Pyrazole 40.0g (587.5mmol) was added spoon-by-spoon ino stirred conc. sulfuric acid (96%) 270mL in a 1L wide-mouth flask with cooling on ambient oil bath. 70% nitric acid 40mL was then added dropwise over 10 minutes (exothermic). The bath temperature was raised to 55C. The reaction mixture was stirred at 55C for 7 hours, then cooled to R.T. and poured onto ice (1kg) in a large beaker. The mixture was made basic (pH=8) by addition of concentrated ammonia (exothermic) and the pH of the obtained hot mixture was adjusted with 6M HCl to about pH=3. The mixture was allowed to crystallize at RT for 8 hours, the precipitated crude product was collected by filtration and washed with ice-cold water. Cooling the supernatants to +5C overnight (fridge) produced additional crude product. The combined two fractions of crude nitropyrazole (containing some inorganics) were re-crystallized from water (250mL, to RT overnight), the pure product (46.401g) was collected by filtration, washed with ice-cold water and dried on highvac. Evaporating the supernatants and re-crystallizing the residue from water 50mL provided additional 4.110g of pure product. Combined Y=50.511g (76%) of white large crystals. 1H(d6-DMSO, 400MHz): 13.938(br s, 1H), 8.558(s, 2H)
Cs2CO3 16.3g (50mmol) was quickly powdered (with a large spatula and a beaker – to break up the lumps, hygroscopic!) and placed in a 0.5L flask under Ar. 4-nitropyrazole 4.110g (36.35mmol) was added followed by anhydrous acetonitrile 300mL and allyl bromide 4.2mL (49.6mmol). The mixture was stirred under Ar for 75 min (HPLC indicated complete conversion in 1 hour), the salts were removed by filtration (washed with additional acetonitrile 100mL) and the filtrates were evaporated. The residue was purified on a column of silica (40g) in a gradient of ethyl acetate in hexane, 0 to 25% ethyl acetate. The purified product was dried on highvac. Y=5.360g (96%) of a colorless liquid.
1H(d6-DMSO, 400MHz): 8.879(s, 1H), 8.277(s, 1H), 6.301(m, 1H), 5.265(m, 1H), 5.191(m, 1H), 4.834(m, 2H)
In later experiments, the simplified nitropyrazole work-up and re-crystallization was used without a detriment to the yield: The nitration mixture (a 40 g-scale experiment) was poured onto crushed ice 1.0kg in a large beaker or polyethylene bucket (3L). With stirring, concentrated ammonia (28-30% NH3) was gradually added until the mixture was basic (about pH=8 by universal indicator paper), this took about 550-600mL of concentrated ammonia, depending on the ammonia concentration. The obtained hot solution was acidified by gradual addition of 6M HCl until pH about 3 was obtained. The mixture was allowed to crystallize at RT in an open beaker overnight (18 hours). The precipitated crude product was collected by filtration, compressed on the Buchner funnel, washed quickly with a small amount of ice-cold water (2x40mL) and dried by suction. The crude product was recrystallized from hot water (200mL, to RT, overnight). The precipitated product (45.5g) was collected by filtration, washed with ice-cold water (2x40mL), dried by suction and on highvac. Cooling the supernatants from re-crystallization in a refrigerator (+2 C) overnight, a second fraction (5.2g) crystallized.
Note 1: It is important to use approximately 1 kg of ice: Too little ice (0.6kg) leads to overheating and splashing during neutralization with ammonia whereas too much ice dilutes the reaction mixture and reduces the yield of the nitropyrazole.
Note 2: The workup/purification of 4-nitropyrazole can be further simplified by not recovering the second fractions from supernatants (with only a small penalty on the yield): 50.0g of pyrazole was gradually added to conc. sulfuric acid (95-96%) 340mL with cooling on water bath, followed by conc. HNO3 (70%) 40mL. The mixture was heated to 55C for 7 h, cooled, poured on ice 1.25kg, alkalized by gradual addition of conc. NH4OH (approx 850mL, to pH>9, exothermic!), acidified to pH=3 with 6M HCl and allowed to cool and crystallise overnight at RT. The product was collected by filtration, quickly rinsed with ice-cold water and dried by suction. The crude product was re-dissolved in refluxing water 250mL and allowed to crystallize at RT for 6 hours. Filtered, rinsed with ice-cold water, dried by suction and on highvac. Y=60.15g (72.5%) of white plates.