Phenolic ethers oxidative demethylation

Oxidation of that compound with chromium trioxide in sulfuric acid leads cleanly to the desired ketone (67). Treatment with hydrobromic acid serves to demethylate the phenolic ether function (68). Direct... 

The acid 350 was demethylated with pyridine hydrochloride, then realkylated with benzyl bromide in aqueous potassium hydroxide to give 351. The latter was converted to the diazoketone 352 by the sequential treatment of 351 with oxalyl chloride and etheral diazomethane. Reaction of 352 with concentrated hydrobromic acid gave the bromoketone 353. The latter was reduced with sodium borohydride at pH 8 -9 to yield a mixture of diastere-omeric bromohydrins 354. Protection of the free hydroxyl as a tetrahydro-pyranyl ether and hydrogenolysis of the benzyl residue afforded 355. The phenol 355 was heated under reflux with potassium m/V-butoxide in tert-butyl alcohol for 5 hr to give a 3 1 epimeric mixture of dienone ethers 356 and 357 in about 50% yield. Treatment of this mixture with dilute acid gave the epimeric alcohols 358 and 359. This mixture was oxidized with Jones reagent to afford the diketone 349. 

The key step in the biosynthesis of morphine involves the oxidative phenolic coupling of reticuline (31) to salutaridine (32). This step can be viewed mechanistically as (1) oxidation of the two aromatic rings to phenoxy radicals followed by an intramolecular radical-radical coupling or (2) oxidation of one ring to a radical cation or cation, followed by an intramolecular electrophilic aromatic reaction. This process is very important in the biosynthesis of a number of natural products, and is a process that nature has used to crosslink peptides containing aromatic residues. The biosynthesis of morphine continues with reduction of salutaridine (32) to salutaridinol (33) followed by an intramolecular Sn2 reaction to give thebaine (34). Dienol ether hydrolysis to codeinone (35), reduction of the ketone to codeine (3) and 0-demethylation completes the biosynthesis of morphine (1). 

A second alkaloid S-methoxycanthin-6-one was demethylated with hydrobromic acid in acetic add to a phenol which formed water insoluble alkali salts. Upon treatment of the phenol with diazomethane in methylene chloride or its O-acetate in moist ether die alkaloid was regenerated. Like canthin 6-one, potassium permanganate oxidation gave )S-carboIine-l-carboxylic acid and the phenol with o-phenylenediamine furnished a hydroxyquinoxa-line. These facts established its structure. Reduction of the alkaloid with zinc in acetic acid resulted in a mixture of canthin-6-one and its 4,5-dihydro-derivative. The latter derivative could be easily dehydrogenated to the former with sulphur or selenium. 

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