4-Cyanobenzaldehyde → tert-Butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate

HRID 71221Notes

Reaction equation

HRID 71221 reaction equation
C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17].C([BH3-])#N.[Na+]>CO>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:20][CH:19]=1)#[N:17]

Participants

5

Reactant 3

HCID 660424-CyanobenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 66677484tert-Butyl azetidine-3-carboxylate acetate

Product 1

HCID 58504367tert-Butyl 1-(4-cyanobenzyl)azetidine-3-carboxylateYield 89%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-cyanobenzaldehyde (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with a 10% aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel column chromatography using a 20% mixture of ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (the desired product and alcohol impurity formed were not separated by column completely, and the mixture was taken for next step). LC/MS M+1=273.18. 1H-NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).

Workup

  1. temperatureto warm to room temperature
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. additionthe residue was diluted with a 10% aqueous solution of sodium bicarbonate
  4. extractionextracted with ethyl acetate
  5. washwashed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationConcentration under reduced pressure
  8. customfollowed by purification by flash silica gel column chromatography

Sources & evidence

ORD record
ord-9dccf2b77a524e0499fe009c59394402
Source dataset
uspto-grants-2014_09
Patent number
US08822510B2

Reaction notes

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