Hexane → (1R,3S,6S)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acid

HRID 2176465Notes

Reaction equation

HRID 2176465 reaction equation
I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CCCCCC>O.C(#N)C.C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.[Ru](Cl)(Cl)Cl>[C:19]([O:18][C:16]([N:10]1[C@H:9]([C:8]([OH:2])=[O:7])[CH2:15][CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:17])([CH3:22])([CH3:21])[CH3:20]

Participants

9

Reactant 3

HCID 8058HexaneHCID 23667635Sodium periodateHCID 89872603tert-Butyl (1R,3S,6S)-3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate

Product 1

HCID 89872562(1R,3S,6S)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acidYield 32.5%

Reagents, catalysts & solvents 5

HCID 61850Ruthenium trichlorideCatalystHCID 962WaterSolvent2×HCID 5943Carbon TetrachlorideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of sodium periodate (15.5 g, 72.6 mmol) in water (80 mL) was added a solution of (1R,3S,6S)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (5.5 g, 24.2 mmol) in ACN (60 mL) and carbon tetrachloride (60 mL). Ruthenium (III)chloride (246 mg, 1.21 mmol) was added immediately and the reaction mixture was stirred vigorously for 75 min at RT, diluted with water (80 mL), filtered, and extracted with DCM (3×100 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to provide crude product (4.75 g) as a light charcoal-color solid. The crude product was dissolved in EtOAc (20 mL) with heating and allowed to stand at RT with seeding. After about 15 min, rapid crystal formation was observed. About 1 h later, hexane (10 mL) was added and the mixture was refrigerated overnight, filtered, washed with 2:1 ice-water-cooled hexanes:EtOAc (50 mL) and dried under high vacuum to provide the title intermediate (1.9 g) ([a]D=−135.2) The mother liquid was re-crystallized to provide additional product (300 mg) ([a]D=−142.6). 1H NMR: (DMSO-d6, 400 MHz) δ (ppm) 4.1 (m, 1H), 2.60 (m, 1H), 1.70 (m, 1H), 1.30 (m, 3H), 1.17 (m, 9H), 0.96 (m, 1H), 0.50 (m, 1H), 0.0 (m, 1H)

Workup

  1. filtrationfiltered
  2. extractionextracted with DCM (3×100 mL)
  3. washThe combined organic phase was washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under vacuum
  6. customto provide crude product (4.75 g) as a light charcoal-color solid
  7. temperaturewith heating
  8. customto stand at RT with seeding
  9. waitAfter about 15 min
  10. waitAbout 1 h later
  11. waitthe mixture was refrigerated overnight
  12. filtrationfiltered
  13. washwashed with 2:1 ice-water-
  14. temperaturecooled hexanes
  15. dry with materialEtOAc (50 mL) and dried under high vacuum

Sources & evidence

ORD record
ord-ff28adf0b01e434cb6cbb92dae22ff6f
Source dataset
uspto-grants-2015_06
Patent number
US09066944B2

Reaction notes

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