Fotografía y Niño y Eje Cafetero
C. El Pacto regional
2-Chloro-5-(oxazolo[4,5-b]pyridin-2-yl)aniline (35a)109
Prepared from 2-amino-3-hydroxypyridine 34 (4.00 g, 36.3 mmol, 1.0 eq.) and 3-amino-4- chlorobenzoic acid (6.23 g, 36.3 mmol, 1.0 eq.) using general method A. 35a was obtained as a white solid (4.90 g, 55%). mp 205-208 C; IR (solid) ν max: 3453 (NH), 3345 (NH), 1614, 1406, 1261, 781 (C-
Cl); 1H NMR (500 MHz, Chloroform-d) δ 8.57 (dd, J = 4.9, 1.5 Hz, 1H, C5’-H), 7.84 (dd, J = 8.1, 1.5 Hz, 1H, C7’-H), 7.73 (d, J = 2.0 Hz, 1H, C6-H), 7.61 (dd, J = 8.3, 2.0 Hz, 1H, C4-H), 7.40 (d, J = 8.3 Hz, 1H,
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C3-H), 7.29 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 4.30 (br s, 2H, NH2); 13C NMR (126 MHz, Chloroform-d) δ
165.3 (C2’), 156.4 (C3’a), 146.9 (C5’), 143.6 (C1), 143.2 (C7’a), 130.2 (C3), 125.9 (C5), 123.6 (C2), 120.3 (C6’), 118.4 (C4), 118.3 (C7’), 114.8 (C6); m/z(ES+) 246.04 ([M+H]+, 100 %); HRMS (ES+) Calcd for C12H9ON3Cl [M+H]+: 246.0429, found 246.0431. Spectroscopic data are in accordance with the
literature.109
2-Bromo-5-(oxazolo[4,5-b]pyridin-2-yl)aniline (35b)
Prepared from 2-amino-3-hydroxypyridine 34 (600 mg, 5.45 mmol) and 3-amino-4-bromobenzoic acid (1.18 g, 5.45 mmol, 1.0 eq.) using general method A. 35b was obtained as a pale brown solid (1.38 g, 87%). mp 211-212 C; IR (solid) ν max: 3418 (NH), 3287 (NH), 3171, 1736, 1620, 1597, 1543, 1404;1H NMR (300 MHz, DMSO-d6) δ 8.54 (dd, J = 4.9, 1.4 Hz, 1H, C5’-H), 8.23 (dd, J = 8.2, 1.4 Hz, 1H, C7’-H), 7.70 (d, J = 2.1 Hz, 1H, C6-H), 7.61 (d, J = 8.2 Hz, 1H, C3-H), 7.46 (dd, J = 8.2, 4.9 Hz, 1H, C6’-H), 7.31 (dd, J = 8.2, 2.1 Hz, 1H, C4-H), 5.79 (br s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6) δ 164.7 (C2’), 155.5 (C3’a), 146.7 (C1), 146.5 (C5’), 142.7 (C7’a), 133.3 (C3), 125.8 (C5), 120.7 (C6’), 119.0 (C7’), 115.9 (C4), 113.5 (C6), 111.8 (C2); m/z (ES+) 289.99 ([79BrM+H]+, 100 %), 291.99 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C12H9ON3Br [M+H]+: 289.9924, found 289.9927.
2-(Oxazolo[4,5-b]pyridin-2-yl)aniline (35c)
Prepared from 2-amino-3-hydroxypyridine 34 (600 mg, 5.45 mmol, 1.0 eq.) and 2-amino-4- chlorobenzoic acid (935 mg, 5.45 mmol, 1.0 eq.) using general method A. 35c was obtained as a white solid (690 mg, 52%). mp 256-259 C; IR (solid) ν max: 3402 (NH), 3310 (NH), 3201, 1612, 1543,
1481, 1404, 772 (C-Cl); 1H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 5.2 Hz, 1H, C5’-H), 8.19 (d, J = 8.2
Hz, 1H, C7’-H), 7.94 (d, J = 8.3 Hz, 1H, C3-H), 7.50 – 7.35 (m, 3H, C6’-H, NH2), 7.01 (s, 1H, C6-H), 6.73
(d, J = 8.3 Hz, 1H, C4-H);13C NMR (126 MHz, DMSO-d6) δ 164.2 (C2’), 155.2 (C3’a), 150.3 (C1), 146.2
(C5’), 141.1 (C7’a), 138.1 (C5), 129.9 (C3), 120.5 (C6’), 118.5 (C7’), 115.6 (C4), 115.1 (C6), 104.6 (C2);
m/z (ES+) 246.04 ([M+H]+, 100%); HRMS (ES+) Calcd for C12H9ON3Cl [M+H]+: 246.0429, found
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3-(Oxazolo[4,5-b]pyridin-2-yl)aniline (35d)109
Prepared from 2-amino-3-hydroxypyridine 34 (300 mg, 2.70 mmol, 1.0 eq) and 3-aminobenzoic acid (370 mg, 2.70 mmol, 1.0 eq.) using general method A. 35d was obtained as an off-white solid (500 mg, 88%). mp 186-189 C; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (dd, J = 4.9, 1.5 Hz, 1H, C5’-H), 8.21
(dd, J = 8.1, 1.5 Hz, 1H, C7’-H), 7.48 (app. t, J = 2.0, 1H, C2-H), 7.44 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 7.38 (ddd, J = 7.8, 2.0, 1.1 Hz, 1H, C4-H), 7.26 (app. t, J = 7.8 Hz, 1H, C5-H), 6.84 (ddd, J = 7.8, 2.0, 1.1 Hz, 1H, C6-H), 5.55 (br s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6) δ 165.6 (C2’), 155.6 (C3’a), 149.5
(C1), 146.4 (C5’), 142.6 (C7’a), 129.9 (C5), 126.3 (C3), 120.5 (C6’), 118.9 (C7’), 118.1 (C6), 114.9 (C4), 112.3 (C2); m/z (ES+) 218.08 ([M+H]+, 100 %); HRMS (ES+) Calcd for C12H10ON3 [M+H]+: 212.0818,
found 212.0818. Spectroscopic data are in accordance with the literature.109
4-(Oxazolo[4,5-b]pyridin-2-yl)aniline (35e)110
Prepared from 2-amino-3-hydroxypyridine 34 (600 mg, 5.45 mmol, 1.0 eq.) and 4-aminobenzoic acid (747 mg, 5.45 mmol, 1.0 eq.) using general method A. 35e was obtained as a pale yellow solid (906 mg, 79%). mp 257-259 C (lit. 252-254 C110); IR (solid) ν max: 3395 (NH), 3310 (NH), 3202, 1605, 1489,
1404;1H NMR (500 MHz, DMSO-d6) δ 8.41 (dd, J = 4.9, 1.3 Hz, 1H, C5’-H), 8.07 (dd, J = 8.1, 1.3 Hz,
1H, C7’-H), 7.91 (d, J = 8.6 Hz, 2H, C3-H), 7.31 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 6.71 (d, J = 8.6 Hz, 2H, C2-H), 6.17 (br s, 2H, NH2); 13C NMR (126 MHz, DMSO-d6) δ 166.0 (C2’), 156.4 (C3’a), 153.4 (C1),
145.7 (C5’), 142.3 (C7’a), 129.6 (C3), 119.3 (C6’), 117.8 (C7’), 113.5 (C2), 111.7 (C4); m/z (ES+) 212.0 ([M+H]+, 100%); HRMS (ES+) Calcd for C12H10ON3 [M+H]+: 212.0818, found 212.0818. Spectroscopic
data are in accordance with the literature.110
2-Fluoro-5-(oxazolo[4,5-b]pyridin-2-yl)aniline (35f)
Prepared from 2-amino-3-hydroxypyridine 34 (75 mg, 0.68 mmol, 1.0 eq.) and 3-amino-4- fluorobenzoic acid (105 mg, 0.68 mmol, 1.0 eq.) using general method A. 35f was obtained as an off-
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white solid (65 mg, 50%). mp 214-216 C; IR (solid) ν max: 3464 (NH), 3318 (NH), 3194, 3039, 1613,
1497, 1404, 1173 (C-F); 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.9, 1.4 Hz, 1H, C5’-H), 8.21 (dd,
J = 8.2, 1.4 Hz, 1H, C7’-H), 7.69 (dd, J = 8.6, 2.2 Hz, 1H, C6-H), 7.51 – 7.35 (m, 2H, C6’-H, C4-H), 7.25 (dd, J = 11.3, 8.4 Hz, 1H, C3-H), 5.65 (br s, 2H, NH2); 13C NMR (101 MHz, DMSO-d6) δ 164.8 (C2’),
155.6 (C3’a), 153.1 (d, J = 245.3 Hz, C2), 146.4 (C5’), 142.7 (C7’a), 137.5 (d, J = 13.8 Hz, C1), 122.4 (d, J
= 2.7 Hz, C5), 120.53 (C6’), 118.9 (C7’), 116.0 (d, J = 19.8 Hz, C3), 115.8 (d, J = 7.4 Hz, C4), 115.0 (d, J = 6.3 Hz, C6); m/z (ES+) 230.07 ([M+H]+, 100 %); HRMS (ES+) Calcd for C12H9ON3F [M+H]+: 230.0724,
found 230.0725.
2-Methyl-5-(oxazolo[4,5-b]pyridin-2-yl)aniline (35g)
Prepared from 2-amino-3-hydroxypyridine 34 (500 mg, 4.54 mmol, 1.0 eq.) and 3-amino-4- methylbenzoic acid (686 mg, 4.54 mmol, 1.0 eq.) using general method A. 35g was obtained as a pale brown solid (716 mg, 71%). mp 171-173 C; IR (solid) ν max: 3426 (NH), 3325 (NH), 3055, 1736,
1620, 1551, 1497, 1404, 1234, 779;1H NMR (500 MHz, DMSO-d6) δ 8.51 (dd, J = 4.9, 1.4 Hz, 1H, C5’-
H), 8.19 (dd, J = 8.1, 1.4 Hz, 1H, C7’-H), 7.53 (d, J = 1.8 Hz, 1H, C6-H), 7.42 (dd, J = 8.1, 4.9 Hz, 1H, C6’- H), 7.36 (dd, J = 7.6, 1.8 Hz, 1H, C4-H), 7.17 (d, J = 7.6 Hz, 1H, C3-H), 5.33 (br s, 2H, NH2), 2.15 (s, 3H,
CH3); 13C NMR (126 MHz, DMSO-d6) δ 165.8 (C2’), 155.8 (C3’a), 147.5 (C1), 146.3 (C5’), 142.5 (C7’a),
130.8 (C3), 126.6 (C2), 124.0 (C5), 120.3 (C6’), 118.7 (C7’), 115.3 (C4), 112.3 (C6), 17.7 (CH3); m/z
(ES+) 226.09 ([M+H]+, 100 %); HRMS (ES+) Calcd for C12H12ON3 [M+H]+: 226.0975, found 226.0974. 1H
& 13C NMR data not in accordance with literature.109
4-Amino-2-(oxazolo[4,5-b]pyridin-2-yl)phenol (35h)111
Prepared from 2-amino-3-hydroxypyridine 34 (600 mg, 5.45 mmol, 1.0 eq.) and 5-aminosalicylic acid (835 mg, 5.45 mmol, 1.0 eq.) using general method A. 35h was obtained as a dark yellow solid (690 mg, 49%). mp 191-193 C (lit. 181-183 C111); IR (solid) ν max: 3426 (NH), 3310 (NH), 3202 (OH), 1620,
1535, 1497, 1404, 779;1H NMR (500 MHz, DMSO-d6) δ 10.19 (br s, 1H, OH), 8.55 (dd, J = 4.9, 1.4 Hz,
1H, C5’-H), 8.27 (dd, J = 8.1, 1.4 Hz, 1H, C7’-H), 7.48 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 7.27 (d, J = 2.3 Hz, 1H, C3-H), 6.89 – 6.86 (m, 2H, C5-H, C6-H), 5.02 (br s, 2H, NH2); 13C NMR (126 MHz, DMSO-d6) δ
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165.2 (C2’), 153.9 (C3’a), 149.7 (C1), 146.6 (C5’), 141.8 (C4), 141.4 (C7’a), 122.3 (C5), 120.8 (C6’), 119.0 (C7’), 117.9 (C6), 110.4 (C3), 109.5 (C2); m/z (ES+) 228.07 ([M+H]+, 100%); HRMS (ES+) Calcd for C12H10O2N3 [M+H]+: 228.0768, found 228.0768.
3-(Oxazolo[4,5-b]pyridin-2-yl)phenol (35i)112
Prepared from 2-amino-3-hydroxypyridine 34 (55 mg, 0.5 mmol, 1.0 eq.) and 3-hydroxybenzoic acid (69 mg, 0.5 mmol, 1.0 eq.) using general method A. 35i was obtained as a white solid (75 mg, 71%).
mp 198-201 C (lit. 203-204 C112); IR (solid) ν max: 3030 (OH), 2922 (OH), 2603, 1601, 1551, 1449,
1294, 887, 781; 1H NMR (500 MHz, DMSO-d6) δ 10.06 (br s, 1H, OH), 8.54 (dd, J = 4.9, 1.4 Hz, 1H, C5’-
H), 8.24 (dd, J = 8.1, 1.4 Hz, 1H, C7’-H), 7.69 (d, J = 7.9 Hz, 1H, C4-H), 7.72 – 7.66 (m, 1H, C2-H), 7.50 – 7.40 (m, 2H, C6’-H, C5-H), 7.07 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H, C6-H); 13C NMR (126 MHz, DMSO-d
6) δ
164.9 (C2’), 158.0 (C1), 155.5 (C3’a), 146.6 (C5’), 142.8 (C7’a), 130.7 (C5), 127.0 (C3), 120.8 (C6’), 120.0 (C6), 119.1 (C7’), 118.5 (C4), 114.0 (C2); m/z(ES+) 213.06 ([M+H]+, 100 %); HRMS (ES+) Calcd for C12H9O2N2 [M+H]+: 213.0659, found 213.0659. Spectroscopic data are in accordance with the
literature.112
5-(Benzo[d]oxazol-2-yl)-2-bromoaniline (35j)
Prepared from 2-aminophenol (545 mg, 5.00 mmol, 1.0 eq.) and 3-amino-4-bromobenzoic acid (1.08 g, 5.00 mmol, 1.0 eq.) using general method A. 35j was obtained as an off-white solid (653 mg, 45%).
mp 198-200 C; IR (solid) ν max: 3449 (NH), 3310 (NH), 3179, 1612, 1543, 1435, 1242, 1065, 741;1H NMR (500 MHz, DMSO-d6) δ 7.81 – 7.75 (m, 2H, C4’-H, C7’-H), 7.66 (d, J = 2.1 Hz, 1H, C6-H), 7.57 (d, J
= 8.2 Hz, 1H, C3-H), 7.46 – 7.37 (m, 2H, C5’-H, C6’-H), 7.27 (dd, J = 8.2, 2.1 Hz, 1H, C4-H), 5.75 (br s, 2H, NH2); 13C NMR (126 MHz, DMSO-d6) δ 162.2 (C2’), 150.1 (C3’a), 146.6 (C1), 141.5 (C7’a), 133.2
(C3), 126.3 (C5), 125.5 (C5’), 124.9 (C6’), 119.8 (C4’), 115.7 (C4), 113.3 (C6), 111.0 (C2), 110.9 (C7’);
m/z(ES+) 288.99 ([79BrM+H]+, 100 %), 290.99 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C13H10ON2Br
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N-(2-Chloro-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (17)
Prepared from 35a (300 mg, 1.42 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (769 mg, 3.55 mmol, 2.5 eq.) using general method B. 17 was obtained after recrystallisation as a white solid (346 mg, 57%). mp 254-256 C; IR (KBr) ν max: 3416 (NH), 3275, 3059, 3033, 1653 (C=O); 1H NMR (400
MHz, DMSO-d6) δ 10.39 (br s, 1H, NH), 8.61 – 8.53 (m, 2H, C5’-H, C6-H), 8.29 (dd, J = 8.2, 1.5 Hz, 1H,
C7’-H), 8.19 – 8.11 (m, 3H, C4-H, 2 C2’’-H), 7.93 – 7.83 (m, 3H, C3-H, 2 C3’’-H), 7.82 – 7.75 (m, 2H, 2 C6’’-H), 7.57 – 7.46 (m, 3H, C6’-H, 2 C7’’-H), 7.49 – 7.39 (m, 1H, C8’’-H); 13C NMR (101 MHz, DMSO-d6) δ 165.3 (CO), 163.7 (C2’), 155.4 (C3’a), 146.8 (C5’), 143.6 (C4’’), 143.0 (C7’a), 139.0 (C5’’),
136.2 (C1), 133.4 (C2), 132.5 (C1’’), 131.0 (C3), 129.1 (2 C7’’), 128.6 (2 C2’’), 128.3 (C8’’), 127.0 (2
C6’’), 126.8 (2 C3’’), 126.6 (C6), 126.1 (C4), 125.2 (C5), 121.1 (C6’), 119.3 (C7’); m/z(ES-) 423.82 ([M-H]-, 100 %); HRMS (ES-) Calcd for C25H15ClN3O2 [M-H]-: 424.0839, found 424.0853.
N-(2-Bromo-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)benzamide (42)
Prepared from 35b (80 mg, 0.28 mmol, 1.0 eq.) and benzoyl chloride (98 mg, 0.70 mmol, 2.5 eq.) using general method B. 42 was obtained after recrystallisation as a white solid (74 mg, 67%). mp
249-251 C; IR (solid) ν max: 3271 (NH), 3055, 1651 (C=O), 1520, 1404, 1257, 779, 709, 640 (C-Br);1H NMR (400 MHz, DMSO-d6) δ 10.29 (br s, 1H, NH), 8.58 (dd, J = 4.9, 1.4 Hz, 1H, C5’-H), 8.47 (d, J = 2.0
Hz, 1H, C6-H), 8.28 (dd, J = 8.3, 1.4 Hz, 1H, C7’-H), 8.10 – 7.98 (m, 4H, C3-H, C4-H, 2 C2’’-H), 7.69 – 7.62 (m, 1H, C4’’-H), 7.58 (dd, J = 8.3, 6.5 Hz, 2H, 2 C3’’-H), 7.50 (dd, J = 8.3, 4.9 Hz, 1H, C6’-H); 13C NMR (101 MHz, DMSO-d6) δ 165.6 (CO), 163.7 (C2’), 155.3 (C3’a), 146.8 (C5’), 142.9 (C7’a), 137.6
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125.8 (C5), 124.9 (C2), 121.1 (C6’), 119.3 (C7’); m/z (ES+) 394.02 ([79BrM+H]+, 100 %), 396.02 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C19H13O2N3Br [M+H]+: 394.0186, found 394.0188.
N-(2-Bromo-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-2-(3-methoxyphenyl)acetamide (43)
Prepared from 35b (80 mg, 0.28 mmol, 1.0 eq.) and 3-methoxyphenylacetyl chloride (129 mg, 0.70 mmol, 2.5 eq.) using general method B. 43 was obtained after recrystallisation as a white solid (92 mg, 75%). mp 211-213 C; IR (solid) ν max: 3271 (NH), 1667 (C=O), 1551, 1404, 1265, 1157, 802;1H NMR (400 MHz, DMSO-d6) δ 9.87 (br s, 1H, NH), 8.56 (dd, J = 4.8, 1.4 Hz, 1H, C5’-H), 8.52 (s, 1H, C6-
H), 8.27 (dd, J = 8.3, 1.4 Hz, 1H, C7’-H), 7.94 (br s, 2H, C3-H, C4-H), 7.48 (dd, J = 8.3, 4.8 Hz, 1H, C6’- H), 7.27 (t, J = 7.8 Hz, 1H, C5’’-H), 7.02 – 6.95 (m, 2H, C2’’-H, C6’’-H), 6.85 (dd, J = 7.8, 2.3 Hz, 1H, C4’’- H), 3.78 (s, 2H, CH2), 3.76 (s, 3H, OCH3); 13C NMR (101 MHz, DMSO-d6) δ 169.7 (CO), 163.8 (C2’),
159.3 (C3’’), 155.3 (C3’a), 146.8 (C5’), 142.9 (C7’a), 137.2 (C), 137.0 (C), 134.1 (C3), 129.4 (C5”), 125.6 (C5), 125.4 (C4), 124.7 (C6), 121.6 (C2), 121.5 (C6’’), 121.1 (C6’), 119.3 (C7’), 115.0 (C2’’), 112.2 (C4’’), 55.0 (OCH3), 42.6 (CH2); m/z (ES+) 438.04 ([79BrM+H]+, 100 %), 440.04 ([81BrM+H]+, 100%); HRMS
(ES+) Calcd for C21H17O3N3Br [M+H]+: 438.0448, found 438.0449.
N-(5-Chloro-2-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (44)
Prepared from 35c (550 mg, 2.60 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (1.41 g, 6.50 mmol, 2.5 eq.) using general method B. 44 was obtained after recrystallisation as a pale yellow solid (185 mg, 17%). mp 254-256 °C IR (KBr) ν max: 3408 (NH), 3072, 3032, 1684 (C=O), 1590; 1H NMR (500
MHz, Chloroform-d) δ 12.64 (br s, 1H, NH), 9.21 (d, J = 2.0 Hz, 1H, C6-H), 8.63 (dd, J = 4.9, 1.4 Hz, 1H, C5’-H), 8.36 (d, J = 8.3 Hz, 2H, 2 C2’’-H), 8.20 (d, J = 8.5 Hz, 1H, C3-H), 7.92 (dd, J = 8.1, 1.4 Hz, 1H, C7’-H), 7.86 (d, J = 8.3 Hz, 2H, 2 C3’’-H), 7.73 – 7.66 (m, 2H, 2 C6’’-H), 7.49 (dd, J = 8.3, 6.8 Hz, 2H, 2 C7’’-H), 7.44 – 7.39 (m, 1H, C8’’-H), 7.38 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H, C4-H);13C NMR (126 MHz, Chloroform-d) δ 166.1 (CO), 164.0 (C2’), 154.9 (C3’a), 147.3 (C5’),
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145.2 (C4’’), 141.8 (C7’a), 141.0 (C5), 140.6 (C1), 140.1 (C5’’), 133.0 (C1’’), 129.4 (C3), 129.0 (2 C7’’), 128.5 (2 C2’’), 128.2 (C8’’), 127.8 (2 C3’’), 127.4 (2 C6’’), 123.6 (C4), 121.0 (C6’), 120.9 (C6), 118.6 (C7’), 110.8 (C2); m/z (ES+) 447.86 [M+Na]+; HRMS (ES+) Calcd for C25H16ClN3O2Na
[M+Na]+: 448.0829, found 448.0826.
N-(3-(Oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (45)
Prepared from 35d (150 mg, 0.71 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (385 mg, 1.78 mmol, 2.5 eq.) using general method B. 45 was obtained after recrystallisation as a white solid (33 mg, 12%). mp 261-264 °C; IR (KBr) ν max: 3440 (NH), 2962, 2924, 1649 (C=O), 1527;1H NMR (300 MHz, DMSO-d6) δ 10.63 (br s, 1H, NH), 8.87 (t, J = 1.9 Hz, 1H, C2-H), 8.56 (dd, J = 4.9, 1.4 Hz, 1H, C5’- H), 8.27 (dd, J = 8.2, 1.4 Hz, 1H, C7’-H), 8.19 – 8.06 (m, 3H, C6-H, 2 C2’’-H), 8.04 – 7.93 (m, 1H, C4- H), 7.92 – 7.82 (m, 2H, 2 C3’’-H), 7.82 – 7.72 (m, 2H, 2 C6’’-H), 7.64 (t, J = 8.0 Hz, 1H, C5-H), 7.57 – 7.36 (m, 4H, C6’-H, C8’’-H, 2 C7’’-H);13C NMR (75 MHz, DMSO-d 6) δ 165.5 (CO), 164.8 (C2’), 155.5 (C3’a), 146.6 (C5’), 143.4 (C4’’), 142.8 (C7’a), 140.2 (C1), 139.1 (C5’’), 133.3 (C1’’), 129.9 (C5), 129.1 (2 C7’’), 128.5 (2 C2’’), 128.2 (C8’’), 127.0 (2 C6’’), 126.7 (2 C3’’), 126.3 (C3), 124.1 (C6), 122.8 (C4), 120.9 (C6’), 119.1 (CH), 119.0 (CH); m/z (ES-) 389.84 ([M-H]-, 100 %); HRMS (ES-) Calcd for C25H16N3O2 [M-H]-: 390.1245, found 390.1243.
N-(4-(Oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (46)
Prepared from 35e (300 mg, 1.42 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (769 mg, 3.55 mmol, 2.5 eq.) using general method B. 46 was obtained after recrystallisation as an off-white solid (202 mg, 36%). mp 322-325 C; IR (KBr) ν max: 3358 (NH), 3067, 3056, 1672 (C=O), 1599; 1H NMR (400
MHz, DMSO-d6) δ 10.70 (br s, 1H, NH), 8.54 (dd, J = 4.9, 1.4 Hz, 1H, C5’-H), 8.27 (d, J = 8.8 Hz, 2H, 2
47
2H, 2 C3’’-H), 7.83 – 7.72 (m, 2H, 2 C6’’-H), 7.57 – 7.49 (m, 2H, 2 C7’’-H), 7.48 – 7.38 (m, 2H, C6’-H, C8’’-H);13C NMR (101 MHz, DMSO-d6) δ 165.7 (CO), 164.8 (C2’), 155.8 (C3’a), 146.4 (C5’),
143.5 (C), 143.4 (C), 142.7 (C7’a), 139.0 (C5’’), 133.3 (C1’’), 129.1 (2 C7’’), 128.6 (2 CH), 128.6 (2 CH), 128.3 (C8’’), 127.0 (2 C6’’), 126.7 (2 C3’’), 120.6 (C4), 120.5 (C6’), 120.3 (2 C2), 118.8 (C7’);
m/z(ES-) 389.91 ([M-H]-, 100 %); HRMS (ES-) Calcd for C25H16N3O2 [M-H]-: 390.1234, found 390.1243. N-(2-Fluoro-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (47)
Prepared from 35f (51 mg, 0.22 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (119 mg, 0.55 mmol, 2.5 eq.) using general method B. 47 was obtained after recrystallisation as a white solid (75 mg, 83%). mp 230-232 C; IR (solid) ν max: 3441 (NH), 3040, 1674 (C=O), 1520, 1404, 1250 (C-F); 1H NMR (400 MHz, DMSO-d6) δ 10.47 (br s, 1H, NH), 8.65 (dd, J = 7.3, 2.3 Hz, 1H, C6-H), 8.57 (dd, J = 4.9,
1.4 Hz, 1H, C5’-H), 8.28 (dd, J = 8.2, 1.4 Hz, 1H, C7’-H), 8.20 – 8.15 (m, 1H, C4-H), 8.13 (d, J = 8.4 Hz, 2H, 2 C2’’-H), 7.94 – 7.83 (m, 2H, 2 C3’’-H), 7.83 – 7.74 (m, 2H, 2 C6’’-H), 7.62 (dd, J = 10.2, 8.7 Hz, 1H, C3-H), 7.58 – 7.37 (m, 4H, C6’-H, 2 C7’’-H, C8’’-H); 13C NMR (101 MHz, DMSO-d6) δ 165.3
(CO), 163.9 (C2’), 157.8 (d, J = 254.7 Hz, C2), 155.5 (C3’a), 146.67 (C5’), 143.6 (C4’’), 142.9 (C7’a), 139.0 (C5’’), 132.4 (C1’’), 129.1 (2 C7’’), 128.7 (2 C2’’), 128.3 (C8’’), 127.1 (d, J = 12.6 Hz, C1), 127.0 (2 C6’’), 126.7 (2 C3’’), 126.3 (d, J = 9.1 Hz, C4), 125.7 (C6), 122.4 (d, J = 3.0 Hz, C5), 120.9 (C6’), 119.2 (C7’), 117.4 (d, J = 21.6 Hz, C3); m/z(ES+) 410.12 ([M+H]+, 100 %); HRMS (ES+) Calcd for C25H17FN3O2 [M+H]+: 410.1299, found 410.1299.
48
N-(2-Bromo-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (48; Liddean)
Prepared from 35b (300 mg, 1.04 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (563 mg, 2.60 mmol, 2.5 eq.) using general method B. Liddean (48) was obtained after recrystallisation as a white solid (200 mg, 41%). mp 237-240 C; IR (KBr) ν max: 3460 (NH), 3271, 2666, 1653 (C=O), 1521;1H NMR
(500 MHz, DMSO-d6) δ 10.34 (br s, 1H, NH), 8.58 (dd, J = 4.8, 1.4 Hz, 1H, C5’-H), 8.49 (d, J = 2.1 Hz,
1H, C6-H), 8.29 (dd, J = 8.1, 1.4 Hz, 1H, C7’-H), 8.18 – 8.11 (m, 2H, 2 C2’’-H), 8.07 (dd, J = 8.4, 2.1 Hz, 1H, C4-H), 8.03 (d, J = 8.4 Hz, 1H, C3-H), 7.93 – 7.86 (m, 2H, 2 C3’’-H), 7.79 (m, 2H, 2 C6’’-H), 7.56 – 7.47 (m, 3H, C6’-H, 2 C7’’-H), 7.47 – 7.40 (m, 1H, C8’’-H); 13C NMR (126 MHz, DMSO-d6) δ
165.2 (CO), 163.8 (C2’), 155.4 (C3’a), 146.9 (C5’), 143.7 (C4’’), 143.0 (C7’a), 139.1 (C5’’), 137.6 (C1), 134.2 (C3), 132.5 (C1’’), 129.1 (2 C7’’), 128.5 (2 C2’’), 128.3 (C8’’), 127.0 (2 C6’’), 126.9 (C6), 126.9 (2 C3’’), 126.4 (C4), 125.8 (C5), 124.9 (C2), 121.2 (C6’), 119.4 (C7’); m/z(ES-) 467.81 ([79BrM- H]+, 100 %), 469.81 ([81BrM-H]-, 100%); HRMS (ES-) Calcd for C25H15O2N3Br [M-H]-: 468.0348, found
468.0351.
N-(2-Methyl-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (49)
Prepared from 35g (600 mg, 2.66 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (1.44 g, 6.65 mmol, 2.5 eq.) using general method B. 49 was obtained after recrystallization as a white solid (360 mg, 33%). mp 275-277 C; IR (solid) ν max: 3264 (NH), 1670 (C=O), 1520, 1404, 1258, 741;1H NMR
(400 MHz, DMSO-d6) δ 10.17 (br s, 1H, NH), 8.55 (dd, J = 4.8, 1.4 Hz, 1H, C5’-H), 8.36 (d, J = 1.9 Hz,
49
Hz, 1H, C4-H), 7.88 (d, J = 8.3 Hz, 2H, 2 C3’’-H), 7.81 – 7.73 (m, 2H, 2 C6’’-H), 7.58 (d, J = 8.0 Hz, 1H, C3-H), 7.53 (t, J = 7.5 Hz, 2H, 2 C7’’-H), 7.49 – 7.46 (m, 1H, C6’-H), 7.48 – 7.39 (m, 1H, C8’’-H), 2.41 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) δ 165.3 (CO), 164.7 (C2’), 155.6 (C3’a), 146.6 (C5’),
143.3 (C4’’), 142.8 (C7’a), 139.1 (C5’’), 138.8 (C2), 137.4 (C1), 133.0 (C1’’), 131.6 (C3), 129.1 (2 C7’’), 128.5 (2 C2’’), 128.2 (C8’’), 127.0 (2 C6’’), 126.7 (2 C3’’), 125.2 (C6), 124.9 (C4), 123.9 (C5), 120.8 (C6’), 119.0 (C7’), 18.3 (CH3); m/z (ES+) 406.15 ([M+H]+, 100 %); HRMS (ES+) Calcd for
C26H20N3O2 [M+H]+: 406.1550, found 406.1548.
N-(4-Hydroxy-3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-carboxamide (50)
Prepared from 35h (300 mg, 1.32 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (715 mg, 3.30 mmol, 2.5 eq.) the general method B. 50 was obtained after recrystallisation as an off-white solid (346 mg, 64%). mp 330-332 °C; IR (KBr) ν max: 3425 (NH), 3257, 3094, 3044, 1636 (C=O), 1534; 1H NMR (500 MHz, DMSO-d6) δ 10.85 (br s, 1H, OH), 10.44 (br s, 1H, NH), 8.72 (d, J = 2.7 Hz, 1H, C3-H),
8.59 (dd, J = 4.7, 1.4 Hz, 1H, C5’-H), 8.35 (dd, J = 7.9, 1.4 Hz, 1H, C7’-H), 8.11 (d, J = 8.0 Hz, 2H, 2 C2’’-H), 7.92 (dd, J = 8.9, 2.7 Hz, 1H, C5-H), 7.86 (d, J = 8.0 Hz, 2H, 2 C3’’-H), 7.77 (d, J = 7.3 Hz, 2H, 2
C6’’-H), 7.58 – 7.48 (m, 3H, C6’-H, 2 C7’’-H), 7.43 (t, J = 7.3 Hz, 1H, C8’’-H), 7.18 (d, J = 8.9 Hz, 1H, C6-H);13C NMR (126 MHz, DMSO-d6) δ 165.0 (CO), 164.6 (C2’), 154.4 (C1), 153.9 (C3’a), 146.8 (C5’),
143.2 (C4’’), 141.7 (C7’a), 139.1 (C5’’), 133.4 (C1’’), 131.8 (C4), 129.1 (2 C7’’), 128.3 (2 C2’’), 128.2 (C8’’), 127.5 (C5), 127.0 (2 C6’’), 126.7 (2 C3’’), 121.1 (C6’), 119.3 (C7’), 119.1 (C3), 117.6 (C6), 109.8 (C2); m/z (ES-) 405.88 ([M-H]-, 100 %); HRMS (ES-) Calcd for C25H16N3O3 [M-H]-: 406.1185,
50
3-(Oxazolo[4,5-b]pyridin-2-yl)phenyl [1,1'-biphenyl]-4-carboxylate (51)
Prepared from 35i (85 mg, 0.40 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (212 mg, 1.00 mmol, 2.5 eq.) using general method B. 51 was obtained after recrystallisation as a white solid (95 mg, 61%). mp 185-187 °C; IR (solid) ν max: 3063, 1728 (C=O), 1605, 1551, 1481, 1404;1H NMR (500
MHz, Chloroform-d) δ 8.61 (dd, J = 4.8, 1.5 Hz, 1H, C5’-H), 8.30 (dd, J = 8.4, 1.8 Hz, 2H, 2 C2’’-H), 8.27 (dt, J = 7.9, 1.3 Hz, 1H, C4-H), 8.22 (t, J = 1.9 Hz, 1H, C2-H), 7.88 (dd, J = 8.2, 1.5 Hz, 1H, C7’-H), 7.77 (dd, J = 8.4, 1.8 Hz, 2H, 2 C3’’-H), 7.68 (dt, J = 6.0, 1.4 Hz, 2H, 2 C6’’-H), 7.64 (t, J = 7.9 Hz, 1H, C5-H), 7.54 – 7.47 (m, 3H, C6-H, 2 C7’’-H), 7.47 – 7.40 (m, 1H, C8’’-H), 7.32 (dd, J = 8.2, 4.8 Hz, 1H, C6’-H);13C NMR (126 MHz, Chloroform-d) δ 164.9 (C), 164.8 (C), 156.3 (C3’a), 151.5 (C1), 147.1 (C5’), 146.8 (C4’’), 143.3 (C7’a), 139.9 (C5’’), 130.9 (2 C2’’), 130.4 (C5), 129.2 (2 C7’’), 128.5 (C8’’), 128.1 (C3), 127.9 (C1’’), 127.5 (2 C6’’, 2 C3’’), 126.1 (C6), 125.8 (C4), 121.6 (C2), 120.5 (C6’), 118.5 (C7’);
m/z (ES+) 393.12 ([M+H]+, 100 %); HRMS (ES+) Calcd for C25H17O3N2 [M+H]+: 393.1234, found
393.1233.
N-(3-(Oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-sulfonamide (52)
Prepared from 35d (85 mg, 0.40 mmol, 1.0 eq.) and biphenyl-4-sulfonyl chloride (253 mg, 1.00 mmol, 2.5 eq.) using general method B. 52 was obtained after recrystallisation as a white solid (120 mg, 70%). mp 193-195 °C; IR (KBr) ν max: 3067 (NH), 2893, 1551, 1404, 1337 (S=O), 1157 (S=O), 945,
777, 762;1H NMR (500 MHz, DMSO-d6) δ 10.82 (br s, 1H, NH), 8.55 (dd, J = 4.8, 1.4 Hz, 1H, C5’-H),
51
2 C3’’-H), 7.71 – 7.64 (m, 2H, 2 C6’’-H), 7.54 (t, J = 8.0 Hz, 1H, C5-H), 7.49 – 7.43 (m, 4H, C6’-H, C6-H, 2 C7’’-H), 7.43 – 7.36 (m, 1H, C8’’-H);13C NMR (126 MHz, DMSO-d6) δ 164.2 (C2’), 155.3
(C7’a), 146.7 (C5’), 144.6 (C4’’), 142.8 (C3’a), 138.8 (C1), 138.1 (C), 138.0 (C), 130.6 (C5), 129.1 (2 C7’’), 128.7 (C8’’), 127.6 (2 CH), 127.4 (2 CH), 127.1 (2 C6’’), 126.9 (C3), 123.5 (C6), 123.2 (C4), 121.0 (C6’), 119.3 (C7’), 118.2 (C2); m/z (ES+) 428.10 ([M+H]+, 100 %); HRMS (ES+) Calcd for C24H18O3N3S [M+H]+: 428.1063, found 428.1063.
N-(2-Bromo-5-(oxazolo[4,5-b]pyridin-2-yl)phenyl)-[1,1'-biphenyl]-4-sulfonamide (53)
Prepared from 35b (80 mg, 0.28 mmol, 1.0 eq.) and biphenyl-4-sulfonyl chloride (177 mg, 0.70 mmol, 2.5 eq.) using the general method B. 53 was obtained after recrystallisation as a white solid (75 mg, 53%). mp 240-242 °C; IR (solid) ν max: 3233 (NH), 1605, 1543, 1474, 1396 (S=O), 1342, 1258,
1157 (S=O);1H NMR (500 MHz, Chloroform-d) δ 8.66 – 8.60 (m, 2H, C5’-H, C6-H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H, C4-H), 7.96 – 7.88 (m, 3H, C7’-H, 2 C2’’-H), 7.66 (d, J = 8.4 Hz, 2H, 2 C3’’-H), 7.63 (d, J = 8.4 Hz, 1H, C3-H), 7.60 – 7.54 (m, 2H, 2 C6’’-H), 7.44 (t, J = 7.6 Hz, 2H, 2 C7’’-H), 7.42 – 7.37 (m, 1H, C8’’-H), 7.36 (dd, J = 8.1, 4.9 Hz, 1H, C6’-H), 7.17 (br s, 1H, NH);13C NMR (126 MHz, Chloroform-d) δ 164.1 (C2’), 156.2 (C3’a), 147.3 (C5’), 146.6 (C4’’), 143.4 (C7’a), 139.0 (C5’’), 137.1 (C1’’), 135.7 (C1), 133.7 (C3), 129.2 (2 C7’’), 128.8 (C8’’), 128.1 (2 C2’’), 127.9 (2 C3’’), 127.4 (2 C6’’), 127.3 (C5), 125.8 (C4), 121.0 (C6), 120.8 (C6’), 120.0 (C2), 118.7 (C7’); m/z (ES+) 506.02 ([79BrM+H]+, 100 %), 508.02 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C24H17O3N3BrS [M+H]+: 506.0169, found 506.0160.
52
N-(5-(Benzo[d]oxazol-2-yl)-2-bromophenyl)-[1,1'-biphenyl]-4-carboxamide (54)
Prepared from 35j (289 mg, 1.00 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (542 mg, 2.50 mmol, 2.5 eq.) using general method B. 54 was obtained after recrystallisation as a white solid (250 mg, 53%). mp 260-262 C; IR (KBr) ν max: 3269 (NH), 1653 (C=O), 1558, 1508, 1240; 1H NMR (500 MHz, Chloroform-d) δ 9.48 (d, J = 2.1 Hz, 1H, C6-H), 8.61 (br s, 1H, NH), 8.10 – 8.03 (m, 2H, 2 C2’’- H), 7.96 (dd, J = 8.4, 2.1 Hz, 1H, C4-H), 7.82 – 7.73 (m, 4H, C3-H, C4’-H, 2 C3’’-H), 7.70 – 7.64 (m, 2H, 2 C6’’-H), 7.64 – 7.60 (m, 1H, C7’-H), 7.52 – 7.46 (m, 2H, 2 C7’’-H), 7.45 – 7.40 (m, 1H, C8’’-H), 7.39 – 7.36 (m, 2H, C5’-H, C6’-H); 13C NMR (126 MHz, Chloroform-d) δ 165.1 (CO), 162.1 (C2’), 151.0 (C7’a), 145.5 (C4’’), 142.2 (C3’a), 139.9 (C5’’), 136.6 (C1), 133.1 (C3), 132.9 (C1’’), 129.2 (2 C7’’), 128.4 (C8’’), 127.9 (2 C2’’, 2 C3’’), 127.4 (2 C6’’), 125.6 (CH), 124.9 (CH), 124.9 (C5), 124.3 (C4), 120.5 (C6), 120.3 (C4’), 117.0 (C2), 111.0 (C7’); m/z (ES+) 469.05 ([79BrM+H]+, 100 %), 471.05 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C26H18O2N2Br [M+H]+: 469.0546, found 469.0544.
N-(2-Chlorophenyl)-[1,1'-biphenyl]-4-carboxamide (55)
Prepared from 2-chloroaniline (128 mg, 1.00 mmol, 1.0 eq.) and biphenyl-4-carbonyl chloride (542 mg, 2.50 mmol, 2.5 eq.) using general method B. 55 was obtained after recrystallisation as a white solid (250 mg, 81%). mp 144-146 C; IR (solid) ν max: 3279 (NH), 1643 (C=O), 1520, 1435, 1312, 741;
1
H NMR (500 MHz, DMSO-d6) δ 10.13 (br s, 1H, NH), 8.10 (d, J = 8.4 Hz, 2H, 2 C2’-H), 7.85 (d, J = 8.4
Hz, 2H, 2 C3’-H), 7.80 – 7.73 (m, 2H, 2 C6’-H), 7.62 (dd, J = 7.7, 1.6 Hz, 1H, C6-H), 7.57 (dd, J = 8.1, 1.6 Hz, 1H, C3-H), 7.55 – 7.49 (m, 2H, 2 C7’-H), 7.47 – 7.40 (m, 1H, C8’-H), 7.40 (dd, J = 7.7, 1.6 Hz,
53
1H, C5-H), 7.31 (td, J = 7.7, 1.6 Hz, 1H, C4-H); 13C NMR (126 MHz, DMSO-d6) δ 165.0 (CO), 143.4 (C4’),
139.1 (C5’), 135.1 (C1), 132.7 (C1’), 129.6 (C3), 129.1 (C2, 2 C7’), 128.6 (C6), 128.4 (2 C2’), 128.2 (C8’), 127.5 (C4, C5), 127.0 (2 C6’), 126.7 (2 C3’); m/z(ES+) 308.08 ([M+H]+, 100 %); HRMS (ES+) Calcd for C19H15ClNO [M+H]+: 308.0837, found 308.0839.
N-(2-Bromo-5-nitrophenyl)-[1,1'-biphenyl]-4-carboxamide (59)
Biphenyl-4-carbonyl chloride (461 mg, 2.13 mmol, 1.0 eq.) was added to 2-bromo-5-nitroaniline 58
(308 mg, 1.42 mmol, 1.5 eq.) in DCM (15 mL), followed by pyridine (0.17 mL, 2.13 mmol, 1.5 eq.). The reaction was stirred at room temperature for 18 hours. 59 was obtained after recrystallisation (DCM) as a white solid (300 mg, 53%). mp 203-205 C; IR (solid) ν max: 3379 (NH), 1690 (C=O), 1528
(N-O), 1412, 1312, 741, 602 (C-Br); 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H, NH), 8.51 (d, J = 1.8 Hz, 1H, C6-H), 8.12 (d, J = 8.1 Hz, 2H, 2 C2’-H), 8.06 (br s, 2H, C3-H, C4-H), 7.89 (d, J = 8.1 Hz, 2H, 2 C3’-H), 7.81 – 7.75 (m, 2H, 2 C6’-H), 7.52 (t, J = 7.5 Hz, 2H, 2 C7’-H), 7.44 (t, J = 7.5 Hz, 1H, C8’- H); 13C NMR (126 MHz, DMSO-d6) δ 165.2 (CO), 146.9 (C5), 143.8 (C4’), 139.0 (C5’), 137.8 (C1), 134.0 (C3), 132.2 (C1’), 129.1 (2 C7’), 128.6 (2 C2’), 128.3 (C8’), 127.5 (C2), 127.0 (2 C6’), 126.8 (2 C3’), 122.3 (C6), 121.9 (C4); m/z (ES+) 497.02 ([79BrM+Na]+, 100 %), 399.02 ([81BrM+H]+, 100%);
HRMS (ES+) Calcd for C19H14N2O3Br [M+H]+: 397.0182, found 397.0184. N-(5-Amino-2-bromophenyl)-[1,1'-biphenyl]-4-carboxamide (60)
54
To 59 (100 mg, 0.25 mmol, 1.0 eq.) and NH4Cl (67 mg, 1.25 mmol, 5.0 eq.) in MeOH (2 mL) and H2O
(1 mL) at 100 C was added iron powder (70 mg, 1.25 mmol, 5.0 eq.) portionwise. After 3 hours the reaction was cooled to room temperature, filtered through Celite and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with H2O (2 5 mL), brine (5 mL), dried over
MgSO4, filtered and concentrated to yield the desired product 60 as a white solid (83 mg, 90%). 60
was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 9.77 (br s, 1H,
NH), 8.11 – 7.99 (m, 2H, 2 C2’-H), 7.89 – 7.79 (m, 2H, 2 C3’-H), 7.79 – 7.73 (m, 2H, 2 C6’-H), 7.55 – 7.46 (m, 2H, 2 C7’-H), 7.46 – 7.39 (m, 1H, C8’-H), 7.27 (d, J = 8.6 Hz, 1H, C3-H), 6.85 (d, J = 2.7 Hz, 1H, C6-H), 6.44 (dd, J = 8.6, 2.7 Hz, 1H, C4-H), 5.39 (br s, 2H, NH2); 13C NMR (126 MHz, DMSO- d6) δ 164.7 (CO), 148.8 (C5), 143.2 (C4’), 139.1 (C5’), 136.4 (C1), 133.1 (C1’), 132.3 (C3), 129.1 (2 C7’), 128.3 (2 C2’), 128.2 (C8’), 127.0 (2 C6’), 126.7 (2 C3’), 113.6 (C4, C6), 104.5 (C2). N-(3-([1,1'-Biphenyl]-4-carboxamido)-4-bromophenyl)thiophene-2-carboxamide (56)
2-Thiophene carbonyl chloride (36 mg, 0.25 mmol, 3.0 eq.) was added to 60 (30 mg, 0.08 mmol, 1.0 eq.) in DCM (1.0 mL), followed by pyridine (20 µL, 0.25 mmol, 3.0 eq.). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified via the Biotage SP4 (silica-packed SNAP column 4 g; 0-40% EtOAc/hexanes) to give the title product 56 as a white solid (30 mg, 85%). mp 189-191 C; IR (solid) ν max: 3410 (NH), 3279 (NH), 1643 (C=O), 1589, 1515,
1420, 1258, 1018, 802, 741, 694; 1H NMR (500 MHz, Chloroform-d) δ 8.58 – 8.47 (m, 2H, C6-H, NH), 8.11 (br s, 1H, NH), 8.02 – 7.95 (m, 2H, 2 C2’’-H), 7.91 (dd, J = 8.8, 2.6 Hz, 1H, C2-H), 7.77 – 7.69 (m, 2H, 2 C3’’-H), 7.68 – 7.60 (m, 3H, C5’-H, 2 C6’’-H), 7.56 (d, J = 8.8 Hz, 1H, C3-H), 7.54 (dd, J = 5.0, 1.2 Hz, 1H, C3’-H), 7.52 – 7.46 (m, 2H, 2 C7’’-H), 7.45 – 7.39 (m, 1H, C8’’-H), 7.11 (dd, J = 5.0, 3.7 Hz, 1H, C4’-H); 13C NMR (126 MHz, Chloroform-d) δ 165.4 (CO), 160.2 (CO), 145.4 (C4’’), 139.8 (C5’’), 139.1 (C2’), 138.3 (C5), 136.0 (C1), 133.0 (C1’’), 132.8 (C3), 131.3 (C3’), 129.2 (2 C7’’), 128.8 (C5’), 128.4 (C8’’), 128.1 (C4’), 127.8 (2 C2’’, 2 C3’’), 127.4 (2 C6’’), 117.5 (C2), 112.7 (C6), 108.2 (C4);
m/z (ES+) 499.01 ([79BrM+Na]+, 100 %), 501.01 ([81BrM+H]+, 100%); HRMS (ES+) Calcd for C24H17N2O2BrSNa [M+Na]+: 499.0086, found 499.0080.
55
N-(3-([1,1'-Biphenyl]-4-carboxamido)-4-bromophenyl)furan-2-carboxamide (57)
2-Furoyl chloride (47 mg, 0.36 mmol, 3.0 eq.) was added to 60 (44 mg, 0.12 mmol, 1.0 eq.) in DCM (1.2 mL), followed by pyridine (29 µL, 0.36 mmol, 3.0 eq.). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified via the Biotage SP4 (silica-packed SNAP column 4 g; 0-4% MeOH/DCM) to give the title product 57 as a white solid (40 mg, 72%). mp 210-212 C; IR (solid) ν max: 3410 (NH), 3317 (NH), 1674 (C=O), 1647 (C=O), 1508, 1260,
750; 1H NMR (500 MHz, Chloroform-d) δ 8.58 (d, J = 2.6 Hz, 1H, C6-H), 8.57 (br s, 1H, NH), 8.24 (br s, 1H, NH), 8.04 – 8.00 (m, 2H, 2 C2’’-H), 7.94 (dd, J = 8.8, 2.6 Hz, 1H, C2-H), 7.79 – 7.74 (m, 2H, 2 C3’’-H), 7.69 – 7.63 (m, 2H, 2 C6’’-H), 7.58 (d, J = 8.8 Hz, 1H, C3-H), 7.54 (dd, J = 1.7, 0.9 Hz, 1H, C5’- H), 7.53 – 7.46 (m, 2H, 2 C7’’-H), 7.45 – 7.38 (m, 1H, C8’’-H), 7.27 (dd, J = 3.5, 0.9 Hz, 1H, C3’-H), 6.58 (dd, J = 3.5, 1.7 Hz, 1H, C4’-H); 13C NMR (126 MHz, Chloroform-d) δ 165.2 (CO), 156.2 (CO), 147.6 (C2’), 145.4 (C4’’), 144.6 (C5’), 139.9 (C5’’), 137.9 (C5), 136.2 (C1), 133.1 (C1’’), 132.9 (C3), 129.2 (2 C7’’), 128.4 (C8’’), 127.8 (2 C2’’, 2 C3’’), 127.4 (2 C6’), 117.0 (C2), 115.8 (C3’), 112.9 (C4’), 112.3 (C6), 108.0 (C4); m/z (ES+) 461.05 ([79BrM+Na]+, 100 %), 463.05 ([81BrM+H]+, 100%);
HRMS (ES+) Calcd for C
24H18BrN2O3 [M+H]+: 461.0495, found 461.0493.
1-(Benzo[d][1,3]dioxol-5-yl)-4,4,4-trifluorobutane-1,3-dione (68)
To 3’,4’-(methylenedioxy)acetophenone 67 (500 mg, 3.04 mmol, 1.0 eq.) in anhydrous THF (15 mL) at 0 C was added LiHMDS (6.08 mL, 2 eq., 1M in THF) dropwise. Ethyl trifluoroacetate (864 mg, 6.08 mmol, 2.0 eq.) was added after 10 minutes and the reaction was stirred for a further 1 hour at 0 C followed by 2 hours at room temperature. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (3 10 mL). The organic extracts were
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in vacuo to give the title product 68 as a pale yellow solid (790 mg, 100%). IR (solid) ν max: 2911 (OH),
1584 (C=O), 1489, 1437, 1260, 1126 (CF3), 887, 797; 1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J =
8.3, 1.8 Hz, 1H, C6-H), 7.41 (d, J = 1.8 Hz, 1H, C4-H), 6.91 (d, J = 8.3 Hz, 1H, C7-H), 6.47 (s, 1H, C2’-H), 6.10 (s, 2H, C2-H2); 13C NMR (126 MHz, Chloroform-d) δ 186.3 (C1’), 175.4 (C3’), 153.1 (C7a), 148.7
(C3a), 127.5 (C5), 124.4 (C6), 117.7 (br, CF3) 108.7 (C7), 107.5 (C4), 102.4 (C2), 92.1 (C2’). m/z(ES-)
259.02 ([M-H]-, 100 %); HRMS (ES-) Calcd for C11H6O4F3 [M-H]-: 259.0218, found 259.0223.
5-(Benzo[d][1,3]dioxol-5-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70)
A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate 64 (194 mg, 1.25 mmol, 1.0 eq.) and 68 (325 mg, 1.25 mmol, 1.0 eq.) in acetic acid (0.7 mL) was heated at reflux for 5 hours. After cooling to room temperature, the reaction mixture was poured onto ice (1.5 g). The resulting precipitate was filtered off, washed with water (2 5 mL), and dried to yield ethyl 5-(benzo[d][1,3]dioxol-5-yl)-7- (trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 69 (420 mg, 90%). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H, C2-H), 8.30 (s, 1H, C6-H), 8.06 (dd, J = 8.3, 1.8 Hz, 1H, C6’-H), 7.96 (d, J = 1.8
Hz, 1H, C4’-H), 7.14 (d, J = 8.3 Hz, 1H, C7’-H), 6.18 (s, 2H, C2’-H2), 4.34 (q, J = 7.1 Hz, 2H, CO2CH2CH3),
1.37 (t, J = 7.1 Hz, 3H, CO2CH2CH3); 13C NMR (126 MHz, DMSO-d6) δ 161.5 (CO2Et), 157.7 (C5), 150.9
(C7’a), 148.4 (C3’a), 147.9 (C2), 147.8 (C3a), 133.8 (d, J = 36.9 Hz, C7), 129.4 (C5’), 123.8 (C6’), 119.4 (d, J = 275.0, CF3), 108.8 (C7’), 107.3 (C4’), 106.0 (C6), 102.8 (C3), 102.1 (C2’), 59.9 (CO2CH2CH3), 14.4
(CO2CH2CH3). 69 was added to a mixture of NaOH (30 mg, 0.75 mmol) in EtOH/ water (1:3) (0.7 mL),
and the reaction mixture was heated at 65 C for 4 hours. The mixture was cooled to room temperature and acidified with concentrated HCl until pH 1 was reached. The formed precipitate was filtered off, washed with water, and dried to yield a 4:1 mixture of 70 and 69 (260 mg). This mixture was used in the next step without further purification.
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5-(Benzo[d][1,3]dioxol-5-yl)-N-((tetrahydrofuran-2-yl)methyl)-7-(trifluoromethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide (13)
To a solution of oxalyl chloride (53 µL, 0.62 mmol, 2.0 eq.) and 70 (110 mg, 0.31 mmol, 1.0 eq., containing 69 (25%)) in DCM (4 mL) at 0 C was added 2 drops of DMF. The reaction was stirred at room temperature for 2 hours before being concentrated in vacuo. To the resulting acid chloride in MeCN (6 mL) was added tetrahydrofurfurylamine (70 µL, 0.62 mmol, 2.0 eq.) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and purified via
the Biotage SP4 (silica-packed SNAP column 10 g; 0-80% EtOAc/hexanes) followed by recrystallisation from hot EtOH provided the title product 13 as a yellow solid (97 mg, 72%). mp 253- 255 C; IR (solid) ν max: 2918 (NH), 1663 (C=O), 1551, 1503, 1443, 1396, 1319, 1233, 1159 (CF3), 1032,
799; 1H NMR (500 MHz, Chloroform-d) δ 8.74 (s, 1H, C2-H), 8.54 (br s, 1H, NH), 7.96 (d, J = 1.9 Hz, 1H, C4’-H), 7.70 (dd, J = 8.2, 1.9 Hz, 1H, C6’-H), 7.67 (s, 1H, C6-H), 6.97 (d, J = 8.2 Hz, 1H, C7’-H), 6.12 (s, 2H, C2’-H2), 4.15 (qd, J = 7.3, 3.3 Hz, 1H, C2’’-H), 4.09 – 4.00 (m, 1H, C5’’-H2), 3.98 – 3.92 (m, 1H,
C1’’-H2), 3.94 – 3.86 (m, 1H, C5’’-H2), 3.41 (ddd, J = 13.6, 7.7, 4.2 Hz, 1H, C1’’-H2), 2.11 – 2.00 (m, 1H,
C3’’-H2), 2.01 – 1.91 (m, 2H, C4’’-H2), 1.74 – 1.62 (m, 1H, C3’’-H2); 13C NMR (126 MHz, Chloroform-d)
δ 161.6 (CO), 156.7 (C5), 151.6 (C7’a), 149.4 (C3’a), 147.9 (C2), 146.7 (C3a), 135.3 (d, J = 37.3 Hz, C7), 129.4 (C5’), 123.2 (C6’), 119.3 (d, J = 274.6 Hz, CF3), 108.8 (C7’), 107.7 (C4’), 107.0 (C3), 104.0 (d, J =
3.9 Hz, C6), 102.3 (C2’), 78.1 (C2’’), 68.3 (C5’’), 42.8 (C1’’), 28.8 (C3’’), 26.3 (C4’’); 19F NMR (471 MHz, Chloroform-d) δ -68.4; m/z (ES+) 457.11 ([M+Na]+, 100 %); HRMS (ES+) Calcd for C20H17O4N4F3Na
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