Hydroamination of Aromatic Alkynes to Imines Catalyzed by Pd(II)–Anthraphos Complexes

Herein, we report the synthesis, characterization, and catalytic performance of cationic Pd(II)–Anthraphos complexes in the intermolecular hydroamination of aromatic alkynes with aromatic amines. The reaction proceeds with 0.18 mol % of catalyst loading, at 90 °C for 4 h under neat conditions. Good to excellent yields could be obtained for a broad range of amines and alkynes.


■ INTRODUCTION
Nitrogen-based functionalities such as amines, enamines, and imines are ubiquitous structural motifs in biologically active molecules, fine chemicals, pharmaceuticals, or the agriculture industry. 1 Accordingly, substantial efforts were allocated to develop synthetic methods capable of introducing these functional groups. Among those protocols, the hydroamination reaction constitutes an (atom-)efficient technology, allowing the direct formation of C−N bonds through the addition of amines to unsaturated C−C bonds. 2−6 It is in 1936 that Kozlov et al. reported the first homogeneously catalyzed hydroamination of alkynes using a mercury catalyst. 7 Although the stability, activity, and carbophilicity plead for mercury, its toxicity was detrimental. Consequently, alternatives have been sought and discovered among early transition metals (i.e., zirconium and titanium) and lanthanides. 8−11 However, because of their high sensitivity toward moisture and air, they showed severe limitations for oxygen-containing substrates. Then, late-transition metals started to attract attention because of their reduced oxophilicity. As expected, they were found to be more tolerant. 10 In 2006, mechanistic studies by Hartwig et al. investigated structure−activity relationships for bidentate phosphine ligands on the nucleophilic attack of aniline to the metalactivated alkene. They concluded that an increase in the bite angle of the phosphine ligand from 102°to 108°enhanced the reaction rate by an order of magnitude. 20 While the two phosphorus donor atoms reside in a cis arrangement for bidentate ligands, pincer-type ligands force them into a trans arrangement. However, to the best of our knowledge, palladium pincer complexes have not been reported for the intermolecular hydroamination of alkynes. A prototypical tridentate example is the Anthraphos ligand, resulting in a large P−Pd−P angle of 166.2 (1)°. 52,53 Moreover, the palladium(II) Anthraphos system has demonstrated high efficiency for a broad range of reactions such as the formation of CC double bonds in allylation, electrophilic substitution, or dehydrogenation reactions. 53−60 However, they have yet to be studied for hydroamination reactions. The present study aims at fulfilling this gap and discloses the synthesis and catalytic activity of palladium(II) complexes supported by Anthraphos ligands. We found that the selected complexes, in their cationic form, were able to catalyze the intermolecular hydroamination of alkynes with primary aromatic amines, forming Markovnikov (imines) products. Good to excellent yields could be obtained for a broad range of amines and alkynes, in favorable cases, with a catalyst loading as low as 0.18 mol %, at 90°C within 4 h under neat conditions.
The formation and structural identity of the molecular complexes were confirmed by spectroscopic methods in solution and by single-crystal X-ray analysis. Solid-state molecular structures of 5 and 6 in single crystals of 5·THF and 6·2THF were obtained by diffusion of n-pentane into their concentrated THF solutions ( Figure 1). The crystallographic data of the compounds are shown in the Supporting Information (see Table S1). 65 The molecular structures of 5 and 6 are shown with thermal ellipsoids drawn at the 60% probability level. For clarity reasons, the solvent molecules (THF), the SbF 6 anion, and the hydrogen atoms were omitted ( Figure 1). As described in Table S1, complexes 5 and 6 crystallize in the triclinic space group P-1. The palladium center in 5 and 6 adopts a square-planar coordination environment with the coplanar Anthraphos ligand in the tridentate coordination mode to the metal center. In the neutral complex 5, the Cl ligand fills the fourth coordination site, while this is occupied with acetonitrile in cationic complex 6, which prevails in the coordination sphere, despite the presence of large excess of THF as a solvent. Selected bond lengths and bond angles are reported in Figure 1. The bond length between the anthracene carbon C14 and the palladium center in 5 (C14−Pd1, 2.007 (2) Å) is consistent with its analogue [Pd(Anthraphos Ph )Cl] (2.010 (5) Å) reported in the literature 52 and consistent more generally for C aryl −Pd σ-bonds ( Figure 1). 52,66 Similar interatomic distances are observed for complex 6. Finally, the molecular structure confirms the expected large P−Pd−P angle for complexes 5 (167.08 (2)°) and 6 (164.527 (11)°).
The catalytic activity of complexes 4−7 was evaluated for the hydroamination of phenylacetylene (8a) with aniline (9a) by using 2.8 mol % palladium(II) in THF at 70°C for 20 h as standard conditions (Figure 2). While the neutral complexes 4 and 5 showed only low activity, the cationic complexes 6 and 7 proved to be highly active and selective with the exclusive formation of the Markovnikov product 10a. Hence, quantitative conversion and 94% yield could be achieved with complex 6, whereas only 2% conversion and 2% yield were obtained with the analogous neutral complex 4. Similar differences were observed for 5 and 7. The aryl substituents at  the phosphorous donor atom had only a minor influence on the reactivity, with somewhat lower yields for the sterically more encumbered cationic complex 7 as compared to 6.
The influence of the reaction conditions was studied for the most promising catalyst 6 ( Table 1). No conversion was observed in the absence of the complex (entry s). Catalyst loading of the leading catalyst 6 was varied in the range of 2.8 to 0.18 mol % (entries a−e). At 0.3 mol % of catalyst loading still, full conversion and high yields (88%, entry d) were achieved; further reducing the catalyst loading to 0.18 mol % decreased both conversion (89%) and yields (84%) only slightly (entry e). Next, different solvents were considered (entries g−k). When the reaction was performed in nonpolar solvents such as toluene or benzene, full conversion and high yields (80% for toluene and 86% for benzene) were obtained (entries h and j). In contrast, polar aprotic solvents such as dichloromethane (DCM) or acetonitrile produced lower yields (e.g., 73% for DCM and 55% for CH 3 CN; entries g and i). 67 This may reflect competing for coordination of the solvents with the substrates, as suggested by the crystallographic analysis. Notably, the best results were obtained under neat conditions with quantitative yields (entry k). Reducing the reaction time (entries k−o) showed that 4 h was sufficient to achieve high conversions (>99%) and high yields (95%). Further reducing the reaction times decreased yields to 77% (2 h) and 75% (1 h). Decreasing the temperature below 70°C (entries p and r) lowered the conversions (e.g., 81% conversion at 50°C and 25% conversion at 25°C). As a result of this systematic variations, the optimum performance of catalyst 6 was achieved when carrying out the reaction with a catalyst loading of only 0.18 mol % under neat conditions at 90°C for 4 h where quantitative yield could be obtained (entry q). This corresponds to a turnover number of 555 and an average turnover frequency of 139 h −1 as the lower limit.
Based on the optimized set of reaction conditions (0.18 mol % 6, neat conditions, 90°C, 4 h), we examined the substrate scope of the reaction. These results are summarized in Scheme 2. In all cases, the Markovnikov product was obtained exclusively. The only exception was the sterically most encumbered 2,6-diisopropylaniline 9j for which 10% of the anti-Markovnikov product was formed as a side product. These findings were confirmed by several methods (GC, GC−MS analysis, and NMR spectroscopy) and are consistent with previous observations. 9,68 The fluorine substituent in the paraposition still provided high yields (10c, 92%). However, when introducing strong electron-donating (−OMe) or electron-

ACS Omega
http://pubs.acs.org/journal/acsodf Article withdrawing (−CF 3 ) groups in the para-position, the yields of the reaction decreased to 75% (10b) and 56% (10d), respectively. Introducing the −CF 3 group in the meta-position was found to be less deactivating (10e, 68%). Strong electronwithdrawing groups such as halides or nitro groups in the ortho-position deactivated the substrates almost completely, and only marginal yields were observed within 4 h of reaction time (24% of 10g, 7% of 10h, and 0% of 10i). Low yields were observed initially also for the methoxy group in the orthoposition, but these results could be improved for 10f (79%) with a prolonged reaction time (8 h) under otherwise identical conditions. In general, electron-donation in the ortho-position was tolerated well despite the increased steric bulk. When ortho-diisopropyl-substituted substrates were tested (10j), high yields (79% Markovnikov and 10% anti-Markovnikov) could be obtained. Even the sterically highly congested 2,4,6trimethylaniline was hydroaminated, providing 10k in high yield (84%).
Subsequently, various alkynes were tested for their amination with aniline under the standard set of reaction conditions (Scheme 3). Aromatic alkyne derivatives with the electron-withdrawing fluorine substituent 10l and the electrondonating methoxy group 10m in the para-position provided high isolated yields of 79% or 81%, respectively. When the strong electron-withdrawing group (−CF 3 ) 10n was introduced in the para-position, a good isolated yield of 52% was obtained. Considerable side reactions such as the dimerization of the alkyne or the hydrolysis of the imine product to the aldehyde were not observed.

■ CONCLUSIONS
In conclusion, we have reported the synthesis of neutral and cationic palladium(II) complexes bearing the conformationally rigid Anthraphos ligand framework. The cationic variants provide good catalytic efficiency in the hydroamination reaction. The best catalytic performance was obtained, with complex 6 giving quantitative yield for the benchmark reaction of phenylacetylene and aniline at a low catalyst loading of 0.18 mol % at 90°C in a short reaction time of 4 h under neat conditions. A broad class of alkynes was selectively converted with primary aromatic amines into valuable imines as the Markovnikov product was formed exclusively in most cases.

■ EXPERIMENTAL SECTION
Synthesis of Ligands and Complexes. A detailed description of the preparation of ligands and metal complexes is available in the Supporting Information.
General Procedure for the Hydroamination Reaction. A mixture of Pd(II) catalyst 6 (0.18 mol %), selected alkyne (1.0 mmol), and selected amine (1.3 mmol) was stirred at 90°C for 4 h. Subsequently, the reaction mixture was cooled down to room temperature and was subjected to gas chromatography with a flame ionization detector. Therefore,  the sample was weighed and dissolved in tetrahydrofuran (1.0 mL), and tetradecane (40 mg, 0.2 mmol) was added as an internal standard. For the isolated yields, the expected compounds were obtained after crystallization from dry methanol.