Water → (S)-methyl 2-(tert-butoxy)-2-(4-(4-(difluoromethyl)phenyl)-2-methyl-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate

HRID 2406402Notes

Reaction equation

HRID 2406402 reaction equation
[F:1][CH:2]([F:18])[C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.[C:28]([O:32][C@@H:33]([C:38]1[C:39](I)=[C:40]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:46]=3[S:45][C:41]2=[N:42][C:43]=1[CH3:44])[C:34]([O:36][CH3:37])=[O:35])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:28]([O:32][C@@H:33]([C:38]1[C:39]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:18])=[CH:8][CH:7]=2)=[C:40]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:46]=3[S:45][C:41]2=[N:42][C:43]=1[CH3:44])[C:34]([O:36][CH3:37])=[O:35])([CH3:31])([CH3:29])[CH3:30]

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 584525412-(4-(DifluoroMethyl)phenyl)-4,4,5,5-tetraMethyl-1,3,2-dioxaborolaneHCID 69673123Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate

Product 1

HCID 67607847(S)-methyl 2-(tert-butoxy)-2-(4-(4-(difluoromethyl)phenyl)-2-methyl-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetateYield 85.4%

Reagents, catalysts & solvents 2

HCID 178454866HCID 178454866, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-(4-(Difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.04 g, 4.09 mmol), potassium phosphate (1.35 g, 6.36 mmol), water (750 μL) and dichloro [1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II)™ (101 mg, 155 μmol) were added to a stirred solution of (S)-methyl 2-(tert-butoxy)-2-(4-iodo-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (750 mg, 1.58 mmol) in dioxane (11 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, sealed and then stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (30 mL) and then passed through a pad of celite. The layers of the filtrate were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography eluting with ethyl acetate in heptane (10%) to give the title compound (639 mg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=0.96 (s, 9H), 1.85-1.35 (m, 6H), 2.72 (s, 3H), 2.85-2.75 (m, 2H), 3.67 (s, 3H), 4.95 (s, 1H), 6.76 (t, 1H), 6.45 (d, 1H), 7.61-7.51 (m, 3H). LCMS (run time=5 minutes, basic): Rt=3.37 minutes; m/z 474.23 [M+H+].

Workup

  1. customThe reaction mixture was degassed with argon for 2 minutes
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additiondiluted with ethyl acetate (30 mL) and water (30 mL)
  5. customThe layers of the filtrate were separated
  6. extractionthe aqueous layer was extracted with ethyl acetate (3×30 mL)
  7. dry with materialThe combined organic layers were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customto yield the crude product
  10. customThe residue was purified by flash column chromatography
  11. washeluting with ethyl acetate in heptane (10%)

Sources & evidence

ORD record
ord-fcf91a6c0e054be39edbaad140cf7b57
Source dataset
uspto-grants-2014_08
Patent number
US08809363B2

Reaction notes

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