4-bromo-2-phenoxybenzaldehyde

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

Procedure: The title compound was prepared in a 62% from 4-bromo-2-phenoxybenzaldehyde in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.43(s, 1H), 8.14(s, 1H), 7.89(d, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 6.88(d, 1H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02min.

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

Procedure: The title compound was prepared in a 46% yield from 5-bromo-2-fluoro-benzaldehyde and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.32(s, 1H), 7.92(s, 1H), 7.81(d, 1H), 7.46(t, 2H), 7.27(t, 1H), 7.18(d, 2H), 6.90(d, 1H) RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.08 min. tr 13.08 min.

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

Procedure: The title compound was prepared in a 62% from 4-bromo-2-phenoxybenzaldehyde in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.43(s, 1H), 8.14(s, 1H), 7.89(d, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 6.88(d, 1H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02min.

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

Procedure: The title compound was prepared in a 46% yield from 5-bromo-2-fluoro-benzaldehyde and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.32(s, 1H), 7.92(s, 1H), 7.81(d, 1H), 7.46(t, 2H), 7.27(t, 1H), 7.18(d, 2H), 6.90(d, 1H) RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.08 min. tr 13.08 min.

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

Procedure: A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+. The resulting solution was stirred for overnight at room temperature The resulting mixture was extracted with dichloromethane (2×10 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92)

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

Procedure: A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+. The resulting solution was stirred for overnight at room temperature The resulting mixture was extracted with dichloromethane (2×10 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with 4-bromo-2-fluorobenzaldehyde (2.00 g, 9.85 mmol, 1.00 equiv), phenol (0.926 g, 9.84 mmol, 1.00 equiv), potassium carbonate (1.35 g, 9.77 mmol, 0.99 equiv), and N,N-dimethylacetamide (30 mL). The resulting solution stirred for 4 h at 150° C. and then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/99) to provide 2.40 g (88% yield) of 4-bromo-2-phenoxybenzaldehyde as a light yellow solid. 1H NMR 400 MHz (CDCl3) δ 10.51 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.41-7.48 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.25-7.29 (m, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.04 (s, 1H). LCMS (ESI, m/z): 277 [M+H]+. A 250 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen extracted with ethyl acetate (3×20 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/99)

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

Procedure: The title compound was prepared in a 62% from 4-bromo-2-phenoxybenzaldehyde in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.43(s, 1H), 8.14(s, 1H), 7.89(d, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 6.88(d, 1H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.02min.

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

Procedure: The title compound was prepared in a 46% yield from 5-bromo-2-fluoro-benzaldehyde and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.32(s, 1H), 7.92(s, 1H), 7.81(d, 1H), 7.46(t, 2H), 7.27(t, 1H), 7.18(d, 2H), 6.90(d, 1H) RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.08 min. tr 13.08 min.