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ARCHIVE:  April 11, 2003


Dear Dr. Shulgin:

I was speculating about synthetic paths to the unknown MMDA-4. Perhaps 2,3-methylenedioxybenzaldehyde could be nitrated at the 4-position, and the nitro group reduced to the amine, and converted via the phenol to the methoxy group. Then the conversion of the aldehyde to the 2-aminopropyl group would follow conventional chemistry. Just musing! What do you think? -- Robert

Dear Robert:

You have reminded me of one of my extreme frustrations from years ago. There are six positional isomers of trimethoxyamphetamine and six positional isomers of MMDA. They are related as follows:

ring positions trimethoxy methoxymethylenedioxy
3,4,5 TMA MMDA
2,4,5 TMA-2 MMDA-2
2,3,4 TMA-3 MMDA-3a (methoxy at 2)
MMDA-3b (methoxy at 4)
2,3,5 TMA-4 MMDA-4
2,3,6 TMA-5 MMDA-5
2,4,6 TMA-6 (impossible)

There are two MMDA's with the 2,3,4-oxygenated pattern in which the methoxy group can be at the 2-position and the methylenedioxy group at the 3,4-position, or the methoxy at the 4-position and the methylenedioxy at the 2,3-position. And with the 2,4,6-pattern, no oxygen atoms are adjacent to one other, so the methylenedioxy group cannot exist.

I synthesized the six TMA's without difficulty and found TMA-2 and TMA-6 to be the most potent and the most interesting. But my efforts to do this with the MMDA's ran into a snag -- I couldn't find a way to make MMDA-4. Nothing worked. I made the other five isomers and found their activity, but I wanted the sixth. To this day, no one has reported it in the chemical literature.

Just to be sure, I just now logged onto the data-base SciScholar which is a searchable site with the last 35 years or so of Chemical Abstracts, and searched for the structure of MMDA-4. To my surprise there were two literature citations for it which I, of course, downloaded immediately. One was to a paper that I had published in 1969 in which I had mentioned it in a table that listed the human activity of some forty compounds, but indicated in a footnote that the synthesis of this specific compound had not yet been completed. The other was to a Federal Register entry of 1970 which announced that, as a positional isomer of MMDA, it was to be listed in the Drug Abuse Control Amendments to the Federal Food, Drug and Cosmetic Act of 1938. With the passage of the Controlled Substances Act in late 1970, these isomers automatically became Schedule I drugs. Thus neither citation indicated that the compound had been ever been made.

Your proposed synthesis sounds quite reasonable. The first compound you mention, 5-nitro-2,3-methylenedioxybenzaldehyde is indeed a known compound having been reported in a Journal of Medicinal Chemistry paper in 1970. But all the subsequent compounds in your scheme are unknown as of the present time. There is a wry touch of sad humor attached to any future successful synthesis of MMDA-4. The moment the last step is completed, the jubilant chemist has, in the eyes of the law, just committed a felony.

-- Dr. Shulgin

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