Convenient Access to Functionalized Non-Symmetrical Atropisomeric 4,4′-Bipyridines

Emmanuel Aubert,Paola Peluso,Emmanuel Wenger,Victor Mamane

doi:10.3390/compounds1020006

Abstract

Non-symmetrical chiral 4,4′-bipyridines have recently found interest in organocatalysis and medicinal chemistry. In this regard, the development of efficient methods for their synthesis is highly desirable. Herein, a series of non-symmetrical atropisomeric polyhalogenated 4,4′-bipyridines were prepared and further functionalized by using cross-coupling reactions. The desymmetrization step is based on the N-oxidation of one of the two pyridine rings of the 4,4′-bipyridine skeleton. The main advantage of this methodology is the possible post-functionalization of the pyridine N-oxide, allowing selective introduction of chlorine, bromine or cyano groups in 2- and 2′-postions of the chiral atropisomeric 4,4′-bipyridines. The crystal packing in the solid state of some newly prepared derivatives was analyzed and revealed the importance of halogen bonds in intermolecular interactions.

Highlights

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These last years, our groups were involved in the development of halogenated chiral 4,4 -bipyridines and in the study of their performances as halogen- [12,13] and chalcogen [14,15] bond donors in different applications such as organocatalysis [16] and medicinal chemistry [17]
We have shown that homocoupling reactions represent straightforward ways for the synthesis of symmetrical chiral 4,4 -bipyridines [10,18]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Atropisomeric 4,4 -bipyridines are the particular case where rotation around the pyridyl-pyridyl bond is blocked by the presence of three or four substituents They were first used for the preparation of metallo-supramolecular squares [9] and some years later for building chiral MOFs [11]. We have shown that homocoupling reactions represent straightforward ways for the synthesis of symmetrical chiral 4,4 -bipyridines [10,18]. These methods are not relevant for the synthesis of the non-symmetrical derivatives; desymmetrization processes have to be employed. Very limited methods for the desymmetrization of the 4,4 -bipyridine framework to non-symmetrical chiral 4,4 -bipyridines were reported. X-ray diffraction analysis of selected compounds revealed very interesting solid-state packing features

Methods

Findings

Discussion

Conclusion