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. Og (95%)

[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".

OMe br ^ "cho 5-Bromovanillin

Vanillin 5-Bromovanillin br ^ "cho 5-Bromovanillin

To a stirred, cooled (0°C) solution of I52.15g (1.0 mol) of vanillin in 1000ml of methanol was added during 20 min 176.Og (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

Br ^ CHO 5-Bromovanillin

HO" ^ "CHO 5-Hydroxyvanillin

Br ^ CHO 5-Bromovanillin

5-Hydroxyvanillin [3]

HO" ^ "CHO 5-Hydroxyvanillin

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.Og (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 HCI 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 extracted 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 ahd dry at 70°C or in a desiccator to constant weight. Mp. 132.5-134.0°C.]

CT ^ "CHO Myristicinaldehyde

HCT ^ "CHO 5-Hydroxyvanillin Myristicinaldehyde [4, 5]

CT ^ "CHO Myristicinaldehyde

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 ethereal extracts with water to remove DMF and with cold 10% Na2C03. Drying and evaporation followed by recrystallization from hexane afforded myristicinaldehyde in high yields (mp 133-134°C).

Myristicinaldehyde 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 H20 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 amp of 109-110°C.

2-Nitro-isomyristicin MMDA [6]


A suspension of 7.5 grams LAH in 500ml anhydrous Et20 was magnetically stirred, and heated in an inert atmosphere to a gentle reflux. The condensing Et20 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 EtzO 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 H2S04. The phases were separated and sufficient saturated aqueous Na2C03 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 H20 and NaOH effectively dissolved everything, and the resulting basic aqueous phase was extracted with 3x50ml CH2CI2. The pooled extracts were stripped of solvent under vacuum, and the residue dissolved in 200ml Et20 saturated with HCI gas. There was a heavy precipitation of white crystals, which were removed by filtration, Et20 washed and air dried to give 6.37 grams of MMDA HCI, with a mp of 190-191 °C.

[Osmium's voice:]


5-Bromovanillin: (another alternative) [3]

Br" ^ "CHO 5-Bromovanillin

A 2-I. 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%.

Br" ^ "CHO 5-Bromovanillin

MeO v CHO Syringaldehyde

Continue reading here: Syringaldehyde 35dimethoxy4hydroxybenzaldehyde [7

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