Synthesis of 3-alkoxy-4-hydroxyphenylacetic acids from methyl 3-alkoxybenzoates

Article abstract of DOI:10.1081/SCC-100000539

3-Alkoxy-4-hydroxyphenylacetic acids 4 were obtained from 3-alkoxyl-substituted methyl benzoates 1 by reductive alkylation, followed by allylic oxidation and hydrolysis.

Full text of DOI:10.1081/SCC-100000539

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SYNTHESIS OF 3-ALKOXY-4-HYDROXYPHENYLACETIC
ACIDS FROM METHYL 3-ALKOXYBENZOATES
Young-Sik Jung a , Tae-Souk Kang a , Jong-Cheol Lee a , Churl-Min Seong a , Won-Hun Ham
b & No-Sang Park a
a Bioorganic Division , Korea Research Institute of Chemical Technology , P.O. Box 107,
Yusong, Taejon, 305-606, Korea
b College of Pharmacy, SungKyunKwan University , Suwon, 440-746, Korea
Published online: 09 Nov 2006.
To cite this article: Young-Sik Jung , Tae-Souk Kang , Jong-Cheol Lee , Churl-Min Seong , Won-Hun Ham & No-Sang
Park (2001) SYNTHESIS OF 3-ALKOXY-4-HYDROXYPHENYLACETIC ACIDS FROM METHYL 3-ALKOXYBENZOATES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:3, 455-462, DOI:
10.1081/SCC-100000539
To link to this article: http://dx.doi.org/10.1081/SCC-100000539
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SYNTHETIC COMMUNICATIONS, 31(3), 455–462 (2001)
SYNTHESIS OF
3-ALKOXY-4-HYDROXYPHENYLACETIC
ACIDS FROM METHYL
3-ALKOXYBENZOATES
Young-Sik Jung,1,∗ Tae-Souk Kang,1,2 Jong-Cheol Lee,1
Churl-Min Seong,1 Won-Hun Ham,2
and No-Sang Park1,∗
1Bioorganic Division, Korea Research Institute of Chemical
Technology, P.O. Box 107, Yusong, Taejon 305-606, Korea
2College of Pharmacy, SungKyunKwan University,
Suwon 440-746, Korea
ABSTRACT
3-Alkoxy-4-hydroxyphenylacetic acids4 were obtained from
3-alkoxyl-substituted methyl benzoates 1 by reductive alkylation,
followed by allylic oxidation and hydrolysis.
Vanilloids are natural irritants possessing a 4-hydroxy-3-methoxybenzyl
group as essential moiety to express their bioactivity (1–3). Besides their irritancy,
vanilloids have attracted considerable attention for the last decade due to their
strong analgesic properties (4,5). Capsaicin and its ultrapotent analog, resinifera-
toxin (RTX), are the best-known natural vanilloids. In the course of our research
aimed at the development of new vanilloids as analgesic agents (6,7), we were
interested in the synthesis of 4-hydroxyphenylacetic acids, which contain various
∗Corresponding author.
455
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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JUNG ET AL.
alkoxy groups on C-3 position of the ring. Although 3-methoxy-4-hydroxyphe-
nylacetic acid (homovanillic acid) is commercially available, there is no report
for the general synthetic methods of 3-alkoxy-4-hydroxyphenylacetic acids. Only
3-ethoxy-4-hydroxyphenylaceticacidhasappearedin theliteraturewithout adetail
synthetic procedure (4).
Herein we report a general synthetic method of 3-alkoxy-4-hydroxyphe-
nylacetic acids from methyl 3-alkoxybenzoates through three consecutive steps:
1) dissolving metal reductions of methyl 3-alkoxybenzoates followed by alkylation
with methyl bromoacetate; 2) oxidation of the resulting dienes to dienones; and 3)
hydrolysis of the dienones.
H
N
Ph
O
O
H
O
O
H
OMe
OH
O
O
HO
OH
O
OMe
Capsaicin
Reciniferatoxin
Methyl 3-alkoxybenzoates 1a–d were easily obtained from the alkylations of
methyl 3-hydroxybenzoate with the corresponding alkyl bromides or alkyl iodides
for 1a–c or the esterification of 3-phenoxybenzoic acid with methanol for 1d.
Attempts to reduce methyl 3-alkoxybenzoates 1a–e with potassium metal under
Birch reduction conditions (8), followed by alkylation with methyl bromoacetate,
resulted in the dienes 2a–e in 64–100% yields. Allylic oxidation of the dienes
2a–e with pyridinium dichromate (PDC) in benzene provided the dienones 3a–e in
moderateyields(9,10). Treatmentof 3a–ewithaqueoussodiumhydroxidesolution
in MeOH at 0◦C followed by acidic aqueous workup provided the phenylacetic
acids 4a–e in high yields (9).
CO2Me
MeO2C
R1
CH2CO2Me
OR
PDC, t-BuOOH
i) K/NH3, t-BuOH, THF
benzene, r.t.
R1
OR
ii) BrCH2CO2Me, −78°C
(64 - 100%)
(43 - 66%)
2a - 2e
1a - 1e
4a R = Et, R1 = H
b R = i Pr, R1 = H
CH2CO2H
MeO2C CH2CO2Me
aq, NaOH
= Bu, R1 = H
c R
d R = Ph, R1 = H
e R = Me, R1 = OMe
MeOH, 0°C
R1
OR
OH
R1
OR
(64 - 86%)
O
4a - 4e
3a - 3e

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457
In summary, we accomplished a general synthetic method of 3-alkoxy-4-
hydroxyphenylacetic acids from 3-alkoxyl substituted methyl benzoates by reduc-
tive alkylation followed by allylic oxidation and hydrolysis.
EXPERIMENTAL
All reactions were carried out under N2 atmosphere unless otherwise noted.
MeCN was distilled from CaH2 prior to use. Organic extracts or filtrates were
washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
Flash chromatography was performed with Merck-EM Type 60 (230–400 mesh)
silica gel (flash). 1H NMR spectra were measured by Varian Gemini 200 MHz and
Bruker AM-300 NMR spectrometers. Chemical shifts are reported in ppm (δ) rela-
tive to TMS as internal standard. Mass spectrometric data, determined by use of the
electron impact (EIMS) method, are reported as m/z (relative intensity). Elemen-
tal analyses were performed with CE Instruments-ea 1110 Automatic Elemental
Analyzer. Melting points were uncorrected.
Methyl 2-(3-ethoxy-1-methyloxycarbonyl-2,5-cyclohexadienyl)acetate
(2a). To a solution of methyl 3-ethoxybenzoate 1a (2.69 g, 14.9 mmol) in THF
(30 mL) at −78◦C under N2 was condensed NH3 (ca. 100 mL). t-BuOH (1.48 mL,
15.7 mmol) and potassium (1.46 g, 37.3 mmol) were added, and a deep purple
color was maintained for 20 min. A few drops of piperylene were added until the
purple color turned to yellow and then methyl bromoacetate (3.59 mL, 37.9 mmol)
was added at −78◦C. After stirring for 40 min, the cooling bath was removed, and
the reaction mixture was allowed to warm to room temperature. After the NH3
evaporated, the residue was diluted with brine. The mixture was extracted with
diethyl ether and the organic fraction was dried over Na2SO4. Evaporation of sol-
vents afforded a crude of 2a, which was purified by flash chromatography (silica
1
gel, hexane–ethyl acetate 10:1) to provide 2a (2.44 g, 64%) as an oil. H NMR
(200 MHz, CDCl3) δ 1.29 (t, J = 7.0 Hz, 3H, CH3), 2.72–2.85 (m, 4H, CH2 and
CH2CO2), 3.66 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.76–3.80 (m, 2H, OCH2),
4.72 (s, 1H, CH), 5.78–5.88 (m, 2H, CH); 13C NMR 174.8, 171.2, 154.0, 126.4,
125.0, 94.8, 62.1, 52.5, 51.6, 47.8, 45.2, 28.7, 14.4; MS (EI) m/z (relative intensity)
254 (M+, 9), 195 (63), 135 (100).
Methyl2-(3-isopropoxy-1-methyloxycarbonyl-2,5-cyclohexadienyl)ace-
tate (2b). Cyclohexadiene 2b was prepared in 68% yield from the methyl ben-
zoate 1b as described for 2a. Flash chromatography (silica gel, hexane–ethyl ac-
etate 10:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 1.22 (d, J = 6.0 Hz,
6H, CH3), 2.67 (s, 2H, CH2), 2.75 (s, 2H, CH2CO2), 3.65 (s, 3H, OCH3), 3.72
(s, 3H, OCH3), 4.34 (septet, J = 6.0 Hz, 1H, OCH), 4.72 (s, 1H, CH), 5.76–5.88
(m, 2H, CH); 13C NMR 174.7, 171.0, 152.0, 126.2, 125.1, 95.5, 67.6, 52.3, 51.4,

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JUNG ET AL.
47.8, 45.0, 29.0, 21.5, 21.4; MS (EI) m/z (relative intensity) 268 (M+, 5) 209 (27),
195 (5), 149 (14), 107 (100).
Methyl 2-(3-butoxy-1-methyloxycarbonyl-2,5-cyclohexadienyl)acetate
(2c). Cyclohexadiene 2c was prepared in quantitative yield from the methyl
benzoate 1c as described for 2a. Flash chromatography (silica gel, hexane–ethyl
acetate 10:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz,
3H, CH3), 1.41 (qt, J = 7.2, 7.3 Hz, 2H, CH2), 1.65 (tt, J = 6.5, 6.4 Hz, 2H,
CH2), 2.72–2.76 (m, 4H, CH2 and CH2CO2), 3.66 (s, 3H, OCH3), 3.71 (s, 3H,
OCH3), 3.68–3.75 (m, 2H, OCH2), 4.71 (s, 1H, CH), 5.77–5.89 (m, 2H, CH);
13C NMR 174.7, 171.1, 154.1, 126.4, 124.9, 94.6, 66.3, 52.3, 51.4, 30.9, 28.6,
19.2, 13.7; MS (EI) m/z (relative intensity) 282 (M+, 2), 223 (4), 163 (100),
107 (68).
Methyl 2-(3-phenoxy-1-methyloxycarbonyl-2,5-cyclohexadienyl)ace-
tate (2d). Cyclohexadiene 2d was prepared in 74% yield from the methyl ben-
zoate 1d as described for 2a. Flash chromatography (silica gel, hexane–ethyl ac-
etate 10:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 2.73 (s, 2H, CH2CO2),
2.87–2.89 (m, 2H, CH2), 3.62 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 5.06 (s, 1H,
CH), 5.83–5.88 (m, 2H, CH), 7.00–7.15 (m, 3H, ArH), 7.24–7.37 (m, 2H, ArH);
13C NMR 173.7, 170.5, 154.9, 152.9, 129.3, 126.1, 124.7, 123.3, 119.3, 104.8,
52.3, 51.3, 48.0, 44.1, 27.6; MS (EI) m/z (relative intensity) 302 (M+, 2), 243
(27), 185 (83), 156 (100).
Methyl 2-(3,5-dimethoxy-1-methyloxycarbonyl-2,5-cyclohexadienyl)
acetate (2e). Cyclohexadiene 2e was prepared in 75% yield from the methyl
benzoate 1e asdescribed for 2a. Flash chromatography(silicagel, hexane–ethyl ac-
etate 10:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 2.76–2.78 (m, 4H, CH2
and CH2CO2), 3.58 (s, 6H, OCH3), 3.66 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.74
(s, 2H, CH); 13C NMR 175.5, 171.4, 153.6, 94.5, 54.4, 52.5, 51.5, 47.8, 46.2, 31.0;
MS (EI) m/z (relative intensity) 270 (M+, 12), 211 (100), 197 (39), 151 (90),
138 (9).
Methyl 2-(3-ethoxy-1-methyoxycarbonyl-4-oxo-2,5-cyclohexadienyl)
acetate (3a). To a solution of the cyclohexadiene 2a (2.44 g, 9.60 mmol) in
benzene (75 mL) at room temperature was added celite (4.0 g) and PDC (14.5 g,
38.4 mmol). The mixture was stirred for 5 min, after which t-BuOOH (90%,
3.68 mL, 38.4 mmol) was added, and the resulting suspension was stirred for 6 h.
After filtration of the mixture through celite, the filtrate was concentrated. The
crude was dissolved in THF (5 mL) and Et3N (7 mL) was added. After being
stirred for 10 min, the mixture was concentrated in vacuo, giving a residue, which
was subjected to flash chromatography (silica gel, hexane–ethyl acetate 4:1) to give

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459
1
the cyclohexadienone 3a (1.24 g, 48%) as an oil. H NMR (200 MHz, CDCl3)
δ 1.42 (t, J = 7.0 Hz, 3H, CH3), 2.94 and 2.84 (AB quartet, J = 16.0 Hz, 2H,
CH2CO2), 3.74 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.88 (dq, J = 7.0, 1.7 Hz,
2H, OCH2), 5.91 (d, J = 2.6 Hz, 1H, CH), 6.40 (d, J = 10.0 Hz, 1H, CH), 7.08
(dd, J = 10.0, 2.6 Hz, 1H, CH); 13C NMR 180.1, 170.9, 170.2, 151.3, 146.2,
130.1, 114.1, 114.0, 63.5, 53.4, 52.1, 50.0, 42.3, 14.0; MS (EI) m/z (relative in-
tensity) 268 (M+, 12), 236 (37), 209 (59), 165 (40), 149 (48), 136 (100), 107 (22),
59 (68); HRMS (EI) calcd for C13H16O6 268.0947, Found 268.0943.
Methyl 2-(3-isopropoxy-1-methyloxycarbonyl-4-oxo-2,5-cyclohexadie-
nyl)acetate (3b). Cyclohexadienone 3b was prepared in 46% yield from the
cyclohexadiene 2b as described for 3a. Flash chromatography (silica gel, hexane–
ethyl acetate 4:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 1.34 (dd, J = 6.1,
1.3 Hz, 6H, CH3), 2.92 (s, 2H, CH2CO2), 3.71 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 4.39 (septet, J = 6.1 Hz, 1H, OCH), 5.98 (d, J = 2.7 Hz, 1H, CH), 6.40
(d, J = 10.0 Hz, 1H, CH), 7.07 (dd, J = 10.0, 2.7 Hz, 1H, CH); 13C NMR 180.2,
170.7, 169.8, 149.6, 145.6, 130.1, 115.6, 69.7, 53.2, 51.9, 49.9, 42.1, 21.1, 21.0;
MS (EI) m/z (relative intensity) 282 (M+, 1), 223 (36), 176 (27), 152 (6), 137
(100); HRMS (EI) calcd for C14H18O6 282.1103. Found 282.1101.
Methyl 2-(3-butoxy-1-methyloxycarbonyl-4-oxo-2,5-cyclohexadienyl)
acetate (3c). Cyclohexadienone 3c was prepared in 66% yield from the cyclo-
hexadiene 2c as described for 3a. Flash chromatography (silica gel, hexane–ethyl
acetate 4:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 0.96 (t, J = 7.4 Hz,
3H, CH3), 1.46 (qt, J = 7.4, 7.1 Hz, 2H, CH2), 1.79 (tt, J = 7.1, 6.7 Hz, 2H, CH2),
2.96 and 2.85 (AB quartet, J = 16.5 Hz, 2H, CH2CO2), 3.71 (s, 3H, OCH3), 3.75
(s, 3H, OCH3), 3.79 (t, J = 6.7 Hz, 2H, OCH2), 5.92 (d, J = 2.6 Hz, 1H, CH),
6.40 (d, J = 10.0 Hz, 1H, CH), 7.10 (dd, J = 10.0, 2.6 Hz, 1H, CH); 13C NMR
179.8, 170.8, 170.0, 151.3, 145.9, 130.0, 113.8, 67.6, 53.3, 52.0, 49.8, 42.2, 30.5,
19.1, 13.7; MS (EI) m/z (relative intensity) 296 (M+, 4), 265 (56), 237 (49),
181 (65), 137 (100), 107 (9); HRMS (EI) calcd for C15H20O6 296.1260. Found
296.1260.
Methyl 2-(3-phenoxy-1-methyloxycarbonyl-4-oxo-2,5-cyclohexadienyl)
acetate (3d). Cyclohexadienore 3d was prepared in 43% yield from the cyclo-
hexadiene 2d as described for 3a. Flash chromatography (silica gel, hexane–ethyl
acetate 4:1) provided an oil. 1H NMR (200 MHz, CDCl3) δ 2.87 (s, 2H, CH2CO2),
3.66 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 6.17 (d, J = 2.6 Hz, 1H, CH), 6.46 (d,
J = 10.0 Hz, 1H, CH), 6.99–7.03 (m, 1H, CH), 7.06–7.17 (m, 3H, ArH), 7.30–
7.38 (m, 2H, ArH); 13C NMR 179.6, 170.1, 169.7, 154.9, 151.2, 146.2, 130.4,
129.8, 124.4, 123.3, 119.2, 53.6, 50.5, 41.6; MS (EI) m/z (relative intensity) 316

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JUNG ET AL.
(M+, 55), 257 (49), 213 (100), 197 (66), 169 (25); HRMS (EI) calcd for C17H16O6
316.0947. Found 316.0948.
Methyl 2-(3,5-dimethoxy-1-methylxoycarbonyl-4-oxo-2,5-cyclohexadi-
enyl)acetate (3e). Cyclohexadienone 3e was prepared in 44% yield from the
cyclohexadiene 2e as described for 3a. Flash chromatography (silica gel, hexane–
1
ethyl acetate 4:1) provided an oil. H NMR (200 MHz, CDCl3) δ 2.91 (s, 2H,
CH2), 3.72 (s, 6H, OCH3), 3.73 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 6.01 (s, 2H,
CH); 13C NMR 193.4, 171.7, 170.5, 151.6, 113.7, 55.4, 53.4, 52.1, 43.2, 38.0; MS
(EI) m/z (relative intensity) 284 (M+, 8), 253 (100), 224 (35), 151 (38); HRMS
(EI) calcd for C13H16O7 284.0896. Found 284.0884.
3-Ethoxy-4-hydroxyphenylacetic Acid (4a). To a solution of the cyclo-
hexadienone 3a (0.869 g, 3.01 mmol) in MeOH (30 mL) at 0◦C was added
1 N NaOH (15 mL, 15 mmol). After 10 min, the mixture was warmed to room tem-
perature and stirred for 6 h. The solution was acidified with 2 N HCl solution and
then the mixture was extracted with diethyl ether. The organic solution was dried
over Na2SO4 and concentrated in vacuo, giving a residue, which was subjected to
flash chromatography (silica gel, hexane–ethyl acetate 1:4) to give the phenylacetic
1
acid 4a (0.382 g, 64%) as a solid. m.p. 85–90◦C; H NMR (200 MHz, CDCl3)
δ 1.44 (t, J = 6.9 Hz, 3H, CH3), 3.56 (s, 2H, CH2CO2), 4.11 (q, J = 6.9 Hz, 2H,
OCH2), 6.74–6.89 (m, 3H, ArH); 13C NMR 177.5, 145.8, 145.1, 124.9, 122.2,
114.4, 112.7, 64.5, 40.6, 14.8; MS (EI) m/z (relative intensity) 196 (M+, 23), 151
(7), 123 (42), 105 (6), 77 (16), 45 (100); HRMS (EI) calcd for C10H12O4 196.0736.
Found 196.0734.
3-Isopropoxy-4-hydroxyphenylacetic Acid (4b). Phenylacetic acid 4b
was prepared in 86% yield from the cyclohexadienone 3b as described for 4a.
Flash chromatography (silica gel, hexane–ethyl acetate 1:4) provided a solid. m.p.
1
83–85◦C; H NMR (200 MHz, CDCl3) δ 1.36 (d, J = 6.1 Hz, 6H, CH3), 3.48
(s, 2H, CH2CO2), 4.57 (septet, J = 6.1 Hz, 1H, OCH), 6.77–6.89 (m, 3H, ArH);
13C NMR (CDCl3) 178.2, 145.8, 144.5, 124.8, 122.2, 114.5, 114.4, 71.2, 40.7,
22.1; MS (EI) m/z (relative intensity) 210 (M+, 92), 168 (90), 123 (100); HRMS
(EI) calcd for C11H14O4 210.0892, found 210.0896; elemental analysis, calcd. for
C11H14O4: C, 62.85; H, 6.71. Found C, 62.43; H, 6.92.
3-Butoxy-4-hydroxyphenylacetic Acid (4c). Phenylacetic acid 4c was
prepared in 64% yield from the cyclohexadienone 3c as described for 4a. Flash
chromatography (silica gel, hexane–ethyl acetate 1:4) provided a solid. m.p. 55–
1
63◦C; H NMR (200 MHz, CDCl3) δ 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.49 (qt,
J = 7.2, 6.8 Hz, 2H, CH2), 1.80 (tt, J = 6.8, 6.4 Hz, 2H, CH2), 3.56 (s, 2H,
CH2CO2), 4.04 (t, J = 6.4, 2H, OCH2), 6.75–6.89 (m, 3H, ArH); 13C NMR 178.0,

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461
145.9, 144.9, 125.1, 122.0, 114.9, 68.5, 40.8, 31.1, 19.1, 13.7; MS (EI) m/z (rel-
ative intensity) 224 (M+, 91), 168 (78), 123 (100), 107 (5); HRMS (EI) calcd for
C12H16O4 224.1049, found 224.1047; elemental analysis, calcd. for C12H16O4: C,
64.27; H, 7.19. Found C, 64.42; H, 7.59.
4-Hydroxy-3-phenoxyphenylaceticAcid(4d). PhenylaceticAcid4dwas
prepared in 82% yield from the cyclohexadienone 3d as described for 4a. Flash
chromatography (silica gel, hexane–ethyl acetate 1:4) provided a solid. m.p. 128–
1
130◦C; H NMR (200 MHz, CDCl3) δ 3.45 (s, 2H, CH2CO2), 6.86–7.05 (m,
5H, ArH), 7.26–7.35 (m, 3H, ArH); 13C NMR 173.7, 157.4, 147.3, 129.4, 126.3,
125.6, 122.5, 121.1, 117.3, 116.7, 40.3; MS (EI) m/z (relative intensity) 244 (M+,
100), 199 (85), 181 (9), 105 (2); HRMS (EI) calcd for C14H12O4 244.073, found
244.0736; elemental analysis, calcd. for C14H12O4: C, 68.85; H, 4.95. Found C,
68.77; H, 5.35.
3,5-Dimethoxy-4-hydroxyphenylacetic Acid (4e). Phenylacetic acid 4e
was prepared in 75% yield from the cyclohexadienone 3e as described for 4a.
Flash chromatography (silica gel, hexane–ethyl acetate 1:4) provided a solid. m.p.
1
112–120◦C; H NMR (200 MHz, CDCl3) δ 3.57 (s, 2H, CH2CO2), 3.89 (s, 6H,
OCH3), 6.51 (s, 2H, ArH); 13C NMR 174.6, 146.9, 124.8, 106.0, 56.3, 41.1, 29.7;
MS (EI) m/z (relative intesity) 212 (M+, 100) 167 (95); HRMS (EI) calcd for
C10H12O5 212.0685, found 212.0685; elemental analysis, calcd. for C10H12O5: C,
56.60; H, 5.70. Found C, 55.86; H, 5.79.
ACKNOWLEDGMENT
Financial support of this work by the Ministry of Science and Technology
in Korea is gratefully acknowledged.
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Received in Japan March 22, 2000

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