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-a-fluorovinyl Weinreb amide unit with a benzothiazolylsulfanyl substituent at the allylic position was assembled. This
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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-a-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 (2
Z,4
E/
Z)-dienamides in 50%–74% yield. Although olefinations were 4
Z-selective, (2
Z,4
E/
Z)-2-fluoro-2,4-dienamides could be readily isomerized to the corresponding 5-substituted (2
Z,4
E)-2-fluoro-
N-methoxy-
N-methylpenta-2,4-dienamides in the presence of catalytic iodine.
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