1. O-fluorobenzoic acid (10.0 g, 71.4 mmol) was slowly added to chlorosulfonic acid (50 mL) at 0 °C and kept stirring at 0 °C for 1 hour. Once the reaction was complete, the mixture was slowly poured into ice water. The precipitate formed was collected by filtration, washed with water (3 x 100 mL) and dried under vacuum overnight to give 5-(chlorosulfonyl)-2-fluorobenzoic acid (10.5 g, 44.0 mmol) as a brown solid.
2. 5-(Chlorosulfonyl)-2-fluorobenzoic acid (10.0 g, 41.9 mmol) was dissolved in 60 mL of SOCl2 and refluxed for 1.5 hours. After evaporation to remove the SOCl2, the residue was dissolved in toluene (150 mL) and 3,4-difluoroaniline (6.5 g, 50.3 mmol) was added. The mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuum. Purification by fast chromatography (hexane/EtOAc = 6:4 v/v) afforded 3-((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1-sulfonyl chloride (92% yield, 13.51 g, 38.6 mmol).
3. To a solution of 3-((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1-sulfonyl chloride (10.0 g, 28.6 mmol) in CH2Cl2 (200 mL) was added alkynylpropylamine hydrochloride (3.1 g, 34.3 mmol) and Et3N (7.8 mL, 57.2 mmol) at 0 °C. After stirring at room temperature overnight, the solution was poured into saturated ammonium chloride solution (250 mL) and extracted with CH2Cl2 (3 x 100 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuum. The resulting solid was washed with ether (50 mL) and hexane (50 mL) to afford N-(3,4-difluorophenyl)-2-fluoro-5-(N-(prop-2-yn-1-yl)aminosulfonyl)benzamide (74% yield, 7.8 g, 21.1 mmol) as a white powder.
4. An aqueous (1 mL) solution of bromocyclopropane (0.6 mL, 4.9 mmol) and sodium azide (483 mg, 7.4 mmol) was heated at 120 °C for 30 min under microwave radiation. Acetonitrile (1 mL) solution of compound 12 (0.1 g, 0.3 mmol), sodium ascorbate (10 mg, 0.05 mmol) and copper sulfate (20 mg, 0.12 mmol) were added. The mixture was heated at 80°C under microwave radiation for 30 min, poured into saturated ammonium chloride solution (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried with sodium sulfate and concentrated in vacuum. Purification by fast chromatography (hexane:EtOAc = 6:4 v/v) afforded compound 13 (19% yield, 23 mg, 0.05 mmol) as a white powder.
5. 1H NMR (400 MHz, acetone-d6) δ 9.92 (s, 1H), 8.25 (dd, J = 6.6,2.5 Hz, 1H), 8.06-7.95 (m, 2H), 7.77 (s, 1H), 7.58-7.52 (m, 1H), 7.48 (dd, J = 10.1,8.7 Hz, 1H) for compound 13 , 7.37 (dt, J = 10.6,9.0 Hz, 1H), 7.21 (brs, 1H), 6.11-5.94 (m, 1H), 5.32-5.16 (m, 1H), 4.99 (dt, J = 6.0,1.5 Hz, 2H), 4.32 (s, 2H).13C NMR (101 MHz, acetone-d6) δ 188.9,167.9,162.1,150.2,149.2 (d, J = 12.9 Hz), 146.8 (d, J = 13.0 Hz), 142.8,137.9 (d, J = 5.9 Hz), 128.5,124.6,120.4-118.2 (m), 117.5 (dd, J = 6.0,3.6Hz ), 110.6 (d, J = 22.1 Hz), 81.5,73.3,33.2,29.7,12.8 (d, J = 9.6 Hz).19F NMR (377 MHz, acetone-d6) δ-110.6 (s), -139.6-139.7 (m), -146.1-146.3 (m).HRMS (ESI): C19H17F3N5O3S m/z [M + H]+ Calculated value: 452.1004, measured value: 452.0999.
