Org Prep Daily

July 1, 2008


Filed under: procedures — milkshake @ 10:54 pm

A 2L round flask equipped with a large egg-shaped stirbar was flushed with a stream of Ar. Solid LiBr 0.96g (11mmol) was added, followed by anhydrous THF 0.5L and diisopropyl amine 17mL (120 mmol). The obtained solution was cooled to 0C, BuLi 2.5M solution 44mL (110 mmol) was added by syringe over 10min, the mixture was stirred for additional 5 min and the ice bath was then replaced with a dry ice/acetone bath. Meanwhile, 2-bromo-5-cyanopyridine 19.838g (108.4 mmol) was dissolved under Ar in anh THF 0.25L and the solution was cooled to 0C. Using a wide canula, the ice-cooled solution of the cyanopyridine was transferred into the LDA solution at -78C, along the flask wall and with vigorous stirring, over a 10 min period (the flask and the cannula was rinsed with additional anh THF, 2x15mL). After complete addition the reaction mixture was gently swirled by hand – to wash down any crystals of the cyanopyridine on the flask wall above the reaction mixture. The mixture was then stirred for additional 15 min at -78C. Iodine 30.5g (120 mmol) solution in anh. THF 220mL pre-cooled on ice bath was added rapidly (4 min, along the flask wall), the reaction mixture was stirred at -78C for additional 30 min, the cooling bath was then removed and the flask was allowed to warm up close to the ambient temperature (over approx 1 hour interval). Without any quench, the reaction mixture was concentrated on rotovap from a 25C bath. A solution of sodium metabisulfite 35g in water 250mL was carefully combined with saturated bicarbonate solution 550mL (CO2 effervescence!) and this combined solution was then added to the oily evaporation residue. The resulting slurry was stirred vigorously for 30 min, the precipitated product was then collected by filtration, washed with copious quantity of water and dried by suction. The obtained crude product was suspended in methanol 1L and the mixture was refluxed for 30 min. Activated charcoal 4g was added (carefully) and the mix was refluxed for additional 10 min, then filtered while warm. The charcoal was washed with some additional refluxing methanol, 100mL. The combined filtrates were placed in a fridge at 0C overnight. The crystallised product (tan prisms, 19.434g, 99% pure by HPLC) was collected by filtration, washed with chilled methanol (100mL) and dried by suction and on highvac. The supernatants were evaporated and the residue was re-crystallised from methanol 0.3L (re-dissolved at reflux, then placed in a freezer at -20C overnight), to yield the second, dark brown-colored crop 5.920g (95% pure by HPLC). The combined yield was 25.354g (75.5% th).

1H(d6-DMSO, 400MHz): 8.752(d, 0.3Hz, 1H); 8.495(d, 0.3Hz, 1H)

Note: One should use 1:1 LDA/substrate ratio and keep the lithiation time short. Exceeding the LDA stoechiometry encourages formation of non-polar impurities that are rather difficult to remove. Also, the starting cyanopyridine has tendency to fall out of the THF solution at low temperature – so it is important to wash down any crystals stuck on the flask walls above the reaction mix.

Credit: I am grateful to my colleague Par who found that this substrate lithiates with LDA into the 4-position.


  1. all apologies if this is a stupid question, but what does the LiBr do?
    scale envy! it’s been forever since i’ve had occasion to break out a 2L flask! do you have any secrets for working on tiny scale?

    Comment by Ψ*Ψ — July 1, 2008 @ 11:43 pm

  2. Maybe LiBr does nothing, I don’t really know. A colleague was lithiating 2-Cl-5-CN-pyridine and he got some results based on lit precedent, with Li-TMP 2 equivs but he did not like it much. Then he found out that the 2-Br analog can be done with LDA – but he mentioned once that there still was some isomeric impurity. I couldn’t ask him about his yields/isomeric ratios when I needed to re-synthesize the material recently – he has left, and his notebook entries are less than detailed. The Schlosser group used LiBr 10 mol% as an additive for LDA lithiation of 5-CF3-2-Cl pyridine, to improve the regioselectivty so I used it too – and it worked quite cleanly, I have not seen any isomeric mono-iodo. But I never did the control experiment without LiBr.

    Comment by milkshake — July 1, 2008 @ 11:58 pm

  3. If I recall correctly LiBr can be added to breakup any BuLi/LDA oligomers that are present, thus increasing the overall basicity of the reagent. Another possibility is that the pyridine forms a cluster around a Li+, leaving only the 4 position open to deprotonation (the H on C2 is also acidic)… pyridines are fun and weird.

    Comment by milo — July 2, 2008 @ 7:03 am

  4. LiBr acutally stabilizes LDA by further favoring dimerization. It is more likely that here, it assists in chelating pyridine, as Milo said.

    Or rather that it isn’t doing anything at all.

    Comment by Gus Musselmann — July 2, 2008 @ 12:33 pm

  5. OK, thread hijack… Is there a way I can make ‘fuming sulfuric acid’ out of good ‘ole 98% H2SO4? Again, I live and work on an island, where chemicals take forever to arrive, for they are paddled in on the same canoe that brings food to the Survivor: Singapore outcasts. 🙂

    A colleague told me that fuming nitric acid is made by distilling a 1:1 mixture of HNO3:H2SO4… but what about fuming sulfuric?

    I am following a prep from the 1920s to make 2-nitro-3-hydroxytoluene from meta-cresol, so they bis-sulfonylate, then mono-nitrate, then hydrolyze the hell out of the C-S bonds by dumping H2O into this mixture of acids. However they mention they start with fuming sulfuric acid, then add ordinary ‘concentrated nitric acid’ for the 2nd step. Any suggestions around this will be appreciated.

    I tried using simple conc. H2SO4 and conc. HNO3 and I got 11% conversion…

    Comment by HPCC — July 3, 2008 @ 5:44 am

  6. Unfortunately there is no good way of making fuming sulfuric acid in the lab – you would have to have a source of SO3 and saturate your sulfuric acid it with it – its extremely nasty. I guess you could mix up P2O5 with sulfuric acid but this is terrible. You need to wait for the boat.

    If you want to play around and modify the procedure to get around the oleum long delivery time, you can try to sulfonate your material using a large quantity of conc sulfuric acid and follow the sulfonation progress on NMR – watching for disappearance of aromatic protons, to see if you are getting the bis-sulfonylated product – and then you add KNO3 solid (carefully!), it will generate anhydrous HNO3 in situ so you wont have dilution from water present in HNO3

    You can measure 1H-NMR directly in H2SO4 without lock, it is somewhat tricky to get good shims but people did it. Alternatively you can sample your reaction mix and use a solvent like deuterated methanol or D2O, to get a lock – the aromatic protons will be far away from the big signal heap of protons from the sulfuric acid

    Comment by milkshake — July 3, 2008 @ 3:13 pm

  7. I used to put a sealed capillary of D6 DMSO in my sample. I could lock and not worry about the solvent reacting.

    Comment by milo — July 4, 2008 @ 11:37 am

  8. How do you put the reference to in this case?

    Comment by liquidcarbon — July 11, 2008 @ 5:12 am

  9. you mean the solvent signal as a reference – Why not? Spectra don’t have to be referenced to tetramethylsilane anymore.

    Comment by milkshake — July 11, 2008 @ 6:11 pm

  10. This may sound stupid question, I don’t know the reason for the very fast kinetics for these reactions..Could you please explain



    Comment by marto — July 13, 2008 @ 6:21 pm

  11. Marto, I would tell you the reason – if I knew it… as it is I have no good explanation. I know only the empiric rule that 2,5-dihalo substituted pyridines like to lithiate with LDA into the 4-position quite rapidly but one should not use 2-fluoro starting material because then one obtains mixtures containing 3-sustituted products also. (2-F being more ortho-directing than 2-Cl, 2-Br).

    Maybe you could write a polite e-mail with this question to prof. Schlosser.

    Comment by milkshake — July 14, 2008 @ 2:24 pm

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