2,2,6,6-Tetramethylpiperidine → 2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid

HRID 1621586Notes

Reaction equation

HRID 1621586 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][N:3]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC>C1COCC1.O>[F:1][C:2]1[C:7]([B:18]([OH:23])[OH:19])=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 130352,2,6,6-TetramethylpiperidineHCID 21531Triisopropyl borateHCID 665999572-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridineHCID 178418339Butyllithium

Product 1

HCID 666000612-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acidYield 97.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (1.078 g, 4.359 mmol) and triisopropyl borate (2.50 mL, 10.9 mmol) were dissolved in THF (11.5 mL). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.11 mL, 6.54 mmol) was dissolved in THF (12 mL) and the flask was cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 3.8 mL, 6.1 mmol) was added via syringe, and the yellow solution was stirred under nitrogen for 15 min. Then, the contents were transferred via syringe to the other flask, which was pre-cooled in a dry ice/acetone bath. After completing the transfer, the reaction was stirred under nitrogen at −78° C. for 1 h. Then, the reaction was allowed to slowly warm up to room temperature while being stirred overnight. The reaction was treated with water (30 mL) and stirred for about 30 min. The layers were separated, and the organic phase was extracted with 1 N aqueous NaOH (15 mL). The organic phase was discarded, and the aqueous phase was treated with aqueous 5N HCl to lower the pH to around 5-6. The aqueous phase was extracted with 10:1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to afford 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g). 1H NMR (400 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 2H), 4.16 (q, J=7.37 Hz, 1H), 2.47 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, +ve ion) 292 (M+H)+.

Workup

  1. temperaturethe flask was cooled in an ice water bath
  2. customThen, the contents were transferred via syringe to the other flask, which
  3. temperaturewas pre-cooled in a dry ice/acetone bath
  4. stirringthe reaction was stirred under nitrogen at −78° C. for 1 h
  5. stirringwhile being stirred overnight
  6. stirringstirred for about 30 min
  7. customThe layers were separated
  8. extractionthe organic phase was extracted with 1 N aqueous NaOH (15 mL)
  9. additionthe aqueous phase was treated with aqueous 5N HCl
  10. extractionThe aqueous phase was extracted with 10:1 DCM/MeOH
  11. concentrationconcentrated
  12. customdried under high vacuum

Sources & evidence

ORD record
ord-d5bc595877274756b15df6a737b8da1b
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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