€
T. Rimpilainen, A. Nunes, R. Calado et al.
European Journal of Medicinal Chemistry 220 (2021) 113459
134.72, 134.56, 130.20, 129.88, 128.58, 128.00, 126.44, 125.19,
124.73, 117.62, 114.62, 113.49, 69.88, 53.47, 28.18, 21.12. HRMS (ESI/
TOF): m/z calcd for C22H19BrN2Oþ3 [M]þ, 438.0574; found 438.0571.
132.23, 131.27, 129.07, 127.63, 126.29, 126.24, 126.20, 126.14, 125.94,
125.49, 125.11, 124.55, 122.70, 117.91, 112.24, 70.07, 53.79, 28.47.
HRMS (ESI/TOF): m/z calcd for C22H18F3N2Oþ3 [MþH]þ, 415.1264;
found 415.1286.
4.1.3.4. 4-Nitro-2-((5-nitroindolin-1-yl) (p-tolyl)methyl)phenol (1d).
Obtained in 85% yield as an orange red solid, after purification by
flash chromatography using CH2Cl2/EtOAc (97:3) as eluent (Rf ¼ 0.3,
4.1.3.9. 4-Nitro-2-((5-nitroindolin-1-yl) (4-(trifluoromethyl)phenyl)
methyl)phenol (5d). Obtained in 77% yield as an orange red solid,
after purification by flash chromatography using CH2Cl2/EtOAc
(97:3) as eluent (Rf ¼ 0.1, CH2Cl2). m. p. 164e167 ꢀC. 1H NMR
Hex/EtOAc (2:8)). m. p.141e144 ꢀC. 1H NMR (500 MHz, CDCl3)
d 8.17
(s, 1H), 8.13 (dd, J ¼ 8.9, 2.6 Hz, 1H), 7.98 (d, J ¼ 2.9 Hz, 1H),
7.91e7.94 (m, 2H), 7.18 (q, J ¼ 8.6 Hz, 4H), 7.03 (d, J ¼ 9.2 Hz, 1H),
6.25 (d, J ¼ 8.6 Hz, 1H), 6.02 (s, 1H), 3.44e3.54 (m, 2H), 3.10 (t,
(300 MHz, CDCl3)
d
8.11 (dd, J ¼ 2.6, 9.1 Hz, 1H), 7.89e7.91 (m, 3H),
7.60 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 6.94 (d, J ¼ 8.8 Hz,
1H), 6.21 (d, J ¼ 9.4 Hz, 1H), 6.01 (s, 1H), 3.36e3.43 (m, 2H), 3.07 (t,
J ¼ 8.6 Hz, 2H), 2.36 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 160.38,
156.40, 141.22, 138.88, 138.53, 133.55, 130.90, 129.84, 128.07, 126.58,
126.42, 125.51, 125.15, 120.80, 116.65, 106.05, 60.25, 51.24, 26.96,
21.11. HRMS (ESI/TOF): m/z calcd for C22H19N3Oþ5 [M]þ, 405.1319;
found 405.1302.
J ¼ 8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 159.96, 156.12, 141.45,
141.13, 139.18, 130.61, 128.46, 126.40, 126.15, 125.89, 125.77, 125.17,
120.93, 116.65, 105.75, 59.44, 51.12, 27.04. HRMS (ESI/TOF): m/z
calcd for C22H15F3N3Oꢂ5 [M ꢂ H]-, 458.0969; found 458.0962.
4.1.3.5. 1-((2-Hydroxy-5-nitrophenyl) (p-tolyl)methyl)indoline-4-
carbonitrile (1e). Obtained in 39% yield as a pale yellow solid, af-
ter purification by flash chromatography using CH2Cl2 as eluent
(Rf ¼ 0.3, CH2Cl2). m. p. 182e183 ꢀC. 1H NMR (300 MHz, CDCl3)
4.1.3.10. 2-((5-Chloroindolin-1-yl) (o-tolyl)methyl)-4-nitrophenol
(6b). Obtained in 62% yield as a pale yellow solid, after purifica-
tion by flash chromatography using Hex/CH2Cl2 (8:2) as eluent
(Rf ¼ 0.5, CH2Cl2). m. p. 134e136 ꢀC. 1H NMR (300 MHz, CDCl3)
d
10.37 (br. s, 1H), 8.12 (dd, J ¼ 2.9, 8.8 Hz, 1H), 7.98 (d, J ¼ 2.9 Hz,
d
8.11 (dd, J ¼ 2.6, 9.1 Hz, 1H), 7.87 (d, J ¼ 2.9 Hz, 1H), 7.35 (d,
1H), 7.27 (d, J ¼ 7.6 Hz, 2H), 7.19 (d, J ¼ 8.2 Hz, 2H), 7.05e7.14 (m,
2H), 6.98 (d, J ¼ 8.8 Hz, 1H), 6.62 (dd, J ¼ 1.8, 7.0 Hz, 1H), 5.41 (s, 1H),
3.31e3.39 (m, 1H), 3.09e3.27 (m, 3H), 2.35 (s, 3H). 13C NMR
J ¼ 7.0 Hz, 1H), 7.13e7.23 (m, 4H), 6.93e6.98 (m, 2H), 6.27 (d,
J ¼ 8.2 Hz, 1H), 5.69 (s, 1H), 3.23e3.28 (m, 1H), 2.92e3.10 (m, 3H),
2.38 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 162.34, 149.10, 141.08,
(75 MHz, CDCl3)
d
161.73, 151.07, 141.10, 139.11, 136.66, 134.11,
136.21, 136.00, 133.68, 131.25, 128.65, 128.29, 127.42, 127.17, 126.84,
126.61, 125.20, 124.49, 117.60, 112.06, 110.00, 64.22, 53.19, 28.26,
20.46. HRMS (ESI/TOF): m/z calcd for C22H19ClN2Oþ3 [M]þ, 394.1079;
found 394.1096.
130.01, 128.58, 128.52, 126.29, 125.33, 124.81, 124.32, 117.60, 117.13,
115.42, 109.14, 68.59, 52.81, 27.93, 21.13. HRMS (ESI/TOF): m/z calcd
for C23H19N3Oþ3 [M]þ, 385.1421; found 385.1425.
4.1.3.6. 1-((2-Hydroxy-5-nitrophenyl) (p-tolyl)methyl)indolin-5-ol
(1f). Obtained in 20% yield as an orange solid, after purification
by flash chromatography using Hex/EtOAc (6:4) as eluent (Rf ¼ 0.7,
4.1.3.11. 2-((5-Bromoindolin-1-yl) (o-tolyl)methyl)-4-nitrophenol
(6c). Obtained in 91% yield as an orange red solid, after purifica-
tion by flash chromatography using Hex/EtOAc (8:2) as eluent
(Rf ¼ 0.6, Hex/EtOAc (1:1)). m. p. 158e160 ꢀC$1H NMR (300 MHz,
EtOAc). m. p. 100e105 ꢀC. 1H NMR (300 MHz, CDCl3)
d 8.09 (dd,
J ¼ 2.9, 9.4 Hz, 1H), 7.93 (d, J ¼ 2.9 Hz, 1H), 7.29 (d, J ¼ 8.2 Hz, 2H),
7.15 (d, J ¼ 8.2 Hz, 2H), 6.94 (d, J ¼ 9.4 Hz, 1H), 6.69 (d, J ¼ 2.3 Hz,
1H), 6.45 (dd, J ¼ 2.9, 8.8 Hz, 1H), 6.29e6.36 (m, 1H), 5.17 (s, 1H),
3.16e3.23 (m, 1H), 2.96e3.05 (m, 1H), 2.79e2.94 (m, 2H), 2.33 (s,
CDCl3)
d
10.65 (br. s, 1H), 8.12 (dd, J ¼ 2.9, 8.8 Hz, 1H), 7.88 (d,
J ¼ 2.9 Hz, 1H), 7.35 (d, J ¼ 7.6 Hz, 1H), 7.15e7.28 (m, 4H), 7.09 (dd,
J ¼ 2.1, 8.5 Hz, 1H), 6.97 (d, J ¼ 8.8 Hz, 1H), 6.23 (d, J ¼ 8.8 Hz, 1H),
5.70 (s, 1H), 3.23e3.31 (m, 1H), 2.93e3.11 (m, 3H), 2.38 (s, 3H). 13
C
3H). 13C NMR (75 MHz, CDCl3)
d
163.04, 151.63, 143.67, 140.57,
NMR (75 MHz, CDCl3) d 162.22, 149.60,141.11, 136.15, 136.03, 134.01,
138.73, 135.29, 134.48, 129.78, 128.53, 126.91, 125.06, 124.66, 117.59,
113.58, 113.35, 112.60, 71.63, 53.95, 28.64, 21.12. HRMS (ESI/TOF):
m/z calcd for C22H19N2Oꢂ4 [M ꢂ H]-, 375.1350; found 375.1343.
131.25, 130.32, 128.66, 128.26, 128.01, 127.16, 125.20, 124.50, 117.54,
112.41, 63.82, 53.04, 28.20, 20.43. HRMS (ESI/TOF): m/z calcd for
C
22H20BrN2Oþ3 [MþH]þ, 439.0652; found 439.0645.
4.1.3.7. 2-((5-Methoxyindolin-1-yl) (p-tolyl)methyl)-4-nitrophenol
(1g). Obtained in 68% yield as a pale yellow solid, after purifica-
tion by flash chromatography using Hex/EtOAc (8:2) as eluent
(Rf ¼ 0.7, Hex/EtOAc (1:1)). m. p. 157e158 ꢀC. 1H NMR (300 MHz,
4.1.3.12. 4-Nitro-2-((5-nitroindolin-1-yl)
(o-tolyl)methyl)phenol
(6d). Obtained in 85% yield as a dark red solid, after purification by
flash chromatography using Hex/EtOAc (6:4) as eluent (Rf ¼ 0.2,
Hex/EtOAc (7:3)). m. p. 197e198 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
CDCl3)
d
8.01 (dd, J ¼ 2.3, 8.8 Hz, 1H), 7.87 (d, J ¼ 2.9 Hz, 1H), 7.22 (d,
d
11.58 (s, 1H), 8.15 (dd, J ¼ 8.9, 2.6 Hz, 1H), 7.91 (dd, J ¼ 8.6, 2.3 Hz,
J ¼ 8.2 Hz, 2H), 7.08 (d, J ¼ 7.6 Hz, 2H), 6.87 (d, J ¼ 8.8 Hz, 1H), 6.69
(d, J ¼ 2.3 Hz, 1H), 6.46 (dd, J ¼ 2.9, 8.8 Hz, 1H), 6.32 (d, J ¼ 8.8 Hz,
1H), 5.12 (s, 1H), 3.65 (s, 3H), 3.10e3.16 (m, 1H), 2.84e2.96 (m, 1H),
1H), 7.87 (d, J ¼ 1.1 Hz,1H), 7.71 (d, J ¼ 2.9 Hz,1H), 7.27 (d, J ¼ 4.0 Hz,
2H), 7.21e7.24 (m, 1H), 7.15 (d, J ¼ 7.4 Hz, 1H), 7.08 (d, J ¼ 8.6 Hz,
1H), 6.19 (s, 1H), 6.17 (d, J ¼ 9.2 Hz, 1H), 3.37e3.48 (m, 3H),
3.06e3.16 (m, 2H), 2.15 (s, 3H). 13C NMR (126 MHz, DMSO‑d6)
2.75e2.81 (m, 2H), 2.26 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 163.03,
155.85, 143.71, 140.61, 138.70, 135.34, 134.26, 129.79, 128.53, 126.93,
125.04, 124.65, 117.59, 113.19, 111.86, 111.68, 71.61, 55.65, 53.99,
28.73, 21.12. HRMS (ESI/TOF): m/z calcd for C23H22N2Oþ4 [M]þ,
390.1574; found 390.1574.
d 161.92,156.10, 139.67, 137.09,136.27, 136.12,130.93, 130.47,128.02,
126.74, 126.50, 126.37, 125.86, 125.81, 124.35, 120.28, 115.85, 103.80,
54.66, 50.67, 26.25, 18.81. HRMS (ESI/TOF): m/z calcd for
C
22H18N3Oꢂ5 [M ꢂ H]-, 404.1252; found 404.1221.
4.1.3.8. 2-(Indolin-1-yl(4-(trifluoromethyl)phenyl)methyl)-4-
nitrophenol (5a). Obtained in 80% yield as a pale yellow solid, after
purification by flash chromatography using Hex/EtOAc (7:3) as
eluent (Rf ¼ 0.3, Hex/EtOAc (7:3)). m. p. 115e118 ꢀC. 1H NMR
4.1.3.13. 1-((2-Hydroxy-5-nitrophenyl) (o-tolyl)methyl)indoline-4-
carbonitrile (6e). Obtained with 98% yield as a pale yellow solid,
after purification by flash chromatography using Hex/EtOAc (7:3) as
eluent (Rf ¼ 0.5, Hex/EtOAc (1:1)). m. p. 177e179 ꢀC. 1H NMR
(300 MHz, CDCl3)
d
8.13 (dd, J ¼ 2.6, 9.1 Hz, 1H), 7.95 (d, J ¼ 2.9 Hz,
(300 MHz, Methanol-d4)
d
8.10 (dd, J ¼ 2.6, 9.1 Hz, 1H), 7.96 (d,
1H), 7.56e7.66 (m, 4H), 7.20 (d, J ¼ 7.0 Hz, 1H), 6.92e7.05 (m, 3H),
6.49 (d, J ¼ 7.6 Hz, 1H), 5.42 (s, 1H), 3.19e3.26 (m, 1H), 2.93e3.08
J ¼ 2.3 Hz, 1H), 7.14e7.22 (m, 4H), 6.95e7.01 (m, 2H), 6.79 (d,
J ¼ 7.6 Hz, 1H), 6.22 (d, J ¼ 8.2 Hz, 1H), 6.06 (s, 1H), 3.40 (q,
J ¼ 8.8 Hz, 1H), 3.25e3.33 (m, 1H), 3.12e3.18 (m, 2H), 2.23 (s, 3H).
(m, 3H). 13C NMR (75 MHz, CDCl3)
d 162.46, 149.89, 141.95, 140.95,
8