[C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].[Na+].[F:19]C1(F)N(C)CCN1C>ClCCl>[C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([F:19])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2](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)].
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