Synthesis of Regiospecifically Fluorinated Conjugated Dienamides

Abstract

Modular synthesis of regiospecifically fluorinated 2,4-diene Weinreb amides, with defined stereochemistry at both double bonds, was achieved via two sequential Julia-Kocienski olefinations. In the first step, a Z-α-fluorovinyl Weinreb amide unit with a benzothiazolylsulfanyl substituent at the allylic position was assembled. This was achieved via condensation of two primary building blocks, namely 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (a Julia-Kocienski olefination reagent) and 2-(benzo[d]thiazol-2-ylthio)acetaldehyde (a bifunctional building block). This condensation was highly Z-selective and proceeded in a good 76% yield. Oxidation of benzothiazolylsulfanyl moiety furnished a second-generation Julia-Kocienski olefination reagent, which was used for the introduction of the second olefinic linkage via DBU-mediated condensations with aldehydes, to give (2Z,4E/Z)-dienamides in 50%–74% yield. Although olefinations were 4Z-selective, (2Z,4E/Z)-2-fluoro-2,4-dienamides could be readily isomerized to the corresponding 5-substituted (2Z,4E)-2-fluoro-N-methoxy-N-methylpenta-2,4-dienamides in the presence of catalytic iodine.

Synthesis of Monofluoroalkenes: A Leap Forward

“…The Zajc group also examined the synthesis of fluorinated conjugated dienamides, which was achieved by two subsequent Julia-Kocienski olefinations. 70 Firstly, a BT-sulfonebearing an α-fluorinated Weinreb amide reacted with an αbenzothiazol-2-ylsulfanyl-substituted acetaldehyde to give the corresponding monofluoroalkene, (Z)-4-(benzothiazol-2-ylsulfanyl)-2-fluoro-N-methoxy-N-methylbut-2-enamide. Then the sulfide was oxidized to the corresponding sulfone with H 5 IO 6 and CrO 3 .…”