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

HRID 631173Notes

Reaction equation

HRID 631173 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 (8) (1.0 equiv.), 3,5-dichloropicolinonitrile (9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25M) 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 (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-3d784862ff3846f498f7d560c26d6033
Source dataset
uspto-grants-2016_04
Patent number
US09320748B2

Reaction notes

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