Phosphine-phosphite Ligands Research Articles

Synthesis of P-stereogenic 1-phosphanorbornane-derived phosphine-phosphite ligands and application in asymmetric catalysis.

A convenient synthesis of enantiopure mixed donor phosphine-phosphite ligands has been developed incorporating P-stereogenic phosphanorbornane and axially chiral bisnaphthols into one ligand structure. The ligands were applied in Pd-catalyzed asymmetric allylic substitution of diphenylallyl acetate, Rh-catalyzed asymmetric hydroformylation of styrene and Rh-catalyzed asymmetric hydrogenation of an acetylated dehydroamino ester. Excellent branched selectivity was observed in the hydroformylation although low ee was found. Moderate ee's of up to 60% in allylic substitution and 50% in hydrogenation were obtained using bisnaphthol-derived ligands.

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydrocyanation of Silyl-Substituted 1,3-Diynes.

A regiodivergent nickel-catalyzed hydrocyanation of 1-aryl-4-silyl-1,3-diynes is reported. When appropriate bisphosphine and phosphine-phosphite ligands are applied, the same starting materials can be converted into two different enynyl nitriles with good yields and high regioselectivities. The DFT calculations unveiled that the structural features of different ligands bring divergent alkyne insertion modes, which in turn lead to different regioselectivities. Moreover, the synthetic value of the cyano-containing 1,3-enynes has been demonstrated with several downstream transformations.

Efficient modular phosphorus-containing ligands for stereoselective catalysis

Abstract Over several years, our research team has contributed to ligand design for metal-catalyzed stereoselective transformations. This has been achieved with the synthesis and application to organic transformations of interest of an array of structurally diverse P-containing ligands. These range from highly modular enantiopure phosphine–phosphite ligands to supramolecularly regulated enantioselective phosphorus-based catalysts. Our research in supramolecular interactions has also led to the discovery of an unprecedented halogen-bonded rhodium-catalyst.

Structural Investigations on Enantiopure P–OP Ligands: A High‐Performing P–OP Ligand for Rhodium‐Catalysed Hydrogenations

A second generation of phosphine–phosphite (P–OP) ligands, incorporating a more sterically bulky phosphite group than previous P–OP ligand designs, gave very efficient catalysts for the Rh‐catalysed asymmetric hydrogenation of a diverse array of substrates (11 examples, 93–99 % ee) containing structurally diverse substituents and chelating groups at the C=C double bond. The presence of the sterically bulky (Sa)‐3,3′‐diphenyl‐5,5′,6,6′,7,7′,8,8′‐octahydro‐[1,1′‐binaphthalene]‐2,2′‐diol‐derived phosphite fragment caused significant increases in enantioselectivity (up to Δee = 58 %), and provided improved results compared to those obtained with the first generation of P–OP‐derived rhodium catalysts {i.e., rhodium complexes incorporating phosphine–phosphite ligands with (Ra)‐ and (Sa)‐BINOL‐derived phosphite groups; BINOL = [1,1′‐binaphthalene]‐2,2′‐diol}. Overall, the optimal ligand L8 provided very high enantioselectivities for a range of structurally diverse olefins (up to 99 % ee).

Chiral Phosphine-Phosphite Ligands in Asymmetric Gold Catalysis: Highly Enantioselective Synthesis of Furo[3,4-d]-Tetrahydropyridazine Derivatives through [3+3]-Cycloaddition.

The AuI -catalyzed reaction of 2-(1-alkynyl)-2-alken-1-ones with azomethine imines regio- and diastereoselectively affords furo[3,4-d]tetrahydropyridazines in a tandem cyclization/intermolecular [3+3]-cycloaddition process under mild conditions. By employing a chiral gold catalyst (prepared in situ from a Taddol-derived phosphine-phosphite ligand, Me2 SAuCl, and AgOTf) high yields and enantioselectivities (up to 94 % yield, up to 96 % ee) are obtained. The method provides an efficient modular route to substituted heterotricyclic furan derivatives and can be easily scaled up (using catalyst loads of only 0.15 mol %).

Broad Scope Synthesis of Ester Precursors of Nonfunctionalized Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-Dialkyl-, α,β-Diaryl-, and α-Alkyl-β-aryl-vinyl Esters.

The catalytic asymmetric hydrogenation of trisubstituted enol esters using Rh catalysts bearing chiral phosphine-phosphite ligands (P-OP) has been studied. Substrates covered comprise α,β-dialkyl, α-alkyl-β-aryl, and α,β-diarylvinyl esters, the corresponding hydrogenation products being suitable precursors to prepare synthetically relevant chiral nonfunctionalized alcohols. A comparison of reactivity indicates that it decreases in the order: α,β-dialkyl > α-alkyl-β-aryl > α,β-diaryl. Based on the highly modular structure of P-OP ligands employed, catalyst screening identified highly enantioselective catalysts for α,β-dialkyl (95-99% ee) and nearly all of α-alkyl-β-aryl substrates (92-98% ee), with the exception of α-cyclohexyl-β-phenylvinyl acetate which exhibited a low enantioselectivity (47% ee). Finally, α,β-diarylvinyl substrates showed somewhat lower enantioselectivities (79-92% ee). In addition, some of the catalysts provided a high enantioselectivity in the hydrogenation of E/Z mixtures (ca. Z/E = 75:25) of α,β-dialkylvinyl substrates, while a dramatic decrease on enantioselectivity was observed in the case of α-methyl-β-anisylvinyl acetate (Z/E = 58:42). Complementary deuteration reactions are in accord with a highly enantioselective hydrogenation for both olefin isomers in the case of α,β-dialkylvinyl esters. In contrast, deuteration shows a complex behavior for α-methyl-β-anisylvinyl acetate derived from the participation of the E isomer in the reaction.

The Wender Cedrene Synthesis Revisited: A Catalytic Enantioselective Entry to the Chiral Key Intermediate

The seminal synthesis of the sesquiterpene (±)-α-cedrene reported by Wender in 1981 offers a uniquely short and elegant access to the bridged-tricyclic target compound by exploiting an intramolecular arene-olefin photocycloaddition. However, the synthesis was performed only in the racemic series so far. This synthesis was now re-investigated and the catalytic methods for the enantioselective preparation of the chiral key intermediate were evaluated. It was found that Cu-catalyzed allylic substitution of a cinnamyl chloride with MeMgBr in the presence of a Taddol-derived chiral phosphine-phosphite ligand affords the corresponding (1-methylallyl)arene with high enantioselectivity (94% <i>ee</i>). Hydroboration and subsequent Suzuki coupling gave (<i>R</i>)-curcuphenol methyl ether from which (–)-α-cedrene was prepared along the route paved by Wender.

ChemInform Abstract: Low‐Pressure Cobalt‐Catalyzed Enantioselective Hydrovinylation of Vinylarenes.

An efficient and practical protocol for the enantioselective cobalt-catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L2 CoCl2 ] complexes are employed that are activated in situ with Et2 AlCl. A modular chiral TADDOL-derived phosphine-phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH2 , CN, and CO2 R, are tolerated.

Hydrophosphination of Bicyclo[1.1.0]butane-1-carbonitriles.

Hydrophosphination of bicyclo[1.1.0]butyl nitriles with phosphine boranes and phosphites provided novel cyclobutyl-P derivatives. The reaction generally favors the syn-diastereomer, and the nitrile can be reduced and converted to other functional groups, thus enabling the preparation of bidentate ligands that access new conformational space by virtue of their attachment to the torsionally malleable but sterically restrictive cyclobutane scaffold. The enantioselective hydrogenation of dehydrophenylalanine using a bidentate phosphine-phosphite ligand illustrates the synthetic utility of the newly prepared scaffold.

Features and Application in Asymmetric Catalysis of Chiral Phosphine-Phosphite Ligands.

Chiral phosphine-phosphites are a class of ligands for asymmetric catalysis characterized by two coordinating functionalities with different electronic properties. These ligands also possess a highly modular structure and, due to versatile synthetic processes, they can be tuned precisely in the catalyst optimization process. Research regarding the application of these ligands in several enantioselective catalytic processes has provided outstanding results in a good number of them. These processes include not only Rh catalyzed reactions, such as olefin hydrogenation and hydroformylation, but also other reactions, such as hydrogenation of olefins and imines by Ru complexes, of imines and N-heterocycles by Ir derivatives, allyl alkylation or conjugate addition by Cu catalysts, or hydrocyanation of olefins by Ni ones. Overall, the use of these ligands has led to the preparation of a wide variety of chiral building blocks with high enantiomeric excess. Therefore, phosphine-phosphites have become in an important class of ligands in asymmetric catalysis.

Asymmetric Hydrogenation of Seven‐Membered C=N‐containing Heterocycles and Rationalization of the Enantioselectivity

Iridium(I) complexes with phosphine-phosphite ligands efficiently catalyze the enantioselective hydrogenation of diverse seven-membered C=N-containing heterocyclic compounds (eleven examples; up to 97 % ee). The P-OP ligand L3, which incorporates an ortho-diphenyl substituted octahydrobinol phosphite fragment, provided the highest enantioselectivities in the hydrogenation of most of the heterocyclic compounds studied. The observed stereoselection was rationalized by means of DFT calculations.

Stereoselective Rh-Catalyzed Hydrogenative Desymmetrization of Achiral Substituted 1,4-Dienes.

Highly efficient catalytic stereoselective hydrogenative desymmetrization reactions mediated by rhodium complexes derived from enantiopure phosphine-phosphite (P-OP) ligands are described. The highest performing ligand, which contains a TADDOL-derived phosphite fragment [TADDOL = (2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)], presented excellent catalytic properties for the desymmetrization of a set of achiral 1,4-dienes, providing access to the selective formation of a variety of enantioenriched secondary and tertiary alcohols (six examples, up to 92% ee).

Low-Pressure Cobalt-Catalyzed Enantioselective Hydrovinylation of Vinylarenes.

An efficient and practical protocol for the enantioselective cobalt-catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L2 CoCl2 ] complexes are employed that are activated in situ with Et2 AlCl. A modular chiral TADDOL-derived phosphine-phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH2 , CN, and CO2 R, are tolerated.

Highly Stereoselective Synthesis and Hydrogenation of (Z)-1-Alkyl-2-arylvinyl Acetates: a Wide Scope Procedure for the Preparation of Chiral Homobenzylic Esters

A synthesis of (Z)-1-alkyl-2-arylvinyl acetates 3 with broad scope is reported by using two complementary methods. The first one uses a stereospecific gold-catalyzed addition of acetic acid to 1-iodo-alkynes, followed by a Suzuki coupling. By the second, 1-methyl-2-arylvinyl substrates have been obtained selectively as the Z isomers by O-acylation of enolates of methyl benzyl ketones. In addition, the asymmetric hydrogenation of enol esters 3 has been covered for the first time. Using rhodium catalysts based on chiral phosphine-phosphite ligands (P-OP), highly enantioselective hydrogenations (up to 99% ee) have been achieved for a wide range of substrates. Thus, the synthesis and enantioselective hydrogenation of 3 provides a convenient and versatile procedure for the synthesis of valuable chiral homobenzylic esters.

Modular solid-phase synthesis, catalytic application and efficient recycling of supported phosphine-phosphite ligand libraries.

In spite of decades of research in the field of homogeneous asymmetric catalysis the discovery of new high performance catalysts still relies heavily on trial-and-error. There is still a lack of efficient combinatorial methods which enable the synthesis and screening of vast ligand libraries, especially for bidentate phosphorus ligands. Here we present a highly modular solid-phase synthetic approach which provides facile access to libraries of phosphine-phosphite ligands in quantitative yield requiring only minimal work-up. The obtained library of supported phosphine-phosphites was successfully applied in rhodium catalyzed asymmetric hydrogenation obtaining high enantioselectivities up to 98%. Also, these polymer supported ligands could be successfully recycled under batch conditions exhibiting only a small decline of activity and no loss of selectivity.

Hydrogenative Kinetic Resolution of Vinyl Sulfoxides.

Enantiopure sulfoxides are valuable precursors of organosulfur compounds with broad application in organic and pharmaceutical chemistry. An unprecedented strategy for obtaining highly enantioenriched sulfoxides based on a hydrogenative kinetic resolution using Rh-complexes of phosphine-phosphite ligands as catalysts is reported. After optimization, highly efficient conditions for the kinetic resolution of racemic sulfoxides have been identified. This methodology has been applied to a set of racemic aralkyl or aryl vinyl sulfoxides and allowed the isolation of both recovered and reduced products in excellent yields and enantioselectivities (up to 99% and 97% ee, respectively; 16 examples).

Asymmetric Hydrogenation of 1-Alkyl and 1-Aryl Vinyl Benzoates: A Broad Scope Procedure for the Highly Enantioselective Synthesis of 1-Substituted Ethyl Benzoates

The enantioselective hydrogenation of enol esters of formula CH2═C(OBz)R with rhodium catalysts based on phosphine–phosphite ligands (P–OP) has been studied. The reaction has a broad scope, and it is suitable for the preparation of products possessing a wide variety of R substituents. For the cases where R is a primary alkyl, high catalyst activity (S/C = 500) and enantioselectivities (95–99% ee) were obtained with a catalyst characterized by an ethane backbone and a PPh2 fragment. In contrast, for R = t-Βu, a catalyst possessing a benzene backbone provided the best results (97% ee). Derivatives with a cycloalkyl R substituent were particularly difficult substrates for this reaction. A broader catalyst screening was required for these substrates, which identified a catalyst possessing a P(m-xylyl)2 fragment as the most appropriate one, affording enantioselectivities between 90 and 95% ee. Outstanding enantioselectivities (99% ee) and high catalyst activity (S/C = 500–1000) were also obtained in the case o...

Metallacrown Ether Catalysts Containing Phosphine–Phosphite Polyether Ligands for Rh‐Catalyzed Asymmetric Hydrogenation – Enhancements in Activity and Enantioselectivity

AbstractA new class of tunable metallacrown ether rhodium catalysts based on α,ω‐(phosphine–phosphite) polyether ligands were prepared either by a template‐induced method or by a nontemplate procedure. For the asymmetric hydrogenation of α‐arylenamides with the addition of K+ cations, the ortho‐diphenylphosphine‐substituted metallacrown ether catalyst showed high enantioselectivities (up to 99 % ee), which are comparable to or better than the results obtained for phosphine–phosphite ligands with two or more chiral elements. Remarkable enhancements in enantioselectivity and noticeably increased catalytic activity were achieved through the supramolecular recognition between K+ cations and the metallacrown ether catalyst.

Synthesis and Reactivity of Chiral, Wide‐Bite‐Angle, Hybrid Diphosphorus Ligands

AbstractEffective and modular synthetic approaches toward phosphine–phosphite ligands and phosphine–phosphonite ligands featuring a diphenyl ether backbone have been developed. The phosphine–phosphite ligands are obtained by a two‐step protocol from 2‐bromo‐2′‐methoxydiphenyl ether. The phosphine–phosphonite ligands are prepared in a four‐step synthetic protocol that involves a novel, unsymmetrical diphenyl ether derived phosphine–phosphorusdiamide as key building block. Structural studies on PtII complexes with either phosphine–phosphite or phosphine–phosphonite ligands indicate strict cis coordination for these ligand systems. High‐pressure NMR spectroscopy studies of Rh complexes under syngas indicate the presence of two ea isomers for Rh(H)(CO)2(PP). The existence of this mixture is further supported by high‐pressure IR spectroscopy studies. In order to benchmark the activity and selectivity of these novel, wide‐bite‐angle, mixed‐donor ligands, they were screened in Pd‐catalyzed asymmetric allylic alkylation as well as Rh‐catalyzed hydrogenation and hydroformylation reactions. The ligands give 100 % conversion and low‐to‐moderate enantioselectivity in the allylic alkylation of 1,3‐diphenyl‐2‐propenyl acetate and cyclohexyl‐2‐enyl acetate with dimethyl malonate. In the hydroformylation of styrene, good conversion and regioselectivities are achieved but only moderate enantioselectivity. The ligands give good conversions in asymmetric hydrogenation of typical substrates, with good‐to‐excellent enantioselectivities of up to 97 % depending on the substrate.

ChemInform Abstract: [Ir(P—OP)]‐Catalyzed Asymmetric Hydrogenation of Diversely Substituted C=N‐Containing Heterocycles.

Iridium(I) complexes of enantiomerically pure phosphine-phosphite ligands ([Ir(Cl)(cod)(P-OP)]) efficiently catalyze the enantioselective hydrogenation of diverse C═N-containing heterocyclic compounds (benzoxazines, benzoxazinones, benzothiazinones, and quinoxalinones; 25 examples, up to 99% ee). A substrate-to-catalyst ratio as high as 2000:1 was reached.