Dichloromethane → 3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester

HRID 708271Notes

Reaction equation

HRID 708271 reaction equation
Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.ClCCl.[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].[NH4+].[Cl-]>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:29]([O:33][C:34]([N:36]1[CH2:39][CH:38]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]

Participants

8

Reactant 4

HCID 6344Dichloromethane2×HCID 25517Ammonium ChlorideHCID 582039088-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneHCID 178452187HCID 178452187, compound

Product 1

HCID 582040483-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl esterYield 69.2%

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 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (5.000 g, 0.01234 mol) was dissolved in N,N-dimethylacetamide (35 mL) and the solution was degassed for 5 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.5037 g, 0.0006168 mol) and copper(I) iodide (0.2349 g, 0.001234 mol) were added and the reaction was further purged with N2. (1-(Tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (0.01480 mol, 0.38M in DMA, 40 mL), was added and the reaction was heated to 80° C. overnight. Saturated NH4Cl and methylene chloride were added. The mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The crude was purified by flash chromatography (10-80% ethyl acetate in hexanes) to afford 3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester as a white solid (4.11 g). MS(ESI+) 482.2

Workup

  1. customthe solution was degassed for 5 minutes
  2. customthe reaction was further purged with N2
  3. extractionThe mixture was extracted 3 times with methylene chloride
  4. dry with materialdried with MgSO4
  5. concentrationconcentrated
  6. customThe crude was purified by flash chromatography (10-80% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-b3532165bfee4e47942b12c0d81d3692
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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