(E)-but-2-enal

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

Procedure: To a 10° C. solution of 5 (13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/1H2O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10° C. for 24 h. The reaction mixture was then diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (7% EtOAc/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo:endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers tr=14.1 min and 15.3 min, endo isomers tr=16.5 min and 20.8. IR (CH2Cl2) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm−1; 1H NMR (500 MHZ, CDCl3) δ 9.36 (d, J=5.8 Hz, 1H, CHO), 7.73-7.78 (m, 2H, ArH), 7.43-7.57 (m, 7H, ArH), 7.35-7.40 (m, 1H, ArH), 7.16-7.26 (m, 3H, ArH), 7.04-7.08 (m, 1H, ArH), 3.08 (dq, J=6.9, 4.1 Hz, 1H, CHCH3), 2.56 (dd, J=5.8, 4.2 Hz, 1H, CHCHO), 0.96 (d, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHZ) δ 201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C24H20O2) requires m/z 341.1541, found m/z 341.1542; [α]D=−82.4 Ĉ=1.0, CHCl3). washed with H2O (10 mL) The aqueous layer was extracted with Et2O (10 mL×2) the combined organics were dried (Na2SO4) concentrated Purification by silica gel chromatography (7% EtOAc/hex)

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

Procedure: 20 g of 5-aminouracil (40 mmol), 80 ml of 20% HCl and 4 ml of crotonaldehyde (50 mmol) were heated together under reflux for 1 hour. The solution was evaporated to dryness under rotarary evaporation. Water was added to the residue so as to make the mixture just stirrable and then it was triturated with ammonium hydroxide with strong stirring until the pH increased to 10-11. Stirring was continued for another 10 minutes. The precipitate was filtered and was washed with minimal methanol and then chloroform and dried to give 17.58 g (63%) of 1. under reflux for 1 hour The solution was evaporated to dryness under rotarary evaporation Water was added to the residue so as it was triturated with ammonium hydroxide increased to 10-11 Stirring The precipitate was filtered was washed with minimal methanol chloroform and dried

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

Procedure: 2-Bromo-4-fluorobenzenamine (10 g, 52.6 mmol) was weighed into a round bottom flask, and dissolved in 40 mL of 6N HCl. The reaction mixture was then heated to reflux, followed by drop-wise addition of (E)-but-2-enal (4.578 mL, 55.3 mmol) mixed with 1.0 mL deionized water over 25 minutes. Following complete addition the reaction was heated at 100° C. for an additional 35 minutes, until all the 2-bromo-4-fluorobenzenamine had been consumed. The reaction was cooled to ambient temperature, followed by addition of 50 mL of Et2O. The reaction was stirred for 5 minutes followed by removal of Et2O by partitioning. The aqueous layer was replaced into the original reaction flask and ZnCl2 (3.586 g, 26.3 mmol) was then added in two portions followed by cooling to 0° C. over 30 minutes. The pH of the crude reaction mixture was then adjusted to pH=8.0 using concentrated NH4OH. The crude mixture was then extracted with Et2O, followed by ethyl acetate. The combined organics were then dried over Na2SO4, and then concentrated in vacuo, affording the desired product as a brown solid (10.7 g, 85% yield). MS APCI (+) m/z 240.2 and 242.2 (M+1 of each Br isotope) detected. The reaction mixture was then heated to reflux mixed with 1.0 mL over 25 minutes addition the reaction had been consumed followed by addition of 50 mL of Et2O followed by removal of Et2O by partitioning was then added in two portions by cooling to 0° C. over 30 minutes The pH of the crude reaction mixture The crude mixture was then extracted with Et2O The combined organics were then dried over Na2SO4 concentrated in vacuo

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

Procedure: 2-(3-aminophenyl)acetic acid (11.0 g, 72.8 mmol) was dissolved in 6 N HCl (200 mL) and heated to reflux. (E)-but-2-enal (11.9 mL, 146 mmol) was added dropwise over 10 minutes. The reaction was heated at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to pH˜12 and ether (100 mL) was added. The aqueous layer was separated, acidified with saturated potassium hydrogen sulfate to pH˜3-4, extracted with 3:1 CHCl3:IPA (3×300 mL), dried (sodium sulfate) and concentrated to give a solid. The solid was dissolved in MeOH (200 mL). The residue was suspended in ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated. The residue obtained was purified by flash chromatography (5:1 DCM:ethyl acetate) to give methyl 2-(2-methylquinolin-7-yl)acetate as a solid. heated to reflux The reaction was heated at reflux for 2 hours was added The aqueous layer was separated extracted with 3:1 CHCl3 IPA (3×300 mL), dried (sodium sulfate) concentrated to give a solid The organic layer was separated washed with brine dried (sodium sulfate) concentrated The residue obtained was purified by flash chromatography (5:1 DCM:ethyl acetate)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%). The solvent was removed under reduced pressure the resulting mixture was heated at reflux for an additional 2 hours The reaction was cooled to ambient temperature The mixture was extracted with dichloromethane the combined dichloromethane extracts were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 3-bromo-2-fluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)-but-2-enal (2.96 ml, 36.2 mmol) was added dropwise at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromo-8-fluoro-2-methylquinoline (2.99 g, 60.2%) as a solid. The solvent was removed under reduced pressure The residue was dissolved in 6 N HCl (100 mL) After cooling to ambient temperature extracted with DCM (2×100 mL) dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate)

Conditions: temp:106.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-4-fluoroaniline (10.00 g, 52.63 mmol) in 6N HCl (150 mL) was added (E)-but-2-enal (7.524 mL, 92.10 mmol) dropwise over 10 minutes at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5:1) to give 7-bromo-6-fluoro-2-methylquinoline (3.26 g, 25.8%) as a solid. After cooling to ambient temperature extracted with DCM (2×100 mL) dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5:1)

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

Procedure: To 3-methoxy-4-methylaniline (1.0 g, 7.29 mmol) in refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (1.02 g, 14.6 mmol). The reaction was heated to reflux for 2 hours then cooled down and neutralized with NH4OH. The organic phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to leave a dark residue. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-methoxy-2,6-dimethylquinoline (580 mg, 29.7% yield) as a beige solid. The reaction was heated to reflux for 2 hours then cooled down The organic phase was extracted with DCM the combined organic phases dried over MgSO4 filtered concentrated under reduced pressure to leave a dark residue The residue was purified by reverse phase chromatography (SP4, 25M eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes)

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

Procedure: To 4-fluoro-3-methoxyaniline (4.0 g, 28 mmol) refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (4.0 g, 57 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The organic phase was extracted with DCM. The combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to provide 6-fluoro-7-methoxy-2-methylquinoline (5.2 g, 96% yield) as a dark brown paste. The reaction was heated to reflux for 2 hours then cooled The organic phase was extracted with DCM The combined organic phases dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To 3-amino-2-methylphenol (5.0 g, 41 mmol) in refluxing 6N HCl (100 mL) was added dropwise (E)-but-2-enal (5.7 g, 81 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 2,8-dimethylquinolin-7-ol (9.0 g, 51% yield) as a brown solid. the reaction was heated to reflux for 2 hours After cooling extracted with DCM The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To 4-fluoro-2-methoxyaniline (370 mg, 2.62 mmol) in refluxing 6N HCl (5 mL) was added dropwise (E)-but-2-enal (367 mg, 5.24 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The aqueous phase was extracted with DCM, and the combined organic phases dried over MgSO4 and concentrated to yield 6-fluoro-8-methoxy-2-methylquinoline (500 mg, 99.8% yield) as a brown solid. The reaction was heated to reflux for 2 hours then cooled The aqueous phase was extracted with DCM the combined organic phases dried over MgSO4 concentrated

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

Procedure: To 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in refluxing 6N HCl (20 mL) was added dropwise (E)-but-2-enal (0.99 g, 14 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-methoxy-2-methylquinoline as a brown solid. the reaction was heated to reflux for 2 hours After cooling extracted with DCM The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure