Acetic Acid → Benzenesulfonamide

A solution of 0.42 g (2.0 mmol) of 6-hydroxymethyl-3-methysulfanyl-1,3-dihydro-indol-2-one in DMF (10 mL) was treated with 0.32 g (2.1 mmol) of t-butyldimethylsilyl chloride and 0.15 g (2.2 mmol) of imidazole and stirred for 16 h. The solution was diluted with 50 mL of hexane and 50 mL of EtOAc, washed with brine, dried over MgSO4 and concentrated to give 0.28 g (43%) of 3-methylsulfanyl-6-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as a clear oil which crystallised upon storage at rt: 1H NMR (DMSO-d6): δ0.01 (s, 6H), 0.97 (s, 9H), 2.00 (s, 3H), 4.52 (s, 1H), 4.72 (s, 2H), 6.85 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 10.54 (s, 1H). A solution of 0.28 g (0.86 mmol) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in THF (10 mL) was stirred with saturated ammonium chloride solution (10 mL), and activated zinc dust (2 g) was added. The mixture was stirred 16 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 0.32 g of impure 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as a gummy white solid: 1H NMR (DMSO-d6): δ0.04 (s, 6H), 0.87 (s, 9H), 3.39 (s, 2H), 4.62 (s, 2H), 6.75 (s, 1H), 6.81 (d, J=7.5 Hz, 1H), 7.10 (d, J=7.5 H), 10.30 (bs, 1H). A solution of 0.32 g (1.2 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (3 mL) was heated to 100° C. for 0.75 h. The excess DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc/MeOH (98:2), to give 0.16 g (41%) of 3-dimethylaminomethylene-6-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one (11:9 mixture of E and Z isomers) as a yellow solid: 1H NMR (DMSO-d6, peak areas normalized using the combined peak areas for 8 9.88 and 9.66 as 1H): δ0.21 (s, 2.70H), 0.34 (s, 3.3H), 0.85 (s, 4.05H), 0.86 (s, 4.95H), 3.25 (s, 2.70H), 3.30 (s, 3.30H), 4.58 (s, 0.9H), 4.59 (s, 1.1 H), 6.64-6.71 (m, 2H), 7.16 (d, J=7.7 Hz, 0.45H), 7.29 (d, J=8.3 Hz, 0.55H), 7.33 (s, 0.55H), 7.47 (s, 0.45H), 9.88 (s,0.55H) 9.96 (s, 0.45H); APCI−MS m/z 331 (M+1)+. A solution of 0.334 g (1.00 mmol) of 3-dimethylamino-methylene-6-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in 2-methylpropanol (3 mL) was treated with 0.174 g (1.00 mmol) of sulfanilamide and 0.25 g (4.0 mmol) of acetic acid. The solution was refluxed for 3 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.134 g (29%) of 6-([t-butyldimethyl-silyloxy]methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide (Z isomer).: 1H NMR (DMSO-d6): δ0.05 (s, 6H), 0.87 (s, 9H), 4.65 (s, 2H), 6.81 (s,1H), 6.85 (d, J=8.0 Hz, 1H), 7.23 (s, 2H), 7.49-7.51 (m, 3H), 7.75 (d, J=8.4 Hz, 2H), 8.56 (d, J=12. 3 Hz, 1H), 10.52 (s, 1H), 10.76 (d, J=12.3 Hz, 1H); APCI−MS m/z 458 (M−H)−. To a solution of 0.125 g (2.80 mmol) of 6-([t-butyldimethylsilyloxy]methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide in THF (5 mL) was added 0.27 mL of a 1 M solution of t-butylammonium fluoride in THF, and the mixture was stirred at rt for 1 h. The resulting yellow precipitate was isolated by filtration, washed with THF and dried. Chromatographic purification of the solid on silica gel, eluting with a hexane to EtOAc gradient, gave 0.053 g (55%) of the title compound: 1H NMR (DMSO-d6): δ4.43 (d, J=5.8 Hz, 2H), 5.08 (t, J=5.8 Hz, 1H), 6.82 (s, 1H), 6.85 (d, J=8.2 Hz, 1H), 7.23 (s, 2H), 7.50 (d, J=7.5 Hz, 2H), 7.74 (d, J=8.7 Hz, 3H), 8.56 (d, J=12.2 Hz, 1H), 10.54 (s, 1H), 10.75 (d, J=12.1 Hz, 1H); APCI−MS m/z 345 (M−H)−. Anal. Calcd for C16H15N3O4S.0.5H2O: C, 54.43, H, 4.55; N, 11.86, S, 9.05. Found C, 54.47, H, 4.63; N, 11.66; S, 8.86.

1. temperatureThe solution was refluxed for 3 h
2. customThe resulting yellow precipitate was isolated by filtration
3. washwashed with ethanol
4. customdried

ORD record

ord-aa5f561fb8e14e5daf79010cc4460021

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06369086B1