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

HRID 63965Notes

Reaction equation

HRID 63965 reaction equation
[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:29]([O:33][C@@H:34]([C:39]1[C:40](I)=[C:41]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:47]=3[S:46][C:42]2=[N:43][C:44]=1[CH3:45])[C:35]([O:37][CH3:38])=[O:36])([CH3:32])([CH3:31])[CH3:30]>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:33][C@@H:34]([C:39]1[C:40]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=2)=[C:41]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:47]=3[S:46][C:42]2=[N:43][C:44]=1[CH3:45])[C:35]([O:37][CH3:38])=[O:36])([CH3:32])([CH3:30])[CH3:31]

Participants

8

Reactant 3

HCID 81531DiisopropylethylamineHCID 27606054,4,5,5-Tetramethyl-2-(4-(trifluoromethyl)phenyl)-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 67607979(S)-methyl 2-(tert-butoxy)-2-(2-methyl-4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro benzo[4,5]thieno[2,3-b]pyridin-3-yl)acetateYield 72.7%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-(4-(Trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (115 g, 0.42 mmol), N-ethyl-N-isopropylpropan-2-amine (120 μL, 0.64 mmol) and water (500 μL) 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 (100 mg, 0.21 mmol) in dioxane (2 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, then tetrakis(triphenylphosphine)palladium(0) (25 mg, 21 μmol) was added and the vessel was sealed and heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (30 mL) and the mixture was passed through a pad of celite. The layers of the filtrate were separated and the organic layer was washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to yield the crude product as a brown gum. The residue was purified by flash column chromatography eluting with ethyl acetate in heptane (10%) to give the title compound (75 mg, 72%) 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), 3.69 (s, 3H), 4.91 (s, 1H), 7.40 (d, 1H), 7.61 (d, 1H), 7.71 (m, 2H). LCMS (run time=5 minutes, basic): Rt=3.64 minutes; m/z 492.06 [M+H+].

Workup

  1. customThe reaction mixture was degassed with argon for 2 minutes
  2. customthe vessel was sealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customThe layers of the filtrate were separated
  5. washthe organic layer was washed with brine (30 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customto yield the crude product as a brown gum
  9. customThe residue was purified by flash column chromatography
  10. washeluting with ethyl acetate in heptane (10%)

Sources & evidence

ORD record
ord-4ae5393f86f44a7db45e1eac58835424
Source dataset
uspto-grants-2016_09
Patent number
US09447116B2

Reaction notes

Loading…