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Synthesis of MMDA and Mescaline from Vanillin

by Rhodium and Osmium
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Introduction

[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 (0C) 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 20C. The mixture was stirred at room temperature for 1h, cooled to 0C, and treated during 30 min with 500 ml of cold (5C) 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 (0C), 70% methanol, and dried in vacuo at 50C overnight to give 218.5 grams (95%) of 5-bromovanillin as pale yellow crystals, mp 163-164C.

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%), mp160-162C. Purity 97%.

5-Bromovanillin (alternative) [12]

A 250 mL RB flask was charged with 5 g vanillin (32.9 mmol) and dissolved in 50 mL glacial HOAc. The mixture was stirred with a magnetic stirbar. When all vanillin was dissolved, 2 x 1 mL bromine (39.0 mmol) was added with a 5 min interval. After one hour, 150 mL cold (4C) dH2O was added. The yellow-orange precipitate was filtered and the RB flask rinsed with another 50 mL cold dH2O, which was used to wash the precipitate as well. The precipitate was then washed with another 25 mL cold dH2O and dried to yield 7.5 g 5-bromovanillin (32.5 mmol) as a powder. Total yield: 98.7% Purity: 96% (via GC).

3-Methoxy-4,5-dihydroxybenzaldehyde (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 70C or in a desiccator to constant weight. Mp. 132.5-134.0C.]

3-Methoxy-4,5-dihydroxybenzaldehyde (5-Hydroxyvanillin) [9]

5-bromovanillin (200 g, 0.91 mol), sodium hydroxide (245 g, 6.1 mol) and copper powder (1 g, 0.016 mol) were slurried into 3 L water. The reaction mixture was heated at reflux for 24-27 hours. Disodium hydrogen phosphate (4.5 g, 0.032 mol) is added for the last half hour of reflux. The reaction is then cooled to less than 50C, filtered to remove a precipitate of cupric hydrogen phosphate and acidified with hydrochloric acid (460 g). The reaction mixture was placed in a continuous extractor and extracted with ethyl acetate (3 L). The ethyl acetate extract was stirred with activated carbon and filtered. The filtrate was washed with saturated aqueous EDTA solution followed by salt. The solution was then dried over magnesium sulfate and filtered. The ethyl acetate solution was concentrated to a crude solid. The crude product was dissolved in boiling toluene (2 L), treated with activated carbon, filtered and cooled to crystallize. The product, 3-methoxy-4,5-dihydroxybenzaldehyde was isolated in approximately 60% yield (86 g) with a mp 132-133C (lit. Mp 132-134C).

3-Methoxy-4,5-dihydroxybenzaldehyde (5-Hydroxyvanillin) [10]

2.8g 5-Iodovanillin, 1.6g hydrated CuSO4 and 76mL 4N NaOH were refluxed(105) for 4.5h with continuous stirring under N2. After cooling to 60-70, the mixture was filtered under suction and the residue washed with 3x10mL hot water. The alkaline solution was cooled to 10 and acidified to pH 3-4, by the dropwise addition of concentrated HCl. During this addition the mixture was stirred continuously and the tmperature maintained below 25C. The resulting mixture, which contained a small amount of percipitate, was extracted continuously with ether for 16h. After being dried over anhydrous MgSO4, the ether was removed (60-65) to leave 1.5g dark gray product. All but 0.10g was dissolved in hot benzene, from which, after concentration to 75mL, 1.15g 5-hydroxyvanillin crystallized, yield 68%, mp 128-129. Recrystallization from benzene, with charcoaling, gave a chromatographically pure product, mp 133-134; reported 132-134 by Bradley et. al. [11]. With the exception of traces of 5-hydroxyvanillin the mother liquors contained only vanillin as indicated by GLC.

Paper Chromatography

5-Hydroxyvanillin, vanillin and 5-iodovanillin were separated by descending chromatography using Whatman No.1 paper and the solvent system of n-butanol saturated with 2% ammonia. A saturated solution 2,4-dinitrophenylhydrazine in 1N HCl was the spay reagent. For these compounds the Rf values were 0.38, 0.50 and 0.48 respectively.

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 110-120C 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 133-134C).

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 109-110C.

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 80C 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 182-184C. 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 190-191C.

[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 5C. 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. 0-5C 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. 163-164C, 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 51-52C.

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
[7] Tet Lett 34, 1007-1010 (1993)
[8] Pihkal #72
[9] Syn Comm 28, 1517-1524 (1998)
[10] Canadian Journal of Chemistry 40, 2175-2177 (1962)
[11] J. Chem. Soc 793 (1930)
[12] GC_MS, communication at The Hive (2003)