2-Chloro-6-methoxyquinoxaline

Step A: 7-Methoxyqu lin-2(lH)-oneA 50percent solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene was added to a solution of 4-methoxybenzene-l, 2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was refluxed for 2 h. The reaction was concentrated in vacuo and crystallized from ethanol to afford a mixture of 6- methoxyquinoxalin-2(lH)-one and 7-methoxyquinoxalin-2(lH)-one (5.73 g, 32.50 mmol, 42 percent yield). MS (LC/MS) R.T. = 0.68; [M+H]50percent solution of ethyl2-oxoacetate (18.47 ml., 93mmol) in toluene was added to a solution of 4-methoxybenzene-I, 2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was ref/uxed for 2 h.The reaction was concentrated in vacuo and crystallized fromethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)oneand 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50mmol, 42percent yield). A mixture of 6-methoxyquinoxalin-2(1H)-one and7-methoxyquinoxalin-2(1H)-one (5.67 g, 32.20 mmol) wasrefluxed in phosphorus oxychloride (120 mL) for I h. Thereaction was concentrated and quenched by addition of ice, then basified with sodium carbonate, and extracted with ethylacetate (3x200 mL). The organic layers were combined andconcentrated in vacuo. The crude product was absorbed ontosodium sulfate and purified by column chromatography (0 to5percent ethyl acetatelhexanes) to afford 2-chloro-6-methoxyquinoxaline(2.21 g, 11.36 mmol, 35percent yield).To a solution of 4-methoxybenzene-1, 2-diamine (5 g, 36.2 mmol) in ethanol (50 ml) was added ethyl 2-oxoacetate (4.06 g, 39.8 mmol)). The reaction mass was heated at reflux for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and then evaporated to dryness to get the crude compound. The crude compound was washed with pet ether to get crude compound (5.1 g, 80percent yield) as a mixture of regioisomers (black solid). This crude compound was taken to the next step without separation of isomers.To a solution of 4-methoxybenzene-1, 2-diamine (3.58 g, 25.9 mmol) in dry EtOH (30 mL) was added 50percent ethyl 2-oxoacetate in toluene (6.2 mL) and the mixture was heated under reflux for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was washed with EtOH to give a mixture of 6-methoxyquinoxalin-2-ol and 7-methoxyquinoxalin-2-ol as a brown solid (2.6 g, 57percent). 1H NMR (300 MHz, DMSO-d612.30 (s, 1H), 8.13 (s, 1H), 7.23-7.25 (m, 1H), 7.15-7.20 (m, 2H), 3.78 (s, 3H). LC-MS (ESI) mlz 177 (M+H)+. [000179] Step 2: The mixture of 6-methoxyquinoxalin-2-ol and 7-methoxyquinoxalin-2-ol (1.6 g, 9.1 mmol) in POC13 (30 mL) was heated under reflux for 1 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was quenched with ice, basified with saturated aq Na2CO3, and extracted with EtOAc. The organic layer was dried over Na2504, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3percent EtOAc in petroleum ether to give the following products:[000180] Pure 2-chloro-6-methoxyquinoxaline as a white solid (150 mg), 1H NMR (300 MHz, CDC13 8.71 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.44 (dd, J = 9.3, 2.7 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 3.95 (s, 3H). LC-MS (ESI) mlz 195 (M+H)+.[000181] Pure 2-chloro-7-methoxyquinoxaline as a white solid (100 mg). 1H NMR (300 MHz, CDC13 8.62 (s, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.41 (dd, J = 9.3, 2.7 Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 3.96 (s, 3H). LC-MS (ESI) mlz 195 (M+H)+.[000182] A mixture of 2-chloro-6-methoxy quinoxaline and 2-chloro-7- methoxyquinoxaline as a white solid (1.27 g, 85percent).Step B: 2-Chloro-6-methoxyquinoxaline A mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.67 g, 32.20 mmol) was refluxed in phosphorus oxychloride (120 mL) for 1 h. The reaction was concentrated and quenched by addition of ice, then basified with sodium carbonate, and extracted with ethyl acetate (3.x.200 mL). The organic layers were combined and concentrated in vacuo. The crude product was absorbed onto sodium sulfate and purified by column chromatography (0 to 5percent ethyl acetate/hexanes) to afford 2-chloro-6-methoxyquinoxaline (2.21 g, 11.36 mmol, 35percent yield).

Molecular Weight:194.62
XLogP3:2.2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:194.0246905
Monoisotopic Mass:194.0246905
Topological Polar Surface Area:35
Heavy Atom Count:13
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes