P,N-Coordinating Ylide-Functionalized Phosphines (NYPhos): A Ligand Platform for the Selective Monoarylation of Small Nucleophiles.

Palladium-catalyzed coupling reactions of small nucleophiles are of great interest, but challenging due to difficulties in selectivity control. Herein, we report the development of a new platform of P,N-ligands consisting of ylide-functionalized phosphines with aminophosphonium groups (NYPhos) to address this challenge. These phosphine ligands are easily accessible in a wide structural diversity with highly modular electronic and steric properties. Based on a family of 14 ligands the selective monoarylation of acetone as well as other challenging ketones and amides was accomplished with record-setting activities even for aryl chlorides at room temperature including late-stage functionalizations of drug molecules. Moreover, ammonia and other small primary amines could be coupled at mild conditions. Isolation and structure analyses of palladium complexes within the catalytic cycle confirmed that the P,N-coordination mode is necessary to achieve the observed selectivities. It also demonstrated the facile adjustability of the N-donor strength, which is beneficial for the targeted design of tailored P,N-ligands for future applications.

Correlation of Experimental and Calculated Reaction Enthalpies with Ligand Donor Strengths.

Ylide-functionalized phosphines (YPhos) have recently proven to be strongly donating ligands that enable high catalyst activities in gold(I)-mediated transformations. We now report on a calorimetric study dealing with the [Au(YPhos)Cl] system and assess YPhos-Au bond dissociation enthalpies (BDE). Comparison with other commonly used phosphines confirmed the high binding strengths of the YPhos ligands. Furthermore, the values of the reaction enthalpies were shown to correlate with the electronic properties of the ligands measured via the Tolman electronic parameter or the calculated molecular electrostatic potential at phosphorus. Notably, the reaction enthalpies can conveniently be derived by computational methods, thus making these easy-to-obtain descriptors for ligand donor property quantification.

Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings.

Palladium-catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α-trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record-setting activities, enabling the elusive coupling of aryl chlorides with α-trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α-aryl alkylnitriles, α-arylcarbonyls and biaryls.

From Stable PH-Ylides to α-Carbanionic Phosphines as Ligands for Zwitterionic Catalysts.

Although ylides are commonly used reagents in organic synthesis, the parent methylphosphine MePH2 only exists in its phosphine form in the condensed phase. Its ylide tautomer H3 P+ -CH2 - is considerably higher in energy. Here, we report on the formation of bis(sulfonyl)methyl-substituted phosphines of the type (RO2 S)2 C(H)-PR2, which form stable PH ylides under ambient conditions, amongst the first examples of an acyclic phosphine which only exists in its PH ylide form. Depending on the exact substitution pattern the phosphines form an equilibrium between the PH ylide and the phosphine form or exist as one of both extremes. These phosphines were found to be ideal starting systems for the facile formation of α-carbanionic phosphines. The carbanion-functionalization leads to a switch from electron-poor to highly electron-rich phosphines with strong donor abilities and high basicities. Thus, the phosphines readily react with different electrophiles exclusively at the phosphorus atom and not at the carbanionic center. Furthermore, the anionic nature of the phosphines allows the formation of zwitterionic complexes as demonstrated by the isolation of a gold(I) complex with a cationic metal center. The cationic gold center allows for catalytic activity in the hydroamination of alkyne without requiring a further activation step.

Single-Site and Cooperative Bond Activation Reactions with Ylide-Functionalized Tetrylenes: A Computational Study.

Due to their transition metal-like behavior divalent group 14 compounds bear huge potential for their application in bond activation reactions and catalysis. Here we report on detailed computational studies on the use of ylide-substituted tetrylenes in the activation of dihydrogen and phenol. A series of acyclic and cyclic ylidyltetrylenes featuring various α-substituents with different σ- and π-donating capabilities have been investigated which demonstrate that particularly π-accepting boryl groups lead to beneficial properties and low barriers for single-site activation reactions, above all in the case of silylenes. In contrast, for the thermodynamically more stable germylenes and stannylenes an alternative mechanism involving the active participation of the ylide ligand in the E-H bond (E=H or PhO) activation process by addition across the element carbon linkage was found to be energetically favored. Furthermore, the boryl substituted tetrylenes allowed for a further activation pathway involving the active participation of the boron element bond. These cooperative mechanisms are especially attractive for the heavier cyclic ylidyltetrylenes in which the loss of the protonated ylide group is prevented due to the cyclic framework. Overall, the present studies suggest that cyclic ylide-substituted germylenes and stannylenes bear huge potential for cooperative bond activations at mild conditions which should be experimentally addressed in the future.

Au⋠⋠⋠H-C Hydrogen Bonds as Design Principle in Gold(I) Catalysis.

Secondary ligand-metal interactions are decisive in many catalytic transformations. While arene-gold interactions have repeatedly been reported as critical structural feature in many high-performance gold catalysts, we herein report that these interactions can also be replaced by Au⋅⋅⋅H-C hydrogen bonds without suffering any reduction in catalytic performance. Systematic experimental and computational studies on a series of ylide-substituted phosphines featuring either a PPh3 (Ph YPhos) or PCy3 (Cy YPhos) moiety showed that the arene-gold interaction in the aryl-substituted compounds is efficiently compensated by the formation of Au⋅⋅⋅H-C hydrogen bonds. The strongest interaction is found with the C-H moiety next to the onium center, which due to the polarization results in remarkably strong interactions with the shortest Au⋅⋅⋅H-C hydrogen bonds reported to date. Calorimetric studies on the formation of the gold complexes further confirmed that the Ph YPhos and Cy YPhos ligands form similarly stable complexes. Consequently, both ligands showed the same catalytic performance in the hydroamination, hydrophenoxylation and hydrocarboxylation of alkynes, thus demonstrating that Au⋅⋅⋅H-C hydrogen bonds are equally suited for the generation of highly effective gold catalysts than gold-arene interactions. The generality of this observation was confirmed by a comparative study between a biaryl phosphine ligand and its cyclohexyl-substituted derivative, which again showed identical catalytic performance. These observations clearly support Au⋅⋅⋅H-C hydrogen bonds as fundamental secondary interactions in gold catalysts, thus further increasing the number of design elements that can be used for future catalyst construction.

Palladium Complexes Based on Ylide-Functionalized Phosphines (YPhos): Broadly Applicable High-Performance Precatalysts for the Amination of Aryl Halides at Room Temperature.

Palladium allyl, cinnamyl, and indenyl complexes with the ylide-substituted phosphines Cy3 P+ -C- (R)PCy2 (with R=Me (L1) or Ph (L2)) and Cy3 P+ -C- (Me)PtBu2 (L3) were prepared and applied as defined precatalysts in C-N coupling reactions. The complexes are highly active in the amination of 4-chlorotoluene with a series of different amines. Higher yields were observed with the precatalysts in comparison to the in situ generated catalysts. Changes in the ligand structures allowed for improved selectivities by shutting down ß-hydride elimination or diarylation reactions. Particularly, the complexes based on L2 (joYPhos) revealed to be universal precatalysts for various amines and aryl halides. Full conversions to the desired products are reached mostly within 1 h reaction time at room temperature, thus making L2 to one of the most efficient ligands in C-N coupling reactions. The applicability of the catalysts was demonstrated for aryl chlorides, bromides and iodides together with primary and secondary aryl and alkyl amines, including gram-scale applications also with low catalyst loadings of down to 0.05 mol %. Kinetic studies further demonstrated the outstanding activity of the precatalysts with TOF over 10.000 h-1 .

Phosphinoyl-Substituted Ketenyl Anions: Synthesis and Substituent Effects on the Structural Properties.

Ketenyl anions are versatile intermediates in synthetic chemistry and have recently become accessible as isolable reagents from metalated ylides by exchange of the phosphine with CO. Herein, we report on a systematic study of substituent effects on the structure and bonding situation in ketenyl anions. A series of phosphinoyl-substituted ketenyl anions {[R2P(X)CCO]- with X = O, NTol, S, Se} were prepared by carbonylation of the corresponding yldiides and isolated as their corresponding potassium salts. NMR and IR spectroscopic analyses together with computational studies demonstrate that the more electron-withdrawing oxo- and iminophosphinoyl substituents increase the s-character in the bond to the ketene moiety and hence the ynolate character of the anion. This trend is particularly seen in solution, whereas the solid-state properties are influenced by packing effects affecting the bonding situation.

From a Fluorenyl Substituted Ylide-Functionalized Phosphine to a Neutral Phosphide via P-C Bond Cleavage.

Bulky ylide-substituted phosphines have recently found application as potent ligands in homogeneous catalysis. The attempted synthesis of the ylide-substituted fluorenylphosphine YPh P(Cy)Flu [YPh =Cy3 P(Ph)C; Flu=9-methylfluorenyl] now resulted in the unexpected elimination of 9-methylenefluorene during the deprotonation step of the intermediary α-phosphino phosphonium salt to yield the secondary ylide-substituted phosphine YPh P(Cy)H. This phosphine underwent formal H2 elimination under basic conditions to form a cyclic phosphonium ylide with a P-C-P-C four-membered ring via deprotonation of one cyclohexyl group of the PCy3 moiety. Upon coordination to transition metals the secondary ylidylphosphine forms a neutral phosphide ligand by shift of the proton into the ylide-backbone and formation of zwitterionic metal complexes.

Formation of exceptional monomeric YPhos-PdCl2 complexes with high activities in coupling reactions.

The use of well-defined palladium(ii) complexes as precatalysts for C-X cross-coupling reactions has improved the use of palladium catalysts in organic synthesis including large-scale processes. Whereas sophisticated Pd(ii) precursors have been developed in the past years to facilitate catalyst activation as well as the handling of systems with more advanced monophosphine ligands, we herein report that simple PdCl2 complexes function as efficient precatalysts for ylide-substituted phosphines (YPhos). These complexes are readily synthesized from PdCl2 sources and form unprecedented monomeric PdCl2 complexes without the need for any additional coligand. Instead, these structures are stabilized through a unique bonding motif, in which the YPhos ligands bind to the metal through the adjacent phosphine and ylidic carbon site. DFT calculations showed that these bonds are both dative interactions with the stronger interaction originating from the electron-rich phosphine donor. This bonding mode leads to a remarkable stability even towards air and moisture. Nonetheless, the complexes readily form monoligated LPd(0) complexes and thus the active palladium(0) species in coupling reactions. Accordingly, the YPhos-PdCl2 complexes serve as highly efficient precatalysts for a series of C-C and C-X coupling reactions. Despite their simplicity they can compete with the efficiency of more complex and less stable precatalysts.

Ylide-Substituted Phosphines with a Cyclic Ylide-Backbone: Angle Dependence of the Donor Strength.

Ylide-substituted phosphines (YPhos) have been shown to be highly electron-rich and efficient ligands in a variety of palladium catalyzed transformations. Here, the synthesis and characterization of novel YPhos ligands containing a cyclic backbone architecture are reported. The ligands are easily synthesized from a cyclic phosphonium salt and the chlorophosphines Cy2PCl (L1) and Cy(FluMe)PCl (L2, with FluMe = 9-methylfluorenyl) and were characterized in both solution and solid states. The smaller PCy2-substituted ligand, L1, readily formed the biscoordinate L1 2 Pd species when treated with Pd2(dba)3 and showed no activity in palladium-catalyzed amination reactions even when applied as defined palladium(II) η3-allyl, t-Bu-indenyl, or cinnamyl precursors. Bulkier fluorenyl-substituted ligand L2 similarly was inactive, despite its ability to form the stable monophosphine complex L2·Pd(dba). Assessment of the electronic properties by experimental and computational methods revealed that L1 and L2 are considerably less electron-rich than previously synthesized YPhos ligands. This was shown to be the result of the small P-C-S bond angle, which is sterically enforced due to the cyclic nature of the backbone. Density functional theory calculations revealed that the small angle results in an increased s-character of the lone pair at the ylidic carbon atom and leads to a polarization of the C-P bond toward the carbon atom, thus decreasing the electron density at the phosphorus atom. The results demonstrate the tunability of the donor strength of YPhos ligands by modification of the ligand backbone beyond simple changes of the substitution pattern and are thus important for future ligand design, with a careful balance of many factors to be considered to achieve catalytic activity.