6-Bromoisoquinoline

A mixture of 4-bromobenzaldehyde (300.0 g, 1620.0 mmol) and amino acetaldehyde dimethyl acetal (170.4 g, 1620 mmol) in anhydrous toluene (1.5 L) was refluxed under a Dean-Stark condenser for 12 h. The solution was concentrated under vacuum. The residue was dissolved in anhydrous THF and cooled to -10 °C. Ethyl chloroformate (193.3 ml_, 1782 mmol) was added and stirred for 10 min at -10 °C, and then allowed to warm to room temperature. Subsequently trimethyl phosphite (249.6 ml_, 1782.0 mmol) was added dropwise to the reaction mixture and stirred for 10 h at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in anhydrous DCM (1.5 L) and stirred for 30 minutes. The reaction mixture was cooled to 0 °C, and titanium tetrachloride (1.2 L, 6480 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 6 days. The reaction mixture was poured into ice and pH was adjusted to 8 - 9 with aqueous 6N NaOH solution. The suspension was extracted three times with EtOAc. The organic layer was extracted with 3 M HCI. The acidic aqueous solution was adjusted to pH to 7 - 8 with 3N NaOH solutions and extracted two times with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the product. Crude compound was dissolved in minimum amount of DCM and mixed with pentane to get compound A1 as light brown solid. Yield: 90 g (35percent). RGeneral procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg, 0.47 mmol, 22percent) [20, 21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL), o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.6-Bromo-1-(2-thiazolyl)isoquinoline (9b): 6-Bromoisoquinoline (14b, 30 mg, 0.14 mmol) was synthesizedstarting from 4-bromobenzaldehyde (13c, 200 mg, 1.08 mmol) in 14percent yield. Compound 9b wassynthesized starting from 6-bromoisoquinoline (14b, 100 mg, 0.48 mmol) in 15percent yield over two steps(21 mg, 0.07 mmol), obtained as an orange powder, m.p. 103–105 °C.Preparation Example G-1. Isoquinoline-6-carboxylic acid A solution prepared by adding (4-bromobenzylydene)-(2, 2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N, N-dimethylformamide (3.8mL) were added zinc cyanide (431 mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.A solution prepared by adding (4-bromobenzylydene)-(2, 2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N, N-dimethylformamide (3.8mL) were added zinc cyanide (431mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.Step 2To a stirred solution of N-(4-bromobenzyl)-2, 2-dimethoxyethanamine (10 g, 0.037 mol) in CH

Molecular Weight:208.05
XLogP3:2.9
Hydrogen Bond Acceptor Count:1
Exact Mass:206.96836
Monoisotopic Mass:206.96836
Topological Polar Surface Area:12.9
Heavy Atom Count:11
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes