Dibromomethane → Tert-butyl 3-(6-chloropyridin-3-yl)azetidine-1-carboxylate

HRID 1772127Notes

Reaction equation

HRID 1772127 reaction equation
BrCBr.Cl[Si](C)(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn]>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH:18]2[CH2:19][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]2)=[CH:26][CH:27]=1

Participants

8

Reactant 5

HCID 3024DibromomethaneHCID 6397ChlorotrimethylsilaneHCID 521585Tris(furan-2-yl)phosphaneHCID 15165112-Chloro-4-iodopyridineHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylate

Product 1

HCID 57537370Tert-butyl 3-(6-chloropyridin-3-yl)azetidine-1-carboxylateYield 57.1%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 6228DimethylformamideSolvent4×

Conditions

Temperature
70 °C

Procedure

A 250-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with zinc (2.54 g, 38.9 mmol), DMF (32 mL), and dibromomethane (736 mg, 4.24 mmol). After stirring at 70° C. for 10 min, the reaction mixture was cooled to room temperature, and chlorotrimethylsilane (423 mg, 3.89 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and a solution of 1-(tert-butoxycarbonyl)-3-iodoazetidine (9.31 g, 38.9 mmol) in DMF (32 mL) was added. After stirring at 40° C. for 1 h, a solution of 2-chloro-4-iodo-pyridine (10.0 g, 35.3 mmol) in DMF (16 mL) was added, followed by a solution of (dibenzylideneacetone)dipalladium(0) (1.62 g, 1.77 mmol) and tri(2-furyl)-phosphine (820 mg, 3.53 mmol) in DMF (16 mL). After stirring at 70° C. for 16, the reaction mixture was partitioned between saturated aqueous ammonium chloride (200 mL) and diethyl ether (200 mL). The layers were separated, and the aqueous phase was extracted with diethyl ether (200 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 54% yield (5.42 g) of 117a as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 7.70 (dd, 1H, J=8.5, 2.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 4.37 (t, 2H, J=8.5 Hz), 3.91 (dd, 2H, J=8.5, 4.5 Hz), 3.73 (m, 1H), 1.46 (s, 9H); MS (ESI+) m/z 269.0 (M+H).

Workup

  1. customA 250-mL round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. temperaturethe reaction mixture was cooled to room temperature
  4. stirringThe resulting mixture was stirred at room temperature for 30 min
  5. stirringAfter stirring at 40° C. for 1 h
  6. stirringAfter stirring at 70° C. for 16
  7. customthe reaction mixture was partitioned between saturated aqueous ammonium chloride (200 mL) and diethyl ether (200 mL)
  8. customThe layers were separated
  9. extractionthe aqueous phase was extracted with diethyl ether (200 mL)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationThe filtrate was concentrated under reduced pressure
  13. customThe resulting residue was purified by column chromatography

Sources & evidence

ORD record
ord-7a397ad757aa4f198e14fe498e771876
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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