3-BROMO-4-FORMYLPYRIDINE

Off-white solid

To a solution of diisopropylamine (27.6 g, 273.0 mmol) in tetrahydrofuran (300 mL) was added dropwise a solution of n-butyllithium (91 mL, 228.0 mmol, 2.5 M) in tetrahydrofuran at —78 °C under nitrogen. The mixture was stirred at —78 °C for 1 h, followed by the dropwise addition of 3-bromopyridine (30.0 g, 190.0 mmol). The mixture was stirred at —78 °C for 20 mm before dimethylformamide (55.0 g, 760.0 mmol) was added dropwise. After addition, the reaction mixture was stirred at —78 °C for 1 h and was then warmed to ambient temperature before being quenched by addition of saturated aqueous ammonium chloride (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 3), the combined organic layers were concentrated in vacuo, and the resulting residue was purified by flash chromatography on Si02 to give the desired product (12.0 g, 34.0percent). ‘H NMR (400 MHz, CD3OD, ö): 10.37 (s, 1 H), 8.91 (s, 1 H), 8.80 — 8.61 (m, 1 H), 7.78 —7.63 (m, 1 H). LCMS (mlz): 187.0 (M+1).n-BuLi (2 M in haxane, 24 mL, 48 mmol) was added to a solution of diisopropylamine (8 mL, 57 mmol) in anhydrous THF (80 mL) at -78 °C over 40 min and the resulting mixture was stirred at -78 °C for 1 hr. 3-Bromopyridine (9) (3.85 mL, 40 mmol) was then added over 5 min. After stirring for an additional 10 min, anhydrous methyl formate (10 mL, 160 mmol) was added drop-wise while the temperature was kept below -70 °C. The reaction mixture was warmed up to RT over 3 h. and quenched with saturated aqueous NaHCOUnder an NUnder an N2 atmosphere, a 1.6 M solution of n-butyllithium inhexane (7.06 mL, 11.3 mmol) was added slowly to a cooled(78 C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol)in THF (25 mL). After 30-min stirring at 0 C, the mixture wascooled to 78 C and a solution of 3-bromopyridine (5, 1.63 g, 1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixturewas stirred at 78 C for 15 min, and then a solution ofN-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was addedslowly. The solution was stirred at 78 C for 50 min. Then itwas allowed to warm to room temperature and stirred for another1.5 h. Saturated NH4Cl solution (40 mL) was added. The aqueouslayer was extracted with EtOAc (3 30 mL). The combined organiclayers were washed with brine (60 mL) and dried over Na2SO4.Filtration and evaporation afforded crude product, which waspurified by fc (5.5 cm, EtOAc/cyclohexane 1:4). Yellow solid(EtOAc/cyclohexane2:1, Rf = 0.55), yield 914 mg (48percent). 1H NMR(600 MHz, CDCl3): d (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72(d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO).The starting material was prepared as follows: A mixture of crude 2-bromo-4-(diethoxymethyl)pyridine (162; 20.0 g, 76.9 mmol) and aqueous HBr (100 mL) was stirred at room temperature for 30 mm, then neutralized with saturated NaHCO3 (50 mL) to pH 8-10 at 0 °C. The resulting mixture was extracted with CH2C12 (3 x 50 mL) and the combined organic layers were washed with brine, dried (Mg504) and concentrated. The residue was purified by silica gel column chromatographyto obtain 3-bromoisonicotinaldehyde (Compound 163; 15.0 g, quantitative) as a white solid. MS (ESI) calcd for C6H4BrNO:184.95.

Molecular Weight:186.01
XLogP3:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:184.94763
Monoisotopic Mass:184.94763
Topological Polar Surface Area:30
Heavy Atom Count:9
Complexity:107
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes