I'm trying to make a crown-ether-like compound by reaction of an alcohol with a tosylate in an SN2 type reaction. My alcohol is only soluble in the likes of warm DMF, DMSO or Pyridine. I'm guessing DMF would be a good choice because DMSO and Pyridine could act as a nucleophile and I don't want to use the tosylate in much more than a stoichiometric ratio.
I tried the reaction with DMF and NaOH at 100 C, but it looks like the base decomposed my alcohol quite significantly. I'm wondering if there is a milder base I could use that would still sufficiently deprotonate the alcohol in DMF? The alcohol is an ethyl alcohol, not a phenol so I guess it's not especially acidic.
Hi Gary,
You said you have ethyl alcohol , you can use sodium metal to deprotonate your alcohol at about zero degree (ice bath),and also do your reaction at this low temperature.
Regards,
Thanks for those suggestions! I think sodium metal will be too reactive for my compound - especially considering my reaction will have to be performed at higher temperatures in DMF because of it's low solubility (it's not ethyl alcohol, rather an ethyl alcohol substituent on a larger molecule). Triethylamine might be worth a try, but I think it won't be basic enough to deprotonate an alcohol. So I guess something in between those two might be good...?
Tetramethylguanidine is strong enough and have reduced nucleophilicity. Potassium carbonate is also useful base in DMF
I think it's worth trying sodium hydride (maybe 1.5-2 eq) as a base in DMF. It can also act as a reducing agent, however, so you'll have to think about if it will be compatible with the rest of your molecule. Hope you get it working!
Could also try DBU or Cs2CO3 in DMF.
This might also be useful:
http://www.sciencedirect.com/science/article/pii/S0040403999000830
You can try potassium tert-butylate in tert butyl alcohol (1.0 - 1.5 equiv). If DMF is dry, all the primary and secondary alcohols in the solution will be deprotonated completely.
Thanks! I tried DBU, but didn't see the product on MALDI. Potassium tert-butoxide also caused degradation of my substrate. I did use those strong bases in large excess though, so it might be worth trying with just a small excess. I think my alcohol is probably stabilised by possible hydrogen bonding with two neighbouring pyrazine units so maybe more difficult to deprotonate than a usual primary alcohol.
1) solid NaOH (powder) at room temperature in DMF
2) t-BuOK in DMF or DMSO
Perhaps it is a case of kinetic acidity. If it is true, probably it should attempt to increase time of treatment of alcohol with base instead of using of large excess of base.
DMSO+NaH -> dimsyl sodium with Iodide catalysis is used for peralkyllations of sugars. It is a very powerful system if there are no compatibility issues otherwise. (https://en.wikipedia.org/wiki/Sodium_methylsulfinylmethylide)
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