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Amphetamine from benzaldehyde and MEK

Amphetamine from benzaldehyde and MEK

  1. Nootropic
    On the search for a new synthesis route to amphetamines, swin was targeting alpha-methylhydrocinnamic amide as intermediate, from where it is just one more step. In the beginning, he thought about an aldol condensation with benzaldehyde and n-propanal, to give a-methylcinnamaldehyde, which could be hydrated to a-methylhydrocinnamaldehyde, a perfect precursor for beckmann rearrangement and subsequent hoffmann degradation. But then, he stepped on the books of Otto Snow, in particular Amphetamine Syntheses and Love Drugs... - actually swin could not believe that he never heard about them before. Reading Amphetamine Syntheses, he reached the chapter about cinnamic acids, and then he found what he was searching for: the synthesis of methyl-(a-methyl-styryl)-ketone, the product of a crossed aldol condensation between benzaldehyde and methyl-ethyl-ketone, MEK. On This methyl ketone is performed a haloformation reaction with hypochlorite to give a-methyl cinnamic acid, which also needs to be hydrated and converted to the amide. This last step of amide formation was the point why swin decided to go the cinnamic acid route instead of the aldehyde, because the acid is easily aminated by bubbling NH3 through it, where the aldehyde needs hydroxylamine to perform beckmann. The step of the hydration was planned to be carried out as catalytic transfer hydrogenation with Pd/C and ammonium formate as internal hydrogen source.
    Meanwhile, I have finished a writeup for the whole process, which I would like to share with you.