Overview
The central theme of the Molander group’s research is the development of new synthetic methods and their application to the synthesis of organic molecules. The group’s focus centers on catalysis, specifically using robust, air- and water-stable potassium organotrifluoroborates (R-BF3K) as partners in cross-coupling. To this end, we have recently engaged a new strategy involving a photoredox-based oxidation of organotrifluoroborates resulting in radicals that can be effectively funneled into a cross coupling catalytic cycle. Additionally we are exploring the unique chemistry of these boron-based salts and their application towards the synthesis of boron-containing heterocycles known as azaborines. We have also been exploring organofluorine chemistry as well as reductive cross-coupling. These four areas of research are detailed below:
Photoredox cross coupling
Transition metal-catalyzed cross-coupling reactions have revolutionized the synthesis of organic compounds ranging from small molecules to polymers and macromolecular entities. However, despite significant efforts to expand the scope of these processes, they remain largely limited to reactions involving sp and sp2 hybridized centers, with sp3 hybridized reagents often coupling in unsatisfactory yields due to sluggish reaction rates and/or generation of undesired side products. To date, strategies aiming to address these difficulties have either employed more highly reactive organometallic nucleophiles (organoboranes, Grignard reagents, organozincs, organolithiums, etc.), which lack air and moisture stability, or more forcing reaction conditions (excesses of reagents and/or aqueous base, high temperatures, long reaction times), which negatively affect functional group tolerance and/or reaction yield. Importantly, the myriad challenges encountered in the cross-coupling of sp3 hybridized organometallic reagents can ultimately be attributed to the high activation energy required for transmetalation. In an effort to achieve a general solution to this problem, we sought to develop an alternative mechanistic pathway for transmetalation of organoboron nucleophiles that would consist of low-barrier processes, thus enhancing reaction rates and allowing couplings to be performed at ambient temperatures.
We have developed a dual catalytic system involving the cooperative actions of an Ir photoredox catalyst and a Ni-based cross-coupling catalyst that has proven effective in promoting C-C bond formation between various alkyltrifluoroborates and aryl halides. We are currently exploring the scope of this process with a variety of organoboron preursors, particularly those that have proven recalcitrant to cross-coupling under conventional protocols. Future efforts will also focus on improvements in practicality and cost, as well as mechanistic investigations and exploration of other photocatalytic processes involving organoboron compounds or photoredox/transition metal dual catalysis manifolds.
Synthesis of azaborines
Methods toward the rapid synthesis of azaborine isosteres for heteroaryl systems, utilizing organotrifluoroborates as the source of boron, have been an ongoing interest in our laboratory. These molecules provide a unique class of heterocyclic systems with unusual electronic properties that enable a variety of different elaboration strategies to the core. After screening fluorophiles to activate trifluoroborates toward nucleophilic reactions, BF3·NH2Et was selected for further optimization due to its ease of handling as an air-stable solid. The substrate scope demonstrates functional group tolerance with a variety of boron or phenylenediamine substituents for the indole isostere. Current work is focused on the functionalization of the indole core, understanding the physical properties associated with these isosteres, and looking toward the synthesis and elaboration of new cores of interest.
organofluorine chemistry
Methods toward the rapid synthesis of azaborine isosteres for heteroaryl systems, utilizing organotrifluoroborates as the source of boron, have been an ongoing interest in our laboratory. These molecules provide a unique class of heterocyclic systems with unusual electronic properties that enable a variety of different elaboration strategies to the core. After screening fluorophiles to activate trifluoroborates toward nucleophilic reactions, BF3·NH2Et was selected for further optimization due to its ease of handling as an air-stable solid. The substrate scope demonstrates functional group tolerance with a variety of boron or phenylenediamine substituents for the indole isostere. Current work is focused on the functionalization of the indole core, understanding the physical properties associated with these isosteres, and looking toward the synthesis and elaboration of new cores of interest.
reductive cross coupling
Because of the dramatic advances in sp2 −sp2 couplings over the past decade, drug target molecules have shown increasing trends toward flat, planar structures. Incorporation of saturated ring systems (especially those containing heteroatoms) onto complex structures is desirable, as it allows a larger amount of three-dimensional space to be occupied in comparison to planar aromatics, potentially permitting greater selectivity toward a druggable target while maintaining acceptable physical properties for good absorption and selectivity. A method for late-stage incorporation of nonaromatic species onto an aryl ring without having to metalate either of the partners would clearly be more efficient and versatile. Reductive cross-coupling offers improves atom economy, cost, and efficiency compared to traditional cross-coupling approaches especially when working with recalcitrant coupling partners such as the saturated heterocyclic halides with aryl halides.