Cesium fluoride → (S)-Methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2',4'-difluoro-6'-((S)-pent-4-en-2-yloxy)-[1,1'-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate

HRID 1482021Notes

Reaction equation

HRID 1482021 reaction equation
[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C([Sn](CCCC)(CCCC)[C:44]1[C:49]([O:50][C@H:51]([CH2:53][CH:54]=[CH2:55])[CH3:52])=[CH:48][C:47]([F:56])=[CH:46][C:45]=1[F:57])CCC.[F-].[Cs+].[SnH4]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:48]5[C:49]([O:50][C@H:51]([CH2:53][CH:54]=[CH2:55])[CH3:52])=[CH:44][C:45]([F:57])=[CH:46][C:47]=5[F:56])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

8

Reactant 4

HCID 25953Cesium fluorideHCID 123161StannaneHCID 118308811(S)-Methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetateHCID 131736659(S)-Tributyl(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)stannane

Product 1

HCID 118308876(S)-Methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2',4'-difluoro-6'-((S)-pent-4-en-2-yloxy)-[1,1'-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetateYield 53.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.25 g, 0.428 mmol, 1 equiv) and (S)-tributyl(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)stannane (0.25 g, 0.513 mmol, 1.2 equiv) in DMF (2 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (49 mg, 0.043 mmol, 0.1 equiv), CsF (195 mg, 1.28 mmol, 3 equiv), and CuI (20 mg, 0.107 mmol, 0.25 equiv). The reaction was heated at 80° C. for 2 h. After 2 h, more stannane (300 mg) was added. Stir for 2 h and remove from heat. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (160 mg, 53%) as a film. LCMS (ESI, M+1): 702.25.

Workup

  1. customremove
  2. temperaturefrom heat
  3. temperatureUpon cooling to ambient temperature
  4. additionthe reaction was diluted with EtOAc
  5. washwashed with water
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane)

Sources & evidence

ORD record
ord-7ddec2cf04e647f2b9dd596dd1b812af
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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