310
E.N. da Silva Júnior et al. / European Journal of Medicinal Chemistry 52 (2012) 304e312
4H), 7.49e7.33 (m, 3H); 13C NMR (100 MHz, CDCl3)
d: 177.3, 177.0,
6.6.4. 3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2,2-dime
thyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (28)
147.6,141.9,138.6,135.3,135.1,131.0,130.4,129.6,129.0,128.7,128.0,
127.7, 126.0, 122.0; (þ)-ESI-MS (C18H10ClN3O2), m/z (%) 302.3 (46),
311.2 (23), 325.4 (41), 330.4 (100), 336.2 (92), 332.3 (26), 338.2 (38),
358.3 (28).
The alkyne employed was 1-ethynyl-4-methoxybenzene
(109 mg, 0.83 mmol), and the resulting compound 28 was
a yellow solid (266 mg, 0.8 mmol, 80% yield); mp 220e225 ꢃC; IR
(KBr) 1654 (CaO), 1617 (CaO) cmꢁ1 1H NMR (400 MHz, CDCl3)
; d:
6.6. General procedure for the synthesis of nor-
1,2,3-triazoles 25e29
b
-lapachone-based
8.05 (dd, 1H, J ¼ 7.3, 0.9 Hz), 7.73 (dd, 1H, J ¼ 7.5, 1.2 Hz), 7.69e7.60
(m, 1H), 7.67 (s, 1H), 7.62 (d, 2H, J ¼ 8.8 Hz), 6.81 (d, 2H, J ¼ 8.8 Hz),
5.92 (s, 1H), 5.23 (s, 1H), 3.72 (s, 3H), 1.69 (s, 3H), 1.16 (s, 3H); 13C
The substituted alkyne (0.83 mmol) was reacted with 3-azido-
2,2-dimethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione 24
NMR (100 MHz, CDCl3) d: 180.2, 174.6, 171.2, 159.6, 147.4, 134.8,
133.3, 131.5, 129.9, 127.0, 126.7, 125.6, 123.0, 118.5, 114.1, 111.4, 96.0,
66.8, 55.3, 27.7, 21.1; (þ)-ESI-MS (C23H19N3O4), m/z (%) 311.3 (11),
402.2 (100), 403.4 (15), 424.2 (49), 425.2 (14). Anal (C23H19N3O4): C,
68.82; H, 4.77; N, 10.47. Found: C, 68.89; H, 4.41; N, 10.23.
(223.4 mg, 0.83 mmol) in 12 mL of CH2Cl2/H2O (1:1), CuSO4$5H2O
(9.3 mg, 0.04 mmol) and sodium ascorbate (22 mg, 0.11 mmol). The
mixture was agitated at room temperature until formation of the
product was complete and monitored by TLC. The organic phase
was extracted with CH2Cl2, dried over sodium sulfate and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel using a gradient
mixture of hexane/ethyl acetate with increasing polarity up to 100%
ethyl acetate as an eluent.
6.6.5. 2,2-Dimethyl-3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)-2,3-dihydr
onaphtho[1,2-b]furan-4,5-dione (29)
The alkyne employed was 1-ethynyl-4-methylbenzene (96 mg,
0.83 mmol), and the resulting compound 29 was a yellow solid
(271 mg, 0.8 mmol, 85% yield); mp 225e228 ꢃC; IR (KBr) 1652
(CaO), 1616 (CaO) cmꢁ1; 1H NMR (400 MHz, CDCl3)
d: 8.18 (dd, 1H,
6.6.1. 3-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-
2,3-dihydronaphtho[1,2-b]furan-4,5-dione (25)
J ¼ 7.5, 1.0 Hz), 7.85e7.73 (m, 3H), 7.79 (s, 1H), 7.7, (d, 2H, J ¼ 8.0 Hz),
7.2 (d, 2H, J ¼ 8.0 Hz), 6.04 (s, 1H), 2.37 (s, 3H), 1.80 (s, 3H), 1.27 (s,
The alkyne employed was 1-ethynyl-4-fluorobenzene (99 mg,
0.83 mmol), and the resulting compound 25 was a yellow solid
(251 mg, 0.7 mmol, 78% yield); mp 212e216 ꢃC; IR (KBr) 1649
3H); 13C NMR (100 MHz, CDCl3)
d: 180.1, 174.6, 171.3, 147.7, 138.1,
134.9, 133.3, 131.5, 130.0, 129.4, 127.4, 126.7, 125.7, 125.6, 119.0, 111.4,
96.1, 67.0, 27.7, 21.3, 21.2; (þ)-ESI-MS (C23H19N3O3), m/z (%) 386.2
(100), 387.2 (27), 408 (37). Anal (C23H19N3O3): C, 71.67; H, 4.97; N,
10.90. Found: C, 70.47; H, 4.54; N, 10.37.
(CaO), 1612 (CaO) cmꢁ1 1H NMR (400 MHz, CDCl3)
; d: 7.81 (s, 1H),
8.11 (bd, 1H, J ¼ 7.5 Hz), 7.69 (dt, 1H, J ¼ 7.5, 1.4 Hz), 7.74 (td, 1H,
J ¼ 7.5, 1.4 Hz), 7.81 (bd, 1H, J ¼ 7.5 Hz), 7.02 (t, 2H, J ¼ 8.8 Hz), 7.71
(dd, 2H, J ¼ 5.3, 8.8 Hz), 1.77 (s, 3H), 1.23 (s, 3H), 6.01 (s, 1H); 13C
6.7. Synthesis of 3-(3-methylbut-2-en-1-yl)-1,4-dioxo-1,4-dihydr
onaphthalen-2-yl-4-methylbenzenesulfonate (30)
NMR (100 MHz, CDCl3)
d
: 180.3, 174.8, 171.5, 162.8 (d, J ¼ 247 Hz),
146.6, 134.9, 133.5, 131.4, 129.9, 127.6 (d, J ¼ 8.4 Hz), 126.8, 126.5 (d,
J ¼ 3.3 Hz), 125.6, 119.2, 115.8 (d, J ¼ 21.6 Hz), 111.4, 96.2, 67.0, 27.8,
21.3; (þ)-ESI-MS (C22H16FN3O3), m/z (%) 311.2 (40), 330.4 (11), 390.2
(100), 412.2 (92). Anal (C22H16FN3O3): C, 67.86; H, 4.14; N, 10.79.
Found: C, 67.77; H, 4.03; N, 10.39.
Lapachol (1) (242 mg, 1 mmol) and tosyl chloride (295 mg,
2.5 mmol) were added to a solution of potassium carbonate (138 mg,
1 mmol) in CH2Cl2 (10 mL) at 0 ꢃC. The mixturewas stirred for 48 h at
room temperature, the solvent was evaporated under reduced
pressure, and the solid residue was purified by recrystallization with
ethyl acetate. The resulting compound 30 was a yellow solid
(297 mg, 0.7 mmol, 75% yield, mp 130e131 ꢃC); IR nmax (cmꢁ1, KBr):
3432, 2957, 2924,1678,1621,1591,1458,1452,1364,1328,1289,1194,
1180, 1155, 1089, 1033, 927, 811, 797, 741, 725, 669, 639, 583, 537; 1H
6.6.2. 3-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-
2,3-dihydronaphtho[1,2-b]furan-4,5-dione (26)
The alkyne employed was 1-bromo-4-ethynylbenzene (150 mg,
0.83 mmol), and the resulting compound 26 was a yellow solid
(298 mg, 0.8 mmol, 80% yield); mp 216e218 ꢃC; IR (KBr) 1645
NMR (500 MHz, CDCl3)
d
: 8.11 (dd, 1H, J ¼ 8.5, 1.9 Hz), 8.08 (dd, 1H,
(CaO), 1610 (CaO) cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
: 8.17e8.15 (m,
J ¼ 8.5,1.9 Hz), 8.02 (d, 2H, J ¼ 8.2 Hz), 7.78e7.71 (m, 2H), 7.43 (d, 2H,
1H), 7.82e7.70 (m, 4H), 7.64 (d, 2H, J ¼ 8.5 Hz), 7.48 (d, 2H,
J ¼ 8.0 Hz), 5.10 (t,1H, J ¼ 7.3 Hz), 3.37 (d, 2H, J ¼ 7.2 Hz), 2.51 (s, 3H),
J ¼ 8.5 Hz), 6.01 (s, 1H), 1.78 (s, 3H), 1.24 (s, 3H); 13C NMR (100 MHz,
1.72 (s, 3H), 1.66 (s, 3H); 13C NMR (125 MHz, CDCl3)
d: 184.9, 178.9,
CDCl3)
d: 180.2, 174.6, 171.4, 146.5, 135.0, 133.5, 132.0, 131.5, 130.0,
149.1, 146.0, 141.5, 135.6, 134.4, 132.2, 131.1, 130.0, 129.0, 126.8, 118.6,
77.6, 77.4, 77.1, 26.1, 24.9, 22.1,18.3; HRMS (ESI) (m/z) 397.1104. Calcd
for [C22H20O5SH]þ: 397.1104. Anal. Calcd for C22H20O5S: C, 66.65; H,
5.08; S, 8.09. Found: C, 66.44; H, 5.08; S, 8.35.
129.0, 127.3, 126.6, 125.6, 122.2, 119.3, 111.2, 96.0, 67.0, 27.7, 21.2.
Anal (C22H16BrN3O3): C, 58.68; H, 3.58; N, 9.33. Found: C, 57.69; H,
3.27; N, 8.87.
6.6.3. 2,2-Dimethyl-3-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)-
2,3-dihydronaphtho[1,2-b]furan-4,5-dione (27)
6.8. Synthesis of 3-(3-methylbut-2-enyl)-1,4-dioxo-1,4-dihydro
naphthalen-2-yl methanesulfonate (31)
The alkyne employed was 1-ethynyl-4-nitrobenzene (122 mg,
0.83 mmol), and the resulting compound 27 was a yellow solid
(265 mg, 0.7 mmol, 77% yield); mp 245e246 ꢃC; IR (KBr) 1642
The same procedure described above was employed using mesyl
chloride. The resulting compound 31 was a yellow solid (299 mg,
0.9 mmol, 93.7% yield, mp 130e131 ꢃC); IR nmax (cmꢁ1, KBr): 3446,
3042, 2935, 1675, 1664, 1627, 1593, 1576, 1373, 1335, 1299, 1259,
1234, 1185, 1161, 1100, 1039, 1029, 979, 931, 846, 835, 787, 719, 632,
(CaO), 1608 (CaO) cmꢁ1 1H NMR (400 MHz, CDCl3)
; d: 8.2 (d, 2H,
J ¼ 8.8 Hz), 8.16 (dd, 1H, J ¼ 7.0, 1.4 Hz), 7.9 (d, 2H, J ¼ 8.8 Hz), 7.8 (s,
1H), 7.8 (dd, 1H, J ¼ 7.0, 1.4 Hz), 7.7e7.6 (m, 2H), 6.0 (s, 1H), 1.8 (s,
3H), 1.2 (s, 3H); 13C NMR (100 MHz, CDCl3)
d: 180.0, 174.6, 171.5,
599, 517, 473; 1H NMR (500 MHz, CDCl3)
d: 8.10e8.11 (m, 2H),
147.5, 145.5, 136.4, 135.0, 133.6, 131.6, 130.1, 126.5, 126.3, 125.7,
124.2, 120.5, 111.0, 96.0, 67.2, 28.0, 21.4; (þ)-ESI-MS (C22H16N4O5),
m/z (%) 301.3 (100), 311.2 (61), 320.2 (25), 338.7 (30), 344.3 (50),
361.0 (22), 381.2 (27), 390.3 (37), 406.5 (32), 417.2 (22). Anal
(C22H16N4O5): C, 63.46; H, 3.87; N, 13.46. Found: C, 63.53; H, 3.58;
N, 13.16.
7.74e7.78 (m, 2H), 5.13 (t, 1H, J ¼ 7.27 Hz), 3.63 (s, 3H), 3.44 (d, 2H,
J ¼ 7.5 Hz), 1.8 (s, 3H), 1.68 (s, 3H); 13C NMR (125 MHz, CDCl3)
d:
184.5, 180.0, 149.3, 142.0, 134.8, 134.4, 132.4, 130.7, 127.3, 126.9,
118.2, 50.8, 40.8, 26.1, 24.9, 18.4; HRMS (ESI) (m/z) 321.0789. Calcd
for [C16H16O5SH]þ: 321.0797. Anal (C16H17O5S): C, 59.99; H, 5.03; S,
10.01. Found: C, 59.94; H, 4.80; 12.02.