxylation of benzylic C-H bonds using ruthenium complexes supported by a D4-sym-metric porphyrin bearing a crafted chiral cavity. Thus, complex 23 reacts in a stoichiometric manner with ethylbenzene to give phenethyl alcohol with a... 

Oxidation of Unactivated C—H Bonds Table 8 Benzylic Hydroxylation of Methylpyridines... 

Scheme 30 Iron(II)-catalyzed oxidative alkylation of benzylic C-H bonds...

The syntheses of benzyl derivatives from benzylic C—H are well developed. Traditionally, multi-step syntheses had to be used. Furthermore, a stoichiometric amount of base was used and toxic halides were produced. To avoid such problems, various catalytic methods have been developed recently via direct functionalization of benzylic C—H bonds. More recently, our group has reported the FeCl2-catalyzed oxidative activation of benzylic C—H bonds followed by a cross-coupling reaction to form C—C bonds (Equation 11.1) [7]. The reactions selectively cleave benzylic C—H bonds and avoid further oxidation. The present methodology opens a window for iron-catalyzed C—H bond oxidation and C—C bond formation. 

In 2005, Itoh and co-workers developed a new dinucleating ligand L13. Combining L13 with FeCls gave a dinuclear Fe complex. With this catalyst, hydroxylation of benzylic C—H bonds was realized. Among these cases, one example was the asymmetric hydroxylation of tetrahydronaphthalene, affording the desired oxidized product 146 with only 9.9% ee (Scheme 1.57). 

A number of papers showcase a variety of hypervalent iodine reagents for the goal of oxidizing a benzylic C—H bond. While some might not consider this C—H activation, as the argument could be made that the benzylic position is already activated, these reactions will nonetheless be covered here. 

In 2008, using an inexpensive copper salt as the catalyst, Powell and coworkers developed the oxidative coupling of benzylic C-H bonds with 1,3-dicarbonyl compounds (Scheme 3.17). Kinetic isotope studies support a mechanism involving a benzylic H-atom abstraction. 

Palladium-catalyzed directed intramolecular activations of aryl C-H bonds have been reported, as in the phenyla-tion of heterocycle analogs. Palladacycles are proposed intermediates, acting as effective catalysts, and the mechanism is likely to proceed via oxidation of Pd(ll) to Pd(iv) by the iodonium salt, as for the Equation (57), which described the activation of benzylic i/-CH bonds (Equations (121)—(123).109... 

The palladium-catalyzed reaction of benzol]quinoline in the presence of PhI(OAc)2 as an oxidant in MeCN gives an 11 1 mixture of 10-acetoxy- and 10-hydroxybenzo[ ]quinolines in 86% yield (Equation (98)).135 This chelation-directed oxidation can be extended to the benzylic C-H bond of 8-methylquinoline. The inactivated sp3 C-H bonds of oximes and pyridines undergo the same palladium-catalyzed oxidation with PhI(OAc)2 (Equation (99)).1... 

The comparison of physical and chemical properties of Parylene-N and Parylene-F is shown in Table 18.4. Parylene-N is considerably less stable in air than in nitrogen as a result of oxidative degradation. However, the similarity between its behavior in air and in nitrogen suggests that Parylene-F has very good thermal oxidative stability, which is most likely the result of the high stability of the C—F bond, and provides evidence that oxidative attack starts at the benzylic C—H bonds in Parylene-N.15... 

Although Parylene-N possesses an outstanding combination of physical, electrical, and chemical properties, the benzylic C—H bonds present are potential sites for thermal and oxidative degradation. It is well known that replacing a C— bond with a C—F bond not only enhances the thermal stability of the resulting polymer, but also reduces the dielectric constant. Because incorporation of fluorine is known to impart thermal and oxidative stability, it became of interest to prepare poly(a,a,a, a -tetrafluoro- p -xylylene), Parylene-F Joesten reported that the decomposition temperature of poly(tetrafluoro-j9-xylylene) is ca. 530°C. Thus, it seemed that the fluorinated analog would satisfy many of the exacting requirements for utility as an on-chip dielectric medium. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

MoO(02)2(dmpz)2, 120, containing 3,5-dimethylpyrazole (dmpz) in the coordination sphere, in the presence of H2O2, selectively oxidizes benzylic C—H bonds of several alkylbenzenes to the corresponding alcohols and ketones (see, e.g., equation 82). 

Toluene is oxidized to cresols (ortho meta para ratio = 5 1 4) and not to the benzyl derivatives, despite the low dissociation energy of the benzylic C—H bond. p-Xylene undergoes oxidation to 2,5-dimethylphenol. 

During the oxidation of benzylic benzocycloalkanols, the angle between the benzylic C-H bond and the aromatic plane is found to be well... 

Both the radical cation of VA and Mnm(S +) attack and degrade the lignin polymer LiP also has the ability to oxidize nonphenolic aromatic molecules, most likely by attacking a benzylic C—H bond. 

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