3-hydrazinobenzoic acid 13.95g (91.68 mmol) suspension in water 100mL was diluted with acetic acid 100mL and 1,1,3,3-tetramethoxypropane 15.5mL (15.11g; 92mmol) was added to the mixture, followed by conc. HCl 10mL. The mixture was stirred under reflux on a 100C oil bath for 45 min. (The condensation was complete in less than 30 min). The dark reaction mixture was poured into a large beaker and the stirred mixture was diluted with gradual water addition up to 1L total volume. After 30 min stirring the obtained slurry was allowed to crystallize in a fridge (+1C) overnight. The precipitated m-(N-pyrazolyl)-benzoic acid was collected by filtration, washed with ice-cold water (100mL), dried by suction and on highvac.
Y=15.38g of a light tan powder (89% th.) 1H(d6-DMSO, 400MHz): 13.217(br s, 1H), 8.609(dd, 2.5Hz, 0.4Hz, 1H), 8.377(t, 1.9Hz, 1H), 8.095(ddd, 8.1Hz, 2.4Hz, 1.0Hz, 1H), 7.861(ddd, 7.7Hz, 1.4Hz, 1.0Hz, 1H), 7.784(dd, 1.7Hz, 0.4Hz, 1H), 7.627(t, 7.9Hz, 1H), 6.572(dd, 2.5Hz, 1.8Hz, 1H)
15.11g of m-(N-pyrazolyl)-benzoic acid from the previous step (80.29mmol) was gradually added to conc. sulfuric acid (96%) 55mL with cooling on ambient water bath. After 20 min stirring, when the starting material mostly dissolved in sulfuric acid, 8.0 mL of 70% nitric acid was added dropwise and the mixture was stirred on ambient water bath for 75min, then poured on ice (200g). The total volume of the slurry was adjusted to 0.5L with water and the mixture was stirred for 15 min, the precipitated crude product was collected by filtration, washed thoroughly with water and dried by suction. The crude product was dissolved in a mixture of ethanol 500mL and water 100mL at reflux, the hot solution was diluted with hot water 400mL and the mixture was allowed to crystallise at RT overnight. The precipitated product was collected by filtration, washed with 1:1 ethanol+water mixture (300mL), dried by suction and on highvac. Y=13.85g of a pale yellow fluffy crystalline solid (73.5% th), containing 4.5% of a nitropyrazole impurity.
1H(d6-DMSO, 400MHz): 14.076(br s, 1H), 8.775(dd, 2.5Hz, 0.3Hz, 1H), 8.251(t, 1.4Hz, 1H), 8.200(d, 0.4Hz, 2H), 7.891(d, 1.5Hz, 1H), 6.661(dd, 2.6Hz, 1.7Hz, 1H)
Note: Even though pyrazole is a fairly electron-rich ring, in conc. sulfuric acid it becomes fully protonated so the bezoic acid portion of the molecule nitrates faster; the nitration is rather messy but the desired 1,3,5-substituted product crystallizes well.
To obtain the isomeric meta-(4-nitropyrazol-1-yl)-benzoic acid, one can nitrate by very slow addition of 2.5 equivs of 90% white fuming nitric acid dissolved in Ac2O 4 equivs, into AcOH slurry of the substrate at 60C – a very dangerous system.