--------------------------------------------------------------------------------
			Proposed Synthesis of MMDA and Mescaline 
				by Rhodium and Osmium  980519
--------------------------------------------------------------------------------

[Rhodium's voice:]

The synthesis of MMDA in Pihkal is one of the longest and most tedious in the 
book. If one is going the route via myristicin, the Sisifos work of isolating 
the tiny amount of essential oil present in nutmeg, followed by fractional 
distillation to purify the myristicin fraction is also added to the labor of the 
poor chemist. Therefore I propose a new route to this "essential amphetamine".


5-Bromovanillin [1] 

To a stirred, cooled (0°C) solution of 152.15g (1.0 mol) of vanillin in 1000ml 
of methanol was added during 20 min 176.0g (1.1 mol) of bromine at such a rate 
that the temperature was kept below 20°C. The mixture was stirred at room 
temperature for 1h, cooled to 0°C, and treated during 30 min with 500 ml of 
cold (5°C) water. Stirring was continued for 15 min and the product was 
collected by filtration. It was washed with water (4x500 ml), then with 500 ml 
of cold (0°C), 70% methanol, and dried in vacuo at 50°C overnight to give 218.5 
grams (95%) of 5-bromovanillin as pale yellow crystals, mp 163-164°C. 

5-Bromovanillin (alternative) [2] 

To vanillin (15.2g, 0.1 mol) in glacial acetic acid (75 ml) is added bromine 
(17.6g, 0.11 mol). After stirring for 1h, the reaction mixture is diluted with 
ice/water (200ml), the precipitated solid is filtered, washed with water, and 
dried to give 5-bromovanillin, yield 22.0g (95%), mp160-162°C. Purity 97% (GLC). 


5-Hydroxyvanillin [3] 

Sodium hydroxide, 61.2 grams (1.53 mol), was dissolved in 750 ml of water in a 
2000ml round-bottomed flask. To the still-warm solution was added 50.0g (0.217 
mol) of 5-bromovanillin and 0.5 g of Cu powder. A white solid precipitated. 
The reaction mixture was refluxed vigorously under N2 and with magnetic 
stirring. The color changed gradually from yellow to green to dark green and, 
after ca 6 hours, all solid material was dissolved. After 27 hours of refluxing, 
the reaction was over, and the solution was acidified with 113ml conc HCl to 
pH ~2, and was extracted*) with ether (or other suitable organic solvent), and 
precipitated as the bisulfite adduct through shaking the organic phase with an 
excess of saturated aqueous sodium bisulfite. The adduct was washed sparingly 
with cold water, and dissolved in an excess of 10% sodium carbonate solution 
to release the aldehyde again. The solution was exctracted with DCM and 
evaporated to yield the title compound. 

*) [Osmium's voice: In the original patent a continuous, 27 hours extraction 
   with hot toluene was used. This is very impractical. I recommend the 
   following: after extraction and removal of the extraction solvent, dissolve 
   the crude product in 400 - 450 ml hot toluene, put that solution in a beaker 
   and cool it for at least 2 hours in an ice bath. Filter the precipitated 
   product, wash with about 100 ml ice-cold toluene and dry at 70°C or in a 
   desiccator to constant weight. Mp. 132.5-134.0°C.]


Myristicinaldehyde [4, 5] 

58g KF (0.5 mol) was shaken together with a solution of 16.8g (0.1 mol) 
5-hydroxyvanillin in 300ml DMF and the solution warmed up a bit. 19.1g 
(0.11 mol) of methylene bromide (or 9.35g methylene chloride) was added to 
the cooled solution, and the mixture was heated to 110-120°C for 1.5 hours. 
The cooled reaction mixture was then separated by ether extraction followed 
by washing the etheral extracts with water to remove DMF and with cold 10% 
Na2CO3. Drying and evaporation followed by recrystallization from hexane 
afforded myristicinaldehyde in high yields (mp 133-134°C). 


2-Nitro-isomyristicin [6] 

A solution of 9.8 grams myristicinaldehyde in 35 ml glacial acetic acid was 
treated with 5.3 ml nitroethane and 3.2 grams of anhydrous ammonium acetate, 
and heated on the steam bath for 1.5h. It was removed, treated with H2O with 
good stirring, to just short of turbidity, seeded with product nitropropene, 
and allowed to come slowly to room temperature. The bright yellow solids that 
formed were removed by filtration, washed with a small amount of aqueous 
acetic acid, and sucked as free of solvent as possible. After recrystallization 
from 60ml boiling EtOH, gave, after filtering and air drying, 5.1 grams of 
2-nitro-isomyristicin as light yellow solids with a mp of 109-110°C. 


MMDA [6] 

A suspension of 7.5 grams LAH in 500ml anhydrous Et2O was magnetically stirred, 
and heated in an inert atmosphere to a gentle reflux. The condensing Et2O 
leached out a total of 9.8 g 2-nitro-isomyristicin from a Soxhlet thimble in a 
shunted reflux condenser. This, in effect, added the nitropropene to the 
reaction medium as a warm saturated Et2O solution. When the addition was 
complete, the solution were refluxed for an additional 5 hours, then the 
solution was cooled, and the excess hydride destroyed by the addition of 
400 ml of 0.75M H2SO4. The phases were separated and sufficient saturated 
aqueous Na2CO3 was added to the aqueous phase to bring the pH up to about 
6.0. This was heated to 80°C and filtered through a coarse sintered glass 
funnel to remove some insoluble fines. The clear filtrate was brought up 
almost to a boil, and treated with a solution of 10.2 grams of 90% picric acid 
in 110 ml of boiling EtOH. Crystals of the picrate formed immediately at the 
edges, and as the reaction flask was cooled in an ice tub, the entire reaction 
set to a yellow mass of crystals. These were removed by filtration, washed 
sparingly with 80% EtOH, and air dried to give 14.0 grams of the picrate salt 
of MMDA, with a mp of 182-184°C. This salt was treated with 30 ml 5% NaOH, 
and the red solution decanted from some insolubles. Additional H2O and NaOH 
effectively dissolved everything, and the resulting basic aqueous phase was 
extracted with 3x50ml CH2Cl2. The pooled extracts were stripped of solvent 
under vacuum, and the residue dissolved in 200ml Et2O saturated with HCl gas. 
There was a heavy precipitation of white crystals, which were removed by 
filtration, Et2O washed and air dried to give 6.37 grams of MMDA HCl, with 
a mp of 190-191°C. 



[Osmium's voice:]


5-Bromovanillin: (another alternative) [3]

A 2-l. 3-necked flask, equipped with a mechanical stirrer, thermometer and 
500 ml dropping funnel was charged with 115.7g (0.722 mol, 37.4 ml) Br2. 
In the meantime, a soln. of 100 g (0.658 mol) of vanillin in 705 g (470 ml) 
of 48% HBr was prepared in the dropping funnel. While the reaction flask was 
immersed in an ice bath, the soln. of vanillin was dropped into the bromine 
with stirring over a period of 1 hr., keeping the temperature at about 5°C. 
The bromovanillin precipitated as light yellow crystals. The slurry was 
stirred for an additional hour in the ice bath, diluted with 940 ml of water 
and kept for 1 hr. 0-5°C with stirring. The crystals were collected on a 
sintered glass funnel and washed thoroughly with a total of 1000 ml of water. 
The material was dried at room temperature to constant weight. 
Yield: 150.9 g (99.4%), m.p. 163-164°C, VPC purity 98%. 


Syringaldehyde: (3,5-dimethoxy-4-hydroxybenzaldehyde): [7]

5-bromovanilline (5mmol) is refluxed with EtOAc (3mmol) and CuBr (1mmol) in 
5 M NaOMe/MeOH (10 ml) for 14 hours. Classical work-up (addition of water 
and acidification followed by extraction of the phenol) leads to pure 
syringaldehyde (95%). When starting from the more soluble 5-bromovanilline 
dimethyl acetal, reaction is achieved within 2 hours (yield 98%). 
Preparation of this acetal is probably not worth the extra work. 

Substituting EtONa for MeONa seems to work, too, producing 2-ethoxy-3-OH-
4-methoxybenzaldehyde, useful for ethoxy-derivatives of Mescaline.


The above synthesis, although performed on a small scale, is easily scaled 
up to industrial size (French Pat. 2,669,922, CA 118; P6734u). It is a 
general procedure for substituting aryl-Br with -OMe or -OEt, giving us 
the possibility to produce other compounds from already known substances, 
e.g bromination of MDA yields 6-Br-MDA. This is converted by the above 
procedure to MMDA-2, #133, active at 25-50mg, 8-12 hrs. 

Asaronealdehyde (2,4,5-trimethoxy-benzaldehyde) can be produced in the 
following way: Methylate resorcinol. Product is 1,3-di-MeO-benzene. 
Do a Vilsmeyer aldehyde synthesis with POCl3/N-methylformanilide to obtain 
2,4-di-MeO-benzaldehyde. Brominate and treat as described above to obtain 
asaronaldehyde.

Syringaldehyde is easily methylated or ethylated with the known procedures 
in high yields forming the highly-desirable 3,4,5-trimethoxybenzaldehyde 
or the 3,5-di-MeO-4-EtO-benzaldehyde (Escaline, #72, 40-60 mg, 8-12 hrs.).


3,4,5-Trimethoxybenzaldehyde [3] from 5-hydroxyvanillin: 

Into a 1-l. round-bottomed flask equipped with a magnetic stirrer and a 
reflux condenser were placed: 50 g (0.298 mol) 5-hydroxyvanillin, 500 ml 
acetone, 91.0 g (0.716 mol) dimethylsulfate, 100 g (0.806 mol) finely 
ground Na2CO3.H2O, 10 ml of 10% KOH in methanol. Of course equimolar 
amounts of anhydrous Na2CO3 or K2CO3 can be used. 
The heterogenous mixture was stirred under vigorous reflux for 24 hours, 
after which the reflux condenser was replaced with a descending condenser. 
The solvent was distilled at a bath temp. of ca. 100° until the distillation 
ceased. To the solid residue was added 400 ml of water and the heterogenous 
mixture was stirred VIGOROUSLY for 2 hours at room temperature followed by 
one hour at 0-5° (ice-cooling). The light brown crystals were filtered by 
suction, washed with 3*150 ml of ice water and air dried to constant weight. 
Yield 55.1g (94%), m.p. 72.5-74°. After distillation at 0.5mm/130°, there 
was obtained a 90% yield of 3,4,5-trimethoxybenzaldehyde, m.p. 73.5-75, 
VPC purity 99.3%. (This distillation is probably unnecessary, because 
the aldehyde is already quite pure).


3,5-Dimethoxy-4-ethoxybenzaldehyde [8] from syringaldehyde:

A well-stirred suspension of 21.9 g syringaldehyde in 45 mL H2O was heated 
to reflux in a heating mantle. There was then added a solution of 15 g NaOH 
in 60 mL H2O. The heating and stirring was continued until the generated 
solids redissolved. Over a period of 10 min, there was added 23 g diethyl 
sulfate, then refluxing was continued for 1 h. Four additional portions 
each of 5 g diethyl sulfate and of 6 mL 20% NaOH were alternately added to 
the boiling solution over the course of 2 h. The cooled reaction mixture 
was extracted with Et2O, the extracts pooled and dried over anhydrous 
MgSO4, decolorized with Norite, and stripped of solvent. The crude 
3,5-dimethoxy-4-ethoxy-benzaldehyde weighed 21.8 g and melted at 51-52°C.

See the same reference in Pihkal for details on how to use ethyl iodide 
instead of diethyl sulfate.

References: 

[1] Syn Comm 20(17), 2659-2666 (1990) 
[2] Synthesis, 308 (1983) 
[3] US Pat 3,855,306 
[4] Tet Lett 38, 3361-3364 (1976) 
[5] JACS 99(2), 498-504 (1977) 
[6] Pihkal, #132 (p. 787)
[7] Tetrahedron Letters, Vol. 34, No. 6, pp.1007-1010, (1993) 
[8] Pihkal, #72
