A facile approach to 2,2′-bipyridine based thiacrown ethers and their sulfoxides by DA-rDA reaction of 5,5′-bi-1,2,4-triazine thiamacrocycles. The conformation studies

Diels-Alder/retro Diels-Alder (DA-rDA) reactions of 5,5′-bi-1,2,4-triazine thiamacrocycles 4a – c afforded medium-size 2,2′-bipyridine based thiacrown ethers 5a – c in good yield. The latter were oxidized to non-racemic monosulfoxides 7a – c using Davis oxaziridine and tested as chiral auxilaries in the asymmetric addition of diethyl zinc to benzaldehyde. The theoretical calculations at DFT /B3LYP/6-311G** level were conducted thus establishing cis or trans conformational preferences of the target thiamacrocycles.


Introduction
The macrocycles containing 2,2′-bipyridine (bpy) subunit have a wide range of applications in many areas of chemistry such as catalysis, metal extraction and molecular recognition. 1oreover, C2-symmetric bpy crown-ethers have been developed recently for the enantioselective recognition of amino acids derivatives and chiral organic ammonium salts. 2 Despite the vast knowledge on sulfur-metal interactions in coordination chemistry, 3 the use of S-based ligands derived from bpy appeared to be still rather undeveloped.Such ligands should be able to coordinate to softer metal ions than those containing nitrogen or oxygen as donor atoms, and may constitute a valuable starting materials for the construction of more complex molecular and supramolecular systems. 4However, synthetic efforts in this area have been hampered by the lack of the efficient methods of their synthesis. 5In our preliminary work 6 we have shown that 1,2,4triazine bis-sulfides, tethered to poly(ethylene glycol) chains undergo a remarkably facile, intramolecular cyclization into previously unknown 5,5′-bi-1,2,4-triazine thiacrown ethers (Scheme 1).The latter undergo an inverse electron demand Diels-Alder/retro Diels-Alder (DA-rDA) reaction with electron rich dienophiles affording bpy, or annulated bpy thiacrown ethers. 6rom our preliminary findings and additional applications, 7 one may assume that the approach is general one for the rings of 13 or more members.Here we would like to present a full account of this work on the synthesis of 16-, 19-, and 22-membered bpy thiacrown ethers and their conformational studies using the theoretical calculations.The obtained macrocycles were oxidized to non-racemic monosulfoxides by Davis oxaziridine 8 and tested as chiral auxiliaries in an asymmetric addition of diethylzinc to benzaldehyde.
Earlier, it was reported that DA-rDA reactions of 5,5′-bi-1,2,4-triazines with 2,5norbornadiene in boiling p-cymene led to 2,2′-bipyridine derivatives in good yields. 9However, this dienophile has never been used in the inverse electron demand DA-rDA reaction of 1,2,4triazine or bi-1,2,4-triazine based macrocycles.We initially attempted the DA-rDA reaction of 4a with 2,5-norbornadiene under the reaction conditions mentioned above, (method A), but in addition to the unreacted 4a, the mixture was obtained containing, as its major component the expected bpy thiacrown ether 5a accompanied by some amounts of monoadduct 6a (Scheme 2).Attempts to increase cycloaddition yields failed, even when long times were used; compound 6a was still present in the reaction mixture.The similar mixture of products was obtained in reaction of compound 4b with 2,5-norbornadiene, (Scheme 2).The decrease in reactivity of 6a and 6b with 2,5-norbornadiene reflected the decreasing electron-withdrawing effect of pyridine ring in these heterocycles, as compared to starting bi-1,2,4-triazine 4a.However, when bi-1,2,4-triazine macrocycles 4a-c were reacted with 2,5-norbornadiene in a sealed Carius tube at elevated temperature under high pressure, (method B), the only products were the corresponding symmetrical derivatives 5a-c obtained in good yields (Table 1).As the Diels-Alder reaction is know to posses a large negative volume of activation, thus action would serve to raise the ground-state energy of the reactants relative to the transition state, thereby lowering the activation energy. 10The spectroscopic properties of the bpy thiacrown ethers 5a-c are entirely consistent with the functional group present.The preferred conformations of these macrocycles are ascertained by the size of polythioetheral bridge and are determined by analyzing the chemical shifts of 3-pyridyl hydrogens. 11The resonances of such hydrogens in compounds 5a-b (range from 7.46-7.59ppm) indicate cis arrangement for these biheterocycles.In case of compound 5c (n = 4) however, the chemical shift of 3-H (δ = 8.02 ppm) shows a trans conformation for this pentethylene chain ligand.This is consistent with the chemical shifts of pyridine protons (3H, δ = 8.11 ppm) in the parent 6,6′bis(ethylsulfanyl)-2,2′-bipyridine (Figure 1).Moreover, these data also prove that twenty two-membered macrocyclic system 4c exists in trans conformation.In contrast, compounds 4a-b, containing sixteen and nineteen-membered macrocyclic rings exist in cis conformation exclusively.Finely, we have evaluated the asymmetric sulfoxidation of compounds 5a-c using chiral oxaziridine developed by Davis. 8The reactions were performed in methylene chloride at room temperature (Scheme 3).Under these conditions the monosulfoxides 7a-c could be obtained in reasonable or good yield.

Scheme 3. Asymmetric sulfoxidation of cyclophanes 5a-c.
The preliminary use of these monosulfoxides as chiral auxilary was tested in asymmetric addition of the diethyl zinc to benzaldehyde, however their catalytic efficiency was poor and the ee values of the chiral alcohol thus obtained were much lower than the values observed for other catalysts. 13o establish the conformation preferences of 2,2′-bipyridine thiamacrocycles the theoretical calculations for 5a-c at DFT/B3LYP/6-311++G(d,p) level were undertaken.View of the molecules in conformation obtained after energy minimization and geometrical parameters optimization is shown in Figure 2. The molecules 5a and 5b containing respectively sixteen-and nineteen-membered macrocyclic ring adopt the cis (syn) conformation with the torsion angle φ = N1-C2-C2'-N2' about the central bond of the bipyridyl system of -23.5 o for 5a and 15.1o for 5b.In the molecule 5c with twenty two-membered macrocyclic system the bipyridyl group is in trans (anti) conformation with the torsion angle of 163.4 o .The calculated conformations of 2,2′-bipyridine systems in 5a-c are very similar to those obtained from X-ray analysis of structurally related annulated 2,2′-bipyridine thiamacrocycles. 7In the case of 5a the cis conformation is forced by the strain effect in the twelve-membered thiaethereal chain during the cyclization process.The elongation of the thiaethereal chain in 5b and 5c can give the possibility to change the mutual orientation of pyridine rings.The energy effects of the free rotation between the pyridine rings, taking into account the one degree of freedom described by torsion angle φ, were calculated for 5b and 5c using the AM1 method.The differences in heat of formation, ΔHF, of the conformations were calculated after minimization and all geometrical parameters optimization for each rotation, with a 10 o increment from -180 to 180 o of φ (Figure 3).The calculated conformations with minima of energy are in good agreement with those calculated at ab initio DFT level and those observed in the crystalline state of respective annulated 2,2′-bipyridine thiamacrocycles structurally related to 5b and 5c.The energy difference between conformers in maximum (trans) and minimum (cis) of in 5b is ~14.9 kcal/mol.This barrier of energy can inhibit the free rotation at C2-C2' central bond and can prevent the 2,2′-bipyridyl group changing the cis conformation in room temperature.The energy differences between rotamers of 5c, of about 6.6 kcal/mol, are relatively lower and the tendency in the energy minima distribution to gauche and trans conformations is good visible.One should notice, that the polarization vectors of N1-C2 and N1'-C2' bonds (as well as C2-C3 and C2'-C3' bonds) in pyridine rings are in the most profitable anti-parallel position in trans conformation of 2,2′-bipyridyl system.The existence of this electronic effect is confirmed by the charge distribution at N1 (-0.505 e), C2 (+0.184 e), N1' (-0.508 e) and C2' (+0.193 e) atoms obtained for 5c from natural bond order (NBO) analysis at DFT/B3LYP/6-311++G9d,p) level.The similar values of charges are also observed at N1, C2, N1' and C2' atoms of -0.488 e, +0.183 e, -0.460 e and +0.207 e, respectively for 5a, and -0.478 e, +0.199 e, -0.489 e and +0.185 e, respectively for 5b, but the cis conformation of 2,2′-bipyridyl system in these molecules is the resultant effect of electrostatic dipole-dipole interaction, steric and strain effects in thiaetheral chain, with the predomination of the later.Theoretical calculations showed, that the C2 symmetry of macrocycles 5ac is not retained and the conformations of the left and right parts of molecules (cis-trans-gauche-gauchegauche-gauche and cis-gauche-trans-trans-trans-gauche in 5a, cis-gauche-gauche-transgauche-gauche-gauche and cis-gauche-trans-trans-trans-gauche-gauche in 5b and cis-gauchetrans-trans-gauche-gauche-trans-gauche-trans and cis-gauche-trans-gauche-gauche-transgauche-trans-trans in 5c) are somewhat different, similarly as in the case of annulated 2,2′bipyridine thiamacrocycles.

Conclusions
We have demonstrated a facile approach to 2,2′-bipyridine thiacrown ethers.The preferred conformations of these macrocycles are ascertained by the size of polyetheral bridge and can be determined by 1 H NMR and the theoretical calculations at the DFT level.Further studies on application of the obtained macrocycles as complexing agents are in progress.

General procedure for the preparation of sulfoxides (7a-c) (Davis method)
To a solution of the sulfide 5a-c (1 mmol) in anhydrous methylene chloride (30 ml), (+)-(8,8'dichlorocamphorylsulfonyl)oxaziridine (0.75 mmol) was added and the reaction mixture was stirred at room temperature for 24 h.Afterwards, the solvent was evaporated and the residue was purified by flash chromatography using CH2Cl2-acetone (10:1.

Table 1 .
Reaction conditions, yields and mp of compounds 5a