Synthesis of
3,4,5-Trimethoxybenzaldehyde from Gallic Acid
and other Alkoxybenzaldehydes

Hisashi Ishii, et. al.
Chem. Pharm. Bull. 31, 3024-3038 (1983)

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Several benzaldehyde derivatives were prepared for use as synthetic starting materials:

  1. 3,5-Dimethoxybenzaldehyde1 (19c) was prepared by methylation of 3,5-dihydroxybenzoic acid (24) with dimethyl sulfate in acetone in the presence of potassium carbonate followed by reduction with lithium aluminium hydride and by oxidation with Collins reagent2 in 80.3% overall yield.
  2. 3,4,5-Trimethoxybenzaldehyde3 (19d) was also prepared by methylation of gallic acid (27) with the same reagent followed by reduction with Vitride4 and by oxidation5 with pyridinium dichromate6 (PDC) in 80.7% overall yield.
  3. 2-Methoxy-4,5-methylenedioxy-7 (19e) and 2,4,5-trimethoxy-8 (19f) benzaldehydes were obtained by Vilsmeier–Haack reaction of O-methylsesamol-7 (30) and 1,2,4-trimethoxybenzene9 (31), respectively.
  4. 5-Methoxy-2,3-methylenedioxy- (19g) and 2,3,5-trimethoxy-10 (19k) benzaldehydes were derived from 5-methoxy-2,3-methylenedioxy-11 (32) and 2,3,5-trimethoxy-12 (33) bromobenzenes by treatment with ethyl lithium followed by formylation with N,N-dimethylformamide (DMF).

Experimental


3,5-Dimethoxybenzaldehyde (19c)

Methyl 3,5-Dimethoxybenzoate (25)

A solution of 3,5-dihydroxybenzoic acid (24) (1.01g) and Me2SO4 (4 ml) in acetone (20 ml) containing K2CO3 (5.02g) was refluxed for 4h. After removal of K2CO3 by filtration, the excess reagent was decomposed with conc. NH4OH aq. The mixture was diluted with a large quantity of water and extracted with Et2O. The ethereal solution was washed with water, dried over Na2SO4, and evaporated to dryness in vacuo. Recrystallization of the residue from MeOH-H2O gave colorless pillars (1.16 g), mp 41°C (lit. mp 42-44°C13a; mp 41°C13b).

3,5-Dimethoxybenzyl Alcohol (26)

A suspension of LiAlH4 (1.22g) in abs. Et2O (12.8ml) was gradually added to a solution of the ester (25) (5.02g) in abs. Et2O (19.4ml). The suspension was refluxed for 3h. After decomposition of the excess of the LiAlH4 with wet Et2O followed by water, the ethereal layer was separated. The ethereal layer was dried over K2CO3 and evaporated to dryness in vacuo to give colorless needles (4.58g), mp 48°C (lit.1 mp 47-48°C).

3,5-Dimethoxybenzaldehyde (19c)

A solution of the alcohol (26) (5.04g) in CH2Cl2 (100ml) was added to the complex prepared from CrO3 (17.9 g) and pyridine (28.3 g) in CH2Cl2 (400 ml). The mixture was stirred at room temperature for 15 min. The precipitate was removed by decantation and washed with Et2O. The organic layers were combined and diluted with Et2O. After being washed with 5% NaOH aq., 5% HCl aq., 5% NaHCO3 aq. and sat. NaCl aq. successively, the ethereal solution was dried over MgSO4 and evaporated to dryness in vacuo. The residue was chromatographed on Al2O3 with benzene to give colorless pillars (4.37g), mp 46-47°C (lit.1 mp 45-46°C).


3,4,5-Trimethoxybenzaldehyde

Methyl 3,4,5-Trimethoxybenzoate (28)

A solution of gallic acid·H2O (27) (29.9g) in DMF (100ml) was added to a suspension of K2CO3 (97g) in DMF (200ml) 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 (44g) and Me2SO4 (30ml), then the reaction mixture was stirred at room temperature for a further 4.5h, 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 (lit.14 mp 83-84°C).

3,4,5-Trimethoxybenzyl Alcohol (29)

A solution of the ester (28) (9.86g) in abs. benzene (40ml) was added dropwise to Vitride4 (22 ml) under ice cooling. After the mixture had been stirred at room temperature for a further 1 h, the complex was decomposed with 25% H2SO4 aq. (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 (7.84g).

3,4,5-Trimethoxybenzaldehyde (19d)

Pyridinium dichromate6 [(C5H5N+H)2·Cr2O72-] (16.9g) was added to a solution of the crude alcohol (29) (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 4h. 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 (lit.3 mp 77°C), which were recrystallized from benzene-hexane.


2-Methoxy-4,5-methylenedioxybenzaldehyde (19e)

Phosphorus oxychloride (26ml) was added to a solution of O-methylsesamol7 (30) (34.60 g), bp 110-115°C (22 mmHg) [lit.7 bp 110-114°C (18 mmHg)], in DMF (67 ml) under ice cooling for 1.5 h. After the addition, the mixture was heated at 80°C for 1 h with stirring, then cooled. Saturated AcONa aq. (170 ml) was added to the reaction mixture under ice cooling to give colorless needles (36.4 g), mp 115-117°C (lit.7 mp 111.5-112°C), which were recrystallized from EtOH.


2,4,5-Trimethoxybenzaldehyde (19f)

Phosphorus oxychloride (5.5 ml) was added to a stirred solution of 1,2,4-trimethoxybenzene9 (31) (8.42g) in DMF (17 ml) under ice cooling. After the addition, the mixture was heated at 80°C for 1 h with stirring, then cooled. Saturated AcONa aq. (30 ml) was added to the reaction mixture under ice cooling to give colorless needles (9.80g), mp 114-115.5°C (lit.8 mp 114°C), which were recrystallized from EtOH.


5-Methoxy-2,3-methylenedioxybenzaldehyde (19g)

A solution of EtBr (3.3 ml) in abs. Et2O (12 ml) was added to a suspension of Li metal (0.40g) in abs. Et2O (13 ml) between -20 and -30°C for 10 min with stirring. When the Li metal had completely dissolved, a solution of 5-methoxy-2,3-methylenedioxybromobenzene11 (32) (5.10 g) in abs. Et2O (15 ml) was added dropwise to the solution at -20 to -30°C. The mixture was stirred at the same temperature for 1.4h, then a mixed solution of DMF (19ml) and abs. Et2O (20ml) was added and the reaction mixture was allowed to stand at room temperature for 2 h, poured into water, and extracted with Et2O. The ethereal solution was dried over K2CO3 and evaporated to dryness.

A solution of NaHSO3 (21.5g) in water (33 ml) was added to the residue and the mixture was heated at 100°C for 2h to give the bisulfite compound as a precipitate. The precipitate was collected by filtration, washed with benzene, and dissolved in water (70 ml). The aqueous solution was made alkaline with 10% NaOH aq. (13 ml), heated at 100°C for 30 min, then cooled. The resulting precipitate was collected by filtration and recrystallized from MeOH to give slightly yellow needles (2.62g), mp 79-80°C.


2,3,5-Trimethoxybenzaldehyde (19k)

A solution of EtBr (24ml) in abs. Et2O (125ml) was added to a suspension of Li metal (4.35 g) in abs. Et2O (190 ml) between -20 and -30°C over 10 min with stirring. After the Li metal had completely dissolved, a solution of 2,3,5-trimethoxybromobenzene12 (33) (5.10 g) in abs. Et2O (125 ml) was added dropwise to the above solution between -20 and -30°C. After the mixture had been stirred at the same temperature for 1.4 h, a mixture of DMF (62.6 ml) and abs. Et2O (190 ml) was added. The whole was stirred for 1 h, then poured into a large quantity of water. After Et2O extraction, the ethereal solution was dried over K2CO3 and evaporated to dryness. Distillation of the residue at 140-148°C (5 mmHg) gave colorless needles, mp 60-64°C [lit. mp 71°C;10a mp 61-62°C;10b mp 63°C10c].

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