2-CHLORO-6-METHOXYNICOTINALDEHYDE

Compound 5 was added (4.14 mL, 34.8 mmol) over 5 min to the solution of tert-butyllithium (1.7M in pentane, 22.5 mL, 38.3 mmol) in 69 mL of THF at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, then dimethylformamide (3.5 mL, 45.0 mmol) was added and the mixture was stirred at -78 °C for 1.5 h. After the addition of glacial acetic acid (4.0 mL, 69.0 mmol) , the reaction mixture was allowed to warm to room temperature over a 30-min period and diethyl ether (200 mL) was added. The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL) , and was dried over Na2S04. Concentration under reduced pressure afforded the product which was recrystallized from hexane to yield 4.6 g (76percent) of compound 6 as light yellow solid, mp: 67.0-68.0 °C; 1 H NMR (300 MHz, CDC13) δ[ ppm] : 10.29 (d, J=0.8 Hz, 1H) , 8.05 (d, J=7.9 Hz, 1H) , 7.02 (dd, Jl=7.9 Hz, J2=0.8 Hz, 1H) , 4.08 (s, 3H) ; 13C NMR (75 MHz, CDC13) δ [ppm] :188.0, 164.2, 154.6, 140.0, 117.6, 117.5, 54.8; IR V (ATR cm-1) : 3103, 2869, 1683, 1567, 1468, 1378, 1273, 1005.Compound 5 was added (4.14 mL, 34.8 mmol) over 5 min to the solution of tert-butyllithium (1.7M in pentane, 22.5 mL, 38.3 mmol) in 69 mL of THF at -78 C. The reaction mixture was stirred at -78 C for 1 h, then dimethylformamide (3.5 mL, 45.0 mmol) was added and the mixture was stirred at -78 C for 1.5 h. After the addition of glacial acetic acid (4.0 mL, 69.0 mmol) , the reaction mixture was allowed to warm to room temperature over a 30-min period and diethyl ether (200 mL) was added. The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL) , and was dried over Na2S04. Concentration under reduced pressure afforded the product which was recrystallized from hexane to yield 4.6 g (76%) of compound 6 as light yellow solid, mp: 67.0-68.0 C; 1 H NMR (300 MHz, CDC13) delta[ ppm] : 10.29 (d, J=0.8 Hz, 1H) , 8.05 (d, J=7.9 Hz, 1H) , 7.02 (dd, Jl=7.9 Hz, J2=0.8 Hz, 1H) , 4.08 (s, 3H) ; 13C NMR (75 MHz, CDC13) delta [ppm] :188.0, 164.2, 154.6, 140.0, 117.6, 117.5, 54.8; IR V (ATR cm-1) : 3103, 2869, 1683, 1567, 1468, 1378, 1273, 1005.Palladium (II) acetate (0.08 g, 0.36 mmol) , caesium carbonate (2.23 g, 6.83 mmol), 2-di-tert-butylphosphino-2 ' , 4 ' , 6 ' - triisopropylbiphenyl (t-Butyl XPhos) (0.290 g, 0.68 mmol), compound 6 (0.59 g, 3.41 mmol), and 4 (0.88 g, 4.44 mmol) and toluene (30 mL) were combined and purged by a stream of argon for 3 minutes. The reaction was sealed and heated at 80 C for 4h. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The product was purified by flash chromatography on silica gel using 0-60% ethyl acetate in hexane. The product was recrystallized from diethyl ether (488 mg, 35%). mp : 132.0-133.0 C; 1H NMR (600MHz, CDC13) delta [ppm] : 10.22 (d, J=0.8 Hz, 1H) , 8.06 (d, J=8.4 Hz, 1H) , 7.44-7.41 (m, 3H) , 7.37-7.34 (m, 1H) , 7.32-7.30 (m, 2H) , 7.28 (d, J=7.5 Hz, 1H) , 7.26 (m, 1H) , 6.45 (dd, Jl=8.4 Hz, J2=0.8 Hz, 1H) , 5.52 (s, 2H) , 4.08 (3H), 2.28 (s, 3H) ; 13C NMR (151 MHz, DMSO-d6) delta [ppm] : 187.8, 166.6, 165.2, 143.2, 142.0, 140.5, 135.0, 134.8, 130.5, 129.5, 128.7, 128.3, 127.1, 125.7, 112.5, 103.9, 67.8, 54.1, 16.5; IR V (ATR cm-1): 3063, 2961, 2870, 1671, 1591, 1460, 1330, 1277; HRMS (ESI-TOF) Calcd for C21H19N03Na [M+Na]+ : 356.1263; found [M+Na]+: 356.1256.To a stirred solution of 31(6.83 g, 30.7 mmol) in THF (120 mL) was added i-PrMgCl·LiCl (ca.1.0 Msolution in THF, 32.2 mL, 32.2 mmol) at -20C. After 2 h, DMF (7.2 mL, 92.1 mmol) was added dropwise at -20C. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material including 12was applied to the following reaction without further purification.To a suspension of the crude material including 12and NaOAc (3.78 g, 46.1 mmol) in the 1 : 1 mixture of n-BuOH and toluene (total 120 mL) was added Pd(dppf) Cl2 (1.12 g, 1.54 mmol) at room temperature. The resulting mixture was stirred under ordinary CO pressure (balloon) at 100C for 18 h. The reaction was quenched with saturated aqueous NH4Cl, filtered through a pad of Celite and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, n-hexane-EtOAc=2 : 1) to afford 13(4.75 g, 65% 2 steps) as a yellow oil.13: IR (film, cm-1): 2963, 2876, 1721, 1692, 1595, 1481, 1337, 1277, 1261, 1219, 1138, 1072, 1022; 1H-NMR (CDCl3, 500 MHz) delta: 10.39 (s, 1H), 8.18 (d, J=8.50 Hz, 1H), 6.94 (d, J=8.50 Hz, 1H), 4.44 (t, J=6.80 Hz, 2H), 4.06 (s, 3H), 1.83-1.76 (m, 2H), 1.54-1.45 (m, 2H), 0.99 (t, J=7.37 Hz, 3H); 13C-NMR (CDCl3, 125 MHz) delta: 189.1, 166.1, 165.2, 150.7, 138.6, 125.9, 114.1, 66.3, 54.5, 30.5, 19.2, 13.7; HR-MS (ESITOF): Calcd for C12H15NO4Na [(M+Na)+] 260.0893. Found 260.0891.

Molecular Weight:171.58
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:39.2
Heavy Atom Count:11
Complexity:142
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes