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Article

A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis

by
Sylwia Ostrowska
1,
Lorenzo Palio
1,
Agnieszka Czapik
2,
Subhrajyoti Bhandary
1,
Marcin Kwit
2,
Kristof Van Hecke
1 and
Steven P. Nolan
1,*
1
Department of Chemistry, Center for Sustainable Chemistry, Ghent University, Krijgslaan 281 (S-3), 9000 Ghent, Belgium
2
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, 61-614 Poznan, Poland
*
Author to whom correspondence should be addressed.
Catalysts 2023, 13(3), 559; https://doi.org/10.3390/catal13030559
Submission received: 14 February 2023 / Revised: 7 March 2023 / Accepted: 8 March 2023 / Published: 10 March 2023
(This article belongs to the Special Issue Theme Issue in Memory to Prof. Jiro Tsuji (1927–2022))
Browse Figures
Review Reports Versions Notes

Abstract

:
Palladacyclic architectures have been shown as versatile motifs in cross-coupling reactions. NHC-ligated palladacycles possessing unique electronic and steric properties have helped to stabilize the catalytically active species and provide additional control over reaction selectivity. Here, we report on a synthetic protocol leading to palladacycle complexes using a mild base and an environmentally desirable solvent, with a focus on complexes bearing backbone-substituted N-heterocyclic carbene ligands. The readily accessible complexes exhibit high catalytic activity in the Buchwald–Hartwig amination. This is achieved using low catalyst loading and mild reaction conditions in a green solvent.

Graphical Abstract

1. Introduction

The use of palladium in cross-coupling reaction catalysis has seen huge growth in the last 50 years since its discovery in the 1970s [1,2,3,4]. Various transition metal complexes are easily prepared from palladium and most of them have shown high catalytic activity compatible with most functional groups [5]. Although monoligated Pd(0) species constitute active catalytic species in cross-coupling reactions [6], such complexes are often unstable in air and difficult to synthesize [7]. The use of Pd(II) precatalysts is in most cases the solution to this problem, requiring an additional activation step from Pd(II) to Pd(0) species that then enters the catalytic cycle. The activation or reduction occurs in situ, can be promoted by reaction conditions, and usually involves a reductive elimination leading to a monoligated Pd(0)-L complex. Several types of Pd(II) precatalysts are nowadays widely used in organic synthesis, among which palladacyclic compounds occupy a prominent position [3,8,9,10,11,12,13,14,15,16,17].
Palladacycles are compounds that have at least one Pd–C bond in their molecular architectures, which are further intramolecularly stabilized by a dative bond between the metal and a built-in donor heteroatom Y (typically Y = N, P, S, or O) yielding a five- or six-membered chelate ring [8]. Since the seminal research of Cope and Siekman in 1965 on the isolation of stable cyclopalladated azobenzenes [18,19] and the subsequent pioneering contributions from Herrmann and Beller that showed the capacity of cyclopalladated ligand 1 (Figure 1) to catalyze the Heck coupling with an unprecedented catalytic activity, (due to easily formed palladium nanoparticles, in this instance), there have been significant developments in the design of new palladacyclic frameworks [20]. Various cyclopalladated ligand systems have been reported that have been successfully used in C–C and C–N cross-couplings [16,17]. However, almost all precatalysts required an exogenous additive or, in some cases, one single catalytic cycle to be activated. Another category of precatalysts that has emerged as a powerful catalytic system is the recently developed Buchwald palladacycles 2–3 (Figure 1) [21]. These are formed from Pd and a hemilabile ligand that subsequently dissociates during the initial catalytic cycle.
The first and second generation (G1 and G2) (Figure 1) precatalysts have shown excellent activity in Suzuki–Miyaura [21,22] and Sonogashira [23] couplings, amination [24], and C–H arylation [25] reactions. For example, with the G2 precatalyst, Suzuki–Miyaura coupling reactions of five-membered 2-heterocyclic boronic acids with (hetero)aryl halides were achieved under extremely mild reaction conditions in a short reaction time [22]. However, these precatalysts still possess some drawbacks. The G1 displays a short lifetime in solution and cannot be activated with a weak base at room temperature, and its preparation involves the handling of unstable organometallic intermediates. For the second generation G2, in addition to being poorly soluble in organic solvents, it is also not stable in solution for extended periods of time, and bulkier phosphines such as BrettPhos, an important ligand in C–N bond formation, tBuXPhos, tBuBrettPhos, and RockPhos could not been incorporated to lead to well-defined and isolable complexes.
Historically, tertiary phosphines have dominated the area as supporting ligands of first-choice [26]. During the past two decades, N-heterocyclic carbenes (NHCs) have seen interest grow exponentially, as ligands in Pd-mediated cross-coupling reactions and the development of well-defined complexes have played vital roles in their now ubiquitous use [1,2,3,5]. The synthesis of such stable, well-defined complexes has been made possible thanks to the high Pd–NHC bond stability that prevents active catalyst decomposition [1,3,27]. In particular, considering the unique higher σ-donating and weaker π-accepting abilities compared to phosphine relatives, NHCs [3,14,27] form stronger metal–ligand bonds. This characteristic of NHCs has been deployed in the formation of new types of palladacycles, coined NHC–C,N-Pdcycles [1,28]. It is worthy of note that NHCs not only endow the Pd center with increased electronic density facilitating the oxidative addition step, but also contribute to the structural stability of active LPd(0) species, rather than the formation of Pd nanoparticles [13,15,29] throughout the catalytic cycle. Therefore, researchers have focused on this interesting field of palladacycles and intensively explored their potential applications [12,30]. Today, many examples of palladacycles exist that show high catalytic activity in Suzuki–Miyaura [31,32,33,34,35,36,37,38,39,40,41,42], Sonogashira [41,42,43], Heck [44,45,46], Buchwald–Hartwig [47,48,49,50] coupling reactions, and carbonylation reactions [51,52,53,54,55].
We have previously reported on the synthesis of amino-palladacycles 4a and 4b (Figure 1) [56] which build on the palladacyclic architecture bearing secondary phosphine ligands (3 in Figure 1) reported by a group at Solvias [57].
The activity of the most efficient IPr-containing palladacycle 4a, was investigated in the Buchwald–Hartwig, α-ketone arylation, reductive dehalogenation, and Suzuki−Miyaura reactions [56,58]. The reactions could be performed at low catalyst loadings (1−0.05 mol%) and under mild conditions (rt to 65 °C). Precatalyst 4a proved to be quite versatile and displayed a wide reaction scope in numerous cross-coupling reactions. In the Buchwald–Hartwig amination, primary and secondary alkyl and aryl amines were coupled in high yields [56]. Similarly, in the α-ketone arylation, aryl and alkyl ketones reacted well [59,60].
In general, the known design strategies for NHC-C, Y-Pdcycles include two synthetic methods. The first makes use of stable precursors of N-heterocyclic carbene ligands, a simple palladium salt and a suitable organic compound as a donor source which, under the influence of a strong base present in the system, lead to the production of the palladacycle. The second method uses palladacycle dimers possessing bridging halides which are cleaved by free N-heterocyclic carbenes, giving a monomeric palladacycle (Figure 2a).
Palladacycles of the latter generations bearing N-heterocyclic carbenes (NHCs) as supporting ligands have not been studied. To our knowledge, no examples of G2-like precatalyst bearing NHCs as ligands are reported in the literature. We now report on such a study dealing with the synthesis of this type of palladacycle via a weak base route using environmentally safe solvents (Figure 2b). Furthermore, their role as precatalysts in the Buchwald–Hartwig aryl amination reaction has been examined.

2. Results and Discussion

2.1. Synthesis of [Pd(NHC)(NH2)(CC)Cl] Palladacycles

Analyzing previous reports on the use of the weak base route in the synthesis of metal complexes of transition metals [60,61,62,63], we began our study by examining the reaction of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr·HCl) with the palladacycle dimer 5 using K2CO3 as a base and acetone as a solvent (Table 1, entry 1). Gratifyingly, the targeted [Pd(IPr)(NH2)(CC)Cl] complex 7 was obtained at a very good yield (91%) after 2 h when the reaction was heated in acetone at 60 °C (Table 1, entry 1). Then, wanting to optimize reaction parameters for the synthesis of 7, we conducted experiments where solvents, bases, and temperatures were modified. As shown in Table 1, after lowering the temperature to 40 °C, the reaction time required to reach full conversion had to be extended to 12 h, and the pure complex was only obtained in an 82% yield (Table 1, entry 2). Next, the effects of the base on the reaction yield was examined. When NEt3 was used, no product was observed, even when reaction times were extended to 24 h (Table 1, entry 3). The use of sodium acetate led to product 7 at a 66% yield after 6 h.
Replacing acetone with toluene, a 52% yield of the product was obtained with reactions being conducted at 40 °C and 60 °C for 18 h (Table 1, entries 5–6). When the system was heated to 80 °C, a 77% efficiency was obtained after 6 h of reaction, while heating the system to 100 °C allowed a 90% yield after 1 h (Table 1, entry 7–8). The use of ethyl acetate as a solvent led to a 71% yield when the reaction was carried out at 40 °C, an 82% yield when the reaction was conducted at 50 °C, and a 75% yield was obtained when the reaction was performed at 60 °C (Table 1, entries 9–11). Ethanol proved to be a totally ineffective solvent, producing a <5% yield after 3 h (Table 1, entry 12); moreover, decomposition of the complex and precipitation of palladium black were observed under these conditions.
With optimal reaction conditions in hand, which coincidentally happen to be the initial conditions examined, an attempt was made to synthesize complexes bearing other NHC ligands. Palladacycles with 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) ligands were synthesized in very good isolated yields of 82% and 95%, respectively, (Figure 3). In both cases, excellent yields and purities were obtained with a simple work-up procedure. Unfortunately, attempts to synthesize a complex bearing the sterically much more demanding 1,3-bis [2,6-bis(diphenylmethyl)-4-methylphenyl] imidazol-2-ylidene (IPr*) ligand proved unsuccessful. Furthermore, [Pd(IPr)(NH2)(CC)Cl] and [Pd(IMes)(NH2)(CC)Cl] complexes were synthesized on a gram-scale with high isolated yields (Figure 3), highlighting the scalability of this simple procedure. It should be noted that when carrying out the reaction to obtain 7 on a gram scale, acetone was used to give complete conversion after 16 h; however, the yield of the pure complex was only 46%, an issue that emerges on larger scale reactions because of the moderate solubility of both the base and the IPr.HCl salt in this solvent. Using toluene instead leads to improved solubility, as well as greatly reduced decomposition and by-product formation. In toluene, the pure product is obtained at a 74% yield.
All synthesized palladium complexes were fully characterized using NMR spectroscopy and elemental analysis. In particular, the disappearance of the imidazolium proton in the 1H NMR spectra and the presence of the carbene carbon signal at ca. 160 ppm in the 13C NMR spectra are clearly indicative of the formation of the complexes of interest. Moreover, crystals of 7 and 8, suitable for X-ray diffraction study on single crystals, were grown with the slow diffusion of pentane into a saturated CH2Cl2 solution of the complexes; the corresponding molecular structures are showed in Figure 4.

2.2. [Pd(NHC)(NH2)(CC)Cl] Palladacycles as Catalysts in the Buchwald–Hartwig Amination Reaction

To test the catalytic activity of the synthesized complexes, we selected the Buchwald–Hartwig amination reaction as a test reaction. The coupling of 4-chloroanisole with morpholine in THF and 2-MeTHF with KOtBu, 1 mol% of 7 at 80 °C was chosen as a model reaction [64]. A very high yield (91%) of the product was achieved after 4 h in 2-MeTHF (Table 2, entries 1–2). The role and identity of the solvent was examined; moving from Me-THF to dioxane does affect the efficiency of the reaction. Indeed, the use of 1,4-dioxane allowed a 98% conversion to be obtained when the reaction was carried out at 80 °C, and 100% when the reaction was carried out at 100 °C (Table 2, entries 3–4).
Searching for a greener solvent allowed us to make use of cyclopentyl methyl ether (CPME). The use of CPME over other commonly employed ether solvents, such as THF, diethyl ether, or 1,4-dioxane, is preferred in view of its stability under acidic and basic conditions; it also does not lead to the formation of peroxides, thereby decreasing risks associated with this reaction [65]. The model reaction in this solvent in the presence of KOtBu gave an excellent conversion after 1 h when the reaction was carried out at 80 °C (Table 2, entries 5–8). Conducting this reaction at a lower temperature, i.e., 60 °C or 70 °C, led to no conversion (Table 2, entries 9–10). The ideal activation temperature appears to be 80 °C, as increasing the temperature does not affect conversion. The use of K2CO3 and Cs2CO3 as weak bases in the reaction did not lead to catalyst activation (Table 2, entries 11, 13), while the use of NaOAc gave only moderate conversion (Table 2, entry 10). The possibility of reducing the catalyst loading was also examined (Table 2, entries 14–18). The reaction proceeds using a 0.5 mol% catalyst loading. The last optimization step examined the activity of palladacycle dimer 5 and palladacycle 8. The starting palladacycle dimer 5 proved inactive in the control experiment and complex 8 yielded an 88% conversion under optimized reaction conditions (Table 2, entries 19–20).
With the optimal reaction conditions in hand (Table 2, entry 14) Buchwald–Hartwig amination reactions were carried out between various (hetero)aryl chlorides and amines in the presence of 0.5 mol% of 7 (Figure 5).
Aryl chlorides were used as effective coupling partners in these reactions. Despite the unreactive nature of the C−Cl bond, these reactions required low catalyst loading and reaction times, ranging from 1 h to a maximum of 4 h. It was interesting to observe that varying the nature of the aryl group substituents had a minimal influence on reaction rates. Sterically hindered aryl chlorides, such as 2-methoxychlorobenzene or 2-methylchlorobenzene, have rates slightly lower than unhindered relatives. We were pleased to find that a large variety of substrates, such as heterocyclic alkylamines, dialkylamines, aryl−alkylamines, and primary amines are all efficient coupling partners. Aryl chlorides bearing electron donating and withdrawing functional groups reacted smoothly with secondary alkyl and arylalkyl amines. A series of secondary amines (aliphatic and aromatic) was also successfully coupled using this methodology. Various anilines, including sterically hindered di-ortho-substituted examples, were well-tolerated and typically produced excellent yields with these as nucleophiles. The only exception found was for the less-active and very bulky derivatives, where lower yields were obtained.
This catalytic system proved less efficient for more challenging coupling partners, such as heteroaryl chlorides and primary amines. Heteroaryl chlorides are known for possible catalyst deactivation and poor solubility that cause significant difficulties in C−N coupling. The use of a long-chain halide turned out to be equally ineffective under these conditions, even after extending the reaction time to 24 h. The comparison of the catalytic activity of known palladacycles in the Buchwald–Hartwig reaction is presented in Table S1.
The mechanism of the Buchwald–Hartwig amination reaction was first described more than 20 years ago [66,67,68]. It is generally assumed to proceed through steps similar to those known for palladium-catalyzed C–C coupling reactions. These steps include oxidative addition of the aryl halide to the Pd (0) groupings, addition of an amine to the oxidative addition complex, deprotonation of the amine, and then reductive elimination. Based on our previous studies [56] and those of the Indolese group [57,69], we propose a mechanism (Figure 6) in which the activation of the palladacyclic catalyst is initiated by the attack of the alkoxide on the palladium, resulting in the formation of palladium alkoxide. Subsequently, this electron-rich palladium type (0), stabilized by the presence of the NHC ligand, enters the catalytic cycle where oxidative addition of aryl halides takes place. The reaction proceeds in the classical manner.
The palladacycle activation step proposed in the mechanism is supported by experiments. Specifically, we performed a reaction in which 1 eq. palladacycle 7 was treated with 1.1 eq. KOtBu in CPME by heating this mixture at 80 °C for 1 h. After completion of the reaction, the 1H NMR spectrum (CDCl3) revealed the formation of a new complex at a 28% yield. Moreover, decomposition compounds of the palladium complex that are difficult to identify were also observed. Due to the overlap of signals relevant to the interpretation of the tert-butyl group, we were unable to determine unequivocally whether the new complex we obtained is the alkoxide form of palladium. We therefore repeated this reaction in deuterated benzene as a solvent to facilitate the spectroscopic analysis.
The 1H NMR spectrum after 5 min of heating revealed the disappearance of a signal from the CH3 groups in KOtBu (1.04 ppm) and the formation of a new signal from the CH3 groups in -OtBu (1.05 ppm), shifted slightly towards a higher field. All other signals characteristic of the starting material had also shifted. For example, the signal for CH(CH3)2 was shifted from 1.43 ppm to 1.48 ppm. We additionally performed a reaction in which 1 eq. palladacycle 7 was reacted with 1 eq. 1-chloro-4-methoxybenzene and 1.1 eq. KOtBu in CPME by heating this mixture at 80 °C for 1 hr. After completion of the reaction, we observed a signal at 11.2 min on the gas chromatogram which suggested the presence of an aminobiphenyl fragment of the palladacycle released under these conditions. This retention time was confirmed by comparison with an authentic sample. These experiments strongly support the “activation” of the Pd(II) precatalyst by an alkoxide base as the key event leading to an in-cycle catalytically active species.

3. Materials and Methods

3.1. Materials

All reactions were performed under N2 unless otherwise mentioned. All solvents and other reagents were purchased from commercial sources (ChemLab (Zedelgem, Belgium), Sigma-Aldrich (Overijse, Belgium), Umicore (Brussels, Belgium)), and used as received without further purification unless otherwise stated. 1H NMR and 13C-{1H} NMR spectra were recorded on Bruker Avance-400 or 300 (Billerica, United States) instruments at 298 K. Chemical shifts (ppm) in 1H and 13C NMR spectra are referenced to the residual solvent peak (CDCl3: δ H = 7.26 ppm, δ C = 77.2 ppm). Coupling constants (J) are given in hertz. Abbreviations used in the designation of the signals are: s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet. All GC analyses were performed on an Agilent 7890 A Gas Chromatograph (Santa Clara, United States) with an FID detector using J&W HP-5 column (30 m, 0.32 mm). Elemental analyses were recorded on elementar Analysensysteme GmbH—vario EL III Element Analyzer, (Langenselbold, Germany).

3.2. Methods

3.2.1. General Procedure for Synthesis of [Pd(NHC)(NH2)(CC)Cl] Complexes (Small Scale)

A 4 mL scintillation vial equipped with a septum cap and a stirring bar was charged with Di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II) (1 eq., 50 or 100 mg scale), NHC⋅HCl (2.1 eq.), K2CO3 (3 eq.), and acetone (1 mL). The reaction mixture was stirred at 60 °C for 1–2 h. The solvent was removed under vacuum and purification of the product was carried out with filtration through a Millipore membrane filter with ethyl acetate (3 mL). Evaporation of the solvent, washing with pentane (3 × 3 mL), and drying under high vacuum afforded the products as microcrystalline powders.

3.2.2. General Procedure for Synthesis of [Pd(NHC)(NH2)(CC)Cl] Complexes (Larger Scale)

A 15 mL scintillation vial equipped with a septum cap and a stirring bar was charged with Di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II) (1.00 g, 1.51 mmol), IPr⋅HCl (1.35 g, 3.17 mmol), K2CO3 (0.626 g, 4.53 mmol), and acetone (3 mL). The reaction mixture was stirred at 60 °C for 16 h. The solvent was removed under vacuum and purification of the product was carried out with filtration through a Millipore membrane filter with ethyl acetate (6 mL). Evaporation of the solvent, washing with pentane (5 × 5 mL), and drying under high vacuum afforded the product 7 as microcrystalline yellow powder (1.71 g, 74%).
A 15 mL scintillation vial equipped with a septum cap and a stirring bar was charged with Di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II) (1.00 g, 1.51 mmol), IMes⋅HCl (1.08 g, 3.17 mmol), K2CO3 (0.626 g, 4.53 mmol), and acetone or toluene (3 mL). The reaction mixture was stirred at 60 °C for 4 h. The solvent was removed under vacuum and purification of the product was carried out with filtration through a Millipore membrane filter with ethyl acetate (6 mL). Evaporation of the solvent, washing with pentane (5 × 5 mL), and drying under high vacuum afforded the product 8 as microcrystalline yellow powder (1.59 g, 81%).

3.2.3. Procedures for the Catalytic Tests Buchwald–Hartwig Reaction

The appropriate amount of palladium complex (0.2–1 mol%), base (1.2 mmol), and a stirring bar were charged into a 4 mL scintillation vial. If the base was sensitive to air and moisture, it was weighed inside a glovebox. Under an argon atmosphere, 4-chloroanisole (1.0 mmol), morpholine (1.2 mmol), and an appropriate degassed solvent (2.0 mL) were added to the vial at room temperature. The reaction mixture was stirred at the indicated temperature for the indicated time. The course of the reaction was monitored with gas chromatography using dodecane as an internal standard.

3.2.4. General Procedure for the Buchwald–Hartwig Reaction

[Pd(IPr)(NH2)(CC)Cl] (0.5 mol%), aryl chloride (1.0 mmol), amine (1.2 mmol) (if the substrate was solid), and a stirring bar were charged into a 4 mL scintillation vial. The vial was charged with KOtBu (1.2 mmol) under inert atmosphere (in the glovebox as a standard procedure), the vial was closed with a cap, and the vial was taken outside of the glovebox. Under argon atmosphere, aryl chloride (1.0 mmol), amine (1.2 mmol) (if the substrate was liquid), and degassed dry cyclopentyl methyl ether (2.0 mL) were added at room temperature and the reaction mixture was stirred at 80 °C for the indicated time. After the indicated time, the crude mixture was purified with filtration through silica gel and the product was isolated by the removal of volatiles under reduced pressure.

4. Conclusions

In summary, a new class of catalysts with a potentially broad spectrum of activity in cross-coupling chemistry has been synthesized and fully characterized. The catalysts consist of a palladacycle scaffold stabilized by the presence of a highly donating, sterically demanding NHC ligand. The catalysts are well-defined, air stable, and very active in the cross-coupling of aryl chlorides with amines. Their synthesis is simple and is achieved by mixing NHC.HCl with a palladacycle and K2CO3 in acetone at 60 °C in air. The proposed mechanism of activation is based on the generation of aryl-alkoxy palladium species. The palladium (0) species formed upon elimination of the ether is stabilized by coordination to an electron-rich, sterically demanding NHC.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal13030559/s1, screening tables, preparation of palladacycles, analytical data palladacycles, biaryls, amino aryls, 1H and 13C NMR spectra, elemental analysis, more detailed materials and methods; Figure S1: Molecular structure of compound 7 and atoms numbering scheme. The hydrogen atoms omitted for clarity. Displacement ellipsoids shown at the 30% probability level; Figure S2: Molecular structure of compound 8 and atoms numbering scheme. The hydrogen atoms omitted for clarity. Displacement ellipsoids shown at the 30% probability level; Table S1: Buchwald-Hartwig amination catalyzed by NHC-Pdcycles; Table S2: Selected crystal data and structure refinement details (7); Table S3: Selected geometric parameters (Å, °) (7); Table S4: Selected crystal data and structure refinement details (8); Table S5: Selected geometric parameters (Å, °) (8) [14,50,56,64,65,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86].

Author Contributions

Conceptualization, S.P.N. and S.O.; methodology, S.O. and L.P.; investigation, S.O. and L.P.; XRD analysis, A.C., S.B., M.K. and K.V.H.; writing—original draft preparation, S.O.; writing—review and editing, S.O. and S.P.N.; supervision, S.P.N.; funding acquisition, S.P.N. All authors have read and agreed to the published version of the manuscript.

Funding

S.O. is grateful for the generous support by the Polish National Agency for Academic Exchange (Bekker Fellowship). S.P., K.V.H. and S.B. acknowledge The Research Foundation—Flanders (FWO) for a research grant (G0A6823N and 1275221N). We are grateful to the SBO (D2M to SPN) and the BOF (starting and senior grants to SPN) as well as the iBOF C3 project for financial support. Umicore is gratefully acknowledged for gift of materials.

Data Availability Statement

All experimental data is contained in the article and Supplementary Materials.

Acknowledgments

The FWO, BOF and the Polish National Academy for Academic Exchange are acknowledged for funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 13 00559 g001 550
Figure 1. Herrmann–Beller precatalyst (1) and Buchwald precatalyst generations G1 (2a), G2 (2b), Solvias precatalyst (3) and Nolan precatalyst (4).
Figure 1. Herrmann–Beller precatalyst (1) and Buchwald precatalyst generations G1 (2a), G2 (2b), Solvias precatalyst (3) and Nolan precatalyst (4).
Catalysts 13 00559 g001
Catalysts 13 00559 g002 550
Figure 2. (a) Design strategies/synthetic routes to NHC–C,N-Pdcycles; (b) Synthesis for NHC-C,N-Pdcycles using the weak base route.
Figure 2. (a) Design strategies/synthetic routes to NHC–C,N-Pdcycles; (b) Synthesis for NHC-C,N-Pdcycles using the weak base route.
Catalysts 13 00559 g002
Catalysts 13 00559 g003 550
Figure 3. Scheme of the synthesis of palladacycle [Pd(NHC)(NH2)(CC)Cl] complexes.
Figure 3. Scheme of the synthesis of palladacycle [Pd(NHC)(NH2)(CC)Cl] complexes.
Catalysts 13 00559 g003
Catalysts 13 00559 g004 550
Figure 4. (Left) X-ray structure of palladacycle 7; selected bond distances (Å) and angles (deg): Pd1-Cl5 2.4146(9), Pd1-N3 2.095(3), Pd1-C1 1.996(3), Pd1 C67 2.004(4), CCDC 2241786; (Right) X-ray structure of palladacycle 8; selected bond distances (Å) and angles (deg): Pd1-Cl1 2.4331 (8), Pd1-C1 2.001 (3), Pd1-N3 2.109 (2), Pd1-C22 1.996 (3), C1-Pd1-N3 173.63 (12), CCDC 2225057. Ellipsoids are drawn at the 30% probability level, and hydrogen atoms have been omitted for clarity.
Figure 4. (Left) X-ray structure of palladacycle 7; selected bond distances (Å) and angles (deg): Pd1-Cl5 2.4146(9), Pd1-N3 2.095(3), Pd1-C1 1.996(3), Pd1 C67 2.004(4), CCDC 2241786; (Right) X-ray structure of palladacycle 8; selected bond distances (Å) and angles (deg): Pd1-Cl1 2.4331 (8), Pd1-C1 2.001 (3), Pd1-N3 2.109 (2), Pd1-C22 1.996 (3), C1-Pd1-N3 173.63 (12), CCDC 2225057. Ellipsoids are drawn at the 30% probability level, and hydrogen atoms have been omitted for clarity.
Catalysts 13 00559 g004
Catalysts 13 00559 g005 550
Figure 5. Scope of the Buchwald–Hartwig amination catalyzed by 7. Reaction conditions: aryl chlorides (1.0 mmol); amine (1.2 mmol); base (1.2 mmol); cat. Pd (7); solvent (2.0 mL); N2; Isolated yield; * GC yield, 24 h.
Figure 5. Scope of the Buchwald–Hartwig amination catalyzed by 7. Reaction conditions: aryl chlorides (1.0 mmol); amine (1.2 mmol); base (1.2 mmol); cat. Pd (7); solvent (2.0 mL); N2; Isolated yield; * GC yield, 24 h.
Catalysts 13 00559 g005
Catalysts 13 00559 g006 550
Figure 6. Mechanistic proposal.
Figure 6. Mechanistic proposal.
Catalysts 13 00559 g006
Table
Table 1. Selected entries for the optimization of reaction conditions leading to palladacycle 7.
Table 1. Selected entries for the optimization of reaction conditions leading to palladacycle 7.
Catalysts 13 00559 i001
EntrySolventBaseT
(°C)		Time
(h)		Conv. a
(%)		Yield a (%)
1AcetoneK2CO3602>9991
2AcetoneK2CO34012>9982
3AcetoneEt3N602400
4AcetoneNaOAc606>9966
5TolueneK2CO34018>9952
6TolueneK2CO36018>9952
7TolueneK2CO3806>9958
8TolueneK2CO31001>9990
9EtOAcK2CO3403>9971
10EtOAcK2CO3503>9982
11EtOAcK2CO3603>9975
12EtOHK2CO3403>993
Reaction condition: Pd dimer = 1eq; (IPr⋅HCl) = 2.1 eq; base = 3 eq; Pd dimer loading = 50 mg; a All conversions and yields were determined by 1H NMR, using 1,3,5-trimethoxybenzene as internal standard.
Table
Table 2. Buchwald–Hartwig amination; selection of optimal conditions.
Table 2. Buchwald–Hartwig amination; selection of optimal conditions.
Catalysts 13 00559 i002
EntryLoading Cat. [mol%]SolventBaseTemp. [°C]Time [h]Conversion
[%] a
11THFKOtBu80483
21Me-THFKOtBu80491
311,4-dioxaneKOtBu80498
411,4-dioxaneKOtBu1004100
51CPMEKOtBu100499
61CPMEKOtBu804100
71CPMEKOtBu802100
81CPMEKOtBu80194
91CPMEKOtBu6024NR
101CPMEKOtBu7024NR
111CPMEK2CO38024NR
121CPMENaOAc80262 (63) b
131CPMECs2CO3802NR
140.5CPMEKOtBu802100
150.5CPMEKOtBu80198
160.2CPMEKOtBu8028 (8) b
170.3CPMEKOtBu80214 (15) b
180.4CPMEKOtBu80233 (54) b
19 c0.5CPMEKOtBu8024NR
20 d0.5CPMEKOtBu80284 (84) b
Reaction conditions: 4-chloroanisole (1.0 mmol); morpholine (1.2 mmol); base (1.2 mmol); cat. Pd (7); solvent (2.0 mL); N2; a GC yield, dodecane as internal standard; b 24 h; c complex 5 was used; d complex 8 was used.
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Ostrowska, S.; Palio, L.; Czapik, A.; Bhandary, S.; Kwit, M.; Van Hecke, K.; Nolan, S.P. A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis. Catalysts 2023, 13, 559. https://doi.org/10.3390/catal13030559

AMA Style

Ostrowska S, Palio L, Czapik A, Bhandary S, Kwit M, Van Hecke K, Nolan SP. A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis. Catalysts. 2023; 13(3):559. https://doi.org/10.3390/catal13030559

Chicago/Turabian Style

Ostrowska, Sylwia, Lorenzo Palio, Agnieszka Czapik, Subhrajyoti Bhandary, Marcin Kwit, Kristof Van Hecke, and Steven P. Nolan. 2023. "A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis" Catalysts 13, no. 3: 559. https://doi.org/10.3390/catal13030559

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