(2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-fluoropyrrolidine-2-carboxylic acid → (2S,4R)-N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride

HRID 220740Notes

Reaction equation

HRID 220740 reaction equation
C(C1C=C(C)C(S(F)(F)[F:13])=C(C)C=1)(C)(C)C.[C:17]([N:34]1[CH2:38][C@H:37]([F:39])[CH2:36][C@H:35]1[C:40](O)=[O:41])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>ClCCl>[C:17]([N:34]1[CH2:38][C@H:37]([F:39])[CH2:36][C@H:35]1[C:40]([F:13])=[O:41])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]

Participants

4

Reactant 2

HCID 10970300(2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-fluoropyrrolidine-2-carboxylic acidHCID 441847004-tert-Butyl-2,6-dimethylphenylsulfur trifluoride

Product 1

HCID 46841192(2S,4R)-N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluorideYield 97%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of 4-(tert-butyl)-2,6-dimethylphenylsulfur trifluoride (10.5 mmol) in 5 ml of dichloromethane was added slowly to a stirred solution of (2S,4R)—N-Fmoc-4-fluoropyrrolidine-2-carboxylic acid (7 mmol) in 15 mL of dichloromethane in a fluoropolymer (PFA) reactor cooled on an ice bath. After complete addition, the ice bath was removed and stirred at room temperature for 0.5 h. 19F NMR analysis of the reaction mixture showed that (2S,4R)—N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride (Ib) was produced in 97% yield. All the volatiles were removed at reduced pressure, and dichloromethane (2 ml) was added to the residue, followed by the addition of pentane (30 ml). After stirring well, a supernatant liquid was removed and the residue was washed with pentane (25 ml×2). Finally the product (Ib) (1.75 g, 70% yield) was obtained as white powder by dissolving the solid in dichloromethane and precipitating with pentane. 19F-NMR (CDCl3) (a 6:4 mixture of two rotamers) δ 29.69 (s, 0.6 F, COF), 29.39 (s, 0.6 F, COF), −177.05 (m, 0.6 F, CF), −177.99 (m, 0.4 F, CF): 1H-NMR (CDCl3) 8 (as a mixture of rotamers) 2.0-2.9 (m, 2H), 3.4-4.8 (m, 6H), 5.05-5.5 (m, 1H), 7.2-7.9 (m, 8H): 13C-NMR (CDCl3) 8 (as a mixture of two rotamers) δ0.40 (d, J=179.9 Hz, CF), 91.39 (d, J=180.6 Hz, CF), 154.16 (CON), 154.85 (CON), 161.49 (d, J=367.8 Hz, COF): High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+392.1272 [calcd 392.1269 for (C21H20FNO4+Na)].

Workup

  1. temperaturecooled on an ice bath
  2. additionAfter complete addition
  3. customthe ice bath was removed
  4. customwas produced in 97% yield
  5. customAll the volatiles were removed at reduced pressure, and dichloromethane (2 ml)
  6. additionwas added to the residue
  7. additionfollowed by the addition of pentane (30 ml)
  8. stirringAfter stirring well
  9. customa supernatant liquid was removed
  10. washthe residue was washed with pentane (25 ml×2)
  11. customFinally the product (Ib) (1.75 g, 70% yield) was obtained as white powder
  12. customprecipitating with pentane

Sources & evidence

ORD record
ord-c5c15871ab46438fb2cba8c7f5e9fc30
Source dataset
uspto-grants-2012_06
Patent number
US08203003B2

Reaction notes

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