Organic synthesis help needed
Posted Nov 30, 2019, 8:53 PM UTC
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What do you need help with? It’s not clear from your post?
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Neither propargyl bromide nor its TMS protected form has given recognizable products. I think the 50% is a statement of hope by OP. The responses don’t carryover to r/Chemhelp, it would helpful to post there.
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I would re-distill propargyl bromide behind the blast shield (it is explosive when neat), from oil bath, at slightly reduced pressure, it does go bad on storage. Typically it is supplied as toluene solution, there is azeotrope with toluene so you end up with some toluene in the product which does not matter (best determined by NMR). Collect the product into Schlenk storage flask and store in a fridge (not freezer). For propargylation, I would also try powdered KOH in benzene or toluene with 18-crown-6, KOH should be basic enough to deprotonate the Me-pyrididine. You can also try tBuOK.
The best way to mill KOH to powder is to use KOH flakes, not pellets (Fisher sells technical KOH flakes) and dry mill them in an old electric blender. (Mortar and pestle method does not work well because KOH is so hygroscopic. )
I should add, propargyl bromide smell is very obnoxious (and it is quite toxic) so be sure not to spill it around
Also, if you try LDA, do not use bottled LDA it goes bad over time in THF, make fresh one from iPr2NH and BuLI in THF at 0C.
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Seconding, I've done propargylation in toluene with 5% aqueous KOH and TBA hydrogen sulfate, worked pretty nicely for me. That's done in one step, so the chance for decomposition may be lower.
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in direct comparison of the two systems - KOH powder + 10mol% of 18-crown-6 in toluene /vs. 50% KOH + phase transfer quaternary ammonium in toluene, the crown ether+ KOH was slightly more powerful. 50% KOH with phase transfer was useful for propargylation of primary alcohols, whereas KOH + 18-crown-6 can do it just as well but also NH -propargylate Boc protected primary amine (in the form RNH-Boc). But he can try both
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If OP's LDA has gone bad from storage I don't think their BuLi is going to have fare much better. I don't think they need to in situ generate LDA. Just titrate what they have over diphenylacetic acid and adjust the volume added accordingly.
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no, your assumption is incorrect. The decomposition rate is solvent dependent. Commercial LDA solutions are suplied in THF or THF -containing mixtures, and THF has limited stability to strong bases. That is why I would not recommend buying commercial LDA or KHMDS solution in THF. In comparison, KHDMS solutions in hydrocarbon like toluene tend to be good (but the best is really to buy solid KHMDS). In comparison, BuLi is supplied in hexane or cycloxehane. It does go bad over time, by elimination to LiH and butene (this forms the slight cloudiness at the bottom of BuLi solution) but this process is very slow at room temp. If you take a titration of BuLi solution bottle in hexane, and repeat few months later, the number will be almost the same. Of course, if your cap septa is bad and you let air in, you will see formation of nBuOLi as a crystalline solid sticking to the glass wall of the flask above the level. Then the titer does not stay good.
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Hello, thanks for your idea. Have you got any procedures I can look up following a similar protocol? I have not used KOH flakes with crown ether before. Also, I have tried also with TMS protected PB so could use that anyway
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TMS on propargyl bromide will not help you because it comes off very rapidly (MeOH, K2CO3, 10 min stir at RT).
KOH should be used as powder. I recommended flakes because their milling in a blender is easier than pellets.
Pocedure: the substrate to be propargylated in benzene or toluene, KOH powder (several equiv) and 18-crown-6 (0.1eq.) stirred at room temp. Propargyl bromide 1.5eq. added dropwise to the slurry. Followed by TLC over the couse of several hours. More propargyl bromide can be added later if the progress stalls, but it is better to avoid a large excess of propargyl bromide.
Also, I recommend that you try tBuOK instead of KOH under the same conditions.
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Also, surely KOH would not be a strong enough base to deprotonate the methyl H (pka around 40) ?
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Why can't you do it the other way around? Form the aryl bromide (Wohl-Ziegler) and the propargyl lithium. Slow add at low T and you're good. Then you don't have to worry about the base screwing with your pyridine (which, given no data at all, is what I think is going wrong with your rxn). If you're intent on doing the alkylation as proposed you can try to use a milder base (Na/KHMDS or KOH) and that should take care of the alpha-metallation problems.
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Yeah I've just tried to do a radical bromination (to then be followed by lithium-halogen exchange) - I am running a column tomorrow to try to isolate the product although the mass spec isn't too promising (I have the peaks I'm looking for but v low intensity and a bunch of other prominent peaks). What do you mean by the alpha-metallation problems exactly?
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Labman I think you should directly alert OP and make the title clearer that it's not you when you cross post these. It's a good idea but I think people get confused and OP doesn't get the extra assistance.
It's pretty clear to me that this post should be here or in r/chemistry, not Chemhelp which is really for homework.