Iodine → 2-Methoxy-pyrrolidine-1-carboxylic acid benzyl ester

HRID 890231Notes

Reaction equation

HRID 890231 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])C.C(O)(=O)C.IC1C=CC=CC=1.II.CO>C(Cl)Cl>[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[O:21][CH3:19])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]

Participants

6

Reactant 4

HCID 807IodineHCID 887MethanolHCID 101987Benzyloxycarbonyl-L-prolineHCID 12217721Iodo benzene diacetate

Product 1

HCID 109224852-Methoxy-pyrrolidine-1-carboxylic acid benzyl esterYield 100%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-(−)-N-benzyloxycarbonylproline (10 g, 40 mmol) in CH2Cl2 (500 mL) was added iodobenzene diacetate (26 g, 80 mmol, 2.0 equiv) and iodine (5.2 g, 20 mmol, 0.50 equiv). The resulting mixture was stirred at rt for 5 h. Methanol (20 mL) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction was then quenched by the addition of 10% Na2S2O3 (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with 10% Na2S2O3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product (28 g) as a yellow oil. Purification by flash chromatography (silica gel, 10-30% EtOAc/hexane) provided the expected product (9.41 g, 77%) as a yellow oil along with the corresponding hydroxy product (8.85 g, 11%) as a white solid: mp 44-46° C. The hydroxy product could subsequently be quantitatively recycled to the desired methoxy compound by treatment with pyridinium p-toluene sulfonate (PPTS) in MeOH at rt for 20 h. Data for step 1 compound: HPLC (Phenominex 4.6×50 mm) retention time 2.94 min; LC/MS m/z 236 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 5.15-5.29 (m, 3H), 3.52 (td, 1H, J=8.8, 1.3 Hz), 3.32-3.48 (m, 3H), 3.26 (s, 1H), 1.99-2.15 (m, 1H), 1.84-1.98 (m, 2H), 1.67-1.82 (m, 1H). Data for compound 3: LC/MS m/z 222 [M+H]+; 1 H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 5H), 5.47-5.55 (m, 1H), 5.15 (s, 2H), 3.55-3.65 (m, 1H), 3.30-3.42 (m, 1H), 1.78-2.02 (m, 4H).

Workup

  1. stirringthe reaction mixture was stirred at rt for 1.5 h
  2. customThe reaction was then quenched by the addition of 10% Na2S2O3 (200 mL)
  3. extractionextracted with CH2Cl2 (2×100 mL)
  4. washThe combined organic extracts were washed with 10% Na2S2O3 (200 mL), brine (200 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customto give the crude product (28 g) as a yellow oil
  8. customPurification by flash chromatography (silica gel, 10-30% EtOAc/hexane)

Sources & evidence

ORD record
ord-04458d9666714c8faf052ef9787e781a
Source dataset
uspto-grants-2006_02
Patent number
US06995183B2

Reaction notes

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