Journal of Medicinal Chemistry
Article
2H, Ar), 7.32−7.43 (m, 5H, Ar), 7.16 (d, J = 16.7 Hz, 1H, alkene),
7.17 (d, J = 16.6 Hz, 1H, alkene), 6.97 (d, J = 8.8 Hz, 2H, Ar), 5.80
(dd, Jx,a = 7.6 Hz, Jx,b = 10.1 Hz, 1H, CHx), 4.45 (dd, Jb,x = 10.1 Hz, Jb,a
= 14.9 Hz, 1H, CHb), 3.84 (dd, Ja,x = 7.5 Hz, J a,b = 14.9 Hz, 1H, CHa),
3.79 (s, 3H, OCH3). 13C NMR (DMSO-d6): δ 162.3, 159.3, 141.3,
140.6, 129.3, 125.6 (C), 130.1, 128.7, 128.2, 128.1, 128.1, 125.6, 125.1,
114.2, 113.8 (CH), 80.0 (CH, oxazole), 62.6 (CH2 oxazole), 55.2
(OCH3). Anal. Calcd for C24H21NO2 (355.43): C, 81.10; H, 5.95; N,
3.94. Found: C, 81.14; H, 6.30; N, 3.75.
127.4, 126.8, 126.2, 118.3, 115.7, 115.5 (CH), 59.4 (CH), 43.5 (CH2).
Anal. Calcd for C26H22N3OF·0.3H2O (416.88): C, 74.90; H, 5.46; N,
10.08. Found: C, 74.79; H, 5.48; N, 10.40.
(E)-N-(2-(1H-Imidazol-1-yl)-2-phenylethyl)-4-(4-methoxystyryl)-
benzamide (8c). Purification by flash column chromatography
(CH2Cl2−MeOH 97:3 v/v) gave a white solid: yield 30%, Rf = 0.66
(CH2Cl2−MeOH 9:1 v/v), mp = 188−190 °C. 1H NMR (DMSO-d6):
δ 8.69 (t, J = 5.3 Hz 1H, NH), 7.85 (s, 1H, imid), 7.74 (d, J = 8.4 Hz,
2H, Ar), 7.62 (d, J = 8.4 Hz, 2H, Ar), 7.52 (d, J = 8.6 Hz, 2H, Ar), 7.38
(m, 5H, Ar and imid), 7.28−7.33 (m, 2H, Ar and alkene), 7.13 (d, J =
16.6 Hz, 1H, alkene), 6.96 (d, J = 8.6 Hz, 2H, Ar), 6.92 (s, 1H, imid),
(E)-2-(4-(3,5-Dimethoxystyryl)phenyl)-5-phenyl-4,5-dihydro-
oxazole (7d). A yellow oil was obtained after purification by flash
column chromatography (petroleum ether−ethyl acetate 100:0 v/v
increasing to 70:30 v/v): yield 77%, Rf = 0.60 (petroleum ether−
5.68 (dd, Jx,b = 5.7 Hz, J = 9.1 Hz, 1H, CHx), 4.03−4.10 (m, 1H,
x,a
CHb), 3.94−3.99 (m, 1H, CHa), 3.78 (s, 3H, OCH3). 13C NMR
(DMSO-d6): δ 166.3 (CO), 159.3, 140.4, 139.3, 132.3, 129.3 (C),
130.0, 129.9, 128.7, 128.4, 128.3, 128.1, 127.6, 126.8, 125.9, 125.1,
114.2, 113.8 (CH), 59.5 (OCH3), 55.2 (CH), 43.4 (CH2). HRMS
(EI): m/z calcd for C27H26N3O2 (M+H)+ 424.2020, found 424.2021.
(E)-N-(2-(1H-Imidazol-1-yl)-2-phenylethyl)-4-(3,5-dimethoxy-
styryl)benzamide (8d). Purification by flash column chromatography
(CH2Cl2−MeOH 97:3 v/v) gave a white solid: yield 62%, Rf = 0.46
(CH2Cl2−MeOH 9:1 v/v), mp = 210−212 °C. 1H NMR (DMSO-d6):
δ 8.73 (t, J = 5.5 Hz 1H, NH), 7.84 (s, 1H, imid), 7.72 (d, J = 8.4 Hz,
2H, Ar), 7.66 (d, J = 8.4 Hz, 2H, Ar), 7.38−7.40 (m, 5H, Ar and imid),
7.27−7.35 (m, 5H, Ar and alkene), 6.91 (s, 1H, imid), 6.81 (d, J = 2.0
1
EtOAc 1:3 v/v); H NMR (CDCl3): δ 8.03 (d, J = 8.4 Hz, 2H, Ar),
7.59 (d, J = 8.4 Hz, 2H, Ar), 7.36−7.43 (m, 5H, Ar), 7.16 (d, J = 16.4
Hz, 1H, alkene), 7.12 (d, J = 16.4 Hz, 1H, alkene), 6.71 (d, J = 2.2 Hz,
2H, Ar), 6.45 (t, J = 2.2 Hz, 1H, Ar), 5.69 (dd, Jx,a = 8.1 Hz, Jx,b = 10.2
Hz, 1H, CHx), 4.51 (dd, Jb,x = 10.2 Hz, Jb,a = 14.7 Hz, 1H, CHb), 4.03
(dd, Ja,x = 8.0 Hz, Ja,b = 14.7 Hz, 1H, CHa), 3.86 (s, 6H, 2×OCH3). 13
C
NMR (CDCl3): δ 163.9, 161.1, 141.0, 140.3, 138.9, 126.6 (C), 130.5,
128.8, 128.7, 128.3, 128.3, 126.5, 125.8, 104.8, 100.5 (CH), 81.1 (CH,
oxazole), 63.2 (CH2 oxazole), 55.4 (2×OCH3). HRMS (EI): m/z
calcd for C25H24NO3 (M+H)+ 386.1751, found 381.1753.
(E)-2-(4-(3,4,5-Trimethoxystyryl)phenyl)-5-phenyl-4,5-dihydro-
oxazole (7e). A yellow solid was obtained after purification by flash
column chromatography (petroleum ether−ethyl acetate 100:0 v/v
increasing to 70:30 v/v): yield 55%, Rf = 0.75 (petroleum ether−
EtOAc 1:3 v/v), mp = 120−122 °C. 1H NMR (CDCl3): δ 8.03 (d, J =
8.3 Hz, 2H, Ar), 7.59 (d, J = 8.3 Hz, 2H, Ar), 7.36−7.43 (m, 5H, Ar),
7.16 (d, J = 16.2 Hz, 1H, alkene), 7.06 (d, J = 16.2 Hz, 1H, alkene),
6.78 (s, 2H, Ar), 5.69 (dd, Jx,a = 8.0 Hz, Jx,b = 10.1 Hz, 1H, CHx), 4.51
(dd, Jb,x = 10.1 Hz, Jb,a = 14.9 Hz, 1H, CHb), 4.03 (dd, Ja,x = 8.0 Hz, Ja,b
Hz, 2H, Ar), 6.45 (t, J = 2.0 Hz, 1H, Ar), 5.68 (dd, Jx,b = 5.7 Hz, Jx,a
=
9.4 Hz, 1H, CHx), 4.05−4.11 (m, 1H, CHb), 3.95−4.00 (m, 1H, CHa),
3.79 (s, 6H, 2×OCH3). 13C NMR (DMSO-d6): δ 166.3 (CO),
160.7, 139.9, 139.3, 138.7, 132.8 (C), 136.8, 130.2, 128.7, 128.5, 128.1,
128.0, 127.6, 126.8, 126.3, 118.3, 104.7, 100.3 (CH), 59.4 (2×OCH 3),
55.2 (CH), 43.4 (CH2). Anal. Calcd for C28H27N3O3·0.1H2O
(455.34): C, 73.86; H, 5.98; N, 9.23. Found: C, 73.61; H, 5.61; N,
9.18.
= 14.9 Hz, 1H, CHa), 3.97 (s, 3H, OCH3), 3.94 (s, 6H, 2×OCH3). 13
C
(E)-N-(2-(1H-Imidazol-1-yl)-2-phenylethyl)-4-(3,4,5-trimethoxy-
styryl)benzamide (8e). Purification by flash column chromatography
(CH2Cl2−MeOH 96:4 v/v) gave a white solid: yield 71%, Rf = 0.48
(CH2Cl2−MeOH 9:1 v/v), mp = 96−98 °C. 1H NMR (DMSO-d6): δ
8.72 (t, J = 5.4 Hz 1H, NH), 7.84 (s, 1H, imid), 7.77 (d, J = 8.3 Hz,
2H, Ar), 7.65 (d, J = 8.3 Hz, 2H, Ar), 7.28−7.39 (m, 8H, Ar and imid
and alkene), 6.96 (s, 2H, Ar), 6.91 (s, 1H, imid), 5.68 (dd, Jx,b = 5.8
Hz, J x,a = 9.4 Hz, 1H, CHx), 4.05−4.11 (m, 1H, CHb), 3.95−4.00 (m,
NMR (CDCl3): δ 163.8, 153.5, 141.1, 140.3, 138.4, 132.6, 126.5 (C),
130.5, 128.8, 128.7, 128.3, 127.3, 126.3, 125.8, 103.9 (CH), 81.1 (CH,
oxazole), 63.2 (CH2 oxazole), 61.0 (OCH3), 56.2 (2×OCH3). Anal.
Calcd for C26H35NO4·0.1H2O (417.29): C, 74.84; H, 6.04; N, 3.36.
Found: C, 74.53; H, 6.01; N, 3.41.
N-Methanesulfonyl-N-phenyl-4-(5-phenyl-4,5-dihydrooxazol-2-
yl)benzenesulfonamide (11). A white solid was obtained after
purification by flash column chromatography (petroleum ether−
ethyl acetate 100:0 v/v increasing to 50:50 v/v): yield 55%, Rf = 0.56
(petroleum ether−EtOAc 1:1 v/v), mp = 148−150 °C. 1H NMR
(DMSO-d6): δ 8.18 (d, J = 8.5 Hz, 2H, Ar), 7.96 (d, J = 8.5 Hz, 2H,
Ar), 7.50 (t, J = 7.5 Hz, 1H, Ar), 7.43−7.47 (m, 4H, Ar), 7.38−7.40
1H, CHa), 3.96 (s, 3H, OCH3), 3.84 (s, 6H, 2×OCH ). 13C NMR
3
(DMSO-d6): δ 166.3 (CO), 153.1, 140.1, 139.3, 137.7, 132.6, 132.4
(C), 136.8, 130.5, 128.7, 128.5, 128.1, 127.7, 126.8, 126.8, 126.0,
118.3, 104.2 (CH), 60.1 (OCH3), 55.4 (2×OCH3), 55.9 (CH), 43.5
(CH2). Anal. Calcd for C29H29N3O4·0.3H2O (488.97): C, 71.24; H,
6.10; N, 8.59. Found: C, 70.95; H, 5.78; N, 8.64.
(m, 3H, Ar), 7.18 (d, J = 7.6 Hz, 2H, Ar), 5.74 (dd, Jx,a = 8.2 Hz, Jx,b
=
10.3 Hz, 1H, CHx), 4.55 (dd, Jb,x = 10.3 Hz, Jb,a = 15.3 Hz, 1H, CHb),
N-(2-(1H-Imidazol-1-yl)-2-phenylethyl)-4-phenylsulfonyl-benz-
amide (12). Purification by flash column chromatography (CH2Cl2−
MeOH 90:10 v/v) gave a white solid: yield 18%, Rf = 0.74 (CH2Cl2−
4.08 (dd, Ja,x = 8.2 Hz, Ja,b = 15.3 Hz, 1H, CHaHCH2), 3.55 (s, 3H,
13
−SO2CH3).
C NMR (DMSO-d6): δ 162.4, 140.6, 140.3, 133.6,
1
132.9 (C, Ar), 131.1, 130.5, 129.5, 128.9, 128.7, 128.6, 125.7 (CH, Ar),
81.7 (CH, CH−OH), 63.3 (CH2), 43.9 (CH3). Anal. Calcd for
C22H20O5N2S2 ·0.1H 2O (457.88): C, 57.27; H, 4.44; N, 6.11. Found:
C, 57.23; H, 4.62; N, 6.13.
MeOH 9:1 v/v), mp = 178−180 °C. H NMR (DMSO-d6): δ 10.35
(bs, 1H, NHSO2R), 8.90 (t, J = 5.5 Hz, 1H, NH), 7.78−7.85 (m, 5H,
Ar and imid), 7.30−7.41 (m, 4H, Ar), 7.33 (m, 2H, Ar), 7.20−7.34 (m,
2H, Ar),7.06−7.09 (m, 2H, Ar and imid), 7.03 (m, 1H, Ar), 6.90 (s,
1H, imid), 5.62 (dd, Jx,b = 5.7 Hz, Jx,a = 9.5 Hz, 1H, CHx), 4.02−4.10
(m, 1H, CHb), 3.93−4.00 (m, 1H, CHa). 13C NMR (DMSO-d6): δ
165.6 (CO), 141.7, 139.1, 137.9, 137.3 (C, Ar), 129.1, 128.7, 128.5,
128.0, 126.8, 126.7, 124.3, 120.2, 118.2 (CH), 59.3 (CH), 43.4 (CH2).
HRMS (EI): m/z calcd for C24H23O3N4 (M+H)+ 447.1485, Found
447.1476.
General Method: Synthesis of Imidazole Derivatives 8 and 12. A
mixture of oxazole 7 or 11 (1 mmol) and imidazole (40 mmol)
dissolved in isopropyl acetate (5 mL) was heated at 125 °C for 48 h.
After completion of the reaction, the mixture was partitioned between
water (100 mL) and ethyl acetate (150 mL). The organic layer was
washed three times with water (3 × 100 mL), dried over MgSO4, and
concentrated in vacuo.
(E)-N-(2-(1H-Imidazol-1-yl)-2-phenylethyl)-4-(4-fluorostyryl)benz-
amide (8b). Purification by flash column chromatography (CH2Cl2−
MeOH 97:3 v/v) gave a pale yellow solid: yield 74%, Rf = 0.60
(CH2Cl2−MeOH 9:1 v/v), mp = 192−194 °C. 1H NMR (DMSO-d6):
δ 8.69 (t, J = 5.3 Hz 1H, NH), 7.84 (s, 1H, imid), 7.76 (d, J = 8.3 Hz,
2H, Ar), 7.65−7.69 (m, 5H, Ar and imid), 7.33−7.39 (m, 6H, Ar),
Synthesis of 4-[2-(4-Fluorophenyl)ethyl]-N-(2-imidazol-1-yl-2-
phenylethyl)benzamide (8f). Pd/C catalyst 10% (0.17 g) was added
to a solution of compound 8f (0.2 g, 0.4 mmol) in THF (20 mL), and
the reaction was stirred under a H2 atmosphere for 72 h. After that
time the mixture was filtered through Celite. The solvent was removed
under reduced pressure, and the oil formed was purified by flash
column chromatography (CH2Cl2−MeOH 100:0 v/v increasing to
98:2 v/v) to give the pure product as a white solid: yield 52%, Rf =
0.60 (CH2Cl2−MeOH 9:1 v/v), mp = 130−132 °C. 1H NMR
(DMSO-d6): δ 8.63 (t, J = 5.5 Hz 1H, NH), 7.83 (s, 1H, imid), 7.65
(d, J = 8.2 Hz, 2H, Ar), 7.38 (m, 4H, Ar), 7.32 (m, 2H, Ar), 7.27 (d, J
7.21−7.26 (m, 3H, Ar), 6.91 (s, 1H, imid), 5.66 (dd, Jx,b = 6.0 Hz, Jx,a
=
9.3 Hz, 1H, CHx), 4.03−4.10 (m, 1H, CHb), 3.94−3.99 (m, 1H, CHa).
13C NMR (DMSO-d6): δ 166.3 (CO), 162.8, 160.9, 139.9, 139.3,
133.3, 132.8 (C), 136.8, 129.1, 128.7, 128.6, 128.6, 128.1, 128.1, 127.6,
K
dx.doi.org/10.1021/jm5009314 | J. Med. Chem. XXXX, XXX, XXX−XXX