874
S. Kerscher-Hack et al. / European Journal of Medicinal Chemistry 124 (2016) 852e880
4.48 (d, J ¼ 5.5 Hz, 2 H, NCH2), 5.41 (dt, J ¼ 15.5/5.5 Hz, 1 H,
NCH2CH), 6.18 (d, J ¼ 15.5 Hz, 1 H, CHC), 6.71e6.75 (m, 2 H, Har),
6.81 (d, J ¼ 1.4 Hz, 1 H, H[4H-Imid.]), 6.85 (d, J ¼ 1.4 Hz,1 H, H[5H-Imid.]),
6.91e7.04 (m, 2 H, Har), 7.16 (d, J ¼ 7.5 Hz, 2 H, Har), 7.22 (t, J ¼ 7.5 Hz,
113.49 (d, 2 C, Car), 119.49 (d, 1 C, C[5C-Imid.]), 119.96 (d, 2 C, Car),
125.21 (d, 2 C, Car), 125.68 (d, 1 C, NCH2CH), 126.75 (d, 2 C, Car),
127.19 (d, 1 C, C[4C-Imid.]), 128.19 (d, 2 C, Car), 129.08 (d, 2 C, Car),
130.69 (d,1 C, CHCH2O),135.26 (s,1 C, Car),140.54 (s, 2 C, Car),146.34
(s, 1 C, C[2C-Imid.]), 147.01 (s, 2 C, Car), 158.75 (s, 1 C, Car), 172.85 (s, 1 C,
COO); MS (EI, 70 eV) m/z (%): 508 (10, Mþ), 463 (7), 373 (11), 271
(100); HRMS (EI, 70 eV): (C32H32N2O4) calc. 508.2362, found
508.2352.
2 H, Har), 7.32 (t, J ¼ 7.5 Hz, 2 H, Har), 7.77 (d, J ¼ 7.5 Hz, 2 H, Har); 13
C
NMR (CD3OD):
d
¼ 14.65 (q,1 C, CH3CH2), 22.62 (t,1 C, CH2CH2COO),
32.95 (t, 1 C, CH2COO), 48.40 (t, 1 C, CH2CH), 55.80 (q, 1 C, OCH3),
61.79 (t, 1 C, CH2CH3), 62.38 (s, 1 C, CHC), 115.03 (d, 2 C, Car), 121.29
(d, 1 C, C[5C-Imid.]), 121.53 (d, 2 C, Car), 125.15 (d, 1 C, NCH2CH), 126.66
(d, 2 C, Car), 127.38 (d, 1 C, C[4C-Imid.]), 128.79 (d, 2 C, Car), 128.85 (d,
2 C, Car), 129.34 (d, 2 C, Car), 137.00 (s, 1 C, Car), 138.06 (d, 1 C, CHC),
141.40 (s, 2 C, Car), 148.22 (s, 1 C, C[2C-Imid.]), 151.40 (s, 2 C, Car), 160.18
(s, 1 C, Car), 173.99 (s, 1 C, COO); MS (EI, 70 eV) m/z (%): 478 (2, Mþ),
455 (2), 433 (2), 297 (46), 203 (42), 107 (100); HRMS (EI, 70 eV):
(C31H30N2O3) calc. 478.2257, found 478.2240.
5.1.7.15. 3-(1-{(2Z)-4-[9-(4-Methoxyphenyl)-9H-fluoren-9-yloxy]
but-2-en-1-yl}-1H-imidazol-2-yl)propanoic acid ethyl ester (39i).
According to GP5: 3-(1H-Imidazol-2-yl)propanoic acid ethyl ester
(39a) [29] (111 mg, 0.660 mmol), DMF (4 mL), tBuOK (82 mg,
0.73 mmol), 9-[(2Z)-4-(2-methylsulfonyloxy)but-2-en-1-yloxy]-9-
(4-methoxyphenyl)-9H-fluorene (32) (375 mg, 0.858 mmol), CC
(CHCl3/MeOH ¼ 100:1). Yield: 182 mg (54%); colourless solid, m.p.
85e87 ꢀC; TLC: Rf ¼ 0.32 (CH2Cl2/MeOH ¼ 100:2); IR (KBr): 3135,
3105, 3055, 2971, 2925, 2840, 2041, 1967, 1900, 1730, 1605, 1508,
5.1.7.13. 3-[1-(2-{(1E)-3-[9-(4-Methoxyphenyl)-9H-fluoren-9-yl]
propenyloxy}ethyl)-1H-imidazol-2-yl]-propanoic acid ethyl ester
(39g). According to GP5: 3-(1H-Imidazol-2-yl)propanoic acid ethyl
ester (39a) [29] (100 mg, 0.595 mmol), DMF (4 mL), tBuOK (74 mg,
0.66 mmol), 9-{(1E)-3-[2-(2-methyl-sulfonyl)ethoxy]propenyl}-9-
(4-methoxyphenyl)-9H-fluorene (34) (349 mg, 0.774 mmol), CC
(acetone/iso-hexane ¼ 8:2 and CH2Cl2/MeOH ¼ 100:0.75). Yield:
1449, 1246. 1170, 1076, 1031 cmꢃ1
;
1H NMR (CD2Cl2):
d
¼ 1.21 (t,
J ¼ 7.1 Hz, 3 H, CH2CH3), 2.74e2.77 (m, 4 H, CH2CH2COO), 3.65 (dbr,
J ¼ 6.4 Hz, 2 H, CH2O), 3.73 (s, 3 H, OCH3), 4.08 (q, J ¼ 7.1 Hz, 2 H,
CH2CH3), 4.31 (dbr, J ¼ 6.7 Hz, 2 H, NCH2), 5.50 (dtt, J ¼ 11.2/6.7/
1.6 Hz, 1 H, NCH2CH), 5.76 (dtt, J ¼ 11.2/6.4/1.6 Hz, 1 H, CHCH2O),
6.70 (d, J ¼ 1.3 Hz, 1 H, H[5H-Imid.]), 6.74e6.79 (m, 2 H, Har), 6.79 (d,
J ¼ 1.3 Hz,1 H, H[4H-Imid.]), 7.23e7.26 (m, 2 H, Har), 7.26e7.32 (m, 4 H,
Har), 7.38e7.42 (m, 2 H, Har), 7.73 (d, J ¼ 7.5 Hz, 2 H, Har); 13C NMR
215 mg (68%); colourless oil; TLC: Rf
MeOH ¼ 100:3); IR (KBr): 3036, 2932, 2858, 2728, 1606, 1507, 1447,
1374, 1353, 1296, 1279, 1246, 1177, 1117, 1030 cmꢃ1 1H NMR
(CD2Cl2):
¼ 1.21 (t, J ¼ 7.1 Hz, 3 H,CH2CH3), 2.78 (t, J ¼ 6.9 Hz, 2 H,
¼
0.35 (CH2Cl2/
;
d
(CD2Cl2):
d
¼ 14.41 (q,1 C, CH2CH3), 22.03 (t,1 C, CH2CH2COO), 31.92
CH2CH2COO), 2.89 (t, J ¼ 6.9 Hz, 2 H, CH2CH2COO), 3.61 (tbr,
J ¼ 5.4 Hz, 2 H, NCH2CH2), 3.73 (s, 3 H, OCH3), 3.92 (dd, J ¼ 5.6/
1.3 Hz, 2 H, CH2CH), 4.01 (t, J ¼ 5.4 Hz, 2 H, NCH2), 4.08 (q, J ¼ 7.1 Hz,
2 H, CH2CH3), 5.42 (dt, J ¼ 15.5/5.6 Hz, 1 H, CH2CH), 6.38 (d,
J ¼ 15.5 Hz, 1 H, CHC), 6.73e6.79 (m, 2 H, Har), 6.83 (s, 1 H, H[4H-
Imid.]), 6.84 (s, 1 H, H[5H-Imid.]), 6.99e7.05 (m, 2 H, Har), 7.23 (d,
J ¼ 7.4 Hz, 2 H, Har), 7.29 (td, J ¼ 7.4/1.0 Hz, 2 H, Har), 7.37 (td, J ¼ 7.4/
1.0 Hz, 2 H, Har), 7.78 (d, J ¼ 7.4 Hz, 2 H, Har); 13C NMR (CD2Cl2):
(t, 1 C, CH2CH2COO), 43.22 (t, 1 C, NCH2), 55.56 (q, 1 C, OCH3), 59.71
(t, 1 C, CH2O), 60.80 (t, 1 C, CH2CH3), 89.07 (s, 1 C, CH2OC), 113.85 (d,
2 C, Car), 119.35 (d, 1C, C[5C-Imid.]), 120.57 (d, 2 C, Car), 125.55 (d, 2 C,
Car), 127.11 (d, 2 C, Car or NCH2CH), 127.38 (d, 2 C, Car or NCH2CH),
127.38 (d, 1 C, C[4C-Imid.]), 128.64 (d, 2 C, Car), 129.61 (d, 2 C, Car),
130.63 (d,1 C, CHCH2O),135.63 (s, 1 C, Car), 141.07 (s, 2 C, Car), 146.66
(s, 1 C, C[2C-Imid.]), 147.40 (s, 2 C, Car), 159.37 (s, 1 C, Car), 172.98 (s, 1 C,
COO); MS (CI, CHþ5 ) m/z (%): 509 (2, [MþH]þ), 271 (100); MS (ESIþ)
m/z (%): 509.4 (100, [MþH]þ); HRMS (ESIþ): (C32H33N2O4) calc.
509.2440, found 509.2435.
d
¼ 14.41 (q, 1 C CH2CH3), 22.13 (t, 1 C, CH2CH2COO), 32.09 (t, 1 C,
CH2CH2COO), 46.05 (t, 1 C, NCH2), 55.58 (q, 1 C, OCH3), 60.79 (t, 1 C,
CH2CH3), 61.46 (s, 1 C, CHC), 69.75 (t, 1 C, NCH2CH2), 71.62 (t, 1 C,
CH2CH), 114.15 (d, 2 C, Car), 120.03 (d, 1 C, C[5C-Imid.]), 120.72 (d, 2 C,
Car), 125.42 (d, 1 C, CH2CH), 125.86 (d, 2 C, Car), 127.36 (d, 1 C, C[4C-
Imid.]), 127.88 (d, 2 C, Car), 127.96 (d, 2 C, Car), 128.51 (d, 2 C, Car),
136.09 (d, 1 C, CHC), 136.28 (s, 1 C, Car), 140.28 (s, 2 C, Car), 147.13 (s,
1 C, C[2C-Imid.]), 150.56 (s, 2 C, Car), 158.97 (s, 1 C, Car), 173.15 (s, 1 C,
COO); MS (CI, CHþ5 ) m/z (%): 523 (100, [MþH]þ); HRMS (ESIþ):
(C33H35N2O4) calc. 523.2597, found 523.2588.
5.1.7.16. 3-[1-(2-{2-[9-(4-Methoxyphenyl)-9H-fluoren-9-yloxy]
ethoxy}ethyl)-1H-imidazol-2-yl]propanoic acid ethyl ester (39j).
According to GP5: 3-(1H-Imidazol-2-yl)propanoic acid ethyl ester
(39a) [29] (100 mg, 0.595 mmol), DMF (4 mL), tBuOK (74 mg,
0.66 mmol), 9-{2-[2-(2-methylsulfonyloxy)ethoxy]-ethoxy}-9-(4-
methoxyphenyl)-9H-fluorene (33) (352 mg, 0.774 mmol), CC
(acetone/iso-hexane ¼ 8:2 and CH2Cl2/MeOH ¼ 100:1). Yield:
177 mg (57%); colourless oil; TLC: Rf
¼
0.32 (CH2Cl2/
5.1.7.14. 3-(1-{(2E)-4-[9-(4-Methoxyphenyl)-9H-fluoren-9-yloxy]
but-2-en-1-yl}-1H-imidazol-2-yl)propanoic acid ethyl ester (39h).
According to GP5: 3-(1H-Imidazol-2-yl)propanoic acid ethyl ester
(39a) [29] (101 mg, 0.600 mmol), DMF (4 mL), tBuOK (74 mg,
MeOH ¼ 100:2); IR (KBr): 3106, 3064, 3038, 2933, 2871, 1837, 2045,
1957, 1914,1732, 1698, 1581,1509,1449,1375, 1301,1282, 1249, 1171,
1132, 1102, 1082, 1034 cmꢃ1; 1H NMR (CDCl3):
d
¼ 1.23 (t, J ¼ 7.1 Hz,
3 H, CH2CH3), 2.85e2.92 (m, 2 H, CH2CH2COO), 2.92e3.00 (m, 2 H,
CH2CH2COO), 3.11 (t, J ¼ 4.9 Hz, 2 H, CH2OC), 3.49 (t, J ¼ 4.9 Hz, 2 H,
CH2CH2OC), 3.70 (t, J ¼ 5.3 Hz, 2 H, NCH2CH2), 3.75 (s, 3 H, OCH3),
4.07 (t, J ¼ 5.3 Hz, 2 H, NCH2), 4.12 (q, J ¼ 7.1 Hz, 2 H, CH2CH3),
6.74e6.80 (m, 2 H, Har), 6.94 (d, J ¼ 1.2 Hz, 1 H, H[4H-Imid.]), 6.96 (d,
J ¼ 1.2 Hz, 1 H, H[5H-Imid.]), 7.21e7.29 (m, 6H, Har), 7.32e7.40 (m, 2 H,
0.66
mmol),
9-[(2E)-4-bromobut-2-en-1-yloxy]-9-(4-
methoxyphenyl)-9H-fluorene (25) (329 mg, 0.780 mmol), CC
(CHCl3/MeOH ¼ 100:1). Yield: 208 mg (68%); colourless oil; TLC:
Rf ¼ 0.39 (CH2Cl2/MeOH ¼ 100:3); IR (KBr): 3062, 3039, 2979, 2933,
2859, 2045, 1963, 1732, 1608, 1509, 1449, 1249, 1170, 1107,
1034 cmꢃ1
;
1H NMR (CDCl3):
d
¼ 1.23 (t, J ¼ 7.1 Hz, 3 H, CH2CH3),
Har), 7.67 (d, J ¼ 7.5 Hz, 2 H, Har); 13C NMR (CDCl3):
¼ 14.19 (q, 1 C,
d
2.79e2.92 (m, 4 H, CH2CH2COO), 3.52 (dd, J ¼ 5.0/1.3 Hz, 2 H, CH2O),
3.74 (s, 3 H, OCH3), 4.12 (q, J ¼ 7.1 Hz, 2 H, CH2CH3), 4.45 (dd, J ¼ 5.5/
1.3 Hz, 2 H, NCH2), 5.46 (dtbr, J ¼ 15.5/5.0 Hz, 1 H, CHCH2O), 5.77
(dtbr, J ¼ 15.5/5.5 Hz, 1 H, NCH2CH), 6.72e6.80 (m, 3 H, Har, H[5H-
Imid.]), 6.93 (d, J ¼ 1.2 Hz, 1 H, H[4H-Imid.]), 7.20e7.20 (m, 6 H, Har),
7.36 (td, J ¼ 7.5/1.6 Hz, 2 H, Har), 7.66 (d, J ¼ 7.5 Hz, 2 H, Har); 13C
CH2CH3), 21.62 (t,1 C, CH2CH2COO), 31.87 (t,1 C, CH2CH2COO), 45.89
(t, 1 C, NCH2), 55.21 (q, 1 C, OCH3), 60.60 (t, 1 C, CH2CH3), 62.86 (t,
1 C, CH2OC), 70.24 (t, 1 C, NCH2CH2), 70.83 (t, 1 C, CH2CH2OC), 88.43
(s, 1 C, CH2OC), 113.49 (d, 2 C, Car), 119.98 (d, 2 C, Car or d, 1 C, C[5C-
Imid.]), 120.01 (d, 2 C, Car or d, 1 C, C[5C-Imid.]), 125.26 (d, 2 C, Car),
126.55 (d, 2 C, Car, or d, 1 C, C[4C-Imid.]), 126.78 (d, 2 C, Car, or d, 1 C,
NMR (CDCl3):
d
¼ 14.18 (q, 1 C, CH2CH3), 21.66 (t, 1 C, CH2CH2COO),
C[4C-Imid.]), 128.19 (d, 2 C, Car), 129.04 (d, 2 C, Car), 135.32 (s, 1 C, Car),
31.75 (t, 1 C, CH2CH2COO), 47.14 (t, 1 C, NCH2), 55.17 (q, 1 C, OCH3),
60.56 (t, 1 C, CH2CH3), 63.09 (t, 1 C, CH2O), 88.44 (s, 1 C, CH2OC),
140.58 (s, 2 C, Car), 146.58 (s, 1 C, C[2C-Imid.]), 147.05 (s, 2 C, Car),
158.76 (s, 1 C, Car), 172.95 (s, 1 C, COO); MS (CI, CHþ5 ) m/z (%): 527