Dichloromethane → HCID 69935223, compound

HRID 874947Notes

Reaction equation

HRID 874947 reaction equation
[Cl-].[Li+].[C:3]([N:10]1[CH2:13][CH:12](I)[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(Cl)Cl>C1COCC1.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:12]2[CH2:13][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]2)=[N:17][CH:18]=1)#[N:21]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 433294Lithium ChlorideHCID 50057186-Bromopyridine-3-carbonitrileHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylate

Product 1

HCID 69935223HCID 69935223, compoundYield 17%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalyst2×HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
80 °C

Procedure

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)+

Workup

  1. customZinc dust was purified
  2. washby washing with HCl
  3. customdried thoroughly
  4. customto use in this reaction
  5. custompurged flask
  6. additionfreshly distilled THF (5.0 mL) was added
  7. temperaturecooled to room temperature
  8. temperatureThe process of heating
  9. temperaturecooling
  10. additionTrimethylsilyl chloride (0.1 mL) was added to the reaction mixture
  11. stirringThe reaction mixture was stirred at room temperature for 2 h
  12. customIn a separate dry flask
  13. customThe resulting reaction mixture
  14. stirringThe reaction mixture was stirred at room temperature for 10 h
  15. customquenched with saturated ammonium chloride solution
  16. additiondiluted with EtOAc
  17. extractionThe product was extracted with EtOAc
  18. washthe combined extracts were washed with H2O and brine
  19. customSolvent was removed under reduced pressure
  20. customthe crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-92926537323547c69305d472f750dfef
Source dataset
uspto-grants-2015_03
Patent number
US08981084B2

Reaction notes

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