The Journal of Organic Chemistry
Note
were dissolved in DMF (30.0 mL). The resulting solution was
degassed under argon for 10 min. Then, 253.0 mg of Pd(PPh3)2Cl2
(1.06 mmol, 8 mol %) and H2O (10.0 mL) were added to the reaction
flask, and this solution was stirred at 90 °C for 4 h. The reaction
mixture was run through a Celite plug, diluted with toluene (10.0 mL),
and concentrated en vacuo. This product was purified by column
chromatography (3:1 hexanes/EtOAc, v/v) and dried under vacuum
to yield 1.32 g of tert-butyl 6-(furan-3-yl)-2,3-dimethoxybenzoate (6b,
Arnottin I (1). A total of 150.0 mg (0.354 mmol, 1.0 equiv) of tert-
butyl 6-(5,8-dihydro-5,8-epoxynaphtho[2,3-d][1,3]dioxol-6-yl)-2,3-di-
methoxybenzoate (7b) was added to a flame-dried round-bottomed
flask and dissolved in anhydrous MeOH (5 mL). Next 15.2 mg
(0.0884 mmol, 0.25 equiv) of p-toluenesulfonic acid was added to this
solution and the mixture stirred at 50 °C under nitrogen atmosphere
for 24 h. The reaction mixture was then cooled to 0 °C and filtered,
and the off-white solid was washed with cold MeOH. This product was
dried under vacuum to yield 113.4 mg of arnottin I (1, 92% yield). Mp
1
96% yield) as a white solid. Mp 46−48 °C; H NMR (400 MHz,
1
>250 °C; H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 1H),
CDCl3) δ 7.55 (dd, J = 1.6, 0.9 Hz, 1H), 7.42 (t, J = 1.7 Hz, 1H), 7.07
(d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.56 (dd, J = 1.8, 0.9 Hz,
1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 167.0, 151.8, 145.8, 142.8*, 142.7*, 139.7*, 139.6*, 130.4,
124.8, 123.7, 122.5, 113.1, 111.2*, 111.1*, 82.3, 61.5, 56.0, 28.1
(*denotes rotamers); IR (neat, cm−1) 2973, 2935, 1715, 1482, 1291,
1265, 1059, 1029, 795; TLC Rf = 0.60 (3:1 hexanes/EtOAc, v/v);
HRMS (DART) m/z calcd for C17H21O5 (M + H)+: 305.1389, found
305.1375.
7.85 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.45
(d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.10 (s, 2H), 4.03 (s, 3H), 3.99 (s,
3H); 1H NMR (600 MHz, DMSO-d6) δ 8.08 (d, J = 8.7 Hz, 1H), 8.03
(d, J = 8.7 Hz, 1H), 7.66 (app t, J = 9.4 Hz, 2H), 7.59 (s, 1H), 7.34 (s,
1H), 6.17 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H); 13C NMR (151 MHz,
DMSO-d6) δ 155.7, 152.5, 150.8, 148.0, 147.9, 144.8, 130.5, 128.7,
122.5, 120.8, 118.8, 117.7, 117.7, 114.1, 111.5, 103.5, 101.0, 96.9, 60.2,
56.3; IR (neat, cm−1) 3010, 2943, 1734, 1489, 1463, 1276, 1122, 1039,
821; TLC Rf = 0.50 (1:1 hexanes/EtOAc, v/v); HRMS (DART) m/z
calcd for C20H15O6 (M + H)+: 351.0869, found 351.0855.
Methyl 6-(Furan-3-yl)-2,3-dimethoxybenzoate (6a). A total of
2.00 g (18.0 mmol) of methyl 6-bromo-2,3-dimethoxybenzoate (5a)
yielded 3.53 g (12.5 mmol, 82% yield) of methyl 6-(furan-3-yl)-2,3-
dimethoxybenzoate (6a) according to the above procedure. Mp 43−
45 °C; 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 1.6, 0.9 Hz, 1H),
7.42 (t, J = 1.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 8.5 Hz,
1H), 6.50 (dd, J = 1.8, 0.9 Hz, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.83 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 168.3, 151.6, 145.9, 143.0,
139.1, 128.3, 124.5, 123.8, 122.6, 113.6, 110.3, 61.5, 55.8, 52.3; IR
(neat, cm−1) 2950, 1723, 1500, 1258, 905, 804; TLC Rf = 0.40 (2:1
hexanes/EtOAc, v/v); HRMS (DART) m/z calcd for C14H14O5 (M +
H)+: 262.0841, found 262.0838
Arnottin II (2). Arnottin I (1, 12.0 mg, 0.035 mmol) was
suspended in 0.5 mL of THF:MeOH:H2O (3:1:1, v/v/v) and 7.0 mg
(0.17 mmol, 5.0 equiv) of LiOH·H2O was added. The reaction was
heated at 50 °C for 2 h over which time the solution became red. The
flask was cooled to 0 °C and 1 M HCl was added dropwise until the
solution turned yellow-orange indicating a pH of 2−3. The solution
was extracted with Et2O (2 × 1.0 mL), dried over Na2SO4 and
concentrated at 23 °C yielding an unstable yellow-orange solid. The
flask was cooled to 0 °C and HFIP (0.50 mL) was added. PIFA (17.0
mg, 0.041 mmol, 1.1 equiv) in 0.50 mL of HFIP was added over 1 h at
0 °C via syringe pump and then the reaction was stirred at 23 °C. After
12 h the reaction was quenched with 1 M HCl (1.0 mL), extracted
with CH2Cl2 (2 × 1.0 mL), dried over Na2SO4 and concentrated.
Flash chromatography (2:1 hexanes/EtOAc, v/v) yielded arnottin II
(2, 7.0 mg, 0.02 mmol, 56% yield) as an off yellow solid. Mp 206−208
°C; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.05 (d, J = 8.3 Hz,
1H), 6.78 (m, 2H), 6.68 (d, J = 9.9 Hz, 1H), 6.09 (m, 4H), 4.17 (d, J =
0.8 Hz, 3H), 3.86 (s, 4H); 13C NMR (126 MHz, CDCl3) δ 191.1,
167.6, 154.1, 153.6, 149.1, 148.6, 139.2, 134.6, 130.3, 128.4, 123.2,
119.2, 117.4, 115.6, 108.1, 107.7, 102.6, 84.5, 62.8, 57.0; IR (neat,
cm−1) 1682, 1770, 2853, 2921; TLC Rf = 0.45 (1:1 hexanes/EtOAc v/
v); HRMS (DART) m/z calcd for C20H15O7 (M + H)+: 367.0818,
found 367.0811.
tert-Butyl 6-(5,8-Dihydro-5,8-epoxynaphtho[2,3-d][1,3]-
dioxol-6-yl)-2,3-dimethoxybenzoate (7b). A total of 335.0 mg
(1.036 mmol, 1.4 equiv) of 6-(trimethylsilyl)benzo[d][1,3]dioxol-5-yl-
trifluoromethanesulfonate (4)9 and 225.0 mg (0.74 mmol, 1.0 equiv)
of tert-butyl 6-(furan-3-yl)-2,3-dimethoxybenzoate (6b) were dissolved
with acetonitrile (10.0 mL) in a flame-dried flask. The solution was
charged with argon; then 337.0 mg (2.22 mmol, 3.0 equiv) of CsF was
added, and the reaction mixture was let to stir at 23 °C for 24 h. The
solution was diluted with water (30.0 mL) and extracted with ethyl
acetate (3 × 15.0 mL). The combined organic layers were washed with
water (30.0 mL) and brine (30.0 mL), dried over MgSO4, and
concentrated under reduced pressure. The product was purified by
column chromatography (3:1 hexanes/EtOAc, v/v) to yield 201.6 mg
of tert-butyl 6-(5,8-dihydro-5,8-epoxynaphtho[2,3-d][1,3]dioxol-6-yl)-
2,3-dimethoxybenzoate (7b, 64% yield) as an off-white solid. Mp 150
ASSOCIATED CONTENT
■
1
°C (decomp.); H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.5 Hz,
S
* Supporting Information
1H), 6.94 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.83 (t, J = 0.5 Hz, 1H),
5.94 (d, J = 1.4 Hz, 1H), 5.86 (d, J = 1.4 Hz, 1H), 5.79 (t, J = 0.8 Hz,
1H), 5.73 (dt, J = 1.8, 0.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 1.49 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 166.7, 153.3, 152.6, 146.2,
144.8, 144.4, 143.4, 143.0, 136.7, 129.7, 122.9, 122.1, 112.6, 104.0,
103.7, 101.3, 85.0, 84.0, 82.4, 61.5, 56.1, 28.1; IR (neat, cm−1) 2973,
2935, 1715, 1482, 1292, 1265, 1142, 1059, 1029, 795; TLC Rf = 0.31
(3:1 hexanes/EtOAc, v/v); HRMS (DART) m/z calcd for C20H17O7
(M − C4H8)+: 369.0974, found 369.0960.
1H and 13C NMR spectra for all new compounds is provided.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
■
Notes
Methyl 6-(5,8-Dihydro-5,8-epoxynaphtho[2,3-d][1,3]dioxol-
6-yl)-2,3-dimethoxybenzoate (7a). A total of 780.0 mg (2.23
mmol) of methyl 6-(furan-3-yl)-2,3-dimethoxybenzoate (6a) yielded
375.0 mg (0.98 mmol, 66% yield) of methyl 6-(5,8-dihydro-5,8-
epoxynaphtho[2,3-d][1,3]dioxol-6-yl)-2,3-dimethoxybenzoate (7a) as
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award Number
T32GM008500 from the National Institute of General Medical
Sciences.
1
per the above procedure. Mp 56−58 °C (decomp); H NMR (500
MHz, CDCl3) δ 6.98 (d, J = 8.6 Hz, 1H), 6.93 (m, 2H), 6.81 (m, 2H),
5.93 (d, J = 1.4 Hz, 1H), 5.87 (d, J = 1.4 Hz, 1H), 5.75 (t, J = 0.8 Hz,
1H), 5.71 (dt, J = 1.8, 0.8 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 167.9, 153.5, 152.4, 146.3,
144.7, 144.3, 143.1, 142.6, 136.5, 127.6, 123.4, 122.0, 113.1, 103.9,
103.5, 101.2, 84.9, 83.9, 61.6, 56.0, 52.5; IR (neat, cm−1) 2941, 1724,
1460, 1254, 1035; TLC Rf = 0.5 (2:1 hexanes/EtOAc v/v); HRMS
(DART) m/z calcd for C21H19O7 (M + H)+: 383.1131, found
383.1129.
REFERENCES
■
(1) (a) Ishii, H.; I, T.; Haginiwa, J. Yakugaku Zasshi 1977, 97, 890.
(b) Ishikawa, T.; Murota, M.; Watanabe, T.; Harayama, T.; Ishii, H.
Tetrahedron Lett. 1995, 36, 4269.
(2) For the synthesis of arnottin I see: (a) Ishii, H.; Ishikawa, T.;
Murota, M.; Aoki, Y.; Harayama, T. J. Chem. Soc., Perkin Trans. 1 1993,
3341
J. Org. Chem. 2015, 80, 3339−3342