Construction of Pyridine Backbone Via Electrochemical Skeletal Editing of Pyrrole-Derivatives
Authors: Morimoto Tatsuya , Okamoto Kazuhiro , Shida Naoki , Atobe Mahito 
Published: February 2024

Pyridine skeleton is one of the most important nitrogen-containing heterocycles that finds extensive applications in pharmaceuticals. For instance, apalutaminde and lvosidenib are used for cancer treatment and aminopyralid used is in herbicides. In fact, pyridine is the second most commonly used nitrogen-containing heterocyclic ring among drugs approved by the U.S. Food and Drug Administration, and the most commonly used among aromatic compounds.[1] Therefore, the development of efficient synthetic methods for pyridine derivatives is highly desirable.

A common synthetic approach of pyridine-containing molecules relies on the modification of C-H bond of pyridine-derivatives, while this strategy limits the chemical space of available structures due to the inherent difficulties in the selective C-H functionalization in pyridine rings. In this context, skeletal editing has emerged as an innovative approach to address heavily functionalized pyridines via single atom-insertion into five-membered rings. It can not only be used in the field of late-stage functionalization but also open up a new route of retrosynthesis of drug candidates. Moreover, this reaction can more easily diversify the molecule because a library of existing skeletons can be used. For example, if a ring-expanding reaction from the pyrrole skeleton to the pyridine skeleton becomes possible, which can create molecules with the pyridine skeleton using a vast molecular library containing pyrrole skeletons. These will enable the synthesis of highly diverse molecules that were previously impossible to create.

Some approaches to convert a pyrrole skeleton into a pyridine skeleton have been developed using single-atom insertion reactions, such as Ciamician-Dennsted reaction. [2] This reaction can create 3-halopyridines through haloform-derived carbenes, but it is not widely used because of the harsh conditions and low yield. Bonge-Hansen and colleagues have recently reported the reaction which transforms the indole skeleton into the quinoline skeleton.[3] In this ring expansion reaction, a carbon atom derived from ethyl diazoacetate (EDA) is inserted into the indole skeleton. While this reaction is so useful, it requires not only expensive rhodium catalysts to increase the electrophilicity of the EDA, but also requires pre-reaction of the EDA to create α-halo EDA. On the other hand, Levin has recently reported a powerful reaction that use α-chlorodiazirines as a carbon source.[4] This reaction is advantageous since it does not require any transition metal catalysts, while installable functional group is limited to the available α-chlorodiazirine-derivatives.

With these backgrounds in mind, in this work, we demonstrate an electrochemical ring-expansion reaction that converts a pyrrole skeleton into a pyridine skeleton. The pyrrole derivatives are easily oxidized by anodic oxidation to generate electrophilic radical cation species. Owing to its high reactivity, it can easily react with other nucleophiles including EDA under ambient conditions. This reaction is economical and eco-friendly because it does not need a metal catalyst.

Reactions were performed using tetra-substituted pyrrole with various N-substituted groups (1) as a model compound. Under the optimized condition with using 1 (PG = H) as a substrate and EDA as a nucleophile, the carbon insertion product (2) was successfully obtained as an isomeric mixture. Remarkably, when using 1 with an electron-withdrawing N-protecting group, carboxylated product at 4-position of pyridine ring, 3, was obtained. These results imply that the insertion position varies depending on the electronic nature of protecting groups. Furthermore, it was also revealed that carbon insertion and decarboxylated product in a single step, 4, was selectively obtained by installing a specific N-protecting group.

In conclusion, we have demonstrated that the first electrochemical skeletal editing reaction using pyrrole-derivatives and EDA. In the presentation, detail of the optimizations, as well as the implementation of flow electrochemistry will also be discussed

[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2014, 57, 10257−10274.

[2] G. L. Ciamician, M. Dennstedt, Ber. Dtsch. Chem. Ges.
1881, 14 (1), 1153−1163.

[3] M. Mortén, M. Hennum, T. Bonge-Hansen, Beilstein J. Org. Chem.
2015, 11, 1944–1949.

[4] B. D. Dherange, P. Q. Kelly, J. P. Liles, J. P. Sigman, M. D. Levin, J. Am. Chem. Soc.
2021, 143, 11337−11344

Figure 1