Hydrochloric Acid → 3-Benzyl-3-azabicyclo(3.2.1)octan-8-one

HRID 1804642Notes

Reaction equation

HRID 1804642 reaction equation
[CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]=[O:10].Cl.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18](O)(C)(C)C>O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:12][CH:16]2[C:9](=[O:10])[CH:13]([CH2:14][CH2:15]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 712Formaldehyde2×HCID 6386tert-ButanolHCID 7504BenzylamineHCID 8452Cyclopentanone

Product 1

HCID 156391343-Benzyl-3-azabicyclo(3.2.1)octan-8-oneYield 44%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 962WaterSolvent

Conditions

Temperature
800 °C

Procedure

To a solution of benzylamine (21.85 ml, 200 mmol) in tert-butanol (48 ml) was added paraformaldehyde (12 g, 400 mmol), conc. HCl (18 ml, 220 mmol) and cyclopentanone (46 ml, 520 mmol) and the resulting mixture heated at 800° C. for 3 h. The mixture was cooled and diluted with water (200 ml) and extracted with EtOAc (3×200 ml); combined organic layers discarded and remaining aqueous layer evaporated. The residue dissolved in acetic acid (200 ml) and added over 1 h to a mixture of paraformaldehyde (12 g, 400 mmol) and cone. HCl (16.4 ml, 200 mmol) in acetic acid (200 ml) heated at 95° C. After complete addition mixture continued heating at 95° C. for 1 h then cooled to RT and evaporated. The residue was partitioned between EtOAc and sat. NaHCO3, the organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (450 ml), gradient rising from 100% Hexanes to 25% EtOAc in Hexanes (1500 ml), then 25% EtOAc in Hexanes (1000 ml), to afford the title compound 19 g (44%) as a clear oil. 1H NMR (CDCl3): 1.88 (m, 2H), 2.07 (m, 2H), 2.18 (s, 2H), 2.56 (d, J 10.0 Hz, 2H), 2.99 (m, 2H), 3.61 (d, J 2.0 Hz, 2H), 7.29 (m, 1H), 7.35 (m, 4H).

Workup

  1. temperatureThe mixture was cooled
  2. extractionextracted with EtOAc (3×200 ml)
  3. customevaporated
  4. dissolutionThe residue dissolved in acetic acid (200 ml)
  5. temperatureAfter complete addition mixture continued heating at 95° C. for 1 h
  6. temperaturethen cooled to RT
  7. customevaporated
  8. customThe residue was partitioned between EtOAc and sat. NaHCO3
  9. washthe organic layer washed with sat. NaCl
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. customevaporated
  13. customThe residue was purified by MPLC (Biotage Horizon: FLASH 65i) eluent

Sources & evidence

ORD record
ord-ead2c20ae12f4e7db17cc36bd1375789
Source dataset
uspto-grants-2013_01
Patent number
US08354403B2

Reaction notes

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