Org Prep Daily

August 27, 2008


Filed under: procedures — milkshake @ 7:15 pm

 A mixture of anh. acetonitrile 12mL and isopropyl alcohol 1.4mL (18mmol) in a 25mL flask was cooled to 0C and N,N,N’,N’-tetramethylguanidine 1.9 mL (15mmol) was added under Ar, followed by azidotrimethyl silane 2.0 mL (15mmol), dropwise over 5 min – an exothermic reaction. The resulting solution of TMG-azide was warmed up to RT and then transferred by syringe to 2-chloro-4-iodo-5-trifluoromethylpyridine 3.075g (10 mmol) solid. The mixture was stirred under Ar on a 40C bath for 6 hours, then cooled to ambient temperature and portioned between half-saturated NaHCO3 solution 70mL and ether 80mL. The aqueous phase was re-extracted with ether 80mL. The organic extracts were washed with additional half-saturated bicarbonate 70mL, combined, dried with magnesium sulfate and filtered. The obtained solution of crude azidopyridine was placed on ambient water bath, water 1mL was added followed by 1M trimethylphosphine solution in toluene 11mL (11 mmol; exothermic reaction). The mixture was stirred at RT for 30 min, then washed twice with water (2x250mL) to remove Me3PO, the aqueous phases were re-extracted with ether (250mL). The combined extracts were dried (MgSO4) and evaporated. The residue (2.0g) was re-crystallized from cyclohexane 120mL to provide 1.517g of a 95%-pure product as white feathers (77% overal).

1H(d6-DMSO, 400MHz): 8.170(s, 1H), 6.932(br s, 2H), 6.758(s, 1H); 19F(d6-DMSO, 376.5Mhz): -61.93 (s, 3F);

Note: The neat crude monoazido intermediate can be isolated as a colorless oil (and separated from a crystalline side-product, posibly derived from bis-azido pyridine) but 4-pyridylazides are rather unstable and reducing them in diluted state without further purification is a safer alternative. TMS-N3 is skin and gloves-permeable and causes unpleasant acute azide poisoning (= nasty headaches). PMe3 has a pungent, obnoxious odor.   

This procedure uses organic-soluble azide salt. TMG.HN3 can be isolated and stored; it is an extremely-hygroscopic crystalline solid (Org Prep Daily September 25, 2006). The preparation of the starting iodo pyridine was also discussed here, in Strange bits from Schlosser, on June 7, 2008.


  1. I accidentally caught a sniff of something disgusting while doing inventory today. Turned out to be Me3P, being kept in a non-ventilated area.

    Comment by LiqC — August 28, 2008 @ 7:50 am

  2. The neat crude monoazido intermediate can be isolated as a colorless oil Aw, go ahead – scratch to induce crystalliization!

    Comment by Uncle Al — August 28, 2008 @ 1:24 pm

  3. Our safety officer in the previous group used to place 2-3 mg of compound in a tile and heat it with a hammer from a certain distance to check it if it is explosive in nature before we shipped the compounds to our collaborators.

    Comment by pmgb — August 28, 2008 @ 1:48 pm

  4. TMSN3 is toxic and penetrates skin and Me3P has a pungent stench. I would rather used LiHMDS.

    Comment by horks — August 28, 2008 @ 2:47 pm

  5. You cannot use ammonia or amide anion in this case – o-CF3 substituted anilines are sensitive to base, they eliminate HF and form a reactive quinoid that does Diels-Alder with olefins and addition reactions with nucleophiles.

    In this case it is even more sensitive than in case of benzene ring – simple heating with 7M NH3 in methanol in a pressure flask destroys the CF3 – I never figured out what these polar products are, I suppose something derived from cyanopyridine – there was no fluorine in the molecule afterwards…

    Comment by milkshake — August 28, 2008 @ 3:48 pm

  6. I think that u r well experienced in academia and industry after reading ur several articles in this blog. i wonder , why don’t u write ur feeling or i mean the difference/comparision ( merit and demerit) of job in industry and academia(post doc).

    santosh, S. Korea

    Comment by santosh kumar gurung — August 29, 2008 @ 10:38 am

  7. santosh, this is diffcult to answer in general terms because each place is different. Generally the tendency is that companies, especially larger pharma companies, pay better than academia – but sometimes you may have more freedom in academia. Either way, my suggestion is that you try to get into the best, most reputable place because it will look good on your resume when you change your job, and you will make useful contacts there. Unfortunately chemistry is not very secure job nowadays, be prepared to change your employer and place where you live within few years. Best luck!

    Comment by milkshake — August 29, 2008 @ 4:56 pm

  8. Milkshake,

    while you’re talking about trifluoromethylated N-heterocyles…you know any good methods for deprotecting a methyl ether ortho to a CF3?

    Comment by Jim — September 3, 2008 @ 5:12 pm

  9. I would try some acidic conditions – methoxy groups on pyridines are easily cleavable by heating with aqueous HCl. If this does not work you can try HBr (under Ar).

    Then the usual reagents – pyridinium hydrochloride (neat melt at 145-150C) or BBr3 (DCM, 0C). You can also try the LiBr or LiCl reflux in a high-boiling solvent like collidine but I have no experience with the method.

    I woud stay away from basic nucleohiles like thiolate salts.

    Comment by milkshake — September 3, 2008 @ 5:26 pm

  10. Any good hints as to how to clean palladium black off glassware? Thanks!

    Comment by Klug — September 4, 2008 @ 11:17 am

  11. I was using fresh aqua regia to clean NMR tubes from precipitated Pd metal – it worked almost instantly (but it is a vicious mix – gloves, hood, no org solvents, etc.)

    Comment by milkshake — September 4, 2008 @ 11:25 am

  12. Thanks, milkshake.

    Comment by Klug — September 4, 2008 @ 12:56 pm

  13. Klug HNO3 should work well too especially if you heat (old days most labs had steam lines and would blast a short time but heat gun works too)

    Comment by CMC guy — September 5, 2008 @ 3:38 pm

  14. Just save the flask with the Pd Black, and use it for your balloon hydrogenations. 😉

    Comment by Ryan K. — September 8, 2008 @ 4:01 pm

  15. Any suggestions on what is less likely than PtO2 to eat halogen when doing hydrogenation? Thanks.

    Comment by Quinine — September 12, 2008 @ 12:33 am

  16. I have been using Aldrich 5% Pt-C in EtOAc under H2 baloon, to hydrogenate nitro to NH2 in the presence of aryl-Br, Cl and F – but the progress had to be monitored because Pt/H2 will cause de-halogenation when left going for too long.

    If this is still too fast for your application maybe you can pre-wash your Pt-C catalyst with a LiBr or NaBr solution, I remember faintly there was this procedure for desactivating the “hot spots” on a Pt catalyst.

    Comment by milkshake — September 12, 2008 @ 12:54 am

  17. I am reducing a pyrazine ring. I used 10% Pd/C and it wiped off Br very quickly. Will try the LiBr and NaBr wash of the catalyst.

    Comment by Quinine — September 12, 2008 @ 1:15 pm

  18. I would start with 5% Pt on C, if it over-reduces I would then try to modify the catalyst. I think Pd is not a good choice.

    Comment by milkshake — September 12, 2008 @ 1:37 pm

  19. Does anyone have any tips for using Raney Nickel? I can’t find much info online…

    Comment by Ryan K. — September 13, 2008 @ 9:09 pm

  20. I don’t know much more over what is in Org Syn.

    Comment by milkshake — September 14, 2008 @ 5:57 am

  21. I hope nobody has to scale this one up. I have actually sourced commercial qtys of TMSN3. The manufacturer begged me to consider not using it. I relented and lived to try another route.

    Comment by gaussling — November 30, 2008 @ 7:01 pm

  22. Hi MS,

    I prepared HCl salt of heterocycle with cyclopropane moiety.But i find difficulty in removing the Dioxane from the HCl salt (HCl in dioxane was used for the salt generation). i triturated the salt in DCM and eveoprated in Rota..and kept the salt under high vacuum for 2 h. but still the peak appears..Please sugest me any idea for the removal of Dioxane residues.



    Comment by marto — May 19, 2009 @ 9:22 am

  23. unfortunately it may take longer time because of the boiling point, and dioxane has 8 protons and low MW and a sharp peak around 3.5 so very little of it will show up in proton spectra as a strong signal.

    I suppose you can re-dissolve your salt in water and lyophilize the frozen solution but this will take long time – especially on larger scale.

    Maybe a better variant would just be to put the solid salt into a large round flask, add a large egg-shaped stirbar and dry stir the whole damned thing on highvac on a warm oil bath (60C) overnight. Also if you have temperature-controled vacuum oven you can use it instead, with some dry Ar or nitrogen passing slowly through the bleed valve while heating on highvac, thats what process people do to accelerate the drying on a big scale.

    Comment by milkshake — May 19, 2009 @ 11:58 am

  24. Hi MS,

    Thanks very much..

    Comment by marto — May 20, 2009 @ 8:30 am

  25. Hi MS,

    Many thanks for your help..we were able to remove the traces of solvents as suugested by you..

    I would like to do the cyano replacement of 4-(chloromethyl)pyridin-2-amine? Is it possible to do cyanation reaction in presence of free NH2? please suggest me any conditions for this convesrion? If protection needed what PG would be ideal for this reaction?..thanks for the help..


    Comment by marto — June 22, 2009 @ 11:56 pm

  26. I would first put Alloc group on, with allyl chloroformate and K2CO3 1 equiv in water-THF 1:1 at 0C.

    You can cleave Alloc with 20% Et2NH in dichloromethane (or THF) with 1 mol% of Pd(PPh3)4 as a catalyst , its very fast at room temp and the sideproduct is volatile (AllylNEt2)

    Comment by milkshake — June 23, 2009 @ 3:01 pm

  27. Hi MS,

    I am trying to hydrolyze the 6,5,4 alkylpyridine 2,3 dicarbonitrile derivatives selectively

    Basic hydrolysis of dicyano compound under mild conditions gave one compound selectively. Based on our experience with related compounds, 3-cyano hydrolyses slower than 2-cyano. We anticipate 2-cynao hydrolyze to give the corresponding amide derivative whereas 3- cyano is intact in the major product.

    It’s difficult to characterize the two isomers. We had taken 13 C and DEPT for the isomers and also plan for 1 D NOE. Is there any other method we can assign the structure of two isomers conclusively?


    Comment by marto — October 2, 2010 @ 12:56 am

    • I don’t have any NMR expertise. Pyridine 2-carboxamide should have quite different proton spectrum than pyridine 3-carboxamide (because of the NH bond between amide NH2 and pyridine ring nitrogen) – why don’t you look up proton spectra of the two isomers, to see what the NH2 signals are like.

      Also, with some luck you should be able to see a through-space interaction between pyridine CH in the 4 position and the carboxamide NH2 in the 3 postion, in a NOE experiment

      Comment by milkshake — October 2, 2010 @ 3:11 pm

  28. Thanks for the suggestions.

    Comment by marto — October 3, 2010 @ 4:20 am

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