HCID 21864764, compound → 3-(5-Nitro-benzofuran-7-yl)-1-aza-bicyclo[2.2.2]oct-2-ene

HRID 1161988Notes

Reaction equation

HRID 1161988 reaction equation
C([Sn](CCCC)(CCCC)[C:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH:7]=1)CCC.I[C:23]1[C:31]2[O:30][CH:29]=[CH:28][C:27]=2[CH:26]=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=1>CN(C=O)C.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:32]([C:25]1[CH:24]=[C:23]([C:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH:7]=2)[C:31]2[O:30][CH:29]=[CH:28][C:27]=2[CH:26]=1)([O-:34])=[O:33]

Participants

6

Reactant 2

HCID 21864764HCID 21864764, compoundHCID 233522803-(Tributylstannyl)-1-azabicyclo[2.2.2]oct-2-ene

Product 1

HCID 668925663-(5-Nitro-benzofuran-7-yl)-1-aza-bicyclo[2.2.2]oct-2-eneYield 82.6%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 6212ChloroformSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
160 °C

Procedure

3-Tributylstannanyl-1-aza-bicyclo[2.2.2]oct-2-ene (2.14 g, 5.36 mmol; prepared according to Bioorg. Med. Chem. Lett. 1994, 4, 2837-2840) was added to a mixture of 7-iodo-5-nitro-benzofuran (0.52 g, 1.79 mmol), Pd(PPh3)4 (0.206 g, 0.17 mmol) in DMF (10 mL). The mixture was heated at 160° C. for 10 min in a sealed reaction vessel using controlled microwave energy. The reaction mixture was diluted with CHCl3 and then filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by repetitive chromatography on silica using gradient elution, (CHCl3→CHCl3+10% MeOH+0.4% NH3) followed by CHCl3+10% MeOH+0.4% NH3 to give 399.5 mg of 3-(5-nitro-benzofuran-7-yl)-1-aza-bicyclo[2.2.2]oct-2-ene. This intermediate was dissolved in a solvent system of EtOH:THF (4:1; 20 mL) and Raney-Ni (˜1.0 mL suspension in EtOH) was added followed by hydrazine monohydrate (6 equiv). The mixtures are stirred vigorously for 3 h and then filtered through Celite pre-treated with water. The filtrate was concentrated, followed by the addition of toluene and re-evaporation to yield 340 mg of the crude intermediate (7-(1-aza-bicyclo[2.2.2]oct-2-en-3-yl)-benzofuran-5-ylamine). Most of this material (325 mg; 1.35 mmol) was dissolved in DCM (5 mL). Pyridine (1.05 mL) was added followed by 2-methoxy-5-methyl-benzenesulfonyl chloride (267 mg, 1.20 mmol). The resultant mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica using gradient elution (CHCl3→CHCl3+10% MeOH+0.4% NH3) to give 230 mg of the free base of the title compound. The free base was dissolved in MeOH and 1 M HCl in ether was added to the solution. More ether was added and the precipitate was collected by filtration to give 182 mg of the HCl-salt. The product was dissolved in CH3CN:MeOH (2:1) and then purified by preparative reversed phase HPLC. The pure HPLC fractions was pooled and then concentrated to give the TFA-salt of the final product. The TFA-salt was converted to the HCl-salt: yield 100 mg of N-[7-(1-aza-bicyclo[2.2.2]oct-2-en-3-yl)-benzofuran-5-yl]-2-methoxy-5-methyl-benzenesulfonamide hydrochloride; 1H NMR (270 MHz, DMSO-d6) δ ppm 1.57-1.76 (m, 2H), 2.00-2.20 (m, 3H), 2.21 (s, 3H), 3.00-3.17 (m, 2H), 3.27-3.66 (m, obscured in part by solvent signal, 3H), 3.86 (s, 3H), 6.99-7.09 (m, 2H), 7.20-7.42 (m, 4H), 7.53-7.60 (m, 1H), 8.05-8.10 (m, 1H), 9.98 (m, s, 1H); GC-MS (EI+) for C23H24N2O4S m/z 425 (M)+.

Workup

  1. filtrationfiltered through a pad of Celite
  2. concentrationconcentrated under reduced pressure
  3. customThe residue was purified by repetitive chromatography on silica using gradient elution, (CHCl3→CHCl3+10% MeOH+0.4% NH3)

Sources & evidence

ORD record
ord-5e72fdbf80524d4693c0b874d86f9b81
Source dataset
uspto-grants-2010_10
Patent number
US07820675B2

Reaction notes

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