L.-Q. Wu et al.
Bioorganic Chemistry 113 (2021) 104995
4.1.2.7. 2-Hydroxy-5-methoxy-3-(2-methylprop-1-enyl)naphthalene-1,4-
dione (3g). Yellow solid, m.p. 122–123 ◦C; 1H NMR (400 MHz,
DMSO‑d6) δ: 10.51 (s, 1H), 7.72 (t, 1H, J = 7.6 Hz), 7.63 (dd, 1H, J = 0.8,
7.6 Hz), 7.52 (dd, 1H, J = 0.8, 8.4 Hz), 5.82 (t, 1H, J = 1.6 Hz), 4.12 (s,
3H), 1.88 (d, 3H, J = 1.2 Hz), 1.54 (d, 3H, J = 0.8 Hz); 13C NMR (100
MHz, DMSO‑d6) δ: 184.1, 181.8, 159.3, 152.1, 140.2, 134.6, 132.6,
122.6, 120.2, 119.7, 118.6, 115.9, 56.8, 26.6, 21.8; IR (KBr): 3369,
1638, 1582, 1474, 1449, 1382, 1267, 1191, 1064, 1035, 973, 889, 758,
666; HRMS-ESI (m/z): calcd for C15H14NaO4 [M + Na]+ 281.0784,
found: 281.0786.
4.1.3.3. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-7-methoxy-2,2-
dimethylnaphtho [1,2–b]furan-4,5-dione (5c). Orange solid, m.p.
192–193 ◦C, yield 69%; 1H NMR (400 MHz, CDCl3) δ: 8.07 (d, 1H, J =
8.4 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.69 (d, 1H, J = 2.4 Hz), 7.44–7.22 (m,
4H), 6.23 (s, 1H), 3.97 (s, 3H), 1.81 (s, 3H), 1.11 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 180.4, 174.6, 171.6, 163.9, 146.3, 133.6, 133.0, 128.0,
127.5, 12.67, 124.2, 120.5 (2C), 119.3, 114.9, 109.2, 95.4, 65.7, 56.1,
28.0, 21.3; IR (KBr): 3001, 1656, 1601, 1563, 1448, 1413, 1350, 1278,
1114, 1097, 844, 822, 743; HRMS-ESI (m/z): calcd for C21H17N3NaO4
[M + Na]+ 398.1111, found: 398.1112.
4.1.2.8. 2-Hydroxy-5,7-dimethyl-3-(2-methylprop-1-enyl)naphthalene-
1,4-dione (3h). Yellow solid, m.p. 144–145 ◦C, yield 58%; 1H NMR
(400 MHz, DMSO‑d6) δ: 10.60 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 5.84 (t,
1H, J = 1.2 Hz), 2.60 (s, 3H), 2.39 (s, 3H), 1.87 (d, 3H, J = 1.2 Hz), 1.54
(d, 3H, J = 0.8 Hz); 13C NMR (100 MHz, DMSO‑d6) δ: 187.0, 182.1,
152.7, 142.9, 140.4, 139.3, 131.9, 127.6, 125.4, 122.1, 116.0, 26.5,
22.7, 21.8, 21.3; IR (KBr): 3344, 2976, 2907, 1600, 1435, 1377, 1326,
1293, 1190, 1092, 898, 880, 756, 677; HRMS-ESI (m/z): calcd for
4.1.3.4. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-7-fluoro-2,2-
dimethylnaphtho[1,2–b]furan-4,5-dione (5d). Orange solid, m.p.
210–211 ◦C, yield 70%; 1H NMR (400 MHz, CDCl3) δ: 8.08 (d, 1H, J =
8.4 Hz), 7.90–7.86 (m, 2H), 7.49–7.36 (m, 4H), 6.20 (s, 1H), 1.82 (s,
3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 179.2, 174.2, 170.2,
165.8 (d, JC-F = 250.9 Hz), 146.2, 134.1 (d, JC-F = 8.1 Hz), 128.1(d, JC-F
= 14.2 Hz), 127.9, 124.3, 123.2, 123.1, 121.7 (d, JC-F = 22.4 Hz), 120.6
(2C), 117.5 (d, JC-F = 24 Hz), 109.0, 95.7, 65.4, 28.0, 21.3; IR (KBr):
3054, 1656, 1617, 1582, 1415, 1267, 1247, 1080, 797, 737; HRMS-ESI
(m/z): calcd for C20H14FN3NaO3 [M + Na]+ 386.0911, found: 386.0910.
3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-7-chloro-2,2-dime-
C
16H16NaO3 [M + Na]+ 279.0992, found: 279.0992.
4.1.2.9. 2-Hydroxy-6,7-dimethoxy-3-(2-methylprop-1-enyl)naphthalene-
1
◦
thylnaphtho[1,2–b]furan-4,5-dione
(5e).
Orange
solid,
m.p.
1,4-dione (3i). Red solid, m.p. 161–162 C, yield 83%; H NMR (400
MHz, DMSO‑d6) δ: 10.75 (s, 1H), 7.41 (d, 1H, J = 9.2 Hz), 5.80 (t, 1H, J
= 1.6 Hz), 3.93 (s, 3H), 3.92 (s, 3H), 1.87 (d, 3H, J = 1.2 Hz), 1.54 (d,
3H, J = 0.8 Hz); 13C NMR (100 MHz, DMSO‑d6) δ: 184.3, 180.8, 154.1,
152.7, 140.0, 127.3, 124.5, 120.0, 115.5, 108.3, 107.9, 56.5 (2C), 26.5,
21.8; IR (KBr): 3347, 1633, 1576, 1463, 1302, 1207, 1126, 1038, 978,
885, 751, 637; HRMS-ESI (m/z): calcd for C16H16NaO5 [M + Na]+
311.0890, found: 311.0894.
204–205 ◦C, yield 34%; 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, 1H, J =
2.0 Hz), 8.08 (d, 1H, J = 8.0 Hz), 7.81–7.73 (m, 2H), 7.50–7.37 (m, 3H),
6.20(s, 1H), 1.82 (s, 3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
179.3, 173.9, 170.1, 146.2, 140.3, 134.7, 133.1, 132.7, 130.1, 128.2,
126.8, 125.1, 124.3, 120.6 (2C), 108.9, 95.8, 65.4, 28.0, 21.3; IR (KBr):
3067, 1655, 1615, 1579, 1493, 1398, 1215, 1100, 1082, 865, 747;
HRMS-ESI (m/z): calcd for C20H14ClN3NaO3 [M + Na]+ 402.0616,
found: 402.0614.
4.1.3. Synthesis of 3-(1-benzotriazole)-nor-β-lapachone 5
Bromine (2 mL) was added to a solution of nor-lapachol 3 (228 mg, 1
mmol) in 25 mL of chloroform. The bromo intermediate precipitated
immediately as an orange solid, and the reaction mixture was left under
stirring conditions for an additional 10 min. After the removal of excess
bromine, a solution of benzotriazoles (1 mmol) in 25 mL of chloroform
was added and stirred overnight. The mixture was poured into 50 mL of
water. The organic phase was separated and washed with saturated
NaHCO3 solution, dried over Na2SO4, filtered, and evaporated under
reduced pressure to yield a solid, which was purified by column chro-
matography using petroleum ether and ethyl acetate as a eluent.
4.1.3.5. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-7-bromo-2,2-
dimethylnaphtho[1,2–b]furan-4,5-dione
(5f). Orange
solid,
m.p.
205–206 ◦C, yield 55%; 1H NMR (400 MHz, CDCl3) δ: 8.29 (d, 1H, J =
2.0 Hz), 8.07 (d, 1H, J = 8.4 Hz), 7.91 (dd, 1H, J = 2.0, 8.0 Hz), 7.71 (d,
1H, J = 8.0 Hz), 7.47–7.36 (m, 3H), 6.20 (s, 1H), 1.82 (s, 3H), 1.13 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 179.2, 173.8, 170.2 146.2, 137.7,
133.5, 133.1, 132.5, 128.6, 128.2, 126.8, 125.5, 124.3, 120.6 (2C),
108.9, 95.8, 65.4, 28.0, 21.3; IR (KBr): 1653, 1613, 1579, 1486, 1397,
1230, 1094, 1075, 1009, 739; HRMS-ESI (m/z): calcd for
C
20H14BrN3NaO3 [M + Na]+ 446.0111, found: 446.0114.
4.1.3.1. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-2,2-dime-
thylnaphtho[1,2–b]furan-4,5-dione (5a). Orange solid, m.p. 198–199 ◦C,
yield 58%; 1H NMR (400 MHz, CDCl3) δ: 8.21–8.05 (m, 2H), 7.88–7.72
4.1.3.6. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-9-methoxy-2,2-
dimethylnaphtho
[1,2–b]furan-4,5-dione
(5g). Red solid, m.p.
254–255 ◦C, yield 52%; 1H NMR (400 MHz, CDCl3) δ: 8.07 (d, 1H, J =
8.4 Hz), 7.84 (dd, 1H, J = 0.8, 7.2 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.45 (d,
1H, J = 3.2 Hz), 7.38–7.32 (m, 2H), 6.18 (s, 1H), 4.01 (s, 3H), 1.80 (s,
3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 180.7, 174.4, 172.2,
158.5, 146.2, 134.5, 133.4, 133.1, 128.0, 124.1, 123.3, 120.5 (2C),
119.2, 114.2, 109.3, 94.7, 64.8, 56.7, 28.1, 21.3; IR (KBr): 1698, 1648,
1595, 1480, 1355, 1279, 1109, 1067, 750; HRMS-ESI (m/z): calcd for
(m, 3H), 7.47–7.38 (m, 3H), 6.25 (s, 1H), 1.84 (s, 3H), 1.13 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ: 180.2, 174.6, 171.0, 146.2, 134.9, 133.2,
133.1, 131.5, 130.0, 128.2, 126.8, 125.5, 124.3, 120.5, 120.2, 109.1,
95.5, 65.6, 28.0, 21.3; IR (KBr): 2925, 1653, 1619, 1491, 1406, 1249,
1218, 1076, 749; HRMS-ESI (m/z): calcd for C20H15N3NaO3 [M + Na]+
368.1006, found: 368.1006.
C
21H17N3NaO4 [M + Na]+ 398.1111, found: 398.1114.
4.1.3.2. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-2,2,7-trime-
thylnaphtho[1,2–b] furan-4,5-dione (5b). Red solid, m.p. 190–191 ◦C,
yield 43%; 1H NMR (400 MHz, CDCl3) δ: 8.09–7.92 (m, 2H), 7.74 (d, 1H,
J = 7.6 Hz), 7.57 (d, 1H, J = 7.6 Hz), 7.46–7.37 (m, 3H), 6.23 (s, 1H),
2.52 (s, 3H), 1.82 (s, 3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
180.6, 174.6, 171.3, 146.2, 144.5, 135.3, 131.5, 131.1, 130.8, 128.1,
125.6, 125.3, 124.2, 120.6 (2C), 109.1, 95.3, 65.6, 28.0, 21.8, 21.3; IR
(KBr): 2923, 1655, 1608, 1564, 1505, 1417, 1355, 1239, 1161, 1097,
1078, 791, 746, 662; HRMS-ESI (m/z): calcd for C21H17N3NaO3 [M +
Na]+ 382.1162, found: 382.1166.
4.1.3.7. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-2,2,7,9-tetrame-
thylnaphtho[1,2–b]furan-4,5-dione (5h). Red solid, m.p. 197–198 ◦C,
yield 41%; 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, 1H, J = 8.0 Hz), 7.91
(s, 1H), 7.44–7.35 (m, 4H), 6.20 (s, 1H), 2.69 (s, 3H), 2.45 (s, 3H), 1.81
(s, 3H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 180.0, 174.7, 173.6,
146.2, 143.8, 139.4, 139.2, 133.1, 132.8, 129.8, 128.1, 124.2, 122.1,
120.5 (2C), 109.2, 94.8, 64.9, 28.2, 22.1, 21.5, 21.4; IR (KBr): 2922,
1649, 1608, 1585, 1450, 1343, 1282, 1246, 1103, 1075, 778, 746;
HRMS-ESI (m/z): calcd for C22H19N3NaO3 [M + Na]+ 396.1319, found:
396.1318.
9