Selective O-demethylation
A mixture of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (3.4 g, 0.009 mol), sodium ethanethiolate (3.8 g, 0.045 mol) in 34 mL DMF was heated at 50 oC for overnight (12 h). The reaction mixture was cooled to rt and diluted with water (100 mL) and ethyl acetate (100 mL). The unreacted starting material was separated by extracting into the organic layer using 2 x 100 mL ethyl acetate. The pH of the aqueous layer was adjusted to pH = 7 by carefully adding 1 mL of saturated aqueous citric acid solution. A oil gets separated which soon becomes a white solid. The solid was filtered off, washed with water, redissolved in dichloromethane, dried over sodium sulfate to give 2-((1-benzylpiperidin-4-yl)methyl)-6-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one as a white solid (2.4 g, 74% yield). NMR complies.
Ref. WO 2008/073452 A1, US 2008/0153878 A1
Why the sealed tube? Convenience, or something more technical? Can you comment on the pretty decent selectivity? This isn’t a test….I really want to know
anniechem
August 22, 2008 at 6:33 pm
ooh tasty reaction – And the selectivity is very nice too. except the smell (Thats why the tube, ethyl mercaptan is far worse than methyl,. t-butyl or benzyl)
milkshake
August 22, 2008 at 6:39 pm
Thanks. I really dont know the reason for selectivity (I guess it has to do something with the carbonyl). I used sealed tube just like that. You are right- it is convenient (looks neat). Yes. Smell is an issue although EtSNa smells lot less than EtSH. Any suggestion how to reverse the selectivity in this perticular reaction?
pmgb
August 22, 2008 at 8:55 pm
I don’t have experience with selective aryl ether demethylation, but I remember that people did selective de-methylation using AlCl3 in solvents like dichloroethane. AlCl3 should enolize your indanone so maybe this could reverse the regioselectivity of the deprotection.
We have been using a liquid complex of Me3N.HCl with 2 equivs of AlCl3, you dry the commercial amine hydrochloride in vacuo on oil bath, cool and then add solid AlCl3 2 equivs (a good, iron-free 99%+ grade) and allow the mix to liquefy (which is very exothermic), then cool, dilute with dichloroethane and allow to settle in a closed bottle from a small amount of sediment. You can use it at 0C, and use an excess of reagent – you will need at least 5 equivs because yo have few basic sites in the molecule.
milkshake
August 23, 2008 at 3:17 pm
Thank you very much.
pmgb
August 23, 2008 at 6:12 pm