Demethylation reagents

The present procedure illustrates the facile demethylation of methyl aryl ethers by lithium diphenylphosphide.3 This reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers in high yield.4 Use of excess reagent allows cleavage in the presence of enolizable ketones.5 In the present case, the cleavage may be performed without protection of the aldehyde, but two equivalents of reagent are required, and the yield is reduced to ca. 60%. 

Scheme 18. Demethylation of atropine (26). Reagents i, Cl3CCH2OCOCl ii, Zn, AcOH.

A new and interesting chioroformate reagent, a-chloroethyl chioroformate, was recently introduced for selective N-dealkylation of tertiary amines (106). When it was applied to the demethylation of 3a-acetoxytropane (2), the corresponding nor salt (198) was obtained in 97% yield (Scheme 20). 

Scheme 20. Demethylation of 3oc-acetoxytropane (2). Reagents i, CHjCHClOCOCl, ClCH2CH2Cl, 0°C - A, 1 hr ii, MeOH, A.

Selective de-ethylation of 2-ethoxyanisole is observed using KOtBu as the reagent in the presence of 18-crown-6 as the phase transfer agent (PTA). With the addition of ethylene glycol (E.G.), the selectivity is reversed and demethylation occurs (Eq. (33) and Tab. 3.13). If the involvement of microwaves is favorable in both examples, the second reaction should be more strongly accelerated than the first [87]. 

The reaction is not useful for N-demethylation because of slow rate and low yield. In fact, selective N-debenzylation is possible with this reagent. 

Demethylation of methylated sugars by means of hydrogen peroxide in the presence of ferrous ions (the Fenton reagent) has been re-... 

Nucleophilic bis-O-demethylation of dimethoxybenzenes in one flask is often difficult. It can, however, be achieved by use of sodium TMS thiolate in l,3-dimethyl-2-imidazolidinone (DMEU) at high temperature in a sealed tube101. The same reagent system converts nitriles into primary thioamides at or slightly above room temperature in varying yields102. 

Cleavage of alkyl ary ethers (4, 305). The most difficult step in a recent synthesis of aklavinone (3) is demethylation of 1 to 2. Lewis acid reagents (BBr3) were useless because of preferential attack of the allylic hydroxyl nucleophilic demethylation (LiSCH3) results in concomitant aromatization of ring A. Demethylation "with Lil buffered with benzoic acid in pyridine-collidine at 145° was successful and proceeded in 92% yield.4, Aklavinone is the aglycone of an antitumor anthracycline that is less toxic than adriamycin. 

Oxidation is, of course, the dominant reaction. For example, vaporized trifluralin ( a, a, < -trifluoro-2,6-dinitro-ll,ll-dipropyl-p-toluidine) was demethylated (Figure 7) (26), and its atmospheric half-life was found to be 8 minutes (27). However, the reaction occurred to a small extent even at night, and oxidation by ozone was implicated. In fact, there is evidence (28) that parathion photooxidation actually required the presence of ozone or other highly reactive oxidants. Degradation not requiring external reagents also may proceed rapidly trifluralin was cyclized to a substituted benzimidazole (11, 26), and dieldrin again formed photodieldrin (29). 

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. 

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