Palladium Catalyzed Amination of Aryl Chlorides

Development of Extremely Active Phosphine Ligands with Large Substrate Scopes

  • ig. 1: Selection of important phosphine ligands used in palladium catalyzed C-N cross-coupling reactions.ig. 1: Selection of important phosphine ligands used in palladium catalyzed C-N cross-coupling reactions.
  • ig. 1: Selection of important phosphine ligands used in palladium catalyzed C-N cross-coupling reactions.
  • Fig. 2: (left) Design principle of ylide-substituted phosphines and (right) YPhos ligand L1 used in C-N cross-coupling reactions and molecular structure of complex L1∙ Pd(dba).
  • Fig. 3: Results of the coupling of different aryl chlorides with a series of amines using YPhos ligand L1.

Arylamines are important building blocks in many pharmaceuticals, natural products, agrochemicals and organic materials. In recent years, the palladium catalyzed C-N cross-coupling reaction (Buchwald-Hartwig amination) has become one of the most important synthetic method for their preparation. This development is mainly due to the improvements in the activity of the catalysts, which led to continuous improvements of the synthetic protocols.

The activity, productivity and scope of a homogenous catalyst is crucially influenced by the employed ligand bound to the metal center. Thus, the design and further development of new ligands and defined pre-catalysts (i.e. pre-formed metal complexes of these ligands) has become key step for the improvement of the catalyst properties. This allowed the establishment of general, broadly applicable and reliable synthetic protocolls as well as the realization of processes under relatively mild reaction conditions [1,2].

Development of phosphine ligands in homogenous catalysis

Although N-heterocyclic carbenes have found increasing attention in recent years also as ligands in homogenous catalysis including amination reactions [3], phosphines remain the most important class of ligands in academic research as well as industrial processes. Starting with the first systematic studies in the 1990s by Buchwald and Hartwig with P(o-Tol)3 (o-Tol = ortho-tolyl) as ligand, the continuous further development of phosphines repeatedly led to higher activities and productivities of the C-N coupling catalysts as well as a broader substrate scope, lower reaction temperatures and the possible use of milder bases [4]. While the second generation of phosphines used in aminations particularly included bidentate ligands such as BINAP or dppf (Fig. 1) [5], subsequent research endeavors focused on monodentate, sterically encumbering and electron-rich tri- or dialkyl phosphines, above all ligands with cyclohexyl (Cy), tert-butyl (tBu) or adamantyl (Ad) groups [6]. Mechanistic studies revealed that especially these types of ligands can promote high activities by stabilizing low coordinate palladium species.

Prominent examples for such monophosphines are Beller’s CataCXium A [7], Stradiotto’s DalPhos ligands [8], or Buchwald’s biarylphosphines [9]. Figure 1 gives an overview over important phosphine ligands applied in many amination reactions.

Ylide-substituted phosphines (YPhos ligands)

Since two decades, the development of new phosphine ligands remains a highly active field of research. Nonetheless, despite the myriad of ligands which are reported each year, only few systems reach activities comparable to those of established ligand systems. However, further improvements are still desirable to reach higher activities and productivities for a broader substrate scope under milder reaction conditions. The latter still often represents a challenge in coupling reactions, particularly in case of the coupling of difficult substrates such as aryl chlorides, which usually require elevated reaction temperatures. This can be especially problematic for the synthesis of complex, sensitive molecules, which are often part of pharmaceutically active compounds.

Recently, we reported on a novel class of monodentate ligands, the ylide-substituted phosphines (YPhos, Fig. 2, left) [10]. These phosphines exhibit an ylide moiety which is directly bound to the phosphorus centre. This design leads to a considerable increase of the electron-density at the phosphorus atom compared to commonly applied phosphine ligands. Variation of the substituent Z in the ylide backbone as well as the R’ groups at phosphorus allows for a fine-tuning of the donor properties of the phosphine, thus also giving way to donor strength comparable to those of N-heterocyclic carbenes. Given these electronic properties and the large steric demand, these phosphines seemed to be ideal candidates for palladium catalyzed amination reactions including the more challenging aryl chlorides.

Catalytic application and comparison of the catalyst activity

In collaboration with the group of Prof. Dr. Lukas Gooßen at the Ruhr-University Bochum we could now proof this hypothesis [11]. While first catalytic applications with triphenyl phosphonium substituted YPhos ligands failed due to competing decomposition reactions. Simple introduction of the tricyclohexyl phosphonium moiety in ligand L1 at once led to remarkably high activities (Fig. 2). In a facile synthetic protocol using L1 with the commonly employed palladium sources Pd2(dba)3 and Pd(OAc)2, full conversions of the coupling of 4-chlorotoluene with N-methylaniline were observed within only one hour reaction time at room temperature with only 0.5 mol% catalyst loading. No tedious optimizations of the reaction conditions or the ligand design or the formation of defined pre-catalysts was found to be necessary.

A comparison of the catalytic activity with established phosphine ligands also demonstrated that the YPhos ligand can compete or even surpass the activity of the ligands which were optimized over several years. This high activity of L1 can be explained by the high donor strength of the YPhos ligand, but also by its unique architecture. The molecular structure of the isolated palladium complex with L1 and dba as ligands (Fig. 2, right) indicated a weak agostic interaction which supports the stabilization of low-coordinate palladium species within the catalytic cycle. It is also noteworthy, that the used YPhos ligand is easily prepared also in multi-gram scale. As such, L1 can be synthesized in only two reaction steps from commercially available starting materials.

Substrate Scope

Figure 3 gives an overview over the results of the amination of different aryl chlorides with a series of amines using L1 under the optimized reaction conditions (0.5 mol% L1, 0.25 mol% Pd2(dba)3, 1.5 equiv. KOtBu, rt, 1 h). At first, the impact of different aryl chlorides on the catalyst activity was studied. Fortunately, substrates with electron-donating as well as electron-withdrawing groups were both quantitatively consumed and the products could be isolated in high yields. This also holds true for hetero aromatics and sterically demanding compounds, albeit these substrates required somewhat longer reaction times. High isolated yields were also obtained with a variety of different amines. Substrates, like piperidine or morpholine, which have often been studied with other catalysts, revealed to be easy targets and were quantitatively coupled at room temperature. Even the coupling of bulky substrates such as to the arylamines 3ea, 3ej or 3ha could be realized with L1 at room temperature. With the established ligand systems available so far elevated reaction temperatures were required to successfully synthesize these compounds.

 

Summary

The results described in this article impressively demonstrate the huge potential of ylide-substituted phosphines in palladium catalyzed C-N coupling reactions of aryl chlorides with amines at room temperature. The instantanously reached activities under mild reaction conditions with a wide variety of different substrates underlines the applicability and capability of this class of ligands. On-going research activities are now focussing on further expanding the use of L1 in other homogenous catalytic transformations as well as on the commercialization of the YPhos ligands to also allow for their use in large-scale processes in industry.

Acknowledgement
Together with Umicore, the groups of Gessner and Gooßen work on the development of the described technology in order to bring it to market.

 

Author:
Viktoria H. Gessner

Contact
Prof. Dr. Viktoria H. Gessner
Inorganic Chemistry II
Ruhr-University Bochum
Bochum, Germany
viktoria.gessner@rub.de

 

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References:

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