Org Prep Daily

June 7, 2008

Strange bits from Schlosser

Filed under: lit highlights, mechanisms, procedures — milkshake @ 3:10 am

2,5-dihalopyridines lithiate with LDA into the 4 postion quite nicely. With 5-CF3-2-halopyridines the lithiation goes all over and separating the isomers is pain; a colleague found that with LDA in Et2O he can improve the selectivity up to 3:1- which was sufficient for his purposes - so it appears the regioselectivity of lithiation and the isomerisation of the lithiated species is sensitive to the media effect. Now it turns out Schlosser group published a lithiation procedure that uses iPr2NCO2Li – “a carbonated LDA” - together with LDA and LiBr – and with these additives all of sudden the lithiation becomes almost completely 4-selective for the 5-CF3 substrates. We needed the material so the trick came handy - yet I don’t pretend to understand what is actually happening here. And those mysterious isomerisations…

Anyway, if you ever consider this carbamate as a modifier for your lithiations, I found a more practical protocol: rather than spooning out a fairly hygroscopic solid lithium salt from a flask and into the LDA solution as described in the publication, I have been preparing and evaporating the reagent into the flask used for the next lithiation step and then transfering the LDA solution to this solid – in that way I was able to run the lithiations on a 250 mmol scale. (Keeping things dry takes more effort here in Florida).

7 Comments »

  1. Former Wittig guy… Manfred is my hero~

    Comment by kinasepro — June 7, 2008 @ 12:32 pm

  2. Schlosser definitely works on useful things – together with Knochel and Buchwald methodology papers, his research is worth close following.

    On related subject – I noticed that KinasePro is now free-access again. How are your plans for subscription database service coming along? I am mentioning this because we don’t have a person who would follow all the patent literature here at the institute and KinasePro was very helpful – in fact one of the patents that you found gave us an idea for a new project direction.

    Comment by milkshake — June 8, 2008 @ 3:55 am

  3. Just one, huh? That’s too bad.

    Subscription? meh. When I get laid off I’ll kick off a brilliant pro-worthy internet-based med-chem marketing-scheme of-unholy-goodness. Only too bad for the rest of the world I’m just that damn good and it hasn’t happened yet. :P

    Patents? Kinasecentral may suck, but at least it’s being updated.

    Comment by kinasepro — June 9, 2008 @ 11:04 pm

  4. If it makes you feel better, everybody in our group is now working on it – and that’s a pretty sizeable medchem lab.
    Your joke about lay-offs: these spirits that you are invoking cannot be controled (and they don’t give a damn about your merit).

    Comment by milkshake — June 9, 2008 @ 11:26 pm

  5. Hey milkshake
    How bout a post showing your favourite reagent titration methods/references

    Comment by Q — June 18, 2008 @ 9:07 pm

  6. I dont know if it is really worth posting: People here at the institute used cyclooctadiene internal standard additive to measure BuLi concentration by integrating proton signals – a notion I take as faintly ridiculous because one has to be extra careful drying the NMR tube, keeping everything under Ar, then measuring protons without lock in non-deuterated media. And the NMR integration comparison of two unrelated signals is not as accurate (there is always few % absolute error depending on the time allowed between scans). If it does make a difference whether your old bottle of BuLi is 1.6M or 1.45M for exact stoechiometry work, I just wouldn’t trust the NMR-produced numbers.

    And lately I have been quite lazy for LDA solutions – I would either take a new bottle BuLi or if its old I inspect it closely for sediment and color and discard dubious stuff. I would use slight excess of LDA for my work and add little more iPr2NH then needed – and it usually makes a little difference whether I used 1.05 or 1.15 eq of LDA in my reaction.

    But for chemistry that needs exact stoechiometry, few years ago I was titrating my BuLi (and Grignards) using the old phenanthroline method:

    I would oven-dry a vial that fits 14/20 septa (and long enough so that Hamilton syringe needle can reach to the bottom), add a small stirbar and a small amount (about 1 or 2 mg, does not have to be exact) of phenanthroline and flush it with dry N2. Then I would add few mL of anhydrous THF. I would take a glass Hamilton syringe, 1 mL or 0.5mL, rinse it with BuLi to be titrated, then add exact amount (0.5mL for example) of BuLi to the phenanthroline solution at room temp. It instantly turns pink. I would take another small Hamilton syringe, 0.10 mL or 0.050mL (with cemented needle) and wash it with a good quality iPrOH a from freshly-opened bottle (one can use also 2-butanol) and weight the syringe on analytical balance full to the 100uL mark, then again with iPrOH squeezed out, to confirm that 0.100mL is 78.5mg or whatever – depending on your ambient temperature and precision of the Hamilton syringe calibration – and then I would add slowly neat iPrOH to the BuLi solution with phenanthroline in it with stirring against a white sheet of paper, until the pink sharply turns to light yellow. You must be careful not to over-titrate with the alcohol -because then you add another 0.5mL of BuLi (turns pink back) and repeat, then once again. Once you set it up, your 3 or 4 titrations will go pretty quickly (10 minutes altogether).

    The first reading is going to be slightly off – lower in fact because of the BuLi consumed to form the colourful adduct with phenanthroline but the other two or three reading should be very close one to another – so take the average and calculate the concentration from the iPrOH consumption.

    The method works for Grignards also but the color change is not as nice as with BuLi. MeLi titrates nicely just as BuLi. For tBuLi and secBuLi you may want to use ether as a solvent and have it on ice because these react with THF at room temp quite fast.

    (Some people used menthol as a solid alcohol that can be weighted out but then you have to make stock solution or do inverse addition each time in a different vial, etc. I like the multiple titration in the same vial better because it is fairly fool-proof, whatever moisture you got there will be taken care off during the first titration and you can repeat the titration very easily. The most important detail is to not to over-titrate because adding an excess of iPrOH over the color change point would reduce value of your next reading.)

    Comment by milkshake — June 19, 2008 @ 1:23 am

  7. I have been somewhat suspicious of NMR titrations of BuLi, but the phenanthroline one is new to me. When I was in Miami we would use the diphenylacetic acid titration method, but given the humidity I can scarcely believe we accomplished as much lithium acetylide chemistry as we did.

    Comment by Rhenium — June 19, 2008 @ 9:05 pm


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