First synthesis of [1,3,5-13C3]gallic acid

Abstract

An efficient and high-yielding synthesis for [1,3,5-¹³C₃]gallic acid from non-aromatic precursors is presented. [3,5-¹³C₂]4H-Pyran-4-one was first prepared from the reaction between triethyl orthoformate and [1,3-¹³C₂]acetone. The third ¹³C-atom was introduced into the ring by reaction of the pyranone with diethyl [2-¹³C]malonate. The resulting ethyl 4-hydroxy-[1,3,5-¹³C₃]benzoate was brominated in the 3- and 5-positions to give ethyl 3,5-dibromo-4-hydroxy-[1,3,5-¹³C₃]benzoate. Subsequent hydrolysis of the ester and substitution of the bromine atoms with hydroxyl groups was achieved under basic conditions in a single step to yield the desired [1,3,5-¹³C₃]gallic acid. The synthesis of [2,6-¹³C₂]4H-pyran-4-one is also presented to demonstrate the potential of the methodology for the regioselective placement of ¹³C-atoms into benzene rings.