4-bromo-1,2-dimethoxybenzene

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

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

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

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

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

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

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

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

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Dimethoxy-6-nitro-bromobenzene (16). 3,4-Dimethoxybromobenzene (5 g, 23 mmol) was slowly added to a stirred solution of 35 mL concentrated nitric acid and 105 mL glacial acetic acid maintained at 10° C. The reaction mixture was stirred at 15° C. for 1 h and then diluted with 200 mL ice cold water. The resulting mixture was extracted thrice with 200 mL portions of ether. The combined organic phase was dried and evaporated in vacuo. The crude product was recrystallized from ethanol to give bright yellow needle shaped crystals of compound 16 in 92% yield; mp=122-124° C.; IR (Nujol) 1510, 1312; 1H NMR δ 3.94 (3H, s), 3.97 (3H, s), 7.12 (1H, s), 7.57 (1H, s); 13C NMR δ 56.9, 57.2, 108.0, 109.5, 117.0, 148.7, 153.3; Anal. calcd for C8H8NO4Br: C, 36.72, H, 3.14, N, 5.30; Found: C, 36.70, H, 3.13, N, 5.29. The resulting mixture was extracted thrice with 200 mL portions of ether The combined organic phase was dried evaporated in vacuo The crude product was recrystallized from ethanol to give bright yellow needle

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A hexane solution of butyl lithium (9 mL, 22 mmol, 2.5M) was slowly added to a stirring solution of 4-bromoveratrole (2.9 mL, 20 mmol) in 40 mL of tetrahydrofuran under nitrogen at -70° C. After 15 minutes a solution of 4-cyanopyridine in 12 mL of tetrahydrofuran was added to the reaction mixture and stirring was continued for 45 minutes. The reaction was then allowed to warm to -10° C. and the reaction was carefully quenched with hydrochloric acid (45 mL, 1N). The mixture was stirred for 30 minutes at room temperature. The pH was then adjusted to 12 with 50 mL of a 10% aqueous solution of sodium hydroxide. The mixture was extracted with ether (3×50 mL). The combined ethereal extracts were washed with brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo to a brown solid. The crude product was purified by flash column chromatography (silica gel, 3% methanol/methylene chloride) to afford after vacuum drying (60° C., 1 mm) 1.9 g (39%) of the product: mp 117-118° C.; 1H NMR (CDCl3) δ 8.85-8.76 (m, 2 H), 7.60-7.50 (m, 3 H), 7.40-7.30 (m, 1 H), 6.97-6.88 (m, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ 193.7, 153.9, 150.1, 149.3, 145.2, 128.7, 125.9, 122.6, 111.5, 109.9, 56.1, 56.0; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.05; H, 5.39; N, 5.85. the reaction was carefully quenched with hydrochloric acid (45 mL, 1N) The mixture was stirred for 30 minutes at room temperature The mixture was extracted with ether (3×50 mL) The combined ethereal extracts were washed with brine (100 mL) then dried over magnesium sulfate concentrated in vacuo to a brown solid The crude product was purified by flash column chromatography (silica gel, 3% methanol/methylene chloride) to afford after vacuum drying (60° C., 1 mm) 1.9 g (39%) of the product

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

Procedure: 3,4,3',5'-Tetramethoxybenzophenone was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using butyl lithium (9 mL, 22 mmol, 2.5M), 4-bromoveratrole (2.9 mL, 20 mmol) and 3,5-dimethoxybenzonitrile (3.75 g, 23 mmol). The crude product was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.54 g (26%) of the product: mp 107-110° C.; 1H NMR (CDCl3) δ 7.53-7.39 (m, 2 H), 6.95-6.84 (m, 3 H), 6.70-6.60 (m, 1 H), 3.96 (s, 3 H), 3.95 (s, 3 H), 3.83 (s, 6 H); 13C NMR (CDCl3) δ 195.0, 160.4, 153.0, 148.9, 140.1, 130.0, 125.4, 112.0, 109.7, 107.5, 104.1, 56.0, 55.5; Anal. Calcd for C17H18O5. Theoretical: C, 67.54; H, 6.00. Found: C, 67.38; H, 5.96. The crude product was purified by flash column chromatography (silica gel, methylene chloride)

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

Procedure: A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.31 mmol), 4-bromoveratrole (83 mg, 0.37 mmol), and aqueous potassium carbonate solution (2M, 0.62 mL, 1.24 mmol) in toluene (1.8 mL) and ethanol (0.6 mL) was degassed with nitrogen for 5 minutes then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.8 mg, 0.016 mmol). The reaction mixture was heated to 110° C. for 2.5 h. The reaction was cooled to room temperature and poured into water and ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography was performed on the crude product using heptanes/ethyl acetate (4:1 to 1:1) to give the title compound (90 mg 84%). MS (ES+) 346.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (br. s., 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.04 (d, J=8.29 Hz, 1H), 6.98 (s, 1H), 6.93 (d, J=8.29 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H). was degassed with nitrogen for 5 minutes The reaction was cooled to room temperature The layers were separated the aqueous layer was back-extracted twice with ethyl acetate The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo