1,4-Dioxane → 4-Cyano-3-(3-methyl-isoquinolin-4-yl)-benzoic acid methyl ester

HRID 1909052Notes

Reaction equation

HRID 1909052 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][C:3]=2[CH3:12])[CH:17]=1

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 37777034-Bromo-3-methyl-isoquinolineHCID 56973105HCID 56973105, compound

Product 1

HCID 665996304-Cyano-3-(3-methyl-isoquinolin-4-yl)-benzoic acid methyl esterYield 67.1%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

Into a 40 mL screw-top vial with a stirbar was added 3 (500 mg, 2.25 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (776 mg, 2.70 mmol, 1.2 eq) (prepared according to procedure in J. Am. Chem. Soc., 127, 10539, (2005)), and K3PO4 (1.004 g, 4.73 mmol. 2.1 eq) in a 10:1 mixture of 1,4-dioxane:H2O (10 mL/1 mL). To the solution was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (31.9 mg, 2 mol %), the vial capped and the contents heated to 100° C. for 4 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The solid was filtered and the filtrate washed with water (2×30 mL), brine, followed by drying over Na2SO4, and concentrating to a yellow oil. The crude product was purified using Biotage MPLC system (25S column size, 0-30% ethyl acetate/heptane, over 30CV, then 30% isocratic for 10CV) giving white solid as the product (455 mg, 1.51 mmol, 67%). 1H NMR (CDCl3, 400 MHz): δ 9.34 (s, 1H), δ 8.30-8.27 (dd, 1H), δ 8.13 (s, 1H), δ 8.08-8.05 (m, 1H), δ 8.00-7.98 (d, 1H), δ 7.64-7.61 (m, 2H), δ 7.17-7.15 (m, 1H), δ 3.99 (s, 1H), δ 2.51 (s, 3H); LRMS (m/z): 303 (M+H)

Workup

  1. customthe vial capped
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationThe solid was filtered
  4. washthe filtrate washed with water (2×30 mL), brine
  5. dry with materialby drying over Na2SO4
  6. concentrationconcentrating to a yellow oil
  7. customThe crude product was purified

Sources & evidence

ORD record
ord-96ac3a0861394c9d99533f60fe2d2b17
Source dataset
uspto-grants-2013_12
Patent number
US08598217B2

Reaction notes

Loading…