Potassium Fluoride → 9-Bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

HRID 1530548Notes

Reaction equation

HRID 1530548 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.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.[F-].[K+]>CC#N>[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:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:10]3)[C:6]=2[CH:16]=1

Participants

5

Reactant 3

HCID 522689Potassium FluorideHCID 27343783-Pyridinylboronic acid2×HCID 5820440710-Bromo-2-iodo-5,6-dihydrobenzo[F]imidazo[1,2-D][1,4]oxazepine

Product 1

HCID 683129989-Bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azuleneYield 18%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (150 mg, 0.39 mmol), 3-pyridylboronic acid (51 mg, 0.42 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (8 mg, 0.01 mmol) and KF (1 mL, 2M aqueous solution) in MeCN (1 mL) was heated at 85° C. for 30 h. Further 3-pyridylboronic acid (26 mg, 0.21 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4 mg, 0.01 mmol). The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-100% EtOAc in cyclohexane) then (C18, gradient 15-60% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 9-Bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid (17 mg, 18%). LCMS: RT 3.40 min [M+H]+ 342.0 and 344.0. 1H NMR (CDCl3, 400 MHz): δ 8.81 (1H, d, J=2.55 Hz), 8.55 (1H, ddd, J=4.87, 1.80, 0.93 Hz), 8.13 (1H, dt, J=7.96, 1.06 Hz), 7.76 (1H, td, J=7.73, 1.82 Hz), 7.68 (1H, s), 7.34 (1H, dd, J=8.68, 2.56 Hz), 7.17 (1H, ddd, J=7.49, 4.86, 1.22 Hz), 6.91 (1H, d, J=8.68 Hz), 4.50-4.44 (4H, m)

Workup

  1. washwas washed with MeOH
  2. washthe product eluted with 2M NH3/MeOH
  3. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-100% EtOAc in cyclohexane)
  4. washwas washed with MeOH
  5. washthe product eluted with 2M NH3/MeOH

Sources & evidence

ORD record
ord-52a8b20e126b461cba6cd8d0585a8563
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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