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

<span class="Chemical">Nitrogen-based functionalities such as <class="Chemical">span class="Chemical">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.[10,12−14] Since then, many catalytic systems based on late-transition metals capable of performing the hydroamination reaction under mild conditions have been developed.[2,8−11,15−32] Palladium, as a metal, has attracted much attention for the reaction of alkyl or aryl amines with a large variety of unsaturated substrates (e.g., alkynes,[19,33−38] alkenes,[20,39−47] allenes,[48,49] enynes,[50] and 1,3-dienes[51]).

In 2006, mechanistic studies by Hartwig et al. investigated structure–activity relationships for bidentate <span class="Chemical">phosphine ligands on the nucleophilic attack of <class="Chemical">span class="Chemical">aniline to the metal-activated 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.

Results and Discussion

<span class="Chemical">Palladium complexes [<class="Chemical">span class="Chemical">Pd(AnthraphosPh)Cl] (4, Ph = phenyl) and [Pd(AnthraphosXyl)Cl] (5, Xyl = 3,5-dimethylphenyl) were prepared by following modified reported procedures in the individual steps, as described in Scheme .[52,57,61,62]

Scheme 1

Reagents and Conditions: (a) BuLi, −78 °C, R2PCl (R = Ph or Xyl), THF, 2 h, 80 °C; (b) PdCl2(NCC6H5)2, 2-Methoxyethanol, Reflux, Overnight; (c) AgSbF6, THF/CH3CN, 2 h, r.t.

The two ligand frameworks <span class="Chemical">AnthraphosPh and <class="Chemical">span class="Chemical">AnthraphosXyl were synthesized, starting from commercially available 1,8-dibromoanthracene (1, molecular structure from X-ray diffraction in the Supporting Information).[63,64] The addition of chlorodiphenylphosphine or bis(3,5-dimethylphenyl)chlorophosphine to the lithiated organic backbone 1 in THF led to AnthraphosPh (2) in 87% yield and AnthraphosXyl (3) in 76% yield. A subsequent overnight reaction under reflux conditions of ligands 2 and 3 with bis(benzonitrile)palladium(II) chloride in 2-methoxyethanol led to precatalysts [Pd(AnthraphosPh)Cl] (4, in 80% yield) or [Pd(AnthraphosXyl)Cl] (5, in 75% yield). Finally, the cationic versions of complexes 4 and 5 were obtained by chloride abstraction using silver hexafluoroantimonate in a mixture of THF/CH3CN at r.t. for 2 h, leading to [Pd(AnthraphosPh)CH3CN]SbF6 (6) in 67% yield and [Pd(AnthraphosXyl)CH3CN]SbF6 (7) in 63% yield (Scheme ).

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·class="Chemical">THF and 6·2<class="Chemical">span class="Chemical">THF were obtained by diffusion of n-pentane into their concentrated THF solutions (Figure ). 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 SbF6 anion, and the hydrogen atoms were omitted (Figure ). 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 . 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(AnthraphosPh)Cl] (2.010 (5) Å) reported in the literature[52] and consistent more generally for Caryl–Pd σ-bonds (Figure ).[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)°).

Figure 1

Molecular structure of (a) 1,8-bis-((3,5-dimethylphenyl)phosphino)-9-anthrylpalladium(II) chloride ([Pd-AnthraphosXyl-Cl]) (5) and (b) 1,8-bis-(diphenylphosphino)-9-anthrylpalladium(II) acetonitrile hexafluoroantimonate ([Pd-AnthraphosPh-CH3CN]SbF6) (6). Selected interatomic distances (Å) and angles (°) for 5: C14–Pd1, 2.007 (2); Pd1–P16, 2.2714 (7); Pd1–P1, 2.2818 (7); P16–Pd–P1, 167.08 (2); C15–C2–P1, 111.81 (17); C13–C12–P16, 111.83 (18); C2–P1–Pd1, 102.66 (8); C12–P16–Pd1, 103.05 (8). Selected interatomic distances (Å) and angles (°) for 6: C14–Pd1, 2.0149 (10); Pd1–P16, 2.3035 (3); Pd1–P1, 2.3001 (3); P16–Pd–P1, 164.527 (11).

Molecular structure of (a) 1,8-bis-((3,5-dimethylphenyl)phosphino)-9-anthryl<span class="Chemical">palladium(II) <class="Chemical">span class="Chemical">chloride ([Pd-AnthraphosXyl-Cl]) (5) and (b) 1,8-bis-(diphenylphosphino)-9-anthrylpalladium(II) acetonitrile hexafluoroantimonate ([Pd-AnthraphosPh-CH3CN]SbF6) (6). Selected interatomic distances (Å) and angles (°) for 5: C14–Pd1, 2.007 (2); Pd1–P16, 2.2714 (7); Pd1–P1, 2.2818 (7); P16–Pd–P1, 167.08 (2); C15–C2–P1, 111.81 (17); C13–C12–P16, 111.83 (18); C2–P1–Pd1, 102.66 (8); C12–P16–Pd1, 103.05 (8). Selected interatomic distances (Å) and angles (°) for 6: C14–Pd1, 2.0149 (10); Pd1–P16, 2.3035 (3); Pd1–P1, 2.3001 (3); P16–Pd–P1, 164.527 (11).

The catalytic activity of complexes 4–7 was evaluated for the hydroamination of <span class="Chemical">phenylacetylene (8a) with <class="Chemical">span class="Chemical">aniline (9a) by using 2.8 mol % palladium(II) in THF at 70 °C for 20 h as standard conditions (Figure ). 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.

Figure 2

Hydroamination of phenylacetylene: investigation of the palladium precursors. Yields were determined by GC analysis using tetradecane as an internal standard. Reaction conditions: 8a (1 mmol), 4–7 (2.8 mol %), and 9a (1.3 mmol) in THF (2 mL) at 70 °C for 20 h.

Hydroamination of <span class="Chemical">phenylacetylene: investigation of the <class="Chemical">span class="Chemical">palladium precursors. Yields were determined by GC analysis using tetradecane as an internal standard. Reaction conditions: 8a (1 mmol), 4–7 (2.8 mol %), and 9a (1.3 mmol) in THF (2 mL) at 70 °C for 20 h.

The influence of the reaction conditions was studied for the most promising catalyst 6 (Table ). 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 class="Chemical">toluene or <class="Chemical">span class="Chemical">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 CH3CN; 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.

Table 1

Hydroamination of Phenylacetylene: Investigation of the Palladium Precursors and Variation of the Reaction Conditionsa

entry	cat.	cat. loading	solvent	T (°C)	t (h)	conv. 8a (%)	yield 10a (%)
a	6	1.6 mol %	THF	70	20	100	90
b	6	1.2 mol %	THF	70	20	100	89
c	6	0.6 mol %	THF	70	20	100	89
d	6	0.3 mol %	THF	70	20	100	88
e	6	0.18 mol %	THF	70	20	89	84
f	7	0.18 mol %	THF	70	20	81	66
g	6	0.18 mol %	acetonitrile	70	20	69	55
h	6	0.18 mol %	benzene	70	20	100	86
i	6	0.18 mol %	DCM	70	20	91	73
j	6	0.18 mol %	toluene	70	20	100	80
k	6	0.18 mol %	neat	70	20	100	>99
l	6	0.18 mol %	neat	70	8	100	>99
m	6	0.18 mol %	neat	70	4	>99	95
n	6	0.18 mol %	neat	70	2	98	77
o	6	0.18 mol %	neat	70	1	96	75
p	6	0.18 mol %	neat	50	4	81	81
q	6	0.18 mol %	neat	90	4	100	>99
r	6	0.18 mol %	neat	25	1	25	25
s		no cat.	neat	90	1	0	0

Yields were determined by GC analysis using tetradecane as an internal standard. Reaction conditions: 8a (1 mmol), 6 and 7 (0.18–1.6 mol %), and 9a (1.3 mmol) in solvent (2 mL) at r.t. to 90 °C for 1–20 h.

Yields were determined by GC analysis using <span class="Chemical">tetradecane as an internal standard. Reaction conditions: 8a (1 mmol), 6 and 7 (0.18–1.6 mol %), and 9a (1.3 mmol) in solvent (2 mL) at r.t. to 90 °C for 1–20 h.

Based on the optimized set of reaction conditions (0.18 mol % 6, neat conditions, 90 °C, 4 h), we ex<span class="Chemical">amined the substrate scope of the reaction. These results are summarized in Scheme . In all cases, the Markovnikov product was obtained exclusively. The only exception was the sterically most encumbered <class="Chemical">span class="Chemical">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 para-position still provided high yields (10c, 92%). However, when introducing strong electron-donating (−OMe) or electron-withdrawing (−CF3) groups in the para-position, the yields of the reaction decreased to 75% (10b) and 56% (10d), respectively. Introducing the −CF3 group in the meta-position was found to be less deactivating (10e, 68%). Strong electron-withdrawing 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 ortho-position, 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 2,4,6-trimethylaniline was hydroaminated, providing 10k in high yield (84%).

Scheme 2

Hydroamination of Phenylacetylene: Investigation of the Amines Using Pd Complex 6 as the Catalyst

Yields were determined by GC analysis using tetradecane as an internal standard. The results are given in conversion (left) and yield (right). Reaction conditions: 8a (1 mmol), 6 (0.18 mol %), and 9a–9k (1.3 mmol) at 90 °C for 4 h.

For 8 h of reaction time.

Yields were determined by GC analysis using <span class="Chemical">tetradecane as an internal standard. The results are given in conversion (left) and yield (right). Reaction conditions: 8a (1 mmol), 6 (0.18 mol %), and 9a–9k (1.3 mmol) at 90 °C for 4 h.

Subsequently, various <span class="Chemical">alkynes were tested for their amination with <class="Chemical">span class="Chemical">aniline under the standard set of reaction conditions (Scheme ). Aromatic alkyne derivatives with the electron-withdrawing fluorine substituent 10l and the electron-donating methoxy group 10m in the para-position provided high isolated yields of 79% or 81%, respectively. When the strong electron-withdrawing group (−CF3) 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.

Scheme 3

Intermolecular Hydroamination of Alkynes: Investigation of the Alkynes Using Pd Complex 6 as the Catalyst

Yields were determined by GC analysis using tetradecane as an internal standard. The results are given in conversion (left) and yield (right). Reaction conditions: 8a–8d (1 mmol), 6 (0.18 mol %), and 9a (1.3 mmol) at 90 °C for 4 h.

Yields were determined by GC analysis using <span class="Chemical">tetradecane as an internal standard. The results are given in conversion (left) and yield (right). Reaction conditions: 8a–8d (1 mmol), 6 (0.18 mol %), and 9a (1.3 mmol) at 90 °C for 4 h.

Conclusions

In conclusion, we have reported the synthesis of neutral and cationic <span class="Chemical">palladium(II) complexes bearing the conformationally rigid <class="Chemical">span class="Chemical">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 <span class="Chemical">metal complexes is available in the Supporting Information.

General Procedure for the Hydroamination Reaction

A mixture of <span class="Chemical">Pd(II) catalyst 6 (0.18 mol %), selected <class="Chemical">span class="Chemical">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.