Alkylation of 4-methoxythiophenol (I) with ethyl 2-bromopropionate (II) gives thioether (III), which is further oxidized to sulfone (IV) employing oxone in MeOH/THF. Alkylation at the alpha-position of sulfone (IV) with 4-(2-piperidin-1-ylethoxy)benzyl chloride (V) in the presence of K2CO3 and crown ether furnishes adduct (VI). After alkaline hydrolysis of ethyl ester (VI), the resultant carboxylic acid (VII) is activated as the corresponding acid chloride (VIII) employing oxalyl chloride and DMF. Finally, reaction of acid chloride (VIII) with hydroxylamine in cold aqueous THF produces the target hydroxamic acid. (1-4)
The alkylation of diethanolamine (I) with benzyl bromide (II) by means of K2CO3 in refluxing acetone gives the tertiary amine (III), which is treated with SOCl2 in hot toluene to yield the bis-(2-chloroethyl)amine (IV). The cyclization of (IV) with 2-[4-(4-chlorophenoxy)phenylsulfonyl]acetic acid ethyl ester (V) by means of K2CO3 and 18-crown-6 in refluxing acetone affords the piperidine derivative (VI). The hydrolysis of the ester group of (VI) by means of NaOH in THF/methanol provides the corresponding acetic acid derivative (VII), which is treated with oxalyl chloride in DMF/dichloromethane to give the acid chloride (VIII). Finally, this compound is treated with hydroxylamine and TEA to provide the target hydroxamic acid. (1,2) The intermediate 2-[4-(4-chlorophenoxy)phenylsulfonyl]acetic acid ethyl ester (V) has been obtained as follows. The condensation of 2-(4-hydroxyphenylsulfanyl)acetic acid ethyl ester (IX) with 4-bromochlorobenzene (X) by means of NaH and CuCl2 in refluxing pyridine gives 2-[4-(4-chlorophenoxy)phenylsulfanyl]acetic acid ethyl ester (XI), which is finally oxidized with oxone to yield the target intermediate (V). (2)
The alkylation of piperidine-4-carboxylic acid methyl ester (I) with benzyl bromide (II) and TEA in ethanol gives 1-benzylpiperidine-4-carboxylic acid methyl ester (III), which is condensed with 4-(4-chlorophenoxy)benzenesulfonyl fluoride (IV) by means of BuLi and diisopropylamine or LiHMDS in THF to yield the sulfone (VI). The hydrolysis of the ester group of (VI) with LiOH in methanol affords the carboxylic acid (VII), which is treated with oxalyl chloride in acetone to provide the acyl chloride (VIII). Finally, this compound is treated with hydroxylamine to furnish the target hydroxamic acid. The intermediate sulfonyl fluoride (IV) has been obtained by reaction of the corresponding sulfonyl chloride (V) with KF and CaF2 in acetonitrile.