Triethylamine → 3-Chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile

HRID 2167665Notes

Reaction equation

HRID 2167665 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH3:13])#[CH:2].[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19](Cl)[CH:20]=1.C(N(CC)CC)C>CN(C=O)C.[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>[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=2[CH3:13])[CH:20]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 27696993,5-Dichloro-2-cyanopyridineHCID 581665151-Ethynyl-4-(methoxymethoxy)-2-methylbenzene

Product 1

HCID 670655293-Chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1.0 equiv.), 3,5-dichloropicolinonitrile (6-9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60° C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.

Workup

  1. customflushed with nitrogen
  2. temperatureAfter cooling to room temperature
  3. additionwater was added
  4. extractionThe mixture was extracted with EA (2×)
  5. washThe combined organic layers were washed with 10% aq NH4OH (2×), brine
  6. concentrationconcentrated
  7. filtrationThe crude material was filtered through a pad of silica (wetted with hexane)
  8. washThe silica was eluted with 10% EA in Hex
  9. concentrationconcentrated
  10. washThe resulting solids were washed in hot ether
  11. filtrationfiltered
  12. customto give a yellow solid, which
  13. customwas used in the next step without further purification
  14. concentrationThe filtrate was concentrated
  15. custompurified by Combiflash

Sources & evidence

ORD record
ord-6445163a7757466b86d1b807ad73bd25
Source dataset
uspto-grants-2015_06
Patent number
US09045470B2

Reaction notes

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