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(10 mL) and the product was extracted with EtOAc (450 mL). The
combined organic layers were dried over Na2SO4, filtered, and con-
centrated in vacuo to afford product 19 (0.76 g, 95%) as a white
solid.
N2-(2-Benzamidophenyl)-N6-(2-(4-methoxybenzamido)phenyl)-
pyridine-2,6-dicarboxamide (4): Prepared according to the gener-
al procedure for a coupling reaction with carboxylic acid 19
(183 mg, 0.51 mmol, 100 mol%), amide 10c (136 mg, 0.56 mmol,
110 mol%), HOBt (83 mg, 0.56 mmol, 110 mol%), EDC (0.11 mL,
0.61 mmol, 120 mol%), Et3N (0.09 mL, 0.61 mmol, 120 mol%), and
THF (50 mL) to yield the product (90 mg, 30%) as a white solid. Rf
(hexane/EtOAc 3:7)=0.51; mp 172–1748C; IR (film): n˜ =3345, 1698,
The product could not be visualized by TLC analysis; mp 208–
2108C; IR (film): n˜ =3270, 1753, 1673, 1645, 1601, 1519, 1484, 1452,
1
1339, 1317, 757, 742, 697, 678 cmÀ1; H NMR (500 MHz, [D6]DMSO):
d=10.74 (s, 1H), 10.20 (s, 1H), 8.40 (dd, 1H, J1 =7.3 Hz, J2 =1.6 Hz),
8.30–8.24 (m, 2H), 8.04–8.02 (m, 2H), 7.98 (dd, 1H, J1 =8.0, J2 =
1.5 Hz), 7.63 (dd, 1H, J1 =7.9, J2 =1.5 Hz), 7.60–7.57 (m, 1H), 7.52–
7.49 (m, 1H), 7.36 (td, 1H, J1 =7.7, J2 =1.6 Hz), 7.31 ppm (td, 1H,
J1 =7.7, J2 =1,6 Hz); 13C NMR (125 MHz, [D6]DMSO): d=166.2, 165.0,
161.6, 149.2, 146.8, 140.1, 134.2, 131.74, 131.70, 130.4, 128.4, 127.9,
127.3, 126.7, 126.1, 125.5, 125.4, 124.4 ppm; HRMS (ESIÀ): m/z calcd
for [C20H14N3O4]: 360.0984 [MÀH]À; found: 360.0978; D=À1.8 ppm.
1
1682, 1648, 1633, 1605, 1509, 1439, 1307, 1258, 755 cmÀ1; H NMR
(500 MHz, [D6]DMSO): d=11.04 (s, 1H), 10.98 (s, 1H), 10.22 (s, 1H),
10.11 (s, 1H), 8.38–8.36 (m, 2H), 8.30–8.27 (m, 1H), 7.76 (dd, 2H,
J1 =8.2, J2 =1.0 Hz), 7.73–7.71 (m, 4H), 7.68–7.67 (m, 1H), 7.62–7.61
(m, 1H), 7.44–7.41 (m, 1H), 7.37–7.32 (m, 4H), 7.20 (t, 2H, J=
7.8 Hz), 6.70 (d, 2H, J=8.9 Hz), 3.74 ppm (s, 3H); 13C NMR
(125 MHz, [D6]DMSO): d=166.0, 165.5, 161.9, 161.3, 161.2, 148.3,
148.2, 140.4, 134.0, 131.6, 131.10, 131.07, 130.8, 129.5, 128.1, 127.5,
125.9, 125.9, 125.8, 125.7, 125.6, 125.3, 125.11, 125.07, 113.3,
55.3 ppm; HRMS (ESI+): m/z calcd for [C34H27N5O5Na]: 608.1904
[M+Na]+; found: 608.1903; D=À0.2 ppm.
General procedure for the coupling reactions:[24] HOBt and the
amide derivative were added to a stirred solution of an asymmetric
pyridine carboxylic acid in THF at room temperature. The mixture
was cooled to 08C and stirred for 30 min. EDC and Et3N were
added to the reaction mixture and the solution was stirred for fur-
ther 30 min at 08C. The solution was warmed to room tempera-
ture, stirred overnight, and concentrated in vacuo. The residue was
dissolved in EtOAc, washed with several portions of 1m HCl and fi-
nally with brine, dried over Na2SO4, filtered, and concentrated in
vacuo to afford the product.
N2-(2-Acetamidophenyl)-N6-(2-benzamidophenyl)pyridine-2,6-di-
carboxamide (5): Prepared according to the general procedure for
a coupling reaction with carboxylic acid 19 (479 mg, 1.33 mmol,
100 mol%), amide 10d (230 mg, 1.53 mmol, 115 mol%), HOBt
(207 mg, 1.53 mmol, 115 mol%), EDC (0.30 mL, 1.66 mmol,
125 mol%), Et3N (0.23 mL, 1.66 mmol, 125 mol%), and THF (70 mL)
to yield the product (588 mg, 90%) as a white solid. Rf (hexane/
EtOAc 2:8)=0.55; mp 227–2298C; IR (film): n˜ =3227, 3037, 1693,
N2-(2-Benzamidophenyl)-N6-phenylpyridine-2,6-dicarboxamide
(2): Prepared according to the general procedure for a coupling re-
action with carboxylic acid 17 (1.080 g, 4.46 mmol, 100 mol%) in
THF (20 mL), HOBt (0.603 g, 4.46 mmol, 100 mol%), amide 10a
(0.947 g, 4.46 mmol, 100 mol%), EDC (0.84 mL, 4.73 mmol,
106 mol%), Et3N (0.66 mL, 4.73 mmol, 106 mol%), and THF (30 mL)
to yield the product (1.843 g, 95%) as a white solid. Rf (hexane/
EtOAc 1:1)=0.41; mp 229–2328C; IR (film): n˜ =3316, 3232, 1677,
1666, 1646, 1597, 1511, 1481, 1445, 1311, 754, 705 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d=11.25 (s, 1H), 11.12 (s, 1H), 9.65 (s, 1H), 9.07
(s, 1H), 8.47 (d, 1H, J=7.6 Hz), 8.43 (d, 1H, J=7.8 Hz), 8.11 (t, 1H,
J=7.8 Hz), 7.94 (d, 1H, J=7.5 Hz), 7.80 (d, 2H, J=7.5 Hz), 7.72–7.69
(m, 2H), 7.40 (t, 1H, J=7.4 Hz), 7.28–7.24 (m, 3H), 7.22–7.16 (m,
3H), 7.08–7.05 (m, 1H), 1.71 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3): d=170.8, 166.4, 162.7, 161.7, 149.0, 148.4, 139.6, 133.8,
132.1, 131.1, 130.8, 130.2, 129.7, 128.7, 127.5, 126.66, 126.64,
126.33, 126.25, 125.9, 125.7, 125.53, 125.51, 125.1, 124.8, 23.4 ppm;
HRMS (ESI+): m/z calcd for [C28H23N5O4Na]: 516.1627 [M+Na]+;
found: 516.1642; D=À3.0 ppm.
1660, 1645, 1597, 1528, 1445, 1312, 750, 706 cmÀ1 1H NMR
;
(500 MHz, [D6]DMSO): d=11.14 (s, 1H), 10.76 (s, 1H), 10.34 (s, 1H),
8.40 (td, 2H, J1 =7.7, J2 =1.1 Hz), 8.31–8.28 (m, 1H), 7.89–7.86 (m,
3H), 7.77 (d, 2H, J=8.1 Hz), 7.64 (dd, 1H, J1 =7.8, J2 =1.4 Hz), 7.45–
7.33 (m, 5H), 7.27 (t, 2H, J=7.8 Hz), 7.18–7.15 ppm (m, 1H);
13C NMR (125 MHz, [D6]DMSO): d=166.4, 161.3, 148.6, 148.5, 140.1,
137.7, 134.0, 131.7, 131.0, 128.6, 128.2, 127.6, 125.94, 125.88, 125.6,
125.2, 125.1, 124.4, 121.0 ppm; HRMS (ESI+): m/z calcd for
[C26H20N4O3Na]: 459.1433 [M+Na]+; found: 459.1426; D=
À1.6 ppm.
N2-(2-Benzamidophenyl)-N6-(2-isobutyramidophenyl)pyridine-
2,6-dicarboxamide (6): Prepared according to the general proce-
dure for a coupling reaction with carboxylic acid 19 (310 mg,
0.85 mmol, 100 mol%), amide 10e (170 mg, 0.95 mmol,
110 mol%), HOBt (129 mg, 0.95 mmol, 110 mol%), EDC (0.19 mL,
1.05 mmol, 120 mol%), Et3N (0.15 mL, 1.05 mmol, 120 mol%), and
THF (50 mL) to yield the product (383 mg, 77%) as a white solid. Rf
(hexane/EtOAc 3:7)=0.50; mp 192–1938C; IR (film): n˜ =1650, 1599,
N2-(2-Benzamidophenyl)-N6-(2-(4-cyanobenzamido)phenyl)pyri-
dine-2,6-dicarboxamide (3): Prepared according to the general
procedure for a coupling reaction with carboxylic acid 19 (359 mg,
1.00 mmol, 100 mol%), amide 10b (237 mg, 1.00 mmol,
100 mol%), HOBt (135 mg, 1.00 mmol, 100 mol%), EDC (0.19 mL,
1.10 mmol, 110 mol%), Et3N (0.15 mL, 1.10 mmol, 110 mol%), and
THF (50 mL) to yield the product (544 mg, 94%) as a light-brown
solid. Rf (hexane/EtOAc 3:7)=0.56; mp 252–2548C; IR (film): n˜ =
1513, 1480, 1450, 1302, 750 cmÀ1 1H NMR (500 MHz, CDCl3): d=
;
11.06 (s, 1H), 10.97 (s, 1H), 9.54 (s, 1H), 8.72 (s, 1H), 8.46 (d, 1H,
J=7.7 Hz), 8.44 (d, 1H, J=7.8 Hz), 8.12 (t, 1H, J=7.8 Hz), 7.87 (dd,
1H, J1 =7.8, J2 =1.6 Hz), 7.80–7.77 (m, 3H), 7.59 (d, 1H, J=7.7 Hz),
7.34 (t, 1H, J=7.4 Hz), 7.20–7.10 (m, 5H), 7.05–7.02 (m, 1H), 2.40
(septet, 1H, J=6.9 Hz), 0.89 ppm (d, 1H, J=6.9 Hz); 13C NMR
(125 MHz, CDCl3): d=177.6, 166.6, 162.1, 162.0, 148.7, 148.6, 139.7,
133.8, 132.0, 130.7, 130.4, 130.1, 128.7, 128.6, 127.6, 127.5, 126.6,
126.5, 126.1, 125.6, 125.53, 125.45, 125.2, 124.9, 36.1, 19.3 ppm;
HRMS (ESI+): m/z calcd for [C30H28N5O4]: 522.2135 [M+H]+; found:
544.1946; D=À0.9 ppm.
2230, 1667, 1599, 1515, 1480, 1441, 1306, 754 cmÀ1 1H NMR
;
(500 MHz, [D6]DMSO): d=11.00 (s, 1H), 10.85 (s, 1H), 10.38 (s, 1H),
10.29 (s, 1H), 8.38–8.36 (m, 2H), 8.30–8.27 (m, 1H), 7.91 (d, 2H, J=
8.4 Hz), 7.77–7.75 (m, 1H), 7.72 (d, 2H, J=7.2 Hz), 7.65–7.63 (m,
2H), 7.59 (d, 2H, J=8.5 Hz), 7.56–7.54 (m, 1H), 7.45–7.42 (m, 1H),
7.39–7.31 (m, 4H), 7.22–7.19 ppm (m, 2H); 13C NMR (125 MHz,
[D6]DMSO): d=166.1, 164.5, 161.3, 161.1, 148.33, 148.29, 140.3,
138.2, 133.7, 131.9, 131.7, 131.1, 130.8, 130.7, 130.5, 128.3, 128.1,
127.7, 126.2, 126.0, 125.7, 125.6, 125.5, 125.2, 125.09, 125.06, 125.0,
118.1, 113.7 ppm; HRMS (ESI+): m/z calcd for [C34H24N6O4Na]:
603.1751 [M+Na]+; found: 603.1745; D=À1.0 ppm.
N2-(2-Benzamidophenyl)-N6-(2-pivalamidophenyl)pyridine-2,6-di-
carboxamide (7): Prepared according to the general procedure for
a coupling reactions with carboxylic acid 19 (340 mg, 0.95 mmol,
100 mol%), amide 10 f (200 mg, 1.04 mmol, 110 mol%), HOBt
(141 mg, 1.04 mmol, 110 mol%), EDC (0.20 mL, 1.13 mmol,
120 mol%), Et3N (0.16 mL, 1.13 mmol, 120 mol%), and THF (50 mL)
Chem. Eur. J. 2015, 21, 9493 – 9504
9502
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