Metallaphotoredox-catalyzed carbon–carbon cross-coupling of organohalides with bicyclo[1.1.1]pentyl (BCP)-thianthrenium reagents and discovery of thianthrenium-based bifunctional BCP reagent

The 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) are promising saturated bioisosteres of the para-substituted benzene rings in medicinal chemistry, maintaining two exit vectors in a 180° dihedral angle. Approximately 45% of the available drug molecules contain a benzene ring. The replacement of a phenyl ring with the saturated bioisostere became a valuable strategy for the improvement of pharmacokinetic properties of the drug candidates since the first study of the bicyclo[1.1.1]pentane (BCP) analogue of (S)-(4-carboxyphenyl)glycine in 1996. As an example, the BCP analog of the γ-secretase inhibitor avagacestat exhibited increased metabolic stability, membrane permeability, and increased aqueous solubility while retaining similar biological activity. There are mainly two approaches for the synthesis of the substituted BCPs, developed over the past 20 years. One is the mono- or difunctionalization of the highly reactive [1.1.1]propellane via the radical or anionic pathways; however, the propellane is volatile and has limited shelf stability even at –20 °C, therefore, need to be freshly prepared prior to use. Another approach involves the cross-coupling strategy using BCP-based reagents, including BCP Grignard reagents, BCP iodides, BCP boronates, and BCP redox-active esters, to incorporate the BCP moiety into a target molecule; however, these methods often necessitate organometallic reagents, involve multiple preparation steps, or lack generality and versatility for various transformations. On the other hand, stable and versatile alkylating BCP thianthrenium reagents were developed to achieve diverse transformations of phenols, alcohols, and various nitrogen nucleophiles. The high reduction potential and facile mesolytic cleavage of the exocyclic C–S bond in BCP thianthrenium reagents are crucial for achieving versatile reactivity. Based on the importance of the BCP moiety and the biaryl motifs in drug development, we designed an efficient metallaphotoredox-catalyzed system for the cross-coupling of aryl bromides and the BCP thianthrenium reagents. Unlike copper catalysis, which has been successfully used in thianthrene and BCP chemistry, we employed the synergistic cooperation of nickel and photoredox catalysis. The single electron transfer (SET) between the photoredox catalyst and BCP thianthrenium reagents generates the synthetically useful BCP radical, and the nickel catalyst has the ability to undergo favorable oxidative addition with aryl bromides than copper and can undergo oxidative ligation to the BCP radical. The combination of metallaphotoredox catalysis with the BCP thianthrenium reagent allows a mild reaction condition where a variety of functional groups in the aryl bromides are tolerated. Additionally, we demonstrate the synthetic utility of this method through the functionalization of heteroaromatic bromides and pharmaceutical compounds. To further diversify the reactivity of the BCP thianthrenium reagents, we employed the alkyl halides as a coupling partner for the reductive C(sp3)–C(sp3) cross-coupling reaction, as the alkyl bromides are more readily available compared to the corresponding organometallic reagents. Unlike the common nickel-catalyzed reductive conditions used in cross-electrophile coupling reactions, we employed a dual copper-photoredox catalyzed system that combines silyl radical-mediated activation of alkyl halides. The combined dual catalyst system addresses the homocoupling problem with the distinct redox properties of the thianthrenium salts, which differ from the alkyl halides. The silyl radical-mediated halogen atom abstraction followed by copper oxidative ligation circumvents the potentially slow oxidative addition of the alkyl halides to copper. The method describes a broad tolerance of functional groups, and a range of alkyl bromides, including benzyl, primary and secondary alkyl bromides are coupled with the BCP thianthrenium reagents. In addition, we highlight the synthetic utility of the current approach in late-stage functionalization of pharmaceuticals as well as in the construction of BCP analogs of diarylmethanes, which are important structural motifs in pharmaceutically active compounds. Although the available BCP reagents, including BCP thianthrenium reagents enable the rapid preparation of promising BCP compounds, they only have a single reaction site and are typically used as structural linkers or end groups. Therefore, a bifunctional BCP reagent such as the bis-thianthrenium BCP reagent, which has two reactive sites at both BCP bridgehead positions, would allow the construction of diverse 1,3-disubstituted BCP derivatives. The reaction between persistent thianthrene radical cation and the propellane in the presence of a copper catalyst can result in the synthesis of bis-thianthrene-substituted BCP reagent (TT+–BCP–TT+ (BF4–)2), but the reaction successfully works only sometimes. Therefore, it is important to mention that we cannot claim the current reaction approach to make the reagent reliably due to the reproducibility issue. However, the higher reduction potential observed for the TT+–BCP–TT+ (BF4–)2 reagent than our previously developed CF3–BCP–TT+ BF4– reagent would allow the selective functionalization of the TT+–BCP–TT+ (BF4–)2 reagent under metallaphotoredox catalysis; therefore, the construction of the diverse disubstituted BCP derivatives is possible in two steps. Although a considerable advancement is required for developing a reliable synthetic approach and for the reactivity of the TT+–BCP–TT+ (BF4–)2 reagent, this preliminary study indicates that the TT+–BCP–TT+ (BF4–)2 reagent can be used as a bifunctional reagent for the rapid construction of BCP derivatives with a variety of substituents at the bridgehead positions of the BCP moiety.