α-Fluorovinyl Weinreb Amides and α-Fluoroenones from a Common Fluorinated Building Block

Abstract

Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones, to give α-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are ≥98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give α-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of α-fluorovinyl Weinreb amides and α-fluoroenones has been demonstrated. Application of the Weinreb amide to α-fluoro allyl amine synthesis is also shown.

Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

“…In our previous studies, we have developed a general method for the synthesis of Julia olefination reagents via heterogeneous metalation-fluorination of appropriate precursors, specifically 1,3-benzothiazol-2-ylsulfonyl (BT-sulfonyl) derivatives 9,10a,11–13. Further, to date the only reported Julia olefination reagent for the synthesis of fluoroalkylidene derivatives was the benzothiazolyl based α-fluoroethyl BT-sulfone 8.…”

“…Several approaches have been undertaken for the synthesis of fluorinated Julia-Kocienski reagents. These range from synthesis utilizing commercial fluorinated precursors,8,10b,10d,11 to halogen exchange reaction of appropriate chloroderivative,8 to metalation-electrophilic fluorination 9,10a,10c,11–13. Among these, we have extensively investigated the metalation-fluorination approach,9,10a,11–13 since it offers the most general access to fluorinated Julia-Kocienski reagents.…”

Synthetic Methods for Fluorinated Olefins

“…Several other BT sulfone based reagents, such as 3e-3g, have already been prepared (Scheme 7). With these reagents, α-fluorinated ketones, [20] Weinreb amides, [20] α-fluorovinyl sulfones, [21] or fluorinated allylic amines [22] can easily be obtained in good yields. 5941 Scheme 7.…”

Facile synthesis of 4-vinyl- and 4-fluorovinyl-1,2,3-triazoles via bifunctional “click-olefination” reagents

“…Furthermore, the Cu-catalyzed azide-alkyne click ligation has yielded facile and efficient access to triazoles, often with high regioselectivity 2,3. Using the fluorinated building block approach,4 we5,6 and others7 have been developing syntheses of regiospecifically fluorinated molecules via the Julia-Kocienski olefination 5-7. Since both the triazole moiety8 and the fluorine atom9 are widely prevalent in pharmacological agents, a modular methodology allowing facile assembly of triazole rings as well as the fluorovinyl moiety, would be of high interest.…”

“…These olefinations were performed under reaction conditions that were previously shown to favor a trans disposition of aryl and alkyl substituents, i.e. E -isomer in reactions of the unfluorinated Julia-Kocienski reagents18 and Z -isomer with α-fluorobenzyl BT-sulfones 6a…”