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Fluorine-directed and -activated Nazarov cyclizations: selective synthesis of fluorinated cyclopentenones

corresponding

KOHEI FUCHIBE, JUNJI ICHIKAWA*
*Corresponding author
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Japan

Abstract

The Nazarov cyclization is a useful tool for constructing a cyclopentenone skeleton. However, the classical ones have a limitation regarding the position of the formed C–C double bond. This account involves three types of regioselective Nazarov cyclizations based on the electronic effects of fluorine substituents (type I–III cyclizations). 2,2-Difluorovinyl vinyl ketones and 1-(trifluoromethyl)vinyl vinyl ketones underwent fluorine-directed Nazarov cyclizations in the presence of Me3SiOTf; the regioselectivity was governed by the β-cation destabilizing effect of fluorine substituents (−I effect), leading to the formation of 3-fluorocyclopent-2-en-1-ones and 5-(trifluoromethyl)cyclopent-2-en-1-ones, respectively (type I and II cyclizations). Furthermore, 1-fluorovinyl vinyl ketones readily underwent fluorine-directed and fluorine-activated Nazarov cyclization in the presence of Me3SiB(OTf)4 to afford 2-fluorocyclopent-2-en-1-ones. In this case, the regioselectivity was governed by the α-cation stabilizing effect of the fluorine substituents (+R effect). The stabilization of the fluorinated oxyallyl cation intermediates provided considerable rate enhancement during cyclization (type III cyclization). Throughout these three types of Nazarov cyclizations, fluorine substituent functions as a controller over the reaction pathways and as an activator of the substrates.


The Nazarov cyclization is a useful tool for constructing a cyclopentenone skeleton from divinyl ketones, and thus, it has generated a large interest (1–4). However, the classical Nazarov reactions have a major limitation regarding the position of the formed C–C double bond; the double bond normally occupies the most substituted position in the ring because of its thermodynamic stability. This has restricted the use of the reactions as a general tool in organic synthesis. To address this regioselectivity issue, the charge localization of the intermediary oxyallyl cations has been investigated by utilizing silicon (5–8), tin (9), or oxygen (10–12) functionalities. In contrast, we adopted fluorine substituents for the purpose of achieving regioselective Nazarov cyclizations. The produced cyclopentenones are ubiquitous in natural and artificial compounds. In particular, the biological activities of fluorine-substituted analogs have been previously studied (Figure 1) (13–17).

The fluorine substituents have characteristic electronic effects and properties, which affect the reaction pathways (18–20) and biological activities of fluorinated compounds ...