2(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl- → Ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate

HRID 729705Notes

Reaction equation

HRID 729705 reaction equation
[Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH2:18]([O:20][C:21](=[O:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH3:19].I[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CCCCCCC.C1COCC1.C1(CC)C=CC=CC=1.C1COCC1>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH:22]([CH2:35][CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:21]([O:20][CH2:18][CH3:19])=[O:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]

Participants

7

Reactant 4

HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 2724682Lithium diisopropylamideHCID 27955074-(Iodomethyl)oxaneHCID 12238955Ethyl 4-(methylsulfonyl)phenylacetate

Product 1

HCID 21094178Ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 22742125Tetrahydrofuran heptane ethylbenzolSolvent

Conditions

Temperature
20 °C

Procedure

LDA (38.9 mL of a 1.8M solution in n-C7H16-THF-PhEt, 70.0 mmol) was added to a solution of DMPU (59.3 mL, 490.3 mmol) in anhydrous THF (150 mL) at −78° C. The mixture was stirred for 30 min, before being treated dropwise with a solution of ethyl(4-methanesulfonylphenyl)acetate (Preparation 15, 16.97 g, 70.0 mmol) in anhydrous THF (50 mL). Stirring was continued at −78° C. for 45 min, then a solution of 4-iodomethyltetrahydropyran (19.00 g, 84.0 mmol) in anhydrous THF (40 mL) was added. The mixture was allowed to warm to 20° C. over 16 h, before being quenched with 1M HCl (70 mL). The THF was removed under reduced pressure, then more H2O (40 mL) was added and the remainder extracted with EtOAc (2×250 mL). The EtOAc extracts were dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 9:1 to 1:1) furnished ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=698.3 [2M+NH4]+. A solution of this compound (20.27 g, 59.6 mmol) in MeOH (100 mL) and 2M NaOH (62.5 mL, 125.0 mmol) was heated under reflux for 1 h. The solvents were removed under reduced pressure, then the remaining solid was triturated with Et2O (5×100 mL), before being dissolved in H2O (100 mL). The aqueous solution was washed with EtOAc (50 mL), acidified with 2M HCl to pH 1, and extracted with EtOAc (2×1 L). After drying (MgSO4), filtration and solvent evaporation gave the title compound: m/z (ES+)=642.3 [2M+NH4]+.

Workup

  1. stirringStirring
  2. waitwas continued at −78° C. for 45 min
  3. custombefore being quenched with 1M HCl (70 mL)
  4. customThe THF was removed under reduced pressure
  5. additionmore H2O (40 mL) was added
  6. extractionthe remainder extracted with EtOAc (2×250 mL)
  7. dry with materialThe EtOAc extracts were dried (MgSO4)
  8. filtrationFiltration, solvent evaporation, and flash chromatography (IH-EtOAc, 9:1 to 1:1)

Sources & evidence

ORD record
ord-211845d307964654bc88f1a8f1aa7f5f
Source dataset
uspto-grants-2009_09
Patent number
US07582632B2

Reaction notes

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