A NEW CONVERGENT ROUTE TO 1-SUBSTITUTED ELLIPTICINES

1-(2-Fluoro-4-pyridyl)ethanone was synthesized from 2-fluoropyridine and was ortho-lithiated after activation as the propylene glycol ketal. The resulting 3-lithio derivative was trapped by various electrophiles but reacted in low yield with N-protected 3-indolecarbaldehyde. Model compounds 1-[[[2-(diethylamino)ethyl]amino]-3-pyridyl]ethanol and -ethanone were prepared and selectively condensed with indole. 1-[[[2-(Diethylamino)-ethyl]amino]-3-pyridyl]ethanol and -ethanone bearing a ketal-protected acetyl moiety at the C-4 position have been obtained in high yields starting from the propylene glycol ketal of 1-(2-fluoro-4-pyridyl)ethanone. These reagents could not be condensed with indole either due to side reactions between the C-3 and C-4 functions or to steric hindrance. 1-(2-Substituted-4-bromo-3-pyridyl)ethanols were synthesized via a metalation/halogen-dance strategy starting from 2-fluoropyridine. 1-(2,4-Dihalo-3-pyridyl)-1-chloroethane could be prepared and condensed with 1-indolylmagnesium iodide, which allowed the construction of the expected 3-[1-(3-pyridyl)ethyl]indole skeleton. Functionalization of the pyridine C-4 bromo position was achieved by a vinylstannane cross-coupling reaction using a palladium(0) catalyst. Acidic treatment of the resulting 4-(1-ethoxyethenyl)pyridine led to 1-fluoroellipticine. The whole sequence requires six steps from indole and 2-fluoropyridine and allows an attractive overall yield.