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The copper(I)-catalyzed exchange of bromine by methoxide in 5-bromovanillin and in 3,5-dibromo-4-hydroxybenzaldehyde provides an efficient method for preparing 3,5-dimethoxy-4-hydroxybenzaldehyde, from which 3,4,5-trimethoxybenzaldehyde is obtained by methylation with dimethylsulfate.
3,4,5-Trimethoxy- benzaldehyde (1) is an important starting material used in the synthesis of certain pharmaceuticals, such as the antibacterial trimethoprim (2)1.
Previous syntheses of 1 have been achieved from 3,4,5-trimethoxybenzoyl chloride by a modified Rosenmund reduction2 and by application of the Reissert reaction3. Although both routes are satisfactory for most purposes, certain considerations, primarily economic, led us to examine other approaches to 1.
We describe herein the preparation of 1 that relies on the preparation of syringaldehyde (7) from 5-bromovanillin (5) and from 3,5-dibromo-4-hydroxybenzaldehyde (6) using a copper(I)-catalyzed exchange of bromine by methoxide in DMF4. The high yields obtained (88-91%) by us for the exchange reaction is somewhat surprising since Bacon and Rennison5 had reported that the presence of an aldehyde group is deleterious to the reaction. However, it should be noted that they had carried out the exchange reaction in the presence of 2,4,6-collidine.
Bromination of vanillin (3) in methanol gave 5-bromovanillin (5) directly from the reaction medium in 95% yield. Treatment of 5 in DMF with ca. four equivalents of freshly prepared sodium methoxide in the presence of a catalytic amount of cuprous chloride6 gave, after acidification, syringaldehyde (7) in 91% yield. Methylation of 7 with dimethylsulfate in the presence of Na2CO3 gave 1 in 91% yield. In a similar manner, 4-hydroxybenzaldehyde was brominated to give 3,5-dibromo-4-hydroxybenzaldehyde (6), which was converted into 7 in 88% yield by the copper(I)-catalyzed exchange of the bromo substituents by methoxide.
3,5-Dibromo-4-hydroxy-benzaldehyde was also prepared by the direct bromination of p-cresol with 4.5 equivalents of bromine in chlorobenzene, initially at 25°C and then at reflux, to give the tetrabromide 9, hydrolysis of which with 1N HCl afforded 6 in 60% yield. The major by-products formed in this synthesis of 6 were the ester 10 (20%) and the ether 11 (7%).
Melting points were determined in capillaries on a Thomas-Hoover melting point apparatus and are uncorrected. Unless otherwise indicated, infrared (IR) and nuclear magnetic resonance spectra (NMR) were determined in CHCl3 and CDCl3, respectively; 1H and 13C NMR spectra were recorded at 200 and 50.4 MHz, respectively. Chemical shifts are expressed in parts per million (ppm) relative to tetramethylsilane, and coupling constants (J) are expressed in hertz (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet). Mass spectra (MS) were determined with a direct inlet system with ionization energy of 70 eV; m/z values are given with relative intensities (%) in parentheses. Thin-layer chromatograms (TLC, silica gel G) were purchased from Merck (Darmstadt); spots were visible under short wavelength UV light or made visible by spraying with 10% phosphomolybdic acid in ethanol and heating the plates to 100°C.
To a stirred, cooled (0°C) solution of 152.15 g (1.0 mol) of vanillin in 1.0 L of methanol was added during 20 min 176.0 g (1.1 mol) of bromine at such a rate that the temperature was kept below 20°C. The mixture was stirred at room temperature for 1 h, cooled to 0°C, and treated during 30 min with 500 mL of cold (5°C) water. Stirring was continued for 15 min and the product was collected by filtration. It was washed with water (4 x 500 mL), then with 500 mL of cold (0°C), 70% methanol, and dried in vacuo at 50°C overnight to give 218.5 g (95%) of 5 as pale yellow crystals, mp 163-164°C (Lit.7 mp 163-164°C);
A stirred mixture of 153.0 g (0.84 mol) of syringaldehyde (7) in 1.0 L of acetone, was treated with 127.0 g (1.02 mol) of dimethylsulfate, 118.0 g (1.11 mol) of anhyd. Na2CO3, and 3.0 g (0.053 mol) of KOH in 32 mL of water. The mixture was stirred under reflux for 18 h. cooled to room temperature and filtered. The filter cake was washed with acetone (3 x 200 mL) and the filtrate and washings were concentrated to ca. 200 mL. The stirred solution was diluted with 500 mL of water during 30 min, followed by 1.5 L of water during 15 min. Stirring was continued at room temperature for 15 min and then at 0°C for 30 min, and the product was collected by filtration. It was washed with water (4 x 2.0 L) and dried in vacuo at 25°C for 24 h to give 150.2 (91.5%) of 1 as colorless crystals, mp 73-75°C (Lit.9 74°C). TLC (4:1 ether-hexane) revealed only one spot, Rf 0.57.