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Synthesis of regiospecifically fluorinated conjugated dienamides.

Chowdhury M, Mandal SK, Banerjee S, Zajc B - Molecules (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, NY 10031, USA.

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-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 (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.

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Retrosynthetic analysis for the preparation of conjugated dieneamides.
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Figure 2: Retrosynthetic analysis for the preparation of conjugated dieneamides.

Mentions: Key to our approach was the assembly of a α-fluorovinyl Weinreb amide moiety with functionality at the beta position that could be used in a sequential condensation. We have previously reported the synthesis and studied the reactivity of a Julia-Kocienski reagent for the preparation of α-fluorovinyl Weinreb amides (1, Scheme 1) [31]. Condensation of 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (1) with a 2-(heteroarylthio)ethanal (2, heteroaryl = benzothiazolyl, Scheme 1) and subsequent oxidation would furnish a second-generation Julia-Kocienski reagent for dienamide synthesis. A retrosynthetic approach to conjugated dieneamides is outlined in Scheme 1.


Synthesis of regiospecifically fluorinated conjugated dienamides.

Chowdhury M, Mandal SK, Banerjee S, Zajc B - Molecules (2014)

Retrosynthetic analysis for the preparation of conjugated dieneamides.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440806&req=5

Figure 2: Retrosynthetic analysis for the preparation of conjugated dieneamides.
Mentions: Key to our approach was the assembly of a α-fluorovinyl Weinreb amide moiety with functionality at the beta position that could be used in a sequential condensation. We have previously reported the synthesis and studied the reactivity of a Julia-Kocienski reagent for the preparation of α-fluorovinyl Weinreb amides (1, Scheme 1) [31]. Condensation of 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (1) with a 2-(heteroarylthio)ethanal (2, heteroaryl = benzothiazolyl, Scheme 1) and subsequent oxidation would furnish a second-generation Julia-Kocienski reagent for dienamide synthesis. A retrosynthetic approach to conjugated dieneamides is outlined in Scheme 1.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, NY 10031, USA.

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-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 (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.

Show MeSH
Related in: MedlinePlus