2-Methyl-3-butyn-2-ol → 8-fluoro-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamide

HRID 575453Notes

Reaction equation

HRID 575453 reaction equation
Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:17]3[CH2:18][CH:15]([CH2:16]3)[C:8]3[S:9][C:10]([C:12]([NH2:14])=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>[Cu]I.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.CN(C)C=O.C(N(CC)CC)C>[F:20][C:3]1[C:2]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:19][C:6]2[C:7]3[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[S:9][C:8]=3[CH:15]3[CH2:16][CH:17]([C:5]=2[CH:4]=1)[CH2:18]3

Participants

6

Reactant 2

HCID 82582-Methyl-3-butyn-2-ol2×HCID 866935159-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamide

Product 1

HCID 866935168-fluoro-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamideYield 62.5%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 178418476HCID 178418476, compoundCatalyst2×HCID 22056947triethylamine N,N-dimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Into a pressure tube containing a solution of 9-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamide (31 mg, 0.08 mmol) in 1:1 N,N-dimethylformamide/triethylamine (0.8 mL) was introduced 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and nitrogen gas bubbled through the solution for 3 minutes. Bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) was added and nitrogen bubbling continued a further two minutes before the pressure tube was closed under nitrogen. The reaction mixture was warmed to 80° C. for 20 hr, re-treated with 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) and warmed to 100° C. for an additional 7 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue re-dissolved in ethyl acetate (20 mL). This solution was washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate absorbed onto silica gel. Purification by silica gel flash column chromatography (eluent:heptane/ethyl acetate) furnished partially purified product as a brown solid. After several acetonitile solubilisation-evaporation (in vacuo) cycles, the resulting solid residue was slurried in acetonitrile (1.0 mL) and collected by filtration to furnish the title compound (17 mg, 0.05 mmol, 62%) as a pale-brown solid: 1H NMR (500 MHz, CDCl3) δ1.68 (s, 6H), 1.71-1.73 (m, 2H), 2.87-2.96 (m, 2H), 3.53-3.62 (m, 2H), 6.87 (d, J=10.09 Hz, 1H), 7.92 (d, J=6.94 Hz, 1H), 8.06 (s, 1H); M+H=356.

Workup

  1. custombubbled through the solution for 3 minutes
  2. customwas closed under nitrogen
  3. temperaturewarmed to 100° C. for an additional 7 hr
  4. temperatureAfter cooling to room temperature
  5. customthe reaction mixture was evaporated in vacuo
  6. dissolutionthe residue re-dissolved in ethyl acetate (20 mL)
  7. washThis solution was washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (5 mL)
  8. extractionThe organic extract
  9. dry with materialwas dried over sodium sulfate
  10. filtrationfiltered
  11. customthe filtrate absorbed onto silica gel
  12. customPurification by silica gel flash column chromatography (eluent:heptane/ethyl acetate)
  13. customfurnished partially purified product as a brown solid
  14. customAfter several acetonitile solubilisation-evaporation (in vacuo) cycles
  15. filtrationcollected by filtration

Sources & evidence

ORD record
ord-b6e43cd1f6374a08acb1fd05ced1aa46
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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