U.E. Hille et al. / European Journal of Medicinal Chemistry 44 (2009) 2765–2775
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5.4.7.3. 1-[1-(40-Methoxy-biphenyl-4-yl)-propyl]-1H-imidazole
(9). Synthesised according to Method F using 9a (2.12 g, 8.8 mmol)
and CDI (7.29 g, 45.0 mmol) in NMP; yellow solid; yield: 0.28 g
~
phenol was directly diluted in anhydrous THF, tetrabutylammo-
nium fluoride solution was added (1.0 M in THF, 1.1 eq per TBDMS),
and the reaction mixture was stirred for 4 h. The reaction was
quenched by addition of methanol, and the solvent was removed
under reduced pressure. The crude product was purified by chro-
matography using silica gel.
(11%) Rf ¼ 0.52 (EtOAc/NH3 (aq, 25%) 97.5:2.5); IR (ATR)
n
(cmꢂ1):
2962 (w), 2932 (w), 1605 (m), 1497 (s), 1254 (s), 818 (s); dH (CDCl3,
500 MHz): 0.97 (t, J ¼ 7.3 Hz, 3H), 2.24–2.30 (m, 2H), 3.84 (s, 3H),
5.10 (t, J ¼ 7.6 Hz, 1H), 6.96 (d, J ¼ 8.5 Hz, 2H), 7.00 (bs, 1H), 7.13 (bs,
1H), 7.25 (d, J ¼ 8.5 Hz, 2H), 7.49 (d, J ¼ 8.5 Hz, 2H), 7.52 (d,
J ¼ 8.5 Hz, 2H), 7.89 (bs, 1H); dC (CDCl3, 125 MHz): 11.0 (CH3), 28.4
(CH2), 55.3 (O-CH3), 63.4 (CH), 114.3 (CH), 117.9 (CH), 127.0 (CH),
127.1 (CH), 127.9 (Cq), 128.0 (CH), 132.7 (Cq), 136.0 (CH), 137.9 (Cq),
140.9 (Cq), 159.4 (COMe); MS (ESI): m/z ¼ 293 [Mþ þ H].
5.4.8.1. 40-(1-Imidazol-1-yl-propyl)-biphenyl-4-ol (3). Synthesised
according to Method G using 3a (0.85 g, 2.16 mmol); yellow solid;
(cmꢂ1):
~
n
yield: 0.22 g (37%); Rf ¼ 0.21 (hexane/EtOAc, 5:1); IR (ATR)
2963 (w), 2930 (w), 2364 (w),1607 (m), 1588 (m), 1498 (s), 1272
(m), 1070 (s), 808 (s), 748 (m), 658 (m); dH (DMSO-d6, 500 MHz):
0.82 (t, J ¼ 7.3 Hz, 3H), 2.21–2.25 (m, 2H), 5.23 (t, J ¼ 7.3 Hz, 1H),
6.82 (d, J ¼ 8.8 Hz, 2H), 6.90 (s, 1H), 7.37 (d, J ¼ 8.5 Hz, 2H), 7.46 (d,
J ¼ 8.8 Hz, 2H), 7.54 (d, J ¼ 8.5 Hz, 2H), 7.82 (s, 1H), 9.55 (s, 1H); dC
(DMSO-d6, 125 MHz): 10.9 (CH3), 27.4 (CH2), 61.5 (CH), 115.6 (CH),
117.7 (CH), 126.0 (CH), 127.1 (CH), 127.6 (CH), 128.4 (Cq), 130.3 (CH),
130.7 (Cq), 139.3 (CH), 139.5 (Cq), 157.1 (Cq); MS (ESI): m/z ¼ 279
[Mþ þ H].
5.4.7.4. 1-[1-(30-Methoxy-biphenyl-4-yl)-propyl]-1H-imidazole (10).
Synthesised according to Method F using 10a (2.30 g, 9.0 mmol) and
CDI (7.29 g, 45.0 mmol) in NMP; yellow solid; yield: 0.89 g (30%);
~
Rf ¼ 0.52 (EtOAc/NH3 (aq, 25%) 97.5:2.5); IR (ATR)
n
(cmꢂ1): 2967
(w), 2935 (w), 1503 (s),1249 (s),1218 (s),1024 (s), 806 (s); dH (CDCl3,
500 MHz): 0.95 (t, J ¼ 7.3 Hz, 3H), 2.22–2.28 (m, 2H), 3.84 (s, 3H),
5.05 (t, J ¼ 7.9 Hz,1H), 6.89 (dd, J ¼ 2.2, 8.2 Hz,1H), 6.98 (bs,1H), 7.08
(t, J ¼ 2.2 Hz, 1H), 7.10 (bs, 1H), 7.13 (d, J ¼ 7.9 Hz, 1H), 7.24 (d,
J ¼ 7.9 Hz, 2H), 7.34 (t, J ¼ 7.9 Hz, 1H), 7.54 (d, J ¼ 8.2 Hz, 2H), 7.69
(bs, 1H); dC (CDCl3, 125 MHz): 11.0 (CH3), 28.5 (CH2), 55.2 (CH3-O),
63.0 (CH), 112.8 (CH), 112.8 (CH), 117.7 (CH), 119.5 (CH), 126.0 (CH),
127.5 (CH), 129.0 (Cq), 129.8 (CH), 136.2 (Cq), 139.2 (Cq), 140.9 (Cq),
141.7 (CH), 159.9 (COMe); MS (ESI): m/z ¼ 293 [Mþ þ H].
5.4.8.2. 40-(1-Imidazol-1-yl-propyl)-biphenyl-3-ol (4). Synthesised
according to Method G using 4a (1.32 g, 3.36 mmol); yellow
~
solid; yield: 0.20 g (21%); Rf ¼ 0.13 (EtOAc/MeOH, 9:1); IR (ATR)
n
(cmꢂ1) 2963 (w), 2361 (w), 1583 (m),1564 (m),1477 (s), 817 (s), 781
(s), 740 (s); dH (DMSO-d6, 500 MHz): 0.83 (t, J ¼ 7.3 Hz, 3H), 2.17–
2.22 (m, 2H), 5.24–5.26 (m, 1H), 6.73–6.76 (m, 1H), 6.91 (bs, 1H),
6.99 (t, J ¼ 2.2 Hz, 1H), 7.04 (ddd, J ¼ 0.9, 2.2, 7.6 Hz, 1H), 7.23 (t,
J ¼ 7.6 Hz, 1H), 7.33 (t, J ¼ 1.3 Hz, 1H), 7.41 (d, J ¼ 8.2 Hz, 2H), 7.56 (d,
J ¼ 8.2 Hz, 2H), 7.83 (t, J ¼ 0.9 Hz, 1H), 9.55 (s, 1H); dC (DMSO-d6,
125 MHz): 10.9 (CH3), 27.4 (CH2), 61.5 (CH), 113.4 (CH), 114.4 (CH),
117.4 (CH) 117.7 (CH), 126.7 (CH), 127.1 (CH), 128.5 (CH), 129.8 (CH),
136.4 (CH), 140.4 (Cq), 141.0 (Cq), 157.7 (COH); MS (ESI): m/z ¼ 279
[Mþ þ H].
5.4.7.5. 1-[1-(30,40-Dimethoxy-biphenyl-4-yl)-propyl]-1H-imidazole
(11). Synthesised according to Method
F using 11a (2.41 g,
8.90 mmol) and CDI (7.29 g, 45.0 mmol) in NMP; amber oil; yield:
~
0.69 g (24%); Rf ¼ 0.47 (EtOAc/NH3 (aq, 25%) 97.5:2.5); IR (ATR)
n
(cmꢂ1): 2967 (w), 2937 (w), 2875 (w), 2838 (w), 1668 (m), 1604
(m), 1583 (m), 1480 (s), 1294 (s), 1101 (s), 816 (s), 778 (s), 743 (s); dH
(CDCl3, 500 MHz): 0.99 (t, J ¼ 7.3 Hz, 3H), 2.28–2.35 (m, 2H), 3.92 (s,
3H), 3.94 (s, 3H), 5.21 (t, J ¼ 7.9 Hz, 1H), 6.94 (d, J ¼ 8.2 Hz, 1H), 7.05
(bs, 1H), 7.07 (d, J ¼ 2.2 Hz, 1H), 7.11 (dd, J ¼ 2.2, 8.2 Hz, 1H), 7.21 (bs,
1H), 7.30 (d, J ¼ 8.2 Hz, 2H), 7.55 (d, J ¼ 8.2 Hz, 2H), 8.29 (bs, 1H); dC
(CDCl3, 125 MHz): 11.0 (CH3), 28.5 (CH2), 55.9 (O-CH3), 55.9 (O-
CH3), 62.9 (CH), 110.3 (CH), 111.4 (CH), 117.6 (CH), 119.3 (CH), 126.9
(CH), 127.1 (CH), 129.4 (CH), 133.2 (Cq), 136.3 (CH), 138.7 (Cq), 140.8
(Cq), 148.8 (Cq), 149.1 (Cq); MS (ESI): m/z ¼ 323 [Mþ þ H].
5.4.8.3. 40-(1-Imidazol-1-yl-propyl)-biphenyl-3,4-diol (5). Synthes-
ised according to Method G using 5a (1.00 g, 1.92 mmol); yellow
~
solid; yield: 0.19 g (34%); Rf ¼ 0.31 (EtOAc/MeOH. 95:5); IR (ATR)
n
(cmꢂ1): 3285 (m), 3157 (m), 2963 (m), 2931 (m), 2874 (m), 2828
(m), 1770 (m), 1952 (s), 1945 (s), 1495 (s), 1304 (s), 1219 (s), 1086 (s),
805 (s), 755 (s); dH (DMSO-d6, 500 MHz): 0.81 (t, J ¼ 7.3 Hz, 3H),
2.18–2.24 (m, 2H), 5.20–5.23 (m, 1H), 6.79 (d, J ¼ 8.2 Hz, 1H), 6.88–
6.92 (m, 2H), 7.00 (d, J ¼ 2.2 Hz, 1H), 7.31 (t, J ¼ 1.3 Hz, 1H), 7.35 (d,
J ¼ 8.2 Hz, 2H), 7.48 (d, J ¼ 8.2 Hz, 2H), 7.82 (bs, 1H), 9.01 (bs, 1H),
9.06 (bs, 1H); MS (ESI): m/z ¼ 295 [Mþ þ H].
5.4.7.6. 1-[1-(40-Ethoxy-biphenyl-4-yl)-propyl]-1H-imidazole (12). Syn-
thesised according to Method F using 12a (1.14 g, 4.45 mmol) and CDI
(3.61 g, 22.3 mmol) in NMP; brown solid; yield: 0.60 g (45%); Rf ¼ 0.66
~
(EtOAc/MeOH 95:5); IR (ATR)
n
(cmꢂ1): 3115 (w), 2976 (w), 2936 (w),
5.4.8.4. 40-(1-Imidazol-1-yl-propyl)-biphenyl-3,5-diol (6). Synthes-
2877 (w), 1606 (m), 1497 (s), 1245 (s), 1043 (s), 827 (s), 815 (s), 784 (s),
740 (s), 665 (s); dH (CDCl3, 500 MHz) 0.95 (t, J ¼ 7.3 Hz, 3H), 1.42 (t,
J ¼ 6.9 Hz, 3H), 2.22–2.29 (m, 2H), 4.07 (q, J ¼ 6.9 Hz, 2H), 5.03 (t,
J ¼ 7.7 Hz, 1H), 6.95 (d, J ¼ 8.8 Hz, 2H), 6.97 (bs, 1H), 7.09 (bs, 1H), 7.22
(d, J ¼ 8.2 Hz, 2H), 7.48 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8,2 Hz, 2H), 7.63
(bs, 1H); dC (CDCl3, 125 MHz): 11.1 (CH3), 14.8 (CH3), 28.6 (CH2), 63.1
(CH), 63.5 (CH2), 114.8 (CH), 117.7 (CH), 126.9 (CH), 127.0 (CH), 128.0
(CH), 129.3 (Cq), 132.6 (CH), 136.3 (CH), 138.4 (Cq), 140.7 (Cq), 158.7 (Cq);
MS (ESI): m/z ¼ 307 [Mþ þ H].
ised according to Method G using 6a (2.00 g, 3.83 mmol); yellow
~
solid; yield: 0.06 g (5%); Rf ¼ 0.38 (EtOAc/MeOH, 95:5); IR (ATR)
n
(cmꢂ1): 2975 (w), 1595 (m), 1488 (m), 1351 (m), 1167 (s), 1111 (m),
1091 (m), 1077 (m), 1014 (m), 831 (s), 820 (s), 803 (s), 742 (s); dH
(DMSO-d6, 500 MHz) 0.82 (t, J ¼ 7.3 Hz, 3H), 2.15–2.28 (m, 2H),
5.23–5.26 (m, 1H), 6.21 (t, J ¼ 2.1 Hz, 1H), 6.44 (d, J ¼ 2.1 Hz, 2H),
6.91 (s, 1H), 7.31 (s, 1H), 7.38 (d, J ¼ 8.2 Hz, 2H), 7.49 (d, J ¼ 8.2 Hz,
2H), 7.82 (s, 1H), 9.36 (s, 2H); dC (DMSO-d6, 125 MHz): 10.9 (CH3),
27.5 (CH2), 61.5 (CH), 101.7 (CH), 104.7 (CH), 117.7 (CH), 126.6 (CH),
127.0 (CH), 128.5 (CH), 132.5 (Cq), 136.4 (CH), 139.9 (Cq), 141.5 (Cq),
158.7 (COH); MS (ESI): m/z ¼ 295 [Mþ þ H].
5.4.8. Method G: CDI reaction and deprotection with TBAF
(compounds 3–8, 13–15)
To a solution of the corresponding alcohol (1.0 eq) in NMP
(10 mL/mmol) CDI (5.0 eq) was added at rt. The solution was heated
to reflux for 4–18 h. After cooling to ambient temperature, the
reaction mixture was diluted with water (30 mL) and extracted
with ethyl acetate (3 ꢃ10 mL). The combined organic phases were
washed with brine, dried over MgSO4 and evaporated under
reduced pressure. The crude intermediate of the silyl-protected
5.4.8.5. 30-Fluoro-40-(1-imidazol-1-yl-propyl)-biphenyl-4-ol (7). Syn-
thesised according to Method G using 7a (crude product); yellow
~
solid; yield: 0.05 g; Rf ¼ 0.4 (EtOAc/MeOH, 95:5); IR (ATR)
n
(cmꢂ1):
2974 (w), 2360 (m), 2341 (m),1607 (m),1494 (s), 1283 (m),1223 (m),
1077 (m), 840 (m), 827 (s), 765 (m); dH (DMSO-d6, 500 MHz): 0.84 (t,
J ¼ 7.3 Hz, 3H), 2.14–2.32 (m, 2H), 5.47–5.50 (m, 1H), 6.83 (d,
J ¼ 8.5 Hz, 2H), 6.90 (bs,1H), 7.30 (t, J ¼ 1.3 Hz,1H), 7.41–7.44 (m, 3H),