[Senobim]

Hi,

I have poorly soluble alcohol in DCM, though I need to perform Swern Oxidation on gram scale. Is there any other options, than to make alcohol solution?
I am not sure about reverse addition of oxidasing mixture to alcohol in DCM. Is it possible to add it as a solid?

Thanks in advance!

[pgk]

Is it a highly lipophobic (highly hydrophilic) alcohol or a high molecular weight lipophilic one?
Is it soluble in DMSO?
What are any other functional groups in the molecule that might inhibit DCM solubility?

[Senobim]

It is solluble in MeOH, not sure about DMSO though.

[pgk]

Soluble in MeOH probably means either a small hydrophilic molecule or an aminalcohol or even an alcoholammonium salt.
Of course, you cannot use MeOH as a solvent in Swern oxidation. Besides and in terms of polarity, solubility in MeOH means high propabilty of solubilty in DMSO, too.
1). Soluble in DMSO: Add more amount of DMSO (say twice or triple and more), together with the equimolar amount of oxalyl chloride.
2). Aminalcohol and ammonium salt: There are specific Swern reagents that are (tosylate) surfactants (as well as highly lipophilic Swern reagents for high molecular weight lipophilic alcohols).
Please, indicatively see “recent literature” in the link, bellow:
http://www.organic-chemistry.org/namedreactions/swern-oxidation.shtm

[Senobim]

so in principal i could make an alcohol solution in DMSO and add it to oxidasing mixture (oxalyl chloride + DMSO in DCM at -78)?

[pgk]

You can try. But in principal, you need the equimolar amount of oxalyl chloride per DMSO mole, otherwise the excess of DMSO might destroy the intermediate suffonium salt and lead to low yields. Besides, the excess of reagents accelerates the reaction (kinetic control).

[Senobim]

other option is to add alcohol as a solid, but I am not sure how reaction will proceed, any thoughts about that?

[pgk]

The reaction of a solid in a liquid phase often demands a phase transfer catalyst (solid to liquid). A good phase transfer catalyst for this purpose would be an alkyldimethylsulfoxonium salt, e.g. Butyldimethylsulfoxonium iodide:
BuI + DMSO  → Bu(+)SOMe2, I(-)
But exceptionally, iodide phase transfer catalysts demand an equimolar addition per mole of the reagent and this might complicate the procedure. On the other hand, the preparation of other alkyldimethylsulfoxonium halides, is very difficult.
Try the excess of DMSO/(COCl)2 with a small amount of the alcohol in the minimum amount of DCM, for the beginning and see what they give.

[Senobim]

Problem is I can't prepare a solution of alcohol to transfer it to mixture of oxalyl chloride and DMSO

I can dissolve 200 mg in 30-35 ml of hot DCM, but on gram scale it doesn't work that well.

[pgk]

Try to dissolve in unreacted DMSO/(COCl2) and then transfer to the active mixture of oxalyl chloride and DMSO. It might work.

[Senobim]

what do you mean unreacted DMSO/(COCL)2?

[pgk]

Dissolve in DMSO (if possible) and add the equimolar COCl2.

[Senobim]

Thanks man, i'll try it on mondey and I will post a results!

[Dan]

I've run Swerns with a significant excess (2-3 fold) of DMSO compared with (COCl)₂ before and they worked fine, so I doubt using DMSO as a cosolvent will be a problem.

A practical tip though: Adding a DMSO solution to a vessel at -78 °C tends to end up with a needle blocked with frozen DMSO, which is a total hassle. I recommend adding your alcohol in a DMSO/DCM mixture - the DCM is basically an antifreeze here, 20% DCM content should be enough to keep your needle clear during the addition.

THF can also be used for Swern oxidations. By analogy, I guess (but have not checked the lit.) that you could also use 1,4-dioxane or 1,2-dimethoxyethane. If any of those solvents will dissolve your starting material, they might be worth considering.

[pgk]

Ethers and other oxygen containing solvents might be competitive, regarding the alcohol attack to the reactive intermediate.
Of course, all above are simple thoughts. Chemistry is an experimental science and therefore, everything must be tested and verified on the bench. The essential information is that Swern oxidation works fine, with excess of DMSO (many thanks).