title: On the Kolbe-Schmitt synthesis of pharmacologically useful salicylates: carboxylation of 2,4-di-t-butylphenol and identification and reduction of the formation of 2,2'-dihydroxy-3,3',5,5'-tetra-t-butylbiphenyl in the synthesis of 3,5-di-t-butylsalicylic acid.
abstract: The initial yield of 3,5-di-t-butylsalicylic acid obtained via Kolbe-Schmitt carboxylation of the potassium salt of 2,4-di-t-butylphenol was less than 1% and was accompanied by a 65% yield of 2,2'-dihydroxy-3,3',5,5'- tetra-t-butylbiphenyl, a dimer of the 2,4-di-t-butylphenol formed by ortho coupling of phenoxide radicals. Formation of this dimer was decreased to 8%, and the yield of 3,5-di-t-butylsalicylic acid was increased to 68% by optimizing reaction time and temperature and decreasing the amount of oxygen present during carboxylation. This modification of the Kolbe-Schmitt reaction conditions may be generally helpful in the synthesis of all pharmacologically useful salicylates.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock 72205.
authors.forename: M V
authors.initials: MV
authors.lastname: Chidambaram
authors.forename: J R
authors.initials: JR
authors.lastname: Sorenson
mesh_terms: D001713:Biphenyl Compounds / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry; D013696:Temperature
chemical_list: D001713:Biphenyl Compounds; D010636:Phenols; D012459:Salicylates; C073158:3,5-di-tert-butylsalicylic acid; C073157:2,2'-dihydroxy-3,3',5,5'-tetra-tert-butylbiphenyl; C056559:2,4-di-tert-butylphenol