Syntheses of mescaline[ Back to the Chemistry Archive ] A New Synthesis of Mescaline By Makepeace U. Tsao JACS 5495 (1951)IntroductionThe cactus alkaloid, mescaline, beta-(3,4,5trimethoxyphenyl)-ethylamine, has been studied for some years, because of its most interesting effects on the psychic states of human subjects. Since the elucidation of the chemical structure of the alkaloid through the synthesis by Spath, a few other methods of preparation have been published. A simple synthesis utilizing lithium aluminum hydride is presented in this report. The synthesis may be outlined as follows: Gallic acid ExperimentalMethyl Ester of 3,4,5-Trimethoxybenzoic AcidTo a solution prepared from 100 g. of 3,4,5-trimethoxybenzoic acid (0.47 mole), 20 g. of sodium hydroxide, 55 g. of sodium carbonate and 300 ml. of water is added, with stirring, 94 ml. of methyl sulfate (0.94 mole) during the course of 20 minutes. The reaction mixture is refluxed for one-half hour. The crude ester (65 g., 61 %) precipitates from the cold mixture. From the filtrate 38 g. of starting material is recovered upon acidification with diluted hydrochloric acid. The ester is further purified by solution in the minimum amount of methanol and treatment with norite. Usually it is necessary to repeat this treatment to obtain a colorless crystalline product that melts at 80-82°C. Semmler, who employed a different Process, reported m.p. 83-84°C. 3,4,5-Trimethoxybenzyl AlcoholTo a suspension of 4.6 g. (012 mole) of lithium aluminum hydride in 200 ml. of anhydrous ether is added, in the course of 30 minutes, a solution of 22.6 g. (0.1 mole) of the methyl ester of 3,4,5-trimethoxybenzoic acid in 300 ml. of ether. The solid which forms is carefully decomposed first with 50 ml. of ice-water. After decantation of the ether, 250 ml. of ice-cold 10% sulfuric acid is added. The product is extracted with 150 ml. Of ether. The combined extracts, after drying over sodium sulfate, are freed of ether and the residue distilled; b.p.135-137' (0.25 mm.); yield 14.7 g. (73%). This compound was obtained by a different method by Marx; b.p. 228°C (25 mm.). 3,4,5-Trimethoxybenzyl ChlorideA mixture of 25 g. of 3,4,5trimethoxybenzyl alcohol and 125 ml. of ice-cold concentrated hydrochloric acid is shaken vigorously until a homogeneous solution is obtained. In a few minutes a turbidity develops, followed by a heavy precipitation of gummy product. After 4 hours and dilution with 100 ml. of icewater, the aqueous layer is decanted and extracted with three 50-ml. portions of benzene. Then the gummy organic residue is dissolved in the combined benzene extracts. The benzene solution is washed with water and dried over sodium sulfate. The benzene solution is transferred to a distilling flask and the benzene is removed under diminished pressure. The red semi-solid residue is suspended in a small amount of ice-cold ether and filtered through a chilled funnel. The crystalline product, after washing with small portions of cold ether, weighs 9.7 g. The combined filtrates on standing in refrigerator yield more crystals. The total yield is 13.0 g. (48%). After four recrystallizations from benzene, colorless needles are obtained; m.p. 60-62°C. This compound is extremely soluble in ether, alcohol and acetone, but slightly soluble in petroleum ether. Standing at room temperature for a few weeks causes the crystals to turn into a red semi-solid. An alcoholic solution of pure material gives an instantaneous precipitation with alcoholic silver nitrate. 3,4,5-TrimethoxyphenylacetonitrileA mixture of 9 g. of potassium cyanide in 35 ml. of water and 60 ml. of methanol and 9.7 g. of 3,4,5-trimethoxybenzyl chloride is heated for 10 minutes at 90'. The solvents are partially removed under diminished pressure. The residue is then extracted with 90 ml. of ether in three portions. The combined extracts are washed with water and dried over sodium sulfate. After the removal of the drying agent the ether solution is warmed on a steam-bath and the ether is removed with a stream of air. On chilling, the residue yields scale-like crystals. Recrystallization from ether gives rectangular prism; yield 2.5 g. (27%); m.p. 76-77°C. Baker and Robinson reported a melting point of 77°C for this compound. MescalineIn 150 ml. of anhydrous ether is suspended 0.85 g. of lithium aluminum hydride powder. With stirring, 2.0 g. of 3,4,5-trimethoxyphenylacetonitrile in 150 ml. of anhydrous ether was added during the course of 15 minutes. After 15 minutes stirring, 10 ml. of ice-water is dropped in carefully. Then a mixture of 10 g. of sulfuric acid in 40 ml. of water is added at a moderate rate. The aqueous layer is separated and treated with concentrated sodium hydroxide. The brown off is extracted with three portions of 30 ml. each of ether. The combined extracts are washed once with water and dried over stick potassium hydroxide. To the decanted ether solution is added a mixture of 1 g. of sulfuric acid and 25 ml. of ether. The white precipitate is washed several times with ether; yield 1.2 g. (40%). After two recrystallizations from 95% ethanol, the colorless long thin plates soften at 172°C and melt at 183°C. Synthesis of Mescaline [J Prakt Chem 137, 339 (1933)]0) 3,4,5-trimethoxy-benzoic acid [Org Syn Coll Vol 1, p 537 (1941)]To a cold solution of 80g (2 moles) of sodium hydroxide in 500ml water in a 1000ml flask is added 50g (0.266 mole) of gallic acid. The flask is immediately tightly stoppered (to prevent the solution from darkening, due to oxidation by atmospherical oxygen. Oxygen must not enter the reaction flask at any time!), and the mixture is shaken occasionally until all the acid has dissolved. 89g (67 ml) of dimethyl sulfate (0.71 mole) is then added (Caution! Dimethylsulfate is very toxic, and all spills must be neutralized with ammonia solution!), and the flask is shaken for twenty minutes, and cooled by means of cold water in order to prevent the temperature to rise above 30-35°C. Occasionally the stopper is raised to release any pressure. A second portion of 89g of dimethyl sulfate is added and shaking continued for ten minutes longer. During the second addition the temperature may rise to 40-45°C. The flask is then fitted with a reflux condenser and the contents boiled for two hours. In order to saponify the small amount of ester which is produced, a solution of 20g of sodium hydroxide in 30 ml of water is themn added and the boiling continued for two additional hours. The reaction mixture is then cooled and acidified with dilute hydrochloric acid; the precipitated trimethylgallic acid is filtered with suction and wased well with cold water. The yield is around 50g (90%). 1) 3,4,5-Trimethoxybenzoyl Chloride.Five hundred grams of 3,4,5-trimethoxybenzoic acid (ef. Gilman-Blatt, "Organic Syntheses," John Wiley & Sons, New York 1941, Collective Volume I, 537) is added to 285 cc of thionyl chloride freshly distilled over linseed oil and the mixture is heated for 2 hours on a water bath. The still-hot mixture is then distilled under reduced pressure from a Claisen-flask, avoiding rubber stoppers. There is obtained 510 g. (93 % of theory) of trimethoxybenzoyl chloride boiling at 185 deg C (18 mm.). 2) 3,4,5-Trimethoxybenzaldehyde.To a solution of 200 g. of 3,4,5-trimethoxy benzoyl chloride in 1000 cc of xylene freshly distilled over sodium, there is added 60 g. of a 5 % palladium-barium sulfate catalyst. The mixture is heated in an oil bath maintained at 150 deg C and a vigorous stream of hydrogen is introduced into the boiling solution. The hydrogen should be washed with aqueous permanganate and the dried with sulfuric acid. After 60-80 hours the reaction is complete. The solution is filtered and the aldehyde conveniently isolated as its bisulfite compound. Yield 120 g. (70.6 % of theory), m.p. 74 deg C. 3) 3,4,5-Trimethoxy-nitrostyrene.A solution of 40 cc of nitromethane and 100 g. of trimethoxybenzaldehyde in 200 cc alcohol is cooled to 0 deg C and while it is stirred mechanically there is introduced a solution of 45 g. pure potassium hydroxide in 45 cc water and 90 cc methanol at the rate of about one drop per second, care being taken that the temperature does not rise. Fifteen minutes after the addition is completed the solution is poured into 500 cc concentrated hydrochloric acid mixed with sufficient fee to assure its presence throughout the slow addition and to maintain the temperature of -10 deg C. The precipitated nitrostyrene is separated by filtration and washing and may be purified by recrystallizing from 700 cc alcohol. The pale yellow plates which melt at 120-121 deg C are obtained in a yield of approximately 78% of theory. 4) Mescaline.[A] APPARATUS A cell of porous porcelain (PC) (external dimensions 75x160 mm) with a glazed rim is placed in a glass jar of 500 cc capacity, surrounded by a cooling bath. The anode is a lead or carbon rod, surrounded by a glass coil; the cooling water flows through the coil and discharges into the cooling bath. The cathode is a sheet of lead (220x90x2 mm.), which previous to each experiment is electrolytically coated with lead peroxide, in a bath of dilute sulfuric acid. [B] REDUCTION The cathode liquor consists of a solution of 30g. 3,4,5-trimethoxy- nitrostyrene in 100 cc glacial acetic acid and 100 cc alcohol, to which 50 cc conc. hydrochloric acid has been added. The anode compartment is filled, to the same level occupied by the catholyte, with a solution of 25 cc conc. sulfuric acid in 175 cc water. The reduction requires 12 hours, using a current of 5-6 amperes; the cathode current density should be about 3 amperes per square centimeter. The temperature is regulated by the flow of the cooling water and the catholyte should be kept at 20 deg C for the first six hours; the temp is then allowed to rise until it reaches 40 deg C at the end of the reduction. When the reduction is complete, the catholyte is filtered, evaporated in vacuum and the residue taken up in 300 cc water Unreduced nitrostyrene is extracted sucessively with ethyl acetate and with ether. The crude mescaline hydrochloride solution in a separatory funnel is then treated with a cold concentrated solution of 100 g. of sodium hydroxide and the liberated base exhaustively extracted with ether. The somewhat concentrated and dried (potassium carbonate) solution is treated with a stream of dry hydrogen chloride and the separated hydrochloride twice recrystallized from absolute alcohol. The pure mescaline hydrochloride, thus obtained in 77% yield, forms white leaflets melting at 184°C. Synthesis of Mescaline [Arch Pharm 270, 410 (1932)]1) 3,4,5-Trimethoxyacetylmandelonitrile.Twenty grams 3,4,5-trimethoxybenzaldehyde, prepared according to Slotta [Ber 63, 3029 (1930)], is mixed with 40 cc of saturated sodium bisulfite solution. The separated bisulfite compound in a slurry with water is treated with a solution of 9.5 g. of potassium cyanide in 20 cc water. The resulting nitrile is filtered, washed first with bisulfite solution then with water, and finally dried on a porous plate. The mandelonitrile is acetylated by boiling for 1 hour with 100 cc of acetic anhydride. The excess anhydride is distilled, the residue is dissolved in ether, and the solution washed successively with sodium carbonate solution, with bisulfite solution, and with water. The residue from the dried ether solution distills at 163-165 deg C (0.1 mm); yield 82% based on the 3,4,5-trimethoxybenzaldehyde. 2) Mescaline.Twenty-two grams of 3,4,5-trimethoxyacetylmandelonitrile is dissolved in 200 cc glacial acetic acid and the solution dropped into a suspension of 3 g. palladium black in 75 cc acetic acid and 5 cc concentrated sulfuric acid (for apparatus see Arch. Pharm. 1931, 74). The introduction is made with agitation, at 18 deg C, and under a hydrogen pressure of 2 atm. In 2.5 hours, 95% of the calculated amount of hydrogen is absorbed. An amount of potassium carbonate equivalent to the sulfuric acid is added, the acetic acid is eliminated in vacuo, and the residue dissolved in water. The aqueous solution is washed twice with ether, treated with excess potassium hydroxide, and the separated mescaline taken up in ether. The residue from the ether extract distills at 173°C (10 mmHg) and solidifies to white crystals, mp 35-36°C. A Novel Route for the Synthesis of MescalineM. Nabil Aboul-Enein and Attiat I. EidActa Pharm. Suecia 16, 267-270 (1979)AbstractA new plausible synthetic pathway for the synthesis of the peyote alkaloid mescaline in a satisfactory overall yield is reported. The hallucinogen mescaline (I) is the main alkaloid isolated from the cactus plant Anhalonium Lewinii Hennings or Lophophora Williamsii Lemaire [1]. Several methods have been reported describing the total synthesis of this alkaloid [2-7]. However, all these procedures were found to be tedious and costly as well as giving low overall yields of the alkaloid. In the present work, we would like to report a convenient new simple, facile and non-costly synthetic pathway of mescaline (I) leading to comparatively high overall yields. The scheme illustrates the route resorted to to achieve the base, starting from the inexpensive and easily available 2,6-dimethoxy- phenol (II): II was allowed to undergo Mannich reaction to give the base III. Subsequent quaternization to IV, nucleophilic substitution to V and methylation resulted in 3,4,5-trimethoxybenzyl cyanide (VI) in high yields. Lithium aluminum hydride reduction of the latter afforded the alkaloid mescaline isolated as the hydrochloride in 42% overall yield. ExperimentalMelting points were determined on a Kofler melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer Model 257 grating spectrophotometer and were consistent with the assigned structures. Microanalyses were performed at the National Research Centre, Dokki, Cairo, Egypt. Analytical results obtained were within +-0.4% of the calculated value. 4-Dimethylaminomethyl-2,6-dimethoxyphenol (III)To a solution of 23.1 g (0.15 mol) of 2,6-dimethoxyphenol (II) in 150 ml of methanol was added 17.1 g of 40% aqueous solution of dimethylamine and 12.75 g of 35% formaldehyde solution. The whole mixture was left well closed in the dark at room temperature for 10 days with occasional shaking. Thereafter, the methanol was driven off in vacuo and 45 ml of water was added to the residue. The separated product was filtered and recrystallized from petroleum-ether (bp 60-80°C), mp 79-80°C, yield 25.3 g (80 %). Quaternization of III to IVTo a solution of 21 g (0.099 mol) of III in 90 ml of absolute ethanol, 28.2 g (0.198 mol) of methyl iodide was added under stirring and cooling, resulting in an exothermic reaction accompanied by the precipitation of the product IV. After complete addition, the reaction mixture was allowed to stand overnight. The separated solid was recrystallized from ethanol, mp 185-187°C, yield 35g (99%). 3,5-Dimethoxy-4-hydroxybenzyl cyanide (V)A solution of 35.3g (0.1 mol) of the methiodide IV and 26g (0.4 mol) of KCN in 200 ml of water was refluxed for 2.5 h. After cooling, the solution was cautiously acidified with 2 M HCl and extracted with CHCl3. The CHCl3 extract was dried (Na2SO4) and the solvent removed in vacuo to give 15.4 g of an oil (80 %), which is used as such without further purification in the next step. 3,4,5-Trimethoxybenzyl cyanide (Vl)To a solution of 30g (0.156 mol) of V in 200 ml of dry acetone was added 27.6g (0.2 mol) of K2CO3 and 31.2g (0.22 mol) of methyl iodide. The mixture was refluxed for 20 h. After cooling and filtration, the filtrate was evaporated in vacuo. The residue was extracted with CHCl3. The CHCl3 extract was washed with 2M NaOH, 10% Na2S2O3, and then with water. After drying over Na2SO4 and removal of the solvent, the crystalline was recrystallized from petroleum-ether (60-80°C), mp 76-77°C, yield 27g (83.8 %) (Lit. [4] 76-77°C). VI was further identified by comparing mixed melting point and comparative IR spectrum with an authentic sample. Mescaline hydrochloride (I)To a suspension of 10 g LiAlH4 in 300 ml of dry tetrahydrofuran was added a solution of 20.7 (0.1 mol) of VI in 60ml of dry tetrahydrofuran over a period of 30 min. After complete addition, the whole mixture was refluxed for 3 h and then cooled. The complex and excess hydride were decomposed with saturated Na2SO4 solution and filtered. The combined filtrate and washings were evaporated in vacuo. The calculated amount of methanolic hydrogen chloride was added to the residue and the mescaline hydrochloride was recrystallized from 2-propanol, mp 180-181°C, yield 19.5g (79%) (Lit. [8] 180-181°C). Mescaline hydrochloride was further identified by comparing mixed melting point and comparative IR spectrum with an authentic sample. References [1] A. Hoffer and H. Osmond, The Hallucinogens, Academic Press
(1967) 3,4,5-TrimethoxybenzaldehydeA solution of 39.6 g (0.2 mole) of 3,4,5-trimethoxybenzyl alcohol in 250 ml of methanol was stirred and cooled to 0°C. Bromine (54 ml) was added with stirring over a period of one hr keeping the temperature at 0°C. The stirred mixture was allowed to acquire room tempterature gradually and stirred further for 2 hr. A saturated solution of sodium thiosulfate (about 30 ml) was added to effect complete decomposition of excess bromine. 3,4,5-Trimethoxybenzaldehyde was filtered off and recrystallized from benzene to give 31 g (80%) as colourless needles, m.p. 73-74°C. Reference: J. Chem. U.A.R., 11, No. 3, 401-404 (1968) 3,4,5-trimethoxybenzaldehyde can be also prepared by Rosenmund reduction of 3,4,5-trimethoxybenzoyl chloride as described in Organic Syntheses, CV 6, 1007. Procedure A pressure vessel (Note 1) is charged in order with 600mL of dry toluene (Note 2), 25g (0.30 mole) of anhydrous sodium acetate (Note 3), 3g of dry, 10% palladium-on-carbon catalyst (Note 4), 23g (0.10 mole) of 3,4,5-trimethoxybenzoyl chloride (Note 5), and 1mL of Quinoline S (Note 6). The pressure vessel is flushed with nitrogen, sealed, evacuated briefly, and pressured to 50 p.s.i. with hydrogen. The mixture is shaken with 50 p.s.i. of hydrogen for 1 hour at room temperature (Note 7), then heated at 35–40° C for 2 hours. Agitation is continued overnight while the reaction mixture cools to room temperature. The pressure on the vessel is released, the vessel is opened, and the mixture is filtered through 10g of Celite filter aid, and the insoluble material is washed with 25mL of toluene. The combined filtrates are washed successively with 25mL of 5% sodium carbonate solution and 25mL of water. The toluene solution is dried over 5g of anhydrous sodium sulfate and filtered. The filtrate is concentrated by distillation at reduced pressure using a water aspirator. The residue (Note 8) is distilled through a 10-cm. Vigreux column with warm water circulating through the condenser, to prevent crystallization of the distillate, yielding 12.5–16.2g (64–83%) of 3,4,5-trimethoxybenzaldehyde, b.p. 158–161° C (7–8 mm.), m.p. 74–75° C (Note 9) and (Note 10). Notes:
3,4,5-Trimethoxybenzaldehyde from Gallic AcidMethyl 3,4,5-Trimethoxybenzoate: A solution of gallic acid hydrate (29.9 g) in DMF (100 ml) was added to a suspension of K2CO3 (97 g) in DMF (200 ml) with vigorous stirring. Dimethyl sulfate (66 ml) was added dropwise to the above mixture at 20-25°C. After completion of the addition, the mixture was stirred at room temperature for 2.5 h. The above procedure was repeated using a further amount of K2CO3 (44 g) and Me2SO4 (30 ml), then the reaction mixture was stirred at room temperature for a further 4.5 h, poured into water, and extracted with Et2O. The ethereal solution was dried over K2CO3 and evaporated to dryness. Recrystallization of the residue from MeOH gave pale yellow prisms (32.7 g), mp 85-86°C. 3,4,5-Trimethoxybenzyl Alcohol: A solution of Methyl 3,4,5-Trimethoxybenzoate (9.86 g) in abs. benzene (40 ml) was added dropwise to Vitride (22 ml) under ice cooling. After the mixture had been stirred at room temperature for a further hour the complex was decomposed with 25% H2SO4 (290ml). The benzene layer was separated from the aqueous layer, which was extracted with benzene. The organic layers were combined, washed with 5% NaHCO3 aq.. and then dried over MgSO4. Evaporation of the benzene solution gave an oily product (7.84 g). 3,4,5-Trimethoxybenzaldehyde: Pyridinium dichromate (16.9 g) was added a solution of the crude alcohol (5.92 g) in dry CH2C2, (43 ml) at 18-19°C with stirring. After stirring at room temperature for 3.5 h, further PDC (3.38 g) was added to the mixture and the whole was stirred at room temperature for 4 h. The reaction mixture was diluted with benzene and the diluted solution was filtered through a column packed with Celite 545 with the aid of an air-pump. Evaporation of the benzene filtrate under reduced pressure gave colorless prisms (5.74g), mp 76-78°C. Reference: Chem Pharm Bull 31, 3024 (1983) Synthesis of 3,4,5-Trimethoxybenzaldehyde from 4-Hydroxytoluene (p-Cresol)Syn Comm 32(18), 2809-2814 (2002)3,4-Dibromo-4-hydroxybenzaldehyde3-Necked round-bottomed flask equipped with a condenser attached to a calcium chloride drying tower,a mechanical stirrer,a thermometer,and a dropping funnel was charged with a solution of 43.2 g (0.40 mol)of p-cresol in 200 mL of o-dichlorobenzene. The solution was cooled to 10 C and treated during 1 h with a solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-benzene at such a state that the temperature was kept below 40 C. The mixture was stirred, heated at 160°C and simultaneously dropped with another solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-benzene during 3 h. This deep red mixture was sequentially stirred for 30 min. After being cooled to room temperature and 145 mL of water being added,the mixture was heated to 120°C and kept at the temperature for 4 h. After being cooled to 5°C, the mixture was separated into upper organic layer, middle aqueous layer and lower solid layer. The solid product was collected by filtration and washed with water up to neutrality. It was dried in vacuo at 50°C to give 91.4 g (81.6%)of the off-white solid m.p.180–182°C (lit.179 –182 C). 3,4,5-TrimethoxybenzaldehydeAbout 142.0 g (0.74–0.79 mol) of freshly prepared 28–30 wt %sodium methoxide, 8 mL of DMF, 4 g of cuprous chloride and 56.0 g (0.20 mol) of 3,4-Dibromo-4- hydroxybenzaldehyde were added into a 500 mL magnetically stirred stainless steel autoclave. After the air was replaced with N2, the autoclave was heated to 120°C and kept at the temperature for 3 h. After being cooled to room temperature, the reaction mixture was taken out from the autoclave and transferred into a round-bottomed flask. Solvents were evaporated from the flask in vacuo below 60°C, and the residue was treated with 200 mL of water. The mixture was stirred and heated to 90°C for dissolution, then cooled to 0°C for crystallization. After NaBr dissolved in the stock was removed by filtration, yellow green sodium phenolate 8 was obtained. The filter cake was dissolved in 300 mL of water, added with 1.5 g of active carbon,and then heated to 95°C for 30 min. After hot-filtration for removing the filter residue (catalyst included), the filtrated stock was cooled to 40°C, and was treated by slowly dropping 50.0 g (0.40 mol) of dimethylsulfate and 30 wt% 112 g (0.84 mol) of NaOH aqueous solution during 2 h. The pH value should be carefully controlled within 8.5–9.3. Stirring was continued at 50°C for 30 min and then at 0°C for 30 min, and the product was collected by filtration. It was washed with water up to neutrality and dried in vacuo at 45°C to give 32.4 g (82.6%) of 3,4,5-trimethoxybenzaldehyde as colorless crystals, m.p. 74–75°C (lit. 73–75°C). 3,4,5-Trimethoxybenzaldehyde from 3,4,5-Trimethoxybenzyl chlorideJ. Chem. U.A.R., 11, No. 3, 401-404 (1968)Sommelet Method--To a solution of 11 g of hexamethylenetetramine (hexamine) in 70 mL of chloroform was added 18 g (0.07 mole) of 3,4,5-trimethoxybenzyl chloride. The solution was refluxed for 4 hr during which time a precipitate of the quaternary salt was formed. The solvent was removed under reduced pressure and 35 mL of acetone was added. The precipitate was filtered off and heated for 20 min with 100 mL of water. Concentrated hydrochloric acid (17.5 mL) was added and the refluxing was continued for 5 min. After concentration under reduced pressure and cooling the precipitated aldehyde was filtered off. It forms colourless needles from benzene (12 g, 66% yield), mp 72-74°C. 3,4,5-TrimethoxybenzaldehydeA solution of 39.6 g (0.2 mole) of 3,4,5-trimethoxybenzyl alcohol in 250 ml of methanol was stirred and cooled to 0°C. Bromine (54 ml) was added with stirring over a period of one hr keeping the temperature at 0°C. The stirred mixture was allowed to acquire room tempterature gradually and stirred further for 2 hr. A saturated solution of sodium thiosulfate (about 30 ml) was added to effect complete decomposition of excess bromine. 3,4,5-Trimethoxybenzaldehyde was filtered off and recrystallized from benzene to give 31 g (80%) as colourless needles, m.p. 73-74°C. Reference: J. Chem. U.A.R., 11, No. 3, 401-404 (1968) Preparation of 3,4,5-trimethoxybenzaldehyde[Arch. ital. sci. farmacol. [3] 2, 376-83 (1952); Chem Abs 3314h (1956)] To 300g gallic acid in 300ml H2O was added 900ml warm 50% NaOH while bubbling alkaline pyrogallol-washed nitrogen through the solution and then 900g Me2SO4 within 1h at 40-50°C. The mixt. cooled and 75 g. NaOH added, the mixt. refluxed for 3 hrs. and cooled again, 900ml conc HCl with 1 kg crushed ice added, the ppt. sepd., washed with H2O, dissolved in 2000ml 40% EtOH, and kept 12 hrs. at 0°C pptg. 3,4,5-trimethoxybenzoic acid. 200 g 3,4,5-trimethoxybenzoic acid was refluxed with 114g SOCl2 for 2 h, excess SOCl2 distd. off at reduced pressure, the mixt. cooled, and the solidified product suspended in petroleum ether, refluxed 10 min. with 1% activated carbon, filtered, and cooled to 0°C yielding 3,4,5-trimethoxybenzoyl chloride. To 150g 3,4,5-trimethoxybenzoyl chloride in 2100ml Et2O was added slowly with stirring 120g aniline in 510ml Et2O and the mixt. allowed to stand 1h, filtered, stirred with 2% NaCl, filtered, and washed with NaCl soln. yielding the anilide, of which (100 g) with 75 g PCl5, warmed to 70°C to evolve HCl and heated further to dist. off excess PCl5 yielded the imidochloride. To 90 g if the imidochloride in 2000ml Et2O was added an ethereal SnCl2 soln., the mixt. held at 0° for 12 hrs., the pptd. Sn salt sepd., washed with Et2O, and refluxed with AcOH-HCl-H2O (200:175:325 ml) for 1h, cooled, diluted with H2O and extd. 3 times with Et2O, dried. and crystd. to yield 3,4,5-trimethoxybenzaldehyde. Reduction of 3,4,5-TrimethoxybenzylcyanideThe same general procedure can be used for the reduction of 2,5-dimethoxy-benzylcyanide Placed 11.6 g (0.056 m)of 3,4,5-tri-MeO-benzylcyanide in flask, added 300 ml of methanol, and then 20 g of NiCl2*6H2O. Under magnetic stirring added 19g (0.5 mol) of NaBH4 in small portions over 30 min. Immediately black color appeared. Temp. during the addition rose to 40-50°C, and evolution of H2 observed. Flask was cooled with an ice/water bath to prevent violent boiling. When addition of borohydride was complete ice bath was removed and flask stirred for 3 hours at room temperature, after cooling 200 ml of 3N HCl added to the reaction mixture and the black solids filtered [recycling the nickle boride]. After removal of methanol at the rotovap unreacted nitrile [~1gm] was extracted with DCM, the aqueous layer made alkaline with conc. ammonia soln [turns deep blue upon addition of ammonia] and then extracted with DCM 3x100 ml. Combined extracts were washed with brine, dried over MgSO4 and evaporated. Obtained an oil (8.2g, 71% yield) which was converted to the HCl salt by dissolving in 20 ml IPA, acidified w/110 drops conc. HCl [to pH4] and precipitated by the addition of 100 ml diethyl ether to yield 8.5 gm snow white needles [62% yield overall]. 3,4,5-Trimethoxybenzaldehyde from 3,4,5-Trimethoxybenzoic acidStep (a): preparation of 3,4,5-Trimethoxy-ethyl carbonate. 10.8 g (0.10 moles) of ethyl chloroformate are dissolved in ml 100 of tetrahydrofuran. This solution is then added under stirring and cooling at 5-10°C., during 10-30 minutes to a solution of 21.2 g (0.10 moles) of 3,4,5-trimethoxy-benzoic acid and 12.12 g (0.12 moles) of triethylamine in 200 ml of tetrahydrofuran. At the end of the addition the reaction mixture is kept at the room temperature during 2 hours under continuous stirring. The so-formed precipitate is filtered, throughly washed with tetrahydrofuran and discarded. On the joined reaction solution and washing liquids, we may directly proceed to the catalytic reduction for the preparation of the 3,4,5-trimethoxy-benzaldehyde. The 3,4,5-trimethoxy-benzoyl-ethyl carbonate may be isolated by means of complete evaporation under a vacuum of the mother liquids at the temperature between 50-70°C. The residue is a white microcristalline solid (26.7 g; yield 94%) with mp 92-94°C. The substance is remarkably stable and keeps well also at room temperature. It is not affected by moisture. Step (b): Reduction to 3,4,5-trimethoxy-benzaldehyde To a solution of 28.4 g (10.1 moles) of 3,4,5-trimethoxy-benzoylethyl carbonate in ml 300, prepared as described in step (a), 14.2 g of Pd supported on BaSO.sub.4 (10%) and 0.1 ml of a solution of sulfur and quinoline prepared following Rosemund and Zetzsche and diluted 1:3000 are added. The mixture is hydrogenated in a PARR apparatus in an hydrogen atmosphere at ordinary pressure and 25.degree. C. under efficient shaking during 12 hours. The catalyst is removed by filtration and recovered, whereas the organic solution is washed with a 5% NaOH solution and finally evaporated in a vacuum. 17.64 g of 3,4,5-trimethoxybenzaldehyde are obtained, with the same characteristics generally described in the literature. Reference: US Pat 4,240,984 |
3,4,5-trimethoxybenzoic
acid