Transition metal free cross-coupling: sp2-sp3 boronic esters

Organoboron compounds have become an essential type of building blocks in preparative chemistry. In this kind of molecules, the versatile element boron is bound to an organic moiety and two oxygen atoms. Those structures, especially boronic esters with their oxygens additionally bound to carbon chains, can be subjected to cross-coupling reactions to connect various organic frameworks. Such transformations are extremely important, as they enable the construction of complex molecular assemblies by building up different parts efficiently and simultaneously without a remaining undesired functional group. Hence, the development of the Suzuki-Miyaura reaction, which primarily uses catalysts containing the rare transition metal palladium to facilitate this process and couples organoborons to other substrates bearing halides, was the cause to award Akira Suzuki with the Nobel Prize in 2010. Indeed, it is the most widely used method in the preparation of drug candidates and is commonly employed in the synthesis of e.g. agrochemicals. However, when trying to connect carbons that are not bearing double bonds, this procedure can usually not be implemented. Due to that reason, it is limited mainly to flat molecular structures. Another strategy to take advantage of organoborons is to react them directly with organometallic compounds, generated from inexpensive main group metals, without catalysis. After creating reactive yet good to handle organometallics with the alkali metal lithium, those lithium organyls can form stable intermediate complexes, the boronates. Professor Varinder K. Aggarwal from Bristol University succeeded to utilize such boronates to construct a broad range of structural motifs that would be difficult to obtain otherwise by initiating rearrangement or migration processes of the substituents bound to the boron atom. The choice of the right conditions and reagents enables to build up three- dimensional scaffolds in very efficient procedures. Probably the major advantage of this concept is the impressively high level of stereospecificity, meaning how the reaction sequence influences the geometry of the molecules and how exclusive the bonds of affected carbons with four different substituents are oriented in the preferred direction. To overcome limitations of Suzuki- Miyaura and to benefit from the latter described so-called lithiation-borylation reactions, the novel strategy is to install a simple directing group (DG) on an aromatic substrate that is to be connected to a carbon center without a double bond via a boronic ester. The DG will be a dimethylaminomethane and verify lithiation at the right position, which then can be bound to the boronic ester. After an activation step, a cascade will be initiated to release the DG as a traceless leaving group and form a new 3D molecule. Finally and without any transition metal assistance, the boron is sitting where the DG was before and can be used for further reactions. 1

The proposed stepwise approach for the permanent assembly of molecular building blocks could indeed be successfully investigated and published. The few efficient techniques in preparative chemistry to connect saturated and three dimensionally defined scaffolds to aromatic residues without suffering from losses in spacial integrity require structural features, which narrow down the utility of the methods. Instead of a classic palladium based catalytic cycle, the newly established strategy exploits the distinctive properties of the element boron and the controlled stepwise conversion of boronic acid compounds. A benzyl amine unit serves as an easily insertable nitrogen centered moiety for selective functionalization of the adjacent site, the ortho-position, where a lithium atom is installed, turning it into a highly reactive species. By adding the boronic acid molecule, which carries the saturated and spacially defined building block, a transition stage is furnished. Upon targeted activation a rearrangement is triggered, where the nitrogen functionality is cleaved off and subsequently the boron atom is bypassed. Hence, the planned carboncarbon bond is created. The obtained intermediate structure, its stability and further useful properties appeared as one of the major discoveries of this project. In order to reach an aromatic state again, which is characteristic for the target framework, a novel rearrangement process could be developed. Here, the lithium is becoming catalytically active by deshielding it. As a consequence, it is rendered to assist the boron residue with the migration within the molecular scaffold. The described methodology allows for time-efficient synthesis and its steps can be conducted consecutively inside the same vessel. Employing this procedure, a broad range of challenging organic frameworks becomes accessible. It needs to be mentioned that certain classes of starting materials are not suitable due to rapid side reactions. However, also in such cases interesting transformations can be observed. The chemical potential of the above mentioned stable intermediate towards further preparative value became the main focus of the subsequent investigations. Its tendency to reach aromaticity, an energetically preferred situation, again is advantageous for a set of additional reaction types. This effect enables the incorporation of functional groups based on oxygen as well as nitrogen, among others, with a pragmatic approach. By means of variations of materials and conditions on every stage of the methodology, ongoing research is dedicated to the exploration of its scope and possibilities.