Water → (3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl)methanol

HRID 1993163Notes

Reaction equation

HRID 1993163 reaction equation
[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[CH2:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH2:25].[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:25])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1

Participants

6

Reactant 4

HCID 962WaterHCID 5234Sodium ChlorideHCID 789669-Borabicyclo(3.3.1)nonaneHCID 576810508-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine

Product 1

HCID 57681011(3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (4.48 g, 20.4 mmol) in anh THF (255 mL) at −78° C. under Ar, 9-BBN (61.2 mL, 0.5M in THF, 30.6 mmol) was added dropwise over 8 min (a suspension). The cooling bath was replaced with ice-H2O and the reaction was allowed to warm slowly to rt. After being stirred for 17 h, H2O (100 mL,) was added followed by, after ˜5 min, NaBO3.H2O (12.2 g, 122.3 mmol) added in one lot. The reaction was stirred at rt for 5 h and then filtered through Celite. The Celite and residual solids were washed with DCM and EtOAc. The filtrate was concentrated under reduced pressure to yield an aq solution, which was saturated with NaCl and extracted with EtOAc (3×). The extracts were dried (Na2SO4) and concentrated under reduced pressure to yield a light yellow oil which was purified by flash chromatography on SiO2 (9:1 DCM:MeOH) to afford the title compound as a light yellow oil; HPLC: tR (mass-directed HPLC, polar7min) 2.52 min; MS (ES+): 238.0. The addition may be carried out at 0° C. Suspension quickly clears up after the exchange of cooling baths. The final product contained 1,5-cis-octanediol derived from 9-BBN. Based on 1H NMR estimated roughly to be 66% target material and 33% of the byproduct. The crude product was taken onto next step crude, stereoselectivity of the product was 4-5:1 as judged by 1H NMR.

Workup

  1. customafter ˜5 min
  2. stirringThe reaction was stirred at rt for 5 h
  3. filtrationfiltered through Celite
  4. washThe Celite and residual solids were washed with DCM and EtOAc
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customto yield an aq solution, which
  7. extractionextracted with EtOAc (3×)
  8. dry with materialThe extracts were dried (Na2SO4)
  9. concentrationconcentrated under reduced pressure
  10. customto yield a light yellow oil which
  11. customwas purified by flash chromatography on SiO2 (9:1 DCM:MeOH)

Sources & evidence

ORD record
ord-89df6a861ade4f1385ccee0b33f3e93b
Source dataset
uspto-grants-2010_01
Patent number
US07651687B2

Reaction notes

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