Author Topic: Hofman Alkylation  (Read 1010 times)

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xeno_tropic

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Hofman Alkylation
« on: July 18, 2003, 09:54:00 PM »
I believe "Hofman Alkylation" is the proper term for what I am going to describe.
I always thought reductions in the manufacture of amphetamines were a bit silly.
I mean, ephedrine or pseudoephedrine can be had, however, allyl or propenyl benzenes are plentiful and cheap.
I can't recall the Markovnikov rule right off the top of my head, I think it goes that the halide goes to the carbon with the most hydrogens. Why not convert the phenylalkene to a phenylalkyl halide with HX, then alkylate N-methylacetamide (would the alkyl group be more likely to alkylate the nitrogen or the keto-oxygen?), removing the acetyl group afterwards, or not (would it make a difference? I know N-acetyl tyrosine is more potent in it's effects than non-acetyl).
Or, the Gabriel synthesis. The phenylalkyl halide + potassium phthalimide in dry alcohol. On this one, I know hydrazine is dangerous, would arginine work to de-phthalate the product, or, again, would it make a difference except in weight/potency? Would calcium or sodium (or potassium) remove the acyl group?
Substituted allyl/propenyl benzenes are present in essential oils, thus are highly available.
 What was the final word, btw, on the Delepine reaction. I've heard yes, no, it only works on this or that.
James

Rhodium

  • Guest
Novel (discarded) amphetamine syntheses
« Reply #1 on: July 19, 2003, 04:12:00 AM »
Essentially every route you describe above has been tried (both in the literature and by The Hive Collective), and they have all been abandoned due to unworkability and/or low yields. Sorry. Unless you have any revolutionary references to show, it seems to me that the topic is pretty dead.

For example, the alkylation of acetamide with phenethylbromide followed by hydrolysis to Phenethylamine has been published in J. Am. Chem. Soc. 48, 2175 (1926). In the alkylation step, the phenethyl-acetamide was formed in only 40% yield, and after that the hydrolysis gave 80-90%, making the yield only 32-36% overall. Also, if applied to a phenyl-2-bromopropane as you suggest, the halide is secondary, and due to sterical hindrance and higher susceptibility to elimination, the yield is likely to be even lower. Chem.Pharm.Bull. 24, 1992-1999 (1976) improves the yield somewhat by using sodium hydride for deprotonation of the acetamide, and introduces a protection group (allyl) on it to avoid dialkylation of the amide, but then that has to be removed (Pd(OAc)2, Cu(OAc)2, LiCl) and the amide hydrolyzed, and the time, reagent cost and number of steps needed to arrive at the desired product increase so much that the route is even less interesting than the 75-year-old one...

xeno_tropic

  • Guest
Re: Novel (discarded) amphetamine syntheses
« Reply #2 on: July 19, 2003, 12:24:00 PM »
Oh, well, there are always other amines, azetidine, aziridine, etc.
And, sonochemistry, DMAP, etc. to get the yields up.
James

Rhodium

  • Guest
N-alkylaziridines are very toxic
« Reply #3 on: July 20, 2003, 01:38:00 AM »
Aziridine for what? I hope you are referring to the addition of grignard reagents to it to form PEAs, rather than alkyl halide addition to it - N-alkylaziridines are very toxic, and are used in chemotherapy to inhibit cell division.