Journal of Medicinal Chemistry
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a yellow film. H NMR (400 MHz, CDCl3): δ ppm 8.90 (1 H, br s),
7.80−7.84 (1 H, m), 7.74 (1 H, ddd, J = 8.4, 6.8, 1.5 Hz), 7.64−7.69 (2 H,
m), 7.48−7.59 (4 H, m), 7.11 (1 H, d, J = 8.3 Hz), 6.27 (1 H, dd, J = 8.3, 2.2
Hz), 5.58 (1 H, d, J = 2.2 Hz), 4.01 (1 H, d, J = 9.8 Hz), 3.83−3.97 (3 H, m),
3.56−3.63 (4 H, m), 3.48 (2 H, tt, J = 12.0, 2.1 Hz), 2.82−2.91 (4 H, m),
2.22 (3 H, s), 1.93−2.05 (2 H, m), 1.82−1.88 (1 H, m), 1.65−1.73 (1 H, m).
HRMS (ESI): m/z 492.2644 [M + H]+ (C32H33N3O2 requires 492.2652).
6-Bromo-1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-
1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran], 25d. 25d was pre-
pared according to general coupling procedure C using 6-bromo-
2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran], 10 (98 mg, 367 μmol),
and 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline, 23d (100 mg,
367 μmol). After purification, 6-bromo-1-(7-fluoro-3-methyl-2-(2-pyr-
idinyl)-4-quinolinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran],
8.66−8.81 (1 H, m), 8.00 (1 H, dt, J = 7.8, 2.0 Hz), 7.89 (1 H, dd, J = 9.4,
5.9 Hz), 7.81 (1 H, dd, J = 10.0, 2.5 Hz), 7.48 (1 H, dd, J = 7.8, 4.7 Hz),
7.23−7.30 (1 H, m), 7.09 (1 H, d, J = 8.2 Hz), 6.34 (1 H, dd, J = 8.2,
2.3 Hz), 5.61 (1 H, d, J = 2.3 Hz), 3.68−3.81 (6 H, m), 2.90−3.02 (4 H, m),
2.30 (3 H, s), 1.52 (3 H, s), 1.47 (3 H, s). HRMS (ESI): m/z 469.2398
[M + H]+ (C29H29FN4O requires 469.2405).
6-Bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-
tetrahydrospiro[indoline-3,4′-pyran], 25a. General coupling proce-
dure C using 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran],
10 (0.3 g, 1.12 mmol), and 4,6-dichloro-2,3-dimethylquinoline, 23a
(0.2783 g, 1.23 mmol), gave 6-bromo-1-(6-chloro-2,3-dimethylquino-
lin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran], 25a (0.264 g,
51% yield), as a brown solid. 1H NMR (500 MHz, DMSO-d6): δ ppm
8.03 (1 H, d, J = 9.0 Hz), 7.71 (1 H, dd, J = 8.9, 2.3 Hz), 7.65 (1 H, d,
J = 2.2 Hz), 7.22 (1 H, d, J = 7.8 Hz), 6.83 (1 H, dd, J = 7.8, 1.5 Hz), 5.94
(1 H, d, J = 1.5 Hz), 4.04 (1 H, d, J = 9.8 Hz), 3.80−3.93 (3 H, m), 3.39−
3.54 (2 H, m), 2.68 (3 H, s), 2.22 (3 H, s), 1.94−2.06 (2 H, m), 1.85
(1 H, d, J = 13.4 Hz), 1.73 (1 H, dd, J = 13.4, 1.5 Hz). Mass spectrum
(ESI): m/e = 457.1 [(M + H) (79Br)]+ and 459.1 [(M + H) (81Br)]+.
1-(6-Chloro-2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-
1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran], 26a. A suspension
of 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-
tetrahydrospiro[indoline-3,4′-pyran], 25a (230 mg, 0.50 mmol) and
morpholine (87 μL, 1 mmol) was degassed with argon for 20 min. To
the suspension were added CuI (19 mg, 0.1 mmol), K2CO3 (207 mg,
1.5 mmol), and L-proline (23 mg, 0.2 mmol), and the mixture was stirred
at 120 °C. After 24 h the mixture was cooled to room temperature. To
the mixture was added water (30 mL), and the mixture was extracted
with CH2Cl2 (2 × 40 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
mixture was purified by column chromatography on a silica gel column
using 0% to 100% gradient of ethyl acetate in hexane as eluent to give
1-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-
hexahydrospiro[indole-3,4′-pyran], 26a (0.055 g, 23.4% yield), as a
yellow oil. 1H NMR (500 MHz, DMSO-d6): δ ppm 7.97−8.03 (1 H, m),
7.67 (2 H, dd, J = 4.5, 2.1 Hz), 7.10 (1 H, d, J = 8.1 Hz), 6.26 (1 H, dd, J =
8.1, 1.5 Hz), 5.46 (1 H, d, J = 1.5 Hz), 3.94 (1 H, d, J = 9.5 Hz), 3.82−
3.91 (2 H, m), 3.78 (1 H, d, J = 9.8 Hz), 3.54−3.59 (4 H, m), 3.40−3.52
(2 H, m), 2.80−2.87 (4 H, m), 2.68 (3 H, s), 2.21 (3 H, s), 1.92−2.02
(2 H, m), 1.78 (1 H, d, J = 13.2 Hz), 1.68 (1 H, d, J = 12.5 Hz). Mass
spectrum (ESI): m/e = 464.2 [M + H]+.
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25d (55 mg, 30% yield), was obtained as a yellow film. H NMR
(400 MHz, CDCl3): δ ppm 8.74 (1 H, d, J = 5.1 Hz), 7.89−7.98 (2 H, m),
7.85 (1 H, dd, J = 10.0, 2.5 Hz), 7.75 (1 H, dd, J = 9.2, 6.1 Hz), 7.41 (1 H,
ddd, J = 6.7, 4.5, 2.5 Hz), 7.28−7.33 (1H, m), 7.07 (1 H, d, J = 7.8 Hz), 6.89
(1 H, dd, J = 7.8, 2.0 Hz), 6.11 (1 H, d, J = 2.0 Hz), 3.93−4.10 (4 H, m),
3.45−3.60 (2 H, m), 2.38 (3 H, s), 2.08−2.25 (2 H, m), 1.91 (1 H, dd, J =
13.9, 2.5 Hz), 1.81 (1 H, dd, J = 13.7, 2.3 Hz). Mass spectrum (ESI): m/e
504 [(M + H) (79Br)]+ and 506 [(M + H) (81Br)]+.
1-(7-Fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpho-
linyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran], 26d. A sus-
pension of 6-bromo-1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolin-
yl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran], 25d (100 mg,
0.198 mmol), morpholine (35 μL, 397 μmol) and DMSO (2.5 mL)
was degassed with argon for 15 min in a Schlenk tube. To the mixture
were added copper(I) iodide (8 mg, 40 μmol), L-proline (9 mg, 79 μmol)
and potassium carbonate (82 mg, 595 μmol), and the mixture was heated
at 120 °C overnight. After this time the reaction mixture was cooled to
roomtemperature and diluted withCH2Cl2 (100 mL)and water (40 mL).
The separated organic layer was dried over MgSO4, filtered and evap-
orated in vacuo. Column chromatography (hexane:ethyl acetate, 1:0 to
0:1) gave the desired product as a yellow oil. The product was further
purified by reverse phase HPLC to give 1-(7-fluoro-3-methyl-2-(2-
pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro-
[indole-3,4′-pyran], 26d (13 mg, 13% yield). 1H NMR (400 MHz,
CDCl3): δ ppm 8.76 (1 H, dd, J = 3.7, 1.0 Hz), 7.75−8.00 (4 H, m),
7.41 (1 H, ddd, J = 7.1, 5.0, 1.6 Hz), 7.21−7.27 (1 H, m), 7.13 (1 H,
d, J = 8.2 Hz), 6.35 (1 H, dd, J = 8.2, 2.3 Hz), 5.61 (1 H, d, J = 2.3
Hz), 3.96−4.09 (3 H, m), 3.89−3.96 (1 H, m), 3.70−3.79 (4 H, m),
3.49−3.60 (2 H, m, J = 12.2, 12.2, 2.9, 2.7 Hz), 2.91−3.04 (4 H, m),
2.38 (3 H, s), 2.09−2.22 (2 H, m), 1.76−1.93 (2 H, m). HRMS
(ESI): m/z 511.2504 [M + H]+ (C31H31FN4O2 requires 511.2510).
tert-Butyl 6-Bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoin-
doline-1-carboxylate, 28. To an ice-cooled solution of tert-butyl 6-
bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate, 27 (5.27 g,
14.16 mmol), in CH2Cl2 (94 mL) was added triethylamine (7.89 mL,
56.6 mmol) followed by methanesulfonyl chloride (2.21 mL, 28.3
mmol). The solution was stirred for 1 h, and then it was concentrated
under reduced pressure. Purification by column chromatography
(eluting with a gradient of 10−60% ethyl acetate in hexane) gave tert-
butyl 6-bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoindoline-1-
1-(2,3-Dimethyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-
hexahydrospiro[indole-3,4′-pyran], 26b. A mixture of 1-(6-chloro-
2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-
hexahydrospiro[indole-3,4′-pyran], 26a (0.027 g, 0.058 mmol),
triethylamine (0.008 mL, 0.058 mmol), and 10% Pd/C (0.02 g,
0.0188 mmol) in methanol−ethyl acetate (2:1, 3 mL) was stirred under
hydrogen at room temperature. After 3 h, the mixture was filtered
through a Celite pad and the pad was washed with methanol and ethyl
acetate to give a tan solid. The tan solid was purified by column
chromatography on a silica gel column using 0 to 100% gradient of ethyl
acetate in hexane as eluent to give 1-(2,3-dimethyl-4-quinolinyl)-6-(4-
morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran], 26b
1
carboxylate, 28 (4.21 g, 56%), as a white foam. H NMR (400 MHz,
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CDCl3): δ ppm 8.15 (1 H, d, J = 1.6 Hz), 7.43 (1 H, m, J = 8.1, 1.7 Hz),
7.33 (1 H, d, J = 8.0 Hz), 4.58 (2 H, d, J = 10.2 Hz), 4.46 (2 H, d, J =
10.4 Hz), 2.98 (6 H, s), 1.67 (9 H, s). Mass spectrum (ESI): m/e = 550.0
[(M+ Na) (79Br)]+ and 552.0 [(M+ Na) (81Br)]+.
(9.5 mg, 38% yield), as a yellow solid. H NMR (500 MHz, DMSO-
d6): δ ppm 7.97 (1 H, d, J = 8.3 Hz), 7.71 (1 H, d, J = 8.1 Hz), 7.62−7.68
(1 H, m), 7.42−7.49 (1 H, m), 7.08 (1 H, d, J = 8.3 Hz), 6.23 (1 H, dd,
J = 8.2, 2.1 Hz), 5.41 (1 H, d, J = 2.2 Hz), 3.77−3.96 (4 H, m), 3.52−3.59
(4 H, m), 3.41−3.51 (2 H, m), 2.81 (4 H, dd, J = 5.4, 2.9 Hz), 2.68 (3 H,
s), 2.22 (3 H, s), 1.91−2.03 (2 H, m), 1.78−1.85 (1 H, m), 1.65−1.72 (1
H, m). HRMS (ESI): m/z 430.2505 [M + H]+ (C27H31N3O2 requires
430.2496).
1-(3-Methyl-2-phenyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-
hexahydrospiro[indole-3,4′-pyran], 26c. 26c was prepared according to
general procedure C using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-
[indoline-3,4′-pyran], 13 (0.216 g, 0.788 mmol), and 4-chloro-3-
methyl-2-phenylquinoline, 23b (0.100 g, 0.394 mmol). After purification,
1-(3-methyl-2-phenyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-
hexahydrospiro[indole-3,4′-pyran], 26c (0.071 g, 37% yield), was
obtained. 1H NMR (500 MHz, DMSO-d6): δ ppm 8.06−8.10 (1 H, m),
6-Bromospiro[indoline-3,3′-thietan]-2-one, 29. To a solution of
tert-butyl 6-bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoindoline-
1-carboxylate, 28 (3.70 g, 7.0 mmol), in anhydrous dimethylformamide
(33 mL, deoxygenated with argon for 10 min) was added sodium sulfide
nonahydrate (1.01 g, 4.20 mmol) under an argon atmosphere. The
solution was stirred at 110 °C for 3 h, poured into saturated aqueous
ammonium chloride solution and extracted with ethyl acetate. The com-
bined organic extracts were dried over MgSO4, filtered and evaporated
in vacuo. Purification by column chromatography (eluting with a gra-
dient of 10−50% ethyl acetate in hexane) gave 6-bromospiro[indoline-
3,3′-thietan]-2-one, 29 (0.248 g, 13%), as a yellow solid. 1H NMR (400 MHz,
CDCl3): δ ppm 7.78−7.98 (2 H, m), 7.31 (1 H, dd, J = 7.9, 1.7 Hz),
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dx.doi.org/10.1021/jm300679u | J. Med. Chem. 2012, 55, 7667−7685