10.1002/cmdc.202000147
ChemMedChem
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127.4, 126.6, 122.9, 52.8, 52.6, 48.2, 36.6 ppm; IR (film): ṽ = 3326, 3028,
2951, 1725, 1698, 1570, 1499, 1438, 1349, 1293, 1243, 1193, 1160, 1126,
1108, 1089, 996 cm–1; HRMS (ESI): m/z calculated for C17H19O4N2 [M+H]+:
315.1339, found: 315.1336.
D2O): δ = 173.1, 166.1, 144.3 (br), 142.9, 140.8, 129.5 (br), 128.5, 128.4(9),
128.1 (br), 126.3, 125.7, 44.2, 34.3, 28.3, 27.5 ppm; IR (film): ṽ = 3182,
2980, 2931, 2858, 1619, 1532, 1453, 1384, 1290, 1244, 1205, 1105 cm–1
;
HRMS (ESI): m/z calculated for C17H17O4N2 [M−H]−: 313.1194, found:
313.1191.
3-(Phenethylamino)pyridine-2,4-dicarboxylic acid (26): Pyridine 26
(101 mg, 71%) was obtained from dimethyl pyridine-2,4-dicarboxylate 35
(157 mg, 0.5 mmol) according to General Procedure B. Yellow solid, m.p.:
>220 °C (decomposition); 1H NMR (600 MHz, 300 K, D2O): δ = 7.85 (d, J
= 5.5 Hz, 1H), 7.63 (d, J = 5.5 Hz, 1H), 7.37−7.34 (m, 2H), 7.31−7.30 (m,
2H), 7.28−7.26 (m, 1H), 3.66 (t, J = 6.5 Hz, 2H), 2.97 ppm (t, J = 6.5 Hz,
2H); 13C NMR (150 MHz, 300 K, D2O): δ = 173.1, 165.6, 144.8, 141.0,
139.0, 129.0, 128.9(8), 128.7, 127.4 (br), 126.6, 126.4 (br), 45.9 (br), 35.6
(br) ppm; IR (film): ṽ = 3194, 3028, 2924, 1617, 1531, 1497, 1455, 1387,
1293, 1244, 1210, 1107 cm–1; HRMS (ESI): m/z calculated for C15H13O4N2
[M−H]−: 285.0881, found: 285.0879.
rac-Dimethyl
3-((1-phenylethyl)amino)pyridine-2,4-dicarboxylate
(38): According to General Procedure A, pyridine 38 (304 mg, 48%) was
obtained from dimethyl 3-chloropyridine-2,4-dicarboxylate 24 (459 mg, 2.0
mmol) after column chromatography (25 g Ultra; 50 mL/min; 100%
cyclohexane (3 CV) followed by a linear gradient (10 CV): 0%→30% ethyl
acetate in cyclohexane). Yellow solid, m.p.: 95−96 °C; 1H NMR (600 MHz,
300 K, CDCl3): δ = 8.67 (brd, J = 6.6 Hz, 1H), 7.99 (d, J = 4.7 Hz, 1H), 7.50
(d, J = 4.6 Hz, 1H), 7.27−7.24 (m, 2H), 7.21−7.19 (m, 1H), 7.13 (d, J = 7.4
Hz, 2H), 4.74 (app. quint., J = 6.7 Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 1.60
ppm (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, 300 K, CDCl3): δ = 167.8,
167.2, 144.7, 143.0, 136.3, 134.1, 128.6, 127.5, 127.3, 126.2, 124.3, 55.1,
52.8, 52.5, 25.6 ppm; IR (film): ṽ = 3322, 3029, 2952, 1721, 1697, 1589,
1568, 1509, 1437, 1375, 1292, 1243, 1193, 1166, 1126, 999 cm–1; HRMS
(ESI): m/z calculated for C17H19O4N2 [M+H]+: 315.1339, found: 315.1341.
Dimethyl 3-((3-phenylpropyl)amino)pyridine-2,4-dicarboxylate (36):
According to General Procedure A, pyridine 36 (379 mg, 58%) was
obtained from dimethyl 3-chloropyridine-2,4-dicarboxylate 24 (459 mg, 2.0
mmol) after column chromatography (25 g Ultra; 50 mL/min; 100%
cyclohexane (3 CV) followed by a linear gradient (10 CV): 0%→20% ethyl
acetate in cyclohexane). Clear yellow oil; 1H NMR (600 MHz, 300 K,
CDCl3): δ = 8.11 (brt, J = 4.7 Hz, 1H), 8.02 (d, J = 4.7 Hz, 1H), 7.60 (d, J
= 4.6 Hz, 1H), 7.30−7.27 (m, 2H), 7.22−7.19 (m, 1H), 7.17−7.15 (m, 2H),
3.97 (s, 3H), 3.89 (s, 3H), 3.06−3.03 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H),
2.02−1.96 ppm (m, 2H); 13C NMR (150 MHz, 300 K, CDCl3): δ = 167.7,
167.5, 145.9, 141.0, 135.7, 133.3, 128.4, 128.3(7), 127.4, 126.1, 122.6,
52.8, 52.5, 46.2, 33.1, 32.0 ppm; IR (film): ṽ = 3329, 3027, 2950, 2865,
1727, 1696, 1586, 1571, 1499, 1438, 1294, 1243, 1195, 1157, 1126, 1108,
997 cm–1; HRMS (ESI): m/z calculated for C18H21O4N2 [M+H]+: 329.1496,
found: 329.1493.
rac-3-((1-Phenylethyl)amino)pyridine-2,4-dicarboxylic
Pyridine 29 (103 mg, 72%) was obtained from dimethyl pyridine-2,4-
dicarboxylate 38 (157 mg, 0.5 mmol) according to General Procedure B.
acid
(29):
1
Yellow solid, m.p.: >270 °C (decomposition); H NMR (600 MHz, 300 K,
D2O): δ = 7.92 (d, J = 5.4 Hz, 1H), 7.55 (d, J = 5.4 Hz, 1H), 7.36−7.31 (m,
4H), 7.29−7.26 (m, 1H), 4.97 (q, J = 6.7 Hz, 1H), 1.56 ppm (d, J = 6.7 Hz,
3H); 13C NMR (150 MHz, 300 K, D2O): δ = 172.7, 167.2 (br), 144.1, 143.2,
141.7, 133.5 (br), 130.9 (br), 128.7, 127.3, 126.3, 126.2, 54.6, 23.8 ppm;
IR (film): ṽ = 3182, 3030, 2927, 1612, 1519, 1452, 1374, 1288, 1243, 1211,
1125, 1102, 1019 cm–1; HRMS (ESI): m/z calculated for C15H13O4N2
[M−H]−: 285.0881, found: 285.0877.
3-((3-Phenylpropyl)amino)pyridine-2,4-dicarboxylic
acid
(27):
rac-Dimethyl
3-((1-phenylpropyl)amino)pyridine-2,4-dicarboxylate
Pyridine 27 (91 mg, 61%) was obtained from dimethyl pyridine-2,4-
dicarboxylate 36 (164 mg, 0.5 mmol) according to General Procedure B.
Yellow solid, m.p.: >220 °C (decomposition); 1H NMR (600 MHz, 300 K,
D2O): δ = 7.84 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.28−7.25 (m,
2H), 7.22−7.21 (m, 2H), 7.19−7.17 (m, 1H), 3.32 (t, J = 6.3 Hz, 2H), 2.73
(t, J = 7.3 Hz, 2H), 1.99 ppm (app. quint., J = 6.8 Hz, 2H); 13C NMR (150
MHz, 300 K, D2O): δ = 173.1, 166.0, 144.6, 141.7, 140.3, 128.7 (br), 128.5
(2C), 127.2 (br), 126.4, 125.8, 44.2, 32.6, 30.8 ppm; IR (film): ṽ = 3194,
2980, 2935, 2864, 1618, 1603, 1531, 1497, 1467, 1454, 1385, 1291, 1244,
1207, 1175, 1104, 1030 cm–1; HRMS (ESI): m/z calculated for C16H15O4N2
[M−H]−: 299.1037, found: 299.1034.
(39): According to General Procedure A, pyridine 39 (268 mg, 41%) was
obtained from dimethyl 3-chloropyridine-2,4-dicarboxylate 24 (459 mg, 2.0
mmol) after column chromatography (25 g Ultra; 50 mL/min; 100%
cyclohexane (3 CV) followed by a linear gradient (12 CV): 0%→20% ethyl
acetate in cyclohexane). Yellow solid, m.p.: 83−85 °C; 1H NMR (600 MHz,
300 K, CDCl3): δ = 8.77 (brd, J = 6.7 Hz, 1H), 7.97 (d, J = 4.6 Hz, 1H), 7.49
(d, J = 4.6 Hz, 1H), 7.26−7.24 (m, 2H), 7.21−7.19 (m, 1H), 7.09 (d, J = 7.7
Hz, 2H), 4.52 (q, J = 6.7 Hz, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 2.00−1.93 (m,
1H), 1.90−1.83 (m, 1H), 1.00 ppm (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz,
300 K, CDCl3): δ = 167.8, 167.2, 145.1, 141.4, 136.1, 133.9, 128.4, 127.5,
127.2, 126.9, 124.2, 61.1, 52.7, 52.4, 32.6, 10.6 ppm; IR (film): ṽ = 3307,
3002, 2948, 2874, 1713, 1678, 1585, 1503, 1455, 1431, 1370, 1285, 1239,
1190, 1165, 1121, 1103, 1043, 1000, 962 cm–1; HRMS (ESI): m/z
calculated for C18H21O4N2 [M+H]+: 329.1496, found: 329.1495.
Dimethyl 3-((3-phenylbutyl)amino)pyridine-2,4-dicarboxylate (37):
According to General Procedure A, pyridine 37 (398 mg, 58%) was
obtained from dimethyl 3-chloropyridine-2,4-dicarboxylate 24 (459 mg, 2.0
mmol) after column chromatography (25 g Ultra; 50 mL/min; 100%
cyclohexane (3 CV) followed by a linear gradient (10 CV): 0%→15% ethyl
acetate in cyclohexane). Clear yellow oil; 1H NMR (600 MHz, 300 K,
CDCl3): δ = 8.06 (brs, 1H), 8.01 (d, J = 4.7 Hz, 1H), 7.60 (d, J = 4.6 Hz,
1H), 7.30−7.28 (m, 2H), 7.21−7.17 (m, 3H), 3.99 (s, 3H), 3.93 (s, 3H),
3.06−3.04 (m, 2H), 2.66 (t, J = 7.2 Hz, 2H), 1.77−1.67 ppm (m, 4H); 13C
NMR (150 MHz, 300 K, CDCl3): δ = 167.8, 167.5, 145.9, 141.8, 135.6,
133.2, 128.3 (2C), 127.4, 125.9, 122.5, 52.8, 52.5, 46.7, 35.4, 29.9, 28.5
ppm; IR (film): ṽ = 3330, 3027, 2948, 2859, 1727, 1696, 1585, 1571, 1504,
1438, 1294, 1243, 1193, 1153, 1126, 1109, 999 cm–1; HRMS (ESI): m/z
calculated for C19H23O4N2 [M+H]+: 343.1652, found: 343.1656.
rac-3-((1-Phenylpropyl)amino)pyridine-2,4-dicarboxylic acid (30):
Pyridine 30 (66 mg, 88%) was obtained from dimethyl pyridine-2,4-
dicarboxylate 39 (82 mg, 0.25 mmol) according to General Procedure B.
Yellow solid, m.p.: >240 °C (decomposition); 1H NMR (600 MHz, 300 K,
D2O): δ = 7.90 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.37−7.35 (m,
2H), 7.31−7.27 (m, 3H), 4.83 (t, J = 6.7 Hz, 1H), 1.96−1.86 (m, 2H), 1.56
ppm (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, 300 K, D2O): δ = 172.3, 165.8,
144.4, 142.5, 142.4, 130.3, 128.6, 128.5(7), 127.3, 127.0, 126.7, 60.1, 31.3,
9.9 ppm; IR (film): ṽ = 3196, 3065, 2965, 2933, 1621, 1596, 1523, 1494,
1455, 1382, 1286, 1242, 1208, 1103 cm–1; HRMS (ESI): m/z calculated for
C16H15O4N2 [M−H]−: 299.1037, found: 299.1033.
3-((4-Phenylbutyl)amino)pyridine-2,4-dicarboxylic acid (28): Pyridine
28 (99 mg, 63%) was obtained from dimethyl pyridine-2,4-dicarboxylate 37
(171 mg, 0.5 mmol) according to General Procedure B. Yellow solid, m.p.:
>210 °C (decomposition); 1H NMR (600 MHz, 300 K, D2O): δ = 7.88 (d, J
= 5.5 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.32−7.30 (m, 2H), 7.26−7.25 (m,
2H), 7.21−7.19 (m, 1H), 3.33 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H),
1.77−1.72 (m, 2H), 1.68−1.64 ppm (m, 2H); 13C NMR (150 MHz, 300 K,
Dimethyl
3-((4-(trifluoromethyl)benzyl)amino)pyridine-2,4-
dicarboxylate (40): According to General Procedure A, pyridine 40 (307
mg, 42%) was obtained from dimethyl 3-chloropyridine-2,4-dicarboxylate
24 (459 mg, 2.0 mmol) after column chromatography (25 g Ultra; 50
mL/min; 100% cyclohexane (3 CV) followed by a linear gradient (10 CV):
0%→25% ethyl acetate in cyclohexane). Clear yellow oil; 1H NMR (600
MHz, 300 K, CDCl3): δ = 8.51 (brt, J = 4.7 Hz, 1H), 8.10 (d, J = 4.7 Hz, 1H),
8
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