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3,4,5-TRIMETHOXYBENZALDEHYDE
2813
Synthesis of 3,4,5-Trimethoxybenzaldehyde 1: About 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 6 were added
into a 500 mL magnetically stirred stainless steel autoclave. After the air
was replaced with N2, the autoclave was heated to 120ꢀC 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
60ꢀC, and the residue was treated with 200 mL of water. The mixture was
stirred and heated to 90ꢀC for dissolution, then cooled to 0ꢀC for crystal-
lization of 8. 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
95ꢀC for 30 min. After hot-filtration for removing the filter residue (catalyst
included), the filtrated stock was cooled to 40ꢀC, 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 con-
trolled within 8.5–9.3. Stirring was continued at 50ꢀC for 30 min and then at
0ꢀC for 30 min, and the product was collected by filtration. It was washed
with water up to neutrality and dried in vacuo at 45ꢀC to give 32.4 g (82.6%)
of 1 as colorless crystals, m.p. 74–75ꢀC (lit. 73–75ꢀC).[5] 1H NMR: ꢀ ¼ 3.89
(s, 9H, OCH3), 7.10 (s, 2H, ArH), 9.80(s, 1H, CHO); IR (KBr) ꢁ ¼ 2943,
2830, 1670, 1585, 1498, 1125 cmÀ1; EIMS m/z ¼ 196 (Mþ, 100), 181
(MÀCH3, 59), 165 (MÀOCH3, 5%).
REFERENCES
1. Hoffmann-La Roche Inc. Process for Preparing 2,4-Diamino-5-(substi-
tuted benzyl)-pyrimidines. US Patent 4,115,650, Sep. 19, 1978.
2. Manchand, P.S.; Rosen, P.; Belica, P.S.; Oliva, G.V.; Perrotta, A.V.;
Wong, H.S. Synthesis of Antibacterial 2,4-Diamino-5-benzylpyrimi-
dines. Ormetoprim and Trimethoprim. J. Org. Chem. 1992, 57(13),
3531–3535.
3. Rao, D.V.; Stuber, F.A. An Efficient Synthesis of 3,4,5-
Trimethoxybenzaldehyde from Vanillin. Synthesis 1983, (4), 308.
4. Kitajima, N.; Takemura, K.; Moro-oka, Y.; Yoshikuni, T.; Akada, M.;
Tomotaki, Y.; Taniguchi, M. The Selective Liquid-Phase Oxidation of
3,4,5-Trimethoxytoluene to 3,4,5-Trimethoxybenzaldehyde. Bull. Chem.
Soc. Jpn. 1988, 61(3), 1035–1037.
5. Manchand, P.S.; Belica, P.S.; Wong, H.S. Synthesis of 3,4,5-
Trimethoxybenzaldehyde. Synth. Commun. 1990, 20(17), 2659–2666.