7-Chlorothieno[3,2-b]pyridine → 6-(7-Chlorothieno[3,2-b]pyridin-2-yl)nicotinaldehyde

Temperature

-40 °C

7-Chlorothieno[3,2-b]pyridine (6) (4.02 g, 23.70 mmol) was dissolved in THF (150 mL) to give a colorless solution. The solution was cooled to −40° C. in an acetonitrile/dry ice bath. n-BuLi (9.95 mL, 24.88 mmol, 2.5M in hexanes) was added dropwise. The dark mixture was then stirred for 15 min followed by an addition of zinc chloride (24.88 mL, 24.88 mmol, 1M in ether). The mixture was warmed to 0° C., then tetrakistriphenylphosphine palladium (1.095 g, 0.948 mmol) was added. The mixture was then stirred for 10 min and 6-bromonicotinaldehyde (7) (4.41 g, 23.70 mmol) was added. The mixture was heated to reflux and a precipitate formed rapidly. After 3 h, the reaction mixture was cooled down to r.t., quenched with 2 mL NH4Cl and left overnight. The solid was isolated by suction filtration, rinsed with small amount of THF and triturated with a mixture of water (200 mL) and EtOAc (100 mL) followed by an additional trituration with acetic acid (1×100 mL), to afford intermediate 50 (4.95 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.39 (dd, J=2.1, 8.4 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H). MS (m/z): 275.1 (M+H).

1. customto give a colorless solution
2. temperatureThe mixture was warmed to 0° C.
3. stirringThe mixture was then stirred for 10 min
4. temperatureThe mixture was heated
5. temperatureto reflux
6. customa precipitate formed rapidly
7. waitAfter 3 h
8. temperaturethe reaction mixture was cooled down to r.t.
9. customquenched with 2 mL NH4Cl
10. waitleft overnight
11. customThe solid was isolated by suction filtration
12. washrinsed with small amount of THF
13. customtriturated with a mixture of water (200 mL) and EtOAc (100 mL)

ORD record

ord-eefa2725aad64460b52618b545c4aa86

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569503B2