Ring-Opening Fluorination of Carbo/Heterocycles and Aromatics: Construction of Complex and Diverse Fluorine-Containing Molecules.

Fluorine-containing molecules have attracted much attention in medicinal, agrochemical, and materials sciences because they offer unique physical and biological properties. Therefore, many efficient fluorination reactions have been developed over the years. Recent advancements in fluorination chemistry have expanded the range of substrates, and regioselectivity/stereoselectivity control has also been achieved. Ring-opening fluorination is an efficient method to construct complex fluorine-containing molecules with diversity, starting from simple cyclic compounds. This review aims to summarize developments in ring-opening fluorination, particularly with larger-sized cyclic compounds. Fluorine introduction and bond cleavage of cyclic compounds such as carbocycles, heterocycles, and aromatics provide efficient access to fluorine-containing compounds that are difficult to be synthesized by conventional methods.

Ring-Opening Fluorination of Isoxazoles.

A ring-opening fluorination of isoxazoles has been developed. Upon treatment of isoxazoles with an electrophilic fluorinating agent (Selectfluor), fluorination followed by deprotonation leads to tertiary fluorinated carbonyl compounds. This method features mild reaction conditions, good functional group tolerance, and a simple experimental procedure. Diverse transformations of the resulting α-fluorocyanoketones were also demonstrated, furnishing a variety of fluorinated compounds.

Ring-opening fluorination of bicyclic azaarenes.

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon-fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.

Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy.

Pd-catalyzed asymmetric dearomative arylation of C3-substituted indoles is realized via a desymmetrization strategy. A BINOL-derived chiral phosphoramidite ligand is found to be highly efficient for the stereoselective control in this reaction. This method provides a convenient synthesis of spiroindolenines bearing two stereogenic centers in good yields (up to 98%) with excellent diastereo- and enantioselectivities (up to >20:1 dr and 97% ee), which could also be applied in asymmetric dearomative arylation of the simple C3-tethered indoles.

Dearomative Allylation of Naphthyl Cyanohydrins by Palladium Catalysis: Catalyst-Enhanced Site Selectivity.

A dearomative allylation of naphthyl cyanohydrins with allyl borates and allyl stannanes under palladium catalysis was developed. At the initial stage of this study, the dearomative reaction (C4 substitution of the aromatics) was competing with benzyl substitution. To circumvent this issue, the use of palladium and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio was found to enhance the site selectivity, furnishing the desired dearomatized products. Further derivatizations of products were also successful.

Catalytic three-component C-C bond forming dearomatization of bromoarenes with malonates and diazo compounds.

A Pd-catalyzed dearomative three-component C-C bond formation of bromoarenes with diazo compounds and malonates was developed. Various bromoarenes ranging from benzenoids to azines and heteroles were transformed to the corresponding substituted alicyclic molecules. The key to this reaction is the generation of a benzyl-palladium intermediate, which reacts with malonates to form a Pd-O-enolate species. Strikingly, the present method enabled rapid access to multi-substituted alicycles through subsequent elaboration of dearomatized products.

Pd-Catalyzed Dearomative Allylation of Benzyl Phosphates.

Dearomative C-C bond formation of benzyl phosphates has been developed. In the presence of a palladium/PAr3 catalyst, benzyl phosphates reacted with allyl borates to generate the allylated product in a dearomative fashion. The resulting dearomatized molecules were successfully derivatized by Simmons-Smith cyclopropanation and oxidation.