Mechanism of Phosphine‐Catalyzed Allene Coupling Reactions: Advances in Theoretical Investigations

Organocatalysis has emerged as an effective strategy for chemical synthesis. Within this area, phosphine‐catalyzed coupling reactions have attracted considerable attention because of their versatility and wide range of applications in the construction of new C?C bonds. Recently, various experimental studies on the phosphine‐catalyzed coupling reaction of allenes have been reported, and mechanistic and computational studies have also progressed considerably. As a nucleophile, phosphine can react with an allene to form a zwitterionic phosphoniopropenide intermediate. After stepwise cycloaddition and proton transfer, the phosphine catalyst can be regenerated by C?P bond cleavage. Alternatively, the zwitterionic phosphoniopropenide intermediate could also be protonated by a Brønsted acid to generate a phosphonium intermediate, which can be used to construct new C?C bonds by electrophilic addition. In this review, we have summarized details of mechanistic studies of phosphine‐catalyzed allene coupling reactions that follow these two reaction modes. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of the phosphine‐catalyzed allene coupling reaction are also discussed in this review.     

Kinetics and Mechanism of the Racemization of Aryl Allenes Catalyzed by Cationic Gold(I) Phosphine Complexes

The kinetics of the racemization of aromatic 1,3‐disubstituted allenes catalyzed by gold phosphine complexes has been investigated. The rate of gold‐catalyzed allene racemization displayed first‐order dependence on allene, and catalyst concentration and kinetic analysis of gold‐catalyzed allene racemization as a function of allene and phosphine electron‐donor ability established the accumulation of electron density on the phosphine atom and the depletion of electron density on the terminal allenyl carbon atoms in the rate‐limiting transition state for racemization. These and other observations were in accord with a mechanism for allene racemization involving rapid and reversible inter‐ and intramolecular allene exchange followed by turnover‐limiting, unimolecular conversion of a chiral gold η²‐allene complex to an achiral η¹‐allylic cation intermediate through a bent and twisted η¹‐allene transition state. With respect to proper ligand selection, these studies reveal that both electron‐poor phosphine ligands and polar solvents facilitate racemization.     

Phosphine‐Catalyzed Enantioselective γ‐Addition of 3‐Substituted Oxindoles to 2,3‐Butadienoates and 2‐Butynoates: Use of Prochiral Nucleophiles

The first phosphine‐catalyzed enantioselective γ‐addition with prochiral nucleophiles and 2,3‐butadienoates as the reaction partners has been developed. Both 3‐alkyl‐ and 3‐aryl‐substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all‐carbon quaternary center at the 3‐position in high yields and excellent enantioselectivity. The synthetic value of these γ‐addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.     

Phosphine‐Catalyzed Activation of Vinylcyclopropanes: Rearrangement of Vinylcyclopropylketones to Cycloheptenones

We report a phosphine‐catalyzed activation of electron‐deficient vinylcyclopropanes (VCPs) to generate an ambident C₅ synthon that is poised to undergo consecutive reactions. The utility of the activation is demonstrated in a phosphine‐catalyzed rearrangement of vinylcyclopropylketones to cycloheptenones in good yields with a broad substrate scope. Mechanistic investigations support a stepwise process comprising homoconjugate addition, water‐assisted proton transfer, and 7‐endo‐trig S_N2′ ring closure.     

Enantioselective Allylic Amination of Morita‐Baylis‐Hillman Acetates Catalyzed by Chiral Thiourea‐Phosphine

The enantioselective allylic amination of Morita‐Baylis‐Hillman acetates catalyzed by chiral cyclohexane‐based thiourea‐phosphine catalysts was investigated. In the presence of 20 mol% rosin‐derived thiourea‐phosphine 3j , the chiral amines were obtained in up to 88% yield and up to 85% ee.     

Tuning Catalysts to Tune the Products: Phosphine‐Catalyzed Aza‐Michael Addition Reaction of Hydrazones with Allenoates

A new tunable phosphine‐catalyzed aza‐Michael β‐addition reaction between allenoates and various hydrazones has been developed. These reactions are most‐efficiently promoted by a catalytic amount of phosphine catalysts. These atom‐economical reactions are operationally simple and their corresponding adducts can been achieved in high yields and high selectivity under mild reaction conditions. Further studies revealed that different phosphine catalyst can produce different adducts from the same starting materials.     

Organophosphorus‐Catalyzed Deoxygenation of Sulfonyl Chlorides: Electrophilic (Fluoroalkyl)sulfenylation by PIII/PV=O Redox Cycling

A method for electrophilic sulfenylation by organophosphorus‐catalyzed deoxygenative O‐atom transfer from sulfonyl chlorides is reported. This C?S bond‐forming reaction is catalyzed by a readily available small‐ring phosphine (phosphetane) in conjunction with a hydrosilane terminal reductant to afford a general entry to sulfenyl electrophiles, including valuable trifluoromethyl, perfluoroalkyl, and heteroaryl derivatives that are otherwise difficult to access. Mechanistic investigations indicate that the twofold deoxygenation of the sulfonyl substrate proceeds by the intervention of an off‐cycle resting state thiophosphonium ion. The catalytic method represents an operationally simple protocol using a stable phosphine oxide as a precatalyst and exhibits broad functional‐group tolerance.     

Phosphine‐Catalyzed Annulations of 4,4‐Dicyano‐2‐Methylenebut‐3‐enoates with Maleimides and Maleic Anhydride

A novel phosphine‐catalyzed [4+1] annulation of maleimides with 4,4‐dicyano‐2‐methylenebut‐3‐enoates has been developed to afford spirocyclic products, and the maleimides serves as C₁ synthons. Moreover, a phosphine‐catalyzed formal [3+2] annulation between 4,4‐dicyano‐2‐methylenebut‐3‐enoates and maleic anhydride has been also achieved, and maleic anhydride behaved as a C₃ synthon in the reaction, thus efficiently affording the functionalized cyclopentenones. A stable phosphinium‐containing zwitterionic compound is the key reactive intermediate in both annulations and was successfully isolated. Plausible mechanisms have been proposed on the basis of control experiments and deuterium‐labeling experiments.     

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote C?H Groups in Pyrazolo[1,5‐a]pyrimidines

The regiodivergent palladium‐catalyzed C H arylation of pyrazolo[1,5‐a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine‐containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine‐free catalyst targets the most electron‐rich position (C3).     

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

The regiodivergent palladium‐catalyzed C? H arylation of pyrazolo[1,5‐a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine‐containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine‐free catalyst targets the most electron‐rich position (C3).     

Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by Palladium Catalysis: A Carbene Strategy

An efficient palladium‐catalyzed asymmetric synthesis of axially chiral vinyl arenes from aryl bromides and hydrazones is reported. The products were easily oxidized to axially chiral biaryl compounds, and the phosphine oxides were readily reduced to phosphine ligands.     

Asymmetric Synthesis of Spiropyrazolones through Phosphine‐Catalyzed [4+1] Annulation

An enantioselective synthesis of spiropyrazolones from allenoate‐derived MBH acetates and pyrazolones through a phosphine‐mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α‐substituted allenoates were utilized as a C₄ synthon for phosphine‐catalyzed [4+1] annulation.     

Diastereoselective Synthesis of P‐Chirogenic and Atropisomeric 2,2′‐Bisphosphino‐1,1′‐binaphthyls Enabled by Internal Phosphine Oxide Directing Groups

Diphosphine ligands that merge both axial and P‐centered chirality may exhibit superior or unique properties. Herein we report the diastereoselective introduction of P‐centered chirality at the 2‐position of the axially chiral 2′‐(phosphine oxide)‐1,1′‐binaphthyl scaffold. A lithium–bromide exchange reaction of a 2‐bromo‐2′‐(phosphine oxide)‐1,1′‐binaphthyl and treatment with dichlorophosphines followed by a nucleophilic organometallic reagent afforded unsymmetrical 2‐phosphino‐2′‐(phosphine oxide)‐1,1′‐binaphthyls with binaphthyl axial chirality and one or two phosphorus stereocenters with a variety of P substituents. The final diastereomerically pure 2,2′‐bisphosphino‐1,1′‐binaphthyls were obtained by reduction of the phosphine oxide directing group. Preliminary results demonstrated that a ligand with this hybrid chirality could induce higher stereoselectivity in the metal‐complex‐catalyzed asymmetric hydrogenation of a dialkyl ketone.     

Accessing Ambiphilic Phosphine Boronates through C−H Borylation by an Unforeseen Cationic Iridium Complex

Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium‐catalyzed C?H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane‐protected phosphine). A complimentary catalyst system (quinoline‐based silane ligand with [(COD)IrOMe]₂) was optimal for biphenyl‐based phosphines. Selective polyborylation was also shown providing bis‐ and tris‐borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.     

Amino Acid Derived Phosphine‐Catalyzed Enantioselective 1,4‐Dipolar Spiroannulation of Cyclobutenones and Isatylidenemalononitrile

Cyclobutenones have been explored as a new type of chiral 1,4‐dipole four‐carbon synthon, which readily undergoes organophosphine‐mediated C?C bond cleavage and asymmetric intermolecular 1,4‐dipolar spiroannulation with isatylidenemalononitrile in the presence of amino acid‐derived chiral phosphine catalyst to furnish enantioenriched 3‐spirocyclohexenone 2‐oxindoles in good yield with up to 87 % ee. To our knowledge, this is the first example of asymmetric transformation of cyclobutenones and the phosphine‐catalyzed asymmetric 1,4‐dipolar cycloaddition consisting of C?C bond activation is unprecedented.     

An Exclusively trans‐Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst

Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)‐catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition‐metal‐catalyzed atom‐economic addition of a carbamoyl chloride across an alkyne.     

Phosphine‐Directed CH Borylation Reactions: Facile and Selective Access to Ambiphilic Phosphine Boronate Esters

Ambiphilic ligands have received considerable attention over the last two decades due to their unique reactivity as organocatalysts and ligands. The iridium‐catalyzed C? H borylation of phosphines is described in which the phosphine is used as a directing group to provide selective formation of arylboronate esters with unique scaffolds of ambiphilic compounds. A variety of aryl and benzylic phosphines were subjected to the reaction conditions, selectively providing stable, isolable boronate esters upon protection of the phosphine as the borane complex. After purification, the phosphine‐substituted boronate esters could be deprotected and isolated in pure form.     

Phosphine‐Directed C?H Borylation Reactions: Facile and Selective Access to Ambiphilic Phosphine Boronate Esters

Ambiphilic ligands have received considerable attention over the last two decades due to their unique reactivity as organocatalysts and ligands. The iridium‐catalyzed C H borylation of phosphines is described in which the phosphine is used as a directing group to provide selective formation of arylboronate esters with unique scaffolds of ambiphilic compounds. A variety of aryl and benzylic phosphines were subjected to the reaction conditions, selectively providing stable, isolable boronate esters upon protection of the phosphine as the borane complex. After purification, the phosphine‐substituted boronate esters could be deprotected and isolated in pure form.     

Rücktitelbild: Phosphine‐Catalyzed Remote β‐C?H Functionalization of Amines Triggered by Trifluoromethylation of Alkenes: One‐Pot Synthesis of Bistrifluoromethylated Enamides and Oxazoles (Angew. Chem. 13/2015)

An unprecedented phosphine‐catalyzed remote β‐C H functionalization of amine derivatives triggered by trifluoromethylation of an alkene with Togni’s reagent was disclosed. This reaction proceeded through the highly selective and concomitant activation of an unactivated alkene and the β‐C H bond of an amine derivative, providing bistrifluoromethylated enamides in excellent yields with good regio‐, chemo‐, and stereoselectivity. Furthermore, the newly developed one‐pot protocol provides a facile and step‐economical access to valuable trisubstituted 5‐(trifluoromethyl)oxazoles. Mechanistic studies showed that this reaction may initiate with a novel phosphine‐catalyzed radical trifluoromethylation of unactivated alkene via a phosphorus radical cation.     

Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

The first highly enantioselective phosphine‐catalyzed formal [4+4] annulation has been developed. In the presence of amino‐acid‐derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole‐derived α,β‐unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight‐membered rings by phosphine catalysis.