Phosphoric Acid → 1-(2-(Tert-butoxy)pyridin-4-yl)-4-chloro-5-phenylphthalazine

HRID 593716Notes

Reaction equation

HRID 593716 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:18])=[N:4][N:3]=1.[C:19]([O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1)([CH3:22])([CH3:21])[CH3:20].P(=O)(O)(O)O.[K]>O1CCOCC1.O.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].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>[C:19]([O:23][C:24]1[CH:29]=[C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:18])=[N:4][N:3]=2)[CH:27]=[CH:26][N:25]=1)([CH3:22])([CH3:20])[CH3:21]

Participants

9

Reactant 4

HCID 1004Phosphoric AcidHCID 5462222PotassiumHCID 457859932-(tert-Butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 904244121,4-Dichloro-5-phenylphthalazine

Product 1

HCID 904241491-(2-(Tert-butoxy)pyridin-4-yl)-4-chloro-5-phenylphthalazineYield 70.8%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 11710396Tricyclohexylphosphonium TetrafluoroborateCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of 1,4-dichloro-5-phenylphthalazine (0.400 g, 1.45 mmol), 2-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.484 g, 1.75 mmol) in dioxane (20 mL) and water (2 mL) was added phosphoric acid, potassium salt (0.617 g, 2.91 mmol). The reaction mixture was purged with nitrogen gas for 30 min and then Pd2(dba)3 (0.013 g, 0.015 mmol) was added followed by tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.029 mmol). The purging was continued for a further 15 min and the reaction mixture heated to 95° C. for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using Combiflash Isco (REDISEP®, SiO2, 12 g, 0-30% ethyl acetate/petroleum ether) to get 1-(2-(tert-butoxy)pyridin-4-yl)-4-chloro-5-phenylphthalazine (0.400 g, 33.2%) as a brown solid. LCMS (Condition 11): retention time 1.22 min, [M+1]=390.2. 1H NMR (400 MHz, DMSO-d6) δ 1.70 (s, 9 H), 6.84 (br s, 1 H), 7.05 (dd, J=1.2 Hz, J=5.2 Hz, 1 H), 7.36-7.44 (m, 2 H), 7.47-7.51 (m, 3 H), 8.06 (dd, J=1.2 Hz, J=7.6 Hz, 1 H), 8.15 (dd, J=0.8 Hz, J=4.8 Hz, 1 H), 8.26 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.47 (d, J=1.2 Hz, J=8.4 Hz, 1 H).

Workup

  1. customThe reaction mixture was purged with nitrogen gas for 30 min
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was purified by flash chromatography

Sources & evidence

ORD record
ord-93214ca7b7ca41e6ac298f1c052fe855
Source dataset
uspto-grants-2016_01
Patent number
US09242966B2

Reaction notes

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