As part of our research program on the synthesis of new DNA minor groove binders active against kinetoplastid parasites (i.e. T. brucei, T. cruzi, and L. donovani), we needed to prepare 2-isopropoxy-4-nitrobenzoic acid (1). A previously reported synthetic approach consisting in the reaction of 2-hydroxy-4-nitrobenzoic acid with an excess of 2-iodopropane had been reported earlier. The di-alkylated isopropyl 2-isopropoxy-4-nitrobenzoate intermediate (2), was then saponified using harsh basic conditions (i.e. 45% aqueous NaOH in THF/EtOH at 80 °C) to yield pure 1 (72% overall) by acid workup according to the reported procedure.
However, our efforts to obtain 1 following this protocol were unsuccessful. In its place, (Z)-1,2-bis(4-carboxy-3-isopropoxyphenyl)diazene-1-oxide derivative (3) was isolated as main product (92%) of the reaction. Full characterization this trans-azoxybenzene derivative was carried out by means of IR, 1H, 13C, and 15N NMR spectroscopy.
Adjusting the internal temperature of the saponification step was key to control the outcome of the reaction towards the formation of either products 1 or 3. We show that working at room temperature and using lithium hydroxide instead of concentrate NaOH is an excellent alternative to achieve the synthesis of the desired 2-isopropoxy-4-nitrobenzoic acid (1). On the other hand, working at high temperature (80 ºC, as reported previously) is an excellent method for the high-yield synthesis of trans-azoxybenzene.
