Dichloromethane → 4-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one

HRID 708218Notes

Reaction equation

HRID 708218 reaction equation
Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:15]4=[O:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.IC1C=CC2C3N=C(N4C(C)=NN(C)C4=O)SC=3CCOC=2C=1.[CH3:47][C:48]([OH:65])([CH3:64])[CH2:49][N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O.C1COCC1>[OH:65][C:48]([CH3:64])([CH3:47])[CH2:49][N:50]1[CH:54]=[C:53]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]=[C:8]([N:14]5[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:15]5=[O:21])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:52]=[N:51]1

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 582041312-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-olHCID 670505734-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneHCID 670505884-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one

Product 1

HCID 582037474-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneYield 27%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A microwave vial was charged with an approximately 1:1 mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one (41 mg), 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (33 mg, 0.13 mmol), PdCl2(dppf)2.DCM (3.5 mg, 0.004 mmol), cesium carbonate (68 mg, 0.21 mmol), THF (1 mL) and water (0.2 mL). The vial was sealed and the mixture evacuated and purged with argon (×3). The reaction mixture was heated at 80° C. for 17 hours then a further 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (15 mg) and PdCl2(dppf)2.DCM (4 mg) were added, the vial was re-filled with argon as before and stirring at 80° C. was continued for a further 20 hours. After cooling the reaction mixture was concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-4% MeOH in DCM) to give 473 as a white solid (12 mg, 27%). LCMS: RT=4.14 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.14 (1H, d, J=8.26 Hz), 8.08 (1H, s), 7.87 (1H, s), 7.33 (1H, dd, J=8.26, 1.84 Hz), 7.22 (1H, d, J=1.82 Hz), 4.68 (1H, s), 4.31 (2H, t, J=5.01 Hz), 3.98 (2H, s), 3.35 (3H, s), 3.28 (2H, m), 2.65 (3H, s), 1.04 (6H, s)

Workup

  1. customThe vial was sealed
  2. customthe mixture evacuated
  3. custompurged with argon (×3)
  4. additionDCM (4 mg) were added
  5. additionthe vial was re-filled with argon as before and
  6. temperatureAfter cooling the reaction mixture
  7. concentrationwas concentrated in vacuo
  8. customThe resultant residue was purified by flash chromatography (SiO2, 0-4% MeOH in DCM)

Sources & evidence

ORD record
ord-ae2d249b3dc84c72b1d54bf00fed88a7
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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