Org Prep Daily

February 18, 2009


Filed under: procedures — milkshake @ 9:45 pm

The aldehyde 800mg (2.565 mmol) slurry in dichloromethane (not anhydrous, 6mL) was placed on ambient water bath, Deoxyfluor 0.80mL (1.7 equiv.) was added in one portion and the mix was stirred under Ar for 150 min, then quenched by addition of few spoons of crushed ice.  The reaction mix was partitioned between ether 120mL and water 120mL, separated and the aqueous phase was re-extracted with ether 120mL. The organic extracts were washed with aqueous sat. NaHCO3 120mL, combined, dried (MgSO4) and evaporated. The crude product was purified on a column of silica (40g) in hexane-dichloromethane 1:1 mix, isocratic. Y=672mg of pearl-shiny white soft flakes. (78.5% th)

1H(d6-DMSO, 400MHz): 8.464 (s, 1H), 8.386(s, 1H), 7.072 (t, 53.5Hz, 1H); 19F(d6-DMSO, 376.5Mhz): -115.74 (d, 53.7 Hz, 1F)

The starting aldehyde preparation was described here on July14 2008.

Note: This kind of reactions is often initiated by one drop of ethanol but here common-grade DCM serves equally well. Deoxyfluor is a more stable alternative of the popular DAST reagent –  and it is just as nasty (HF burns). Gloves, sash down,  larger-scale experiments should be quenched by pouring the mix on ice as the quench is very  exothermic.  The aqueous washings contain HF so one may want to use gloves during the work-up as well.


  1. Nice reaction! That may be useful at some point.

    Comment by psi*psi — February 19, 2009 @ 2:15 am

  2. good ol’ HF.

    users should have access to calcium gluconate gel in case of skin exposure.

    Comment by joel — February 19, 2009 @ 3:33 pm

  3. And welcome back… 🙂
    Is the fluorine coupling with the 1H on the central carbon, or with the other fluorine?

    Comment by Rhenium — February 19, 2009 @ 4:34 pm

  4. yeah its the F-H coupling. When I looked at proton spectra and saw the ginormous triplet 54 Hz apart, it took me few moments to figure out that thing

    Comment by milkshake — February 19, 2009 @ 4:42 pm

  5. Welcome back Milshake!
    We were waiting for new reactions.

    We had to do a fluorination of a ketone with DeoxoFluor. Scale was aroung 100g and it needed heat. We did first pilots in Deoxofluor neat at 80°C using special plastic flasks (very cool ones) ( but reaction was not very reproducible so we diluted it with a bit of THF. We cooked the mixture under reflux for 20h.
    Work-up was best pouring mixture over ice/NaHCO3 (sat sol) mixture and extraction. Yields were around 70-80% after chrom, not bad.

    Comment by vasili — February 20, 2009 @ 2:25 pm

  6. Vasili, I agree ketones need much more severe conditions, and sometimes dimerization can be a problem depending on the ketone – I have had mixed results. I am glad I did not have to do the big scale reactions like you did.

    Comment by milkshake — February 20, 2009 @ 4:08 pm

  7. happy birthday, by the way 😉

    Comment by psi*psi — February 21, 2009 @ 2:09 am

  8. thank you – you are a formidable stalker 🙂

    Comment by milkshake — February 21, 2009 @ 5:33 am

  9. Happy birthday, and nice halogen fiesta. Can you selective coupling reactions with the aryl bromide and iodide?

    Comment by Hap — February 21, 2009 @ 7:41 pm

  10. Yes We Can: In pyridines the 4 position is more activated than the 2 position, and having the iodine there also helps. In this case the main problem was poor stability of the 4-amino-5-difluoromethyl product towards base, the 5-difluoromethyl on 4-aminopyridine is unfortunately pretty reactive and likes to go back to aldehyde. (But I found some mild Buchwald conditions that helped to avoid this complication).

    Comment by milkshake — February 22, 2009 @ 9:12 pm

  11. hi!
    can you comment if it works with formamides!
    and also how does it compare with the oxalyl chloride followed by o-tolyl difluoro toluamide and/or triethylamine.3HF salt(or something likethat) to install the fluoros…
    will be a great help

    Comment by milkshake's favorite indian — February 27, 2009 @ 11:41 pm

  12. I am sorry but I don’t understand completely what you mean, my dear Indian, you need to be more specific.There are several alternative methods how to make difluoromethyl compounds from aldehydes but they tend to be unpleasant and/or harsh. I have personal experience only with oxidative fluorination of a cyclic dithioacetal derived from a o.o-disubstituted benzaldehyde, with NIS and pyridine.9HF if I remember correctly, and I had to work in a plastic vessel and it was a dark disgusting brew that needed serious effort afterwards – to clean it up from all the sulfurous junk, spent reagents and iodine. In this particular case one would look into alternatives only if DAST-like reagent could not do the job.

    Comment by milkshake — February 28, 2009 @ 2:54 am

  13. I was actual trying to make difluoro substituted alkyl amines and I chanced upon a method of making difluoro derivatives through the aldehyde route(the prep you have given
    here).So I tried making these through the formamides.Specifically I tried a patent procedure(I do not hv the reference now)which basically converts formamides to dichloro amines using oxalyl chloride and then substituting the chloros with fluoros using NEt3.3HF.It failed in my hands although my substrate was more hindered.I was judt curious whether the prep you published gere works with form amides.Thanks for the help

    Comment by milkshake's favorite indian — February 28, 2009 @ 10:19 am

  14. I think if one was to convert it into a thioformamide, with Lawesson agent, it would have a better chance, with Deoxyfluor, but I have not done it myself

    Comment by milkshake — March 1, 2009 @ 6:39 pm

  15. Lawesson’s reagent – *shudder*.
    Woollin’s reagent – run, and don’t look back.

    Comment by Jose — March 2, 2009 @ 8:30 pm

  16. I know, the workup makes you socially-impaired – people tend to make rude comments about soap and water when you take the public transport

    Comment by milkshake — March 2, 2009 @ 9:07 pm

  17. Any suggestions on how best to remove most of the DCC and DCU after dehydrating an aldol product with CuCl and DCC in toluene? Does adding water to react with remaining DCC, stir, filter through celite, dry, rotavap and then flash sound OK?

    Comment by Rennip — March 11, 2009 @ 1:38 pm

  18. this sounds perfectly reasonable and I would also add some small amount of acid, like acetic acid to promptly convert all DCC into urea. (DCC without protonation hydrates very slowly – although Cu(+) should accelerate it). After you work-up and isolate your product, if there is still some small amount of urea present, one can dissolve the crude in some ethyl acetate or acetonitrile, let it sit for an hour or so a filter again.

    Comment by milkshake — March 11, 2009 @ 1:56 pm

  19. Rennip- better choice is to swap out the DCC upfront as for some reason the cyclohexylurea seems often unremovable (traces in NMR) even with lots of effort whereas other analogs works as well without out same headaches (diisopropylcarbodiimide in particular had good luck with). Most process chemists employ other transformations all together for safety and costs but if have to do this type coupling DCC is last on the list.

    Comment by CMC Guy — March 11, 2009 @ 4:40 pm

  20. To each his own – as we used to say in Europe. Unless on solid phase, I always preferred DCC and EDC.HCl.

    DIC is now several times more expensive than DCC and the DIC-derived urea typically is to be removed on a column – except that it partially precipitates from many solvents so this is not ideal. What would concern me on scale is the nasty delayed allergies that some people develop on repeated contact with DCC, and the brittle low-melting solid tends to fly around when crushed.

    The urea from DCC is somewhat soluble in DCM and chloroform and DMF, and it dissolves quite well in solvent mixtures containing few % of alcohols or traces of water, TFA etc. So a solvent for DCC-urea removal is best aprotic, non-halogenated. (Although CCl4 works well). I never had difficulty removing it from my product.

    Comment by milkshake — March 11, 2009 @ 5:20 pm

  21. Some suggestion: What about some short article about chromatography using alumina (column and TLC)? I think, not too many people use alumina nowadays and some personal experiences would be nice, especially in comments.

    Comment by Dany — March 12, 2009 @ 8:27 am

  22. I have zero experience with alumina chromatography – but my former advisor swore by alumina chromatography and he said it saved him when he was doing alkaloid synthesis thesis project and had to carry tertiary amine intermediates through several steps.

    My only exposure to alumina was a filtration of methyl iodide for a scale-up project: Aldrich sells a very expensive grade of re-distilled MeI that worked for us fine straight from the bottle, and a cheap grade that did not. The cheap grade had some methanol in it and also CuI particles (from being stabilised with copper shot) that were apparently messing up our lithiations; filtering the cheap stuff through a pad of neutral alumina took care of the problem.

    Comment by milkshake — March 12, 2009 @ 4:03 pm

  23. milkshake does seem strange our DCU/DIU observations are at opposite polls, and guess could reflect the compounds we each dealt with. I do offer correction/addition that somehow did not make it from my brain to fingers as my applications were couplings (amides and esters) rather than the dehydration.

    In grad school we had some alumina prep plates in the lab that on rare occasions people would attempt to use (i.e. after Silica unsuccessful) but typically not that great outcomes (I have heard the same reported outcome regarding alkaloid utility). It did not seem to correlate as the Al-TLCs would show much better separations but the plates poor resolution (suspected high binder ratio hurt performance). Non-sequater: Once we got a Chromatron in the lab a few of us pretty much did most work on that.

    I likewise learned that a good idea to pass R-Xs through Al2O3 which became SOP although can’t remember if was neutral, acidic or basic that was choice.

    Comment by CMC Guy — March 13, 2009 @ 1:34 pm

  24. It is not right to say 1 drop of ethanol, it is actually 0.2 eq of ethanol. Please see JOC, 1999, 64, 7048-7054 for details.

    Comment by ppm — March 22, 2009 @ 11:36 pm

  25. sorry to upset you but in the paper that I saw on various uses of Deoxyfluor, they always used “one drop”. I can dig it out somewhere in the organo-F lit folder but I am too lazy at the moment

    Comment by milkshake — March 23, 2009 @ 1:01 am

  26. I took the H NMR of Deoxo-Fluor (yellow liquid, ALDRICH) and found that it is not pure. Did you distill it before use. I am trying to fluorinate ethyl bromopyruvate but getting a very low yield of product with lot of colored polymeric impurity.

    Comment by ppm — March 26, 2009 @ 2:19 pm

  27. Bromopyruvate may be a difficult substrate, I would definitely look in the literature whether someone has ever published any work on fluorination of pyruvates.

    In your case a better alternative could be to buy BrCF2CO2Et from TCI and try to homologate it by copper or zinc metallation chemistry on the bromine and then quench with an electrophile. Again, you need to look up the literature.

    I took Deoxyfluor straight from the bottle and did not bother with NMR, given how nasty this reagent is. First I used a small, old and long-opened bottle of the reagent, then afterwards a new big bottle from Aldrich, they both worked fine for me. I store the reagent in the freezer.
    I don’t recommend distilling Deoxyfluor – one needs to have extremely high vacuum to make it distill at a resonable temperature, and these reagents are quite heat sensitive. I heard of a guy who had a runaway exothermic decomposition with neat DAST on a large scale – a potentially horrible accident.

    Comment by milkshake — March 26, 2009 @ 5:33 pm

  28. Selectfluor is another (relatively) safer reagent.

    DAST is quite OK, if precautions are taken. I have run the “Fluoro-Pummerer” reaction on decent scales and have gotten good yields. I have also used DAST on fluoroallylic alcohols. Used an excess of DAST, but careful workup prevented accidents.

    Comment by Vinod Jairaj — March 28, 2009 @ 3:16 am

  29. DAST and Deoxyfluor are very similar one to another, the later is more stable so it is recommended for large-scale work and for the reactions run above room temperature.

    Selectfluor is different, it is a very well-behaved non-hygroscopic crystalline salt that does not decompose on storage, and it is a source of positive fluorine, “F+” and it can be used in methanol, even in water.

    Also, I am not sure F- Pummerer would work well with bromopyruvate. I made a dithiane from o,o’-dichlorobenzaldehyde and 1,3-propanedithiol, lithiated it and quenched it with ClCO2Et to get the Aryl-dithiane-ester. Everything worked fine up to that point but when I attempted F-Pummerer with NIS and HF.9py it all went to an awful mess. Then I checked the literature and noticed there were no preceddents for this transformation with carboxyester next to the thioketal. As always, a week of experimentation can save you an hour in the library.

    Comment by milkshake — March 28, 2009 @ 4:18 am

  30. Vinod, hey man where have you have been hiding? Please get on touch man.

    Comment by Jason Tatalovich — May 30, 2009 @ 5:06 am

  31. Hi MS,
    Converted 2-hydroxy substituted pyridine (all other substitutions are alkyl group) into 2-Py -OTf and tried amination with ammonia but the reaction is low yielding. Cynation reaction with Zn(CN)2 was unsuccessful.

    Conversion into corresponding chloro is also low yielding with POCl3/PCl5

    Please suggest me any good leaving group at 2-position that can be accessed from the hydroxy group

    Is it worth converting to N-Oxide and try for amination and cynation so that the reaction could be more yielding and reproducible
    Thanks for the help

    Comment by marto — October 6, 2010 @ 7:58 am

    • I would try your triflate with a Pd- catalyst, and use it both cyanation and amination. For example powdered K4Fe(CN)6 is a good cyanide source, one uses it with 5 mol% of Pd(OAc)2 in DMF at 120C without any phosphine ligand, for cyanation. For Pd-catalyzed amination I would look up papers from Buchwald.

      POCl3 chlorination: I don’t know what is in your molecule, POCl3 will react with many functional groups such as amide but what you can do is to sample your reaction mix and follow the progress of your reaction by NMR, in CDCl3, to see how many products you got in there. POCl3 has no signals to interfere with NMR and the ClPO(OH)2 sideproduct should have only one signal. Also, POCl3 chlorination can be done at lower temperature if you add a base like iPrNEt2 or N,N-dimethylaniline to soak up the generated HCl. An example is here:

      Comment by milkshake — October 6, 2010 @ 8:38 am

  32. Thanks very much for the suggestions.

    Comment by marto — October 7, 2010 @ 1:12 am

    • Hi MS,

      I am struggling to find a synthetic route to ethyl-2-amino-4-bromopyridine-6-carboxylate. This is commercially available but really
      expensive. It would be really helpful if you could suggest some cheaper SM to synthesize this compound. SCifinder/Reaxys search did not
      give any hits for its synthesis.

      Thanks for the help.


      Comment by marto — July 19, 2011 @ 5:53 am

      • sorry i am having problems with lit access at the moment so i cannot really help you

        Comment by milkshake — July 19, 2011 @ 10:29 am

  33. Hi MS,

    I am trying to convert geminal dichloro compound (alpha to ester and methyl) into corresponding difluoride using spray dried KF/different solvents and getting only the mono substituted product.How to drive the reaction into complete substitution?. Your suggestions very much appreciated.



    Comment by marto — September 17, 2012 @ 1:37 pm

    • I have not done it myself but the typical conditions for this kind of reaction are pretty harsh – sulfolane, KF (spray-dried grade from Aldrich, dried on highvac) and 250-300C. Sometimes the low-molecular eight products can be distilled directly out of the reaction mix/

      Can you by any chance use BrCF2CO2Et (commercial, from TCI) and Wurtz-like coupling conditions with stoechiometric activated Cu in DMSO and aryl iodide? – I had good luck with this reaction

      Also, please keep in mind that alpha,alpha-difluoro esters are quite hydrolytically unstable so try to keep pH below 4 and work fast during the aqueous workup

      Comment by milkshake — September 17, 2012 @ 3:18 pm

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