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3,4,5-Trimethoxybenzaldehyde from Gallic Acid

A Collection of various Literature Procedures

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Rosenmund reduction of 3,4,5-trimethoxybenzoyl chloride1


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, bp 158?161?C/7?8 mmHg, mp 74?75?C (Note 9) and (Note 10).


  1. Both glass-lined and stainless-steel autoclaves have been used successfully. The checkers used a 1200 mL Hastelloy autoclave.
  2. Reagent grade toluene was heated at reflux to remove a small forerun, then allowed to cool.
  3. Anhydrous sodium acetate was dried in a vacuum oven at 115? C for 48 hours. The use of less than 3 moles of sodium acetate per mole of acid chloride results in a lower yield of product.
  4. A catalyst available from Engelhard Industries was used after being dried in a vacuum oven at 115? C for 48 hours. Caution! Palladium-on-carbon is pyrophoric, and vacuum drying increases this hazard. Catalysts kept in the oven for longer periods of time were extremely pyrophoric.
  5. The acid chloride or the acid may be purchased from Aldrich Chemical Company, Inc. The acid chloride must be pure (99% minimum by GC analysis) whether purchased or prepared. Purification was effected by recrystallization from Skellysolve B.
  6. Quinoline S was prepared according to the procedure in Org. Synth., Coll. Vol. 3, 629 (1955)
  7. Repressuring with hydrogen is required during this period. The amount of repressuring required is dependent upon the free space of the pressure vessel. The submitters report lower yields if the pressure falls below 30 psi. No further repressuring is made at the end of 1 hour.
  8. The crude aldehyde (prior to distillation) is sufficiently pure for most purposes. Isolation of the aldehyde may also be achieved via the bisulfite-addition compound.
    [A. I. Vogel, Textbook of Practical Organic Chemistry, 3rd ed., Wiley, New York, 1956, p. 322.]
  9. The product shows a strong IR band (KBr) at 1690 cm-1 (C=O).
    1H NMR (CCl4): δ 3.84 (s, 3H), 3.87 (s, 6H), 7.03 (s, 2H), and 9.76 (s, 1H).
  10. The submitters state that the aldehyde is obtained in 78?84% yield when the reaction is conducted on a scale 5 times that described. The amount of catalyst and Quinoline S need not be increased proportionately. The pressure vessel is charged with 3L of dry toluene, 123g of anhydrous sodium acetate, 10g of dry, 10% palladium-on-carbon catalyst, 115g of 3,4,5-trimethoxybenzoyl chloride, and 4mL of Quinoline S.

3,4,5-TMBA via the Methyl Benzoate and Benzyl Alcohol2

Methyl 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).


Pyridinium dichromate (16.9 g) was added a solution of the crude alcohol (5.92 g) in dry CH2Cl2, (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.

3,4,5-TMBA by Sommelet Reaction of 3,4,5-Trimethoxybenzyl chloride3

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-TMBA by oxidation of the alcohol with bromine3

A 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.

3,4,5-TMBA via SnCl2 Reduction of 3,4,5-Trimethoxybenzanilide4

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.

3,4,5-TMBA via reduction of the Ethyl Carbonate

Step (a): preparation of 3,4,5-Trimethoxybenzoyl 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-trimethoxybenzaldehyde.

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 300 mL [???], prepared as described in step (a), 14.2 g of Pd supported on BaSO4 (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°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.

Reduction of 3,4,5-Trimethoxybenzylcyanide To Mescaline

The same general procedure can be used for the reduction of 2,5-dimethoxy-benzylcyanide

Placed 11.6 g (0.056 mol) 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 MgSO4and 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 pH 4]and precipitated by the addition of 100 ml diethyl ether to yield 8.5 gm snow white needles [62% yield overall].


  1. Organic Syntheses, Coll. Vol. 6, p. 1007
  2. Chem Pharm Bull 31, 3024 (1983)
  3. J. Chem. U.A.R., 11(3), 401-404 (1968)
  4. Chem. Abs. 3314h (1956)
    [Arch. ital. sci. farmacol. [3] 2, 376-83 (1952)]
  5. US Pat 4,240,984