Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate → Tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)azetidine-1-carboxylate

HRID 921718Notes

Reaction equation

HRID 921718 reaction equation
Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[I-].[C:29]([O:33][C:34]([N:36]1[CH2:39][CH:38]([Zn+])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([CH:38]2[CH2:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:39]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]

Participants

6

Reactant 2

HCID 86708662Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamateHCID 178452187HCID 178452187, compound

Product 1

HCID 89919370Tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
80 °C

Procedure

A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (1 g, 1.882 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.129 g, 0.188 mmol), and copper(I) iodide (0.072 g, 0.376 mmol) in N,N-Dimethylacetamide (0.6 mL) in a dry microwave vial was evacuated and backfilled with N2 for 3 times. (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (5.94 mL, 5.64 mmol, approximately 0.95 M solution in N,N-dimethylacetamide prepared as described in the Journal of Organic Chemistry, 2004, 69, 5120) was then added. The mixture was evacuated and backfilled with N2 one more time and then heated at 80° C. for overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. This was left stirring for 30 min. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by silica gel chromatography eluting with hexane containing 5 to 15% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (0.98 g).

Workup

  1. customwas evacuated
  2. additionwas then added
  3. customThe mixture was evacuated
  4. temperatureAfter cooling to room temperature
  5. customthe reaction was partitioned between EtOAc and sat. aq. NH4Cl solution
  6. waitThis was left
  7. extractionThe aqueous phase was extracted with EtOAc
  8. washthe combined organic phases were washed with brine
  9. dry with materialdried with sodium sulfate
  10. customRemoval of the solvents
  11. washeluting with hexane containing 5 to 15% EtOAc

Sources & evidence

ORD record
ord-5857f4919d894eab9a997e0a86767f8e
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

Loading…