A. Milanese et al. / Bioorganic Chemistry 39 (2011) 151–158
157
br. s, COOH); 13C NMR (125.76 MHz, DMSO-d6) d = 55.70, 114.99,
124.54, 126.08, 126.16, 128.41, 128.75, 130.35, 130.70, 131.50,
132.23, 135.86, 139.84, 159.81, 167.97.
a solution of sodium hydroxide (1.3 g, 0.027 mol) in absolute etha-
nol (25 mL) was added at room temperature. The solution was kept
under stirring overnight at room temperature and glacial acetic acid
(21.0 g, 20.0 mL, 0.35 mol) was added and the solution refluxed
(1 h). The insoluble residue was filtered-off on celite from the hot
solution, washed with tetrahydrofuran (50 mL) then cooled to
25 °C. The solution was concentrated at reduced pressure at ambient
temperature, treated with methanol (100 mL) and warmed-up at
60 °C for 15 min. After cooling at room temperature and filtration,
the solid residue was suspended in methanol (100 mL) then treated
with triethylamine (10.9 g, 15 mL, 0.11 mol) and activated charcoal
(1 h at room temperature). After filtration on celite and washing
with methanol, the filtrate was poured into a flask and refluxed
(65 °C). To this warm solution, a solution of glacial acetic acid
(21.0 g, 20.0 mL, 0.35 mol) in methanol (20 mL) was added dropwise
and a white precipitate was formed. After cooling to room tempera-
ture, the solid was filtrated and washed with methanol to obtain
pure 6-[(3-adamantyl-4-metoxyphenyl)]-2-naphthoic acid (1a)
(7.08 g, 0.017 mol, 70% yield).
4.6. Ethyl 6-(4-methoxyphenyl)-2-naphthoate (2c)
A
mixture of 6-(4-methoxyphenyl)-2-naphthoic acid (2a)
(26.20 g, 0.094 mol), absolute ethanol (400 mL) and toluene
(100 mL) was stirred under nitrogen and sulfuric acid (96%,
21.8 mL, 0.39 mol) was dropwise added with spontaneous temper-
ature rising. The solution was warmed to 78 °C and after 3 h the sol-
vents were removed. TLC analysis showed a 50% conversion to the
ester 2c and the same esterification procedure was repeated on
the crude for additional 9 h. Crushed ice (500 g) was added; the mix-
ture was vigorously stirred and then filtered. The filtrate was
washed with water, suspended in ethanol (250 mL) and triethyl-
amine was added (10 mL, 0.072 mmol) with stirring at room tem-
perature (15 min). After filtration, the solid was washed with
ethanol, dried and the ethyl ester 2c was obtained practically pure
(27.32 g, 0.089 mol, 95% yield). Mp 135–136 °C; HRMS (ESI+): m/z
[M+1]+ Calcd for C20H19O3: 307.13207. Found: 307.13212 1H NMR
(CDCl3) d = 1.46 (3 H, t, J = 7.1 Hz, CH2CH3), 3.88 (3 H, s, ArOCH3),
4.44 and 4.47 (each 1H, AB-system, J = 7.1 Hz, CH2CH3), 7.03 (2H,
XX0-part of AA0XX0 system, quasi d, J = 8.8 Hz, 3- and 5-phenyl H),
7.67 (2H, AA0-part of AA0XX0 system, quasi d, J = 8.8 Hz, 2- and 6-phe-
nyl H), 7.76 (1 H, dd, J = 8.5 and 1.8 Hz, 7-naphthyl H), 7.90 (1 H, d,
J = 8.6 Hz, 4-naphthyl H), 7.99 (1 H, d, J = 8.6 Hz, 8-naphthyl H),
8.01 (1 H, s, 5-naphthyl H), 8.08 (1 H, dd, J = 8.6 and 1.6 Hz, 3-naph-
thyl H), 8.61 (1 H, s, 1-naphthyl H); 13C NMR (125.76 MHz, CDCl3)
d = 14.45, 55.41, 61.12, 114.43, 124.76, 125.71, 126.19, 127.42,
128.20, 128.54, 129.81, 130.72, 130.70, 131.34, 133.01, 135.90,
140.48, 159.61, 167.84.
Mp 320–322 °C; 1H NMR (DMSO-d6) d = 1.74 (6 H, s, H on 1-ada-
mantyl), 2.05 (3 H, s, H on 1-adamantyl), 2.12 (6 H, s, H on 1-
adamantyl), 3.85 (3 H, s, ArOCH3), 7.10 (1 H, d, J = 8.5 Hz, 5-phenyl
H), 7.56 (1 H, d, J = 2.0 Hz, 2-phenyl H), 7.62 (1 H, dd, J = 8.5 and
2.0 Hz, 6-phenyl H), 7.87 (1 H, d, J = 8.5 Hz, 7-naphthyl H), 7.98
(1 H, d, J = 8.5 Hz, 4-naphthyl H), 8.05 (1 H, d, J = 8.6 Hz, 8-naphthyl
H), 8.13 (1 H, d, J = 8.6 Hz, 3-naphthyl H), 8.20 (1 H, s, 5-naphthyl
H), 8.59 (1 H, s, 1-naphthyl H), 13.01 (1 H, s, COOH); 13C NMR
(125.76 MHz, DMSO-d6) d = 28.57, 36.73, 40.24, 55.50, 112.90,
124.24, 125.24, 125.66, 125.89, 126.09, 127.75, 128.48, 129.97,
130.42, 131.08, 131.68, 135.64, 138.19, 140.38, 158.75, 167.63.
Anal. Calcd for C29H32O3: C, 81.27; H, 7.53; O, 11.20. Found: C,
81.36%; H, 7.48%.
4.7. Ethyl 6-[(3-adamantyl-4-methoxyphenyl)]-2-naphthoate (1c)
Acknowledgments
To a solution of ethyl 6-(4-methoxyphenyl)-2-naftoate (2c)
(9.90 g, 0.032 mol) in chloroform (130 mL), 96% sulfuric acid
(6.6 g, 0.065 mol) was added and a yellowish reaction mixture
was obtained. A solution of 1-adamantanol (7.37 g, 0.041 mol) in
chloroform (120 mL) was added dropwise at 20 °C (6 h). After
one night at room temperature the reaction was complete and,
after cooling with an external ice bath, triethylamine (13.05 g,
18.00 mL, 0.129 mol) was added. The reaction was evaporated at
reduced pressure, then methanol (200 mL) and triethylamine
(3.62 g, 5.0 mL, 0.036 mol) were added. After an additional stirring
(1 h), the solid residue was filtered, washed with methanol and
dried. Pure ester 1c (11.16 g, 0.025 mol) was obtained (78.4%
yield). Mp 183–184 °C; HRMS (ESI+): m/z [M+Na]+ Calcd for
The HRMS analyses have been carried out at CIGA (Centro Inter-
dipartimentale Grandi Attrezzature), University of Milan. Dr. Sil-
vana Casati and Prof. Pierangela Ciuffreda are gratefully
acknowledged for their participation at early stags of the work.
This work has been financially supported by Università degli Studi
di Milano (Fondi PUR 2008).
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