---

A CONVENIENT SYNTHESIS OF
3,4-DIMETHOXY-5-HYDROXYBENZALDEHYDE

James E. Ellis and Steven R. Lenger

Parke-Davis Pharmaceutical Research Division, Warner Lambert Co., Chemical
Development Department, 188 Howard Ave., Holland, Michigan 49424

ABSTRACT: Synthesis of 3,4-dimethoxy-5-hydroxybenzaldehyde (1) in three
steps from vanillin with the key step being a copper catalyzed hydrolysis of 5-
bromovanillin to give 4,5-dihydroxy-3-methoxybenzaldehyde.

A series of novel hydroxybutenolide compounds with activity as endothelin
antagonists was discovered recently in our endothelin program. These compounds
are non-peptides and have selective activity at nanomolar concentrations with
endothelin A receptors.1 We required a method to prepare 3,4-dimethoxy-5-
hydroxybenzaldehyde (1) as an intermediate to the hydroxybutenolides as part of
this program. The synthesis of 1 has also been of considerable interest to groups
working in other areas such as gallolignins and flavonoids.2,3,4 In this paper we will
describe the development of a short and facile procedure that allows preparation of
the desired benzaldehyde on moderate scale.

In our initial work, small quantities of 1 were prepared using the method of
Jacob and Shulgin2a which is shown in Scheme 1. Their synthetic route involved 6
steps starting from vanillin (2) with an overall yield of 51%. This route involved
protecting the aldehyde group as its cyclohexylimine (3), which was purified by
vacuum distillation. The purified imine was then converted to 1 in four steps using
a one-pot sequence. The protected bromovanillin, 3, was lithiated with
butyllithium and immediately treated with tributyl borate. After warming to room
temperature, the borate intermediate was reacted with 30% hydrogen peroxide and
then quenched into dilute acid to give 1. Evaluation of this method identified
several potential problems for scale-up. The imine 3 is very high boiling requiring
very good vacuum (< 1 mm Hg). A low temperature system is required for the
lithiation and boronation, which are done at -78 °C. Finally, the peroxide reaction
is quite exothermic and probably difficult to handle on large scale. With these
considerations in mind we started looking for alternate routes to 1.
Several other synthetic routes to 1 have been published. Synthetic routes
to 1 from gallic acid derivatives in 5 steps in less than 25% overall yield were
described Mauthner33 and also by Battersby.3b Both routes required Rosenmund
reduction of benzoyl chloride intermediates to aldehydes to complete the
syntheses. The low overall yields of these routes made them unattractive. More
recently, Iinuma described a route to 1 from o-vanillin (4) that involved 5 steps in
an overall yield of approximately 20% shown in Scheme 2.4 The key reactions in
this route are a Baeyer-Villiger reaction with peroxyformic acid followed by a
Rosenmund-von Braun cyanation with cuprous cyanide run at 200°C. There was
no advantage to this route either since it had a low overall yield combined with the
use of column chromatography and dangerous reagents such as peroxyformic acid
and cuprous cyanide to prepare 1.
We wanted a scalable route with a high degree of atom efficiency. In
planning this synthesis we also hoped to avoid undesirable chromatography, high
vacuum distillations and temperatures outside a range of- 40 to 150°C, all of
which are used in the literature methods.
We have now developed a three step synthesis of 1 from vanillin shown in
Scheme 3 which achieved these goals. The first intermediate was 5-bromovanillin
(5a) which is commercially available or can be prepared by bromination of vanillin
with bromine in acetic acid by the method of Dakin.5

In the key reaction, 5a was converted to 3-methoxy-4,5-dihydroxy
benzaldehyde (6) using copper catalyzed base hydrolysis. The hydrolysis of 5-
bromovanillin has been done by several groups by heating the reaction mixture
containing stoichiometric quantities of copper powder in an autoclave at 210 °C for
1 or 2 hours with isolated yields of approximately 40%.6 We found that the
reaction can be done under milder reaction conditions than previously reported.
To accomplish the hydrolysis, 5a is heated in 8% sodium hydroxide solution with
1.5 mole % copper powder at 101 °C for 24-27 hours, using a modification of the
method of Wehrli.7 The desired 6 was isolated using continuous extraction with
ethyl acetate and obtained in 60-70% yield after recrystallization from toluene.
This hydrolysis required the presence of the 4-hydroxy group to give the desired
hydrolysis. When the same reaction conditions were used with the 4-methoxy
analogue (5-bromo-veratraldehyde, 5b), the aldehyde group reacted in a
Cannizzaro reaction to give 5-bromo-3,4-dimethoxybenzoic acid (7) in good yield
as previously reported by Schriner and McCutchan.8
Methylation of 6 with 1.1 equivalent of dimethyl sulfate and sodium
carbonate in acetone gave the desired benzaldehyde in 70% yield. Only trace
amounts of the regioisomeric product, syringaldehyde (3,5-dimethoxy-4-hydroxy
benzaldehyde), were noted by TLC. The primary by-product is 6-10% of the
over-methylated product, 3,4,5-trimethoxy benzaldehyde, from which the desired
product was easily removed by alkaline extraction followed by acidification. The
crystalline product can be recrystallized from either toluene-heptane or methanolwater.
In conclusion, we have developed a convenient synthesis of the useful
synthetic intermediate 3,4-dimethoxy-5-hydroxybenzaldehyde that can be run on
moderate scale and is operationally scalable. Our overall yield is comparable to the
method of Jacob and Shulgin but our method avoids undesirable distillations and
low reaction temperatures. In addition, our method is safer because it minimizes
the use of toxic or hazardous reagents. The one dangerous reagent common to all
the routes is dimethyl sulfate. This reagent is essentially unavoidable since all the
routes require preparation of methyl ethers. However, it is the least volatile of the
typical methylating agents and thus the easiest to control on large scale.

Experimental
All of the reagents used in this study were purchased from the Aldrich Chemical
Company. All of the reactions were run under a nitrogen atmosphere. The *H
spectra were taken on a Varian 200 MHZ spectrometer, chemical shifts are
expressed in ppm from tetramethylsilane as an internal standard. The melting
points were determined on a Buchi melting point apparatus and are uncorrected.

3-Methoxy-4.5-dihydroxybenzaldehyde (6)
5-bromovanillin (5) (200 g, 0.91 mol), sodium hydroxide (245 g, 6.1 mol) and
copper powder (1 g, 0.016 mol) were slurried into 3 L water. The reaction
mixture was heated at reflux for 24-27 hours. Sodium hydrogen phosphate (4.5 g,
0.032 mol) is added for the last half hour of reflux. The reaction is then cooled to
less than 50 °C, filtered to remove a precipitate of cupric hydrogen phosphate and
acidified with hydrochloric acid (460 g). The reaction mixture was placed in a
continuous extractor and extracted with ethyl acetate (3 L). The ethyl acetate
extract was stirred with activated carbon and filtered. The filtrate was washed
with saturated aqueous EDTA solution followed by salt. The solution was then
dried over magnesium sulfate and filtered. The ethyl acetate solution was
concentrated to a crude solid. The crude product was dissolved in boiling toluene
(2 L), treated with activated carbon, filtered and cooled to crystallize. The
product, 3-methoxy-4,5-dihydroxy benzaldehyde, was isolated in approximately 60
% yield (86 g) with a mp 132-133 °C (lit.7a mp 132-134°C); XH NMR (200 MHz,
d6-DMSO) 3.7 (3H, s, OCH3), 6.98 (1H, d, ArH, J=9Hz), 7.01 (1H, d, ArH,
J=9Hz), 9.5 (2H, s, ArOH), 9.6 (1H, s, CHO).

3.4-dimethoxy-5-hydroxybenzaldehyde (1)
3-Methoxy-4,5-dihydroxybenzaldehyde (100 g, 0.595 mol), dimethyl sulfate
(75.0 g, 0.595 mol) and sodium carbonate (69.4 g, 0.654 mol) were slurried into
acetone. The reaction mixture was heated at reflux for 4-6 hours and then cooled
to room temperature. After filtering to remove inorganic salts, the acetone was
removed by distillation and replaced with toluene. The toluene solution was
stirred at room temperature for one hour and filtered to remove an insoluble tar.
The product was extracted with a dilute sodium hydroxide solution. The water
layer was separated, acidified with hydrochloric acid to a pH of 1-2 and extracted
with toluene. The toluene layer was dried with magnesium sulfate then treated
with activated carbon and filtered. The toluene solution was concentrated to an oil
which readily crystallizes to give 1 in 70% yield (75.8 g). The product can be
recrystallized, if necessary, from a 2:1 mixture of toluene / heptane. 3,4-
dimethoxy-5-hydroxybenzaldehyde was obtained with mp 65.6-66.5°C (lit.4a mp
64-65°C); ^NMR (200 MHz, CDC13) 3.91 (3H, s, OCH3), 3.98 (3H, s,
0CH3), 6.1 (1H, S, ArOH), 7.0 (1H, d, ArH, J=9Hz), 7.1 (1H, d, ArH, J=9Hz),
9.8 (1H, d, CHO).

---