**1. Introduction**

4,4--Bipyridines are useful ligands for the design of coordination polymers and metalorganic frameworks (MOFs) [1], and are key components in the preparation of viologens [2,3]. In contrast to 2,2--bipyridines for which a large number of chiral derivatives were developed [4–6], chiral 4,4--bipyridines were much less explored. In the latter derivatives, the chirality can be brought by specific functions on the pyridine rings [7,8] or by atropisomery [9,10]. Indeed, 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]. 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].

Particularly, we have shown that homocoupling reactions represent straightforward ways for the synthesis of symmetrical chiral 4,4--bipyridines [10,18]. However, these methods are not relevant for the synthesis of the non-symmetrical derivatives; therefore, 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. During their work on the 3,3--dilithiation of octachloro-4,4--bipyridine **1**, Foulger and Wakefield observed that quenching with dichlorodiphenylsilane and di-<sup>π</sup>cyclopentadienyltitanium dichloride generated 4,4--bipyridines **2** and **3**, respectively [19] (Figure 1a). Later, we showed that 3-mono- and 3,5--dilithiation of 2,2--dibromo-5,5-- dichloro-4,4--bipyridine **4** and subsequent electrophilic trapping furnished 4,4--bipyridines

**Citation:** Aubert, E.; Wenger, E.; Peluso, P.; Mamane, V. Convenient Access to Functionalized Non-Symmetrical Atropisomeric 4,4--Bipyridines. *Compounds* **2021**, *1*, 58–74. https://doi.org/10.3390/ compounds1020006

Academic Editor: Juan Mejuto

Received: 19 April 2021 Accepted: 31 May 2021 Published: 1 July 2021

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**5** and **6**, respectively [20] (Figure 1b). Finally, very recently, we used lithiation and crosscoupling reactions in 2-position of 2,2--diiodo-3,3-,5,5--tetrachloro-4,4--bipyridine **7** as non-selective routes to 4,4--bipyridines **8** and **9** [17] (Figure 1c). It is worth mentioning that in all these examples the yields were low to moderate.

**Figure 1.** Non-symmetrical chiral 4,4--bipyridines obtained by desymmetrization of parent 4,4-- bipyridines in the literature (**<sup>a</sup>**–**<sup>c</sup>**) and in the present work (**d**).

Herein, the *N*-oxidation as a straightforward and operatively easy method was used to desymmetrize 3,3-,5,5--tetrachloro-4,4--bipyridine **10**. The advantage of the reported methodology relies on the chemical transformations allowed by the pyridine N-O function, such as halogenation and cyanation [21]. The halogenated 4,4--bipyridines were further functionalized through metal-catalyzed coupling reactions (Figure 1d). Moreover, X-ray diffraction analysis of selected compounds revealed very interesting solid-state packing features.

#### **2. Materials and Methods**

#### *2.1. General Information*

Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance spectra were recorded on a Bruker Avance III instrument operating at 300, 400, or 500 MHz (Bruker Corporation, Billerica, MA, USA). The chemical shifts are given in parts per million (ppm) on the delta scale. The solvent peak was used as reference values for 1H NMR (CDCl3 = 7.26 ppm) and for 13C NMR (CDCl3 = 77.16 ppm). Data are presented as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, b = broad), integration, and coupling constants (J/Hz). High-resolution mass spectra (HRMS) data were recorded on a micrOTOF spectrometer (Bruker Corporation, Billerica, MA, USA) equipped with an orthogonal electrospray interface (ESI). Analytical thin layer chromatography (TLC plates from Merck KGaA, Darmstadt, Germany) was carried out on silica gel 60 F254 plates with visualization by ultraviolet light. Reagents and solvents were purified using standard means. Tetrahydrofuran (THF) was distilled from sodium metal/benzophenone and freshly used. Dry dichloromethane was obtained by passing through activated alumina under a positive pressure of argon using GlassTechnology GTS100 devices. Dry dioxane (over molecular sieve) was purchased from Aldrich, triethylamine and diisopropylamine were distilled over CaH2 and stored over KOH under an argon atmosphere. Anhydrous reactions were carried out in flame-dried glassware and under an argon atmosphere. All other chemicals were used as received.
