Application of BF₃·Et₂O in the synthesis of cyclic organic peroxides (microreview)

A summary of recent applications of Lewis acid BF₃·Et₂O as a catalyst in the synthesis of cyclic organic peroxides is presented.

Introduction

Medicinal chemists and pharmacologists recognize cyclic peroxides as an uncharted chemical space for drug design. Cyclic peroxides exhibit antiparasitic,¹ anticancer,² antifungal,³ and antiviral⁴ activities. Ethanolic extract of Artemisia annua L. possesses antiviral activity against SARS-associated coronavirus.⁵ Such properties have prompted the development of convenient and efficient methods for the synthesis of cyclic peroxides related to natural product – artemisinin. Brønsted acids are mainly used in the synthesis of cyclic peroxides.⁶ However, these acids can lead not only to the formation of peroxides, but also promote their acid-catalyzed rearrangement.⁷ Lewis acids disclose approaches toward synthesis of cyclic peroxides, which cannot be obtained using Brønsted acids.⁸ Among Lewis acids, nonobvious BF₃·Et₂O proved to be one of the most interesting tools for the selective synthesis of peroxides. This microreview describes recent achievements related to the application of BF₃·Et₂O as a catalyst, which opens an efficient and atom-economical access to 1,2-dioxolanes, 1,2,4-trioxolanes, 1,2-dioxanes, derivatives of β- and γ-peroxylactones, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and 1,2,4,5,7,8-hexaoxonanes.

Synthesis of 1,2-dioxolanes

Substituted 1,2-dioxolanes were synthesized from 1,2,4- trioxolanes and olefins using BF₃·Et₂O as a catalyst in CH₂Cl₂ at 0°C. In the presence of BF₃, the 1,2,4-trioxolane (ozonide) cycle decomposed with the formation of BF₃-coordinated carbonyl oxide, which attacked the corresponding alkene to yield 1,2-dioxolane.⁹

Synthesis of 1,2,4-trioxolanes

An ozone-free method for the synthesis of 1,2,4-trioxolanes from 1,5-diketones and H₂O₂ was developed.10 In this case, BF₃·Et₂O promoted selective assembly of the ozonide cycle rather than its destruction mentioned above.⁹

Peter S. Radulov graduated from the Mendeleev University of Chemical Technology of Russia in 2016. At present, he is a graduate student under the supervision of Prof. A. O. Terent'ev (N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences). His research interest is the chemistry of organic peroxides.

Ivan A. Yaremenko received his PhD in organic chemistry in 2013 under the supervision of Prof. A. O. Terent’ev. At present, he is a Senior Researcher in the N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences. His research interests are chemistry of organic peroxides, medicinal and agrochemistry.

Synthesis of 1,2-dioxanes

Peroxidation of acetal containing Michael acceptor fragment afforded 1,2-dioxane (nitro analog of plakoric acid). Urea–H₂O₂ complex (UHP) and BF₃·Et₂O in Et₂O allowed nucleophilic substitution of only one methoxy group.¹¹

Synthesis of β-hydroperoxy- and β-alkoxy-β-peroxylactones

BF₃·Et₂O was used as effective catalyst for the synthesis of β-hydroperoxy-β-peroxylactones from β-keto esters, their silyl enol ethers, enol acetates, or cyclic acetals and H₂O₂.¹²

Furthermore, BF₃·Et₂O–UHP–alcohol system provided β-alkoxy-β-peroxylactones from β-keto esters.¹³

Synthesis of γ-hydroperoxy-γ-peroxylactones

Peroxidation of γ-keto esters under action of BF₃·Et₂O afforded γ-hydroperoxy-γ-peroxylactones in moderate to high yields. It should be noted that application of Brønsted acids as catalysts led to the formation of target peroxides in 15–24% yields.¹⁴

Synthesis of 1,2,4-trioxanes

BF₃·Et₂O-catalyzed peroxyacetalization of hydroperoxy alcohol with aldehydes or ketones provided 1,2,4-trioxanes in high yields.¹⁵

Bridged 1,2,4-trioxanes were synthesized in low yields via intramolecular cyclization of peroxyketals under action of BF₃·Et₂O.¹⁶ Such an approach could disclose access to new bioactive peroxides.

Synthesis of 1,2,4,5-tetraoxanes

Interaction of gem-bishydroperoxides and acetals in the presence of BF₃·Et₂O is a versatile synthetic route toward substituted unsymmetrical 1,2,4,5-tetraoxanes.¹⁷

BF₃·Et₂O was also used for the synthesis of bridged 1,2,4,5-tetraoxanes from β-diketones.¹⁸

Synthesis of tricyclic monoperoxides

Peroxidation of β,δ'-triketones in the presence of BF₃·Et₂O led to the formation of tricyclic monoperoxides in moderate to excellent yields. Despite the presence of three carbonyl groups, peroxidation was selective.¹⁹

Synthesis of 1,2,4,5,7,8-hexaoxonanes

A method for the synthesis of 1,2,4,5,7,8-hexaoxonanes based on BF₃·Et₂O-catalyzed reaction of acetals and 1,1'-peroxybis(1-hydroperoxycycloalkanes) was developed. This approach significantly expanded the structural diversity of 1,2,4,5,7,8-hexaoxonanes and, in most cases, permitted to prepare these compounds in high yields.²⁰