6-(2-Cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one → 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl)-2-methylpropanenitrile

HRID 858618

Reaction equation

HRID 858618 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([C:19]([OH:32])([C:30]#[CH:31])[CH2:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[O:24][C:23](=[O:29])[CH:22]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(NC(C)C)(C)C.CN(C=O)C.[NH4+].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:14]1([C:19]([OH:32])([CH2:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[O:24][C:23](=[O:29])[CH:22]=2)[C:30]#[C:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([F:13])[CH:3]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1

Participants

8

Reactant 2

HCID 224998026-(2-Cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-oneHCID 534036182-(4-Bromo-2-fluorophenyl)-2-methylpropanenitrile

Product 1

HCID 587626542-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl)-2-methylpropanenitrileYield 79.6%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 7912DiisopropylamineSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (3.0 g, 12.4 mmol) in diisopropylamine (32 mL) and DMF (16 mL) was added 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (3.2 g, 12.4 mmol), PdCl2(PPh3)2 (350 mg, 4 mol %), CuI (71 mg, 3 mol %). The mixture was heated to 90° C. for 30 min before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes) to give the product (4.2 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ: 1.65–1.76 (m, 14 H), 1.79 (s, 6 H), 1.82–1.85 (m, 1 H), 2.24 (s, 1 H), 2.59 (s, 1 H), 2.67 (m, 2 H), 5.46 (m, 1 H), 7.11 (dd, J=12.15, 1.60 Hz, 1 H), 7.18 (dd, J=8.10, 1.70 Hz, 1 H), 7.45 (t, J=8.10 Hz, 1 H).

Workup

  1. temperaturewas cooled down to room temperature
  2. extractionextracted with EtOAc (3×50 mL)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried with Na2SO4
  5. customevaporated to dryness
  6. customThe mixture was purified by flash column chromatography (10–50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-6b2cdbf996914e64a4914571ec3101d1
Source dataset
uspto-grants-2006_12
Patent number
US07148226B2

Linked notes

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