5-iodo-2,4-dimethoxybenzaldehyde

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

Procedure: Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl2(PPh3)2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered. The filtrate was concentrated to about 50 ml, and the precipitate was filtered to give first portion of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as light yellow crystals. The filtrate was concentrated, and the residue was recrystallized from EtOAc/hexanes to give 1.85 g of additional product (total 10.35 g, 92%), mp 180–181° C. 1H-NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.11–7.17 (m, 1H), 6.69–6.75 (m, 2H), 6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1056. Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93. filtered The filtrate was concentrated to about 50 ml the precipitate was filtered

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

Procedure: Ex-35B: To a solution of 2.4-dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170–172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169–171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; 1, 43.33; Found: C, 37.12; H, 3.15; I, 43.33. after 3 hours The precipitate was collected by filtration washed with water dried in vacuo (40° C.) to give crude product of 33.02 g The crude product was further purified by recrystallization from THF/heptane (1:1)

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

Procedure: Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl2(PPh3)2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered. The filtrate was concentrated to about 50 ml, and the precipitate was filtered to give first portion of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as light yellow crystals. The filtrate was concentrated, and the residue was recrystallized from EtOAc/hexanes to give 1.85 g of additional product (total 10.35 g, 92%), mp 180–181° C. 1H-NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.11–7.17 (m, 1H), 6.69–6.75 (m, 2H), 6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1056. Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93. filtered The filtrate was concentrated to about 50 ml the precipitate was filtered

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

Procedure: Ex-35B: To a solution of 2.4-dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170–172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169–171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; 1, 43.33; Found: C, 37.12; H, 3.15; I, 43.33. after 3 hours The precipitate was collected by filtration washed with water dried in vacuo (40° C.) to give crude product of 33.02 g The crude product was further purified by recrystallization from THF/heptane (1:1)

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

Procedure: Ex-35B: To a solution of 2.4-dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170–172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169–171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; 1, 43.33; Found: C, 37.12; H, 3.15; I, 43.33. after 3 hours The precipitate was collected by filtration washed with water dried in vacuo (40° C.) to give crude product of 33.02 g The crude product was further purified by recrystallization from THF/heptane (1:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 1.0 g, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), and tri-tert-butylphosphine (100 mg, 0.05 mmol) were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter. The reaction mixture was heated at 60° C. for one hour under nitrogen. HPLC analysis indicated of 100% conversion of 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123) to the title compound prepared through another route (Ex-3A). were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter

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

Procedure: To a solution of 2,4-dimethoxy-benzaldehyde (20.0 g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.25 g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1, v/v) to give the title compound as a white solid (30.62 g, 87.5%), m.p. 170–172° C. 1H NMR (CDCl3) δ 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). The resulting precipitate was collected by filtration washed with water dried in vacuo The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 1.0 g, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), and tri-tert-butylphosphine (100 mg, 0.05 mmol) were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter. The reaction mixture was heated at 60° C. for one hour under nitrogen. HPLC analysis indicated of 100% conversion of 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123) to the title compound prepared through another route (Ex-3A). were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter

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

Procedure: To a solution of 2,4-dimethoxy-benzaldehyde (20.0 g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.25 g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1, v/v) to give the title compound as a white solid (30.62 g, 87.5%), m.p. 170–172° C. 1H NMR (CDCl3) δ 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). The resulting precipitate was collected by filtration washed with water dried in vacuo The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1

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

Procedure: Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl2(PPh3)2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered. The filtrate was concentrated to about 50 ml, and the precipitate was filtered to give first portion of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as light yellow crystals. The filtrate was concentrated, and the residue was recrystallized from EtOAc/hexanes to give 1.85 g of additional product (total 10.35 g, 92%), mp 180–181° C. 1H-NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.11–7.17 (m, 1H), 6.69–6.75 (m, 2H), 6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1056. Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93. filtered The filtrate was concentrated to about 50 ml the precipitate was filtered

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

Procedure: Ex-35B: To a solution of 2.4-dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL) was added iodine monochloride (23.5 g in 60 mL methanol) dropwise over 20 min at ambient temperature. The solution was allowed to stir at this temperature. HPLC showed about 94% conversion after 3 hours. The reaction mixture was then poured into a solution of HCl (0.5M, 600 mL). The precipitate was collected by filtration, washed with water, dried in vacuo (40° C.) to give crude product of 33.02 g. The crude product was further purified by recrystallization from THF/heptane (1:1) to give 5-iodo-2,4-dimethoxybenzaldehyde as an off-white solid (27.5 g, m.p 170–172° C.). The mother liquid was concentrated to dryness. The residual material was dissolved in EtOH (100 mL) and acetone (20 mL) followed by addition of water (20 mL) to give additional product (3.12 g, m.p. 169–171° C.). Overall isolated yield of this reaction was 87.5%. 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). HRMS Calcd. for C9H9IO3: 291.9596 (M+); Found: 291.9602. Anal. Calcd. for C8H9NO3S: C, 37.01; H, 3.11; 1, 43.33; Found: C, 37.12; H, 3.15; I, 43.33. after 3 hours The precipitate was collected by filtration washed with water dried in vacuo (40° C.) to give crude product of 33.02 g The crude product was further purified by recrystallization from THF/heptane (1:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 1.0 g, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), and tri-tert-butylphosphine (100 mg, 0.05 mmol) were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter. The reaction mixture was heated at 60° C. for one hour under nitrogen. HPLC analysis indicated of 100% conversion of 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123) to the title compound prepared through another route (Ex-3A). were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter