Furan → 2-Furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]non-7-yl)methanone

HRID 218072Notes

Reaction equation

HRID 218072 reaction equation
Cl.CNOC.C[Al](C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH:23]2[CH2:25][CH:19]([CH2:20][CH:21]([C:26]([O-])=[O:27])[CH2:22]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[Li:34].[O:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1.[Li]CCCC>C1COCC1>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[Li:34].[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:26]([CH:21]1[CH2:20][CH:19]2[CH2:25][CH:23]([CH2:24][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:18]2)[CH2:22]1)=[O:27]

Participants

9

Reactant 6

HCID 8029FuranHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 16682925TrimethylaluminumHCID 744204333-(Tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylateHCID 178418296HCID 178418296, compoundHCID 178418339Butyllithium

Product 2

HCID 684698392-Furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]non-7-yl)methanoneYield 16%HCID 178418296HCID 178418296, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-10 °C

Procedure

To a suspension of N,O-dimethylhydroxylamine hydrochloride (0.068 g 0.70 mmol) in anhydrous THF (3 mL) was added trimethylaluminum (2.0 M solution in toluene, 0.35 mL, 0.70 mmol) at −10° C. After stirring for 10 min at −10° C., a solution of methyl (3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylate (0.100 g, 0.353 mmol) in THF (1 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction was then cooled to −70° C. and was treated with a freshly prepared 2-furanyllithium in THF (5 mL) solution (Note: the 2-furanyllithium was prepared by treating furan (0.24 g, 3.5 mmol) with n-BuLi (2.5 M solution in THF, 1.4 mL, 3.5 mmol) at −78° C.). The reaction mixture was warmed to ambient temperature over 1 h and quenched with saturated aqueous ammonium chloride solution (5 mL). The volatiles were removed in vacuo, and the residue was triturated with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by HPLC, to yield 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]non-7-yl)methanone (0.018 g, 16% yield). A portion of this material (4.5 mg, 14 μmol) was dissolved in a 1:1 mixture of anhydrous dichloromethane and TFA. After stirring for 1 h at ambient temperature, the volatiles were evaporated, and the resulting residue was dried on high vacuum to yield 3.2 mg (68% yield) of 2-furanyl(3-azabicyclo[3.3.1]non-7-yl)methanone trifluoroacetate as a pale yellow oil (1H NMR (CD3OD): δ 7.68 (s, 1H), 6.75 (d, J=2.68 Hz, 1H), 6.58 (m, 1H), 4.16-4.11 (m, 1H), 3.52-3.14 (m 3H), 2.64-2.57 (m 1H), 2.25-1.87 (m, 8H) (LC/MS (MH+): 220).

Workup

  1. temperatureThe reaction mixture was warmed to ambient temperature
  2. stirringstirred for 1 h
  3. temperatureThe reaction was then cooled to −70° C.
  4. temperatureThe reaction mixture was warmed to ambient temperature over 1 h
  5. customquenched with saturated aqueous ammonium chloride solution (5 mL)
  6. customThe volatiles were removed in vacuo
  7. customthe residue was triturated with ethyl acetate (2×10 mL)
  8. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. custompurified by HPLC

Sources & evidence

ORD record
ord-2f6a3fcd4b0e498f8e7f9dcafe5d5c23
Source dataset
uspto-grants-2012_06
Patent number
US08198296B2

Reaction notes

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