Dichloromethane → 3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-carboxylic acid tert-butyl ester

HRID 707981Notes

Reaction equation

HRID 707981 reaction equation
Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.ClCCl.Br[C:26]1[CH:27]=[CH:28][C:29]2[O:38][CH2:37][CH2:36][C:35]3[S:34][C:33]([C:39]4[N:40]([CH:44]([CH3:46])[CH3:45])[N:41]=[CH:42][N:43]=4)=[N:32][C:31]=3[C:30]=2[CH:47]=1>CC(N(C)C)=O.[Zn].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:18]([O:17][C:15]([N:13]1[CH2:14][CH:11]([C:26]2[CH:27]=[CH:28][C:29]3[O:38][CH2:37][CH2:36][C:35]4[S:34][C:33]([C:39]5[N:40]([CH:44]([CH3:45])[CH3:46])[N:41]=[CH:42][N:43]=5)=[N:32][C:31]=4[C:30]=3[CH:47]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

10

Reactant 5

HCID 6344DichloromethaneHCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 532349749-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Product 1

HCID 582037323-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 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 31374DimethylacetamideSolvent3×

Procedure

Zinc (151 mg, 2.31 mmol) was stirred in DMA (0.4 mL) under an atmosphere of argon. Chlorotrimethylsilane (25 uL, 0.20 mmol) and 1,2-dibromoethane (20 uL, 0.2 mmol) were added (gentle exotherm) and the mixture stirred at room temperature for 15 min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (0.5 g, 1.8 mmol) in DMA (1 mL) was introduced and the reaction was allowed to stir at room temperature for an additional 30 min. Meanwhile, [1,1′-Bis(diphenylphosphino)ferrocen]dichloropalladium(II), in complex with dichloromethane (1:1) (68 mg, 0.083 mmol), copper(I) iodide (32 mg, 0.166 mmol) and 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.65 g, 1.66 mmol) were mixed in DMA (2.5 mL) and stirred under argon for 10 min. Subsequently, the organozinc reagent solution was transferred to this mixture via syringe. The resulting green reaction mixture was stirred at 80° C. whereupon it turned yellow. Stirring was continued for 20 h. At this point, LCMS indicated approximately 33% conversion to the title compound. The mixture was diluted with EtOAc (25 mL) and 1 N HCl (25 mL) and the layers were partitioned. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic portions were washed once with brine. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by rp-HPLC to give 236 (35 mg, 5% yield). LC/MS (ESI+): m/z 468.2 (M+H). 1H NMR (400 MHz, DMSO) δ 1.22 8.47 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.20 (dd, J=8.2, 2.1 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 5.84 (dt, J=13.2, 6.5 Hz, 1H), 4.35 (dd, J=17.3, 12.5 Hz, 4H), 3.82 (s, 3H), 3.44 (t, J=4.9 Hz, 2H), 1.58 (t, J=9.5 Hz, 6H), 1.41 (s, 9H).

Workup

  1. stirringto stir at room temperature for an additional 30 min
  2. stirringstirred under argon for 10 min
  3. stirringThe resulting green reaction mixture was stirred at 80° C. whereupon it
  4. stirringStirring
  5. waitwas continued for 20 h

Sources & evidence

ORD record
ord-132efc4c32b24183988e13b77217e464
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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