Synthesis of 4-Methoxysalicylaldehyde via selective monomethylation of 2,4-dihydroxybenzaldehyde

Article abstract of DOI:10.3184/174751912X13295680217793

4-Methoxysalicylaldehyde, a naturally occurring product, has a range of industrial applications in the preparation of organic compounds, drugs and therapeutic agents. 4-Methoxysalicylaldehyde can be synthesised via selective monomethylation of 2,4-dihydroxybenzaldehyde in toluene in the presence of NaHCO₃ in higher yield using cheaper reagents with little production of dimethylation product compared to previous methods. The location of the methoxyl group was confirmed by conversion to 3-acetyl-7-methoxycoumarin by condensation with ethyl acetoacetate.

Full text of DOI:10.3184/174751912X13295680217793

144 RESEARCH PAPER
MARCH, 144–145
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of 4-methoxysalicylaldehyde via selective monomethylation of
2,4-dihydroxybenzaldehyde
Hai-Shan Jin*, Li-Ming Zhang, Zhi-Wei Yan and Feng-Yan Ma
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou 221116, Jiangsu, P. R. China
4-Methoxysalicylaldehyde, a naturally occurring product, has a range of industrial applications in the preparation of
organic compounds, drugs and therapeutic agents. 4-Methoxysalicylaldehyde can be synthesised via selective mono-
methylation of 2,4-dihydroxybenzaldehyde in toluene in the presence of NaHCO3 in higher yield using cheaper
reagents with little production of dimethylation product compared to previous methods. The location of the methoxyl
group was confirmed by conversion to 3-acetyl-7-methoxycoumarin by condensation with ethyl acetoacetate.
Keywords: 4-methoxysalicylaldehyde, synthesis, monomethylation, 3-acetyl-7-methoxycoumarin
4-Methoxysalicylaldehyde is a naturally occurring compound
present in the roots and bark of Periploca sepium.1 It is also a
useful building block for the synthesis of a large number of
organic molecules and natural products such as chalcones,
flavanones, and coumarins.2–5 In addition, 4-methoxysalicylal-
dehyde has a range of industrial applications in the preparation
of organic compounds, drugs, and therapeutic agents. There
are three main methods for the synthesis of 4-methoxysalicyl-
aldehyde starting from resorcinol described in the literature.
The first is formylation of 3-methoxyphenol by paraformalde-
hyde in the presence of the MgCl2-Et3N base system (Fig. 1).6–8
The second is demethylation of 2,4-dimethoxybenzaldehyde
in the presence of Lewis acid or other reagent (Fig. 2).9-12 These
two methods suffer from shortcomings with regard to multi-
step reaction (e.g., demethylation of 2,4-dimethoxybenzalde-
hyde) and costly reagents (e.g., MgCl2-Et3N, LiCl, CeCl3,
BCl3, and a volatile thiol). Most importantly, the selective
formylation or demethylation is not easy and is always
accompanied by an isomer.
The third method that appears to be more attractive involves
methylation of 2,4-dihydroxybenzaldehyde in alkali condition.
The formation of intermolecular hydrogen bond of the pheno-
lic OH group at the 2-position with carbonyl oxygen of alde-
hyde makes the methylation of the 2-OH more difficult than
the 4-OH. Methods relevant to this transformation include
K2CO3–MeI in acetone under reflux,3,13 NaHCO3–CH3Br in
DMF under reflux,14 K2CO3–methyl p-toluenesulfonate in
CH3CN under reflux,4 and K2CO3–Me2SO4 in acetone under
reflux.5 Unfortunately, all the syntheses of 4-methoxysalicyl-
aldehyde in alkali condition published to date suffer from one
or more the following disadvantages involving using costly
reagents (e.g. CH3I, CH3Br, and 18-crown-6), low boiling point
solvent that is inappropriately recycled in industry (e.g.
acetone), the formation of a dimethyl product, and a low
yield (53–65%). Consequently we considered new reaction
conditions for the preparation of 4-methoxysalicylaldehyde.
We now report the use of toluene as an efficient solvent and
NaHCO3 as a base for the formation of the 4-monomethyl
product formation in excellent yield.
Results and discussion
The 2,4-dihydroxybenzaldehyde 1 was readily prepared via
a Vilsmeier reaction. Initial attempts to effect the monomethyl-
ation of 1 and Me2SO4 for 5 h in the presence of K2CO3 in
DMF at 70 °C gave the undesired 2,4-dimethoxybenzaldehyde
2b exclusively (Table 1, entry 1). A decrease in temperature to
40 °C also gave 2b as the predominate product (entry 2). No
reaction was observed when the base was replaced by NaHCO3,
even after stirring at 40 °C for 10 h (entry 3). To our delight,
when changing the solvent from DMF to acetone, the desired
4-methoxysalicylaldehyde 2a was obtained in a 51% yield as
the major product together with undesired 2,4-dimethoxybenz-
aldehyde 2b as the minor product (entry 4). However, the rapid
evaporation of the volatile acetone is always hazardous to
human health. In addition, the problem of recycling the ace-
tone raised some environmental concerns. Nevertheless, the
result showed that NaHCO3 as a base was feasible for the
course of this reaction to produce 2a as the major product.
Next, toluene is introduced in the reaction, which has been
Table 1 Optimisation of solvent, base, and temperature
Fig. 1 Formylation of 3-methoxyphenol.
Entry
Solvent
Base
T/°C
t/h 2a/%a 2b/%a 1/%b
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
K2CO3
K2CO3
NaHCO3
70
40
40
5
5
10
–
3
–
51
–
16
57
83
63
92
86
–
33
–
–
–
–
–
100
–
100
62
30
–
Acetone NaHCO3 Reflux 10
Toluene NaHCO3
Toluene NaHCO3
Toluene NaHCO3
Toluene NaHCO3
Toluene NaHCO3
60
70
80
90
100
10
10
10
10
10
Fig. 2 Demethylation of 2,4-dimethoxybenzaldehyde.
3
17
–
* Correspondent. E-mail: hsjin@xznu.edu.cn
a Isolated yield. b Recovery of starting material.

JOURNAL OF CHEMICAL RESEARCH 2012 145
4-Methoxysalicylaldehyde (2a): A solution of 2,4-dihydroxybenz-
aldehyde (276 mg, 2 mmol), NaHCO3 (840 mg, 10 mmol), and dimethyl-
sulfate (0.9 mL, 10 mmol) in toluene (10 mL) was stirred at 90 °C
for 10 h. The reaction mixture was cooled to room temperature and
the solid NaHCO3 was filtered and washed with additional toluene.
The solvent (toluene) was recycled and the residue was purified by
flash column chromatography (petroleum ether/ethyl acetate, 1/1,
v/v) to afford 4-methoxysalicylaldehyde 2a (458 mg, 83% yield) as
a colourless oil, which crystallised to a solid overnight in a freezer,
m.p. 39–40 °C (ref.15 41–42 °C). 1H NMR (400 MHz, CDCl3) δ 11.50
(s, 1H), 9.72 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.54 (dd, J = 8.4 Hz,
J = 2.4 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 194.5, 166.9, 164.6, 135.3, 115.2, 108.4, 100.6,
55.7. HRMS (ESI): m/z Calcd for C8H9O3 [M + H]+: 153.0552; found:
153.0551. Spectral data matched the reported data.3
3-Acetyl-7-methoxycoumarin (3): A catalytic amount of piperidine
was added to a mixture of 2a (304 mg, 2 mmol) and ethyl acetoacetate
(260 mg, 2 mmol) in ethanol. The mixture was refluxed for 6 h. After
cooling to room temperature, the mixture was concentrated and the
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 2/1, v/v) to afford 3-acetyl-7-methoxycoumarin 3
(370 mg, 85% yield) as yellow crystals. m.p. 170–171 °C (lit.16 169 °C).
1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H),
6.90 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 3.92
(s, 3H), 2.70 (s, 3H). Data matched the reported data.16
widely accepted by industry due to its high boiling point
and environmentally friendly process for fully recycling the
solvent. We conducted the reaction in toluene at temperatures
ranging from 60 to 100 °C. The results indicated that the tem-
perature played a crucial role, because the methylation, whether
monomethylation or dimethylation, did not occur below 70 °C
(entry 5). In contrast, the reaction gave a useful result at 70 °C,
in which no dimethylation product 2b was found (entry 6).
However, the conversion of starting material 1 was very low.
A further increase in the temperature to 80 °C improved the
conversion of 1 (entry 7). A reaction temperature of 90 °C was
considered to be most suitable to afford desired monomethyl-
ation 2a in toluene (entry 8). Further increasing the tempera-
ture to 100 °C, the reaction still went efficiently to provide
2a as the major product but it was accompanied by the forma-
tion of an amount of the undesired dimethylation product 2b
(entry 9).
Although we have proved that monomethylation has
occurred under the reaction conditions, we have not yet proved
whether or not our compound is 4-methoxysalicylaldehyde
2a because the structures of 2a and 4-hydroxy-2-methoxy-
benzaldehyde have very similar NMR spectra. Consequently,
we cannot distinguish these two compounds only according to
1H NMR and 13C NMR data. To confirm the structure of our
compound, we studied the reaction of 2a and ethyl acetoace-
tate under the basic conditions (Scheme 1). From the results
obtained it was clear that the structure of our compound is
2a since 3-acetyl-7-methoxycoumarin 3 was obtained as the
product in high yield.
In conclusion, we have developed a new protocol for the
synthesis of 4-methoxysalicylaldehyde using toluene as sol-
vent in the presence of NaHCO3. Compared to the previously
reported methods, the advantage of the method described here
is that the yield of the product is higher and the reagent is
cheaper and there was only a small production of dimethyl-
ation product. Particularly noteworthy is that the reaction
can be performed in toluene, which allows the fully solvent
recycle. This will make the present method potentially useful
for industrial applications. With these advantages, we believe
the method presented herein will be a valuable complement
to existing methods of 4-methoxysalicylaldehyde.
We thank the Natural Science Foundation of Xuzhou Normal
University (No. 08XLR06) and Priority Academic Program
Development of Jiangsu Higher Education Institutions for
financial support.
Received 31 December 2011; accepted 27 January 2012
Paper 1101072 doi: 10.3184/174751912X13295680217793
Published online: 22 March 2012
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Scheme 1 Synthesis of 3-acetyl-7-methoxycoumarin.

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