Efficient and convenient synthesis of 3,4,5-trimethoxybenzaldehyde from p-cresol

Article abstract of DOI:10.1081/SCC-120006464

With p-cresol as starting material, 3,4,5-trimethoxybenzaldehyde was synthesized in an overall yield of 67.4% via bromination, hydrolysis, methoxylation and methylation.

Full text of DOI:10.1081/SCC-120006464

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EFFICIENT AND CONVENIENT SYNTHESIS OF 3,4,5-
TRIMETHOXYBENZALDEHYDE FROM p-CRESOL
Ya-Fei Ji a , Zhi-Min Zong a & Xian-Yong Wei b
a School of Chemical Engineering, China University of Mining and Technology, Xuzhou,
Jiangsu, 221008, P.R. China
b School of Chemical Engineering, China University of Mining and Technology, Xuzhou,
Jiangsu, 221008, P.R. China
Available online: 18 Oct 2011
To cite this article: Ya-Fei Ji, Zhi-Min Zong & Xian-Yong Wei (2002): EFFICIENT AND CONVENIENT SYNTHESIS OF 3,4,5-
TRIMETHOXYBENZALDEHYDE FROM p-CRESOL, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 32:18, 2809-2814
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 18, pp. 2809–2814, 2002
EFFICIENT AND CONVENIENT
SYNTHESIS OF
3,4,5-TRIMETHOXYBENZALDEHYDE
FROM p-CRESOL
*
Ya-Fei Ji, Zhi-Min Zong, and Xian-Yong Wei
*
School of Chemical Engineering,
China University of Mining and Technology,
Xuzhou, 221008, Jiangsu, P.R. China
ABSTRACT
With p-cresol as starting material, 3,4,5-trimethoxybenzalde-
hyde was synthesized in an overall yield of 67.4% via bromi-
nation, hydrolysis, methoxylation and methylation.
Key Words: p-Cresol; Bromination; Hydrolysis; Methoxyla-
tion; Methylation; 3,4,5-Trimethoxybenzaldehyde
The most important use of 3,4,5-trimethoxybenzaldehyde 1 as a phar-
maceutical intermediate is to prepare the antibacterial agent trimethoprim
2,[1,2] which is a potent and selective inhibitor of bacterial dihydrofolate
reductase. Trimethoprim is used solely, or in combination with sulfamethoxa-
zole 3, to treat a wide range of bacterial infections in humans and poultry.
Previous synthesis of 1 has been achieved simply from vanillin by
bromination, followed by a cuprous chloride-catalyzed displacement of bro-
*Corresponding authors. E-mail: jyf@imm.ac.cn or weixy@public.xz.js.cn
2809
DOI: 10.1081/SCC-120006464
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2810
JI, ZONG, AND WEI
mine by methoxide.[3] Another synthesis of 1 has been developed through
the liquid-phase oxidation of 3,4,5-trimethoxytoluene to the corresponding
aldehyde with Co(OAc)2–Mn(OAc)2 as catalyst.[4] Although 1 can be
obtained in high yields and fewer steps, the relatively high cost of starting
material vanillin and 3,4,5-trimethoxytoluene necessitates further work to
find an efficient and convenient approach to 1 for a practical industrial
process. Manchand et al.[5] reported an attractive method of the preparation
of 1 that relies on the methylation of syringaldehyde 7, which was synthes-
ized from p-cresol via a series of reactions shown in Scheme 1. However, low
yield (60%) of 3,5-dibromo-4-hydroxybenzaldehyde 6, large amount con-
sumption of solvent DMF due to its liability to thermolysis in the presence
of CH3ONa during the methoxylation of 6, the use of the solvent acetone
and long reaction time (18h) in the methylation of 7 restrict its application
as an efficient industrial process. Therefore, a more economical, convenient
and environment-friendly synthesis of 1 is needed.
In general, the requirement of solvents such as hexamethylphosphor-
ous triamide (HMPT), DMF and pyridines and the requirement of copper-
catalyst characterize the methoxylation of non-activated aromatic
bromides.[6,7] It is difficult to increase reflux temperature due to the release
of ‘‘solvent cage bonded’’ methanol from sodium methoxide.[8] The low
reflux temperature and the low CH3ONa concentration disadvantage the
progress of the methoxylation.
We improved herein a procedure of preparation of 1. As Scheme 2
shows, the bromination of 4 in the solvent o-dichlorobenzene at 40ꢀC and
then at 160ꢀC respectively gave the tetrabromide 5, and then the direct hydro-
lysis of 5 with H2O afforded 6 in an overall yield of 81.6% from 4. Using
o-dichlorobenzene instead of chlorobenzene as solvent and one-pot method
for the synthesis of 6 were one character of our procedure. GC/MS analysis
shows that major by-product formed in the synthesis of 6 was 3,5-dibromo-4-
hydroxybenzoic acid (<1%) while another possible by-product 3,5-dibromo-
4-hydroxybenzyl alcohol was not detected. de la Mare and Newman[9,10]
reported that the hydrolysis of 2,6-dibromo-4-dibromomethylphenol 5 was
very rapid to give 6, which was easily oxidized to afford the corresponding

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3,4,5-TRIMETHOXYBENZALDEHYDE
2811
Scheme 1.
acid. It is consistent with our experimental results. Treatment of 6 with
3.7–3.9 equivalents of freshly prepared sodium methoxide (ca. 28–30 wt%)
in the presence of catalytic amount of cuprous chloride[11] and DMF at
120ꢀC[12] in autoclave gave sodium phenolate of 3,5-dimethoxy-4-hydroxy-
benzaldehyde 8. The sodium phenolate was directly methylated with
dimethylsulfate in NaOH aqueous solution, affording 1 in the yields of
80.0–82.6%. Methanol was used as solvent for methoxylation of 6. Only
small amount of DMF was used as a co-solvent. Using H2O as solvent for
the methylation of 8, NaOH can act as a good acid-capturing agent and
thereby the reaction time was shortened to 2–3 h. Hence, conventionally
used solvent acetone is unnecessary. The use of the high concentration of
sodium methoxide and the utilization of the adequate crystallizability of 8
for isolation are the other two characters of our procedure.
EXPERIMENTAL
Melting points were determined in capillaries on a domestic melting
1
point apparatus and are uncorrected. H NMR spectra were recorded on a
Bruker ARX-300 spectrometer with TMS as the internal standard in CDCl3.
Chemical shifts were expressed in parts per million (ꢀ, ppm). FTIR spectra
were collected using a Nicolet Magna IR-560 spectrometer as neat films.
GC/MS analysis was carried out using HP 6890 gas chromatograph

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2812
JI, ZONG, AND WEI
Scheme 2.
equipped with HP 5973 detector and m/z values were given with relative
intensities in parentheses. Silica gel plates were used for analytical TLC and
the spots were visible with iodine vapor.
Synthesis of 3,4-Dibromo-4-hydroxybenzaldehyde 6: 3-Necked round-
bottomed flask equipped with a condenser attached to a calcium chloride
drying tower, a mechanical stirrer, a thermometer, and a dropping funnel
was charged with a solution of 43.2 g (0.40 mol) of p-cresol in 200 mL of
o-dichlorobenzene. The solution was cooled to 10ꢀC and treated during 1 h
with a solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-
benzene at such a state that the temperature was kept below 40ꢀC. The
mixture was stirred, heated at 160ꢀC and simultaneously dropped with
another solution of 130.0 g (0.81 mol) of bromine in 100 mL of o-dichloro-
benzene during 3 h. This deep red mixture was sequentially stirred for
30 min. After being cooled to room temperature and 145 mL of water
being added, the mixture was heated to 120ꢀC and kept at the temperature
for 4 h. After being cooled to 5ꢀC, the mixture was separated into upper
organic layer, middle aqueous layer and lower solid layer. The solid prod-
uct was collected by filtration and washed with water up to neutrality. It
was dried in vacuo at 50ꢀC to give 91.4 g (81.6%) of the off-white solid 6,
m.p. 180–182ꢀC (lit. 179–182ꢀC).[5] 1H NMR: ꢀ ¼ 6.45 (s, 1H, OH), 7.90
(s, 2H, ArH), 9.76 (s, 1H, CHO); IR (KBr) ꢁ ¼ 3195, 1675, 1560,
1510 cmÀ1; EIMS m/z ¼ 280 (Mþ, 72), 279 (MÀH, 100), 251 (MÀCHO,
14), 199 (MÀHBr, 2%).

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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%).
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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.

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2814
JI, ZONG, AND WEI
6. Lindley, J. Copper-assisted Nucleophilic Substitution of Aryl Halogen.
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´
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Hydrolysis Promoted by Aromatic Hydroxy Group. Part 1. The
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Dibromo-4-bromomethylenecyclohexa-2,5-dienone with Water in
95% 1,4-Dioxane. J. Chem. Soc., Perkin Trans. II 1984, (2), 231–238.
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11. Cuprous Chloride Needed no Deterioration, Just as well Freshly
Prepared.
12. Under our Work Conditions, Reaction Pressure was about 0.4 MPa.
Received in the UK July 31, 2001