4.2. Synthetic procedures
4.2.1. Synthesis of N-propyl benzolactams (28a, 28b and 32).
The mixture of 100 mL of DMF and 68 mmol of benzolactam (27a, 27b or 31) was cooled to 0℃ under stirring. 6.86 g of 60% sodium hydride was carefully added in batches and stirring was continued at 0℃ for 30 min. 68 mmol of 1-bromopropane was then dropwise added, and the reaction was continued for another 30 min. The ice bath was then removed and the reaction was continued for 2 hours at room temperature. The mixture was poured into crushed ice and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed twice with 50 mL of brine, dried overnight with anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether (PE) : ethyl acetate = 10 : 1) to afford pure product.
Data for 28a. Yellow oil, yield 93%. 1H NMR (300 MHz, CDCl3) δ 7.24 (ddd, J = 8.6, 4.8, 0.9 Hz, 2H), 7.01 (td, J = 7.5, 0.9 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 3.66 (t, J = 7.3 Hz, 2H), 3.50 (s, 2H), 1.76–1.64 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
Data for 28b. Yellow oil, yield 96%. 1H NMR (300 MHz, CDCl3) δ 7.26–7.17 (m, 1H), 7.15–7.13 (m, 1H), 7.01–6.97 (m, 2H), 3.89 (t, J = 7.3 Hz, 2H), 2.91–2.86 (m, 2H), 2.63 (dd, J = 8.6, 6.1 Hz, 2H), 1.71–1.61 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
Data for 32. Yellow oil, yield 95%. 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 9.5 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.21 (d, J = 8.7 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.56 (d, J = 9.5 Hz, 1H), 4.11 (t, J = 7.3 Hz, 2H), 1.71–1.59 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).
4.2.2. Synthesis of 5-nitro-1-propylindolin-2-one (29a)
50 mL of concentrated sulfuric acid was cooled to 0℃ and 28 mmol 28a was added under stirring. 31 mmol potassium nitrate was added in batches and the reaction temperature was maintained to not more than 5℃ during addition. The reaction was continued for 4h at this temperature, and then the mixture was poured into ice water and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed twice with 30 mL of brine, dried overnight with anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product which provided pure 29a as a yellow solid by column chromatography (PE : EtOAc = 3 : 1), yield 90%, m.p. 97.0–98.0 ℃. 1H NMR (300 MHz, CDCl3) δ 8.26 (dd, J = 8.7, 2.3 Hz, 1H), 8.15 (m, 1H), 6.92 (d, J ༝ 8.7 Hz, 1H), 3.74 (t, J ༝ 7.3 Hz, 2H), 3.64 (s, 2H), 1.80–1.67 (m, 2H), 0.99 (t, J ༝ 7.4 Hz, 3H).
4.2.3. Synthesis of 6-nitro-1-propyl-3,4-dihydroquino-lin-2(1H)-one (29b) and 6-nitro-1-propyl-quinolin-2(1H)-one (33)
50 mL concentrated sulfuric acid was cooled to 0℃ and 26 mmol 28b (or 32) was added under stirring. 10 mL of nitric acid was dropped in and the temperature was maintained not more than 5℃ during the course. The reaction was continued at this temperature for 2 h, and the reaction mixture was then poured into ice water and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed twice with 30 mL of brine, dried overnight with anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (PE: EtOAc = 3: 1).
Data for 29b. Yellow powder, yield 92%, m.p. 103.0-104.0 ℃. 1H NMR (300 MHz, CDCl3) δ 8.15 (dd, J = 9.0, 2.6 Hz, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 4.02–3.88 (t, J = 7.3 Hz, 2H), 3.08–2.95 (m, 2H), 2.72 (dd, J = 8.8, 6.2 Hz, 2H), 1.67 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
Data for 33. Yellow powder, yield 91%, m.p. 106.0–107.0 ℃. 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 2.6 Hz, 1H), 8.38 (dd, J = 9.3, 2.6 Hz, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 9.4 Hz, 1H), 6.82 (d, J = 9.5 Hz, 1H), 4.28 (t, J = 7.3 Hz, 2H), 1.85–1.72 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).
4.2.4. Synthesis of 5-amino-1-propylindolin-2-one (30a), 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (30b) and 6-amino-1-propylquinolin-2(1H)-one (34).
21 mmol of compound 29a (or 29b or 33) and 0.25 g 5% Pd/C were added to a 100 mL round bottom flask, then sealed with a rubber stopper and replaced three times with hydrogen. 30 mL of methanol was added to the reaction flask with a syringe, and the reduction was undergone at room temperature for 3 h. The catalyst was removed by diatomite filtration and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (PE : EtOAc = 2 : 1) to provide pure product.
Data for 30a. Yellow solid, yield 97%, m.p. 81.0–82.0 ℃. 1H NMR (300 MHz, CDCl3) δ 6.66–6.56 (m, 3H), 3.61 (t, J = 7.5 Hz, 2H), 3.44 (s, 2H), 3.26 (bs, 2H), 1.73–1.61 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).
Data for 30b. Yellow solid, yield 98%, m.p. 84.0–85.0 ℃. 1H NMR (300 MHz, CDCl3) δ 6.79 (d, J = 8.5 Hz, 1H), 6.58–6.52 (m, 2H), 3.84 (t, J = 7.3 Hz, 2H), 3.59 (s, 2H), 2.76 (dd, J = 8.8, 5.8 Hz, 2H), 2.59 (dd, J = 8.8, 5.8 Hz, 2H), 1.68–1.60 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).
Data for 34. Yellow solid, yield 98%, m.p. 101.0–102.0 ℃. 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 9.4 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.95 (dd, J = 8.9, 2.7 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 4.19 (t, J = 7.3 Hz, 2H), 3.77 (bs, 2H), 1.80–1.67 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).
4.2.4. Synthesis of IQB (21) and DHQB (23)
The mixture of 20 mL methylene dichloride (DCE), 10 mmol 30a and 20 mmol of triethylamine was cooled to 0℃. 8 mL DCE solution containing 11 mmol of 4-tolylmethanesulfonyl chloride was dropwise added and stirred for 30 min at 0℃ and then for 2 h at room temperature. 30 mL of water was added and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phase was washed twice with 20 mL of brine and dried with anhydrous sodium sulfate. After evaporating the solvent to dryness in vacuo, the residue was purified by column chromatography (PE : EtOAc = 3 : 1) to give IQB.
Compound QB (3), DHQB (23) were synthesized by the same procedure starting from 30b. While the reaction of 30b with 4-(2,3,5,6-tetrafluoro)tolylmetane sulfonyl chloride in this way would give TFQB (8).
Data for IQB (21). White solid, yield 90%, m.p. 171.8–172.8 ℃. 1H NMR (300 MHz, CDCl3) δ 7.19–7.12 (m, 5H), 7.05 (dd, J = 8.3, 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 4.26 (s, 2H), 3.67 (t, J = 7.3 Hz, 2H), 3.50 (s, 2H), 2.34 (s, 3H), 1.72–1.67 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.36, 142.13, 138.60, 130.91, 130.38, 129.21, 125.65, 125.22, 121.34, 118.87, 108.29, 56.93, 41.40, 35.50, 20.85, 20.42, 11.06. HRMS (m/z) calcd. for C19H22N2O3S [M + H]+ 359.1424, found 359.1418.
Data for QB (3). White solid, yield 91%, m.p. 142.0–143.0 ℃. 1H NMR (300 MHz, CDCl3) δ 7.18–7.14 (m, 4H), 7.02–6.91 (m, 3H), 6.57 (s, 1H), 4.28 (s, 2H), 3.88 (t, J = 7.3 Hz, 2H), 2.88–2.83 (m, 2H), 2.65–2.60 (m, 2H), 2.34 (s, 3H), 1.68–1.63 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 169.53, 138.55, 136.54, 131.39, 130.41, 129.17, 127.64, 125.21, 120.45, 119.51, 115.28, 57.10, 43.41, 31.29, 25.27, 20.85, 20.09, 10.87. HRMS (m/z) calcd. for C20H24N2O3S [M + H]+ 373.1580, found 373.1575.
Data for DHQB (23). Yellowish solid, yield 92%, m.p. 198.0–199.0 ℃. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 9.5 Hz, 1H), 7.36–7.28 (m, 3H), 7.19–7.08 (m, 5H), 6.71 (d, J = 9.5 Hz, 1H), 4.30 (s, 2H), 4.23 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.81–1.74 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 161.46, 138.69, 138.06, 136.21, 131.07, 130.40, 129.23, 125.03, 123.50, 122.48, 121.23, 119.74, 114.98, 57.32, 43.65, 20.83, 20.55, 11.00. HRMS (m/z) calcd. for C20H22N2O3S [M + H]+ 371.1424, found 371.1419.
Data for TFQB (8). White solid, yield 90%, m.p. 178.0-179.0 ℃. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.06–7.02 (m, 3H), 4.56 (s, 2H), 3.79 (t, J = 7.3 Hz, 2H), 2.79–2.77 (m, 2H), 2.76–2.75 (m, 2H), 2.22 (s, 3H), 1.51–1.46 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) δ 168.89, 146.12 (m), 142.92 (m), 135.78, 132.48, 127.34, 119.34, 118.68, 116.98 (t, J = 19.4 Hz), 115.67, 106.82 (t, J = 17.7 Hz), 46.08, 42.64, 31.34, 25.09, 20.10, 11.10, 7.53. HRMS (m/z) calcd. for C20H20F4N2O3S [M + H]+ 445.1204, found. 445.1199
4.2.5. Synthesis of TQB (22), DHTQB (24) and TFTQB (25)
A mixture of 15 mL THF, 2.68 mmol quinabactin and 1.47 mmol phosphorus pentasulfide were stirred at 60℃ for 2 h. After cooling to room temperature, the mixture was filtered with diatomite and the filtrate was concentrated to dryness, the residue was purified to give TQB by column chromatography (PE : EtOAc = 6 : 1). DHTQB and TFTQB were prepared by same procedures.
Data for TQB (22). Yellow solid, yield 89%, m.p. 175.0–176.0 ℃. 1H NMR (300 MHz, CDCl3) δ 7.12–7.05 (m, 4H), 7.09–6.85 (m, 3H), 6.56 (s, 1H), 4.39 (t, J = 7.5 Hz, 2H), 4.22 (s, 2H), 3.12–3.07 (m, 2H), 2.69–2.65 (m, 2H), 2.27 (s, 3H), 1.82–1.74 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 198.32, 138.09, 135.23, 132.30, 129.79, 129.71, 128.59, 124.26, 118.75, 117.99, 116.26, 56.75, 50.67, 41.21, 24.02, 20.21, 18.58, 10.04. HRMS (m/z) calcd. for C20H24N2O2S2 [M-H]− 387.1206, found 387.1221.
Data for DHTQB (24). Yellow solid, yield 75%, m.p. 227.0-228.0 ℃. 1H NMR (300 MHz, DMSO-d6) δ 7.57 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.28 (dt, J = 12.2, 6.0 Hz, 3H), 7.12–7.04 (m, 4H), 6.82 (s, 1H), 4.78 (t, J = 7.3 Hz, 2H), 4.28 (s, 2H), 2.25 (s, 3H), 1.86–1.78 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 198.49, 138.22, 136.31, 133.73, 132.20, 129.82, 129.74, 128.63, 124.39, 124.15, 122.64, 117.64, 115.89, 57.11, 50.37, 20.17, 18.83, 10.07. HRMS (m/z) calcd. for C20H22N2O2S2 [M + H]+ 387.1195, found 387.1191.
Data for TFTQB (24). Yellow solid, yield 87%, m.p. 207.0-208.0 ℃. 1H NMR (300 MHz, CDCl3) δ 7.15–7.05 (m, 3H), 6.78 (s, 1H), 4.52 (s, 2H), 4.49–4.43 (m, 2H), 3.18 (dd, J = 8.4, 5.9 Hz, 2H), 2.78 (dd, J = 8.3, 6.0 Hz, 2H), 2.26 (s, 3H), 1.89–1.78 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 198.50, 144.91 (m), 142.19 (m), 135.64, 131.61, 129.84, 120.99 (t, J = 20.9 Hz), 118.67, 117.98, 116.28, 114.65 (t, J = 16.6 Hz), 50.65, 45.44, 41.21, 24.03, 18.56, 10.01, 6.78. HRMS (m/z) calcd. for C20H20F4N2O2S2 [M + H]+ 461.0975, found 461.0968.
4.2.6. Synthesis of iso-QB (26)
10 mL of chlorosulfonic acid was slowly drop to 10 mmol of 28b below 0℃ under stirring. The obtained mixture was stirred for two hours and then poured into 30 mL ice water, extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed twice with 20 mL brine, and dried with anhydrous sodium sulfate. After evaporating the solvent in vacuo, the crude product 35 was obtained and was directly used for the next reaction without further purification.
A solution of 2 mmol of 35 dissolved in 2 mL DCE was dropped into a mixture of 2 mmol 4-methylbenzylamine, 8 mL DCE and 4 mmol triethylamine at 0℃ under stirring. The reaction was continued for 30 min at 0℃ and then for 4 h at room temperature. Poured the reaction mixture into ice water and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed twice with 10 mL brine and dried with anhydrous sodium sulfate. After evaporating the solvent in vacuo, the residue was purified by column chromatography (PE : EtOAc = 2 : 1) to give 26 as white solid with 90% yield, m.p. 101.5-102.5 ℃. 1H NMR (300 MHz, CDCl3) δ 7.72 (dd, J = 8.6, 2.2 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.09–7.00 (m, 5H), 5.22 (t, J = 6.2 Hz, 1H), 4.09 (d, J = 6.2 Hz, 2H), 3.89 (t, J = 7.3 Hz, 2H), 2.88–2.85 (m, 2H), 2.66–2.61 (m, 2H), 2.27 (s, 3H), 1.66–1.61 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 169.57, 142.92, 137.16, 133.29, 133.01, 128.88, 127.54, 126.77, 126.61, 126.57, 114.50, 46.65, 43.47, 30.97, 24.99, 20.71, 19.96, 10.82. HRMS (m/z) calcd for C20H24N2O3S [M + H]+ 373.1580, found 373.1575.