Lithium Hexamethyldisilazide → 6-Methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

HRID 2092272Notes

Reaction equation

HRID 2092272 reaction equation
[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23].Cl[C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CN(C1C=CC=CC=1C1C=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:23][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1

Participants

7

Reactant 4

HCID 2733832Lithium HexamethyldisilazideHCID 3016205(1,1'-Biphenyl)amine, N,N-dimethyl-HCID 161089744-(2-Chloropyridin-3-yl)pyrimidineHCID 444789036-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine

Product 1

HCID 162149046-Methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamineYield 56.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

6-Methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (0.100 g, 0.30 mmol), 4-(2-chloropyridin-3-yl) pyrimidine (0.057 g, 0.30 mmol), dicyclohexylphosphino)-N,N-dimethylaminobiphenyl (0.0094 g, 0.024 mmol), and Pd2(dba)3 (0.010 g, 0.012 mmol) were all placed in a sealed tube containing 5 mL of anhydrous THF. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.90 mL, 0.90 mmol) was then added to the mixture and nitrogen was bubbled into the reaction mixture for 5 min. The tube was capped and the reaction heated to 70° C. overnight. The reaction was allowed to cool to room temperature and quenched with methanol. The volatiles were removed in vacuo. The residue was taken up in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and the purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine as a yellow solid (80 mg, 56%). MS (M H)+ 473.

Workup

  1. customall placed in a sealed tube
  2. customwas bubbled into the reaction mixture for 5 min
  3. customThe tube was capped
  4. temperatureto cool to room temperature
  5. customquenched with methanol
  6. customThe volatiles were removed in vacuo
  7. washwashed (2×) with an aqueous saturated solution of sodium bicarbonate
  8. dry with materialThe organic layer was then dried with sodium sulfate
  9. customthe purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes

Sources & evidence

ORD record
ord-321a583b13fd42c3bf62fc350d816103
Source dataset
uspto-grants-2013_05
Patent number
US08440674B2

Reaction notes

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