Reaktion #962129

Reaktionsgleichung

N-Boc-3-iodo azetidine

lithium chloride

6-bromonicotinonitrile

CH2Cl2

→

tert-butyl 3-(5-cyanopyridin-2-yl)azetidine-1-carboxylate

Ausbeute 17.0%

Lösungsmittel

THF

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeZinc dust was purified
2. 2
   Waschenby washing with HCl
3. 3
   Sonstigedried thoroughly
4. 4
   Sonstigeto use in this reaction
5. 5
   Sonstigepurged flask
6. 6
   workup.ADDITIONfreshly distilled THF (5.0 mL) was added
7. 7
   Temperaturcooled to room temperature
8. 8
   TemperaturThe process of heating
9. 9
   Temperaturcooling
10. 10
    workup.ADDITIONTrimethylsilyl chloride (0.1 mL) was added to the reaction mixture
11. 11
    workup.STIRRINGThe reaction mixture was stirred at room temperature for 2 h
12. 12
    SonstigeIn a separate dry flask
13. 13
    SonstigeThe resulting reaction mixture
14. 14
    workup.STIRRINGThe reaction mixture was stirred at room temperature for 10 h
15. 15
    Sonstigequenched with saturated ammonium chloride solution
16. 16
    workup.ADDITIONdiluted with EtOAc
17. 17
    ExtraktionThe product was extracted with EtOAc
18. 18
    Waschenthe combined extracts were washed with H2O and brine
19. 19
    SonstigeSolvent was removed under reduced pressure
20. 20
    Sonstigethe crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether)

Vorschrift

Zinc dust was purified by washing with HCl and dried thoroughly prior to use in this reaction. Zinc dust (325 mesh, 1.38 g, 21.2 mmol) and anhydrous lithium chloride (0.9 g, 21.2 mmol) were placed in a nitrogen-purged flask and freshly distilled THF (5.0 mL) was added, followed by 1,2-dibromoethane (0.2 mL). The reaction mixture was heated to 80° C. for 5 min and then cooled to room temperature. The process of heating and cooling was repeated for 2 times. Trimethylsilyl chloride (0.1 mL) was added to the reaction mixture and the suspension was stirred at room temperature for 20 min. A solution of N-Boc-3-iodo azetidine (2 g, 7.0 mmol) in dry THF (5 mL) was added dropwise to the activated zinc. The reaction mixture was stirred at room temperature for 2 h. In a separate dry flask were taken 6-bromonicotinonitrile (770 mg, 4.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (115 mg, 0.14 mmol) in dry THF (4 mL) and stirred for 5 min. The resulting reaction mixture was added dropwise to the organozinc compound. The reaction mixture was stirred at room temperature for 10 h, quenched with saturated ammonium chloride solution, and diluted with EtOAc. The product was extracted with EtOAc and the combined extracts were washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-(5-cyanopyridin-2-yl)azetidine-1-carboxylate (180 mg, yield 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.04-9.03 (m, 1H), 8.27-8.23 (dd, J=8.1 Hz, 2.2 Hz, 1H), 7.56-7.53 (m, 1H), 4.20-4.16 (m, 2H), 4.02-3.97 (m, 2H), 3.58-3.53 (m, 1H), 1.38 (s, 9H). MS (ESI) m/z: Calculated for C14H17N3O2: 259.13. found: 160.2 (M+H-Boc)+

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