General Papers ARKIVOC 2000 (ii) 165-180
The preparation of (±)-2-(4-benzyloxyphenyl)-2-(phenylsulfanyl)acetic acid (8) started from (±)2-( 4-hydroxyphenyl)-2-hydroxyacetic acid (5) (Scheme 2). Alkylation of 5 with benzyl chloride in the presence of potassium carbonate and tetraethylammonium bromide (TEAB) in refluxing acetone gave benzyl (±)-2-(4-benzyloxyphenyl)-2-hydroxyacetate (6). Bromination of 6 with phosphorus tribromide in dry diethyl ether yielded benzyl (±)-2-(4-benzyloxyphenyl)-2bromoacetate (7). Treatment of 7 with potassium benzenethiolate in dioxane under reflux afforded 8; the corresponding acid chloride was condensed with the amine 2c and afforded the amide 9d. The 1H NMR spectra of 9a-d indicated a mixture of E/Z isomers with respect to the rotational isomerism of the amide group. Oxidation of the sulfides 9a-d with sodium metaperiodate in aqueous methanol or acetone afforded a diastereomeric mixture of sulfoxides 10a-d, respectively. When a solution of the sulfoxide 10b in benzene was treated with TFAA at room temperature for 10 min, the expected cyclization was readily induced, and 6,7-dimethoxy-2-methyl-4-phenyl-4( phenylsulfanyl)-1,2,3,4-tetrahydoisoquinolin-3-one (11b) was formed (Scheme 3). Cyclization of 10c also occurred under similar conditions and furnished 11c. 00cking the alkoxy groups enhancing the nucleophilicity of the phenyl ring of the Nbenzylacetamide moiety, and on treatment with TFAA in benzene at room temperature the tetrahydoisoquinolin-3-one 11a was obtained in only 20% yield together with non-cyclized products 12 and 13. Addition of BF3·Et2O9 to a benzene solution of 10a containing TFAA considerably improved the cyclization reaction and increased the yield of 11a at the expense of the side products 12 and 13. On the contrary, the sulfoxide 10d bearing a benzyloxy group in two benzene rings, when treated with TFAA in benzene at room temperature rapidly decomposed to give a complex mixture, and no products could be isolated from this reaction mixture. Previously, we noticed that this Pummerer-type cyclization in some cases9a was strongly dependent on the solvent used. Therefore, we carried out the reaction in several solvents and found that tetrahydrofuran (THF) dramatically improved the cyclization reaction. Thus, reaction of 10d with TFAA in THF induced the expected cyclization at room temperature leading to its completion within 10 min and furnishing 11d. Similarly, the reaction of 10c in THF afforded 11c, although the cyclization in this solvent was slower (300 min) compared with the reaction carried out in benzene as described above. These results demonstrate that the cyclization of 10 readily proceeds under mild conditions. The putative reaction intermediate, the sulfonium ion 14, features the C=S bond in conjugation with the 2-aryl group. This is considered to favor the formation of the electrophilic intermediate 14, and, in turn, facilitates the intramolecular cyclization reaction. We achieved the conversion of the 4-aryl-2-methyl-4-(phenylsulfanyl)-1,2,3,4tetrahydroisoquinolin- 3-ones 11 into 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines 16 by conventional reductive steps (Scheme 3). Reductive removal of the phenylsulfanyl group of 11a-b occurred on treatment with NaBH4-NiCl2 in methanol-THF to afford 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-3ones 15a-b. Subsequent reduction of 15a-b with lithium aluminum hydride (LAH) furnished the
ISSN 1424-6376 Page 167 ©ARKAT USA, Inc
