Methyl aryl ethers, deprotection

Trichloroalane in dichloromethane cleaves isopropyl aryl ethers leaving methyl aryl ethers intact. A variety of functional groups (aryl halides, 1,1-dihaloalkenes, aldehydes and acetates) withstand the reaction conditions but alkynes and TIPS ethers do not survive. Scheme 4 110 illustrates an application of the reaction to a synthesis of the Fagaronine alkaloids,201 TVichloroborane in dichloromethane may also be used for the deprotection of isopropyl ethers.202... 

BBr3 has been widely used to cleave ethers because the reaction proceeds completely under mild conditions. In a special case, BBra has been used to cleave acetals that cannot be deprotected by usual acidic conditions [14]. Because alkyl aryl ethers are cleaved at the alkyl-oxygen bond to give ArOH and alkyl bromides, BBr3 has been most generally used for the demethylation of methyl aryl ethers [13,15]. The presence of a carbonyl substituent facilitates selective deprotection of polymeth-oxyaryl compounds (Eq. 8) [16]. 

The synthesis of 86 commenced with oxazole carboxylic acid 87. Base-catalyzed lithiation and coupling with isatin 88 followed by methyl ester formation and Boc deprotection provided tertiary alcohol 89. A second coupling of the amine 89 with carboxylic acid 90 followed by chlorination afforded chloride 91. Treatment of 91 with TBAF gave a 1 1 mixture of O-aryl ether 92 (CIO) in excellent yield. Refluxing 92 in chloroform resulted in the formation of 93 (70%, with 30% of the isomer), which was subjected to a three-step reaction sequence to furnish intermediate 86 (Scheme 16). 

The three-step sequence used to convert enone 65 to miltirone (56) is shown in Scheme 5.7 and consists of, first, a Wolff-Kishner reduction to convert the C(5) carbonyl moiety into a methylene, followed by deprotection of the aryl methyl ethers and oxidation to an ortho-quinone using ceric ammonium nitrate. The physical and spectroscopic data of our synthetic miltirone are identical with those reported for the natural material. 

Deprotection of aryl methyl ethers may be effected under strongly acidic conditions (e.g. hydriodic acid, Section 9.6.11, p. 1253), but the milder methods employing either iodotrimethylsilane in chloroform solution at 20-50 °C for several hours,40 or boron tribromide at room temperature may be preferable.41... 

Cyclohexanone (202) was converted to compound (203) whose transformation to cyclohexanone (204) was accomplished in three steps. It underwent cyclialkylation with boron trifluoride etherate affording the cyclized product (205) (R=R,=OMe) in 64% yield along with naphthalene (206) (R=Ri= H,H). Compound (205) on heating under reflux with DDQ in benzene produced ketone (207) whose tosylhydrazone on treatment with sodium cyanoborohydride afforded reduced product (208). Deprotection of the aryl methyl ethers and oxidation with ceric ammonium nitrate led to the formation of miltirone (197). 

The phenolic functions are deprotected under rather drastic conditions, by analogy with methods defined previously for the cleavage of aryl methyl ethers.14 Treatment of dianisylphenanthroline 4 with pyridinium hydrochloride at 210°C affords 2,9-di(p-phenol)-l,10-phenanthroline 5 quantitatively (Scheme 9.4). 

Maiti and Roy reported a selective method for deprotection of primary allylic, benzylic, homoallylic and aryl TBS ethers using aqueous DMSO at 90° C. All other TBS-protected groups, benzyl ethers, THP ethers as well as methyl ethers remain unaffected. 

Protection of phenols. Aryl methyllhiomethyl ethers can be obtained in 90 95% yield by reaction of sodium phenoxides with chloromethyl methyl sulfide in HMPT (20 , 16 hours). Deprotection is accomplished (90-95% yield) with HgCta in refluxing CHJCN-H2O (10 hours). 

---