A Team for Accelerating Catalyst and Reaction Developmen

This invited Team Profile was created by the Gessner and Gooßen research groups at Ruhr-University Bochum (Germany). They recently published a series of articles in Angewandte Chemie on the application of ylide-substituted phosphines (YPhos) in palladium-catalyzed coupling reactions. Owing to their inherently strong sigma-donating ability and their modular synthesis, YPhos ligands can be tailored to fit the demands of various catalytic transformations. In the most recent article, machine learning methods were applied to identify a YPhos catalyst that enables the previously elusive Hiyama coupling of aryl chlorides. “Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings”, J. F. Goebel, J. Löffler, Z. Zeng, J. Handelmann, A. Hermann, I. Rodstein, T. Gensch, V. H. Gessner, L. J. Gooßen, Angew. Chem. Int. Ed. 2023, e202216160 ; Angew. Chem. 2023, e202216160 .     

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 Cy₃P⁺−C⁻(R)PCy₂ (with R=Me ( L1 ) or Ph ( L2 )) and Cy₃P⁺−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 β-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.     

A Highly Efficient and Broadly Applicable Cationic Gold Catalyst

Gold catalysts capable of promoting reactions at low‐level loadings under mild conditions are the exception rather than the norm. We examined reactions where the regeneration of cationic gold catalyst (e.g., protodeauration) was the turnover limiting stage. By manipulating electron density on the substituents around phosphorus and introducing steric handles we designed a phosphine ligand that contains two electron‐rich ortho‐biphenyl groups and a cyclohexyl substituent. This ligand formed a gold complex that catalyzed common types of gold‐catalyzed reactions including intra‐ and intermolecular X? H (X=C, N, O) additions to alkynes and cycloisomerizations, with high turnover numbers at room temperature or slightly elevated temperatures (≤50 °C). Our new ligand can be prepared in one step from commercially available starting materials.     

Metal–ligand–Lewis acid multi-cooperative catalysis: a step forward in the Conia-ene reaction

An original multi-cooperative catalytic approach was developed by combining metal–ligand cooperation and Lewis acid activation. The [(SCS)Pd]₂ complex featuring a non-innocent indenediide-based ligand was found to be a very efficient and versatile catalyst for the Conia-ene reaction, when associated with Mg(OTf)₂. The reaction operates at low catalytic loadings under mild conditions with HFIP as a co-solvent. It works with a variety of substrates, including those bearing internal alkynes. It displays complete 5-exo vs. 6-endo regio-selectivity. In addition, except for the highly congested ^tBu-substituent, the reaction occurs with high Z vs. E stereo-selectivity, making it synthetically useful and complementary to known catalysts.

An original multi-cooperative catalytic approach was developed by combining metal–ligand cooperation and Lewis acid activation.     

N2Phos – an easily made,highly effective ligand designed for ppm level Pd-catalyzed Suzuki–Miyaura cross couplings in water

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki–Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000–2500 ppm or 0.10–0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N₂Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand–Pd(0) complex more for N₂Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand–Pd^o complex that is more reactive in oxidative addition to aryl chlorides.

A new, biaryl phosphine-containing ligand, N₂Phos, forms a 1 : 1 complex with Pd resulting in an active catalyst at the ppm level for Suzuki–Miyaura couplings in water, enabled by an aqueous micellar medium. Notably, aryl chlorides are shown to be amenable substrates.     

Dialkylterphenyl Phosphine-Based Palladium Precatalysts for Efficient Aryl Amination of N-Nucleophiles

A series of 2-aminobiphenyl palladacycles supported by dialkylterphenyl phosphines, PR₂Ar′ (R=Me, Et, iPr, Cyp (cyclopentyl), Ar′=Ar^Dipp2, Ar^Xyl2f, Dipp (2,6-C6H3-(2,6-C6H3-(CHMe2)2)2), Xyl=xylyl) have been prepared and structurally characterized. Neutral palladacycles were obtained with less bulky terphenyl phosphines (i.e., Me and Et substituents) whereas the largest phosphines provided cationic palladacycles in which the phosphines adopted a bidentate hemilabile k¹-P,η¹-C_arene coordination mode. The influence of the ligand structure on the catalytic performance of these Pd precatalysts was evaluated in aryl amination reactions. Cationic complexes bearing the phosphines PiPr₂Ar^Xyl2 and PCyp₂Ar^Xyl2 were the most active of the series. These precatalysts have demonstrated a high versatility and efficiency in the coupling of a variety of nitrogen nucleophiles, including secondary amines, alkyl amines, anilines, and indoles, with electronically deactivated and ortho-substituted aryl chlorides at low catalyst loadings (0.25–0.75 mol % Pd) and without excess ligand.     

The precise editing of surface sites on a molecular-like gold catalyst for modulating regioselectivity

It is extremely difficult to precisely edit a surface site on a typical nanoparticle catalyst without changing other parts of the catalyst. This precludes a full understanding of which site primarily determines the catalytic properties. Here, we couple experimental data collection with theoretical analysis to correlate rich structural information relating to atomically precise gold clusters with the catalytic performance for the click reaction of phenylacetylene and benzyl azide. We also identify a specific surface site that is capable of achieving high regioselectivity. We further conduct site-specific editing on a thiolate-protected gold cluster by peeling off two monomeric RS–Au–SR motifs and replacing them with two Ph₂P–CH₂–PPh₂ staples. We demonstrate that the surface Au–Ph₂P–CH₂–PPh₂–Au motifs enable extraordinary regioselectivity for the click reaction of alkyne and azide. The editing strategy for the surface motifs allows us to exploit previously inaccessible individual active sites and elucidate which site can explicitly govern the reaction outcome.

Editing surface motifs on gold cluster catalysts achieves high regioselectivity for the click reactions of azides and alkynes.     

Efficient alkene hydrosilation with bis(8-quinolyl)phosphine (NPN) nickel catalysts. The dominant role of silyl-over hydrido-nickel catalytic intermediates

A cationic nickel complex of the bis(8-quinolyl)(3,5-di-tert-butylphenoxy)phosphine (NPN) ligand, [(NPN)NiCl]⁺, is a precursor to efficient catalysts for the hydrosilation of alkenes with a variety of hydrosilanes under mild conditions and low catalyst loadings. DFT studies reveal the presence of two coupled catalytic cycles based on [(NPN)NiH]⁺ and [(NPN)NiSiR₃]⁺ active species, with the latter being more efficient for producing the product. The preferred silyl-based catalysis is not due to a more facile insertion of alkene into the Ni–Si (vs. Ni–H) bond, but by consistent and efficient conversions of the hydride to the silyl complex.

A cationic nickel complex of the bis(8-quinolyl)(3,5-di-tert-butylphenoxy)phosphine (NPN) ligand, [(NPN)NiCl]⁺, is a precursor to efficient catalysts for the hydrosilation of alkenes with hydrosilanes under mild conditions and low catalyst loadings.     

Monoaurated vs. diaurated intermediates: causality or independence?

Diaurated intermediates of gold-catalysed reactions have been a long-standing subject of debate. Although diaurated complexes were regarded as a drain of active monoaurated intermediates in catalytic cycles, they were also identified as the products of gold–gold cooperation in dual–activation reactions. This study shows investigation of intermediates in water addition to alkynes catalysed by [(IPr)Au(CH₃CN)(BF₄)]. Electrospray ionisation mass spectrometry (ESI-MS) allowed us to detect both monoaurated and diaurated complexes in this reaction. Infrared photodissociation spectra of the trapped complexes show that the structure of the intermediates corresponds to α-gold ketone intermediates protonated or aurated at the oxygen atom. Delayed reactant labelling experiments provided the half life of the intermediates in reaction of 1-phenylpropyne (∼7 min) and the kinetic isotope effects for hydrogen introduction to the carbon atom (KIE ∼ 4–6) and for the protodeauration (KIE ∼ 2). The results suggest that the ESI-MS detected monoaurated and diaurated complexes report on species with a very similar or the same kinetics in solution. Kinetic analysis of the overall reaction showed that the reaction rate is first-order dependent on the concentration of the gold catalyst. Finally, all results are consistent with the reaction mechanism proceeding via monoaurated neutral α-gold ketone intermediates only.

Reaction kinetics and detected α-gold ketone intermediates reveal that gold-mediated hydration of alkynes does not rely on dual activation.     

Iron oxide modified with pyridyl‐triazole ligand for stabilization of gold nanoparticles: An efficient heterogeneous catalyst for A3 coupling reaction in water

Fe₃O₄ nanoparticles were modified with pyridyl‐triazole ligand and the new magnetic solid was applied for the stabilization of very small and uniform gold nanoparticles. The resulting magnetic material, Fe₃O₄@PT@Au, was characterized using various methods. These gold nanoparticles on a magnetic support were applied as an efficient heterogeneous catalyst for the three‐component reaction of amines, aldehydes and alkynes (A³ coupling) in neat water with 0.01 mol% Au loading. Using magnetic separation, this catalyst could be recycled for seven consecutive runs with very small decrease in activity. Characterization of the reused catalyst did not show appreciable structural modification.     

Hyperpositive non-linear effects: enantiodivergence and modelling

The chiral ligand N-methylephedrine (NME) was found to catalyse the addition of dimethylzinc to benzaldehyde in an enantiodivergent way, with a monomeric and a homochiral dimeric complex both catalysing the reaction at a steady state and giving opposite product enantiomers. A change in the sign of the enantiomeric product was thus possible by simply varying the catalyst loading or the ligand ee, giving rise to an enantiodivergent non-linear effect. Simulations using a mathematical model confirmed the possibility of such behaviour and showed that this can lead to situations where a reaction gives racemic products, although the system is composed only of highly enantioselective individual catalysts. Furthermore, depending on the dimer''s degree of participation in the catalytic conversion, enantiodivergence may or may not be observed experimentally, which raises questions about the possibility of enantiodivergence in other monomer/dimer-catalysed systems. Simulations of the reaction kinetics showed that the observed kinetic constant k_obs is highly dependent on user-controlled parameters, such as the catalyst concentration and the ligand ee, and may thus vary in a distinct way from one experimental setup to another. This unusual dependency of k_obs allowed us to confirm that a previously observed U-shaped catalyst order vs. catalyst loading-plot is linked to the simultaneous catalytic activity of both monomeric and dimeric complexes.

An asymmetric reaction consisting of competing monomeric and dimeric catalysts may explain enantiodivergent non-linear effects.     

Encapsulation of N-heterocyclic carbene–gold (I) catalysts within magnetic core/shell silica gels: A reusable alkyne hydration catalyst

In this study, N-heterocyclic carbene–Au(I) complex, chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold (I), was successfully encapsulated within mesopores of a magnetic core/shell (γ-Fe₂O₃@SiO₂) silica gel through post-pore-size reduction by silylation reactions The post-reduction of the pore size not only minimizes the catalyst leaching during the alkyne hydration reactions but also eliminates any need for covalent modification of the catalyst or support surface. The resulting catalyst exhibits high activity in hydration reactions of various alkynes even under low catalytic loadings. The catalyst can be easily recycled from the reaction mixture using a magnet and can be reused in alkyne hydration reactions up to six times with only 52. wt% Au leaching.     

Ethyl‐Zinc(II)‐Cation Equivalents: Synthesis and Hydroamination Catalysis

Ion‐like ethylzinc(II) compounds with weakly coordinating aluminates [Al(OR^F)₄]^? and [(R^FO)₃Al‐F‐Al(OR^F)₃]^? (R^F=C(CF₃)₃) were synthesized in a one‐pot reaction and fully characterized by single‐crystal X‐ray diffraction, NMR and vibrational spectroscopy, and by quantum chemical calculations. The catalytic activity of ion‐like Et‐Zn[Al(OR^F)₄] in intermolecular hydroamination and in the unusual double hydroamination of anilines and alkynes was investigated. Favorable performance was also found in comparison to the Et₂Zn/ [PhNMe₂H]⁺[B(C₆F₅)₄]^? system generated in situ at lower catalyst loadings of 2.5 mol %.     

Catalysis using transition metal complexes featuring main group metal and metalloid compounds as supporting ligands

Recent development in catalytic application of transition metal complexes having an M–E bond (E = main group metal or metalloid element), which is stabilized by a multidentate ligand, is summarized. Main group metal and metalloid supporting ligands furnish unusual electronic and steric environments and molecular functions to transition metals, which are not easily available with standard organic supporting ligands such as phosphines and amines. These characteristics often realize remarkable catalytic activity, unique product selectivity, and new molecular transformations. This perspective demonstrates the promising utility of main group metal and metalloid compounds as a new class of supporting ligands for transition metal catalysts in synthetic chemistry.

Recent development in catalytic application of transition metal complexes having an M–E bond (E = main group metal or metalloid element), which is stabilized by a multidentate ligand, is summarized.     

Oxidative additions of alkynyl/vinyl iodides to gold and gold-catalyzed vinylation reactions triggered by the MeDalphos ligand

The hemilabile Ad₂P(o-C₆H₄)NMe₂ ligand promotes fast, quantitative and irreversible oxidative addition of alkynyl and vinyl iodides to gold. The reaction is general. It works with a broad range of substrates of various electronic bias and steric demand, and proceeds with complete retention of stereochemistry from Z and E vinyl iodides. Both alkynyl and vinyl iodides react faster than aryl iodides. The elementary step is amenable to catalysis. Oxidative addition of vinyl iodides to gold and π-activation of alkenols (and N-alkenyl amines) at gold have been combined to achieve hetero-vinylation reactions. A number of functionalized heterocycles, i.e. tetrahydrofuranes, tetrahydropyranes, oxepanes and pyrrolidines were obtained thereby (24 examples, 87% average yield). Taking advantage of the chemoselectivity for vinyl iodides over aryl iodides, sequential transformations involving first a hetero-vinylation step and then a C–N coupling, a C–C coupling or an heteroarylation were achieved from a vinyl/aryl bis-iodide substrate.

The hemilabile Ad₂P(o-C₆H₄)NMe₂ ligand promotes fast, quantitative and irreversible oxidative addition of alkynyl and vinyl iodides to gold.     

Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with Alkyllithium Reagents

Organolithium compounds are amongst the most important organometallic reagents and frequently used in difficult metallation reactions. However, their direct use in the formation of C−C bonds is less established. Although remarkable advances in the coupling of aryllithium compounds have been achieved, Csp²−Csp³ coupling reactions are very limited. Herein, we report the first general protocol for the coupling or aryl chlorides with alkyllithium reagents. Palladium catalysts based on ylide-substituted phosphines (YPhos) were found to be excellently suited for this transformation giving high selectivities at room temperature with a variety of aryl chlorides without the need for an additional transmetallation reagent. This is demonstrated in gram-scale synthesis including building blocks for materials chemistry and pharmaceutical industry. Furthermore, the direct coupling of aryllithiums as well as Grignard reagents with aryl chlorides was also easily accomplished at room temperature.     

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.     

Comparison of yttrium binaphthylamido alkyl and amide complexes for enantioselective intramolecular hydroamination

A chiral trisamido yttrium complex Y[(R)-C₂₀H₁₂(NC₅H₉)₂][NiPr₂][THF]₂·LiCl coordinated by N-cyclopentyl binaphthylamine ligand has been prepared in situ and characterised by NMR spectroscopy. It has been revealed as an efficient catalyst for intramolecular hydroamination of aminoolefins. Comparison with neutral alkyl, ate alkyl or ate tetraamido complexes coordinated by the same ligand indicated that this complex was the most efficient catalyst of the series for its both activity and enantioselectivity values.     

Selective Transfer Hydrogenation and Hydrogenation of Ketones Using a Defined Monofunctional (P^N(Bn)^N(Bn)^P)–RuII Complex

A defined (P^N^N^P)–Ru complex possessing tertiary amines within the ligand backbone proved to be highly active both in transfer hydrogenations and hydrogenations of a variety of ketones. As compared to the existing catalytic systems, no bifunctional activation of H₂ or of the substrate by the metal center and a secondary amine within the ligand backbone is required to obtain high activities at catalyst loadings of down to 10 ppm.     

On the Edge of the Known: Extremely Electron-Rich (Di)Carboranyl Phosphines

The syntheses of the first B9-connected carboranylphosphines (B9-Phos) featuring two carboranyl moieties as well as access to B9-Phos ligands with bulky electron-donating substituents, previously deemed unattainable, is reported. The electrochemical properties of the B9-Phos ligands were investigated, revealing the ability of the mesityl derivatives to form stabilized phosphoniumyl radical cations. The B9-Phos ligands display an extremely electron-releasing character surpassing that of alkyl phosphines and commonly used N-heterocyclic carbenes. This is demonstrated by their very small Tolman electronic parameters (TEPs) as well as extremely low P−Se coupling constants. Cone angles and buried volumes attest to the high steric demand exerted by the (di)carboranyl phosphines. The dicarboranyl phosphine Au^I complexes show superior catalytic performance in the hydroamination of alkynes compared to the monocarboranyl phosphine analogs.