Diethyl (cyanomethyl)phosphonate → 1-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine

HRID 1966173Notes

Reaction equation

HRID 1966173 reaction equation
CCOP(OCC)([CH2:6][C:7]#[N:8])=O.CC([O-])(C)C.[K+].[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.O.[Cl-].[Na+].O>[C:7]([CH:6]=[C:27]1[CH2:28][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26]1)#[N:8]

Participants

7

Reactant 3

HCID 75676Diethyl (cyanomethyl)phosphonateHCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 23665647Potassium tert-butoxide

Product 1

HCID 457892161-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidineYield 61%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-14 °C

Procedure

Diethyl cyanomethyl phosphonate (745 g, 4.20 mol, 1.20 eqiv) and anhydrous THF (9 L) was added to a four-neck flask equipped with thermowell, addition funnel and nitrogen protection tube. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of t-BuOK in THF (3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the temperature<−5° C. The mixture was stirred for 3 hr at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (1, 600 g, 3.50 mol) in THF (2 L) was added over 2 hr while keeping the reaction temperature<−5° C. The reaction mixture was stirred at −5 to −10° C. over 1 hr and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated brine (4.5 L) and extracted with ethyl acetate (2×9 L). The combined organic layers were combined and washed with brine (6 L), dried over anhydrous Na2SO4. The organic solvent was removed under reduced pressure, diluted with dichloromethane (4 L) and adsorbed onto silica gel (1.5 kg). The product was purified by flash column chromatography (SiO2, 3.5 kg×2), each column was eluted with (8 L of heptane, 8 L of 5% AcOEt/heptane, 12 L of 10% AcOEt/heptane, 40 L of 25% AcOEt/heptane) to give the pure tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 4.62 (m, 2H), 4.72 (m, 2H), 5.41 (m, 1H).

Workup

  1. customequipped with thermowell,
  2. additionaddition funnel and nitrogen protection tube
  3. customthe temperature<−5° C
  4. customthe reaction temperature<−5° C
  5. stirringThe reaction mixture was stirred at −5 to −10° C. over 1 hr
  6. temperatureslowly warmed up to room temperature
  7. stirringstirred at room temperature for overnight
  8. extractionextracted with ethyl acetate (2×9 L)
  9. washwashed with brine (6 L)
  10. dry with materialdried over anhydrous Na2SO4
  11. customThe organic solvent was removed under reduced pressure
  12. additiondiluted with dichloromethane (4 L)
  13. customThe product was purified by flash column chromatography (SiO2, 3.5 kg×2)
  14. washeach column was eluted with (8 L of heptane, 8 L of 5% AcOEt/heptane, 12 L of 10% AcOEt/heptane, 40 L of 25% AcOEt/heptane)

Sources & evidence

ORD record
ord-7afc9d1fce3f46d09878351670bbe7e7
Source dataset
uspto-grants-2013_04
Patent number
US08420629B2

Reaction notes

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