Iodine → 4-Iodo-2-methoxynicotinaldehyde

Temperature

-78 °C

A 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen, is charged with tetrahydrofuran (1 L) and cooled to -78° C. To this stirred solution is added tert-butyllithium (1.7M in pentane, 800 mL, 1.36 mol) via canula followed by 2-methoxypyridine (132.2 g, 1.21 mol) in tetrahydrofuran at -78° C. The mixture is allowed to stir for one hr at -78° C. To the mixture is added N-formyl-N,N',N'-trimethylethylenediamine (176 mL, 1.37 mol) dropwise at -78° C. (prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972). The reaction mixture is stirred for ca. 30 min at -78° C. before warming to -23° C. over ca. 30 min. To the mixture at -23° C. is added ethylene glycol dimethyl ether (1 L) followed by n-butyllithium (2.5M in hexanes, 800 mL, 2.0 mol). The resultant mixture is stirred for ca. 2 h during which time the reaction mixture turns deep green. A 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the 12 liter flask is charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) and the resultant solution is cooled to -78° C. The contents of the 5 liter flask are transferred via canula to the mixture of iodine and ethylene glycol dimethyl ether in the 12 liter flask at -78° C. After the addition is complete, the reaction mixture is stirred for 1 hr at -78° C. The cooling bath is removed and the mixture is allowed to warm to ca. 0° C. then treated with 2 L of water and 2 L of 1N hydrochloric acid. Methyl t-butyl ether (2 L) is added and the layers are separated. The aqueous layer is extracted with 2×1 L of methyl t-butyl ether. The combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution followed by 1.2 L of saturated sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick slurry. To the slurry is added 1 L of hexane resulting in the generation of additional precipitate. The mixture is cooled in an ice/water bath for ca. 30 min then filtered yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. The filtrate is reconcentrated to a slurry and treated with hexane to generate additional precipitate again yielding 4-iodo-2-methoxy-pyridine-3-carbaldehyde. Chromatography (silica gel, 10% ethyl acetate/hexane) yields an analytical sample as a bright yellow solid: mp 98°-99° C. 1H-NMR (400 MHz, CDCl3) 10.21 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.54 (d, J=5 Hz, 1H), 4.06 (s, 3H); IR (CHCl3) 1710, 1560, 1470, 1380, 1305, 1260, 1025 cm-1 ; Elemental analysis: calculated for C7H6NO2I: C 31.97%, H 2.30, N 5.32, 1 48.25; Found: C 32.06, H 2.35; N 5.25, I 48.35.

1. customA 5-liter 3-necked round-bottom flask equipped with an overhead mechanical stirrer and under nitrogen
2. custom(prepared as in Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10972)
3. stirringThe reaction mixture is stirred for ca. 30 min at -78° C.
4. temperaturebefore warming to -23° C. over ca. 30 min
5. customA 12 liter 4-neck round bottom flask is equipped with an overhead mechanical stirrer under nitrogen
6. additionAfter the addition
7. stirringthe reaction mixture is stirred for 1 hr at -78° C
8. customThe cooling bath is removed
9. temperatureto warm to ca. 0° C.
10. additionthen treated with 2 L of water and 2 L of 1N hydrochloric acid
11. additionMethyl t-butyl ether (2 L) is added
12. customthe layers are separated
13. extractionThe aqueous layer is extracted with 2×1 L of methyl t-butyl ether
14. washThe combined organic extracts are washed with 1.2 L of saturated sodium thiosulfate solution
15. dry with materialThe organic extracts are dried over sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customto give a thick slurry
19. temperatureThe mixture is cooled in an ice/water bath for ca. 30 min
20. filtrationthen filtered

ORD record

ord-6761701c9c0b4e3391346191e2272ba5

Source dataset

uspto-grants-1996_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05491237