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Synlett
Volumn , Issue 12, 2009, Pages 1933-1936
Efficient synthesis of 3-alkoxy-4,4-difluoropiperidines
Author keywords

4,4 difluoropiperidines; Deoxofluorination; Fluorine; Ketones; Piperidines
Indexed keywords

ACETIC ACID DERIVATIVE; FLUORINE DERIVATIVE; FUNCTIONAL GROUP; HETEROCYCLIC COMPOUND; MORPHOLINE DERIVATIVE; PIPERIDINE DERIVATIVE; SULFUR DERIVATIVE;
EID: 67651247782     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1217533     Document Type: Article
Times cited : (13)
References (28)
  • 24
    • 84869554352 scopus 로고    scopus 로고
    • 3-Benzyloxy-4,4-difluoro-1-(trifluoroacetyl)piperidine (9a) In a 25 mL flask, 3-benzyloxy-1-(trifluoroacetyl)-4-piperidinone (8a, 0.30 g, 1.00 mmol) was dissolved in anhyd CH2Cl2 (10 mL, The solution was cooled to -78 °C under nitrogen atmosphere and morpholinosulfur trifluoride (Morph-DAST; 0.53 g, 3.00 mmol, 3 equiv, 0.37 mL) was added dropwise. The reaction mixture was allowed to warm to r.t. over 1 h and was stirred for 2 h at the same temperature. The mixture was poured in CH 2Cl2 (10 mL) and H2O (10 mL, The separated aqueous phase was extracted twice with CH2Cl2 (10 mL, and the combined organic phases were dried over MgSO4. After filtration, the solvent was evaporated in vacuo, and the concentrate was purified via flash chromatography over silica gel (hexane-EtOAc, 83:17, Rf, 0.29) yielding 0.24 g of piperidine 9a 0.73 mmol, 73, Ratio of rotam
    • +]. Anal. Calcd: C, 52.02; H, 4.37; N, 4.33. Found: C, 51.76; H, 4.11; N, 4.01.
  • 25
    • 67651239949 scopus 로고    scopus 로고
    • 3-Benzyloxy-4,4-difluoropiperidine (10) In a 25 mL flask, 3-benzyloxy-4,4-difluoro-1-(trifluoroacetyl) piperidine (9a, 0.50 g, 1.55 mmol) was dissolved in MeOH (6 mL, A solution of K2CO3 (0.64 g, 4.64 mmol, 3 equiv) in H2O (3 mL) was added, and the mixture was stirred for 12 h at r.t. After completion of the reaction, the solvent was evaporated in vacuo, and the residue was dissolved in CH2Cl 2 (20 mL) and H2O (20 mL, The separated aqueous phase was extracted twice with CH2Cl2 (20 mL) and the combined organic phases dried over MgSO4. After filtration, the solvent was evaporated in vacuo, yielding 0.35 g of piperidine 10 (1.55 mmol, 100, purity >92, For analytical purposes a 50 mg sample of the compound was subjected to an acid-base extraction 30% yield, excluding the necessity of flash chromatography to yield pure compound 10 as a yellow oil. 1
    • +]. Anal. Calcd: C, 63.42; H, 6.65; N, 6.13. Found: C, 63.08; H, 6.01; N, 5.95.
  • 26
    • 84869554353 scopus 로고    scopus 로고
    • 4-Difluoro-3-hydroxy-1-(trifluoroacetyl)piperidine (11) In a dry pressure vessel, 3-benzyloxy-4,4-difluoro-1-(trifluoroacetyl)piperidine (9a, 1.10 g, 3.40 mmol) was dissolved in EtOAc (10 mL, After adding 10% Pd/C (0.22 g) at 0 °C, the mixture was stirred during 15 h at r.t. under hydrogen pressure of 4.75 bar. The mixture was filtered over Celite®, and the filtrate was evaporated in vacuo to yield 0.75 g of pure piperidine 11 (3.20 mmol, 94, Ratio of rotamers, 53:47; yellow oil. 1H NMR (300 MHz, CDCl3, δmajor, 1.93-2.11 (1 H, m, NCH2CHaHb, 2.18-2.48 (1 H, m, NCH 2CHaHb, 2.60-3.10 (1 H, br s, OH, 3.47 (1 H, d × m, J, 13.8 Hz, NCHaHbCH, 3.46-3.54 (1 H, m, NCHaHbCH2, 3.81-3.95 (1 H, m, NCHaHbCH2, 3.97-4.05 1
    • +]. Anal. Calcd: C, 36.06; H, 3.46; N, 6.01. Found: C, 35.79; H, 3.09; N, 5.88.
  • 27
    • 84869554354 scopus 로고    scopus 로고
    • 4-Difluoro-3,3-dihydroxy-1-(trifluoroacetyl)piperidine (14) In a 10 mL flask, 4,4-difluoro-3-hydroxy-1-(trifluoroacetyl) piperidine (11, 0.10 g 0.43 mmol) was dissolved in anhyd CH2Cl2 (5 mL, After adding Dess-Martin periodinane (0.36 g, 0.86 mmol, 2.0 equiv, the solution was stirred for 15 h at r.t. The mixture was diluted with Et 2O (30 mL, and the organic phase was washed three times with a sat. aq NaHCO3 solution (20 mL, The organic phase was dried over MgSO4, and after filtration the solvent was evaporated in vacuo. The concentrate was dissolved in Et2O (5 mL) and cooled to -40 °C to crystallize residues of the Dess-Martin periodinane reagent. After filtration of the solids, the filtrate was evaporated in vacuo to yield 0.06 g of piperidine 14 (0.26 mmol, 60, Ratio of rotamers, 2:1; colorless oil. 1H NMR (300 MHz, CDCl3, δmajor, 2.11-2.31 2 H
    • +]. Anal. Calcd: C, 33.75; H, 3.24; N, 5.62. Found: C, 33.41; H, 3.49; N, 5.43.

* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.