Before attempting a simultaneous reduction of both the azido and acetoxy functions of 1-acetoxy-1-(5-indanyl)-2-azidopropane, I decided to test the reduction of 1-acetoxy-2-methylamino-1-phenylbutane to see if the patent worked as described.
This was my first CTH reduction, which may in part explain the yields. But the point is: it
works.
It would be great if someone more experienced could give this a try to see how far we can push the yields. The procedure works beautifully and should tolerate far more functional groups (e.g. aryl ethers) than the over-zealous HI/P reduction.
Experimental1-acetoxy-2-methylamino-1-phenylbutane HCl9.7g (45mmol) 2-methylamino-1-phenyl-1-butanol HCl
15.3ml (56mmol) acetic anhydride
Acetic acid
THF
The aminoalcohol HCl was stirred in 20ml acetic acid at 50
oC to create a uniform slurry. Acetic anhydride was added in one portion and the temperature was increased to 80
oC, by which point the salt had fully dissolved. Stirring was continued at 80-85
o for 2 hours then the still hot solution was diluted with 60ml THF,
2 causing a heavy precipitate to fall out of solution almost immediately. The flask was allowed to cool to room temperature then left in the freezer overnight. The precipitate was isolated by filtration, rinsed with THF and dried under vacuum.
Yield: 9.2g (35.6mmol, 79%)
3Methaephetamine9.2g (35.6mmol) 1-acetoxy-2-methylamino-1-phenylbutane HCl
9.0g (107mmol) potassium formate
250mg 10% Pd/C
Water
DCM
Ether
The O-acetoxy compound from the previous step was stirred with 25ml water at 50
oC until all had dissolved. The catalyst was added and the temperature was increased to 70
oC. A solution of HCOOK in 10ml water was then added over 5 minutes. Gas evolution was noted almost immediately. The reaction was stirred at 70-75
oC for 2 hours then allowed to cool. The solution was basic at this point so concentrated HCl was added to bring the pH down to 1. A small amount of celite was added with stirring, then the slurry was filtered and the filtrate washed with 2x50ml DCM. The filtrate was then made strongly basic with NaOH solution and the liberated freebase taken up in 2x50ml ether. The extracts were washed with 2x50ml brine and dried over magnesium sulfate. Removal of the solvent afforded the title product as a clear, colourless oil.
4Yield: 2.9g (18mmol, 51%)
5Comments and references1 This was the remaining intermediate from
Post 475219
(Kinetic: "Benzene -> methaephetamine", Novel Discourse).
2 The precipitate was very fine and difficult to filter. Heptane is recommended in the patent as the precipitate is granular, making this process easier.
3 Some of the product may well still be in solution at this point. It should be possible to remove the acetic acid and excess acetic anhydride under vacuum instead of adding a further solvent to cause precipitation. Unreacted, N-acetylated, or N,O-diacetylated products should not interfere in the CTH reduction and will be removed during the final workup.
4 100mg of which was bioassayed 1 1/2 hours ago. Warm and fuzzy feelings all round.
5 Migration of the acetyl group to the nitrogen is probably the most significant factor in the low yield for the reduction step. According to
https://www.thevespiary.org/rhodium/Rhodium/pdf/acetylephedrine.pdf
the migration will happen more readily with the
threo- (pseudo) isomer. The starting aminoalcohol in my case appears to be mainly this isomer, whereas the patent deals with the
erythro- isomer, which is less prone to migration.