Ok, the hypochlorite oxidation of paracetamol/acetaminophen gives the hydroquinone and the relevant imine which means we have a seriously OTC route to hydroquinone (for those who dislike / can't afford photochems). Methylation of that via KBr in situ has been detailed over @SM which gives a nice, fairly facile route to 1,4-dimethoxybenzene. N-phthaloylalanine chloride would react with that (using Iron(III) Chloride) to give the cathinone, reduction of which would give DMA. All nice & simple, OTC (although a prick to source RP could theoretically be utilized to chlorinate the N-protected amino acid(s) via PCl5, which maintains the OTC'ness of the route, but given the compounds in question, matchbooks/boxes could be realistically utilized).
Now the procedure for DOC (PiHKaL#64) leaves something to be desired in terms of yield, and purity of the end-product (nb. see here), so various researchers have come up with ways to nitrate the DMA and then utilize the Sandmeyer Reaction to prepare the 4-chloro-2,5-dimethoxyamphetamine in lower yields, but with much improved purity.
The generally known papers all use protection and deprotection of the amine (thus losing yield, even just mechanically). So I was suprised to find this gem (Richard A. Glennon, Richard Young, Fredrick Benington and Richard D. Morin, Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane, J. Med. Chem. 1982, 25(10)m pp.1163-1168 - attached), the following excerpt is from page 6/6 (or page 1168 of the journal):
(R)-(-)-l-(2,5-Dimethoxy-4-nitrophenyl)-2-aminopropane Hydrochloride [(-)-9].
To an aqueous solution of 10 g (0.043 mol) of (R)-(-)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride was added an excess of 5N NaOH. The liberated free base was taken up in C6H6-Et20, dried (anhydrous MgSO4), and filtered. Removal of the solvents in vacuo yielded a colorless oil, which was dissolved in 40 mL of HOAc. This solution was added dropwise during 0.5 h to 43 mL of 50% HN03 (d 1.13), and the mixture was stirred and kept at 0-5'C. The resulting clear solution was poured over ice, made alkaline with 50% NaOH, and extracted with C6H6-Et20. Evaporation of the solvent gave a residue, which was dissolved in dilute HCl, and this solution was evaporated in vacuo to a nearly colorless solid residue. Recrystallization from EtOH-EhO gave 10.5 g (88%) of product: mp 231-232'c dec; [.]23D -12.5" (H,O). Anal. (C11H17ClN204) C, H, C1, N. We prepared the racemic (+/-)-9 by direct nitration of (+/-)-1, using the above method, mp (HC1 salt) 207-209'C (lit. mp 203-204'C).
That 88% yield looks tasty, given that the only additional requirement would be the Sandmeyer Reaction step(s)
If the Sandmeyer reaction can be improved,* then it should be possible to attain the end-product (DOC/DOB) in better yields than in PiKHaL, with much improved chemical purity. Actually, if the Sandmeyer Reaction procedure given by the translation (above, op cit) of the German Research can be believed, then a 75.5% yield can be had from the process (which WOULD give better chemical yields than the PiHKaL entry, especially for DOC).
* Also I have located the following (cited by Rhodium), Ronald T. Coutts and Jerry L. Malicky, The Synthesis of Some Analogs of the Hallucinogen l-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM) Can. J. Chem. 1973, pp.1402-1409, which article utilizes the Sandmeyer reaction (albeit going through the N-Acyl amphetamine to affect nitration) to give DOB in decent yields.
PS I have attached the relevant papers so if the links die, the post still makes sense (well, to the extent that that is possible
)
Now the procedure for DOC (PiHKaL#64) leaves something to be desired in terms of yield, and purity of the end-product (nb. see here), so various researchers have come up with ways to nitrate the DMA and then utilize the Sandmeyer Reaction to prepare the 4-chloro-2,5-dimethoxyamphetamine in lower yields, but with much improved purity.
The generally known papers all use protection and deprotection of the amine (thus losing yield, even just mechanically). So I was suprised to find this gem (Richard A. Glennon, Richard Young, Fredrick Benington and Richard D. Morin, Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane, J. Med. Chem. 1982, 25(10)m pp.1163-1168 - attached), the following excerpt is from page 6/6 (or page 1168 of the journal):
(R)-(-)-l-(2,5-Dimethoxy-4-nitrophenyl)-2-aminopropane Hydrochloride [(-)-9].
To an aqueous solution of 10 g (0.043 mol) of (R)-(-)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride was added an excess of 5N NaOH. The liberated free base was taken up in C6H6-Et20, dried (anhydrous MgSO4), and filtered. Removal of the solvents in vacuo yielded a colorless oil, which was dissolved in 40 mL of HOAc. This solution was added dropwise during 0.5 h to 43 mL of 50% HN03 (d 1.13), and the mixture was stirred and kept at 0-5'C. The resulting clear solution was poured over ice, made alkaline with 50% NaOH, and extracted with C6H6-Et20. Evaporation of the solvent gave a residue, which was dissolved in dilute HCl, and this solution was evaporated in vacuo to a nearly colorless solid residue. Recrystallization from EtOH-EhO gave 10.5 g (88%) of product: mp 231-232'c dec; [.]23D -12.5" (H,O). Anal. (C11H17ClN204) C, H, C1, N. We prepared the racemic (+/-)-9 by direct nitration of (+/-)-1, using the above method, mp (HC1 salt) 207-209'C (lit. mp 203-204'C).
That 88% yield looks tasty, given that the only additional requirement would be the Sandmeyer Reaction step(s)
If the Sandmeyer reaction can be improved,* then it should be possible to attain the end-product (DOC/DOB) in better yields than in PiKHaL, with much improved chemical purity. Actually, if the Sandmeyer Reaction procedure given by the translation (above, op cit) of the German Research can be believed, then a 75.5% yield can be had from the process (which WOULD give better chemical yields than the PiHKaL entry, especially for DOC).
* Also I have located the following (cited by Rhodium), Ronald T. Coutts and Jerry L. Malicky, The Synthesis of Some Analogs of the Hallucinogen l-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM) Can. J. Chem. 1973, pp.1402-1409, which article utilizes the Sandmeyer reaction (albeit going through the N-Acyl amphetamine to affect nitration) to give DOB in decent yields.
PS I have attached the relevant papers so if the links die, the post still makes sense (well, to the extent that that is possible
)
Glennon.etal.Behavioral.Properties.4X.DOM.pdf
The yield from that finalhalogenation really is dismal - would be great to have a higher yiellding alternative, must be looked into...