Oxidation benzylic hydroxylation

Keywords C-H oxidation, Benzylic hydroxylation, AUylic oxidation, Desymmetrization of meso compound, Kharash-Sosnovsky reaction. Iron-porphyrin complex, (Salen)manganese(lll) complex... 

Condensation of normeperidine (81) with 3-chloropropan-l-ol affords the compound possessing the alcohol side chain (88). The hydroxyl is then converted to chlorine by means of thionyl chloride (89) displacement of the halogen by aniline yields pimino-dine (90). ° Condensation of the secondary amine, 81, with styrene oxide affords the alcohol, 91 removal of the benzyllic hydroxyl group by hydrogenolysis leads to pheneridlne (92). ... 

Extreme differences between 5% palladium-on-carbon and platinum oxide were found on reduction of the 5-aryl substituted oxazole 14. Over palladium, 15 was formed in quantitative yield by hydrogenolysis of the benzyl hydroxyl, whereas over Pt, scission of the oxazole occurred to give 13 quantitatively (48). Hydrogenation of 15 over platinum oxide gave the phenethylamide 16. 

Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine /3-monooxygenase and occurs by a radical mechanism. A copper-oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Aromatic hydrocarbons are mainly hydroxylated to phenolic products. Complex (12) hydroxylated benzene in MeCN at 20 °C into phenol in ca. 55% yield, and no isotope effect was found for this reaction. Hydroxylation of toluene mainly occurs at the ring positions, with minor amounts of benzylic oxidation products. Hydroxylation of 4-deuterotoluene by (12) occurred with 70% retention and migration of deuterium in the formation of p-cresol. This high NIH shift value is in the same range as that found for liver microsome cytochrome P-450 hydroxylase, and suggests the transient formation of arene oxide intermediates. 

In studies on the oxidation of lignin that had alternately been methylated at the p-hy-droxyl and benzylic hydroxyl groups, Leopold (1952) concluded that methylation caused the low yield of vanillin obtained in the oxidation. As mentioned in Section 6.6.3, the replacement of the OH group by OMe seriously impedes C-C bond cleavage in the water reaction medium. 

Benzylic and allylic positions are hydroxylated by CPO in halide-dependent catalytic transformations. Toluene and p-xylene are oxidized to the respective aldehydes and carboxylic acids [247, 248]. Ethylbenzene and other substrates with longer alkyl chains form the respective benzylic/allylic alcohols with high enantio-selectivity. Straight-chain aliphatic and cyclic (Z)-alkenes are hydroxylated, favoring small unsubstituted substrates in which the double bond is not more than two carbon atoms from the terminus. Steric control is observed for benzylic hydroxylations. 

Imipramine hydrochloride API undergoes oxidation at the benzylic site to form the corresponding benzyl hydroxyl compound (Fig. 98). Subsequent elimination of the hydroxyl occurs to give an extended conjugation in... 

The benzyl hydroxyl containing API cyclandelate undergoes oxidation to the corresponding ketone, 3,3,5-trimethylcyclohexyl phenylglyoxalate (143). Low level benzylic oxidation is observed for the API ibuprofen. Oxidation to form the ketone derivatives at both benzylic sites to yield isobutyl acetophenone and 2-(4-isobutyrylphenyl)-propionic acid has been reported (144). 

Manganese dioxide is a reagent that oxidizes only allylic or benzylic hydroxyl groups to ketones,... 

Oxidations of l-(4-methoxyphenyl)-2-(4-substituted phenyl)ethanols, (6), [identical to alcohols (4a) to (4e) except for methylation of the 4-OH group] were also studied with cerium(IV) as the catalyst (Fisher, T. H., et al., J. Org. Chem., in press). To determine if oxidation occurs by electron abstraction from the benzylic hydroxyl or the aromatic ring, a competitive oxidation procedure was examined on the diaryl ethanol 6a and its methyl ether analog, 1-methoxy-l-(4-methoxyphenyl)-2-phenylethane, (7), (Fisher, T. H., et al., J. Org. Chem., in press). 

Role of the p-Hydroxyl Group. Preliminary nitrobenzene oxidation experiments were conducted on several benzylic hydroxyl compounds, both with and without a p-hydroxyl group (5). Contrary to what was expected from the literature, some compounds without a p-hydroxyl group formed benzaldehyde products. 

The homolytic oxidative reagent, nitrobenzene, either abstracts an electron from a hydroxide ion as reported by Ashby and coworkers (21,22) (Scheme 1 of Figure 3) or from the benzylic hydroxyl group (Scheme 2 of Figure 3). 

The mechanism proposed in Figure 3 can easily be applied to the oxidative depolymerization of the lignin macromolecule by nitrobenzene or copper(II) in aqueous alkali. A recent model of softwood lignin (24) contains 27% free benzylic hydroxyl groups and 12% aromatic ring-conjugated double bonds (stilbene... 

Alkaline hydrolysis of lignin increases the number of reactive benzylic hydroxyl groups and may also be important in further depolymerizing the lignin once the oxidative-cleavage reaction has occurred. The formation of a p-electron-withdrawing -CHO substituent on aryl lignin units should increase the rate of hydrolysis of the ether bonds (26). Hydrolysis also forms p-phenylate ions, which then protect the benzaldehyde from further reaction via the Cannizzaro reaction, as mentioned earlier. 

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

Besides the major glucoronide metabolite, oxidation of the benzylic hydroxyl group of ezetimibe results in a ketone of ezetimibe as the minor metabolite known as SCH 57871. Another minor metabolite is the 4-hydrox) henyl glucoronide, which is the conjugate of SCH 57871 (ketone-glucoronide) [4]. 

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