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

HRID 1941871Notes

Reaction equation

HRID 1941871 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.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+].[C-]#N>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][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:19][CH:20]=1)#[N:23]

Participants

6

Reactant 4

HCID 5975CyanideHCID 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-formylbenzonitrile (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 (caution: potential cyanide generation). The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile but was taken forward to the next step without further purification). 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. concentrationAfter the reaction mixture was concentrated under reduced pressure the residue
  3. additionwas diluted with 10% aqueous sodium bicarbonate solution
  4. extractionextracted with ethyl acetate
  5. customThe organic layer was collected
  6. washwashed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationConcentration under reduced pressure
  9. customfollowed by purification by silica gel chromatography

Sources & evidence

ORD record
ord-a31c4d8f84c341bb967d92b986f52352
Source dataset
uspto-grants-2013_03
Patent number
US08389509B2

Reaction notes

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