2-bromo-6,7,8,9-tetrahydrobenzo[7]annulen-5-one

Conditions: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: J.3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved in 2:1 ether/tetrahydrofuran (120 mL) and 1N HCl in ether (9 mL) was added. The solution was cooled to 0° C. before addition of isoamyl nitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 h at 24° C., concentrated, and applied to 25 (M) Biotage silica gel column. Gradient elution from 15-100% B (A=Hexanes; B=ethyl acetate) over 1 L and gave J.3a (E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1 g (64%). LC (Cond.-J1); RT=1.9 min; LC/MS: Anal. Calcd. for [M+H]+ C11H10NBrO2: 268; found: 268. was added concentrated Gradient elution from 15-100% B (A=Hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(3-Bromo-phenyl)-pentanoic acid (6 g, 23 mmol) in chlorobenzene (300 mL) was added PPA (18 g) and the mixture was heated to reflux for 8 h. The mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure then purified by silica gel chromatography using a solvent system of 10:1 petroleum ether/EtOAc to give 2-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one (2.4 g, 42.9%). MS ESI calcd for C11H11BrO [M+H]+ 239, found 239. the mixture was heated to reflux for 8 h filtered The filtrate was concentrated under reduced pressure then purified by silica gel chromatography

Conditions: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: J.3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved in 2:1 ether/tetrahydrofuran (120 mL) and 1N HCl in ether (9 mL) was added. The solution was cooled to 0° C. before addition of isoamyl nitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 h at 24° C., concentrated, and applied to 25 (M) Biotage silica gel column. Gradient elution from 15-100% B (A=Hexanes; B=ethyl acetate) over 1 L and gave J.3a (E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1 g (64%). LC (Cond.-J1); RT=1.9 min; LC/MS: Anal. Calcd. for [M+H]+ C11H10NBrO2: 268; found: 268. was added concentrated Gradient elution from 15-100% B (A=Hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved Et2O (25 mL), cooled to 0° C. and bromine (0.35 mL, 6.6 mmol) was added dropwise. The solution was stirred at 24° C. until TLC indicated reaction complete (2-18 h; scale dependent). The solvent was removed by rotory evaporation and the crude product applied to a 25 (M) Biotage® silica gel column. Gradient elution from 50-100% B (A=Hexanes; B=10% EtOAc/hex) over 500 mL and gave 2,6-dibromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 700 mg, and 1.5 g of a second fraction containing dibromide (1:1). RT=2.2 minutes (condition 1). reaction complete (2-18 h; scale dependent) The solvent was removed by rotory evaporation Gradient elution from 50-100% B (A=Hexanes

Conditions: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved in 2:1 Et2O/THF (120 mL) and 1N HCl in Et2O (9 mL) was added. The solution was cooled to 0° C. before addition of iso-amylnitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 hours at 24° C., concentrated, and applied to 25 (M) Biotage® silica gel column. Gradient elution from 15-100% B (A=Hexanes; B=EtOAc) over 1 L and gave Example 6, (E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1 g (64%). RT=1.9 minutes (condition 1). LCMS: Anal. Calcd. For C11H10NBrO2: 268. found: 268 (M+H). was added concentrated Gradient elution from 15-100% B (A=Hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: When an equivalent amount of 2-bromo-benzo[b]cycloheptanone or 2-bromo-8-methoxy-benzo[b]cycloheptanone is substituted for the 2-bromo-α-tetralone in step A of example 1 above, there is obtained following the processes of steps A of example 1 and B above, 3-(4-pyridyl)-2,4,5,6-tetra-hydrobenzo[6,7]-cyclohepta[1,2-c]pyrazole(m.p. 217°-219°C) or 9-methoxy-3-(4-pyridyl)-2,4,5,6-tetrahydrobenzo[6,7]cyclohepta [1,2-c]pyrazole (m.p. 200°-201°C) respectively. is obtained