The Journal of Organic Chemistry
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cartridge) using CHCl3 and aqueous ammonia in MeOH (1:15) as an
eluent. The MeOH gradient linearly changed from 0 to 15% during
20 min. Yield: 1.35 g (81%) of a yellow solid; mp 249−251 °C; H
123.2 (Cquart), 122.7 (CH), 120.6 (CH), 119.3 (CH), 109.6 (CH),
97.0 (Cquart), 63.1 (CH2), 54.4 (CH2), 25.9 (CH2), 24.3 (CH2); anal.
calcd for C27H26ClN3O: C, 73.04; H, 5.90; N, 9.46.; Cl, 7.98. Found:
C, 73.04; H, 5.96; N, 9.13; Cl, 8.07. HRMS: calcd for C27H27ClN3O
[M + H]+ 444.1837, found 444.1846.
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NMR (500 MHz, DMSO-d6) δ 12.23 (brs, 1H), 11.00 (brs, 1H),
7.54−7.65 (m, 3H), 7.47−7.53 (m, 2H), 7.42 (d, J 1.4 Hz, 1H), 7.19
(dd, J 8.2 and 1.5 Hz, 1H), 7.13 (AA′XX′, J 8.2 Hz, 2H), 6.89
(AA′XX′, J 8.1 Hz, 2H), 5.82 (d, J 8.2 Hz, 1H), 3.77 (s, 3H), 3.05 (s,
3H), 2.69 (brs, 2H), 2.20−2.40 (brs, 8H), 2.13 (s, 3H) is in
accordance with ref 7d; 13C{1H} NMR APT (125 MHz, DMSO-d6) δ
170.3 (Cquart), 168.6 (Cquart), 166.5 (Cquart), 158.5 (Cquart), 140.3
(Cquart), 137.2 (Cquart), 136.4 (Cquart), 132.1 (Cquart), 130.6 (CH),
129.6 (CH), 129.1 (Cquart), 128.6 (CH), 127.8 (CH), 124.2 (Cquart),
124.0 (CH), 121.6 (CH), 117.4 (CH), 109.6 (CH), 97.7 (Cquart),
59.2 (CH2), 54.6 (CH2), 52.3 (CH2), 51.9 (CH3), 45.7 (CH3), 36.8
(CH3); HRMS: calcd for C31H34N5O4 ([M + H]+) 540.2611; found:
540.2614.
4.3.4. (Z)-5-Nitro-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-
amino]methylidene}-1,3-dihydro-2H-indolin-2-one (2d). Starting
from 0.28 mg of 3d, 0.35 g (76%) of pure 2d was obtained as a
yellow solid with mp 243−245 °C. 1H-NMR (500 MHz, DMSO-d6) δ
12.00 (brs, 1H), 11.43 (brs, 1H), 7.85 (dd, J 8.6 and 2.3 Hz, 1H),
7.61−7.67 (m, 1H), 7.58 (t, J 7.5 Hz, 2H), 7.49 (d, J 7.2 Hz, 2H),
7.07 (AA′XX′, J 8.4 Hz, 2H), 7.01 (d, J 8.6 Hz, 1H), 6.84 (AA′XX′, J
8.4 Hz, 2H), 6.57 (d, J 2.3 Hz, 1H), 3.27 (s, 2H), 2.20 (s, 4H), 1.38−
1.48 (m, 4H), 1.33 (m, 2H); 13C{1H} NMR APT (125 MHz, DMSO-
d6) δ 170.6 (Cquart), 158.9 (Cquart), 141.8 (Cquart), 141.1 (Cquart), 136.6
(Cquart), 135.9 (Cquart), 132.0 (Cquart), 130.7 (CH), 129.8 (CH), 129.4
(CH), 128.5, 124.8 (Cquart), 123.3 (CH), 120.0 (CH), 113.0 (CH),
109.0 (CH), 96.2 (Cquart), 62.1 (CH2), 53.9 (CH2), 25.6 (CH2), 24.1
(CH2); anal. Calcd for C27H26N4O3: C, 71.35; H, 5.77; N, 12.33.
Found: C, 71.19; H, 5.85; N, 11.94. HRMS: calcd for C27H27N4O3
[M + H]+ 455.2078, found 455.2087.
4.3. General Procedure for the Synthesis of 2a−d. The
corresponding 3-bromo oxindole 3a-d (1.1 mmol) was dissolved in a
minimum volume of DMF (0.5−2 mL) and a solution of 4b·HCl (1
mmol, 0.35 g) in DMF (2 mL) was added in one portion. The
reaction mixture was stirred for 12 h at r.t. and then DMF was
evaporated under vacuum. The solid residue was dissolved in CHCl3
and n-heptane (10 + 15 mL) and the resulting solution was
evaporated again. The crude product was purified by preparative flash
chromatography (silica gel, eluent: A: EtOAc, B: EtOAc/hexane/
THF 90:7:3; gradient 0−60% of component B during 20 min).
Analytically pure samples for elemental analysis were obtained by
recrystallization from ACN/CHCl3.
4.3.5. (Z)-5-Amino-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-
amino]methylidene}-1,3-dihydro-2H-indolin-2-one (2e). In a 250
mL autoclave, compound 2d (1.19 mmol, 0.54 g) was dissolved in
MeOH/DCM (2:1, 30 mL) and freshly prepared.31 Raney nickel (0.6
g in 1 mL of MeOH) was added under an inert atmosphere. The
autoclave was pressurized (4 atm) with hydrogen and the reaction
mixture was stirred vigorously for 4 h. Then, the catalyst was removed
(filtration through plug of cellite) and washed with MeOH (10 mL).
The combined filtrates were evaporated with a silica gel (5 g) and
subjected to flash chromatography (silica gel cartridge 12 g; eluents A:
EtOAc, B: EtOAc/MeOH/NH4OH (aq) 90:7:3, gradient 0−70% of
component B during 20 min) to yield 0.44 g (87%) of a yellow solid
4.3.1. (Z)-3-{Phenyl[(4-(piperidin-1-ylmethyl)phenyl)amino]-
methylidene}-1,3-dihydro-2H-indolin-2-one (2a). Starting from
0.23 g of 3a, 0.40 g (97%) of pure 2a was obtained as a yellow
solid with mp 244−247 °C. 1H NMR (500 MHz, CDCl3) δ 11.95 (s,
1H); 8.75 (s, 1H, NH); 7.46−7.56 (m, 3H); 7.43 (m, 2H); 7.05 (d, J
8.2 Hz, 2H); 6.96 (t, J 7.5 Hz, 1H); 6.92 (d, J 7.6 Hz, 1H); 6.71 (d, J
8.2 Hz, 2H; 6.64 (t, J 7.5 Hz, 1H); 5.97 (d, J 7,8 Hz, 1H); 3.34 (s,
2H); 2.30 (s, 4H); 1.53 (m, 4H); 1.40 (m, 2H). 13C{1H} NMR APT
(125 MHz, CDCl3) δ 170.8 (Cquart), 157.1 (Cquart), 137.5 (Cquart),
135.6 (Cquart), 134.6 (Cquart), 133.1 (Cquart), 129.9 (CH), 129.6 (CH),
129.3 (CH), 128.7 (CH), 124.6 (Cquart), 123.4 (CH), 122.5 (CH),
120.6 (CH), 118.8 (CH), 109.2 (CH), 97.7 (Cquart), 63.11 (CH2),
54.4 (CH2), 25.9 (CH2), 24.3 (CH2). HRMS: calcd for C27H28N3O
([M + H]+) 410.2232; found 410,2235. Anal. Calcd for C27H27N3O:
C, 79.19; H, 6.65; N, 10.26. Found: C, 79.09; H, 6.67; N, 10.14.
4.3.2. Methyl (Z)-2-oxo-3-{phenyl[(4-(piperidin-1-ylmethyl)-
phenyl)amino]methylidene}indoline-6-carboxylate (2b). Starting
from 0.30 g of 3b, 0.37 g (80%) of pure 2b was obtained as a
1
with mp 226−228 °C (dec.). H NMR (400 MHz, DMSO-d6) δ
12.09 (brs, 1H), 10.27 (brs, 1H), 7.50−7.60 (m, 3H), 7.40−7.45 (m,
2H), 7.00 (AA′XX′, J 8.2 Hz, 2H), 6.65 (AA′XX′, J 8.2 Hz, 2H), 6.53
(d, J 8.1 Hz, 1H), 6.21 (dd, J 8.1 and 1.0 Hz, 1H), 5.23 (s, 1H), 4.11
(brs, 2H), 3.25 (s, 2H), 2.21 (m, 4H), 1.39−1.48 (m, 4H), 1.28−1.39
(m, 2H) is in accordance with ref 6b; 13C{1H} NMR (100 MHz,
DMSO-d6) δ 170.3, 155.4, 142.0, 137.8, 134.2, 132.8, 130.0, 129.4,
129.2, 128.6, 128.2, 124.6, 122.0, 110.7, 109.4, 105.6, 98.6, 62.1, 53.9,
25.6, 24.1; anal. calcd for C27H28N4O·1/4H2O: C, 75.58; H, 6.70; N,
13.06. Found: C, 75.73; H, 6.68; N, 13.03. HRMS: calcd for
C27H29N4O ([M + H]+) 425.2336, found 425.2334.
4.3.6. (Z)-N-{2-oxo-3-[phenyl((4-(piperidin-1-ylmethyl)phenyl)-
amino]methylene}indolin-5-yl)ethanesulfonamide (2f, Hespera-
din). Compound 2e·1/4H2O (0.93 mmol, 400 mg) was dissolved
in dry pyridine/DCM (18/10 mL) and cooled to 0 °C under an argon
atmosphere. A solution of ethanesulfonyl chloride (2.16 mmol, 205
μL) in DCM (4 mL) was added dropwise under stirring and then the
reaction mixture was further stirred at room temperature for 45 min.
Excess ethanesulfonyl chloride was quenched with EtOH (20 mL);
the solution was evaporated with a silica gel (5 g) and subjected to
preparative flash chromatography (silica gel cartridge 24 g; eluent A:
DCM, B: MeOH/NH3 (aq) 95:5; 5 min 100% A and then 15 min
linear gradient to 80% of component B). The residue obtained after
evaporation was suspended in boiling CHCl3 (100 mL) and MeOH
(ca 1.5 mL) was added dropwise until complete dissolution. Cooling
to 25 °C under stirring (1 h) gave a solid product, which was filtered
off and washed with cold DCM (2 mL). Yield: 0.4 g (83%) of a
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yellow solid with mp 239−242 °C. H-NMR (500 MHz, CDCl3) δ
12.14 (brs, 1H), 8.37 (brs, 1H), 7.58 (s, 1H), 7.46−7.57 (m, 3H),
7.39−7.44 (m, 2H), 7.37 (d, J 8.3 Hz, 1H), 7.07 (AA′XX′, J 8.2 Hz,
2H), 6.74 (AA′XX′, J 8.2 Hz, 2H), 5.95 (d, J 8.2 Hz, 1H), 3.85 (s,
3H), 3.34 (s, 2H), 2.29 (m, 4H), 1.54 (m, 4H), 1.40 (m, 2H);
13C{1H} NMR APT (125 MHz, CDCl3) δ 170.6 (Cquart), 167.4
(Cquart), 159.2 (Cquart), 136.8 (Cquart), 135.5 (Cquart), 134.8 (Cquart),
132.5 (Cquart), 130.3 (CH), 129.6 (CH), 129.5 (Cquart), 129.4 (CH),
128.5 (CH), 124.5 (Cquart), 123.0 (CH), 122.7 (CH), 117.9 (CH),
110.0 (CH), 97.2 (Cquart), 63.1 (CH2), 54.4 (CH2), 51.9 (CH3), 25.9
(CH2), 24.3 (CH2); anal. calcd for C29H29N3O3: C, 74.50; H, 6.25;
N, 8.99. Found: C, 74.37; H, 6.25; N, 8.88. HRMS: calcd for
C29H30N3O3 [M + H]+ 468.2282, found 468.2289.
4.3.3. (Z)-6-Chloro-3-{phenyl[(4-(piperidin-1-ylmethyl)phenyl)-
amino]methylidene}-1,3-dihydro-2H-indolin-2-one (2c). Starting
from 0.27 g of 3c, 0.41 g (93%) of pure 2c was obtained as a yellow
1
yellow solid with mp 237−238.5 °C (ref 10 gives 235 °C). H-NMR
(400 MHz, DMSO-d6) δ 12.11 (brs, 1H), 10.78 (brs, 1H), 10.66 (brs,
1H), 9.10 (s, 1H), 7.51−7.64 (m, 3H), 7.43−7.51 (m, 2H), 7.37
(AA′XX′, J 8.0 Hz, 2H), 6.70−6.82 (m, 4H), 5.87 (s, 1H), 4.07 (s,
2H), 3.15 and 2.60 - 2.90 (2×m, 4H), 2.72 (q, 2H), 1.67−1.83 (m,
4H), 1.63 and 1.30 (2×m, 1H), 1.08 (t, J 7.4 Hz, 3H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 170.4, 155.9, 139.8, 134.3, 132.2, 130.5,
130.4, 129.7, 128.4, 125.2 (brs), 124.4, 122.0, 121.8, 119.6, 113.8,
109.5, 98.7, 58.2, 51.4, 44.4, 22.2, 21.5, 8.1; anal. calcd for
C29H32N4O3S: C, 67.42; H, 6.24; N, 10.84; S, 6.21. Found: C,
1
solid with mp 224−226 °C. H-NMR (500 MHz, CDCl3) δ 11.89
(brs, 1H), 9.49 (brs, 1H), 7.45−7.57 (m, 3H), 7.36−7.43 (m, 2H),
7.06 (AA′XX′, J 8.2 Hz, 2H), 6.93 (s, 1H), 6.72 (AA′XX′, J 8.2 Hz,
2H), 6.60 (d, J 8.3 Hz, 1H); 5.83 (d, J 8.4 Hz, 1H); 3.34 (s, 2H); 2.30
(s, 4H), 1.50−1.60 (m, 4H), 1.40 (m, 2H) is in accordance with ref 8;
13C{1H} NMR APT (125 MHz, CDCl3) δ 171.0 (Cquart), 157.5
(Cquart), 137.2 (Cquart), 136.5 (Cquart), 134.9 (Cquart), 132.8 (Cquart),
130.1 (CH), 129.6 (CH), 129.3 (CH), 128.7 (Cquart), 128.6 (CH),
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J. Org. Chem. 2021, 86, 10621−10629