3.2.2.2. Preparation of Dihydroartemisinin Amino Derivatives 4a–u
Compound
3, CH
3CN, K
2CO
3 and YH were placed in a 100-mL round-bottomed flask, respectively. The mixture reacted at a controlled temperature, while monitoring by TLC. CH
2Cl
2 (15 mL) and saturated NaCl solution (20 mL) were added. The aqueous layer was extracted after liquid separation with CH
2Cl
2 (10 mL × 2), and then the organic layers were combined, washed with saturated brine (20 mL) and then dried with anhydrous Na
2SO
4; CH
2Cl
2 was removed through rotary evaporation under reduced pressure. Pure product was obtained after column chromatography. The experimental results are shown in
Table 3.
Table 3.
Experimental results of target compounds 4a–u.
12β-(2-(Dimethylamino)ethoxy)dihydroartemisinin (
4a): Yield: 98.2%; Yellow oil;
+ 139.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91 (3H, d,
J = 7.2 Hz, H-14), 0.95 (3H, d,
J = 6.0 Hz, H-13), 1.44 (3H, s, H-15), 1.22–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.28 (6H, s, H-18), 2.32–2.38 (1H, m, H-1), 2.51–2.54 (2H, m, H-17), 2.60–2.65 (1H, m, H-11), 3.50–3.57 (1H, m, H-16), 3.91–3.98 (1H, m, H-16), 4.80 (1H, d,
J = 2.7 Hz, H-12), 5.42 (1H, s, H-5).
12β-(2-(Diethylamino)ethoxy)dihydroartemisinin (
4b): Yield: 94.2%; Yellow oil;
+ 116.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.2 Hz, H-14), 0.95 (3H, d,
J = 6.0 Hz, H-13), 1.05 (6H, t,
J = 7.5 Hz, H-19), 1.44 (3H, s, H-15), 1.18–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.32–2.42 (1H, m, H-1), 2.57–2.64 (5H, m, H-18 and H-11), 2.69–2.73 (1H, m, H-17), 3.47–3.55 (1H, m, H-16), 3.91–3.99 (1H, m, H-16), 4.79 (1H, s, H-12), 5.42 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 104.0 (C-4), 102.1 (C-12), 87.8 (C-5), 81.1 (C-6), 66.7 (C-16), 52.5 (C-1), 52.1 (C-17), 47.4 (C-18), 44.4 (C-7), 37.4 (C-11), 36.4 (C-10), 34.6 (C-3), 30.8 (C-9), 26.2 (C-8), 24.7 (C-15), 24.3 (C-2), 20.4 (C-14), 13.0 (C-13), 11.8 (C-19).
12β-(2-Pyrrolidinoethoxy)dihydroartemisinin (
4c): Yield: 91.7%; Brown oil;
+ 140.0 (c 1.1 mg/mL, CH
2Cl
2).
1H-NMR (CDCl
3) δ ppm: 0.91 (3H, d,
J = 7.5 Hz, H-13), 0.95 (3H, d,
J = 6.3 Hz, H-14), 1.44 (3H, s, H-15), 1.22–2.06 (14H, m, H-2, H-3, H-7, H-8, H-9, H-10, H-18 and H-19), 2.32–2.42 (1H, m, H-1), 2.59–2.80 (7H, m, H-11, H-17 and H-18), 3.54–3.61 (1H, m, H-16), 3.95–4.02 (1H, m, H-16), 4.61 (1H, s, H-12), 5.44 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 104.0 (C-4), 102.0 (C-12), 87.8 (C-5), 81.0 (C-6), 67.1 (C-16), 55.3 (C-17) 54.5 (C-18), 52.5 (C-1), 44.4 (C-7), 37.4 (C-11), 36.4 (C-10), 34.6 (C-3), 30.8 (C-9), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 23.4 (C-19), 20.3 (C-14), 13.0 (C-13).
12β-(2-Piperidinoethoxy)dihydroartemisinin (
4d): Yield: 93.8%; m.p.: 70.8–72.1 °C;
+ 135.0 (
c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.2 Hz, H-13), 0.96 (3H, d,
J = 6.0 Hz, H-14), 1.44 (3H, s, H-15), 1.22–2.06 (16H, m, H-2, H-3, H-7, H-8, H-9, H-10, H-19 and H-20), 2.32–2.60 (8H, m, H-1, H-11, H-17 and H-18), 3.55–3.59 (1H, m, H-16), 3.92–4.00 (1H, m, H-16), 4.79 (1H, s, H-12), 5.44 (1H, s, H-5).
12β-(2-Morpholinoethoxy)dihydroartemisinin (
4e): Yield: 86.4%; Yellow syrup;
+ 59.0 (
c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.5 Hz, H-13), 0.96 (3H, d,
J = 6.3 Hz, H-14), 1.44 (3H, s, H-15), 1.26–2.05 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.42 (1H, m, H-1), 2.49–2.63 (7H, m, H-11, H-17 and H-18), 3.54–3.62 (1H, m, H-16), 3.72 (3H, t,
J = 4.5 Hz, H-19), 3.94–4.01(1H, m, H-16), 4.81 (1H, d,
J = 3.3 Hz, H-12), 5.47 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 104.0 (C-4), 102.0 (C-12), 87.9 (C-5), 81.1 (C-6), 66.9 (C-19), 65.6 (C-16), 58.2 (C-17) 53.8 (C-18), 52.5 (C-1), 44.4 (C-7), 37.5 (C-11), 36.4 (C-10), 34.6 (C-3), 30.8 (C-9), 26.2 (C-8), 24.7 (C-15), 24.4 (C-2), 20.4 (C-14), 13.0 (C-13).
10β-(2-(4-N-Boc-piperazino)ethoxy))dihydroartemisinin (
4f): Yield: 81.6%; m.p.: 107.8–109.1 °C;
+122.0 (c 1.0 mg/mL, CH
2Cl
2).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.2 Hz, H-13), 0.96 (3H, d,
J = 6.0 Hz, H-14), 1.43 (3H, s, H-15), 1.46 (9H, s, H-22), 1.22–2.06 (16H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.65 (8H, m, H-1, H-11, H-17 and H-18), 3.40–3.44 (4H, m, H-19), 3.52–3.58 (1H, m, H-16), 3.92–4.00 (1H, m, H-16), 4.80 (1H, s, H-12), 5.46 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm
: 154.6 (C-21), 104.0 (C-4), 101.9 (C-12), 87.8 (C-5), 81.0 (C-6), 79.7 (C-22), 66.0 (C-16), 57.9 (C-17), 53.5 (C-19), 52.0 (C-1), 49.2 (C-18), 44.4 (C-7), 37.4 (C-11), 36.4 (C-10), 34.6 (C-3), 30.8 (C-9), 28.4 (C-23), 26.4 (C-17), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 20.4 (C-14), 13.0 (C-13).
12β-(2-(4-N-Phenylpiperazino) ethoxy))dihydroartemisinin (
4g): Yield: 92.6%; m.p.: 90.0–91.7 °C;
+74.0 (c 1.0 mg/mL, CH
2Cl
2).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.2 Hz, H-13), 0.95 (3H, d,
J = 6.0 Hz, H-14), 1.44 (3H, s, H-15), 1.23–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.32–2.42 (1H, m, H-1), 2.59–2.70 (7H, m, H-11, H-17 and H-18), 3.21 (4H, t,
J = 7.5 Hz, H-19), 3.58–3.65 (1H, m, H-16), 3.98–4.05 (1H, m, H-16), 4.83 (1H, d,
J = 2.7 Hz, H-12), 5.48 (1H, s, H-5), 6.89 (1H, t,
J = 7.2 Hz, H-23), 6.94 (2H, d,
J = 7.8 Hz, H-21), 7.25–7.30 (2H, m, H-22);
13C-NMR (CDCl
3) δ ppm
: 151.3 (C-20), 129.1 (C-22), 120.0 (C-23), 116.0 (C-21), 104.0 (C-4), 102.0 (C-12), 87.9 (C-5), 81.1 (C-6), 66.0 (C-16), 57.9 (C-17), 53.5 (C-19), 52.6 (C-1), 49.2 (C-18), 44.4 (C-7), 37.5 (C-11), 36.4 (C-10), 34.7 (C-3), 30.9 (C-9), 26.2 (C-8), 24.7 (C-15), 24.4 (C-2), 20.3 (C-14), 13.1 (C-13); HRMS calcd for C
27H
40N
2O
5 (M+H)
+ 473.3010, found 473.3014.
12β-(2-((1-(2-(Dimethylamino)ethyl)-1H-tetrazol-5-yl)thio)ethoxy)dihydroartemisinin (
4h): Yield: 71.2%; m.p.: 67.9-69.2 °C;
+ 72.0 (c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J = 7.2 Hz, H-13), 0.96 (3H, d,
J = 5.7 Hz, H-14), 1.44 (3H, s, H-15), 1.20–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.29 (6H, s, H-21), 2.36–2.42(1H, m, H-1), 2.59–2.65(1H, m, H-11), 2.79 (2H, t,
J = 6.6 Hz, H-20), 3.60 (2H, t,
J = 5.7 Hz, H-17), 3.74–3.81 (1H, m, H-16), 4.11–4.18 (1H, m, H-16), 4.32 (2H, t,
J = 6.6 Hz, H-19), 4.82 (1H, s, H-12), 5.42 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 154.1 (C-18), 104.1 (C-4), 102.2 (C-12), 88.0 (C-5), 80.9 (C-6), 66.5 (C-16), 57.2 (C-20), 52.4 (C-1), 45.1 (C-21), 44.2 (C-7), 37.4 (C-11), 36.3 (C-10), 34.5 (C-3), 33.7 (C-17), 30.7 (C-9), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 20.3 (C-14), 12.9 (C-13).
12β-(2-((5-Amino-1,3,4-thiadiazol-2-yl)thio)ethoxy)dihydroartemisinin (
4i): Yield: 86.7%; m.p.: 120.1–121.7 °C;
+ 59.0 (c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91 (3H, d,
J = 7.2 Hz, H-13), 0.96 (3H, d,
J =6.0 Hz, H-14), 1.43 (3H, s, H-15), 1.22–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.42 (1H, m, H-1), 2.56–2.67 (1H, m, H-11), 3.41 (2H, t,
J = 5.7 Hz, H-17), 3.70–3.77 (1H, m, H-16), 4.06–4.14 (1H, m, H-16), 4.82 (1H, s, H-12), 5.44 (1H, s, H-5);
13C-NMR (DMSO and CDCl
3) δ ppm: 103.3 (C-4), 101.3 (C-12), 87.2 (C-5), 80.4 (C-6), 66.1 (C-16), 52.0 (C-1), 43.8 (C-7), 36.7 (C-11), 35.9 (C-10), 34.6 (C-3), 34.1 (C-17), 30.3 (C-9), 25.6 (C-8), 24.1 (C-15), 23.8 (C-2), 20.0 (C-14), 12.6 (C-13); HRMS calcd for C
19H
29N
3O
5S
2 (M+Na)
+ 466.1441, found 466.1440.
12β-(2-((5-Acetamino-1,3,4-thiadiazol-2-yl)thio)ethoxy)dihydroartemisinin (
4j): Yield: 78.0%; m.p.: 108.7–110.1 °C;
+ 83.0 (c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.89 (3H, d,
J = 7.2 Hz, H-13), 0.94 (3H, d,
J =6.0 Hz, H-14), 1.42 (3H, s, H-15), 1.22–2.05 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.42 (1H, m, H-1), 2.49 (3H, s, H-21), 2.58–2.64 (1H, m, H-11), 3.44–3.57 (2H, m, H-17), 3.75–3.81 (1H, m, H-16), 4.13–4.20 (1H, m, H-16), 4.84 (1H, s, H-12), 5.42 (1H, s, H-5), 13.08 (1H, s, H-20);
13C-NMR (CDCl
3) δ ppm: 168.5 (C-20), 104.1 (C-4), 102.2 (C-12), 88.0 (C-5), 81.0 (C-6), 66.5 (C-16), 52.5 (C-1), 44.3 (C-7), 37.4 (C-11), 36.3 (C-10), 34.6 (C-3), 34.1 (C-17), 30.8 (C-9), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 23.0 (C-21), 20.3 (C-14), 12.9 (C-13); HRMS calcd for C
21H
31N
3O
6S
2 (M+Na)
+ 508.1546, found 508.1540.
12β-(2-(1H-Imidazol-1yl)ethoxy)dihydroartemisinin (
4k): Yield: 89.1%; Yellow oil;
+ 68.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.85 (3H, d,
J =7.2 Hz, H-14), 0.94 (3H, d,
J = 6.1 Hz, H-13), 1.44 (3H, s, H-15), 1.22–2.07 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.32–2.38 (1H, m, H-1), 2.61–2.63 (1H, m, H-11), 3.62–3.68 (1H, m, H-16), 4.15–4.21 (3H, m, H-16 and H-17), 4.76 (1H, s, H-12), 5.11 (1H, s, H-5). 7.00 (1H, s, H-19), 7.09 (1H, s, H-18), 7.62 (1H, s, H-20);
13C-NMR (CDCl
3) δ ppm: 128.7 (C-20), 123.1 (C-19), 118.9 (C-18), 104.1 (C-4), 102.0 (C-12), 87.8 (C-5), 80.8 (C-6), 67.0 (C-16), 52.3 (C-1), 47.2 (C-17), 44.0 (C-7), 37.2 (C-11), 36.3 (C-10), 34.4 (C-3), 30.6 (C-9), 26.1 (C-8), 24.6 (C-15), 24.3 (C-2), 20.3 (C-14), 13.0 (C-13); HRMS calcd for C
20H
30N
2O
5 (M+H)
+ 379.2228, found 379.2221.
12β-(2-(4-Methyl-1H-imidazol-1-yl)ethoxy)dihydroartemisinin (
4l): Yield: 76.4%; Yellow oil;
+58.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91(3H, d,
J = 6.9 Hz, H-14), 0.95 (3H, d,
J = 6.3 Hz, H-13), 1.45 (3H, s, H-15), 1.19–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.12 (3H, s, H-21), 2.32–2.43 (1H, m, H-1), 2.59–2.66 (1H, m, H-11), 3.40–3.52 (4H, m, H-16 and H-17), 4.69 (1H, d,
J = 2.7 Hz, H-12), 5.39 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 127.8 (C-18), 127.2 (C-20), 118.8 (C-19), 104.2 (C-4), 102.0 (C-12), 87.8 (C-5), 80.9 (C-6), 66.9 (C-16), 52.4 (C-1), 47.8 (C-17), 44.0 (C-7), 37.2 (C-11), 36.3 (C-10), 34.4 (C-3), 30.6 (C-9), 26.1 (C-8), 24.6 (C-15), 24.2 (C-2), 20.3 (C-14), 13.0 (C-13), 12.7 (C-21); HRMS calcd for C
21H
32N
2O
5 (M+H)
+ 393.2384, found 393.2382.
12β-(2-(2-Methyl-1H-imidazol-1-yl)ethoxy)dihydroartemisinin (
4m): Yield: 76.4%; Yellow oil;
+ 52.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.85 (3H, d,
J =7.2 Hz, H-14), 0.94 (3H, d,
J = 4.8 Hz, H-13), 1.43 (3H, s, H-15), 1.22–2.07 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.29–2.34 (1H, m, H-1), 2.41 (3H, s, H-21), 2.61–2.63(1H, m, H-11), 3.58–3.63 (1H, m, H-16), 3.99-4.16 (3H, m, H-16 and H-17), 4.76 (1H, d,
J = 3.3 Hz, H-12), 5.08 (1H, s, H-5). 6.88 (1H, s, H-19), 6.92 (1H, s, H-18);
13C-NMR (CDCl
3) δ ppm: 126.7 (C-20 and C-19), 118.9 (C-18), 104.2 (C-4), 102.0 (C-12), 87.8 (C-5), 80.9 (C-6), 66.8 (C-16), 52.4 (C-1), 45.8 (C-17), 44.0 (C-7), 37.2 (C-11), 36.3 (C-10), 34.4 (C-3), 30.6 (C-9), 26.1 (C-8), 24.6 (C-15), 24.2 (C-2), 20.3 (C-14), 13.0 (C-13), 12.9 (C-21); HRMS calcd for C
21H
32N
2O
5 (M+H)
+ 393.2384, found 393.2386.
12β-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethoxy)dihydroartemisinin (
4n): Yield: 86.4%; Yellow oil;
+ 49.0 (c 1.0 mg/mL, CH
2Cl
2).
1H-NMR (CDCl
3) δ ppm: 0.81 (3H, d,
J = 7.2 Hz, H-14), 0.87 (3H, d,
J = 6.3Hz, H-13), 1.42 (3H, s, H-15), 1.26–2.08 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.29–2.37 (1H, m, H-1), 2.21 (3H, s, H-21), 2.28 (3H, s, H-22), 2.51–2.59 (1H, m, H-11), 3.64–3.69 (1H, m, H-16), 4.12–4.28 (3H, m, H-16 and H-17), 4.75 (1H, d,
J = 2.7 Hz, H-12), 5.07 (1H, s, H-5), 5.86 (1H, s, H-19);
13C-NMR (CDCl
3) δ ppm: 147.4 (C-20), 139.4 (C-20), 104.6 (C-4), 103.9 (C-19), 101.7 (C-12), 87.6 (C-5), 80.9 (C-6), 66.4 (C-16), 52.3 (C-1), 47.9 (C-17), 44.2 (C-7), 37.0 (C-11), 36.3 (C-10), 34.6 (C-3), 30.7 (C-9), 26.1 (C-8), 24.5 (C-15), 24.0 (C-2), 20.2 (C-14), 13.0 (C-13), 12.8 (C-21), 11.1 (C-22); HRMS calcd for C
22H
34N
2O
5 (M+Na)
+ 429.2360, found 429.2356.
12β-(2-(1H-1,2,4-Triazol-1-yl)ethoxy)dihydroartemisinin (
4o): Yield: 95.4%; m.p.: 93.5–95.2 °C;
+ 96.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.78 (3H, d,
J =7.2 Hz, H-14), 0.94 (3H, d,
J = 4.5 Hz, H-13), 1.42 (3H, s, H-15), 1.19–2.08 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.31–2.39 (1H, m, H-1), 2.58–2.62 (1H, m, H-11), 3.74–3.81 (1H, m, H-16), 4.09–4.17 (1H, m, H-16), 4.36–4.38 (2H, m, H-17), 4.78 (1H, s, H-12), 5.17 (1H, s, H-5), 7.96 (1H, s, H-19), 8.12 (1H, s, H-18).
12β-(2-((5-Methyl-2H-tetrazol-2-yl)ethoxy)dihydroartemisinin (
4p): Yield: 31.2%; m.p.:114.2–115.7 °C;
+ 93.0 (c 1.1 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.75 (3H, d,
J = 7.2 Hz, H-14), 0.94 (3H, d,
J = 4.5 Hz, H-13), 1.42 (3H, s, H-15), 1.21–2.04 (10H, m, H-2, H-3, H-7, H-8, H-9, and H-10), 2.29–2.38 (H, m, H-1), 2.57 (3H, s, H-19), 2.58–2.61 (H, m, H-11), 3.80–3.87 (1H, m, H-16), 4.34–4.37 (1H, m, H-16), 4.46–4.48 (2H, m, H-17), 4.76 (1H, s, H-12), 5.11 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 152.1 (C-18), 104.2 (C-4), 102.3 (C-12), 87.7 (C-5), 80.7 (C-6), 65.8 (C-16), 52.3 (C-1), 47.0 (C-17), 43.9 (C-7), 37.2 (C-11), 36.2 (C-10), 34.3 (C-3), 30.5 (C-9), 26.0 (C-8), 24.5 (C-15), 24.2 (C-2), 20.3 (C-14), 13.0 (C-13), 8.9 (C-19); HRMS calcd for C
19H
30N
4O
5 (M+Na)
+ 417.2108, found 417.2106.
12β-(2-(5-(Methylthio)-2H-tetrazol-2-yl)ethoxy)dihydroartemisinin (
4q): Yield: 83.8%; m.p.: 121.7–123.3 °C;
+ 126.0 (c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.90 (3H, d,
J =7.5 Hz, H-14), 0.96 (3H, d,
J = 6.3 Hz, H-13), 1.43 (3H, s, H-15), 1.21–2.04 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.43 (H, m, H-1), 2.61–2.66 (H, m, H-11), 3.63 (2H, t,
J =5.7 Hz, H-17), 3.75–3.83 (1H, m, H-16), 3.93 (3H, s, H-19), 4.12–4.19 (H, m, H-16), 4.83 (1H, d,
J =2.7 Hz, H-12), 5.43 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 154.0 (C-18), 104.1 (C-4), 102.2 (C-12), 87.9 (C-5), 80.9 (C-6), 66.5 (C-16), 52.4 (C-1), 44.2 (C-7), 37.4 (C-11), 36.3 (C-10), 34.5 (C-3), 33.6 (C-17), 33.4 (C-19), 30.7 (C-9), 26.1 (C-8), 24.6 (C-15), 24.3 (C-2), 20.3 (C-14), 12.9 (C-13); HRMS calcd for C
19H
30N
4O
5S (M+Na)
+ 449.1829, found 449.1821.
12β-(2-(1H-Benzoimidazol-1-yl)ethoxy)dihydroartemisinin (
4r): Yield: 87.4%; Yellow oil;
+ 94.0 (c 1.0 mg/mL, CH
2Cl
2).
1H-NMR (CDCl
3) δ ppm: 0.76 (3H, d,
J = 7.5 Hz, H-14), 0.83 (3H, d,
J = 6.0 Hz, H-13), 1.39 (3H, s, H-15), 1.15–1.99 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.24–2.35 (H, m, H-1), 2.52–2.59 (H, m, H-11), 3.70–3.76 (1H, m, H-16), 4.28–4.43 (3H, m, H-16 and H-17), 4.73 (1H, d,
J =2.7 Hz, H-12), 4.91 (1H, s, H-5), 7.30 (2H, t,
J =2.4 Hz, H-21 and H-22), 7.42 (1H, d,
J =7.5 Hz, H-23), 7.80 (1H, d,
J =7.5 Hz, H-20), 7.95 (1H, s, H-18);
13C-NMR (CDCl
3) δ ppm: 143.5 (C-18), 143.3 (C-19), 133.6 (C-24), 122.9 (C-20), 122.1 (C-21), 120.2 (C-22), 109.6 (C-23), 104.0 (C-4), 102.0 (C-12), 87.6 (C-5), 80.7 (C-6), 65.7 (C-16), 52.2 (C-1), 44.8 (C-17), 43.9 (C-7), 37.0 (C-11), 36.2 (C-10), 34.2 (C-3), 30.5 (C-9), 26.0 (C-8), 24.4 (C-15), 24.2 (C-2), 20.1 (C-14), 12.8 (C-13).
12β-(2-((2-Hydroxyethyl)amino)ethoxy) dihydroartemisinin (
4s): Yield: 44.1%; Yellow oil;
+ 87.0 (c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91(3H, d,
J = 7.2 Hz, H-14), 0.95 (3H, d,
J = 6.0 Hz, H-13), 1.44 (3H, s, H-15), 1.22–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.38–2.47(1H, m, H-1), 2.58–2.73 (5H, m, H-11, H-17 and H-18), 3.49–3.59(3H, m, H-16 and H-19), 3.90–3.98 (1H, m, H-16), 4.80 (1H, s, H-12), 5.42 (1H, s, H-5).
12β-(2-((2-Hydroxyethyl)(methyl)amino)ethoxy)dihydroartemisinin (
4t): Yield: 92.5%; Yellow oil;
+ 182.0 (
c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91 (3H, d,
J = 7.2 Hz, H-14), 0.95 (3H, d,
J = 6.0 Hz, H-13), 1.44 (3H, s, H-15), 1.22–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32 (3H, s, H-21), 2.37–2.47 (1H, m, H-1), 2.58–2.73 (5H, m, H-11, H-17 and H-18), 3.49–3.59 (3H, m, H-16 and H-19), 3.90–3.98 (1H, m, H-16), 4.80 (1H, s, H-12), 5.42 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 104.1(C-4), 102.2 (C-12), 87.9 (C-5), 81.0 (C-6), 66.1 (C-16), 58.9 (C-19), 58.2 (C-17), 56.9 (C-18), 52.5 (C-1), 44.3 (C-7), 42.0 (C-21), 37.4 (C-11), 36.4 (C-10), 34.6 (C-3), 30.8 (C-9), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 20.4 (C-14), 13.0 (C-13); HRMS calcd for C
20H
35NO
6 (M+H)
+ 386.2537, found 386.2545.
12β-(2-(Bis(2-hydroxyethyl)amino)ethoxy)dihydroartemisinin (
4u): Yield: 85.2%; Yellow syrup;
+ 88.0 (
c 1.0 mg/mL, CHCl
3).
1H-NMR (CDCl
3) δ ppm: 0.91 (3H, d,
J = 7.2 Hz, H-14), 0.95 (3H, d,
J = 6.0 Hz, H-13), 1.44 (3H, s, H-15), 1.27–2.06 (10H, m, H-2, H-3, H-7, H-8, H-9 and H-10), 2.32–2.42 (1H, m, H-11), 2.65–2.69 (1H, m, H-1), 2.89–2.97 (6H, m, H-17 and H-18), 3.58–3.62 (1H, m, H-16), 3.67–3.73 (4H, m, H-19), 3.99–4.03 (1H, m, H-16), 4.83 (1H, s, H-12), 5.44 (1H, s, H-5);
13C-NMR (CDCl
3) δ ppm: 104.2 (C-4), 102.4 (C-12), 87.9 (C-5), 80.9 (C-6), 65.6 (C-16), 58.8 (C-19), 54.3 (C-17), 56.4 (C-18), 52.5 (C-1), 44.2 (C-7), 37.3 (C-11), 36.3 (C-10), 34.5 (C-3), 30.7 (C-9), 26.1 (C-8), 24.6 (C-15), 24.4 (C-2), 20.3 (C-14), 13.0 (C-13); HRMS calcd for C
21H
37NO
7 (M+Na)
+ 438.2462, found 438.2456.