Bifunctional Phosphine Research Articles

Phosphine‐Catalyzed Difunctionalization of β‐Fluoroalkyl α,β‐Enones: A Direct Approach to β‐Amino α‐Diazo Carbonyl Compounds

AbstractAn efficient and practical phosphine‐catalyzed vicinal difunctionalization of β‐fluoroalkyl α,β‐enones with TMSN3 has been developed. Using dppb as the catalyst, the reaction worked efficiently to yield various β‐amino α‐diazocarbonyl compounds in high yields (up to 94 %). This work marks the first efficient construction of α‐diazocarbonyl compounds by phosphine catalysis. Meanwhile, the asymmetric variant induced by the nucleophilic bifunctional phosphine P4 led to various chiral fluoroalkylated β‐amino α‐diazocarbonyl compounds in high yields and enantioselectivity. NMR and ESI‐MS studies support the existence of the key reaction intermediates. In contrast, β‐azide carbonyl compounds would be furnished in good yields from β‐fluoroalkylated β,β‐disubstituted enones.

Enantioselective Construction of Bicyclic Pyran and Hydrindane Scaffolds via Intramolecular Rauhut–Currier Reactions Catalyzed by Thiourea-Phosphines

Highly enantioselective intramolecular RC reactions via desymmetrization of cyclohexadienones have been developed. By employing cyclohexadienones with a flexible ether or alkyl group linked internal enone moiety, optically enriched bicyclic pyran and hydrindane skeletons were constructed. Bifunctional phosphine catalysts bearing a thiourea moiety were found to effectively promote the reaction, and preliminary studies suggest that the hydrogen-bonding interaction between thiourea and carbonyl group is crucial and facilitates the otherwise flexible backbones to undergo the desired cyclization.

Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P‐Stereogenic syn‐Phosphiranes from Chiral Epoxides

AbstractNucleophilic substitution results in inversion of configuration at the electrophilic carbon center (SN2) or racemization (SN1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P‐stereogenic syn‐phosphiranes. DFT studies suggested that the novel stereochemistry results from acid‐promoted tosylate dissociation to yield an intermediate phosphenium‐bridged cation, which undergoes syn‐selective cyclization.

Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P‐Stereogenic syn‐Phosphiranes from Chiral Epoxides

Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (SN 2) or racemization (SN 1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P-stereogenic syn-phosphiranes. DFT studies suggested that the novel stereochemistry results from acid-promoted tosylate dissociation to yield an intermediate phosphenium-bridged cation, which undergoes syn-selective cyclization.

Ruthenium complexes with a pyrazole-phosphine ligand

A bifunctional pyrazole-based phosphine ligand was synthesized and applied to preparation of a series of ruthenium complexes. Application of the latter to transfer hydrogenation of acetophenone showed moderate activity. X-ray studies of two ruthenium complexes were carried out.

Designed Bifunctional Phosphine Ligand-Enabled Gold-Catalyzed Isomerizations of Ynamides and Allenamides: Stereoselective and Regioselective Formation of 1-Amido-1,3-dienes.

By using designed biphenyl-2-ylphosphines functionalized with a remote basic groups as ligands, N-alkynyl-o-nosylamides are directly converted to (1E,3E)-1-amido-1,3-dienes with excellent diastereoselectivities under gold catalysis. With allenamides as substrates, the gold-catalyzed isomerizations are high yielding and applicable to a broad substrate scope including various nitrogen protecting groups and exhibit unprecedented (3E)-selectivities for the distal C-C double bond and good regioselectivities. Combining this gold catalysis with one-pot Diels-Alder reactions leads to rapid assembly of valuable bicyclic compounds.

Asymmetric Intermolecular Rauhut−Currier Reaction for the Construction of 3,3‐Disubstituted Oxindoles with Quaternary Stereogenic Centers

AbstractA remote cross Rauhut−Currier reaction utilizing vinyl ketones and para‐quinone methides derived from isatins was realized, which was successfully catalyzed using bifunctional phosphines, furnishing chiral 3,3‐disubstituted oxindoles in excellent enantioselectivities and high yields. The mechanistic studies demonstrated the key role of the alkyl hydrogen of the vinyl ketones, which conceivably interacted with the para‐quinone methide carbonyl group via the hydrogen bond, offering a new insight for the design of novel asymmetric reactions.magnified image

Two- and three-dimensional silver acetylide frameworks with high-nuclearity silver cluster building blocks assembled using a bifunctional (4-ethynylphenyl)diphenyl phosphine ligand

A bifunctional ligand precursor (4-ethynylphenyl)diphenyl phosphine was synthesized and used for constructing silver acetylide frameworks. Its reaction with Ag(I) in the presence of triethylamine afforded silver acetylide [AgL]n, in which L=Ph2P-C6H4-4-CC− could act as a bifunctional ligand bearing both phenylethynide and phosphine binding sites for Ag(I). Reactions of [AgL]n and AgCF3CO2 under different conditions gave four silver acetylides. They are [Ag18L8(CF3COO)6(HCO3)4(DMF)4]n (1, DMF=dimethylformamide), [Ag20L8(CF3COO)12(DMF)6]n (2), [Ag17L6(CF3COO)9(HCO3)2]n (3), and [Ag17L6(CF3COO)9.58(HCO3)1.42]n (4). Crystallographic studies revealed that complex 1 crystallized in the triclinic space group P1¯ with a=14.1252(9)Å, b=18.6012(12)Å, c=25.2137(17)Å, α=108.340(2)°, β=95.386(2)°, γ=95.535(2)°, V=6204.6(7)Å3, and Z=1. Complex 2 crystallized in the monoclinic space group C2/c with a=48.046(4)Å, b=14.1860(10)Å, c=34.943(2)Å, β=98.315(3)°, V=23,566(3)Å3, and Z=4. Complex 3 crystallized in the triclinic space group P1¯ with a=15.5690(7)Å, b=16.7707(8)Å, c=34.0810(16)Å, α=93.4040(10)°, β=100.3690(10)°, γ=94.8250(10)°, V=8697.1(7)Å3, and Z=2. Complex 4 crystallized in the triclinic space group P1¯ with a=15.5396(6)Å, b=16.7595(7)Å, c=34.0225(15)Å, α=93.8140(10)°, β=100.1000(10)°, γ=94.9770(10)°, V=8660.2(6)Å3, and Z=2. The presence of Ag(I)–ethynide, Ag(I)–P and Ag(I)–Ag(I) bonding interactions makes all four silver acetylides to have two- and three-dimensional framework structures with unusual high-nuclearity silver cluster building blocks.

A Reagent-Controlled Phospha-Michael Addition Reaction of Nitroalkenes with Bifunctional N-Heterocyclic Phosphine (NHP)-Thioureas.

Bifunctional N-heterocyclic phosphine (NHP)-thioureas have been successfully applied for phospha-Michael addition reaction of nitroalkenes to afford diversely substituted β-nitrodiazaphosphonates. This transformation takes place at room temperature under catalyst-free conditions and exhibits broad functional group tolerance. The key to success in catalyst, additive-free reaction conditions is the suitable hydrogen-bond activation of the nitro group by a Brønsted acid (thiourea), which artfully combined with the highly nucleophilic NHP motif for a synergetic effect. Importantly, this transformation enables a two-step synthesis of pharmaceutically, biologically significant β-amino phosphonic acids.

Chiral Phosphine‐Catalyzed Enantioselective [3+2] Annulation of Morita–Baylis–Hillman Carbonates with Cyclic 1‐Azadienes: Synthesis of Functionalized Cyclopentenes

AbstractWith the use of a bifunctional chiral phosphine as the catalyst, the asymmetric [3+2] annulation of Morita–Baylis–Hillman carbonates with cyclic 1‐azadienes proceeded smoothly under mild conditions to give various enantiomerically enriched cyclopentene derivatives bearing three consecutive tertiary stereocenters and a sulfamate moiety in moderate to excellent yields with moderate to excellent enantioselectivities and excellent diastereoselectivities.magnified image

Asymmetric Morita-Baylis-Hillman Reaction: Catalyst Development and Mechanistic Insights Based on Mass Spectrometric Back-Reaction Screening.

An efficient protocol for the evaluation of catalysts for the asymmetric Morita-Baylis-Hillman (MBH) reaction was developed. By mass spectrometric back-reaction screening of quasi-enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature-known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate- and enantioselectivity-determining.

ChemInform Abstract: L‐Isoleucine Derived Bifunctional Phosphine Catalyses Asymmetric [3 + 2]‐Annulation of Allenyl‐Esters and ‐Ketones with Ketimines

Abstractaffording a wide range of dihydropyrrolyl spirooxindoles with excellent enantioselectivities

Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations

Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the usefulness of our phosphine catalysts in aza-Morita-Baylis-Hillman (aza-MBH) and MBH reactions. We then showed the great power of amino acid/dipeptide phosphines in a wide range of [3 + 2] annulation processes, including [3 + 2] cycloaddition of allenoates to acrylates/acrylamides, [3 + 2] annulation of imines with allenoates, and [3 + 2] cyclization employing MBH carbonates and activated alkenes. By utilizing α-substituted allenoates and activated alkenes, we developed an enantioselective [4 + 2] annulation to access functionalized cyclohexenes. We also devised a novel enantioselective [4 + 2] annulation process by using α-substituted allenones for the construction of 3,4-dihydropyrans. With the use of β'-acetate allenoate, a [4 + 1] annulation process has been designed to access chiral spiropyrazolones. Another array of reactions that make use of the basicity of zwitterionic phosphonium enolate intermediates have been successfully attained, including the first phosphine-catalyzed asymmetric Michael addition, enantioselective allylic substitution of MBH carbonates by phthalides, and enantioselective γ-additions of prochiral 3-substituted oxindoles, 5H-thiazol-4-ones, 5H-oxazol-4-ones, and oxazol-5-(4H)-ones to 2,3-butadienoates. Bifunctional modes of action in our reported reactions have been supported by experimental results and theoretical studies. With the establishment of the new families of powerful amino acid-derived bifunctional phosphines, the discovery of new modes of phosphine activation, unknown reactions, and more enantioselective processes are well-anticipated.

ChemInform Abstract: Enantioselective [3 + 2] Annulation of α‐Substituted Allenoates with β,γ‐Unsaturated N‐Sulfonylimines Catalyzed by a Bifunctional Dipeptide Phosphine.

The first enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines is described. In the presence of a dipeptide phosphine catalyst, a wide range of highly functionalized cyclopentenes bearing an all-carbon quaternary center were obtained in moderate to good yields and with good to excellent enantioselectivities.

Enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine.

The first enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines is described. In the presence of a dipeptide phosphine catalyst, a wide range of highly functionalized cyclopentenes bearing an all-carbon quaternary center were obtained in moderate to good yields and with good to excellent enantioselectivities.

Effect of Anchimeric Assistance in Addition Reaction of Bifunctional Tertiary Phosphines to Electron-Deficient Alkenes

Effect of Anchimeric Assistance in Addition Reaction of Bifunctional Tertiary Phosphines to Electron-Deficient Alkenes

L-Isoleucine derived bifunctional phosphine catalyses asymmetric [3 + 2]-annulation of allenyl-esters and -ketones with ketimines

l-Isoleucine derived bifunctional N-acylaminophosphine catalyzed a [3 + 2]-annulation reaction between allenyl carbonyl compounds and isatinimines to afford a facile and asymmetric access to 3,2′-dihydropyrrolyl spirooxindoles.

ChemInform Abstract: Highly Enantioselective Construction of Tertiary Thioethers and Alcohols via Phosphine‐Catalyzed Asymmetric γ‐Addition Reactions of 5H‐Thiazol‐4‐ones and 5H‐Oxazol‐4‐ones: Scope and Mechanistic Understandings.

AbstractFor the first time, amino‐acid derived bifunctional phosphines are used as catalysts to synthesize a wide range of substituted thiazolone and oxazolone derivatives.

ChemInform Abstract: Phosphine‐Catalyzed [4 + 2] Cycloaddition of Unsaturated Pyrazolones with Allenoates: A Concise Approach Toward Spiropyrazolones.

A MePPh2-catalyzed [4 + 2] cycloaddition reaction of unsaturated pyrazolones with allenoates was described. The reaction affords the spiropyrazolone derivatives in moderate to excellent yields with moderate to good diastereoselectivities under mild conditions. Using thiourea-based bifunctional phosphines as chiral catalysts, an asymmetric variant of this [4 + 2] cycloaddition reaction has been achieved, giving chiral spiropyrazolone derivatives in moderate to excellent yields with moderate to excellent diastereoselectivities and excellent enantioselectivities (89–95% ee).

ChemInform Abstract: Asymmetric Dual‐Reagent Catalysis: Mannich‐Type Reactions Catalyzed by Ion Pair.

AbstractThis method uses new bifunctional phosphines and methyl acrylate which in situ generate zwitterions serving as catalysts for asymmetric Mannich‐type and aza‐Henry reactions through a homogeneous ion‐pairing mode.