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

HRID 1804441Notes

Reaction equation

HRID 1804441 reaction equation
[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]

Participants

6

Reactant 3

HCID 6386tert-ButanolHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 585043491-(4-Cyanobenzyl)azetidine-3-carboxylic acid

Product 1

HCID 58504367tert-Butyl 1-(4-cyanobenzyl)azetidine-3-carboxylateYield 86%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 63651,1-DichloroethaneSolvent

Procedure

To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDCI (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes−Column: YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).

Workup

  1. customThe volatiles were removed under reduced pressure
  2. customthe residue was partitioned between ethyl acetate (250 mL)
  3. washThe organic layer was washed with water (250 mL)
  4. washwashed with brine (100 mL)
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationConcentration under reduced pressure
  7. customafforded a light yellow oil which
  8. customwas chromatographed on a 5×15 cm silica gel column
  9. washeluting with a 0-40% ethyl acetate/hexane gradient

Sources & evidence

ORD record
ord-815bda311f554133a8c5793b7be0e82a
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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