Tetrahydrofuran → HCID 59382889, compound

HRID 1254410Notes

Reaction equation

HRID 1254410 reaction equation
[C@H:1]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.[CH:25]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1COCC1.[NH4+].[Cl-]>[Cu]I>[C:11]([O:10][C:8]([NH:7][C@H:1]1[C@H:6]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:10][C:8]([NH:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2][C@@H:1]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 86626205(1R,6S)-3-benzyl 7-tert-butyl 3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylateHCID 178419651HCID 178419651, compound

Product 2

HCID 59382889HCID 59382889, compoundYield 23%HCID 86626206(3S,4S)-benzyl 4-(tert-butoxycarbonylamino)-3-cyclohexylpiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst

Conditions

Temperature
-40 °C

Procedure

(1R,6S)-3-benzyl 7-tert-butyl 3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylate (220 mg, 0.663 mmol), CuI (25 mg, 0.2 equiv), and a stirring bar were put in a 100-mL flask. The flask was evacuated and backfilled with N2 gas (3×). Dry THF (5 mL) was added and the mixture was cooled to −40° C. 1 M Cyclohexylmagnesium bromide in THF (2.0 mL, 3 equiv) was added slowly. After 8 min, the reaction mixture was allowed warmed slowly to rt. After 20 min, the reaction mixture turned into black. After stirring a further 2 h, LC-MS showed the reaction was complete. Satd aq NH4Cl solution (5 mL) was added to quench the reaction. The reaction mixture was partitioned between EtOAc (50 mL) and satd aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined EtOAc layers were washed with water (15 mL) and brine (15 mL), and dried over Na2SO4. After concentration, the residue was purified by preparative HPLC to afford (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate (62.3 mg, 23% yield) and (3S,4S)-benzyl 4-(tert-butoxycarbonylamino)-3-cyclohexylpiperidine-1-carboxylate (15 mg). LC-MS (3 min) tR=2.33 min., m/z 439 (M+Na).

Workup

  1. customThe flask was evacuated
  2. additionDry THF (5 mL) was added
  3. temperaturethe reaction mixture was allowed warmed slowly to rt
  4. waitAfter 20 min
  5. customto quench
  6. customthe reaction
  7. customThe reaction mixture was partitioned between EtOAc (50 mL)
  8. extractionThe aqueous layer was extracted with EtOAc (20 mL)
  9. washThe combined EtOAc layers were washed with water (15 mL) and brine (15 mL)
  10. dry with materialdried over Na2SO4
  11. concentrationAfter concentration
  12. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-a719b5758f394a37a4f9170061ce26a7
Source dataset
uspto-grants-2013_06
Patent number
US08455521B2

Reaction notes

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