Palladium-catalyzed Suzuki–Miyaura cross-coupling with -aminophosphonates based on 1,3,4-oxadiazole as ligands

The synthesis of a palladium complex bearing two diethyl[(5-phenyl-1,3,4-oxadiazol-2ylamino)(4-nitrophenyl)methyl]phosphonates as ligands has demonstrated the ability of this type of α-aminophosphonates to coordinate to the palladium(II) ion via their electronically enriched nitrogen atom of the 1,3,4-oxadiazole ring. The complex was fully characterized by elemental analysis, infrared, NMR and mass spectrometry. A solid-state structure revealed the trans coordination of the two nitrogenated ligands. The presence of a hemilabile P(O)(OEt)2 moiety in the α-aminophosphonates was exploited into palladium-catalyzed Suzuki–Miyaura cross-coupling of aryl halides. The formation of (N ,O)-chelate intermediates may increase the steric hindrance and the electronic density of the metal, which should favor the oxidative addition and the reductive elimination/product decoordination elementary steps. With our catalytic systems, good activities for the formation of orthodi/trisubstituted biphenyl compounds were observed from aryl bromides using only 0.5 mol% of palladium. Cross-coupling of aryl chlorides required a catalyst loading of 1 mol% to generate orthosubstituted biphenyls.

In a recent study, we have described the synthesis of three diethyl[(5-phenyl-1,3,4-oxadiazol-2ylamino)(aryl)methyl]phosphonates (1-3; Figure 1), in which, according to natural bond orbital charge analyzes, the nitrogen atom in position 3 of the oxadiazole ring is the more basic one [63]. Coordination of these α-aminophosphonates to a ruthenium precursor occurred via its electron-enricher nitrogen atom as confirmed by X-ray crystallographic structure of the [RuCl 2 (L)(η 6 -p-cymene)] complexes (L = 1-3). In continuation of our research, we now wish to investigate the ability of the 1,3,4-oxadiazole moiety to coordinate to a palladium precursor and the ability of the α-aminophosphonates to act as ligand in the Suzuki-Miyaura cross-coupling of aryl halides. The presence of a phosphonate moiety in these ligands may promote the formation of (N ,O)-chelate intermediates, which would increase the steric hindrance and the electronic density of the metal and therefore favor the oxidative addition and the reductive elimination steps of the cross-coupling reaction.
To the best of our knowledge, no mention of 1,3,4oxadiazole derivatives as ligands, in which a nitrogen atom is directly coordinated to palladium, has been reported for the Suzuki-Miyaura cross-coupling. The functionalization of the 1,3,4-oxadiazole ring by the Suzuki-Miyaura methodology has, however, been  (1)(2)(3)(4) used in this study. described for example by the groups of Khazi [64,65] and Kudelko [66].
To gain insight into the coordinative properties of these α-aminophosphonates 1-4, we investigated the coordination of 2 with the [PdCl 2 (PhCN) 2 ] precursor in dichloromethane for 24 h (Scheme 1). After recrystallization, the [PdCl 2 (2) 2 ] complex (5) was isolated in 82% yield as a yellow solid. Its 1 H NMR spectrum reveals for the CHP(O) proton a downfield shift of 0.1 ppm while the 31 P NMR spectrum shows a singlet for the P(O) signal with a slight up field shift of 0.6 ppm with regard to the free α-aminophosphonate 2. Infrared measurements show that the band at 1601 cm −1 in free ligand 2 (ν(C=N) stretching vibrations of the oxadiazole ring) shifts to 1658 cm −1 in the palladium complex 5, which confirms the coordination of the α-aminophosphonate via its oxadiazole ring. The mass spectrum analysis, which shows a peak corresponding to [M − Cl] + cation with the expected isotopic profile, indicates the coordination of the two α-aminophosphonates to the metal. The structure of the complex 5 was confirmed by a single crystal X-ray diffraction study, which unambiguously demonstrated the presence of two αaminophosphonates moieties trans-coordinated to Scheme 1. Synthesis of trans-[PdCl 2 (2) 2 ] complex (5).
the palladium center via their electron-enricher nitrogen atoms of the oxadiazole rings denoted N1 in Figure 2.
In a second series of catalytic tests, we investigated the influence of the base ( Table 2). The runs were carried out in 1,4-dioxane as solvent at 100°C with one equivalent of α-aminophosphonate 1 per [Pd(OAc) 2 ] precursor. Four bases derived from carbonate anion were tested, as attempts, and the conversions increased with the size of the cations from lithium (traces; Table 2, entry 1) to cesium (65%; Table 2, entry 4). Interestingly, with the latter base, only traces of by-product were observed. Testing other sodium or potassium bases containing hydroxy, acetate or alkoxide anions did not improve the amount of 4-methoxybiphenyl 8a ( Table 2, entries 5-10). Reducing the temperature to 80°C led to a lower rate of the reaction and a conversion of only 38% was measured ( Table 2, entry 11). Changing 1,4-dioxane to THF, DMSO or DMF favored the formation of homocoupling by-product with Ph-Ph/8a ratio up to 88% when DMSO was employed ( Table 2, entries 12-14).
Finally, we investigated the influence of the αaminophosphonate as well as the metal/ligand ratio ( Table 3). The variation of the substituent of the aromatic ring of the α-aminophosphonate favors the formation of the homocoupling by-product in the order 4-CF 3 (1), 4-NO 2 (2), 2-MeO (3) and 4-F (4) ( Table 3, entries 1-4). With the latter ligand (4), although the conversion of 6a into the crosscoupling product 8a was the more important (76%), the biphenyl by-product was observed in a Ph-Ph/8a ratio of 39% (Table 2, entry 4). Unfortunately, the use of an excess of α-aminophosphonate 1 per palladium atom failed to produce a selective active species. Although the formation of the desired 4methoxybiphenyl 8a was favored, the amount of homocoupling by-product was increased (Table 3, entries 5-8). For example, with three ligands per palladium, the conversion reached 85% after 2 hours with two equivalents of α-aminophosphonate 2 (Table 3, entries 9 and 10). Carrying out the experiment using Cs 2 CO 3 in 1,4-dioxane at 100°C in the presence of a drop of mercury did not significantly change the catalytic outcome, which implies that the cross-coupling reaction does not involve palladium nanoparticles as heterogeneous active species (Table 3, entry 11) [38]. Finally, the control experiment performed in free α-aminophosphonate condition led to the formation of the desired product 8a in only 15% conversion (

Conclusion
We have shown in this work that α-aminophosphonates possessing 1,3,4-oxadiazole moieties are able to coordinate to a palladium(II) ion via their electronically enriched nitrogen atom. For the first time, these ligands associated with a palladium precursor, have been shown to be efficient catalytic systems for the Suzuki-Miyaura cross-coupling between aryl bromides or chlorides and aryl boronic acids. A metal loading of 0.5 mol% could be sufficient for the formation of ortho-di/trisubstituted biphenyls with good conversions. The performances of these catalytic systems are probably due to the presence in the α-aminophosphonates of a hemilabile P(O)(OEt) 2 moiety, able to generate (N ,O)chelate palladium complexes. The formation of such species should increase the steric hindrance and the electronic density of the metal, which promote both the oxidative addition and the reductive elimination/product decoordination elementary steps and in fine accelerate the cross-coupling reaction. Further study is aimed at investigating and exploiting in homogeneous catalysis the hemilability of these specific oxadiazole-containing α-aminophosphonates ligands.

General procedure for the palladiumcatalyzed Suzuki-Miyaura cross-coupling reactions
In a Schlenk tube, in an inert atmosphere, a solution of [Pd(OAc) 2 ] in 1,4-dioxane, a solution of the ligand 1 (ratio Pd/1 = 1/1) in 1,4-dioxane, aryl halide (0.5 mmol), aryl boronic acid (0.75 mmol), Cs 2 CO 3 (0.325 g, 0.75 mmol), decane (0.025 mL, internal reference) and a complementary amount of 1,4-dioxane, so that the total reaction volume was 2.0 mL, were introduced. The reaction mixture was then heated at 100°C. After cooling to room temperature, a small amount (0.5 mL) of the resulting solution was passed through a Millipore filter and analyzed by GC. The structure was solved with SHELXT-2014/5 [79], which revealed the non-hydrogen atoms of the molecule. After anisotropic refinement, all of the hydrogen atoms were found with a Fourier difference map.

X-Ray crystallographic study structure
The structure was refined with SHELXL-2018/3 [80] by the full-matrix least-square techniques (use of

Conflicts of interest
Authors have no conflict of interest to declare.