Sodium Fluoride → (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride

HRID 220742Notes

Reaction equation

HRID 220742 reaction equation
[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]

Participants

5

Reactant 3

HCID 5235Sodium FluorideHCID 27791112,2-Difluoro-1,3-dimethylimidazolidineHCID 12043048(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid

Product 1

HCID 46841477(2S,4R)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluorideYield 90.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(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)].

Workup

  1. temperatureIt was cooled with ice
  2. customthe ice bath was removed
  3. stirringstirring
  4. waitwas continued at room temperature for 20 minutes
  5. customAll the volatiles were removed at reduced pressure
  6. additionthe obtained viscous liquid was mixed with 50 ml of pentane
  7. washwashed with water (50 ml×2)
  8. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  9. filtrationfiltered
  10. customRemoval of solvent at reduced pressure

Sources & evidence

ORD record
ord-433def1d56024f31a306e40239c01710
Source dataset
uspto-grants-2012_06
Patent number
US08203003B2

Reaction notes

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