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           "A new route to 3,5-dimethoxy-4-something-phenethylamines" 
                                  by Labrat
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Now this method is a real breakthrough in the field of organic
chemistry. This little procedure makes it possible to make
3,5-dimethoxy-4-something-amphetamines and -phenethylamines. PIHKAL is
filled with compounds having a 2,4,5-trisubstitution pattern, but with
this protocol a chemist can make analogs of most of those compounds.
It's time for PIHKAL II!!! The beauty of this reaction is that it uses
the highly useful trimethoxybenzaldehyde. A synthesis of this compound
is given earlier in this book.

The procedure can be found in these useful articles [JOC 57:3101-6('92)+ 
Synthesis 313('90)]. The reaction diagram is as follows:

I)Preparation of dimethylacetal of 3,4,5-trimethoxybenzaldehyde

10 g 3,4,5-trimethoxybenzaldehyde is added under N2 to a suspension of
150 mg NH4Cl in a solution of 20 ml trimethoxymethane and 20 ml MeOH.
The mixture is stirred at reflux for 3 hrs, then cooled to room
temperature and 1.5 ml triethylamine is added with stirring. After a few 
minutes, 50 ml water is added and the mixture is extracted with 30 ml 
ether (3 times). The organic phase is washed with 30 ml saturated sodium 
carbonate solution, 30 ml water and dried with Na2SO4. After evaporation 
of the solvent a crude product remains, which is distilled at 180 dg 
C/10 mm Hg to give 10.3 g 3,4,5-trimethoxybenzaldehyde dimethylacetal.

This particular reaction makes a protected group from the aldehyde: an
acetal. The function of this protection group is to protect the aldehyde 
group against the harsh reducing conditions in the second reaction. 
Otherwise the aldehyde would be reduced to an alcohol or a methyl group.

II)Reductive electrophilic substitution of the dimethylacetal of
3,4,5-trimethoxybenzaldehyde: 3,5-dimethoxy-4-methyl-benzaldehyde

A solution of 4 g 3,4,5-trimethoxybenzaldehyde dimethylacetal in THF is 
added dropwise to a mixture of freshly cut Na (1.2 g) in 60 ml THF,
cooled to 0 dg C under dry nitrogen. The mixture is stirred at room
temperature for 24 hrs, cooled to O dg C and 25 mmol methyliodide is
added dropwise. After another 24 hrs of stirring at r.t. the reaction
mixture is carefully quenched with 20 ml water, 30 ml ether is added and 
the organic phase is washed with 20 ml water and evaporated. The crude 
product is dissolved in 50 ml of a 1:1 mixture of THF/1 M HCl and 
stirred at room temperature for 5 hours. The mixture is extracted with 
3X30 ml ether, the ether washed with 2X20 ml water and dried with
Na2SO4. After evaporation the crude product is recrystallised from
boiling acetone to give 71% yield of 
3,5-dimethoxy-4-methyl-benzaldehyde.

This reaction is actually two steps in one procedure. First, the
trimethoxycompound is reduced with sodium to the aryl anion, then methyl 
iodide (an electrophile don't ask, I'll give examples of this later) is 
added to the mix producing the 2-Me compound in ONE step! Well, isn't 
that nice? A competing reaction is demethylation, which produces 
phenols. These latter substances are easily removed during workup (the 
phenols can be extracted into acid water). Those phenols should be saved 
to make Tweetios or analogue compounds.

Labrat just mentioned something about electrophiles. The following
electrophiles can be used to make 3,4,5-analogs of the following
compounds:

1)MeI, EtI, PrI  -> Desoxy & ethyl- & propylanalogue
(only primary halides can be used in this reaction)
2)Cl2, Br2, I2   -> DOC-, DOB- and DOI
3)(MeS)2, (EtS)2, (PrS)2  -> Aleph1/2/7 + 2C-T1/2/7- analogues
ofcourse there are more example of electrophiles, but this would take
too much of Strike space in the book. Included are the most interesting 
compounds.

Labrat has added some details for the curious chemist:
-THF is the best solvent for this reaction, Et20 and isooctane give a
much lower yield
-substituting K for Na gave complex results with low yields of the
desired product
-the reaction can be compared with the Birch reduction (in aprotic
solvent) and direct ortho metalation, but it's cheaper and easier
-inverse addition, that is adding the reducing mixture to the
electrophile in THF, makes it possible to use electrophiles that are not 
stable to the sodium. The excess metal precipitates and can be
conveniently filtered off!

The reaction is used to make Desoxy. In PIHKAL a difficult procedure
with low yields overall is used to synthesize this particular compound, 
but this protocol is a much better way to do the same thing.
Desoxy is synthesized from the 3,5-dimethoxy-4-methylbenzaldehyde as
done in PIHKAL, #96: Mescaline.

III) 3,5-dimethoxy-4-methylnitrostyrene

20 g 3,5-dimethoxy-4-methylbenzaldehyde, 40 ml nitromethane and 20 ml
cyclohexylamine in 200 ml glacial acetic acid is heated at 100 dg C for 
1 hour. The reaction mixture is slowly diluted with 400 ml water under 
vigorous stirring, giving a heavy precipitate of the nitrostyrene. The 
yellow crystals are filtered off, washed with water and dried. Then 
recrystallise from ~15 ml MeOH/g nitrostyrene to get about 20 g of the 
nitrostyrene

IV) Desoxy: 3,5-dimethoxy-4-methylphenethylamine

2 g LiAlH4 in 100 ml ether is brought to reflux and there's added
dropwise a saturated solution of 2 g ,5-dimethoxy-4-methylnitrostyrene
in ether. After the addition the mixture was refluxed for 48 hours, then 
cooled to r.t. Excess hydride was decomposed with 150 ml 10% H2SO4. 
Separate the two layers that form in a sep funnel, keeping the aqueous 
layer. Bring the pH to >9 with saturated NaOH solution and extract with 
3X100 ml toluene. Bubble dry HCl gas through the solution until no more 
crystals precipitate. Filtering is done when necessary. Yield ~2 g of 
Desoxy.