3,4-dihydro-2H-pyran → HCID 18411442, compound

HRID 1275599Notes

Reaction equation

HRID 1275599 reaction equation
S(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C-]#N.[Na+].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:35]1C=CC=C[CH:36]=1>O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([O:11][CH:23]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:36]#[N:35])[CH:12]=[CH:13][CH:14]=1

Participants

8

Reactant 5

HCID 80803,4-dihydro-2H-pyranHCID 8929Sodium CyanideHCID 114773-ChlorobenzaldehydeHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 23665763Sodium Bisulfite

Product 1

HCID 18411442HCID 18411442, compoundYield 483.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of sodium bisulfite (27.66 g, 0.266 mol) in water (120 mL) was added 3-chlorobenzaldehyde (25.0 g, 0.178 mol). After stirring for 20 min, a solution of sodium cyanide (12.4 g, 0.2525 mol) in water (80 mL) was added dropwise. Ethyl acetate (50 mL) was added and the resulting mixture was stirred for another 3 h. The organic layer was collected, washed with brine, dried (sodium sulfate), filtered and evaporated to dryness. The residue was dissolved in dichloromethane (200 mL) and cooled in ice. Dihydropyran (20.62 g, 0.2451 mol) and pyridinium p-toluene sulfonate (6.5 g, 25.9 mmol) were then added successively and the mixture was stirred at room temperature for 16 h. The organic layer was successively washed with water (50 mL), 5% sodium bisulfite solution (2×50 mL) and brine (50 mL). The organic fraction was dried (sodium sulfate), filtered and evaporated to give an oil. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (95/5) as eluant afforded 31.5 g (70%) of 2-(3-chlorophenyl)-2-[(tetrahydropyran-2-yloxy)]acetonitrile (mixture of diastereoisomers) as a clear oil which was contaminated with <5% of 3-chlorobenzaldehyde. 1H-NMR (CDCl3) δ7.30-7.60 (m, 4H, Ar-H), 5.59 (s, 0.3H, αH) and 5.41 (s, 0.7H, αH), 5.12 (t, J=2.9 Hz, 0.3H, OCHO) and 4.77 (t, J=2.9 Hz, 0.7H, OCHO), 3.60-4.05 (m, 2H, CH2O), 1.50-2.06 (m, 6H, 3 CH2). Small pieces of sodium (192 mg, 7.9 mmol) was added to anhydrous ethanol (200 mL) under a positive pressure of nitrogen at room temperature. After all the sodium had dissolved, 2-(3-chlorophenyl)-2-[(tetrahydropyran-2-yloxy)]acetonitrile (19.54 g, 77.6 mmol) was added neat and the contents of the flask was rinsed with ethanol (20 mL) and added to the reaction mixture. The progess of the reaction can be monitored by TLC using a mixture of hexane and ethyl acetate (1/1) as solvent system. After stirring for 16 h, the reaction mixture was cooled to ca. -40° C. (dry ice-methanol-water) and an ethanolic solution of ammonia (77.6 mL of a 2M solution, 0.1552 mol) was quickly added followed by solid ammonium chloride (4.02 g, 75.15 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was filtered over a pad of celite. The filtrate was collected and evaporated to dryness and then pumped under high vacuum to afford 2-(3-chlorophenyl)-2-(tetrahydropyran-2-yloxy)acetamidine hydrochloride (23 g) as a white foam in almost quantitative yield. 1H-NMR (CDCl3) δ9.00-9.80 (br., 1H, NH), 8.00-8.80 (br., 1H, NH), 7.30-7.64 (m, 3H, Ar-H), 5.85 (s, 0.4H, αH) and 5.75 (s, 0.6H, αH), 4.84 (t, J=3.3 Hz, 0.4H, OCHO) and 4.57 (t, J=3.3 Hz, 0.6H, OCHO), 3.41-3.83 (m, 2H, CH2O), 2.20-2.60 (br., 1H, NH), 1.46-1.86 (m, 6H, 3 CH2).

Workup

  1. stirringthe resulting mixture was stirred for another 3 h
  2. customThe organic layer was collected
  3. washwashed with brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. customevaporated to dryness
  7. dissolutionThe residue was dissolved in dichloromethane (200 mL)
  8. temperaturecooled in ice
  9. stirringthe mixture was stirred at room temperature for 16 h
  10. washThe organic layer was successively washed with water (50 mL), 5% sodium bisulfite solution (2×50 mL) and brine (50 mL)
  11. dry with materialThe organic fraction was dried (sodium sulfate)
  12. filtrationfiltered
  13. customevaporated
  14. customto give an oil
  15. customPurification by column chromatography on silica gel using
  16. additiona mixture of hexane and ethyl acetate (95/5) as eluant

Sources & evidence

ORD record
ord-07121a6a69b84a39a60e33ff8e51cdcd
Source dataset
uspto-grants-2000_12
Patent number
US06162791

Reaction notes

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