Methanol → 4-Hydroxy-3-(prop-1-ynyl)benzonitrile

HRID 710394Notes

Reaction equation

HRID 710394 reaction equation
[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.S1(C2[C:17](=[CH:18]C=CC=2)[C:15](=O)N1)(=O)=O.C([Mg]Br)#CC.CO>C1COCC1.[Cl-].[Cl-].[Zn+2].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.[Cu]I>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:15]#[C:17][CH3:18]

Participants

9

Reactant 4

HCID 887MethanolHCID 5143SaccharinHCID 109558154-Hydroxy-3-iodobenzonitrile2×HCID 178419101HCID 178419101, compound

Product 1

HCID 667265934-Hydroxy-3-(prop-1-ynyl)benzonitrileYield 186.5%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

A suspension of the product of Step A (0.3 g; 1.22 mmol) in HMDSA (2 ml) and saccharine (0.1 g) was refluxed under N2 until reaction became homogenous (˜30 min). After cooling to room temperature, the HMDSA was removed in vacuo and the residue was diluted to 4 ml with anhydrous THF. At the same time ZnCl2 (0.2 g; 1.47 mmol) was heated to ˜110° C., in separate flask, in vacuo, cooled to room temperature under N2 and diluted to 4 ml with anhydrous THF. To it 0.5 M prop-1-ynyl-magnesium bromide in THF (4.9 ml; 2.45 mmol) was added at room temperature and this was stirred for 10 min under N2. To it a solution of silinated product of Step A was added, followed by Pd(PPh3)4 (0.11 g; 0.095 mmol) and CuI (0.05 g; 0.26 mmol). After stirring for 1 h at room temperature under N2, MeOH (5 ml) was added and solvents were removed under reduced pressure. The residue was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give title compound (0.16 g; 78%), as colourless solid. 1H-NMR (CDCl3) 2.14 (s, 3H); 6.26 (s, 1H); 6.97 (d, 1H, J=8.5 Hz); 7.46 (dd, 1H, J=2.1 Hz, 8.5 Hz); 7.57 (d, 1H, 2.1 Hz).

Workup

  1. temperaturewas refluxed under N2 until reaction
  2. custom(˜30 min)
  3. customthe HMDSA was removed in vacuo
  4. additionthe residue was diluted to 4 ml with anhydrous THF
  5. temperaturecooled to room temperature under N2
  6. stirringAfter stirring for 1 h at room temperature under N2
  7. customsolvents were removed under reduced pressure
  8. additionThe residue was diluted to 20 ml with EtOAc
  9. washwashed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4
  10. filtrationfiltered
  11. customfiltrate evaporated to dryness under reduced pressure
  12. customThe residue was purified by FCC (SiO2, CH2Cl2)

Sources & evidence

ORD record
ord-b0c3833edcb44792b66f6e3c02fd342c
Source dataset
uspto-grants-2015_11
Patent number
US09181182B2

Reaction notes

Loading…