Acetic Acid → 4-[(Oxan-4-yl)oxy]benzonitrile

HRID 529975Notes

Reaction equation

HRID 529975 reaction equation
[OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CC(O)=O>CN(C=O)C.CC(O)(C)C>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 121634-ChlorobenzonitrileHCID 24758Sodium hydrideHCID 74956Tetrahydro-4H-pyran-4-ol

Product 1

HCID 242295274-[(Oxan-4-yl)oxy]benzonitrile

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
60 °C

Procedure

Step-1: To a stirred solution of 4-hydroxytetrahydropyran (3.80 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.0466 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.038 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 30% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(tetrahydropyran-4-yloxy)benzonitrile), as a white solid. (5.7 g, 76%): LC Rt=2.72; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.63-1.75 (m, 2H), 2.02-2.10 (m, 2H), 3.55 (ddd, J=11.8, 9.1, 3.3 Hz, 2H), 3.90 (dt, J=12.0, 4.5 Hz, 2H), 4.76 (septet, J=4.5 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H).

Workup

  1. concentrationThe DMF was concentrated in vacuo
  2. customthe crude product chromatographed over a 120 g Isco column

Sources & evidence

ORD record
ord-3179a4216ef94d799ceb84838bc0f48c
Source dataset
uspto-grants-2016_05
Patent number
US09351964B2

Reaction notes

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