S. Sestito et al. / European Journal of Medicinal Chemistry 118 (2016) 47e63
57
catalytic amount of piperidine. The procedure followed is the same
4.6. (E)-1-(3,4-difluorobenzyl)-N-(3-((1-methyl-1H-imidazol-2-yl)
methylene)-2-oxoindolin-5-yl)-2-oxo-1,2-dihydropyridine-3-
carboxamide (5)
described for derivative 2. The residual material was purified by
crystallization from EtOH, affording the final product as an orange
solid, consisting of E/Z isomeric mixture (ratio:50:50) (26 mg,
ꢁ
1
0
.05 mmol, 30% yield). Mp: 266e270 C. H NMR (400 MHz, DMSO-
): 5.30 (s, 2H, CH ); 6.70 (m, 1H, Ar); 6.82e6.90 (m, 1H, Ar);
To a solution of derivative 1 (70 mg, 0.18 mmol) in EtOH, was
added the 1-methyl-2-imidazolecarboxaldehyde (20 mg,
0.18 mmol) and a catalytic amount of piperidine. The procedure
followed is the same described for derivative 2. The residual ma-
terial was purified by crystallization from EtOH, affording the E-
isomer as an orange solid (28 mg, 0.06 mmol, 32% yield). Mp:
d
6
d
2
7.22e7.65 (m, 5H, Ar); 7.81e8.07 (m, 3H, Ar), 8.19 (s, 0.5H, Ar), 8.31
(
1
s, 1H, Ar), 8.51 (s, 1H, Ar); 8.94 (s, 0.5H, C4 Ar, E-isomer); 10.61 (s,
H, NH); 11.96 (s, 1H, NH) ppm. C NMR (101 MHz, DMSO-d ):
6
13
1
1
1
1
69.29, 167.39, 161.59, 160.96, 160.82, 150.47, 147.92, 143.94, 143.85,
43.50, 138.94, 137.97, 137.35, 137.09, 136.88, 136.32, 134.58, 134.07,
32.39, 132.29, 132.21, 128.78, 128.70, 126.60, 127.48, 124.88, 124.77,
23,45, 121.67, 121.50, 120.92, 120.41, 120.33, 117.78, 117.21, 115.61,
ꢁ
1
284e287 C. H NMR (400 MHz, DMSO-d
(s, 2H, CH
6 3
): d 3.89 (s, 3H, CH ); 5.29
2
); 6.66 (dd, 1H, J ¼ 6.8, 7.2 Hz, Ar); 6.82 (d, 1H, J ¼ 8.4 Hz,
Ar); 7.24e7.26 (m,1H, Ar); 7.32 (s, 1H, Ar); 7.37 (s,1H, Ar); 7.40e7.47
(m, 1H, Ar) 7.50e7.54 (m, 1H, Ar); 7.53 (s, 1H, CH¼); 7.82 (dd, 1H,
J ¼ 2.1, 8.2 Hz, Ar); 8.28 (dd, 1H, J ¼ 2.0, 6.4 Hz, Ar); 8.46 (dd, 1H,
J ¼ 2.0, 7.2 Hz, Ar); 9.38 (d, 1H, J ¼ 2.1 Hz, C4, Ar); 10.54 (s, 1H, NH);
19
1
11.65, 110.11, 109.53, 107.28, 51.53, 51.42. F NMR (376 MHz;
DMSO-d
): ꢀ138.13 (d, 0.5F, J ¼ 24 Hz); ꢀ138.15 (d, 0.5F,
J ¼ 24 Hz); ꢀ139.74 (d, 0.5F, J ¼ 24 Hz); ꢀ139.78 (d, 0.5F, J ¼ 24 Hz)
ppm. Anal. Calcd for C26 S: C, 63.80%; H, 3.50%; N 8.58%;
Found: C, 64.12%; H, 3.75%; N, 8.82%.
6
13
H
17
2
F N
3
O
3
6
11.85 (s, 1H, NH) ppm. C NMR (101 MHz, DMSO-d ): d 169.93,
162.09, 161.34, 150.86, 148.42, 144.30, 143.87, 142.97, 139.68, 134.53,
32.49,130.85, 125.95, 125.57,122.96,122.52,120.90, 120.59, 118.72,
1
19
1
18.32, 118.11, 117.88, 109.63, 107.68, 52.01, 33.78 ppm. F NMR
376 MHz; DMSO-d
): ꢀ138.23 (d, 1F, J ¼ 24 Hz); ꢀ139.70 (d, 1F,
J ¼ 24 Hz) ppm. Anal. Calcd for C26 : C, 64.06%; H, 3.93%; N
4.37%; Found: C, 64.31%; H, 4.02%; N, 14.59%.
(
6
4.5. (E)-1-(3,4-difluorobenzyl)-N-(3-(4-fluorobenzylidene)-2-
19 2 5 3
H F N O
oxoindolin-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (4)
1
To a solution of derivative 1 (70 mg, 0.18 mmol) in EtOH, was
added the 4-fluorobenzaldehyde (23 mg, 0.18 mmol) and a catalytic
amount of piperidine. The procedure followed is the same
described for derivative 2. The residual material was purified by
crystallization from EtOH, affording final product as the E-isomer
that slowly stereomutes in a E/Z isomeric mixture (ratio:55:45)
4.7. Synthesis of 1-(3,4-difluorobenzyl)-3-(6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-2-carbonyl)pyridin-2(1H)-one (6)
The carboxylic acid 19 (125 mg, 0.47 mmol) was condensed
with commercial 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
hydrochloride (109 mg, 0.47 mmol), using TBTU as condensing
reagent (152 mg, 0.47 mmol). The procedure followed is the same
described for derivative 1. DMF and DIPEA were evaporated un-
der reduced pressure and the crude product was purified by flash
chromatography over silica gel, using 0e1% MeOH as a gradient
ꢁ
1
(
(
36 mg, 0.07 mmol, 40% yield). Mp: 224e230 C; H NMR
400 MHz, DMSO-d 5.27 (s, 2H, CH ); 6.66 (t, 1H,
) [t ¼ 0]:
6
d
2
J ¼ 7.0 Hz, Ar); 6.86 (d, 1H, J ¼ 8.4 Hz, Ar); 7.20e7.24 (m, 1H, Ar);
.34e7.39 (m, 2H, Ar); 7.43e7.52 (m, 3H, Ar); 7.64 (s, 1H, CH¼); 7.82
d, 1H, J ¼ 8.4 Hz, Ar); 7.84 (d, 1H, J ¼ 8.4 Hz, Ar); 8.21 (d, 1H,
J ¼ 1.6 Hz, C4, Ar); 8.29 (dd, 1H, J ¼ 2.0, 6.4 Hz, Ar); 8.44 (dd, 1H,
7
(
in CHCl
3
, to obtain pure 6 as a crystalline white solid (99 mg,
19
J ¼ 2.0, 7.2 Hz, Ar); 10.61 (s, 1H, NH); 11.83 (s, 1H, NH) ppm. F NMR
376 MHz; DMSO-d6) [t ¼ 0]: ꢀ110.24 (s, 1F); ꢀ138.18 (d, 1F,
J ¼ 24 Hz, Ar); ꢀ139.71 (d, 1F, J ¼ 24 Hz, Ar) ppm. C NMR
101 MHz, DMSO-d 169.14 (E-isomer), 167.71 (Z-
) [t ¼ 12 h]:
isomer),164.33,162.07,161.98,161.86,161.33, 151.20,148.62,144.38,
44.06 (Z-isomer), 143.97 (E-isomer), 139.73, 137.60 (E-isomer),
36.61 (Z-isomer), 135.62, 135.26 (E-isomer), 135.18 (Z-isomer),
34.54, 132.88, 132.57, 132.44, 132.36, 131.16, 128.12 (E-isomer),
26.77 (Z-isomer), 125.74, 125.49 (E-isomer), 125.19 (Z-isomer),
22.52, 121.40, 120.76, 120.70, 118.24, 117.70, 116.41 (E-isomer),
16.19 (Z-isomer), 115.80 (E-isomer), 115.59 (Z-isomer), 115.20 (E-
isomer), 112.57 (Z-isomer), 110.74 (E-isomer), 109.96 (Z-isomer),
0.23 mmol, 48% yield). The derivative was obtained as mixture of
ꢁ
1
(
d
conformational rotamers (ratio 40:60). Mp: 75e80 C. H NMR
13
(400 MHz, DMSO-d
3.25e3.35 (m, 0.8H, CH
3.66e3.73 (m, 6H, OCH ); 4.32 (s, 1st rotamer, 0.8H, CH
2nd rotamer, 1.2H, CH ); 5.14 (s, 2H, CH
6
) [t ¼ 293K]:
d
2.73 (t, 2H, J ¼ 5.7 Hz, CH
2
2
);
);
(
6
d
2
); 3.40 (t, 1.2H, J ¼ 5.7 Hz, CH
3
2
); 4.63 (s,
1
1
1
1
1
1
2
2
); 6.38 (t, 1H, J ¼ 6.8 Hz,
Ar); 6.57 (s, 1st rotamer, 0.4H); 6.71 (s, 2nd rotamer, 0.6H); 6.74
(s, 1st rotamer, 0.4H); 6.84 (s, 2nd rotamer 0.6H); 7.19e7.22 (m,
1H, Ar); 7.41e7.48 (m, 2H, Ar); 7.51e7.55 (m, 1H, Ar); 7.98e8.02
1
(m, 1H, Ar) ppm. H NMR (250 MHz, CD
3
CN) [t ¼ 373K]:
d 2.74 (t,
2H, J ¼ 5.6 Hz, CH
2
); 3.55 (br s, 2H, CH
); 5.15 (s, 2H, CH
2
); 3.74 (s, 3H, OCH
3
); 3.75
(s, 3H, OCH ); 4.52 (br s, 2H, CH
3
2
2
); 6.33 (t, 1H,
1
1
(
07.71, 51.98 ppm. H NMR (400 MHz, DMSO-d
6
) [t ¼ 24 h]:
d
5.27
J ¼ 6.5 Hz, Ar); 6.73 (s, 2H); 7.19e7.21 (m, 1H, Ar); 7.32e7.42 (m,
s, 1.10H, CH , E-isomer); 5.31 (s, 0.90H, CH , Z-isomer); 6.66 (t,
2
2
2H, Ar); 7.48 (dd, 1H, J ¼ 1.8, 6.8 Hz, Ar); 7.87 (dd, 1H, J ¼ 1.8,
13
0
.55H, J ¼ 7.0 Hz, Ar, E-isomer); 6.71 (t, 0.45H, J ¼ 7.0 Hz, Ar, Z-
3
6.8 Hz, Ar) ppm. C NMR (101 MHz, CDCl ): d 166.21 (2nd
isomer); 6.81 (d, 0.45H, J ¼ 8.4 Hz, Ar, Z-isomer), 6.86 (d, 0.55H,
J ¼ 8.4 Hz, Ar, E-isomer); 7.20e7.24 (m, 1H, Ar, E þ Z-isomers);
rotamer), 165.87 (1st rotamer), 159.09 (2nd rotamer), 158.81 (1st
rotamer), 151.54, 149.11, 147.84, 147.68, 140.42 (1st rotamer),
139.44 (2nd rotamer), 138.84 (1st rotamer), 138.47 (2nd rotamer),
132.97, 129.35 (2nd rotamer), 129.08 (1st rotamer), 126.66 (1st
rotamer), 125.84 (2nd rotamer), 124.51, 117.52, 111.62 (1st
rotamer), 111.30 (2nd rotamer), 109.32(2nd rotamer), 108.67 (1st
rotamer), 106.28 (1st rotamer), 106.21 (2nd rotamer), 55.92,
52.04 (1st rotamer), 51.90 (2nd rotamer), 48.04 (1st rotamer),
44.66(2nd rotamer), 44.14 (2nd rotamer), 40.24 (1st rotamer),
7
.30e7.39 (m, 2H, Ar, E þ Z-isomers); 7.43e7.52 (m, 3H, Ar, E þ Z-
isomers); 7.63 (s, 0.55H, CH¼, E-isomer); 7.70 (dd, 0.45H, J ¼ 2.0,
.4 Hz, Ar, Z-isomer); 7.82 (d, 0.55H, J ¼ 8.4 Hz, Ar, E-isomer); 7.83
d, 0.55H, J ¼ 8.4 Hz, Ar, E-isomer); 7.88 (s, 0.45H, CH¼, Z-isomer);
.95 (d, 0.45H, J ¼ 2.0 Hz, C4 Ar, Z-isomer) 8.21 (d, 1H, J ¼ 2.0 Hz, C4
Ar, E-isomer); 8.28e8.33 (m, 1H, J ¼ 2.0, 6.4 Hz, Ar, E þ Z-isomers);
6
(
7
8
.36 (dd, 0.55H, J ¼ 2.0, 7.2 Hz, Ar, E-isomer); 8.49e8.56 (m, 1.35H,
19
Ar, Z-isomer); 10.62 (s, 0.55H, NH, E-isomer); 10.67 (s, 0.45H, NH, Z-
isomer); 11.83 (s, 0.55H, NH, E-isomer); 11.95 (s, 0.45H, NH, Z-iso-
29.07 (2nd rotamer), 28.04 (1st rotamer) ppm.
(376 MHz; DMSO-d ):
ꢀ136.39 (d, 2nd rotamer, 0.60F,
J ¼ 24 Hz); ꢀ136.44 (d, 1st rotamer, 0.40F, J ¼ 24 Hz); ꢀ137.96
(d, 2nd rotamer, 0.60F, J ¼ 24 Hz); ꢀ137.97 (d, 1st rotamer,
F NMR
6
d
mer) ppm. Anal. Calcd for C28
H
18
F
3
N
3
O
3
: C, 67.06%; H, 3.62%; N
d
d
8
.38%; Found: C, 66.87%; H, 3.52%; N, 8.25%.
d