3-Chloro-5-hydroxybenzaldehyde

A solution of 3-chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see step (i) above) in [CH2CL2] (250 mL) was cooled to [0°C.] Boron tribromide (15.8 mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction mixture for 2 h, H20 (50 mL) was added slowly. The solution was then extracted with [ET2O] (2 x 100 mL). The organic layers were combined, dried [(NA2S04), ] filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex: EtOAc (4: 1) afforded the sub-title compound (5.2 g, 25percent). 'H NMR (300 MHz, CDCl3) 8 9.85 (s, 1H), 7.35 (s, lH), 7.20 (s, lH), 7.10 (s, [LH), ] 3.68 (s, [LH)]A solution of 3-chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see step (i) above) in CHA solution of 3-chloro-5-methoxybenzaldehyde (22. 8 g, 134 mmol; see step (i) above) in CH2C12 (250 mL) was cooled to [0°C.] Boron tribromide (15. [8] mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction mixture for 2 h, [HA0] (50 mL) was added slowly. The solution was then extracted with Et20 (2 x 100 mL). The organic layers were combined, dried [(NA2S04), ] filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex: EtOAc (4: 1) afforded the sub-title compound (5.2 g, [25percent).]A solution of [3-CHLORO-5-METHOXYBENZALDEHYDE] (22.8 g, 134 mmol; see step (i) above) in [CH2C12] (250 mL) was cooled to [0°C.] Boron [TRIBROMIDE] (15.8 mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction mixture for 2 h, [H20] (50 mL) was added slowly. The solution was then extracted with [ET20] (2 x 100 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex: EtOAc (4: 1) afforded the sub-title compound (5.2 g, 25percent). 'H NMR (300 MHz, CDCl3) 8 9.85 (s, [1H), ] 7.35 (s, [LH), ] 7.20 (s, [LH), ] 7.10 (s, [LH), ] 3.68 (s, [1 H)][(II)] 3-Chloro-5-hydroxybenzaldehyde A solution of 3-chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see step (i) above) in [CH2CI2] (250 mL) was cooled to [0°C.] Boron tribromide (15.8 mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction mixture for 2 h, H20 (50 mL) was added slowly. The solution was then extracted with Et20 (2 x 100 mL). The organic layers were combined, dried [(NA2SO4), ] filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex: EtOAc (4: 1) afforded the sub-title compound (5.2 g, 25percent). 'H NMR (300 MHz, [CDC13)] 8 9.85 (s, 1H), 7.35 (s, lH), 7.20 (s, [LH), ] 7.10 (s, lH), 3.68 (s, [1 H)]500 mg (3.27 mmol) of 3-chloro-5-hydroxybenzonitrile are dissolved in a mixture of 4 ml of pyridine/acetic acid/water (2/1/1). (78 mg, 0.5 mmol), 5-amino-nicotinic acid methyl ester (60 mg, 0.4 mmol), Ti(iPrO) 4 (0.1 mL) was stirred under reflux for 5 hours in 1, 2-dichloroethane (DCE, 10 mL).Then NaH3BCN (25 mg, 0.4 mmol) was added to the reaction mixture and stirred under reflux overnight.After quenching with water, extract three times with 10 ml of dichloromethane and combine the organic phases.After washing once with saturated brine, it is dried over anhydrous sodium sulfate and concentrated.The residue was passed through a silica gel column (dichloromethane / methanol = 1/10).Pure compound 30A (80 mg, 63% yield) was obtained as a yellow solid.A flask was charged with potassium t-butoxide (0.840 g, 7.50 mmol, 1.50 equiv) and THF (20 mL). 3-Chloro-5-hydroxybenzaldehyde (780 mg, 5.00 mmol, 1.00 equiv) was added at 0 C and the reaction was stirred for 20 min. Bis(4-chlorophenyl)iodonium tetrafluorob orate (2.62 g, 6.00 mmol, 1.20 equiv) was added at 0 C. The resulting solution was stirred overnight at 40 C and quenched with water (20 mL). The mixture was extracted with DCM (3 x 40 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 300 mg (19% yield) of 3-chloro-5-(4-chlorophenoxy)benzaldehyde as a colorless oil. LCMS (ESI, m/z): 267 [M+H]+.

Molecular Weight:156.56
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:155.9978071
Monoisotopic Mass:155.9978071
Topological Polar Surface Area:37.3
Heavy Atom Count:10
Complexity:127
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes