Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins via successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazoline

摘要

Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-BuLi, B(OMe)(3), and H2O2 produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44-75% overall yields. This procedure allowed the short synthesis of (+/-)-hydrangenol and (+/-)-phyllodulein, naturally occurring 3,4-dihydroisocoumarins of pharmacological interest. A more economical synthesis of (+/-)-phyllodulcin via the trianion intermediate is also described. (C) 2004 Elsevier Ltd. All rights reserved.