Org Prep Daily

September 29, 2006

1-allyl-4-nitropyrazole

Filed under: procedures — milkshake @ 5:04 pm

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.

10 Comments »

  1. Thanks Milkshake, this is my first OPD reaction. Only did the first step on 10g of pyrazole, and am happy to report that even with KP’s fat fingers, heating at 55 °C overnight instead of 7h, swinging the pH from 0 to 12 and back to 1, I was still able to filter 8.5 g on the first crop of nice quality stuff. I could probably go back for more, but thats good enough for gov’t work.

    Sure you could just buy it, but where’s the fun of that?

    Comment by kinasepro — October 13, 2006 @ 10:24 am

  2. I tried to buy 4-nitropyrazole – but it was available only from some small company in Russia. Getting the purchase order through (and having somebody to call Russia) and waiting for few weeks and then answering the billing questions would be quite a chore and we needed multigram quantity of this stuff, so I nitrated. I think the literature scale-up procedure called for NaOH to neutralise and for extraction with EtOAc, but the extraction volumes were too large and I got lots of sodium sulfate decahydrate crashing out. Conc ammonia is surprisingly good for neutralising quantities of sulfuric acid. And I got away from the extraction, the crude product was crystallizing directly from the mixture.

    If you are going to do reduction next, always hydrogenate in a presence of acid, like HCl. The hydrochlorides of 4-aminopyrazoles are storable whereas the free bases oxidise rapidly – they turn into a deep-purple goo within a day. 

    Comment by milkshake — October 13, 2006 @ 12:12 pm

  3. I’ve successfully reproduced this procedure (despite only on a 200 mg scale) with my pyrazole derivative. Do you have a good way for reducing the nitro group to an amino group? Preferably an homogeneous reaction (rather than an hydrogenation over Pd/C)?

    Comment by Ron — October 27, 2006 @ 12:35 am

  4. I would try 5% Pt/C in EtOAc under baloon of H2 in presence of HCl 1 eq. to keep the product as a salt. This method should be reasonably mild to avoid reducing things like aryl-Cl in the molecule. I don’t have experience with other conditions and would not want to experiment because the 3-aminopyrazoles are quite sensitive, especialy to air oxidation.

    Comment by milkshake — October 27, 2006 @ 9:34 am

  5. I have a friend from graduate school that I am going to pass this page on to…thanks alot!!

    Comment by Organic Chemistry — January 19, 2007 @ 6:08 pm

  6. Another question about pyrazoles: I’d like to do a bis-oxidation of 3,5-dimethylpyrazole to the dialdehyde but the only prep I’ve been able to find in the literature is 5 steps (permanganate oxidation, esterification, LAH reduction, protection of the N-H bond, then Swern oxidation). The permanganate oxidation was very messy and a late exotherm unfortunately coated my hood purple/brown, so I’m quite interested in your ideas of a more direct way to make the bis-aldehyde. Do you have any? Thanks!

    Comment by Ron — December 16, 2007 @ 4:05 am

  7. I would buy the diacid (Aldrich, Alfa, Acros… it is not too expensive) or better yet, buy the diethyl ester (Aldrich). I would protect the diester with trityl. Then I would do the LAH or Li-borohydride reduction, then Swern.

    Trityl is a big protecting group but it is cheap and it makes polar pieces easier to handle. It should be stable to LAH.

    Comment by milkshake — December 16, 2007 @ 4:26 am

  8. Hi MS,

    Is there any selective method for the ring nitrogen protection of 4(5) amino imidazole? I would like to use this substrate for peptide coupling reaction involving pyridine acids. Direct use of the unprotected amine in the peptide coupling gave the desired product (Exo amine coupled product) with low yield. (10% isolated yield). I am trying to prepare ring nitrogen protected amine via nitro imidazole (later SEM protection was done) is also unsuccessful. I am repeating the synthesis with N-Benzyl nitro imidazole. Please suggest me any PG better than benzyl and stable under acidic conditions.

    Thanks for your help

    Marto

    Comment by marto — November 19, 2010 @ 3:20 am

    • I don’t have any experience with protecting imidazoles. For ring-protecting imidazole in histidine, people used things like trityl (which comes off with TFA). I remember faintly that I have seen stuff like dimethylsulfamoyl Me2SO2-. It would be best if you can check Greene book “protective groups in organic synthesis”. Ask around at work, someone will probably have it at hand.

      Comment by milkshake — November 19, 2010 @ 4:49 pm

  9. Thanks

    Marto

    Comment by marto — November 20, 2010 @ 3:56 am


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