Potassium Carbonate → 5-(3,6-Dihydro-2H-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide

HRID 469776Notes

Reaction equation

HRID 469776 reaction equation
I[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:41]2[CH2:42][CH2:43][O:44][CH2:45][CH:46]=2)O1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:44]1[CH2:43][CH:42]=[C:41]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])[CH2:46][CH2:45]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 866782085-Iodo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

Product 1

HCID 715091725-(3,6-Dihydro-2H-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamideYield 9%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

5-Iodo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (49.6 mg, 100 μmol), potassium carbonate (39.5 mg, 286 μmol) and PdCl2(dppf) (3.89 mg, 4.76 μmol) were combined to give a light red solid. To this solid was added a solution of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran, (CAN 287944-16-5, 0.02 g, 95.2 μmol) in degassed DMF (2 mL). The reaction mixture was stirred at 80° C. overnight, after cooling extracted with i-propyl acetate (2×75 mL) and washed with water (1×10 mL) to pH 7. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% i-propyl acetate in n-heptane) followed by preparative TLC (silica gel, 1.0 mm, 1:1 n-heptane/i-propyl acetate) to give the title compound (4 mg, 9%) as light brown solid; MS (ESI) 453.1 (M+H)+.

Workup

  1. customto give a light red solid
  2. temperatureafter cooling
  3. extractionextracted with i-propyl acetate (2×75 mL)
  4. washwashed with water (1×10 mL) to pH 7
  5. dry with materialdried with Na2SO4
  6. concentrationconcentrated in vacuo
  7. customto give a brown oil
  8. customThe crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% i-propyl acetate in n-heptane)

Sources & evidence

ORD record
ord-faf88700b0404d118a6a7688b2d660bd
Source dataset
uspto-grants-2014_01
Patent number
US08629166B2

Reaction notes

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