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

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 2and 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.


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][5][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].

General Information
Proton ( 1 H NMR) and carbon ( 13 C 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 1 H NMR (CDCl 3 = 7.26 ppm) and for 13 C NMR (CDCl 3 = 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 CaH 2 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.

Syntheses
To a solution of diisopropylamine (27.5 mmol, 3.85 mL) in THF (200 mL) at −40 • C was added a solution of n-BuLi (1.6 M in hexanes, 27.5 mmol, 17.2 mL) and the mixture was stirred for 20 min. A solution of 3,5-dichloropyridine 11 (50 mmol, 7.4 g) in THF (100 mL) was added during 1 h while maintaining the temperature close to −40 • C. The temperature of the cloudy solution was slowly raised to −15 • C (during 1h) to give a homogeneous dark red solution. The temperature was lowered to −78 • C then a solution of I 2 (30 mmol, 7.62 g) in THF (50 mL) was slowly added. After 10 min at −78 • C, the temperature was raised to room temperature and the reaction was quenched by the addition of aqueous saturated solution of Na 2 S 2 O 3 (100 mL). Water was added (200 mL) and the mixture was extracted three times with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with brine (100 mL) and dried over MgSO 4 . After concentration, the crude compound was purified by chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to give 4,4 -bipyridine 10 (3.64 g) and compound 12 (2.7 g). Compound 12 was diluted with ethyl acetate (200 mL) and I 2 (18 mmol, 4.57g) was added and the mixture was stirred overnight at room temperature in an open flask. The reaction was quenched by the addition of aqueous saturated solution of Na 2 S 2 O 3 (25 mL). Water was added (50 mL) and the organic phases washed with brine (100 mL) and dried over anhydrous MgSO 4 . After concentration, the crude compound was purified by chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to give 4,4 -bipyridine 10 (2.4 g). A total mass of 6.04 g of 10 was obtained which corresponds to an overall yield of 82%. The NMR data for 10 are in complete agreement with the literature [22].

Isolated Molecule Calculations
Molecular structures of 24, 18 and 13 were optimized with Gaussian09 software at DFT level of theory using the B3LYP functional completed with D3 dispersion correction and the Def2TZVPP basis set. Frequency calculations were performed in order to check that true energy minimum were obtained. Electrostatic maps (Figure 2, Figures S31 and S32) were drawn using the AIMAll software, and locations of ESP extrema V S,max were searched using MultiWFN program (Table S4)  Coloring from red = −0.05 a.u. to blue = +0.05 a.u. Black arrows point to some representative electropositive σand π-holes.

Cross-Coupling Reactions with 4,4 -Bipyridine 24
4,4 -Bipyridine 24 bearing two different halogens (Br and I) in 2 and 2 -positions was chosen to perform selective cross-coupling reactions. In particular, 4,4 -bipyridines 28 and 30, which were recently described as good transthyretin fibrillogenesis inhibitors [17], could be obtained in excellent yields and with very high purity by successive Suzuki and Finkelstein reactions, followed by silyl group deprotection in the case of 30. Moreover, their enantiomers could be separated by HPLC on chiral stationary phase [26,27]. High selectivity for mono-coupling products 26 and 27 was obtained by using the Suzuki coupling [28] with one equivalent of arylboronic acid, letting the C-Br bond untouched for a further coupling reaction such as the copper-catalyzed Finkelstein Br/I exchange [18]. Moreover, a new Suzuki cross-coupling of 4,4 -bipyridine 27 with 4-pyridylboronic acid delivered compound 31, which, after silyl group deprotection, furnished the chiral 4,4 -bipyridine 32, bearing two different functional groups (Scheme 4).
In order to rationalize the observed positional disorder that involves the iodine and bromine atoms, DFT calculations were undertaken on the isolated tetramer centered about the type-II hal· · · hal bond's four-membered ring ( Figure S36). From the results (Table S5), it appears that the most stable configuration is obtained for the observed largest component disorder (labelled IBrIBr), where the halogen atoms alternate in the sequence Hal1=I, Hal2=Br, Hal3=I, Hal4=Br, as depicted on Figure 3. However, the other configurations are not excessively less stabilizing, with the most unfavorable case (IIII) being only 8.92 kJ/mol higher in energy. Boltzmann populations calculated, taking into account all the possible configurations, finally lead to an equivalent average disorder population of 0.675, in remarkable qualitative agreement with the refined population parameter (0.7441 (13)). This may indicate that the observed dissymmetry in the disorder population (i.e., different from 50/50) results from the preferential interaction of the σ-hole of iodine atom toward the crown of bromine at the short distance, at the expense of the reverse situation (interaction of bromine σ-hole toward the crown of iodine).
N-oxides 13 and 18 are isostructural, crystallizing in P2 1 /c space group with similar unit cell parameters. Indeed, they present similar crystal packing, with notable differences only about the substituent in 2 position (-H in 13, -CN in 18) (Figures S22 and S23). The analysis of intermolecular interaction energies (Tables S2 and S3) shows that in both structures the main interaction (entry 1) corresponds to the formation of a strong cyclic R2,2(8) hydrogen bond motif about an inversion center, involving the oxygen atom of the N-O as the acceptor (Figure 4; 18: C12-H12· · · O13 = 2.17 Å; 160 • ; 13: 2.07 Å; 162 • ). The main differences between the two structures concern the next two most intense interactions involving 2 − x, 1 − y,1 − z and 1 − x, 1 − y,1 − z molecules. The first dimer is strongly stabilizing in 18, with the cyano groups of the two neighboring molecules arranged in a head-to-tail manner ( Figure S24), associated with a large electrostatic component (Table  S2, entry 2); on the contrary, in 13 the corresponding molecules does not present any contact below van der Waals limit and dispersion is the main stabilizing contribution to the interaction (Table S3, entry 2 and Figure S25). The second dimer (with 1 − x, 1 − y,1 − z, Tables S2 and S3, entry 3) is twice more stabilizing in 18 than in 13 and involves a contact at van der Waals limit between the Cl1 and C14 atoms of the cyano group, the crown of the halogen atom pointing in the direction of the positively charged carbon atom (C3-Cl1· · · C14 = 3.442 Å, 110.04 • ; Q(C14) = 0.94) ( Figure S26); in such a way, both electrostatic and dispersion components are more stabilizing in 18, while in 13 a C3-Cl1· · · Cl1 contact at van der Waals limit (3.490 Å, 78.83 • ) implies the crown of both halogen atoms in a unfavorable disposition ( Figure S27).
The last significant interaction implies 1 − x, y + 1/2, −z + 1/2 molecule (Tables S2 and S3, entry 6) and is slightly more stabilizing for 13 than for 18 due to a more negative electrostatic contribution. In this latter Cl2 atom presents three contacts at distances smaller than van der Waals limits with this neighbor, namely with N7 (3.179 Å, RR = 0.96), C8 (3.380 Å, RR = 0.98) and C12 (3.426 Å, RR = 0.99), but with an orientation that does not involves the halogen σ-hole (C5-Cl2· · · N7 = 109.10 • ) ( Figure S30). The electrostatic stabilization may then result from the head-to-tail relative orientation of the two molecules which bear a dipole moment parallel to their long N-N axis in the case of 13 (1.87 D), whereas in 18 the molecular dipole moment (3.42 D) is almost parallel to the -CN group. In this situation, the neighboring molecules have almost orthogonal dipole moments and thus a reduced overall electrostatic stabilization.

Discussion
The synthesis of 3,3 ,5,5 -tetrachloro-4,4 -bipyridine 10 [22] was greatly improved by adjusting the amount of LDA to 0.55 equivalent with regard to 3,5-dichloropyridine 11. Moreover, a large quantity (44%) of dihydropyridine 12 was also isolated during the reaction, confirming the proposed mechanism for the dimerization process [22]. Indeed, after deprotonation of half equivalent of 11, the nucleophilic lithiated 11-Li added in 4position of the remaining half equivalent of 11 to give 12-Li, which after oxidation with iodine and hydrolysis delivered 10 and non-oxidized 12 ( Figure 5A). After purification, dihydropyridine 12 was very stable in the solid state with no noticeable oxidation after three months on the bench at ambient temperature. In acetone solution, a slow oxidation occurred with almost complete formation of 4,4 -bipyridine 10 after 10 days, as shown by 1 H NMR ( Figure 5B). The desymmetrization route of 4,4 -bipyridines used in this study is based on the N-oxidation of one of the two pyridine nitrogens in the presence of one equivalent of m-CPBA. N-oxidation of electron-deficient pyridines generally requires harsher conditions that necessitate prior N-activation with trifluoroacetic acid anhydride [32,33]. As expected, this first N-oxidation is not selective; however, the chemical nature of the three compounds of the reaction mixture (starting material with free nitrogens, mono N-oxide and bis Noxide) allowed for simple purification with easy recovery of unreacted starting material. The N-oxidation of the electron-deficient pentasubstituted 4,4 -bipyridines 15 and 16 was highly selective with no formation of the bis N-oxide. The high selectivity of the reaction is due to both electronic and steric factors. Indeed, the trisubstituted pyridine ring is electronically impoverished by the three electron-withdrawing groups (Cl, Cl and Br or CN) and the N-pyridine is sterically hindered by the substituent in 2-position (Br or CN).
The choice of the pyridine N-oxides in our synthesis was also guided by the numerous known methodologies for their functionalization [21].  The installed functions in 2,2 -positions represent a potential entry to new functional groups by nucleophilic substitution of the chlorine, hydrolysis of the cyano group and crosscoupling reaction with the C-Br bond. In the latter case, we have used the copper-catalyzed Finkelstein reaction to exchange bromine by iodine, and the Suzuki reaction to introduce aryl groups in 2-positions. In this regard, 4,4 -bipyridine 24 possessing both bromine and iodine in 2,2 -positions is a compound of choice in order to selectively introduce two different aryl groups on the 3,3 ,5,5 -tetrachloro-4,4 -bipyridine scaffold. This was highlighted by the synthesis of 4,4 -bipyridine 32 whose supramolecular arrangement in solution and in the solid state is currently under investigation in our laboratory. Interaction between x, y, z, and 2 − x, 1 − y, 1 − z molecules. Representative distance is given in Å. Only the major component disorder is shown, Figure S20: Packing in the solidstate structure of 24. Interaction between x, y, z, and x, −y + 3/2, z − 1/2 molecules. Representative distance is given in Å. Only the major component disorder is shown, Figure S21: Packing in the solid-state structure of 24. Interaction between x, y, z, and 1 + x, −y + 3/2, z + 1/2 molecules. Representative distance is given in Å. Only the major component disorder is shown, Figure S22: Superimposition of the molecular environment about a central molecule (displayed as ball and sticks) showing the isostructural relationship between 18 (colored as atom type) and 13 (light gray), Figure S23: Focus on the region centered on -CN group in 18, showing the largest differences between 18 (colored as atom type) and 13 (light gray) crystal structures, Figure S24: Packing in the solid-state structure of 18. Interaction between x, y, z, and 2 − x, 1 − y, 1 − z molecules. Representative distances are given in Å, Figure S25: Packing in the solid-state structure of 13. Interaction between x, y, z, and 2 − x, 1 − y, 1 − z molecules. Representative distance is given in Å, Figure S26: Packing in the solidstate structure of 18. Interaction between x, y, z, and 1 − x, 1 − y, 1 − z molecules. Representative distances are given in Å, Figure S27: Packing in the solid-state structure of 13. Interaction between x, y, z, and 1 + x, −y + 3/2, z + 1/2 molecules. Representative distances are given in Å, Figure S28: Packing in the solid-state structure of 18. Interaction between x, y, z, and x, −y + 3/2, z − 1/2 molecules. Representative distances are given in Å, Figure S29: Packing in the solid-state structure of 13. Interaction between x, y, z, and x, −y + 3/2, z − 1/2 molecules. Representative distances are given in Å, Figure S30: Packing in the solid-state structure of 13. Interaction between x, y, z, and 1 − x, y + 1/2, −z + 1/2 molecules. Representative distances are given in Å, Figure S31: Electrostatic potential mapped on the ρ = 0.002 a.u. electron density isosurface of 13. Coloring from red = −0.05 a.u. to blue = +0.05 a.u., Figure S32: Electrostatic potential mapped on the ρ = 0.002 a.u. electron density isosurface of 18. Coloring from red = −0.05 a.u. to blue = +0.05 a.u., Figure S33: Integrated Bader atomic charges for isolated 24 molecule, Figure S34: Integrated Bader atomic charges for isolated 13 molecule, Figure S35: Integrated Bader atomic charges for isolated 18 molecule, Figure S36: Tertamer extracted from the experimental structure of 24 and used for the modeling of I/Br substation disorder. HalX/HalX are I/Br or Br/I, Table S1: Intermolecular interaction energies (kJ/mol) in the packing of solid state structure of 24. R is the distance between molecular centroids (mean atomic position) in Å, Table S2: Intermolecular interaction energies (kJ/mol) in the packing of solid state structure of 18. Largest differences between 18 and 13 are highlighted in bold. R is the distance between molecular centroids (mean atomic position) in Å, Table S3. Intermolecular interaction energies (kJ/mol) in the packing of solid state structure of 13 Largest differences between 18 and 13 are highlighted in bold. R is the distance between molecular centroids (mean atomic position) in Å, Table S4. Electrostatic potential maxima (V S,max ; kcal/mol) on the molecular surface ρ = 0.002 a.u. of 24, Table S5: Type-II hal· · · hal bonds four membered ring tetramer relative energies. Hal1-2-3-4 numbering corresponds to Figure S18. Data Availability Statement: All the data are given in the article and in the associated supporting information.