338
I.G. Salado et al. / European Journal of Medicinal Chemistry 138 (2017) 328e342
Z: 18:82, mp: 193e194 ꢀC. Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
obtained without further purification as an orange solid (260 mg,
51%), ratio E/Z: 40:60, mp: 173e175 ꢀC. Isomer Z: 1H-NMR
d
10.63 (s, 1H), 7.18 (d, J ¼ 2.2 Hz, 1H), 7.04 (dd, J ¼ 8.2, 2.2 Hz, 1H),
6.73 (d, J ¼ 8.2 Hz, 1H), 4.08e3.95 (m, 4H), 1.73e1.54 (m, 6H). 13C-
(400 MHz, DMSO-d6):
J ¼ 1.6, 0.9 Hz, 1H), 6.65e6.60 (m, 1H), 3.91e3.89 (m, 4H), 3.67 (s,
3H), 1.83e1.38 (m, 6H).13C-NMR (100 MHz, DMSO-d6):
159.4,
155.2, 141.6, 133.0, 117.1, 112.3, 111.5, 103.9, 58.4, 56.0, 26.6, 24.1.
Isomer E: 1H-NMR (400 MHz, DMSO-d6):
10.43 (s, 1H), 6.93e6.84
d 10.33 (s, 1H), 6.93e6.84 (m, 1H), 6.80 (dd,
NMR (100 MHz, DMSO-d6):
d 159.1, 137.5, 130.4, 126.0, 125.8, 121.4,
117.6, 111.0, 58.6, 26.7, 23.8. Isomer E: 1H-NMR (400 MHz, DMSO-
d6):
10.72 (s, 1H), 7.31 (dd, J ¼ 8.3, 2.1 Hz, 1H), 7.16 (d, J ¼ 2.1 Hz,
1H), 6.86 (d, J ¼ 8.3 Hz, 1H), 3.30e3.25 (m, 4H), 1.73e1.54 (m, 6H).
13C-NMR (100 MHz, DMSO-d6):
165.7, 142.2, 137.3, 128.2, 126.1,
d
d
d
d
(m, 1H), 6.78 (dd, J ¼ 8.2, 0.7 Hz, 1 H), 6.65e6.60 (m, 1H), 3.71 (s,
124.9, 117.5, 112.4, 56.8, 25.7, 23.8. MS (ESIþ): m/z 266 [M þ 3H],
3H), 3.20e3.15 (m, 4H), 1.83e1.38 (m, 6H). 13C-NMR (100 MHz,
264 [MþH]. Anal. C13H14ClN3O (C, H, N, O).
DMSO-d6):
d 165.9, 155.1, 126.9, 110.40, 56.4, 56.2, 23.9, 23.8. MS
(E,Z)-5-Fluoro-3-(piperidin-1-ylimino)indolin-2-one
(40):
(ESIþ): m/z 260 [M þ 1]. Anal. C14H17N3O2 (C, H, N, O).
Reagents: 5-fluoroisatin (250 mg, 1.5 mmol), piperidin-1-amine
(152.0 mg, 1.5 mmol), MMT-K10 (30 mg) and toluene (5 mL). Re-
action conditions: 30 min at 100 ꢀC. The crude product was purified
by column chromatography (dichloromethane/methanol 150:1) to
afford a yellow solid (311.6 mg, 83%), ratio E/Z: 30:70, mp:
(E,Z)-5-Chloro-3-(morpholinoimino)indolin-2-one (44): Re-
agents: 5-chloroisatin (250 mg, 1.4 mmol), morpholin-4-amine
(141 mg, 1.4 mmol), MMT-K10 (27 mg) and toluene (5 mL). Reac-
tion conditions: 1 h at 100 ꢀC. The crude product was purified by
column chromatography (dichloromethane/methanol 100:1) to
afford a yellow solid (280.8 mg, 77%), ratio E/Z: 26:74, mp:
169e170 ꢀC. Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
d 10.55 (s,
1H), 7.01 (ddd, J ¼ 8.9, 6.7, 2.7 Hz, 1.5H), 6.87 (m, 1.5H), 6.73 (dd,
192e193 ꢀC. Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
d 10.79 (s,
J ¼ 8.4, 4.4 Hz, 1H), 4.04 (m, 4H), 1.77e1.48 (m, 9H). 13C-NMR
1H), 7.25 (d, J ¼ 2.1 Hz, 1H), 7.14 (dd, J ¼ 8.2, 2.2 Hz, 1H), 6.79 (d,
(100 MHz, DMSO-d6):
d
159.4, 158.6 (d, J ¼ 234.4 Hz), 135.0 (d,
J ¼ 8.2 Hz, 1H), 4.04 (dd, J ¼ 6.2, 3.6 Hz, 4H), 3.80 (m, 4H). 13C-NMR
J ¼ 1.3 Hz), 127.8 (d, J ¼ 8.8 Hz), 122.4, 112.8 (d, J ¼ 24.0 Hz), 110.3 (d,
(100 MHz, DMSO-d6): d 159.1, 138.1, 127.3, 127.0, 126.0, 124.5, 118.3,
J ¼ 8.2 Hz), 105.0 (d, J ¼ 25.4 Hz), 58.5, 26.6, 23.8. Isomer E: 1H-NMR
111.3, 66.6, 57.7. Isomer E: 1H-NMR (400 MHz, DMSO-d6):
d 10.84 (s,
(400 MHz, DMSO-d6):
d
10.64 (s, 0.5H), 7.15 (ddd, J ¼ 9.4, 8.5, 2.6 Hz,
1H), 7.39 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.29 (d, J ¼ 2.1 Hz, 1H), 6.90 (d,
0.5H), 7.01 (ddd, J ¼ 8.9, 6.7, 2.7 Hz, 1.5H), 6.87 (m, 1.5H), 3.30 (m,
J ¼ 8.3 Hz, 1H), 3.80 (m, 4H), 3.29 (m, 4H). 13C-NMR (100 MHz,
2H), 1.77e1.48 (m, 9H). 13C-NMR (100 MHz, DMSO-d6):
d
166.0,
DMSO-d6): d 165.3, 143.0, 141.1, 131.5, 126.3, 125.8, 117.1, 112.6, 66.1,
158.2 (d, J ¼ 235.8 Hz), 139.9, 138.2, 117.2 (d, J ¼ 23.5 Hz), 116.8 (d,
J ¼ 8.3 Hz), 112.4 (d, J ¼ 26.1 Hz), 111.7, 56.8, 25.7, 23.9. MS (ESIþ):
m/z 248 [MþH]. Anal. C13H14FN3O (C, H, N, O).
56.0. MS (ESIþ): m/z 268 [M þ 3H], 266 [MþH]. Anal. C12H12ClN3O
(C, H, N, O).
(E,Z)-5-Fluoro-3-(morpholinoimino)indolin-2-one (45): Re-
agents: 5-fluoroisatin (250 mg, 1.5 mmol), morpholin-4-amine
(155 mg, 1.5 mmol), MMT-K10 (30 mg) and toluene (5 mL). Reac-
tion conditions: 30 min at 100 ꢀC. The crude product was purified
by column chromatography (dichloromethane/methanol 100:1) to
afford a yellow solid (149.2 mg, 40%), ratio E/Z: 30:70, mp:
(E,Z)-7-Chloro-3-(piperidin-1-ylimino)indolin-2-one
(41):
Reagents: 7-chloroisatin (250 mg, 1.4 mmol), piperidin-1-amine
(137 mg, 1.4 mmol), MMT-K10 (27 mg) and toluene (5 mL). Reac-
tion conditions: 30 min at 100 ꢀC. The crude product was purified
by column chromatography (dichloromethane/methanol 100:1) to
afford a yellow solid (171.6 mg, 47%), ratio E/Z: 25:75, mp:
191e192 ꢀC. Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
d 10.66 (s,
151e152 ꢀC. Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
d
10.93 (s,
1H), 7.01 (dd, J ¼ 8.7, 2.7 Hz, 1H), 6.90 (ddd, J ¼ 9.8, 8.4, 2.7 Hz, 1H),
1H), 7.19 (ddd, J ¼ 7.6, 4.5, 1.0 Hz, 1H), 7.09 (dd, J ¼ 8.1, 1.0 Hz, 1H),
6.76e6.70 (m, 1H), 4.03e3.96 (m, 4H), 3.77e3.71 (m, 4H). 13C-NMR
6.88 (ddd, J ¼ 8.1, 7.5, 0.5 Hz, 1H), 4.82e3.77 (m, 4H), 1.75e1.53 (m,
(100 MHz, DMSO-d6):
d
159.4, 158.7 (d, J ¼ 235.1 Hz), 135.8 (d,
6H). 13C-NMR (100 MHz, DMSO-d6):
d
159.0, 135.9, 130.5, 128.1,
J ¼ 1.1 Hz), 126.9 (d, J ¼ 9.0 Hz), 125.7 (d, J ¼ 3.3 Hz), 113.9 (d,
J ¼ 24.0 Hz), 110.7 (d, J ¼ 8.4 Hz), 105.7 (d, J ¼ 25.2 Hz), 66.6, 57.6.
126.2, 122.6, 116.7, 114.0, 58.6, 26.7, 23.7. Isomer E: 1H-NMR
(400 MHz, DMSO-d6):
11.02 (s, 1H), 7.33 (dd, J ¼ 8.2, 0.9 Hz, 1H),
7.19 (ddd, J ¼ 7.6, 4.5, 1.0 Hz, 1H), 7.09e7.00 (m, 1H), 3.31e3.25 (m,
1H), 1.75e1.53 (m, 9H). 13C-NMR (100 MHz, DMSO-d6):
165.9,
d
Isomer E: 1H-NMR (400 MHz, DMSO-d6):
d 10.70 (s, 1H), 7.17 (ddd,
J ¼ 9.5, 8.5, 2.6 Hz, 1H), 7.10 (dd, J ¼ 8.8, 2.6 Hz, 1H), 6.85 (dd, J ¼ 8.6,
d
4.5 Hz, 1H), 3.82e3.77 (m, 4H), 3.27e3.21 (m, 4H). 13C-NMR
140.8, 137.3, 124.1, 123.5, 122.1, 118.1, 115.2, 56.8, 25.7, 23.9. MS
(100 MHz, DMSO-d6):
d
165.6, 158.2 (d, J ¼ 236.8 Hz), 141.9 (d,
(ESIþ): m/z 266 [M þ 3H], 264 [MþH]. Anal C13H14ClN3O (C, H, N,
J ¼ 2.5 Hz), 140.6 (d, J ¼ 1.6 Hz), 118.4 (d, J ¼ 23.6 Hz), 116.3 (d,
J ¼ 8.6 Hz), 113.5 (d, J ¼ 25.8 Hz), 112.0 (d, J ¼ 8.1 Hz), 66.1, 56.0. MS
(ESIþ): m/z 250 [MþH]. Anal. C12H12FN3O2 (C, H, N, O).
O).
(E,Z)-5-Bromo-3-(piperidin-1-yimino)indolin-2-one
(42):
Reagents: 5-Bromoisatin (500 mg, 2.2 mmol), piperidin-1-amine
(220.4 mg, 2.2 mmol), MMT-K10 (44 mg), triethylamine
(222.6 mg, 2.2 mmol) and toluene (3 mL). Reaction conditions:
40 min at 110 ꢀC. The crude product was purified by column
chromatography (dichloromethane/methanol 30:1) to afford a
yellow solid (42.2 mg, 6%), ratio E/Z: 23:77, mp: 168e170 ꢀC. Isomer
(E,Z)-7-Chloro-3-(morpholinoimino)indolin-2-one (46): Re-
agents: 7-chloroisatin (250 mg, 1.4 mmol), morpholin-4-amine
(141 mg, 1.4 mmol), MMT-K10 (27 mg) and toluene (5 mL). Reac-
tion conditions: 1 h at 100 ꢀC. The crude product was purified by
column chromatography (dichloromethane/methanol 100:1) to
afford a yellow solid (204.6 mg, 56%), ratio E/Z: 26:74, mp:
178e179 ꢀC (lit [40] 180e181 ꢀC).
Z: 1H-NMR (400 MHz, DMSO-d6):
d
10.63 (s, 1H), 7.30 (d, J ¼ 2.1 Hz,
1H), 7.16 (dd, J ¼ 8.2, 2.0 Hz, 1H), 6.68 (d, J ¼ 8.2, 0.5 Hz, 1 H), 4.08 (t,
(E,Z)-5-Bromo-3-(morpholinoimino)indolin-2-one (47): Re-
agents: 5-bromoisatin (500 mg, 2.2 mmol), morpholin-4-amine
(224.7 mg, 2.2 mmol), MMT-K10 (44 mg) and toluene (3 mL). Re-
action conditions: 40 min at 110 ꢀC. The crude product was purified
by column chromatography (dichloromethane/methanol 30:1) to
afford a yellow solid (28 mg, 10%), ratio E/Z: 25:75, mp: 191e193 ꢀC.
J ¼ 5.6 Hz, 4H), 1.72e1.55 (m, 6H). 13C-NMR (100 MHz, DMSO-d6):
d
158.9,142.6,137.6,128,8,120.4,113.5,111.5, 58.6, 26.7, 23.8. Isomer
E: 1H-NMR (400 MHz, DMSO-d6):
d
10.73 (s, 1H), 7.45 (dd, J ¼ 8.3,
2.1 Hz, 1H), 7.30 (d, J ¼ 2.1 Hz, 1H), 6.82 (d, J ¼ 8.2 Hz, 1H), 3.29 (t,
J ¼ 5.7 Hz, 1H), 1.72e1.55 (m, 9H).13C-NMR (100 MHz, DMSO-d6):
d
165.5, 121.2, 56.8, 25.7. MS (ESIþ): m/z 310 [M þ 3H], 308 [MþH].
Isomer Z: 1H-NMR (400 MHz, DMSO-d6):
d 10.78 (s, 1H), 7.35 (d,
Anal. C13H14BrN3O (C, H, N, O).
J ¼ 2.0 Hz, 1H), 7.24 (dd, J ¼ 8.2, 2.0 Hz, 1H), 6.73 (d, J ¼ 8.2 Hz, 1H),
(E,Z)-5-Methoxy-3-(piperidin-1-ylimino)indolin-2-one (43):
Reagents: 5-Methoxyisatin (350.0 mg, 2.0 mmol), piperidin-1-
amine (198.3, 2.0 mmol) y MMT-K10 (39.6 mg) and toluene
(3 mL). Reaction conditions: 40 min at 110 ꢀC. The final product was
4.02 (t, J ¼ 4.9 Hz, 4H), 3.85e3.71 (m, 4H). 13C-NMR (100 MHz,
DMSO-d6):
d 158.9, 141.1, 138.4, 129.8, 124.3, 121.0, 113.7, 111.9, 66.7,
57.7. Isomer E: 1H-NMR (400 MHz, DMSO-d6):
(dd, J ¼ 8.3, 1.9 Hz, 1H), 7.39 (d, J ¼ 2.0 Hz, 1H), 6.84 (d, J ¼ 8.2 Hz,
d 10.82 (s, 1H), 7.49