1,4-Dioxane → 6-(Benzylthio)-1-(4-chloro-2-methoxyphenyl)isoquinoline

HRID 1473377Notes

Reaction equation

HRID 1473377 reaction equation
[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.CCCCCCC.O>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][C:23]=1[O:30][CH3:31])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 3858606(4-Chloro-2-methoxyphenyl)boronic acidHCID 866874176-(Benzylthio)-1-chloroisoquinoline

Product 1

HCID 866874206-(Benzylthio)-1-(4-chloro-2-methoxyphenyl)isoquinolineYield 74.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21899848Ethylacetate heptaneSolvent

Conditions

Temperature
100 °C

Procedure

A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinoline (from STEP 1 of INTERMEDIATE LLL) (688.23 mg, 2.408 mmol), (4-chloro-2-methoxyphenyl)boronic acid (494 mg, 2.65 mmol), Pd(AmPhos)2Cl2 (85 mg, 0.120 mmol), potassium phosphate (1534 mg, 7.22 mmol), dioxane (6020 μl), and water (2007 μl). The vial was flushed with Ar (g), then 1,4-dioxane (6020 μl) and water (2007 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The mixture was cooled to room temperature, then diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (40-g, 10 to 40%, then 40-70% EtOAc/Heptane, 25-g silica gel loading column) to give 6-(benzylthio)-1-(4-chloro-2-methoxyphenyl)isoquinoline (704.36 mg, 1.797 mmol, 74.6% yield) as a light-yellow foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.56 (d, J=5.8 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.55-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.38-7.27 (m, 5H), 7.11 (dd, J=1.9, 8.1 Hz, 1H), 7.04 (d, J=1.9 Hz, 1H), 4.30 (s, 2H), 3.70 (s, 3H); m/z (ESI) 392.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. addition1,4-dioxane (6020 μl) and water (2007 μl) were added
  3. customThe vial was sealed
  4. temperatureThe mixture was cooled to room temperature
  5. additiondiluted with water
  6. extractionextracted with EtOAc (2×)
  7. dry with materialThe combined organic extracts were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified by chromatography on silica gel (40-g, 10 to 40%

Sources & evidence

ORD record
ord-ba03fca48cbd42718245990a7398c214
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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