3-benzyloxyphenylacetic acid

The most straightforward route toward 15 is likely to be the Friedel-Crafts reaction of 3-benzyloxyphenylacetic acid (19) with iodobenzene (18), as shown in Scheme 5.4. However, preliminary attempts at this type of reaction were met with the very low reactivity of iodobenzene (18) toward Friedel-Crafts substitutions. 

The thermal condensetion of p-benzyloxyphenylacetic acid and of 3-methoxy-4-hydroxy-phenethylamine occurs and gives, with a yield of 86% to 92%, the N-(3-methoxy4-hydroxy-phenethyl-p-benzyloxyphenylacetamide from this latter, by cyclization according to Bischler-Napieralski with phosphorus oxychloride in acetonitrile, followed by reduction with sodium borohydride, there is obtained with a yield of 75% to 80% the 1-(p-benzyloxybenzyl)-6-meth-oxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline, which is methylated with formaldehyde and formic acid giving 1 (p-benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline with a yieid of 90%. 

A soln. of 2-phenyl-4-(2-benzyloxybenzylidene)-5-oxazolone in 10%-NaOH boiled 5 hrs., dil. with water, cooled to 10°, satd. with SO2, the precipitated benzoic acid removed by filtration, the filtrate acidified with coned. HCl, heated 10-15 min. on a steam bath until S02-evolution is complete, cooled, made alkaline with NaOH, 30%-H2O2 added, and after 1 hr. acidified with HGl to Congo red paper o-benzyloxyphenylacetic acid. Y 88%. A. F. Wagner, A. N. Wilson, and K. Folkers, Am. Soc. 81, 5441 (1959). 

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