2,2-difluoro-1,3-dimethylimidazolidine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4R)—N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5.0 mmol) and NaF (0.63 g, 15 mmol) were taken in a Teflon® reactor and suspended in 10 ml of anhydrous dichloromethane. It was cooled with ice. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (0.817 g, 6.0 mmol) in 2 ml of dichloromethane was slowly added. After 5 minutes stirring, the ice bath was removed and stirring was continued at room temperature for 20 minutes. All the volatiles were removed at reduced pressure and the obtained viscous liquid was mixed with 50 ml of pentane and washed with water (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent at reduced pressure gave 1.06 g of (2S,4R)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Ie) as a colorless oil. Yield; 90%. 19F NMR (282 MHz, CDCl3) (as a 4:6 mixture of rotamers) δ (ppm) 28.66 (s, 0.4 F, COF), 28.10 (s, 0.6 F, COF), −177.16 (m, 0.4 F, CF), −177.83 (m, 0.6 F, CF): 1H NMR (300 MHz, CDCl3) (as a mixture of rotamers) δ 1.42 (s, 0.6×9H, t-Bu), 1.44 (s, 0.4×9H, t-Bu), 2.0-2.8 (m, 2H), 3.45-4.0 (m, 2H), 4.51 (m, 1H), 5.22 (dm, 1H, J=51.6 Hz): 13C NMR (75 MHz, CDCl3) (as a mixture of two rotamers) δ 90.70 (d, J=179.9 Hz, CF), 91.61 (d, J=179.9 Hz, CF), 153.07 (s, CON), 154.17 (s, CON), 161.90 (d, J=368.4 Hz, COF), 162.11 (d, J=368.4 Hz, COF): IR (Neat, KBr) 1848 (COF) cm−1: High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1114 [calcd 270.1112 for (C11H18FNO4+Na)]. It was cooled with ice the ice bath was removed stirring was continued at room temperature for 20 minutes All the volatiles were removed at reduced pressure the obtained viscous liquid was mixed with 50 ml of pentane washed with water (50 ml×2) The organic layer was dried over anhydrous magnesium sulfate filtered Removal of solvent at reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5 mmol) and sodium fluoride (0.63 g, 15 mmol) were put in a fluoropolymer (PFA) vessel, and 10 ml of dichloromethane was added into the vessel. The mixture was cooled with ice. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (817 mg, 6 mmol) in 2 ml of dichloromethane was added slowly. After 5 minutes of addition, the ice bath was removed and the mixture warmed to room temperature. The reaction mixture was stirred for a total 20 min. 19F NMR analysis of the reaction mixture showed that (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id) was produced in 85% yield. The mixture was diluted with 10 ml of dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent followed by washing with a small amount of water and then drying gave 846 mg (yield 72%) of (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id): Oil: 19F-NMR (CDCl3) (as a 6:4 mixture of two rotamers) δ 28.22 (s, 0.6 F, COF), 28.14 (s, 0.4 F, COF), −173.18 (m, 1 F, CF): 1H-NMR (CDCl3) 8 (as a mixture of two rotamers) 1.40 (s, 0.55×9H, t-Bu), 1.43 (s, 0.45×9H, t-Bu), 2.2-2.6 (m, 2H), 3.45-3.95 (m, 2H), 4.5-4.7 (m, 1H), 5.22 (br.d, J=51.9 Hz, 1H, CHF): 13C-NMR (CDCl3) 8 (as a mixture of two rotamers); 90.94 (d, J=177.0 Hz, 1H, CF), 92.02 (d, J=177.0 Hz, CF), 153.06 (s, CON), 153.82 (s, CON), 161.50 (d, J=372.1 Hz, COF), 161.66 (d, J=372.8 Hz, COF): High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1109 [calcd 270.1112 for (C11H18FNO4+Na)]. The mixture was cooled with ice After 5 minutes of addition the ice bath was removed was produced in 85% yield washed with water The organic layer was dried over anhydrous magnesium sulfate filtered Removal of solvent by washing with a small amount of water drying