I have been trying to perform what seems like a simple alkylation.
The reaction never proceeds cleanly, and although it's a simple column, yields are never above 35%.
I've tried all kinds of conditions to achieve higher yields and a cleaner reaction.
I decided to go for the big guns, and crack out the NaH for a Williamson style etherification.
Here's the bit I didn't think through. My starting material contains an azide, and although I tried to check the stability of azides to hydride, I didn't think about the by-product - hydrogen!
I couldn't find much evidence around azides and hydride, other than one or two procedures, so I figured if others had used hydride in the presence of azides it would be fine.
So I went and dissolved my material in DMF, and added the NaH, and then I froze, eyes wide, as the effervescence took hold.
There were plenty of bubbles of hydrogen, and I was, at first, a little worried.
Once hydrogen evolution had ceased, I did a quick mass spec. No evidence of azide reduction whatsoever. All I saw was the alkoxide (or sodiated starting material!). Either way no evidence of an amine, sodiated or otherwise.
It was only one equivalent of hydrogen, in a solvent that I assume doesn't dissolve it that well, without any catalyst, I don't know what I was really worried about.
Still wasn't that clean though...
First, NaH in combination with DMF is dangerous and prone to runaway exotherm decomposition on larger scale. It must not be heated - the runaway starts at about 40C. Using a cooling bath when working on scale or replace DMF with DMAc.
ReplyDeleteSecond, KH is superior to NaH for Williamson if used in THF in combination with 18-crown-6 (before use with KH, the crown needs to be pre-dried by azeotropic evaporation with toluene at reduced pressure, followed by drying on highvac overnight). KH in paraffin wax (50%, Aldrich) is much easier to handle than KH in mineral oil (30%, Aldrich) because the oil suspension settles. Since a naked KH solid is highly pyrophoric do not try to remove the wax (or oil) by washing- use it as is. Make sure you quench the reaction thoroughly at the end - KH-containing solids would burst in flame when washing the glassware.
Third, azide is a pseudo-halogen and works as a leaving group too. If you have beta hydrogens to the azide available, heating your azide with a strong base like KOtBu or KH can cause azide elimination to C=C.
Fourth, even with the beta carbon position blocked, I recently found that azide does get slowly reduced with an excess of KH+crown.
I have an alternative proposal: I presume that you have a azido-containing primary alcohol that you are trying to alkylate on oxygen. I suggest that you buy KOH 85% flakes technical product from Fisher and dry-mill it in a blender to get powdered KOH (very hygroscopic. The blender aluminum surfaces get corroded. Use a blender with glass reservoir. Flakes are easier to mill than the common lentil-shaped KOH pellets - thats why the recommendation for using the particular Fisher brand). Store in tight bottle.
For alkylation, use 10 equiv of powdered 85% KOH slurry in benzene with your alcohol in the presence of 18-crown-6 (10 mol% works but 25 mol% crown works better, the used crown does not need to be dried in this case and can be take straight out of bottle) and then add 3-5 equivalents of alkyl bromide into the mix. Stirring in a closed flask overnight does it in most cases.(This alkylation with crown can be performed in anh THF or THF-toluene mixture as a solvent also but benzene gives slightly better results so use benzene if your product is soluble in it)
Fabulous.
ReplyDeleteI'll give that a go.
I was only on a tiny scale, so I wasn't that worried, I am aware of NaH and DMF on large scales, I opt for THF then.
Would this alkylation procedure applicable to other substrates such as sulfonamides?
I am looking to optimise alkylation on a Nosyl amide to apply at larger (50-80 mmol) scales and don't want to use DMF, purely because of removing that much DMF, although possible, will take some time. Plus, some of the materials involved are expensive and time consuming to make, and I'd like it to be reliable and reasonably high yielding.
Sulfonamdes should be even easier to alkylate because of their high acidity. The only question is the stability of Nosyl group. For sulfonamides, I would maybe try to use K2CO3 at first, maybe in acetonitrile as a solvent
ReplyDeleteI've been using pot carb in DMF, I've found it slightly better in DMF over acetonitrile. Maybe increase the equivalents of base from 4 to 10 in acetonitrile, and add a touch of crown ether?
ReplyDeleteThat would do it. Or using Cs2CO3 in MeCN without a crown. (There are differences in grades of Cs2CO3 - surface area and water content - that affect the reproducibility. Sometimes a little water present in Cs2CO3 makes things work better, and Aldrich Cs2CO3 for some people worked better than Acros material. And so on. ) DMF is not so bad a solvent - with some effort (putting good seals and vacuum meter on rotovap combined with a good pump) you can evaporate it under mild enough condition and partitioning the residue between ether-water takes good care of the leftover traces of DMF in the residue. My only complaint with DMF is that TLC-monitoring the reaction is harder (unless you work up an aliquote) and it can contain Me2NH impurity depending on how it was dried and stored (it is sunlight-sensitive) ; fishy-smelling DMF should be avoided. Pure DMF has only aweak greasy and slightly grain-like smell free of fishy overtones.
ReplyDeleteDMF is great, and we have a diaphragm pump set up to a rotovap that pumps to 1 mbar, which gets rid of most of it, followed by ether extraction, although there is a shortage in the UK because of some kind of plant malfunction, Fisher is dry, and everywhere else is short, so we're trying not to use it until Fisher are back running. I include a LiCl wash as well.
ReplyDeleteI like to distill my own and use that regardless of whether it needs to be dry or not, as it usually keeps for bit longer.
Thanks milkshake.