Acetonitrile → (S)-Methyl 4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoate

HRID 1476737Notes

Reaction equation

HRID 1476737 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.C(N(CC)CC)C.[C]=O>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([C:6]([O:5][CH3:1])=[O:7])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 8471TriethylamineHCID 56973617(S)-tert-Butyl (1-(4-bromophenyl)ethyl)carbamateHCID 178418416HCID 178418416, compound

Product 1

HCID 57432297(S)-Methyl 4-(1-((tert-butoxycarbonyl)amino)ethyl)benzoateYield 143.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 887MethanolSolvent

Conditions

Temperature
85 °C

Procedure

To a Parr autoclave with mechanical stirring, add Pd(OAc)2 (120 mg, 0.53 mmol), 1,1′-bis(diphenylphosphino)ferrocene (355 mg, 0.64 mmol), (S)—N-tert-butoxycarbonyl-1-(4-bromophenyl)ethylamine (1.50 g, 5.0 mmol), anhydrous CH3CN (45 mL), anhydrous CH3OH (30 mL), and triethylamine (1.9 mL, 13.63 mmol). Seal the vessel and pressurize with carbon monoxide to 724 kPag. Heat the vessel to 85° C. and stir the mixture overnight. Vent the reaction vessel (Caution—poison gas!) and transfer to a round-bottomed flask, rinsing with CH3OH. Concentrate the mixture under reduced pressure to furnish an orange residue. Add water (50 mL), then extract with EtOAc (2×50 mL). Wash the combined organic phases with saturated aqueous NaCl (25 mL), then separate the layers, dry the organic phase over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure to give crude product. Purify the product by flash chromatography on silica gel eluting with a gradient of 0% to 60% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a white solid (1.00 g, 72% yield). Mass spectrum (m/z) 224 (M+2H−t-Bu)+, 302 (M+Na)+, 581 (2M+Na)+. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, =8.4 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.64 (dq, J=7.4, 6.8 Hz, 1H), 3.82 (s, 3H), 1.34 (br s, 9H), 1.28 (d, J=7.2 Hz, 3H).

Workup

  1. customSeal the vessel
  2. customtransfer to a round-bottomed flask
  3. washrinsing with CH3OH
  4. concentrationConcentrate the mixture under reduced pressure
  5. customto furnish an orange residue
  6. extractionAdd water (50 mL), then extract with EtOAc (2×50 mL)
  7. washWash the combined organic phases with saturated aqueous NaCl (25 mL)
  8. customseparate the layers
  9. dry with materialdry the organic phase over MgSO4
  10. filtrationfilter
  11. customto remove the solids
  12. concentrationconcentrate the filtrate under reduced pressure
  13. customto give crude product
  14. customPurify the product by flash chromatography on silica gel eluting with a gradient of 0% to 60% EtOAc/hexanes
  15. concentrationConcentrate the fractions
  16. additioncontaining the desired product under reduced pressure

Sources & evidence

ORD record
ord-7ea46708d9f542f18c7907968d290b17
Source dataset
uspto-grants-2016_08
Patent number
US09402838B2

Reaction notes

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