Org Prep Daily

February 24, 2008

Arnold Salt

Filed under: procedures — milkshake @ 5:33 pm


Anhydrous DMF 160mL in a 0.5L round flask was cooled on ice bath and neat POCl3 40 mL (436mmol) was added greadually over 10 min period (exothermic). The mixture was warmed up to RT, bromoacetic acid solid 19.00g (136.7 mmol, Aldrich 99%+) was added quickly in one portion (hygroscopic, wear gloves – bromoacetic acid and POCl3 are nasty). The flask was equipped with a reflux condenser and the mixture was stirred under Ar on oil bath at 90C for 9 hours. The mixture turned orange, with a slow CO2 evolution. The mixture was cooled to RT, DMF was distilled out on highvac (RT to 90C at 0.5 Torr) and the obtained thick residue was treated with ice-cold water 100mL on a sonicator bath. An exothermic hydrolysis commenced. When all residue dissolved and the mixture cooled to RT, solid sodium hexafluorophosphate 46.2g (275 mmol) was added in one portion followed by some additional water (50 mL). The mixture was shaken vigorously for 10 min, the precipitated product was collected using a large Buchner funnel. The solid cake was compressed on the frit, washed with ice-cold water (5x20mL), dried by suction and then on highvac.
Y=61.05g (94%) of a yellowish-white solid

1H(d6-DMSO, 400MHz): 8.439(s, 3H), 3.535(s, 9H), 3.376(s, 9H)

Note 1: The formylation is complete in 6 hours at 90C. KPF6 is probably a better source of hexafluorophosphate because unlike the sodium salt it does not hydrolyse readily, does not etch glass and is non-hygroscopic. Aqueous HPF6 can be also used. It is important to remove most DMF from the reaction mixture, this takes some time (I used a rotovap hooked to oil pump).

Note 2:  The product can be re-crystallised to analytical purity from MeCN + some antisolvent (THF) but the crude material is suitable for most purposes. 

Note 3: Bromoacetic acid can be replaced with bromoacetyl chloride or bromide – in such case the POCl3 amount can be reduced by one equivalent

February 21, 2008

5-(N-pyrazolyl)-3-nitrobenzoic acid

Filed under: procedures — milkshake @ 7:14 pm


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.

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