Rosenmund reduction of 3,4,5-trimethoxybenzoyl chloride¹

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

Notes:

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).

3,4,5-Trimethoxybenzaldehyde

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.