alpha-Bromo-o-fluorotoluene → HCID 52951670, compound

HRID 1517627Notes

Reaction equation

HRID 1517627 reaction equation
[F:1][C:2]1[S:6][C:5]2[C:7]3([O:22][CH2:23][CH2:24][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8]3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][CH:14]([CH2:13][N:10]1[CH2:11][CH2:12][C:7]2([C:5]3[S:6][C:2]([F:1])=[CH:3][C:4]=3[CH2:24][CH2:23][O:22]2)[CH2:8][CH2:9]1)[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]

Participants

6

Reactant 4

HCID 67968alpha-Bromo-o-fluorotolueneHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 2733832Lithium HexamethyldisilazideHCID 52951553Spiro[piperidine-4,7′-[7H]thieno[2,3-c]pyran]-1-propanoic acid, 2′-fluoro-4′,5′-dihydro-, 1,1-dimethylethyl ester

Product 1

HCID 52951670HCID 52951670, compoundYield 79.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of tert-butyl 3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)propanoate (4.9 g, 13.78 mmol) in tetrahydrofuran (41 mL) under N2 and cooled to −78° C., lithium bis(trimethylsilyl)amide 1M (41.35 mL, 41.45 mmol) is added dropwise. The resulting mixture is stirred at that temperature for 3 hours. Then, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.33 mL, 11.03 mmol) is added, and the resulting solution is stirred at the same temperature for 30 min. To the resulting mixture, 2-fluorobenzyl bromide (2.33 mL, 19.3 mmol) in dry tetrahydrofuran (1 mL) is added and stirring is continued. The temperature is allowed to go from −78° C. to room temperature overnight. The crude reaction mixture is quenched with aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer is decanted, dried over magnesium sulfate, the solvent is evaporated and the crude obtained is purified by normal phase Isco chromatography using ethyl acetate/hexane from 5/95 to 20/80 to yield 5.06 g of the title compound obtained as colorless oil. MS (m/z): 464 (M+1).

Workup

  1. stirringthe resulting solution is stirred at the same temperature for 30 min
  2. stirringstirring
  3. waitto go from −78° C. to room temperature overnight
  4. customThe crude reaction mixture
  5. customis quenched with aqueous saturated solution of ammonium chloride
  6. extractionextracted with ethyl acetate
  7. customThe organic layer is decanted
  8. dry with materialdried over magnesium sulfate
  9. customthe solvent is evaporated
  10. customthe crude obtained
  11. customis purified by normal phase Isco chromatography

Sources & evidence

ORD record
ord-74895c1a9e954caa8cb39ba2eae87217
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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