Nickel/Brønsted acid dual-catalyzed regio- and enantioselective hydrophosphinylation of 1,3-dienes: access to chiral allylic phosphine oxides

While chiral allylic organophosphorus compounds are widely utilized in asymmetric catalysis and for accessing bioactive molecules, their synthetic methods are still very limited. We report the development of asymmetric nickel/Brønsted acid dual-catalyzed hydrophosphinylation of 1,3-dienes with phosphine oxides. This reaction is characterized by an inexpensive chiral catalyst, broad substrate scope, and high regio- and enantioselectivity. This study allows the construction of chiral allylic phosphine oxides in a highly economic and efficient manner. Preliminary mechanistic investigations suggest that the 1,3-diene insertion into the chiral Ni–H species is a highly regioselective process and the formation of the chiral C–P bond is an irreversible step.

Asymmetric hydrophosphinylation of 1,3-dienes with phosphine oxides using an inexpensive chiral catalyst has been demonstrated, providing access to chiral allylic phosphine oxides with broad substrate scope and high regio- and enantioselectivity.     

Ni-catalyzed asymmetric hydrophosphinylation of conjugated enynes and mechanistic studies

The catalytic asymmetric synthesis of P-stereogenic phosphines is an efficient strategy to access structurally diverse chiral phosphines that could serve as organocatalysts and ligands to transition metals and motifs of antiviral drugs. Herein, we describe a Ni catalyzed highly regio and enantioselective hydrophosphinylation reaction of secondary phosphine oxides and enynes. This method afforded a plethora of alkenyl phosphine oxides which could serve as valuable precursors to bidentate ligands. A new type of mechanism was discovered by combined kinetic studies and density functional theory (DFT) calculations, which was opposed to the widely accepted Chalk–Harrod type mechanism. Notably, the alkene moiety which could serve as a directing group by coordinating with the Ni catalyst in the transition state, plays a vital role in determining the reactivity, regio and enantioselectivity.

A Ni-catalyzed hydrophosphinylation reaction of enynes was reported with excellent regio and enantioselectivity. A protonation mechanism was uncovered by combined kinetic studies and DFT calculations, which may lead to the discovery of other hydrofunctionalization reactions.     

Enantioselective preparation of P-chiral phosphine oxides

A highly efficient chiral auxiliary-based strategy for the asymmetric synthesis of P-chiral phosphine oxides in >98:2 er has been developed. The methodology involves the highly stereoselective formation of P-chiral oxazolidinones that then undergo displacement with a variety of Grignard reagents to prepare the desired phosphine oxides.     

Probing the steric limits of rhodium catalyzed hydrophosphinylation. P-H addition vs. dimerization/oligomerization/polymerization

The reactivity of secondary phosphine oxides containing bulky organic fragments in hydrophosphinylation reactions has been investigated using several rhodium based catalysts. Upon heating in a focused microwave reactor, HP(O)(2-C₆H₄Me)₂ adds to prototypical terminal alkynes affording a complex mixture containing 1,2 and 1,1-addition products. Addition of a second ortho-substituent (HP(O)Mes₂) completely suppresses the hydrophosphinylation reaction for alkyl and aryl substituted alkynes. Variations in the temperature, catalyst loading, solvent, and microwave power were unable to induce an addition reaction in the case of HP(O)Mes₂. While this secondary phosphine oxide did not participate in the hydrophosphinylation reaction, it promoted the polymerization of phenylacetylene. HP(O)R₂ substrates are not commonly thought of as innocent ligands for rhodium complexes in reactions involving alkynes due to facile hydrophosphinylation. While this is certainly true for diphenylphosphine oxide, the chemistry presented herein suggests that HP(O)Mes₂ and related bulky secondary phosphine oxides have great potential as valuable ligands for rhodium catalyzed transformations involving alkynes due to their lack of reactivity towards the addition reaction.     

Reduction of phosphine oxides to phosphines with the InBr3/TMDS system

An efficient method for the reduction of phosphine oxide derivatives into their corresponding phosphines is described. The system InBr₃/TMDS allows the reduction of different secondary and tertiary phosphine oxides as well as aliphatic and aromatic phosphine oxides.     

Air-stable P-stereogenic secondary phosphine oxides as chiral monodentate ligands for asymmetric catalytic carboncarbon bond formation

P-Stereogenic secondary phosphine oxides are configurationally stable in the presence of metal ions both in solution and in the solid state. They have the potential to serve as chiral monodentate phosphorus ligands for asymmetric catalysis. In the asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate, ca. 80% ee was achieved using (R_p)-tert-butylphenylphosphine oxide.     

Stereoselective Synthesis and Resolution of P-Chiral Phosphine Chalcogenides.

Abstract

New synthetic methods and resolution procedures securing ready access to the resolved P-chiral phosphinoylethenes, phosphinoylacetates and secondary phosphine oxides of diversified structures have been developed. The methods are based on processes employing stereoselective nucleophilic displacement at phosphorus, asymmetric deprotonation, immolative vinyl and chirality transfer from sulfur to phosphorus, chemical and enzymatic kinetic resolution, resolution via covalent diastereoisomers, as well as direct resolution of racemates by classical resolving agents and by chromatography on chiral stationary phases.     

Copper-Catalyzed Dynamic Kinetic Asymmetric P−C Coupling of Secondary Phosphine Oxides and Aryl Iodides

Transition-metal-catalyzed enantioselective P−C cross-coupling of secondary phosphine oxides (SPOs) is an attractive method for synthesizing P-stereogenic phosphorus compounds, but the development of such a dynamic kinetic asymmetric process remains a considerable challenge. Here we report an unprecedented highly enantioselective dynamic kinetic intermolecular P−C coupling of SPOs and aryl iodides catalyzed by copper complexes ligated by a finely modified chiral 1,2-diamine ligand. The reaction tolerates a wide range of SPOs and aryl iodides, affording P-stereogenic tertiary phosphine oxides (TPOs) in high yields and with good enantioselectivity (average 89.2 % ee). The resulting enantioenriched TPOs were transformed into structurally diverse P-chiral scaffolds, which are highly valuable as ligands and catalysts in asymmetric synthesis.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Stereospecific Synthesis of α‐ and β‐Hydroxyalkyl P‐Stereogenic Phosphine–Boranes and Functionalized Derivatives: Evidence of the PO Activation in the BH3‐Mediated Reduction

Access to hydroxy‐functionalized P‐chiral phosphine–boranes has become an important field in the synthesis of P‐stereogenic compounds used as ligands in asymmetric catalysis. A family of optically pure α and β‐hydroxyalkyl tertiary phosphine–boranes has been prepared by using a three‐step procedure from readily accessible enantiopure adamantylphosphinate, obtained by semi‐preparative HPLC on multigram scale. Firstly, a two‐step one‐pot transformation affords the enantiopure hydroxyalkyl tertiary phosphine oxides in good yields and enantioselectivities. The third step, BH₃‐mediated reduction, allows the formation of the desired phosphine–boranes with excellent stereospecifity. The mechanistic study of this reduction provides new evidence to elucidate the crucial role of the pendant hydroxy group and the subsequent activation of the P?O bond by the boron atom.     

Synthesis of organic phosphines and phosphine oxides from elemental phosphorus and phosphine in the presence of strong bases

Data on the reactions of elemental phosphorus and phosphine with electrophilic reagents are described systematically and analyzed. These reactions occur in the presence of strong bases and yield primary, secondary, and tertiary phosphines and phosphine oxides. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1695–1702, September, 1998.     

Room temperature, palladium-mediated p-arylation of secondary phosphine oxides

We show that a broad range of aryl iodides are efficiently coupled with secondary phosphine oxides using 1 mol % of a catalyst formed in situ from tris(dibenzylideneacetone)dipalladium and Xantphos (1). Scalemic (S)-methylphenylphosphine oxide [(S)-2e] is shown to undergo arylation without detectable stereoerosion. The application of this method to the synthesis of novel P-chiral phosphines and PCP ligands is demonstrated.     

MECHANISM OF THE REACTION OF DIPHENYL N-BROMOSULFILIMINE WITH SULFIDES,PHOSPHINES AND TERTIARY AMINES

Abstract

The mechanism of the reactions of diphenyl N-bromosulfilimine (I) with such nucleophiles as sulfides, phosphines and tertiary amines was investigated. In the presence of water, (I) reacts with sulfides or phosphines to afford the corresponding sulfoxides or the phosphine oxides in moderate yields; however, the reaction with tertiary amine gave only the N-t-aminosulfilimine derivative. The effect of ring size in the reaction with cyclic sulfides suggests that the reaction proceeds via initial bromine transfer from the nitrogen atom to the sulfur atom of the cyclic sulfides followed by S_N2 type substitution of bromide on the sulfur atom of the cyclic sulfide with the sulfilimino group. The phosphine oxide obtained in the reaction of (I) with optically active methyl n-propyl phenyl phosphine was racemized but retained a small portion of the optical activity. In the case of tertiary amines, even 1,4-diazabicyclo-(2,2,2)-octane (DABCO), in which the back side of the nitrogen atom is blocked, reacted smoothly to afford the corresponding ammonium salts, suggesting the reaction to be of S_N2 type on the nitrogen atom of the sulfilimine.     

Development of sterically hindered SPOs and enantioselective Ni−Al bimetallic catalyzed C−H cyclization of 4-oxoquinazolines with tethered alkenes

The Ni−Al bimetallic catalysis of intramolecular enantioselective and regioselective C−H cyclization of 4-oxoquinazolines with tethered alkenes has been successfully developed. Some new secondary phosphine oxides (SPOs) with large steric hindrance (SPO6-11) were designed and successfully synthesized from readily available chiral amines or amino acids. The developed chiral SPOs as ligands or preligands demonstrate much higher efficiency in the asymmetric catalytic reactions than the reported traditional ones. A new class of chiral tricyclic pyrroloquinazolinones were obtained in up to 95% yield and 99% ee.     

Synthesis of Glycosylphosphine Oxides and Related Compounds

The benzyl-protected glycosyl acetates 1 , 6 , 11 , and 15 react with MeOPPh₂ under catalysis by TMSOTf to yield diastereoselectively the glycosylphosphine oxides 2 , 3 , 8 , 12 , 13 , and 16 , with a strong preference for the 1,2-cis-configurated anomers. Hydrogenolysis of the major products gave the crystalline, unprotected phosphine oxides 4 , 9 , 14 , and 17 , of which 4 was transformed in to the acetate 5 , and 9 into the benzoate 10 . The benzylated phosphine oxides 4 , 8 , 12 , and 16 were reduced with Cl₃SiH in the presence of a tertiary amine to form the phosphines 18 , 21 , 24 , and 26 , which were transformed into the phosphine sulfides 19 , 22 , 25 , and 27 . Moreover, 18 and 21 , were characterized as the borane adducts 20 , and 23 . The structure of the (arabinofuranosyl)phosphine oxide 12 , the corresponding sulfide 25 , and of the borane complex 20 were established by X-ray analysis. According to NMR spectroscopy, the equatorial pyranosylphosphine oxide 8 , the sulfide 22 , and the borane complex 23 adopt a ⁴C₁ conformation. The axial phosphine oxide 2 is a flattened ⁴C₁, the sulfide 19 exists as a B_2,5, and the borane complex 20 is a flattened ⁴C₁ in the solid sate and a B_2,5 in solution. Thus, the conformational behavior of these α-D -glucopyranose derivatives reflects the steric requirement of the P-substituents.     

Studies on tetrahydrofuran solutions of manganese(II) dihalides and tertiary phosphines and their reactions with dioxygen

Solutions of Mn(THF)₂Br₂ and MnI₂ and tertiary phosphines in tetrahydrofuran at 0°C are oxidised by dioxygen or electrochemically giving deep blue-purple solutions which have identical electronic spectra. The principal band with λ_max at 570 nm has ?>9000 1 cm^?1 mol^?1. Tertiary phosphines have been shown to be oxidised to the corresponding tertiary phosphine oxides. No evidence was found for the reversible formation of dioxygen-manganese complexes.     

Catalytic asymmetric synthesis of piperidine derivatives through the [4 + 2] annulation of imines with allenes

Although tertiary phosphines have emerged as remarkably versatile nucleophilic catalysts, there has been only very limited progress in achieving asymmetric catalysis with chiral phosphines. In this report, the first highly enantioselective variant of the Kwon annulation of imines with allenes is described. Thus, C2-symmetric chiral phosphepine 1 serves as an effective catalyst for this powerful process, furnishing an array of functionalized piperidine derivatives with very good stereoselectivity.     

Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C−H Amidations of Phosphine Oxides

An enantioselective C−H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert-leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P-chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P-chiral phosphorus(III) compounds.     

Molecular recognition in the palladium complex promoted asymmetric synthesis of a keto-ester heterofunctionalized P-chiral phosphine

A chiral organopalladium complex promoted asymmetric Diels–Alder reaction between 1-phenyl-3,4-dimethyl-phosphole and methyl-trans-4-oxo-2-pentenoate gives the corresponding keto-carboxylate heterofunctionalized P-chiral phosphine ligand in which the keto group is stereoselectively located in the exo position of the phosphanorbornene skeleton.     

Palladium-catalysed synthesis of biaryl phosphines

Monodentate, biphenyl-type phosphines have emerged as a powerful class of ligands in homogeneous catalysis. Synthetic methods for these ligands are limited, however. We report that the palladium-catalysed Suzuki coupling of OPR₂(o-C₆H₄X) (R=Ph, t-Bu; X=Br, I) with arylboronic acids affords a variety of biaryl phosphine oxides including those that contain heterocycles. The corresponding phosphines are readily obtained by treatment with HSiCl₃. The methodology provides an easy entry to monodentate biaryl and heterobiaryl P^?X (X=N, O, S) phosphines with diverse steric and electronic properties.