2-Methyl-3-butyn-2-ol → HCID 86693503, compound

HRID 575443Notes

Reaction equation

HRID 575443 reaction equation
[F:1][CH:2]([N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15](I)=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3)[F:3].[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>N1CCCCC1.[Cu]I.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>[F:1][CH:2]([F:3])[N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3

Participants

6

Reactant 2

HCID 82582-Methyl-3-butyn-2-olHCID 86693501HCID 86693501, compound

Product 1

HCID 86693503HCID 86693503, compoundYield 39.7%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8082PiperidineSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of -(difluoromethyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (12 mg at 80% purity LCMS-UV215) in piperidine (0.5 mL) was introduced 2-methyl-3-butyn-2-ol (12 mg, 0.14 mmol) and copper(I) iodide (0.3 mg, 0.001 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (0.6 mg, 0.001 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (2×7 mL), water (2×7 mL) and brine (7 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Partial purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile/water (3:1, 0.4 mL). Filtration furnished the title compound (4.5 mg, 0.011 mmol, 6% over 3 steps) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.67 (s, 6H), 1.73 (d, J=11.35 Hz, 2H), 2.93-3.04 (m, 2H), 3.60 (td, J=7.96, 3.31 Hz, 1H), 3.84-3.92 (m, 1H), 5.56 (br. s., 1H), 6.87 (d, J=10.09 Hz, 1H), 7.42 (br. s., 1H), 8.40 (d, J=7.57 Hz, 1H), 8.75 (t, J=58.40 Hz, 1H); M+H=390.

Workup

  1. custombubbling
  2. waitcontinued for a further two minutes
  3. customThe pressure tube was closed under an atmosphere of nitrogen
  4. customAfter evaporation of the reaction mixture in vacuo
  5. washwashed with saturated aqueous sodium bicarbonate (2×7 mL), water (2×7 mL) and brine (7 mL)
  6. extractionThe organic extract
  7. dry with materialwas dried over sodium sulfate
  8. filtrationfiltered
  9. customPartial purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient)
  10. additionwas followed by suspension of the product in acetonitrile/water (3:1, 0.4 mL)
  11. filtrationFiltration

Sources & evidence

ORD record
ord-c8ffe58622864b8cb3793ad564dce65e
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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