1-Benzofuran-5-carbaldehyde

Colorless to light yellow liqui

NBS (0.656 g, 3.69 mmol) and AIBN (8.10 mg, 49.2 lmol) wereadded to a solution of 107 (0.364 g, 2.46 mmol) in chlorobenzene(7.3 mL) at room temperature under an argon atmosphere. Afterstirring for 1 h at 80 C, the mixture was cooled to room temperatureand diluted with EtOAc. The organic layers were washed withsaturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, andconcentrated in vacuo. The residue was purified by silica gel CC(EtOAc/hexane, 3:97) to afford benzofuran-5-carbaldehyde (108)(0.268 g, 1.84 mmol, 75percent) as a colorless oil: 1H-NMR (CDCl3, 400 MHz) d: 6.82 (d, J = 2.0 Hz, 1H, furan-H), 7.54 (d, J = 8.8 Hz, 1H, Ar–H), 7.65 (d, J = 2.0 Hz, 1H, furan-H), 7.79 (d, J = 8.8 Hz, 1H, Ar–H), 8.07 (s, 1H, Ar–H), 9.99 (s, 1H, –CHO); spectroscopic datawere consistent with those reported in the literature (van Otterloet al., 2005).To a solution of 2, 3-dihydrobenzofuran-5-carbaldehyde (1 g, 6.75 mmol, A) in Chlorobenzene (20 mL), NBS (1.44 g, 8.10 mmol), AIBN (22 mg, 0.13 mmol) were added and the mixture was stirred at 80° C. for 1 h. After cooling the reaction mixture to room temperature, it was washed with aqueous NaHCOTo an ice-cold stirred solution of compound A (500 mg, 3.37 mmol, leq) in chlorobenzene (10 ml) were added NBS (721 mg, 4.05 mmol, 1.2 eq) in portions and AIBN (11 mg, 0.07 mmol, 0.02 eq) and the resulting solution was stirred at 80 °C for 4 h. The reaction mixture was cooled to RT, concentrated in vacuo and the residue was washed with saturated aq. NaHCC>3 solution (20 ml). The organic components were extracted with ethyl acetate (50 ml) and the ethyl acetate layer was concentrated in vacuo. The crude material was purified by flash chromatography (Combiflash) using 100-200 mesh silica gel eluting with 5percent ethyl acetate/hexane to obtain the compound B (270 mg, 55percent) as white solid. [0176] EXAMPLE 20 EXAMPLE 15:PREPARATION OF 5-(5-FORMYL-I -BENZOFURAN-2-YL)-6-METHYL-4-[(4- METHYL-1 H-INDOL-5-YL)AMINO]NICOTINONITRILEStep a): Preparation of 5-formylbenzofuran.To a -15To a solution of the product from Step B (2g) in ether (20MI) AT-78°C was added t-BuLi dropwise. After stirring for 20min, DMF (950mg) was added dropwise and the mixture was stirred AT-25°C for 3hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MGS04, filtered and concentrated in vacuo to give 980mg of crude product (67percent); A solution of 5-bromobenzofuran (950 mg, 4.82 MMOL) in anhydrous ether (12 mL) was cooled to-78 °C. 1.7 M TERT-BULI solution in pentane (6 mi, 10.2 MMOL) was added dropwise under argon. After addition, the mixture was stirred at-78 °C for 20 min, followed by addition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added. The mixture was poured to saturated ammonium chloride solution. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate-hexanes, 1: 5 V/V) to give the title compound as a pale yellow solid (490 mg, 70percent).To a solution ol the product from Step B (2 g) in ether (20 ml) at -78 C. was added t-BuLi dropwise. Alter stirring lor 20 min, DMF (950 mg) was added dropwise and the mixture was stirred at -25 C. lor 3 hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 980 mg ol crude product (67percent).Weigh (950 mg, 4.82 mmol)Soluble12 mL anhydrous ether and cooled to -78 ° C. 1.3 M tert-butyllithium in pentane (7.85 mL, 10.2 mmol) was added dropwise to the supernatant. The reaction was stirred at -78 ° C for 2 hours, DMF (0.8 mL, 10.3 mmol) and diethyl ether (1 mL). After 1 h reaction, quench with ammonium chloride at -78 ° C. Ethyl acetate extraction, anhydrous sulfur Sodium sulfate dried, concentrated, and passed through a silica gel column to give a yield of 75percent.A solution of 5-bromobenzofuran (950 mg, 4.82 [MMOL)] in anhydrous ether (12 mL) was cooled to-78 [°C.] 1.7 M [TELT-BULI] solution in pentane (6 [ML, ] 10.2 [MMOL)] was added dropwise under argon. After addition, the mixture was stirred at-78 °C for 20 min, followed by addition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added. The mixture was poured to saturated ammonium chloride solution. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate-hexanes, 1: 5 [V/V)] to give the title compound as a pale yellow solid (490 mg, [70percent).]A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) in anhydrous ether (12 mL) was cooled to-78 °C. 1.7 M tert-BuLi solution in pentane (6 ml, 10.2 mmol) was added dropwise under argon. After addition, the mixture was stirred at-78 °C for 20 min, followed by addition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added. The mixture was poured to saturated ammonium chloride solution. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate-hexanes, 1: 5 v/v) to give the title compound as a pale yellow solid (490 mg, 70percent).To a solution of the product from Step B (2 g) in ether (20 ml) at -78 C. was added t-BuLi dropwise. After stirring for 20 min, DMF (950 mg) was added dropwise and the mixture was stirred at '25 C. for 3 hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 980 mg of crude product (67percent).Step C; To a solution of the product from Step B (2g) in ether (20mut) at-78°C was added t-BuLi dropwise. After stirring for 20min, DMF (950mg) was added dropwise and the mixture was stirred at-25°C for 3hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgS04, filtered and concentrated in vacuo to give 980mg of crude product (67percent).To a solution of the product from Step B (2g) in ether (20ml) at-78°C was added t-BuLi dropwise. After stirring for 20min, DMF (950mg) was added dropwise and the mixture was stirred at-25°C for 3hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgS04, filtered and concentrated in vacuo to give 980mg of crude product (67percent).A mixture [OF 5-BROMO-1-BENZOFURAN (0. 5G), ] Mg (0.92g, 0. [038MOL), I2] (1 crystal) in dry THF (2. [5ML)] under N2 atmosphere was refluxed for 30min. To this was added a solution of 5- [BROMO-1-BENZOFURAN] (4. [5G)] in 25mL of dry THF) as soon as [THE I2 COLOR] disappear and refluxed for another 2h. The reaction mixture was then cooled to-40°C and added dry DMF (3.6g) drop-wise and slowly warmed to RT for a period of 12h. The reaction mixture was then cooled to 0°C and acidified with 3N HCl to pH=2 and stirred for 30min. The reaction mixture was then diluted with water [(500ML), ] extracted with ethylacetate [(2X200ML), ] washed with brine and dried. The solvent was removed under vacuum and purified by column chromatography over silica gel (pet. [ETHER/CH2CL2)] to give 5-formyl-1- [BENZOFURAN] (2g, 54percent) as a liquid. LC-MS: M/Z ESI: 1.47 min, [14734 (M+1).]

Molecular Weight:146.14
XLogP3:1.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:146.036779430
Monoisotopic Mass:146.036779430
Topological Polar Surface Area:30.2
Heavy Atom Count:11
Complexity:156
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes