Lithium Chloride → (1R*,2R*,4'S*,5R*)-8-Benzyl-4'-(2-benzyloxy-5-trifluoromethoxyphenyl)-6-(tert-butoxycarbonyl)-2',3',4',5'-tetrahydro-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

HRID 1017277Notes

Reaction equation

HRID 1017277 reaction equation
[CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH:19]=[CH:18][CH2:17][O:16]3)[C@:9]1([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][C:42]=1I)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[Li+].C([O-])=O.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O>[CH3:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1].[CH2:1]([N:8]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:42]4[CH:43]=[C:44]([O:47][C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:46][C:41]=4[O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:17][O:16]3)[C@:9]1([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][CH:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

10

Reactant 4

HCID 433294Lithium ChlorideHCID 2735122Potassium FormateHCID 113952781-(Benzyloxy)-2-iodo-4-(trifluoromethoxy)benzene2×HCID 70152701(1R*,2R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'(5'H)-furan]

Product 2

HCID 78922-MethylpentaneHCID 70153496(1R*,2R*,4'S*,5R*)-8-Benzyl-4'-(2-benzyloxy-5-trifluoromethoxyphenyl)-6-(tert-butoxycarbonyl)-2',3',4',5'-tetrahydro-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]Yield 119.6%

Reagents, catalysts & solvents 4

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of (1R*,2R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2′(5′H)-furan] (Description 27; 3.1 g, 7.17 mmol), 2-benzyloxy-5-trifluoromethoxyphenyl iodide (8.7 g, 22.1 mmol), tetra-n-butylammonium chloride (2.0 g, 6.2 mmol), lithium chloride (3.45 g, 77.5 mmol), potassium formate (2.8 g, 33 mmol), palladium(II) acetate (250 mg, 1.1 mmol), water (0.5 ml) and N,N-dimethylformamide (30 ml) was stirred at +70° C. for 20 hours. An additional batch of 2-benzyloxy-5-trifluoromethoxyphenyl iodide (3.6 g, 9.1 mmol) and palladium(II) acetate (130 mg, 0.56 mmol) was added and the reaction mixture was stirred at +70° C. for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted into a 1:1 mixture of iso-hexane:diethyl ether (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel. (iso-hexane:diethyl ether 0-45%) to give the title compound (3 g, 60%).

Workup

  1. stirringthe reaction mixture was stirred at +70° C. for 24 hours
  2. customquenched with water
  3. extractionextracted into a 1:1 mixture of iso-hexane
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by chromatography on silica gel

Sources & evidence

ORD record
ord-e9fbea08fbc444728f9c7d7e6eaf70b3
Source dataset
uspto-grants-2002_11
Patent number
US06479486B2

Reaction notes

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