A practical and convenient synthesis of methyl 5-formyl-3-methoxybenzoate

Article abstract of DOI:10.1081/SCC-100104344

A practical and convenient synthesis of methyl 5-formyl-3-methoxybenzoate starting from 3-hydroxy-5-(methoxycarbonyl)benzoate in 65% overall yield is described. Ethyl 5-formyl-3-methoxybenzoate was also prepared in the similar manner.

Full text of DOI:10.1081/SCC-100104344

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A PRACTICAL AND CONVENIENT SYNTHESIS OF
METHYL 5-FORMYL-3-METHOXYBENZOATE
He Zhao a & Andrew Thurkauf a
a Department of Chemistry , Neurogen Corporation , 35 Northeast Industrial Road,
Branford, CT, 06405, U.S.A.
Published online: 16 Aug 2006.
To cite this article: He Zhao & Andrew Thurkauf (2001) A PRACTICAL AND CONVENIENT SYNTHESIS OF METHYL 5-
FORMYL-3-METHOXYBENZOATE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:12, 1921-1926, DOI: 10.1081/SCC-100104344
To link to this article: http://dx.doi.org/10.1081/SCC-100104344
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SYNTHETIC COMMUNICATIONS, 31(12), 1921–1926 (2001)
A PRACTICAL AND CONVENIENT
SYNTHESIS OF METHYL 5-FORMYL-
3-METHOXYBENZOATE
He Zhao* and Andrew Thurkauf
Department of Chemistry, Neurogen Corporation,
35 Northeast Industrial Road, Branford, CT 06405
ABSTRACT
Apractical and convenient synthesis of methyl 5-formyl-3-
methoxybenzoate starting from 3-hydroxy-5-(methoxycarbo-
nyl)benzoate in 65% overall yield is described. Ethyl
5-formyl-3-methoxybenzoate was also prepared in the similar
manner.
Anumber of marketed pharmaceuticals possess a hydroxy benzoic
acid moiety as a substructure. For examples, these structures are present
in the platelet antiaggregatory agent triflusal, the antihypertensive agent
reserpine and the antiarthritic agent mycophenolate mofetil as well as the
analgesic and anti-inflammatory agent aspirin. As part of our drug dis-
covery effort in the area of anti-inflammatory agents, we designed several
isomeric hydroxy 3-benzoic acid derivatives. The 4-hydroxy derivatives
(1, Figure 1) were prepared starting from methyl 5-formylsalicylate (2).1
In order to prepare the isomeric 5-hydroxy-3-benzoic acid derivatives
(3) in a similar fashion, we required a source of methyl 5-formyl-3-methoxy-
benzoate (4).
* Corresponding author.
1921
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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ZHAO AND THURKAUF
Figure 1.
Asearch of the chemical literature revealed only a single report of
the preparation of 4,2 which was accomplished by the selective reduction
of methyl 3-methoxy-5-(methoxycarbonyl)benzoate 6 with DIBAL-H.
No information about yield and physical data were provided within this
citation, however. After attempts at reproducing this procedure proved trou-
blesome, we sought an alternative strategy. We herein report a new practical
Scheme 1. Reagents: a. MeI, K2CO3, Acetone; b. KOH, MeOH/THF; c. i)
BH3Á(CH3)2S, THF; ii) H2O/HOAc; d. MnO2, EtOAc; e. KOH, EtOH/THF; f. i)
LiOH, MeOH/H2O; ii) HCl

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METHYL 5-FORMYL-3-METHOXYBENZOATE
1923
and convenient synthesis of compound 4 from 3-hydroxy-5-(methoxycarbo-
nyl)benzoate 5 in 65% overall yield in four steps without column chromato-
graphy (Scheme 1). The strategy is also applicable to the preparation of ethyl
5-formyl-3-methoxybenzoate 11 from either 5 or ethyl 5-(ethoxycarbonyl)-
3-methoxybenzoate 13.
3-Hydroxy-5-(methoxycarbonyl)benzoate 5 was treated with iodo-
methane and potassium carbonate to yield methoxy compound 6, which
was then selectively hydrolyzed in the presence of 0.9 equivalent powder
potassium hydroxide in methanol/THF to give mono acid 7 in high yield.
When 7 was treated with borane dimethyl sulfide complex, the carboxylic
acid group was selectively reduced in the presence to the ester group. The
resulting alcohol 8 was oxidized to methyl 5-formyl-3-methoxybenzoate 4
using activated MnO2 in ethyl acetate. If ethanol was used instead of metha-
nol during the hydrolysis of diester 6 in order to increase the refluxing
temperature, a transesterification occurred to generate compound 9, which
could also be prepared starting from ethyl 5-(ethoxycarbonyl)-3-hydroxy-
benzoate 123 following the same procedures. Compound 9 was oxidized to
provide ethyl 5-formyl-3-methoxybenzoate 11. Finally, compounds 4 and 11
were converted to acid 14 by treatment with lithium hydroxide in methanol
and water.
In conclusion, practical and convenient syntheses of methyl 5-formyl-
3-methoxybenzoate and ethyl 5-formyl-3-methoxybenzoate were achieved in
good overall yield without column chromatography. These two compounds
can be used as alternative building blocks to methyl 5-formylsalicylate in
medicinal and combinatorial chemistry research.
EXPERIMENTAL
Melting points were determined on a Mel Temp II melting point appa-
ratus and uncorrected. Infrared (IR) spectra were recorded on a Perkin-
Elmer 1600 Fourier-transformed-infrared spectrometer. 1H NMR data were
obtained on a Varian Gemini-400 spectrometer (300 MHz). Chemical shifts
are given in ppm on the d scale from TMS. Atmosphere pressure chemical
ionization mass spectra (APCIMS) were acquired with a Sciex API150 mass
spectrometer under the control of a Sciex masschrom 1.0 data system.
Elemental analyses were obtained from Robertson Microlit Laboratories
Inc., Madison, NJ, and are within 0.4% of theoretical values. Anhydrous
solvents were obtained commercially and used without further drying.
Methyl 3-methoxy-5-(methoxycarbonyl)benzoate (6): To a solution of
methyl 3-hydroxy-5-(methoxycarbonyl)benzoate 5 (29 g, 138 mmol) in acet-
one (200 mL) was added anhydrous potassium carbonate (23 g, 166 mmol)

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ZHAO AND THURKAUF
and iodomethane (39.2 g, 276 mmol). The mixture was heated at reflux
under N2 overnight. After cooling to room temperature, the solids were
filtered through celite and washed with acetone. The filtrate was concen-
trated and redissolved in ether, washed with 1 N HCl, saturated NaHCO3,
and brine, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by crystallization from ether/hexane to give the title compound
5 (29.5 g, 95%) as a white solid: mp 110–112 ꢀC; IR (KBr) 2958, 1730,
1
1593, 1440, 1269, 1053, 762 cmꢁ1; H NMR (CDCl3) d 3.87 (s, 3H), 3.96
(s, 6H), 7.72 (d, J ¼ 1.2 Hz, 2H), 8.25 (d, J ¼ 1.2 Hz, 1H); LC-MS (m/z) 225
(Mþ1); Anal. Calcd. for C11H12O5: C, 58.93; H, 5.39. Found: C, 59.13;
H, 5.38.
Ethyl 5-(ethoxycarbonyl)-3-methoxybenzoate (13): This compound was
prepared from ethyl 5-(ethoxycarbonyl)-3-hydroxybenzoate 12 in the similar
manner as described above for the preparation of compound 6 and purified
by Kugelrohr distillation to afford the title compound 13 (96%) as a color-
less oil: IR (neat) 2982, 1725, 1600, 1460, 1315, 1265, 1107, 1054, 758 cmꢁ1
;
1H NMR (CDCl3) d 1.41 (t, J ¼ 7.2 Hz, 6H), 3.89 (s, 3H), 4.40 (q, J ¼ 7.2 Hz,
4H), 7.75 (d, J ¼ 1.2 Hz, 1H), 8.18 (t, J ¼ 1.2 Hz, 2H); LC-MS (m/z) 253
(Mþ1); Anal. Calcd. for C13H16O5: C, 61.90; H, 6.39. Found: C, 61.71;
H, 6.19.
3-Methoxy-5-(methoxycarbonyl)benzoic acid (7): Powdered potassium
hydroxide (85%, 3.56 g, 54 mmol) was added portionwise to a solution
of methyl 3-methoxy-5-(methoxycarbonyl)benzoate 6 (14.3 g, 60 mmol)
in anhydrous methanol (90 mL) and anhydrous THF (60 mL) over 10 min
with stirring. The mixture was stirred at room temperature for 1 h and
then heated at reflux for additional 6 h. After removal of the solvents
under reduced pressure, the thick slurry was dissolved in water (300 mL)
and washed with CH2Cl2. Concentrated HCl was added to the aqueous
phase to pH ꢂ 3. The resulting white precipitate was collected by vacuum
filtration and dried in vacuo to give the title compound 7 (10.46 g, 83%)
as a white solid: mp 186–188ꢀ C; IR (KBr) 1731, 1693, 1597, 1423, 1318,
1273, 1122, 1057, 754 cmꢁ1 1H NMR (DMSO-d6) d 3.84 (s, 3H), 3.85
;
(s, 3H), 7.61 (m, 1H), 7.63 (m, 1H), 8.04 (m, 1H); LC-MS (m/z) 211
(Mþ1), 209 (Mꢁ1); Anal. Calcd. for C10H10O5: C, 57.14; H, 4.80. Found:
C, 57.00; H, 4.78.
5-(Ethoxycarbonyl)-3-methoxybenzoic acid (9): This compound
was prepared either from methyl 3-methoxy-5-(methoxycarbonyl)benzoate
6 in 81% yield or ethyl 5-(ethoxycarbonyl)-3-methoxybenzoate 13 in 82%
yield using absolute ethyl alcohol and anhydrous THF as solvents in
the similar manner as described above for the preparation of compound 7
to give the title compound 9 as a white solid: mp >300 ꢀC; IR (KBr)
1
3478, 2981, 1712, 1553, 1404, 1294, 1055, 766 cmꢁ1; H NMR (DMSO-d6)

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METHYL 5-FORMYL-3-METHOXYBENZOATE
1925
d 1.32 (t, J ¼ 7.2 Hz, 3H), 3.84 (s, 3H), 4.31 (q, J ¼ 7.2 Hz, 2H), 7.60 (m, 1H),
7.63 (m, 1H), 8.03 (m, 1H), 13.32 (s, 1H); LC-MS (m/z) 225 (Mþ1),
223 (Mꢁ1).
Methyl 5-(hydroxymethyl)-3-methoxybenzoate (8): BH3ꢃ(CH3)2S com-
plex (2.0 M in THF, 24 mL, 48 mmol) was added dropwise to a solution
of 3-methoxy-5-(methoxycarbonyl)benzoic acid 7 (8.4 g, 40 mmol) in
anhydrous THF (40 mL) under argon at 0ꢀC over 30 min. The mixture
was then heated at 60ꢀC overnight. The reaction was quenched and neutra-
lized by addition of 1:2 H2O/glacial acid (6 mL). After removing the sol-
vents, the thick slurry was dissolved in EtOAc, washed with 30% K2CO3,
1N HCl, saturated NaHCO3, brine, and dried over anhydrous Na2SO4. The
solution was then filtered through silica gel with a Buchner funnel and
concentrated to give the title product 8 (7.04 g, 90%) as a colorless oil: IR
(neat) 3417(br s), 2950, 1712, 1602, 1460, 1332, 1056, 873, 768 cmꢁ1
;
1H NMR (CDCl3) d 3.85 (s, 3H), 3.91 (s, 3H), 4.41 (s, 2H), 7.13 (m, 1H),
7.47 (m, 1H), 7.61 (m, 1H); LC-MS (m/z) 197 (Mþ1).
Ethyl 5-(hydroxymethyl)-3-methoxybenzoate (10): This compound
was prepared from 5-(ethoxycarbonyl)-3-methoxybenzoic acid 9 in 90%
yield in the same manner as described above for the preparation of
compound 8 to give the title compound 10 as a colorless oil: IR (neat)
1
3416 (br s), 2939, 1714, 1600, 1461, 1306, 1056, 868, 7770 cmꢁ1; H NMR
(CDCl3) d 1.39 (t, J ¼ 7.2 Hz, 3H), 3.86 (s, 3H), 4.37 (q, J ¼ 7.2 Hz, 2H),
4.72 (s, 2H), 7.13 (m, 1H), 7.48 (m, 1H), 7.62 (m, 1H); LC-MS (m/z)
211 (Mþ1).
Methyl 5-formyl-3-methoxybenzoate (4): To a solution of methyl
5-(hydroxymethyl)-3-methoxybenzoate
8 (5.88 g, 30 mmol) in EtOAc
(200 mL) was added activated MnO2 (85%, 12.5 g, 128 mmol). The reaction
mixture was heated under reflux for 5 h. After cooling to room temperature,
the mixture was filtered through celite and the filtrate concentrated. The
residue was purified by crystallization from ether/hexane to give the title
compound 4 (5.29 g, 91%) as a white solid: mp 60–61ꢀC; IR (KBr) 2354,
1
1720, 1593, 1445, 1389, 1106, 1058, 764 cmꢁ1; H NMR (CDCl3) d 3.91 (s,
3H), 3.96 (s, 3H), 7.58 (dd, J ¼ 1.2 Hz, 1H), 7.82 (dd, J ¼ 1.2 Hz, 1H), 7.61
(dd, J ¼ 1.2 Hz, 1H), 10.02 (s, 1H); LC-MS (m/z) 195 (Mþ1); Anal. Calcd.
for C10H10O4: C, 61.85; H, 5.139. Found: C, 62.03; H, 5.28.
Ethyl 5-formyl-3-methoxybenzoate (11): This compound was prepared
from ethyl 5-(hydroxymethyl)-3-methoxybenzoate 10 in 92% yield in the
same manner as described above for the preparation of compound 4 to
give the title compound 11 as a colorless oil: IR (neat) 2980, 1696,
1
1599, 1455, 1387, 1331, 1227, 1055, 873, 768 cmꢁ1; H NMR (CDCl3) d
1.41 (t, J ¼ 7.2 Hz, 3H), 3.90 (s, 3H), 4.41 (q, J ¼ 7.2 Hz, 2H), 7.57
(dd, J ¼ 1.2 Hz, 1H), 7.2 (dd, J ¼ 1.2 Hz, 1H), 8.11 (t, J ¼ 1.2 Hz, 1H),

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ZHAO AND THURKAUF
10.02 (s, 1H); LC-MS (m/z) 209(Mþ1); Anal. Calcd for C11H12O4: C, 63.45;
H, 5.81. Found: C, 63.49; H, 5.87.
5-Formyl-3-methoxybenzoic acid (14): To a solution of methyl
5-formyl-3-methoxybenzoate 4 (194 mg, 1 mmol) in methanol and water
(8 mL, v/v ¼ 3/1) was added lithium hydroxide monohydrate (82 mg,
2 mmol). The mixture was stirred at room temperature overnight and the
most of methanol was removed under reduced pressure. The aqueous sol-
ution was diluted to 15 mL and washed with CH2Cl2. Concentrated HCl was
added to neutralize the solution until pH ꢂ 3. The product was collected by
vacuum filtration and dried in vacuo to give the title compound 14 (170 mg,
94%) as a white solid: mp 234–236ꢀC; IR (KBr) 2371, 1691, 1281, 1182, 869,
1
749 cmꢁ1; H NMR (CDCl3) d 3.87 (s, 3H), 7.63 (dd, J ¼ 1.2 Hz, 1H), 7.69
(dd, J ¼ 1.2 Hz, 1H), 8.02 (dd, J ¼ 1.2 Hz, 1H), 10.02 (s, 1H), 13.37 (s, 1H);
LC-MS (m/z) 179 (Mꢁ1). The title compound 14 was also prepared from
ethyl 5-formyl-3-methoxybenzoate 11 in 92% yield in the same manner.
REFERENCES
1. Filler, R.; Lin, S.; Zhang, Z. J. Fluorine Chem. 1995, 74, 69.
2. Johnson, M.R.; Melvin, L.S. U.S. Patent 4,118,559, 1978.
3. Collman, J.P.; Zhang, X.; Wong, K.; Brauman, J.I. J. Am. Chem. Soc.
1994, 116, 6245.
Received in the USAAugust 30, 2000

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