Lithium Chloride → (1R*,2R*,4'S*,5R*)-8-Benzyl-2',3',4',5'-tetrahydro-4'-[(2RS)-2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl]-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]

HRID 1017279Notes

Reaction equation

HRID 1017279 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:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][C@H:11]2[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:36]1[C:44]2[O:43][CH:42]([CH3:45])[CH2:41][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=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>[CH2:1]([N:8]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:36]4[C:44]5[O:43][CH:42]([CH3:45])[CH2:41][C:40]=5[CH:39]=[C:38]([O:46][C:47]([F:49])([F:48])[F:50])[CH:37]=4)[CH2:17][O:16]3)[C@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][CH:11]2[S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

9

Reactant 4

HCID 433294Lithium ChlorideHCID 2735122Potassium FormateHCID 184034062,3-Dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran2×HCID 70152619(1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'(5'H)-furan]

Product 1

HCID 70152365(1R*,2R*,4'S*,5R*)-8-Benzyl-2',3',4',5'-tetrahydro-4'-[(2RS)-2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl]-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2'-furan]Yield 44.2%

Reagents, catalysts & solvents 4

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

Procedure

A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′(5′H)-furan] (Description 15; 500 mg, 1.05 mmol), 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (Description 22; 1.11 g, 3.22 mmol), tetra-n-butylammonium chloride (310 mg, 0.96 mmol), lithium chloride (640 mg, 1.48 mmol), potassium formate (420 mg, 5 mmol), palladium(II) acetate (47 mg, 0.21 mmol), water (0.2 ml) and N,N-dimethylformamide (5 ml) was stirred at +65° C. for 24 hours. An additional batch of 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (0.7 g, 2.0 mmol) and palladium(II) acetate (22 mg, 0.1 mmol) was added and the reaction mixture was stirred at +65° C. for 48 hours. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether. 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 (320 mg, 44%) as a 1:1 mixture of epimers.

Workup

  1. stirringthe reaction mixture was stirred at +65° C. for 48 hours
  2. customquenched with saturated aqueous NaHCO3
  3. extractionextracted into diethyl ether
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-45%)

Sources & evidence

ORD record
ord-20f579e6f7e04c23b1c35580719966c6
Source dataset
uspto-grants-2002_11
Patent number
US06479486B2

Reaction notes

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