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I. Mohammed et al. / Bioorg. Med. Chem. 24 (2016) 160–178
(0.42 g, 4.0 mmol) were dissolved in ethanol (10 mL) followed by
stirring at room temperature for about 5 minutes. To the mixture,
acridin-4-ol (0.78 g, 4.0 mmol) and catalytic pyridine (2 drops) was
added and the reaction mixture was refluxed up to 100 °C for about
24 h. The reaction was monitored by TLC (3:2 acetonitrile/water)
and LC–MS. The reaction mixture was later allowed to cool down
and a dark brownish yellow precipitate was isolated upon gravity
filtration, which was washed several times with ethanol to afford
pure compound as an amorphous solid (0.79 g, 42%). 1H NMR
(500 MHz, CDCl3, d): 8.70 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.99 (d,
J = 8.4 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.54
(m, 3H), 7.49 (d, J = 8.9 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.25 (m,
2H), 7.11 (t, J = 7.5 Hz, 2H), 6.68 (m, 3H), 6.23 (s, 1H), 4.53 (s,
1H); 13C NMR (125 MHz, CDCl3, d): 148.3, 147.7, 147.3, 142.7,
140.3, 136.1, 130.5, 129.3, 129.1, 128.9, 128.5, 127.6, 127.5,
127.4, 126.14, 126.10, 126.03, 122.9, 118.5, 117.9, 113.8, 56.8;
HRMS-ESI (m/z): calculated for fragment ion [MꢀC6H6N]+
284.10754 found 284.10760. Anal. Calcd for C26H20N2O: C, 82.95;
H, 5.36; N, 7.44. Found: C, 82.47; H, 5.07; N, 7.28.
d): ꢀ60.9; HRMS-ESI (m/z): [MꢀC7H6NO2]+ calcd for C23H17FN2O3
252.08247, found 252.08319; Anal. Calcd for C23H17FN2O3: C,
71.13; H, 4.41; N, 7.21. Found: C, 70.88; H, 4.21; N, 7.25.
4.1.3.4.6.
4-(((8-Hydroxyquinolin-7-yl)(phenyl)methyl)amino)
benzonitrile (9). Protocol C, amorphous solid (0.35 g, 50%). 1H
NMR (600 MHz, CDCl3, d): 8.77 (dd, J = 1.5 Hz, 4.2 Hz, 1H), 8.61
(br s, 1H), 8.12 (dd, J = 1.4 Hz, 8.3 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H),
7.43 (m, 3H), 7.34 (m, 5H), 7.28 (m, 1H), 6.60 (d, J = 8.8 Hz, 2H),
6.18 (d, J = 5.3 Hz, 1H), 5.05 (d, J = 5.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3, d): 150.6, 149.3, 148.5, 141.3, 138.4, 136.3,
133.8, 129.1, 128.0, 127.5, 126.4, 122.7, 122.2, 120.5, 118.4,
114.6, 113.3, 99.6, 56.5; HRMS-ESI (m/z): [MꢀC7H5N2]+ calcd for
C
23H17N3O 234.09189, found 234.09168. Anal. Calcd for: C,
78.61; H, 4.88; N, 11.96. Found: C, 78.03; H, 4.68; N, 12.09.
4.1.3.4.7. 7-((4-Bromophenyl)((4-nitrophenyl)amino)methyl)
quinolin-8-ol (10). Protocol C, amorphous solid (0.40 g, 45%). 1H
NMR (600 MHz, acetone-d6, d): 9.16 (br s, 1H), 8.85 (dd,
J = 1.5 Hz, 4.2 Hz, 1H), 8.31 (dd, J = 1.5 Hz, 8.3 Hz, 1H), 8.01 (d,
J = 9.3 Hz, 2H), 7.55 (m, 4H), 7.45 (m, 3H), 7.10 (d, J = 6.3 Hz, 1H),
6.83 (d, J = 9.2 Hz, 2H), 6.42 (d, J = 6.3 Hz, 1H); 13C NMR
(150 MHz, acetone-d6, d): 154.2, 150.7, 149.6, 141.7, 139.1, 138.9,
137.1, 132.6, 130.6, 129.0, 127.1, 126.7, 123.5, 123.2, 121.8,
4.1.3.4.2. 7-(Phenyl(phenylamino)methyl)quinolin-8-ol (2). Pro-
tocol A, amorphous solid (0.13 g, 20%). 1H NMR (600 MHz, CDCl3,
d): 8.74 (m, 1H), 8.55 (br s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.61 (d,
J = 8.6 Hz, 1H), 7.48 (d, J = 7.7 Hz, 2H), 7.39 (m, 1H), 7.31 (m, 3H),
7.25 (m, 1H), 7.10 (t, J = 7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.63
(d, J = 7.9 Hz, 2H), 6.14 (d, J = 4.0 Hz, 1H), 4.47 (d, J = 2.9 Hz, 1H);
13C NMR (150 MHz, CDCl3, d): 149.1, 148.2, 147.6, 142.7, 138.5,
136.2, 129.3, 128.9, 127.8, 127.6, 127.5, 126.8, 124.3, 121.9,
118.1, 117.9, 113.8, 57.0; HRMS-ESI (m/z): [MꢀC6H6N]+ calcd for
119.1, 113.0, 55.7; HRMS-ESI (m/z): [MꢀC6H5N2O2]+ calcd for C22
-
H
16BrN3O3 312.00240 and 314.00035, found 312.00243 and
314.00054; HPLC (Method B) Rt = 11.240 min (>95%).
4.1.3.4.8. 4-(((8-Hydroxyquinolin-7-yl)(pyridin-2-yl)methyl)
amino)benzoic acid (15). Protocol A, amorphous solid (0.562 g,
65%). 1H NMR (400 MHz, DMSO-d6, d): 12.05 (br s, 1H), 10.28 (br
s,1H), 8.87 (dd, J = 4.0, 1.3 Hz, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.26
(dd, J = 8.3, 1.3 Hz, 1H), 7.78 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d,
J = 8.7 Hz, 2H), 7.56–7.49, (m, 3H), 7.39–7.27 (m,3H), 6.71 (d,
J = 8.6 Hz, 2H), 6.33 (d, J = 7.0 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6, d): 168.1, 160.6, 151.8, 150.8, 149.6, 149.0, 138.8,
137.8, 136.7, 131.6, 128.4, 126.9, 124.7, 123.2, 122.8, 122.5,
121.8, 118.3, 112.5, 55.5; HRMS-ESI (m/z): [M+H]+ calcd for
C
C
22H18N2O, 234.09189, found 234.09185. Anal. Calcd for
22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 81.02; H, 5.40; N,
8.60; HPLC (Method A) Rt = 4.086 min (>95%).
4.1.3.4.3.
4-(((4-Cyanophenyl)(8-hydroxyquinolin-7-yl)methyl)
amino)benzoic acid (3). Protocol A, pale yellow amorphous solid
(0.879 g, 44%). 1H NMR (500 MHz, DMSO-d6, d): 12.08 (br s, 1H),
10.30 (br s, 1H), 8.88 (dd, J = 4.2 Hz, 1.5 Hz, 1H), 8.30 (dd,
J = 8.3 Hz, 1.5 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.66–7.56 (m,5H),
7.49 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 7.3 Hz,
2H), 6.69 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 7.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3, d): 167.8, 151.8, 150.7, 149.0, 148.2, 138.6,
136.6, 133.0, 131.5, 128.8, 128.3, 126.5, 124.0, 122.5, 119.3,
118.6, 118.3, 112.4, 110.3, 54.4; HRMS-ESI (m/z): [M+H]+ calcd
C22H17N3O3 372.1348, found 372.1349.
4.1.3.4.9. 4-(((8-Hydroxyquinolin-7-yl)(pyridin-3-yl)methyl)
amino)benzoic acid (16). Protocol A, pink amorphous solid solid
(1.05 g, 57%). 1H NMR (400 MHz, DMSO-d6, d): 12.06 (br s, 1H),
10.26 (br s, 1H), 8.83 (d, J = 3.1 Hz, 1H), 8.61 (d, J = 1.0 Hz, 1H),
8.44 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.74–7.70 (m, 1H),
7.63–7.60 (m, 2H), 7.56–7.50 (m, 2H), 7.40–7.32, (m, 3H) 6.66 (d,
J = 8.6 Hz, 2H), 6.25 (d, J = 7.2 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6, d): 167.8, 151.9, 149.5, 148.9, 148.7, 138.6, 137.8,
136.6, 135.6, 131.5, 126.9, 128.7, 126.2, 124.1, 124.0, 122.4,
118.5, 118.3, 112.4, 52.7; HRMS-ESI (m/z): [M+H]+ calcd for
for
C24H17N3O3 396.1343, found 396.1365. Anal. Calcd for
C24H17N3O3: C, 72.90; H, 4.33; N, 10.63. Found: C, 72.63; H, 3.94;
N, 10.42.
4.1.3.4.4.
4-(((8-Hydroxyquinolin-7-yl)(p-tolyl)methyl)amino)
benzoic acid (4). Protocol A, yellow amorphous solid (0.416 g,
22%). 1H NMR (400 MHz, DMSO-d6, d): 12.00 (br s, 1H), 10.10 (br
s, 1H), 8.83 (dd, J = 4.1 Hz, 1.5 Hz, 1H), 8.26 (dd, J = 8.3 Hz, 1.3 Hz,
1H), 7.58 (d, J = 8.8 Hz, 2H), 7.53–7.48 (m, 2H), 7.37–7.51, (m,
1H), 7.26–7.20 (m,3H), 7.12–7.10 (m, 2H), 6.63 (d, J = 8.7 Hz, 2H),
6.17 (d, J = 7.0 Hz, 1H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3,
d): 167.9, 152.2, 150.3, 148.8, 139.5, 138.6, 136.6, 136.5, 131.4,
129.4, 128.1, 127.8, 126.6, 125.2, 122.3, 118.02, 118.00 112.2,
54.1, 21.1. Anal. Calcd for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29.
Found: C, 74.99; H, 4.85; N, 7.15.
C
C
22H17N3O3 372.1343, found 372.1341. Anal. Calcd for
22H17N3O3: C, 71.15; H, 4.61; N, 11.31. Found: C, 70.82; H, 4.24;
N, 11.15.
4.1.3.4.10. 4-((Cyclohexyl(8-hydroxyquinolin-7-yl)methyl)amino)
benzoic acid (17). Protocol B, off-white amorphous solid
(0.406 g, 54%). 1H NMR (500 MHz, DMSO-d6, d): 11.89 (br s, 1H),
9.87 (br s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.26 (dd, J = 8.3,
1.6 Hz, 1H), 7.54–7.51 (m, 3H), 7.46 (d, J = 8.5 Hz, 1H), 7.36 (d,
J = 8.6 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 8.7 Hz, 2H),
4.77 (t, J = 8.4 Hz, 1H), 2.11 (d, J = 11.6 Hz, 1H), 1.80–1.61 (m,
4H), 1.29–1.05 (m, 6H); 13C NMR (150 MHz, DMSO-d6, d): 167.8,
152.8, 150.6, 148.6, 138.3, 136.4, 131.4, 127.8, 126.3, 125.3,
122.0, 118.1, 117.2, 111.5, 55.1, 42.9, 30.4, 29.6, 26.12, 26.10;
HRMS-ESI (m/z): [MꢀC7H6NO2]+ calcd for C23H24N2O3 240.13884,
found 240.13960. Anal. Calcd for C23H24N2O3: C, 73.38; H, 6.43.
N, 7.44. Found: C, 73.28; H, 6.34; N, 7.42.
4.1.3.4.5.
4-(((4-Fluorophenyl)(8-hydroxyquinolin-7-yl)methyl)
amino)benzoic acid (6). Protocol A, off-white powder (0.409 g,
53%). 1H NMR (400 MHz, DMSO-d6, d): 12.02 (br s, 1H), 10.17 (br
s, 1H), 8.85 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.60 (d,
J = 8.7 Hz, 2H), 7.55–7.49 (m, 2H), 7.41–7.38 (m, 3H), 7.26 (d,
J = 7.2 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 6.21
(d, J = 7.1 Hz, 1H); 13C NMR (150 MHz, CDCl3, d): 167.8, 161.7 (d,
1J (19F, 13C) = 243.3 Hz, CFar), 152.0, 150.5, 148.9, 138.6 (d, 4J (19F,
13C) = 3.0 Hz, CFar), 136.6, 131.4, 129.8 (d, 3J (19F, 13C) = 8.2 Hz,
CFar),, 128.2, 126.4, 124.8, 122.3, 118.2, 118.1, 115.6 (d, 2J (19F,
13C) = 21.3 Hz, CFar), 112.3, 53.8; 19F NMR (470 MHz, DMSO-d6,
4.1.3.4.11.
7-(Cyclohexyl(phenylamino)methyl)quinolin-8-ol
(18). Protocol B, off-white amorphous solid (0.257 g, 39%). 1H
NMR (600 MHz, DMSO-d6, d): 9.74 (br s, 1H), 8.84 (d, J = 2.7 Hz,
1H), 8.24 (d, J = 8.2 Hz, 1H), 7.51–7.49 (m, 2H), 7.32 (d, J = 8.5 Hz,