DMMDA

The mechanism behind DMMDA's hallucinogenic effects has not been specifically established, however Shulgin describes that a 75 milligram dose of DMMDA is equivalent to a 75–100 microgram dose of LSD. LSD is a known 5-HT_2A partial agonist.[1] DMMDA also has an affinity for the 5-HT_2A receptor in the human brain.[2] Because similar chemicals, such as MDA and MMDA, act as agonists on the 5-HT_2A, it is likely that DMMDA also acts as an agonist of the 5-HT_2A receptor.[3][4] This may suggest that the hallucinogenic effects of DMMDA result from its agonism of the 5-HT_2A receptor in the human brain. DMMDA also has lower affinities for other serotonin receptors, such as the 5-HT_2B, 5-HT_2C and 5-HT_1B receptor as well as serotonin, dopamine and norepinephrine transporters, which may contribute to DMMDA's psychoactive effects.[2] DMMDA-2's and DMMDA-3’s affinities for the 5-HT_2A receptor are almost the same as DMMDA’s.[5][6] The as of yet unnamed 4,5-dimethoxy-2,3-methylenedioxyamphetamine's affinity for the 5-HT_2A is slighly lower than DMMDA's; the affinity for the receptor stands at around 70% that of DMMDA.[7][2] The two as of yet unnamed remaining isomers of DMMDA are 4,6-dimethoxy-2,3-methylenedioxyamphetamine and 5,6-dimethoxy-2,3-methylenedioxyamphetamine, which both have an affinity for the 5-HT_2A receptor of around 65-70% that of DMMDA.[8][9]

Shulgin explains in his book that DMMDA has 6 isomers similar to TMA.[1] DMMDA-2 is the only other isomer that has been synthesized as of yet. DMMDA-3 could be made from exalatacin (1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene). Exalatacin can be found in the essential oil of both Crowea exalata and Crowea angustifolia var. angustifolia.[10] In other words, exalatacin is an isomer of both apiole and dillapiole, which can be used to make DMMDA and DMMDA-2 respectively. Exalatacin is almost identical to apiole and dillapiole, but differs from them in its positioning of its methoxy groups, which are in the 2 and 6 positions.[10] Additionally, yet another isomer of DMMDA could be made from pseudo-dillapiole or 4,5-dimethoxy-2,3-methylenedioxyallylbenzene.[11]

Precursors in the synthesis of DMMDA and analogs

Shulgin describes the synthesis of DMMDA from apiole in his book PiHKAL.[1] Apiole is subjected to an isomerization reaction to yield isoapiole by adding to solution of ethanolic potassium hydroxide and holding the solution at a steam bath.[1] The isoapiole is then nitrated to 2-nitro-isoapiole or 1-(2,3-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by adding it to a stirred solution of acetone and pyridine at ice-bath temperatures and treating the solution with tetranitromethane. The pyridine acts as a catalyst in this reaction.[1] The 2-nitro-isoapiole is finally reduced to freebase DMMDA by adding it to a well-stirred and refluxing suspension of diethylether and lithium aluminium hydride under an inert atmosphere (e.g. helium).[1] Finally, the freebase DMMDA converted into its hydrochloride salt.[1]

Shulgin's synthesis of DMMDA is reasonably unsafe, since it involves the use of tetranitromethane, which is toxic, carcinogenic and prone to detonating.[12] DMMDA can be made from apiole via other safer methods. Among other methods, DMMDA can be synthesize from apiole via the intermediate chemical 2,5-dimethoxy-3,4-methylenedioxyphenylpropan-2-one or DMMDP2P in the same manner as MDA is made from safrole. DMMDP2P can be made from apiole via a Wacker oxidation with benzoquinone. DMMDP2P can be alternatively made by subjecting apiole to an isomerisation reaction to yield isoapiole followed by a Peracid oxidation and finally a hydrolytic dehydration.[13] Then the DMMDP2P can then be subjected to a reductive amination with a source of nitrogen, such as ammonium chloride, and a reducing agent, such as sodium cyanoborohydride or an amalgam of mercury and aluminium, to yield freebase DMMDA.[14]

• 
  Alexander Shulgin's synthesis of DMMDA.