Benzylic oxidations and reductions

Because it is aromatic, the benzene ring is quite unreactive. While it does undergo electrophilic aromatic substitutions (Chapters 15 and 16), reactions that dismantle the aromatic six-electron circuit, such as oxidations and reductions, are much more difficult to achieve. In contrast, such transformations occur with comparative ease when taking place at benzylic positions. This section describes how certain reagents oxidize and reduce alkyl substituents on the benzene ring. 

Oxidation of alkyl-substituted benzenes leads to aromatic ketones and acids 

Reagents such as hot KMn04 and Na2Cr207 may oxidize alkylbenzenes all the way to benzoic acids. Benzylic carbon-carbon bonds are cleaved in this process, which usually requires at least one benzylic C-H bond to be present in the starting material (i.e., tertiary alkylbenzenes are inert). 

The reaction proceeds through first the benzylic alcohol and then the ketone, at which stage it can be stopped under milder conditions (see margin and Section 16-5). 

The special reactivity of the benzylic position is also seen in the mild conditions required for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. For example, manganese dioxide, MnOa, performs this oxidation selectively in the presence of other (nonbenzylic) hydroxy groups. (Recall that Mn02 was used in the conversion of allylic alcohols into a,j8-unsaturated aldehydes and ketones see Section 17-4.) 

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Zr compounds are also useful as Lewis acids for oxidation and reduction reactions. Cp2ZrH2 or Cp2Zr(0 Pr)2 catalyze the Meerwein-Ponndorf-Verley-type reduction and Oppenauer-type oxidation simultaneously in the presence of an allylic alcohol and benzaldehyde (Scheme 40).170 Zr(C)1 Bu)4 in the presence of excess l-(4-dimethylaminophenyl) ethanol is also an effective catalyst for the Meerwein-Ponndorf-Verley-type reduction.1 1 Similarly, Zr(0R)4 catalyze Oppenauer-type oxidation from benzylic alcohols to aldehydes or ketones in the presence of hydroperoxide.172,173... 

The Cannizzaro reaction takes place by nucleophilic addition of OH" to an aldehyde to give a tetrahedral intermediate, which expels hydride icn as a leaving group. A second aldehyde molecule accepts the hydride ion in another nucleophilic addition step, resulting in a simultaneous oxidation and reduction, or disproportionation. One molecule of aldehyde undergoes a substitution of H by OH" and is thereby oxidized to an acid, while a second molecule of aldehyde undergoes an addition of H" and is thereby reduced to an alcohol. Benzaldehyde, for instance, yields a 1 1 mixture of benzoic acid and benzyl alcohol when heated with aqueous NaOH. 

Dihydroxycoumarin (55) underwent selective methylation (dimethyl sulfate) to the 7-methoxy derivative (56), which upon benzylation and oxidation (selenium dioxide), afforded the 4-formyl coumarin (74). Conversion to the acetal (75) occured upon treatment with triethyl orthoformate, and subsequent catalytic hydrogenation served the dual purpose of removal of the benzyl group and reduction of the coumarin double bond, to give (76). Hydride reduction of the derived acetate (77), followed by acidic workup, gave directly the furobenzofiiran (75) [presumably through the hydroxy aldehyde (75)]. Comparison of the spectra of racemic (75) with those of the naturally derived material showed the compounds to be identical. 

Ring transformation of the mannopyranoside derivative 61, obtained from noncarbohydrate, to 1 has been developed (Scheme 7).225.226 Radical cyclization of the thiocarbonylim-idazolo derivative of 61 gave 62, which upon oxidation and reduction afforded 63 (30%) and 64 (55%). The latter was benzylated to give 65, which was converted into (fi)-oxime 67 via 66. Beckmann rearrangement of 67 followed by desilylation furnished 68. Cyclization of 68 to indolizidine skeleton followed by debenzylation, reduction of the lactam with BMS and hydrolysis afforded (-)-swainsonine (1). 

Removal of the MOM and Boc groups followed by regioselective bromination with Py-HBr in dichloromethane followed by cyclization through an iminium ion intermediate furnished the bicycle 10 as a single isomer. Deprotection of the benzyl ether and reduction of the azide group afforded the amino diol 11, which was treated with BrCH2C02Ph and propylene oxide and subsequent Pb(OAc)4 oxidation of the amine to provide 12 (80%). Intermolecular addition of the phenolic compound 13 to 12 in the presence of TEA occurred at the sterically less hindered convex face to provide the key intermediate 14 (Scheme 2). ... 

The use of PTC in electroorganic oxidation and reduction reactions is widespread because it involves in situ generation and regeneration of oxidizing and reducing agents. Most applications are in liquid-liquid systems, but it can also be used in solid-liquid PTC systems (Chou et al., 1992). Recently, Do and collaborators extensively studied the electrochemical oxidation of benzyl chloride in the presence of a PT catalyst (soluble and immobilized) in both batch (Do and Chou, 1989, 1990, 1992) and in continuous (Do and Do, 1994a,b,c) electrochemical reactors. Mathematical models for both types of reactors were also proposed. 

A further route to P-mannopyranosides involves use of the 1,2-anhydride 33, made by the Danishefsky method from tri-O-benzyl-D-glucal. Epoxide ring opening with alcohols in the presence of zinc chloride gives P-glucosides which, by oxidation and reduction, lead to the P-mannosides including P-mannosyl disaccharides. Danishefsky has also adapted compound 33 for use as a precursor of a-glucosides. Treated with tributylstannylated alochols in the presence... 

Purpose. This experiment illustrates the simultaneous oxidation and reduction of an aromatic aldehyde to form the corresponding benzoic acid and benzyl alcohol. The experiment further demonstrates the techniques for separation of a carboxylic acid from a neutral alcohol. For a detailed discussion of this extraction procedure, see Experiment [4C]. 

The only industrially important processes for the manufacturing of synthetic benzaldehyde involve the hydrolysis of benzal chloride [98-87-3] and the air oxidation of toluene. The hydrolysis of benzal chloride, which is produced by the side-chain chlorination of toluene, is the older of the two processes. It is no longer utilized ia the United States. Other processes, including the oxidation of benzyl alcohol, the reduction of benzoyl chloride, and the reaction of carbon monoxide and benzene, have been utilized ia the past, but they no longer have any iadustrial appHcation. 

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into )S-3-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (HI) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-1-benzyl-3 4-dihydroiioquinoline (IV), on conversion into the methochloride and reduction with tin and hydrochloric acid, gave... 

The (ZZ-ephedrine was resolved into its components by the use of d-and Z-mandelic acids. In 1921 Neuberg and Hirsch showed that benz-aldehyde was reduced by yeast, fermenting in suerose or glueose solution to benzyl aleohol and a phenylpropanolone, which proved to be Z-Ph. CHOH. CO. CH3. This ean be simultaneously, or consecutively, eondensed with methylamine and then eonverted to Z-ephedrine by reduction, e.g., with aluminium amalgam in moist ether, or by hydrogen in presenee of platinic oxide as catalyst (Knoll, Hildebrant and Klavehn ). 

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

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