Synthesis of the First Resorcin[4]arene—functionalized Triazolium Salts and Their Use in Suzuki-Miyaura Cross—Coupling Reactions

: Two bulky triazolium salts, namely 1-­‐‑{4(24),6(10),12(16),18(22)-­‐‑tetramethylenedioxy-­‐‑ 2,8,14,20-­‐‑tetrapentylresorcin[4]arene-­‐‑5-­‐‑yl}-­‐‑4-­‐‑phenyl-­‐‑3-­‐‑methyl-­‐‑1H-­‐‑1,2,3-­‐‑triazolium tetrafluoro borate ( 1 ) and 1,4-­‐‑bis{4(24),6(10),12(16),18(22)-­‐‑tetramethylenedioxy-­‐‑2,8,14,20-­‐‑tetrapentyl resorcin[4]arene-­‐‑5-­‐‑yl}-­‐‑3-­‐‑methyl-­‐‑1H-­‐‑1,2,3-­‐‑triazolium iodide ( 2 ), have been synthesized and assessed in the palladium-­‐‑catalyzed of aryl chlorides, with aryl boronic acids. As a general trend, the reaction rates obtained with 1 were significantly higher (up to 5 times) than those observed for 2 , this mainly reflected a sterically more accessible metal center in the catalytic intermediates formed with 1 . The presence of flexible pentyl chains in these intermediates, which might sterically interact with the metal center, when the latter adopts an exo-­‐‑orientation with respect to the cavity, were likely responsible for the observed good performance.


Introduction
In the last two decades N---heterocyclic carbenes (NHCs) have emerged as powerful ligands for the palladium---catalyzed Suzuki-Miyaura cross---coupling reactions [1---2]. Their performance mainly relies on their strong σ---donor properties, generally considered to be superior to that of phosphines, but also relies on the ease with which they can be made sterically bulky [3], this, generally being achieved by tethering appropriate substituents on their nitrogen atoms. These two features respectively promote the oxidative addition and the reductive elimination steps of the Suzuki-Miyaura catalytic cycle.
As an extension to our studies on the cavity---derived N---heterocyclic carbenes [33---38], here, we have described the synthesis of two sterically highly demanding triazolium salts (1 and 2, Figure  1) and their use as a ligand source in the palladium---catalyzed Suzuki-Miyaura cross---coupling of aryl chlorides with arylboronic acids. Very bulky NHCs are currently sought because of their ability to promote oxidative addition or reductive elimination in the Suzuki-Miyaura reactions [39---41]. Both salts have their triazole unit substituted by a bulky resorcinarenyl group attached to the N1 atom and a methyl group attached to the N3 atom. The ring carbon atom bonded to N3 in 1 is substituted by a phenyl group, that of 2 by a resorcinarene moiety.  Figure  1. The resorcinarenyl---substituted triazolium salts used in this study.
The triazolium salts 1 and 2 were characterized by elemental analysis, ESI---TOF MS analysis, and 1 H and 13 C NMR spectroscopy (see experimental part). Consistent with a Cs---symmetrical compound, the 1 H NMR spectrum of salt 1 showed two AB patterns (intensity 4:4) for the four OCH2O groups and two triplets (intensity 2:2) for the four methine atoms. That of 2 displayed four AB patterns for the eight ---OCH2O---bridges. The signals of the triazolium NCH and NCH3 protons lay in the expected ranges (see experimental part).

Crystal Structures of Triazole 8
Crystals of triazole 8 suitable for an X---ray diffraction study were obtained by slow diffusion of methanol into a dichloromethane solution of the product (Figure  2). Compound 8 crystallized in the monoclinic space group C2/c. The asymmetric unit contains two nearly identical molecules, A and B, but the B sites actually display a double occupancy (0.5:0.5) of the molecules of 8, which are interchangeable through a plane perpendicular, which is perpendicular to the triazole ring and, which bisects the N-Ccarbene-C angle. The two aromatic rings of the resorcinarenes connected to the triazole moiety are roughly perpendicular to the triazole plane (dihedral angles in A: 85.1° and 79.8°). This is in line with the observations made on conventional NHCs that have their N atoms substituted by bulky aryl groups [42]. Both cavitands of 8 adopt the typical bowl---shaped structures of resorcin [4]arene---derived cavitands equipped with ---OCH2O---linkers, with wide rim diameters [43---45] (i.e., the segments linking the C---2 aromatic carbon atoms of opposite resorcinols) of 7.80/8.07 Å and 7.89/8.01 Å in the two macrocycles of molecule A and of 7.91/8.00 Å (averaged), in the cavitands of molecule B. Interestingly, the lower rims of the two resorcinarene units of each molecule are facing each other, thereby creating a pseudo---capsular moiety.

Synthesis of Palladium Complexes 9 and 10
The two triazolium salts were used as a ligand source for the synthesis of two pyridine---enhanced precatalyst preparation, stabilization and initiation (PEPPSI)---type complexes (9 and 10). Pd---PEPPSI complexes are currently considered to be very efficient catalysts for Suzuki-Miyaura coupling reactions [46]. These were obtained by the reactions of 1 or 2 with [PdCl2] in refluxing pyridine, for 24 h in the presence of K2CO3 and a large excess of KBr in the case of salt 2 (Scheme 2). The observed yields (26 % for 9 and 28 % for 10) were relatively low, but this was not unusual for reactions carried out with bulky NHC precursors [38,47]. Both complexes were characterized by elemental analysis and 1 H and 13 C NMR spectroscopy. None of the mass spectra displayed the expected molecular peaks, but unambiguously revealed the formation of PdL species (L = carbene). Thus, the mass spectrum of complex 9 showed an intense peak at m/z = 1193.44, with the profile expected for the corresponding [M ---Cl] + cation. Consistent with the proposed formula, the 1 H NMR of 9 showed two distinct AB systems for the methylenic OCH2O atoms, two triplets for the four methine hydrogen atoms and a singlet at 4.05 ppm (3H), corresponding to the NCH3 group. In the 13 C NMR spectrum, the carbenic C atom appeared as a singlet at 145.99 ppm. As could be inferred from the 1 H---1 H ROESY NMR spectrum, which revealed weak correlations between the pyridinic and pentyl H atoms, the C---Pd bond of 9 must, at least temporarily, be turned away from the cavity. This also means that during a catalytic process, the pentyl groups flanking the resorcinol moiety that bear the triazole unit, might interact with the metal first coordination sphere. Molecular models suggest that such a conformation which has an exo---oriented Pd atom is sterically favored over conformations that have the metal placed above the cavity entrance. However, there is no indication that endo---conformers exist in solution, unlike the observations recently made with the related complexes, based on the classical NHCs [33].
The mass spectrum of 10 showed a strong peak at 1,937.79, corresponding to the [M ---Br --pyridine + acetonitrile] + ions, which possibly formed in the spectrometer in the presence of adventitious acetonitrile. The 1 H NMR spectrum of 10 displayed four NCH3 singlets, at 3.85, 3.78, 3.73 and 3.66 ppm (relative intensities: 26/57/11/6), thus revealing the presence of four distinct conformers ( Figure 3). This observation suggests the existence of high rotational barriers about the N---Cresorc and Ctriazole---Cresorc bonds. The reason why several stable conformers could be seen here (and not in the case of 9), possibly arises from the difficulty of the "ʺPdBr2(pyridine)"ʺ moiety of 10 to adapt its orientation to the steric requirements imposed during the rotations of the resorcinarene moieties, respectively about the N---Cresorc and Ctriazole---Cresorc bonds.  Figure  3. Rotational conformers of complex 10.

Entry
ArCl Triazolium To highlight the influence of the resorcinarenyl substituent on the catalytic outcome, we prepared the triazolium salt 11 devoid of the macrocyclic moiety ( Figure 4). The activity of the corresponding catalytic system turned out to be lower than that observed for 1 or 2 ( Table  2, entries 3, 4, 7 and 8). On the basis of the latter results, as well as recent studies on the use of Suzuki-Miyaura couplings of conventional NHCs substituted by a resorcinarenyl moiety [33,35 and 36], we assigned the high efficiency of triazolium salt 1 in the above reactions, to the presence of two flexible pentyl chains that are able to sterically interact with the metal center (vide supra) in those complexes where the palladium displayed an exo orientation with respect to the cavity ( Figure 5), which then facilitated the reductive elimination step. The observation that salt 2 led to lower conversions than salt 1 was merely due to the high steric encumbrance created about the palladium in the complexes formed from the bulky 2, which impeded the approach of the substrates.

Experimental Section
All manipulations involving sensitive derivatives were carried out in Schlenk---type flasks under dry argon. Solvents were dried by conventional methods and were distilled immediately before use. CDCl3 was passed down a 5 cm---thick alumina column and stored under nitrogen, over molecular sieves (4 Å). Routine 1 H and 13 C{ 1 H} spectra were recorded with Bruker FT instruments (AC 300, 400, and 500). 1 H NMR spectra were referenced to the residual protiated solvents (δ = 7.26 ppm for CDCl3). 13 C NMR chemical shifts were reported, relative to the deuterated solvents (δ = 77.16 ppm for CDCl3). Chemical shifts and coupling constants were reported in ppm and Hz, respectively. Infrared spectra were recorded with a Bruker FTIR Alpha---P spectrometer. Elemental analyses were carried out by the Service de Microanalyse, Institut de Chimie, Université de Strasbourg.  [38], tosyl azide [49], and 2---azido---1,3---dimethoxybenzene [50] were prepared as per the standard procedures found in the literature.  [4]arene (4) To a solution of bromo---cavitand 3 (2.000 g, 2.23 mmol), [Pd(PPh3)4] (0.265 g, 0.23 mmol) and CuI (0.023 g, 0.12 mmol) in NH i Pr2 (100 mL) was added to trimethylsilylacetylene (3.1 mL, 22.30 mmol). The mixture turned rapidly from yellow to black. The resulting suspension was stirred for 48 h at 80°C, then cooled to room temperature. The solution was evaporated to dryness and the resulting residue was dissolved in CH2Cl2 (200 mL). The organic solution was washed with brine (3 x 100 mL) and the aqueous layers were extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure, and the crude product was purified by column chromatography (Et2O/petroleum ether, 10:90; Rf = 0.36) to give 4 (1.453 g, 71 %). 1 [4] arene (5) A solution of 4 (1.000 g, 2.90 mmol) and K2CO3 (1.508 g, 10.91 mmol) in CH2Cl2/MeOH (50 mL; 25:75 v/v) was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue was treated with a mixture of CH2Cl2/H2O (500 mL; 1:1 v/ v). The aqueous layer was washed with CH2Cl2 (2 x 100 mL), then the combined organic layers were dried with MgSO4. After filtration, the solvent was evaporated off, under reduced pressure, to afford 5 as a white solid (0.918 g, yield 100 %). 1

Conclusions
In summary, we have described the first triazolium salts substituted by resorcinarene units (1  and 2). These were assessed in the palladium---catalyzed Suzuki-Miyaura cross---coupling of aryl chlorides with aryl boronic acids. Significantly higher reaction rates were observed with the sterically less hindered triazolium salt 1, which bore a single resorcinarene substituent. Its better performance, compared to that of 2, likely reflected a higher substrate accessibility in the resulting catalytic intermediates, as well as the presence of flexible pentyl groups that might interact with the metal center, so as to facilitate the reductive elimination step. Further studies will be aimed at exploiting the steric as well as the receptor properties of the resorcinarene---derived triazolium salts in carbon---carbon bond forming reactions.