Synthesis of benzannelated sultams by intramolecular Pd-catalyzed arylation of tertiary sulfonamides

A new and efficient approach to five- and six-membered benzannelated sultams by intramolecular C-arylation of tertiary 1-(methoxycarbonyl)methanesulfonamides under palladium catalysis is described. In case of the α-toluenesulfonamide derivative, an unexpected formation of a 2,3-diarylindole was observed under the same conditions.


Crystal structure analyses:
Crystals suitable for X-ray diffractometry of compounds 9c and 22 were obtained by slow evaporation of their solutions in hexane/EtOAc and EtOAc respectively.
X-ray diffraction data were collected at an Xcalibur Eos diffractometer at 100 K using Cu-Kα (λ = 0.154184 nm) radiation. The structures were solved by direct methods using the SHELXS and refined with the SHELXL 5 incorporated in the OLEX2 program package.
Benzene was then removed on a rotary evaporator and the residue was dissolved in a mixture of MeCN (40 mL) and glacial AcOH (20 mL). The resulting solution was cooled to 0 °C, NaBH 3 CN (2.52 g, 40.1 mmol) was then added gradually at 5-10 °C within 10 min, and stirring was continued for 1 h. The reaction mixture was worked up in two different ways.

a)
The reaction mixture was diluted with cold water (150 mL), and the formed precipitate was filtered off, washed with water (200 mL) and dissolved in CH 2 Cl 2 (150 mL). The resulting solution was washed with water (100 mL), 5% NaOH (3 × 35 mL), brine (50 mL) and dried over Na 2 SO 4 . The solvents were removed, and the crude product was purified by recrystallization from a mixture of EtOAc and hexane.
b) The reaction mixture was concentrated, and the residue was taken up in CH 2 Cl 2 (150 mL). The resulting suspension was washed with water (100 mL), the 5% NaOH (3 × 35 mL), brine (50 mL) and finally dried over Na 2 SO 4 . The solvents were removed, and the crude product was purified by column chromatography (eluent: hexane/EtOAc, gradient from 0 to 40% of EtOAc).

GP2a:
A solution of the corresponding sufonyl chloride 2a or 2b (40.0 mmol) in anhydrous MeCN (5 mL) was added in one portion to a stirred solution of the respective amine 7a-c (20.0 mmol) and pyridine (3.16 g, 40.0 mmol) in anhydrous MeCN (20 mL). The reaction mixture was then warmed up to 60 °C and stirred at this temperature for 48 h. Water (50 mL) was then added, the mixture was acidified with conc. HCl to pH 2 and extracted with CH 2 Cl 2 (3 × 75 mL). The combined organic fractions were washed with 5% aq. HCl (2 × 50 mL), brine (50 mL) and dried over anhydrous Na 2 SO 4 . The solvents were removed, and the crude product was purified by column chromatography (eluent: hexane/EtOAc, gradient from 0 to 50% of EtOAc).

N-(2-Iodophenyl)-1-phenylmethanesulfonamide (11):
A solution of αtoluenesulfonyl chloride (19.1 g, 100 mmol) in CH 2 Cl 2 (50 mL) was added in one portion to a stirred solution of 2-iodoaniline (11.0 g, 50.2 mmol) and Nmethylmorpholine (10.1 g, 100 mmol) in CH 2 Cl 2 (100 mL) at rt, and the resulting solution was stirred at rt for 1 h. The reaction mixture was then diluted with CH 2 Cl 2 (100 mL), washed with 5% aq. HCl (3 × 50 mL), water (50 mL), dried over anhydrous Na 2 SO 4 and concentrated. The residue was dissolved in MeOH (50 mL), MeONa (16.2 g, 300 mmol) was then added in one portion, and the mixture was stirred under reflux for 3 h. The solvents were removed, and the residue was dissolved in a mixture of CH 2 Cl 2 (100 mL) and water (50 mL). The mixture was neutralized with 15% aq. HCl, the organic phase was separated, washed with water (2 ×50 mL), brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated on a rotary evaporator. The crude product was purified by recrystallization from hexane/EtOAc to give 11 (