Hydroxylation benzylic

Dihydronaphthalene is often used as a model olefin in the study of epoxidation catalysts, and very often gives product epoxides in unusually high ee s. In 1994, Jacobsen discovered in his study on the epoxidation of 1,2-dihydronaphthalene that the ee of the epoxide increases at the expense of the minor enantiomeric epoxide.Further investigation led to the finding that certain epoxides, especially cyclic aromatically conjugated epoxides, undergo kinetic resolution via benzylic hydroxylation up to a krei of 28 (Scheme 1.4.9). 

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). ... 

The treacheries inherent in naive attempts at pattern recognition are illustrated by the finding that ester known cetiedil, is said to be a peripheral vasodilator. Clemmen-sen reduction of Grignard product removes the superfluous benzylic hydroxyl group and esterification of the sodium salt of the resulting acid ) with 2- l-cycloheptylamino)ethyl chloride produces cetiedil (28). ... 

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. 

O-Methy l-N-benzyl-hydroxylamin O-tert. -Butyl-N-benzyl-hydroxyl-... 

Allylic and benzylic hydroxylation (C=C-C-H -> C=C-C-OH, etc.) is listed in Section 41 (Alcohols from Hydrides). 

Boyd, D.R., Sharma, N.D., Bowers, N.I. et al. (1996) Stereoselective dioxygenase-catalyzed benzylic hydroxyl-ation at prochiral methylene groups in the chemoenzymatic synthesis of enantiopure vicinal aminoindanols. Tetrahedron Asymmetry, , 1559-1562. 

The anti stereospecificity of epoxidation by the peracid is interpreted as due to association of the reagent with the allylic hydroxyl group which directs the entering oxygen atom to the same face of the molecule. The stereospecificity of bromohydrin formation is explicable in terms of steric approach control involving initial attack of the bulky bromine atom on the face opposite to the benzylic hydroxyl group (7). 

Reactions of furanose and pyranose with -benzyl hydroxyl amine at 110°C... 

The palladium-catalyzed C-Se bond formation79-81 and the platinum-catalyzed carboselenation of alkynes with selenoesters have been reported in analogy with the thiolate chemistry. An electron-withdrawing or electron-donating group on the aromatic residue leads to the formation of the desired carboselenation product with acceptable yields. Functionalities like benzyl, hydroxyl, or nitrile group are tolerant with the reaction conditions. This method provides a new access to the functionalized vinylselenide 60,82 molecules of interest as key intermediate (Scheme 19) 85... 

In a more recent study (105), the intramolecular deuterium isotope effect and the relative rates of benzylic hydroxylation for six para-substituted (OCH3, CH2D, H, Cl, Br,... 

TABLE 4.2 Intramolecular deuterium isotope effects for benzylic hydroxylation of substituted toluenes catalyzed by CYP1A2, CYP1B1, CYP2C9, CYP2E1, and CYP101... 

The designations 1 and 2 for the diol epoxides indicate that the benzylic hydroxyl group and the epoxide oxygen are cis (syn) or trans (anti), respectively. 

The enantioselective benzylic hydroxylation of indan and tetralin can be achieved with M. isabellina, affording 78 % conversion to 1-indanol (64 % yield, 86 % (11 )- ee) in a 2-day incubation and 52 % conversion to 1-tetralol (38 % yield, 92 % (11 )- ee) in a 4-day incubation. The good yields and ee allow their use in future scahng-up processes however, to avoid the lack of efficiency, careful control of the temperature, pH and medium is necessary, since the reactions are strongly dependent on the incubation and reaction conditions. Tables 12.2 and 12.3 give details of some of the different incubation condi-tions/results and time-course analysis found in the benzyhc hydroxylation of indan and tetrahn mediated by M. isabellina CCT3498. 

Table 12.2 Benzylic hydroxylation of indan and tetralin mediated by M. isabellina...

Table 12.3 Time-course analysis obtained in the benzylic hydroxylation of indan and tetralin (30 mg) byM. isabellina (3 g fresh weight) ...

Boyd, D.R., McMordie, R.A S., Sharma, N.D., Dalton, H., Williams, P. and Jenkins, R.O., Stereospecific benzylic hydroxylation of bicyclic alkenes by Pseudomonas putida isolation of (+)-/ -l-hydroxy-l,2-dihydronaphthalene, an arene hydrate of naphthalene from metabolism of... 

Fig. 7.n Synthetic strategies to overcome benzylic hydroxylation in a series of cholesterol absorption inhibitors. Positions of metabolism are marked with an asterisk. 

Fig. 7.15 Structures of cholesterol absorption inhibitors SCH 48461 (A) and SCH 58235 (B). Metabolism of SCH 48461 occurs by aromatic hydrox-ylation (1) benzylic hydroxylation (2) and O-demethylation (3, 4). Metabolism is blocked in SCH 58235 at 1 and 4 or results in increases in potency at 2 and 3.

In contrast to phenolic hydroxyl, benzylic hydroxyl is replaced by hydrogen very easily. In catalytic hydrogenation of aromatic aldehydes, ketones, acids and esters it is sometimes difficult to prevent the easy hydrogenolysis of the benzylic alcohols which result from the reduction of the above functions. A catalyst suitable for preventing hydrogenolysis of benzylic hydroxyl is platinized charcoal [28], Other catalysts, especially palladium on charcoal [619], palladium hydride [619], nickel [43], Raney nickel [619] and copper chromite [620], promote hydrogenolysis. In the case of chiral alcohols such as 2-phenyl-2-butanol hydrogenolysis took place with inversion over platinum and palladium, and with retention over Raney nickel (optical purities 59-66%) [619]. 

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