1-Isopropylhydrazine hydrochloride → 9-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

HRID 886325Notes

Reaction equation

HRID 886325 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.Cl.[CH3:18][O:19][CH2:20][C:21]([NH2:23])=[NH:22].[CH3:24][C:25]1([CH3:65])C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[CH:67]([NH:70]N)(C)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:67]4[N:70]([CH:25]([CH3:65])[CH3:24])[N:22]=[C:21]([CH2:20][O:19][CH3:18])[N:23]=4)=[CH:10]3)[C:6]=2[CH:16]=1

Participants

9

Reactant 4

HCID 855731-Isopropylhydrazine hydrochlorideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 135486022-Methoxyethanimidamide hydrochlorideHCID 5820440710-Bromo-2-iodo-5,6-dihydrobenzo[F]imidazo[1,2-D][1,4]oxazepine

Product 1

HCID 582044449-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneYield 769.2%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (2.00 g, 5.1 mmol), 2-methoxy-acetamidine hydrochloride (0.76 g, 6.1 mmol) and TEA (5.00 mL, 35.9 mmol) in DMF (38 mL) was evacuated and refilled with nitrogen (×3). The reaction was treated with Xantphos (0.15 g, 0.26 mmol) and palladium (II) acetate (57 mg, 0.26 mmol) before the reaction was purged with carbon monoxide gas and the reaction stirred at 60° C. for 3.5 h. The reaction mixture was cooled to RT, purged with nitrogen then treated with isopropyl-hydrazine hydrochloride (1.70 g, 15.0 mmol) and acetic acid (19 mL). After stirring at 60° C. for 1.5 h the reaction was diluted with ethyl acetate (350 mL). The solution was washed with 1N NaOH (2×50 mL) followed by brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-3% methanol in DCM) then triturated with diethyl ether to afford 9-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a pale pink solid (0.85 g, 2.0 mmol, 40%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.44 (1H, d, J=2.57 Hz), 7.94 (1H, s), 7.43 (1H, dd, J=8.74, 2.58 Hz), 6.99 (1H, d, J=8.74 Hz), 5.72-5.63 (1H, m), 4.49 (4H, d, J=3.06 Hz), 4.33 (2H, s), 3.27 (3H, s), 1.44 (6H, d, J=6.60 Hz).

Workup

  1. customwas evacuated
  2. additionrefilled with nitrogen (×3)
  3. customwas purged with carbon monoxide gas
  4. temperatureThe reaction mixture was cooled to RT
  5. custompurged with nitrogen
  6. stirringAfter stirring at 60° C. for 1.5 h the reaction
  7. washThe solution was washed with 1N NaOH (2×50 mL)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. customthen triturated with diethyl ether

Sources & evidence

ORD record
ord-55677a5cf06f4c8eb376e236b019cb49
Source dataset
uspto-grants-2012_08
Patent number
US08242104B2

Reaction notes

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