Water → HCID 178434530, compound

HRID 2068623Notes

Reaction equation

HRID 2068623 reaction equation
Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:19][C:20]1[C:24]([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)=[CH:23][NH:22][N:21]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 86646712HCID 86646712, compoundHCID 178434487HCID 178434487, compound

Product 1

HCID 178434530HCID 178434530, compoundYield 30.4%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
140 °C

Procedure

cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.09 g, 0.27 mmol) was combined with 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62 mg, 0.3 mmol), caesium carbonate (0.134 g, 0.41 mmol), and palladium tetrakis(triphenylphosphine) (0.031 g, 0.03 mmol) in DME (3 mL), IMS 0.6 mL) and water (0.3 mL). The reaction mixture was degassed then heated by microwave irradiation to 140° C. for 20 minutes then further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.067 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added. The mixture was heated by microwave irradiation to 140° C. for 20 minutes followed by addition of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g) and further heating at 140° C. for 20 minutes. Further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.097 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added and the mixture heated by microwave irradiation to 140° C. for a final 20 minutes before diluting with water and extraction with DCM (×3). The organic solution was dried over sodium sulfate, filtered and the solvent removed by evaporation. The residue was purified by chromatography on a silica II cartridge, eluting with 10-50% ethyl acetate in cyclohexane and then was further purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound as a white solid (0.027 g). LCMS m/z 330.30 [M+H]+ R.T.=9.62 min (Analytical Method 2).

Workup

  1. customThe reaction mixture was degassed
  2. additionfurther quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.067 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added
  3. temperatureThe mixture was heated by microwave irradiation to 140° C. for 20 minutes
  4. additionfollowed by addition of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g)
  5. temperaturefurther heating at 140° C. for 20 minutes
  6. additionFurther quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.097 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added
  7. temperaturethe mixture heated by microwave irradiation to 140° C. for a final 20 minutes
  8. additionbefore diluting with water and extraction with DCM (×3)
  9. dry with materialThe organic solution was dried over sodium sulfate
  10. filtrationfiltered
  11. customthe solvent removed by evaporation
  12. customThe residue was purified by chromatography on a silica II cartridge
  13. washeluting with 10-50% ethyl acetate in cyclohexane
  14. customwas further purified by HPLC
  15. washeluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes
  16. additionThe fractions containing the desired product
  17. customwere freeze-dried

Sources & evidence

ORD record
ord-4c8ac67c86bb4a938135afdf123d5498
Source dataset
uspto-grants-2012_10
Patent number
US08299063B2

Reaction notes

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