Org Prep Daily

October 2, 2006

5-Iodo-2,4-dichloropyrimidine

Filed under: procedures — milkshake @ 7:41 am

5-Iodouracil 11.245g (47.25mmol) was suspended in POCl3 45mL (10eq.) and N,N-dimethylaniline 12mL (2 eq.) was added into the stirred slurry. (Non-exothermic). The flask was flushed with argon and the mixture was refluxed under Ar blanket on oil bath (120-125C) for 30 minutes. The mixture was cooled to RT and the volatiles were evaporated. The residue was dried on oil pump (with TWO dry ice cold traps, to prevent pump damage). The obtained thick greenish residue was treated with ice/ice water slush (about 150mL) and stirred at RT for 30 min, then placed on ice bath and continued for additional 30 min. The precipitated crude product was collected by filtration, washed with ice water and dried on highvac. This crude material (a gray powder, 12.788g) was dissolved in dichloromethane, applied onto a column of silica (150g) in dichloromethane and eluted with straight dichloromethane. The purified product (12.45g of a light-tan sticky solid) was re-crystallized from a small volume of hexane. The crystals were rinsed with ice-cold hexane and dried on highvac. Y=10.915g (84%) of a yellowish heavy crystalline solid.

1H(CDCl3, 400MHz): 8.851(s, 1H); 13C(CDCl3, 100MHz): 167.14, 165.35, 160.11, 93.21

This procedure is a modification of a prep published in Collections of Czech Chemical Society 29 (1964) 121-9 . The  procedure was succesfully performed on 50g scale, twice (with average Y=83%)

The starting material is a known mutagen, the product is an irritant. Avoid skin contact. POCl3 is a very nasty irritant/lung-edema choking agent and it also happens to reacts with ice /water in an unpredictable manner (it sits and waits until the water warms up. That’s when the runaway suddenly happens.) POCl3 waste is best quenched by pouring it slowly into a diluted aqueous NaOH at room temperature.

12 Comments »

  1. Thanks Milkshake for putting this site together. I’ve appreciated your comments on other blogs, and I think your practical comments and hints to go along with your preps are very informative. Keep up the good work!

    Comment by Canuck Chemist — October 2, 2006 @ 12:33 pm

  2. Second that comment on phosphorus oxychloride. I’ve seen several hood volcanos from large-scale quenches of the stuff. You’d think it would just go ahead and react with water, but no, it’ll sit there for a few hours until it finally realizes that it’s wet. Then it all happens at once.

    Comment by Derek Lowe — October 2, 2006 @ 2:06 pm

  3. My remark about the two 50g scale-ups performed with the same great yield failed to mention explicitly my mishap with the POCl3 distilled out of these reactions. I dumped this waste POCl3 (all 400mL of it) into a big bucket of ice and I closed the hood only half-way. I went out for lunch and fortunately nobody else was around when the volcano erupted. When I returned, the POCl3 was everywhere, floor, walls, air – a complete Ypres battlefield in there. I put on a gas mask and gloves, made a bucket of methanol/ammonia mix and decontaminated everything. The emergency response guys cought up with me just when I was finishing. I got a stern talking-to for cleaning up my mess on my own (and using the mask without being trained) but it was worth it – they would have shut the whole chemistry floor and they would have probably sent some spacesuit men in there and filed a 12-page accident report about it, they would institute a bunch of new rules, and talk about this mishap at every anual safety training.

    Comment by milkshake — October 2, 2006 @ 2:19 pm

  4. Looks like youre working on some kind of kinase inhibitors… I’m guessing Syk, Jak or Aurora kinase. Am I close?

    Comment by Ryan K. — October 2, 2006 @ 3:40 pm

  5. We are not even allowed to hint🙂
    There have been some kinase projects in there alright but the posted experimentals have been dredged out from a sludge of current and old projects – about twelve of them together (some going back more than 10 years) . Good luck to anyone hoping to guess targets or SAR info from such a mix. Experimentals for the intermediates and reagents is the only scoop you will ever get here.

    Comment by milkshake — October 2, 2006 @ 3:58 pm

  6. I third the comment regarding POCl3, I personally have washed the inside of a hood more that once by quenching POCl3. It is so good at chlorinations though… especiall of pyrimidines and pyridines, which I have done more than my fair share of🙂

    Comment by milo — October 2, 2006 @ 4:20 pm

  7. I like.

    Any hints on the selective reactivity of the dichloro-product?

    Comment by kinasepro — October 2, 2006 @ 11:52 pm

  8. The substitution with amines goes preferentialy to the 4-position. Usualy about 10:1 ratio of regioisomers. (It does not hurt to pre-cool the starting material solution and add the amine very slowly – the first Cl-displacement happens quite readily.) Since these pyrimidines are pretty crystalline, it is easy to get rid of the minor regioisomers in one recrystallization.
    The corresponding 2,4-diCl-5-Br pyrimidine is avilable from Aldrich – in the future I may post some procedures on analogs starting from this bromo di-Cl precursor.
    The only reason for messing with iodouracil was that I hoped the Pd-catalyzed couplings would go better on the iodo compounds – but quite the opposite turned out to be true so I continued with bromo-compounds and shelved the iodo series soon after scaling up all this starting material.

    Comment by milkshake — October 3, 2006 @ 12:07 am

  9. Any idea about why this selectivity for 4-position? I have been searching a lot and could not find an answer. Most people think that it is the 2-position that is more reactive, being flanked by two nitrogens.

    Comment by Joe — July 17, 2008 @ 11:19 pm

  10. I don’t have an explanation, I made the same error when I set out to do 2,4-diaminopyrimidine chemistry few years ago – I even found lit references in Beilstein, with the wrongly-asigned regiochemistry (I was lazy and did not search for the other isomer). It took me two weeks and three more steps to realise I had made the incorrect regioisomer….

    I noticed the same holds true for 2,4-dihalopyridines. One can displace the halogen in 4-position with a good selectivity, both in Pd-catalysed reactions and a simple noncatalysed aromatic nucleophilic substitution. But there were examples of Ullman-like reactions where the copper catalyst reversed the selectivity, with a substituted 2,4-di-Cl pyridine and phenol (as a nucleophile) and a base, and then it went predominantly into the 2-position.

    Comment by milkshake — July 18, 2008 @ 6:53 am

  11. The key to safe destruction of POCl is to just add a bit at a time to your quench pot which is half-filled with warm water. Wait for the rxn to subside before tipping in the next bit.

    That way there is never more than 10 – 20ml POCl in your quench pot at any one time.

    I regularly destroy ~100ml of POCl this way.

    Comment by ben — January 3, 2012 @ 11:01 am

  12. Thanks for this page, about to start working with POCl3 for the first time and this has been the most helpful thing I’ve found yet with regards to safe quenching of POCl3. Cheers!

    R.

    Comment by RAJ — December 1, 2013 @ 1:09 pm


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