Tetrahydrofuran → 2-Benzyl-4-(tetrahydro-pyran-2-yloxymethyl)-6-p-tolyl-pyrimidine

HRID 1917266Notes

Reaction equation

HRID 1917266 reaction equation
C1COCC1.CCN(CC)CC.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=O)=[CH:15][CH:14]=1.[CH2:23]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[C:24]#[CH:25].Cl.[C:34]1([CH2:40][C:41]([NH2:43])=[NH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CO>[CH2:40]([C:41]1[N:43]=[C:24]([CH2:23][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:25]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)[N:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

12

Reactant 6

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 10340Sodium CarbonateHCID 134054-Methylbenzoyl ChlorideHCID 98609Tetrahydro-2-(2-propynyloxy)-2H-pyranHCID 124155142-Phenylethanimidamide hydrochloride

Product 1

HCID 666164432-Benzyl-4-(tetrahydro-pyran-2-yloxymethyl)-6-p-tolyl-pyrimidineYield 53.4%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a solution of Pd(PPh3)2Cl2 (0.285 g, 0.41 mmol) and CuI in THF (50 mL) (0.148 g, 0.777 mmol) was added Et3N (1.5 mL, 11.0 mmol), p-toluoyl chloride (1.3 mL, 10.0 mmol) and tetrahydro-2-(2-propynyloxy)-2H-pyran (1.4 mL, 10.0 mmol). After stirring for 2.5 h, a solution of 2-phenylacetamidine hydrochloride (2.0 g, 11.7 mmol) in THF/MeOH (1:1, 10 mL) was added followed by additional MeOH (5 mL) and Na2CO3 (3.2 g, 30.0 mmol). The reaction mixture was heated at reflux for 15 h, cooled to rt, diluted with Et2O and filtered through a small pad of diatomaceous earth. The filtrate was concentrated and purified via SiO2 chromatography (10-45% EtOAc/hexanes) to give 2.0 g (53%) of the title compound. 1H NMR (CDCl3): 8.02-8.00 (m, 2H), 7.68 (s, 1H), 7.46-7.44 (m, 2H), 7.30-7.27 (m, 4H), 7.21-7.19 (m, 1H), 4.87 (d, J=14.7, 1H), 4.77 (t, J=3.5, 1H), 4.62 (d, J=15.1, 1H), 4.31 (s, 2H), 3.91-3.86 (m, 1H), 3.57-3.52 (m, 1H), 2.41 (s, 3H), 1.96-1.87 (m, 1H), 1.84-1.72 (m, 2H), 1.66-1.55 (m, 3H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 15 h
  3. filtrationfiltered through a small pad of diatomaceous earth
  4. concentrationThe filtrate was concentrated
  5. custompurified via SiO2 chromatography (10-45% EtOAc/hexanes)

Sources & evidence

ORD record
ord-8f11950a520e4c4fa8cf10a40a966e78
Source dataset
uspto-grants-2013_12
Patent number
US08618288B2

Reaction notes

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