141106-23-2

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 14.27 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 50 ml of abs. THF and deprotonated at a temperature of −10° C. and −5° C. by adding via syringe 25.2 ml of 1.6 M n-butyllithium (1.55 eq., in hexane). The resultant red ylide solution was cooled to −75° C. and treated with 6.20 g (26.0 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one dissolved in 13 ml of abs. THF. The mixture was then kept for 0.2 h at −78° C. and for 1 h at room temperature, poured onto crushed ice and extracted with diethylether. The organic phase was washed with water and dried over magnesium sulfate, filtrated and the solvent evaporated to yield a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate=95/5). Thereby, 5.85 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]oxepine was obtained as E/Z-mixture which was hydrolyzed as follows: deprotonated at a temperature of −10° C. and −5° C. dissolved in 13 ml of abs poured onto crushed ice extracted with diethylether The organic phase was washed with water dried over magnesium sulfate filtrated the solvent evaporated to yield a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate=95/5)

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

Procedure: 8-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.0 g, 20.7 mmol) in dimethylformamide dimethylacetal (15 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (20 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (5.32 g, 86%). 1H NMR δ (ppm) (CDCl3): 7.73 (1H, s), 7.61 (1H, d, J=8.29 Hz), 7.29 (1H, dd, J=8.29, 1.94 Hz), 7.18 (1H, d, J=1.91 Hz), 4.28-4.21 (2H, m), 3.14 (6H, s), 2.77-2.70 (2H, m). The resulting solid precipitate was collected by filtration washed with cyclohexane dried under vacuum at 40° C.

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

Procedure: Phosphorus oxychloride, POCl3 (1.88 mL, 20.8 mmol) was added dropwise to DMF (5 mL) at 0° C. After 30 min a solution of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one 8 (2.0 g, 8.3 mmol) in 8 mL DMF was added dropwise. The reaction mixture was allowed to reach room temperature to stir 2 hr, then poured slowly over rapidly stirred ice water. The aqueous phase was extracted with ethylacetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give (Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde. to reach room temperature The aqueous phase was extracted with ethylacetate the combined organics were washed with brine dried over sodium sulfate concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) and celite (ca. 40 g) in 100 mL toluene was added crude 4-(3-bromophenoxy)butanoic acid 7 (ca. 58 mmol) in one portion, 10 mL toluene rinse (FIG. 1). The resultant suspension was heated at 110° C. for 5 hr. The toluene was decanted through a plug of celite and the remaining slurry was washed repeatedly with toluene and ethylacetate. The eluent was concentrated and purified by flash column chromatography (4:1 hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7 g, ca. 50% y). 1H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H). rinse (FIG. 1) The toluene was decanted through a plug of celite the remaining slurry was washed repeatedly with toluene and ethylacetate The eluent was concentrated purified by flash column chromatography (4:1 hex:EtOAc)

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

Procedure: Phosphorus oxychloride, POCl3 (1.88 mL, 20.8 mmol) was added dropwise to DMF (5 mL) at 0° C. After 30 min a solution of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (2.0 g, 8.3 mmol) in 8 mL DMF was added dropwise. The reaction mixture was allowed to reach room temperature to stir 2 hr, then poured slowly over rapidly stirred ice water. The aqueous phase was extracted with ethylacetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give (Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde. to reach room temperature The aqueous phase was extracted with ethylacetate the combined organics were washed with brine dried over sodium sulfate concentrated

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

Procedure: To a stirred solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (3.10 g; 12.8 mmol) in Et2O at 0° C. was added Br2 (625 μl; 12.2 mmol) and the reaction mixture was allowed to warm to r.t. over 2 h. Volatiles were evaporated and the residue purified by flash column chromatography (0-20% EtOAc in hexanes) to give 4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one as a colorless solid (4.0 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.21 (m, 2H), 7.55 (d, J=8.0, 1H), 4.87 (app. t, J=5.2, 2H), 4.33-4.39 (m, 1H), 4.09-4.16 (m, 1H), 2.78-2.91 (m, 1H), 2.40-2.49 (m, 1H). Volatiles were evaporated the residue purified by flash column chromatography (0-20% EtOAc in hexanes)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) and celite (ca. 40 g) in 100 mL toluene was added crude 4-(3-bromophenoxy)butanoic acid (ca. 58 mmol) in one portion, 10 mL toluene rinse. The resultant suspension was heated at 110° C. for 5 hr. The toluene was decanted through a plug of celite and the remaining slurry was washed repeatedly with toluene and ethylacetate. The eluent was concentrated and purified by flash column chromatography (4:1 hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7 g, ca. 50% yield). 1H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H). rinse The toluene was decanted through a plug of celite the remaining slurry was washed repeatedly with toluene and ethylacetate The eluent was concentrated purified by flash column chromatography (4:1 hex:EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) and celite (ca. 40 g) in 100 mL toluene was added crude 4-(3-bromophenoxy)butanoic acid (ca. 58 mmol) in one portion, 10 mL toluene rinse. The resultant suspension was heated at 110° C. for 5 hr. The toluene was decanted through a plug of celite and the remaining slurry was washed repeatedly with toluene and ethylacetate. The eluent was concentrated and purified by flash column chromatography (4:1 hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7 g, ca. 50% yield). 1H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H). rinse The toluene was decanted through a plug of celite the remaining slurry was washed repeatedly with toluene and ethylacetate The eluent was concentrated purified by flash column chromatography (4:1 hex:EtOAc)

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

Procedure: To a solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.2 g, 5 mmol) in diethyl ether (20 mL) at 0° C. was added bromine (257 μL, 5 mmol) dropwise under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, allowed to warm up to RT and stirred for 3 h. Further bromine (50 μL, 0.97 mmol) was added and stirring was pursued for 16 h. The solvent was removed in vacuo and the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to give the title compound as a white solid (1.55 g, 97%). 1H NMR (CDCl3): 7.62 (1H, m), 7.26 (2H, m), 4.94 (1H, dd, J=7.7, 6.7 Hz), 4.43 (1H, ddd, J=12.7, 5.6, 4.8 Hz), 4.25-4.15 (1H, m), 2.97-2.86 (1H, m), 2.51 (1H, ddt, J=14.7, 7.7, 4.6 Hz). to warm up to RT stirred for 3 h stirring was pursued for 16 h The solvent was removed in vacuo the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane)

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

Procedure: To a solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.2 g, 5 mmol) in diethyl ether (20 mL) at 0° C. was added bromine (257 μL, 5 mmol) dropwise under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, allowed to warm up to RT and stirred for 3 h. Further bromine (50 μL, 0.97 mmol) was added and stirring was pursued for 16 h. The solvent was removed in vacuo and the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to give the title compound as a white solid (1.55 g, 97%). 1H NMR (CDCl3): 7.62 (1H, m), 7.26 (2H, m), 4.94 (1H, dd, J=7.7, 6.7 Hz), 4.43 (1H, ddd, J=12.7, 5.6, 4.8 Hz), 4.25-4.15 (1H, m), 2.97-2.86 (1H, m), 2.51 (1H, ddt, J=14.7, 7.7, 4.6 Hz). to warm up to RT stirred for 3 h stirring was pursued for 16 h The solvent was removed in vacuo the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane)