Triethylamine → benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate

HRID 81171Notes

Reaction equation

HRID 81171 reaction equation
Cl.[O:2]1[CH2:7][CH2:6][NH:5][CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][N:5]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 10387Benzyl chloroformateHCID 45792192Octahydrocyclopenta[b][1,4]oxazine hydrochloride

Product 1

HCID 86724525benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine) (300 mg, 1.83 mmol) dissolved in dichloromethane (2.4 mL) was added benzyl chloroformate (0.44 mL, 2.57 mmol). Triethylamine (0.72 mL, 5.13 mmol) was added slowly to the reaction mixture, and the reaction was stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient), and then purified by chiral supercritical fluid chromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO2) to afford the trans stereoisomers of benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate. (4aS,7aS)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (faster eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262; (4aR,7aR)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (slower eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262.

Workup

  1. customThe mixture was quenched with saturated aqueous sodium bicarbonate
  2. extractionextracted with dichloromethane (2×)
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient)
  7. custompurified by chiral supercritical fluid chromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO2)

Sources & evidence

ORD record
ord-cb20b3e9ea42489f97b5fd2cec85d1da
Source dataset
uspto-grants-2014_09
Patent number
US08846657B2

Reaction notes

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