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A hypothetical synthesis of N-Methyl-1-(2,4,5Triisopropoxyphenyl)-1-Propane-2-Amine

( Or N-methyl-2,4,5-triisopropoxy-amphetamine, 2,4,5-triisopropoxy-methamphetamine or TIM-2 ) Starting material is vanillin, a common available compound but very useful for the synthesis of substituted (-methyl)phenylethylamines.
O

O
HO O
MeI/DMS

First is vanillin methylated with MeI/DMS to yield veratraldehyde. Because the OH group is a very strong activator for the Ortho position, and the (created)methoxy group is a more para director(in this case because the aldehyde group makes position 6 slightly positive and the added methoxy group eliminates the positive charge on position 2 that was generated by the aldehyde). This is why brominating of veratraldehyde yields 3,4-dimethoxy-6-bromobenzaldehyde instead of the 5 position as yielded if vanillin was brominated.

O O

O
HBr

O O Br

Next we need to convert de bromine on the 6 position into an hydroxyl/phenol group, by means of reflux with alkali hydroxide and Cu powder as a catalyst. This must be performed in a inert atmosphere because the high reactivity of the phenol group in basic environment (Base deprotonates the phenol to a phenolate ion).

O O Br

O
NaOH/Cu dust

O O

O OH

Now we can cleave the methoxy (ether) group to hydroxyl groups with Pyridine/AlCl3. There are other methods to perform this. This reaction yields 2,4,5-dihydroxybenzaldehyde.
O O
HO

O OH

O OH

Pyridine/AlCl

HO

We can now synthesize the desired triisopropoxy ether by alkylating the hydroxyl groups with isopropyl iodide/bromide, iododerivate is more reactive though, because iodine is an excellent leaving group, better than the other(smaller) halogens. (Williamson ether synthesis)

O
HO HO O OH

O O

Isopropyl iodide K2CO 3

If the experimenter is familiar with phenethylamine synthesis, the rest will be peanut. The aldehyde has to be converted to (2,4,5-tri-isopropoxy-phenyl)-1--methyl--nitrostyrene by condensing it with nitroethane in presence of basic amine catalyst, or its salts (like EDDA). Its called, the Aldol condensation.

O O O

O O O NO 2

EtNO 2 NH 2 cat.

Now we have to reduce the nitrostyrene into its corresponding ketone, this can be done with iron powder in acidic media. The Nef reaction is not suitable for this because it wil attack also electron donating groups, in this case the isopropoxy groups.

O O O NO 2

O O O O

Iron CH 3COOH/HCl

The ketone can now reduced to the corresponding N-methylated amine derivate by reductive amination in presence of MeNO2 as a methylamine source. This reduction can carried out with Al/Hg, or Raney Nickel/formic acid, also with Urushibara Nickel/formic acid.

HN
O O O O
AlHg/Nickel catalist + H

O O O

And a new compound was borne!!


This method can also be used to yield the 3,4,5 isomer also called: TIM-1. (Same way how Alexander Shulgin indentified his TMA compounds.). If that is the desired product, dont methylate the vanillin but brominate it as is, bromine wil then end up in de 5th position, rest same synth. The development of this compound(s) was originally a joke between me and my friend (and chemical brother) Tim Schulenberg. I wanted to make a new, not yet existing drug named like him and this came first in my mind. I did research but couldnt find if this coumpound already exist, not on the net but also not in Phikal so its really plausible that this compound does not yet exist. But it is now on my to do list. Greets, Rudy de Vries Rudy.rudydevries@gmail.com