A General and Practical Route to Functionalized Bicyclo[1.1.1]Pentane-Heteroaryls Enabled by Photocatalytic Multicomponent Heteroarylation of [1.1.1]Propellane

1-Aryl-substituted bicyclo[1.1.1]pentanes (BCPs) are an important class of BCP derivatives with widespread application in drug development. Most syntheses of these materials require multiple chemical steps via BCP electrophiles or nucleophiles derived from [1.1.1]propellane. Although one-step, multicomponent radical cross-coupling reactions could provide a more sustainable and rapid route to access diverse heteroarylated BCPs, current approaches are limited to tertiary alkyl radicals, leading to a decrease in their practical value. In this study, a conceptually different approach enabled by a radical multicomponent heteroarylation of [1.1.1]propellane to access functionalized heteroarylated BCPs is described. Importantly, this protocol is compatible with primary-, secondary-, and tertiary aliphatic radicals, as well as various fluoroalkyl radical sources, thus enabling rapid library generation of sought-after BCP derivatives for drug development.     

Scope of aminomethylations via Suzuki-Miyaura cross-coupling of organotrifluoroborates

We previously reported the Suzuki-Miyaura reaction of N,N-dialkylaminomethyltrifluoroborates with aryl bromides. Herein, we report a further investigation of the scope and limitations of this palladium-catalyzed aminomethylation reaction. Aryl chlorides, iodides, and triflates coupled in good to excellent yields to give N,N-dialkylbenzylic amines. The aminomethylation of alkenyl bromides was also examined.     

Scope of the Suzuki-Miyaura aminoethylation reaction using organotrifluoroborates

Potassium beta-aminoethyltrifluoroborates were prepared in good yields via hydroboration of the corresponding enecarbamates using the Snieckus hydroborating reagent. A wide variety of phenethylamines containing a potentially free primary amine after appropriate deprotection have been successfully prepared in good yield using these organotrifluoroborates as partners in Suzuki-Miyaura coupling with aryl bromides, iodides, and triflates.     

Synthesis and cross-coupling of sulfonamidomethyltrifluoroborates

Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting motifs.     

Cross-coupling of mesylated phenol derivatives with potassium ammonio- and amidomethyltrifluoroborates

A large array of aryl and heteroaryl mesylates have been successfully employed as electrophiles in a Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling with potassium ammonio- and amidomethyltrifluoroborates to afford the corresponding products in high yields.     

Oxidation of organotrifluoroborates via oxone

A method for the oxidation of organotrifluoroborates using Oxone was developed. A variety of aryl-, heteroaryl-, alkenyl-, and alkyltrifluoroborates were converted into the corresponding oxidized products in excellent yields. This method proved to be tolerant of a broad range of functional groups, and in secondary alkyl substrates it was demonstrated to be completely stereospecific.     

Rapid and efficient access to secondary arylmethylamines

Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes.     

Oxidative condensations to form benzimidazole-substituted potassium organotrifluoroborates

A library of benzimidazole-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with aromatic 1,2-diamines under oxidative conditions. The efficient Suzuki-Miyaura cross-coupling of products thus formed to various aryl and heteroaryl bromides was achieved in good yields. The method allows the facile preparation of benzimidazole-containing triaromatic products in two steps from simple potassium formyl substituted aryl- or heteroaryltrifluoroborates.     

Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross‐Coupling

The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel‐catalyzed transformations, specifically for carbon–carbon bond formation. Collectively, these advances address the longstanding challenge of late‐stage cross‐coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross‐coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross‐couplings that are accessible exclusively through this approach.     

Diastereoselective Synthesis of Vicinally Bis(trifluoromethylated) Alkylboron Compounds through Successive Insertions of 2,2,2‐Trifluorodiazoethane

The usefulness of embedded CF₃ substituents within organic substructures necessitates the development of diverse methods for incorporating this functional group. A recently reported route to α‐trifluoromethylated alkylboron compounds by an α‐transfer mechanism has now been extended to the synthesis of unprecedented, vicinally ditrifluoromethylated alkylboron compounds in a diastereoselective fashion. The utility of these products is highlighted by conversion of the C? B bond into other functional groups.