Recent advances of Pd-π-allyl zwitterions in cycloaddition reactions?

Juan Du,Yun-Fan Li,Chang-Hua Ding,?

a Guangxi Key Laboratory of Natural Polymer Chemistry and Physics,College of Chemistry and Materials,Nanning Normal University,Nanning 530001,China

b Department of Chemistry,Shanghai Engineering Research Center of Organ Repair,Innovative Drug Research Center,Shanghai University,Shanghai 200444,China

Keywords:Palladium Cycloaddition Pd-π-allyl zwitterions Asymmetric catalysis Heterocycles

ABSTRACT Palladium-catalyzed cycloaddition reactions via Pd-π-allyl zwitterions have been established as significant synthetic transformations to enable numerous carbon-or heterocycles compounds that are key constituents of various biologically active natural products and pharmaceuticals.In addition to the well-known Pd-π-allyl zwitterions,including palladium-trimethylenemethane and Pd-1,3/1,4-zwitterions,chemists have recently discovered new applications of several long ago reported but less-studied Pd-πallyl zwitterions,which can straightforwardly and efficiently construct novel cyclic architectures.Meanwhile,some impressive newly designed zwitterions have been also developed.Those zwitterions are diverse and can serve as transient and highly reactive intermediates for the subsequent cyclization with various acceptors.In this review,we highlight recent advances in applications of these two types of zwitterions in the synthesis of complex polycyclics and medium-sized cyclic compounds.

1.Introduction

Dipolar cycloaddition reactions are of fundamental importance to organic synthesis,as they provide access to cyclic motifs in an efficient and convergent manner,particularly,the capability to rapidly access fused-/bridged-ring systems and medium-sized rings (7 to 11-membered rings) which are common core structures in various bioactive natural products and drugs [1–11].As a result,this strategy has attracted the attention of numerous synthetic chemists.In addition to relatively stable classical 1,3-dipoles[12–15],1,n-dipole variants which are not fully conjugated chemical species,are difficult to generate using non-catalytic methods.Among them,transition metal Pd-catalyzed dipolar cycloadditions have been one of the most straightforward and powerful strategy to this end.Most of dipolar intermediates are a short-lived,nonisolable species and the dipole species could be a zwitterion rather than a true dipole.In 1980s,the best-known palladium-mediated dipole,palladium-trimethylenemethane (Pd-TMM),was firstly generated by Trost’s group [16],which is an all-carbon 1,3-dipole.Thereafter,Shintani and Hayashietal.designedγ-methylene-δpentyl lactone as a precursor of all-carbon 1,4-dipole compound to access larger ring sizes (Scheme 1a) [17,18].It has been used extensively in the preparation of a variety of cyclic products,since it reacts with a multitude of acceptors.With the rapid development of these early studies,increasingly profound dipoles have been emerged and are widely used (Scheme 1a).As shown in Scheme 1a,compared to Pd-TMM dipoles,those new dipoles are designed by introducing heteroatoms,growing carbon chains or designing dipoles containing delocalized anions,which not only allow to construct a larger ring system,but also have more reaction pathways for cyclization reactions.This type of dipolar reaction is characterized by the formation of exocyclic unsaturated bonds.

Scheme 1.Representative Pd-π-allyl zwitterions.

Around the same time as the development of the [3+2] Pd-TMM cycloadditions,an alternative [3+2] cycloaddition strategy was realized by Tsuji and co-workers [19]viaa zwitterion generatedinsituby the reaction of Pd with activated vinylcyclopropanes.Since then,the Pd-catalyzed intermolecular [3+n] and[5+n] cycloadditions have been a powerful,atom-economic tool for the construction of various carbon-and heterocycles through theinsitugenerated Pd-π-allyl 1,3-or 1,5-zwitterions by the reaction of Pd(0) with vinyl three-membered cycles and their analogues [20–30].Meanwhile,Pd-π-allyl zwitterions derived from vinyl benzoxazinanones were first developed as a type of 1,4-dipole by Tunge’s group in 2008 [31],and subsequently gained widespread use [32–39].Several related reviews have been reported (Scheme 1b) [18,40].

In recent years,along with the expansion and applications of those dipoles,some other dipoles that had little application after their initial discovery have recently received renewed attention in palladium-catalyzed cycloaddition reactions and have been rapidly developed (Scheme 1b).Compared to dipoles derived from vinyl three-membered cycles,these newly applied dipoles have longer chains to enable larger cyclization products.It is worth noting that the reaction products usually containing multiple chiral centers can be constructed in one step through cycloaddition reactions of those Pd-π-allyl zwitterions under asymmetric catalysis,which is usually difficult to obtain with other methods.

The discovery of new Pd-π-allyl zwitterions has enabled the construction of the diverse set of carbon-and heterocyclic compounds and improves the high potential of such transformation for the synthesis of highly complex organic molecules.However,the design and exploration of unprecedented dipolar cycloadditions is particularly challenging because these dipole intermediates are often highly reactive and short-lived,leading to multiple unexpected reaction pathways.This paper reviews representative advances in Pd-π-allyl zwitterions in organic synthesis over the past five years in two aspects: (1) different kinds of new Pd-π-allyl zwitterions and their applications as different kinds of synthons in cycloaddition reactions;(2) recent advances in the early zwitterions that were hardly applied after their initial discovery.Although several related reviews have been reported [20,41-44],there is no comprehensive summary for the recent development of Pd-π-allyl zwitterions.This review will provide a systematic and overall summary of the recent developments of Pd-π-allyl zwitterions,including three different types of Pd-stabilized zwitterions (bearing a carbanion,O-centered anion orN-centered anion),as well as the related substrate applicability and reaction mechanisms.

2.Pd-π-allyl zwitterions bearing a carbanion

A wide assortment of compounds,includingγ-methylene-δpentyl lactones,vinylcyclopropanes,and silylated allylic substrates were commonly used to generate Pd-zwitterionic species with a carbanion.In the past years,several novel Pd-π-allyl zwitterions were developed by using new precursors (Scheme 2).They can serve as C3,C4,and C6 synthons to participate in cycloaddition reaction with various dipolarophiles.

Scheme 2.Pd-π-allyl zwitterions bearing a carbanion.

2.1.Pd-π-allyl 1,3/5-zwitterions

In 2020,vinyl indoloxazolidones1were reported as either 1,3-C,N-dipole or 1,3-carbodipole precursors in Pd-catalyzed [3+2] cycloaddition reactions by Shi group [45] and Deng group [46],respectively (Scheme 3).The indolyl substituted Pd-π-allyl zwitterionic intermediates were derived from the palladium catalyzed decarboxylation reaction of vinyl indoloxazolidones1,which could serve as both all-carbon 1,3-dipoles and aza-1,3-dipoles through the anionic delocalization,providing a new platform for the divergent synthesis of polycyclic indoles.The reactions in which they participate as all-carbon 1,3-dipoles are presented firstly,and the reactions in which vinyl indoloxazolidones act as 1,3-C,N-dipoles will be presented later (videinfra).

Scheme 3.The general process of cycloaddition reactions of vinyl indoloxazolidones.

Deng and coworkers [46] first applied vinyl indoloxazolidones1that selectively served as all-carbon 1,3-dipole precursors in the asymmetric [3+2] cycloaddition with electron deficient alkenes2or3,furnishing polysubstituted cyclopenta[b]indoles4and5with high regio-and stereo-selectivities in the presence of phosphoramidite ligandL1(Scheme 4).

Scheme 4.Pd-catalyzed [3+2] cycloadditions of vinyl indoloxazolidones.

The next year,Chen and coworkers [47] also disclosed a palladium-catalyzed regiodivergent asymmetric cycloadditions of vinyl indoloxazolidones1,which could serve as unusual 1,5-carbodipole or 1,3-carbodipole precursors by tuning chiral bisphosphine ligands and reaction conditions,in the assemblies with sulfamate-derived cyclic imines6(Scheme 5).A diversity of [5+2]cycloaddition products7were generally constructed with up to 95% yields and 97% enantioselectivities by employing the combination of Pd2(dba)3and chiral bisphosphine ligandL2.Remarkably,by tuning the structure of bisphosphine ligand from a sterically bulkyL2to a less sterically demandingL3,the asymmetric [3+2]cycloaddition products8between the same substrate assemblies could be separated as the major ones in excellent stereoselectivity since the congested feature of theπ-allyl palladium complex would be beneficial for the [3+2] cycloaddition pathway.During this process,the chiral tartrateA1was found to be beneficial for the enantioselectivity and reactivity,probably acting as a hydrogen donor co-catalyst after assembly with the palladium(II) intermediateviacoordination.Moreover,this delocalized Pd-π-allyl zwitterionsIare similar to the zwitterionic species formed from vinylethylene carbonates (VECs) or vinyloxiranes [48–53] under Pd catalysis,which could perform as either 5-atom synthons or 3-atom synthons for cycloaddition reactions.

Scheme 5.Pd-catalyzed [3+2]/[5+2] cycloadditions of vinyl indoloxazolidones.

Since the seminal study by Trost and Can in 1979 [16],fivemembered ring structures,such as cyclopentanes,pyrrolidines and tetrahydrofurans,have been well constructed through asymmetric [3+2] cyclizations of Pd-TMM with 2π-dipolarophiles.In 2020,Trost and coworkers developed a Pd-TMM containing anαtrifluoromethyl carbanion (Scheme 6) [54].The unique charge distribution of the cationic palladiumπ-allyl motif may stabilize the adjacent fluorocarbanion and prevent the elimination of fluoride.Thus,asymmetric [3+2] cycloadditions of Pd-TMM intermediate with a vast array of acceptors10were realized to deliver valuable CF3-substituted five-membered rings11including cyclopentanes,pyrrolidines and tetrahydrofurans in high yields and stereoselectivities.In addition,other five-membered rings containing polyfluorinated substituents such as difluoromethyl,were also successfully provided using this approach.

Scheme 6.Pd-catalyzed [3+2] cycloadditions via α-CF3 carbanion Pd-TMM.

2.2.Pd-π-allyl 1,4-zwitterions

In 2007,γ-methylidene-δ-valerolactones were first designed and used as precursors of 1,4-zwitterionic specie by Shintani and Hayashi group [17].Since then,this type of precursors has been rapidly developed by reacting with many acceptors as an allcarbon four-atom synthon for [4+n] cycloadditions [55–59].Despite its great reactivity,γ-methylidene-δ-valerolactones require an electron-rich or neutral aromatic ring at theα-position of its ester group to enable the key palladium-mediated decarboxylation,which would limit the further functionalization and applications of the products.Thus,the need of more general dipole precursors and the possibility of achieving high enantioinduction have prompted chemists to explore and develop new atom-economic pathways to construct functionalized carbo-and heterocycles.

Until 2020,Trost and coworkers designed and applied a new 1,4-zwitterionic intermediate precursor that could be accessible in one step,greatly simplifying the synthesis (Scheme 7) [60].The allyl carbonates12would undergo ionization in the presence of Pd(0) complex and subsequently abstract the homoallylic proton,acidified by the electron withdrawing group,with release oftBuOH and CO2.The corresponding Pd-stabilized zwitterionIwas generated,which can then be add to electron-deficient olefins15or16to deliver intermediateII.While the subsequent ring closure of intermediateIIcan yield different products because both C1 and C2 centers are electrophilic.Nucleophilic attack at the C1 terminusviaa classic Tsuji-Trost type mechanism afforded 6-membered adducts13in up to 94% yield,98%eeand >15/1dr(Scheme 7a),while attack at the C2 position yielded a palladacyclobutane intermediate which subsequently would undergo reductive elimination to form the spirocyclic compounds14(Scheme 7b).Various chiral 6-membered rings and spiro[2.4]heptanes were prepared in high yields and selectivity through ligand-controlled and substrate induced regio-and diastereoselectivity.

Scheme 7.Pd-catalyzed cycloadditions via aliphatic 1,4-dipoles.

In the same year,Trost and coworkers [61] also developed another novel palladium-mediated carbonylogous 1,4-dipole byin situdeprotonation from17(Scheme 8).In contrast to the welldeveloped palladium-mediated dipole precursors that usually used electron-neutral or rich olefins,such as cinnamyl,methylmethylene.In this process,electron-deficient system was reported as the precursor.By using their developed C2-unsymmetric phosphoramidite ligandL9,this novel dipole could be used for asymmetric [4+2] cycloaddition reactions with various electron-deficient alkenes18to produce chiral cyclohexanones19in good to excellent results.

Scheme 8.Pd-catalyzed cycloadditions via carbonylogous 1,4-dipoles.

2.3.Pd-π-allyl 1,6-zwitterions and others

In 2022,a new precursor ofπ-allylpalladium zwitterion,δvinylvalerolactone20,was designed for the [6+3] decarboxylative cycloaddition reactions with azomethine imines21by Guo and coworkers (Scheme 9) [62].A range of nine-membered 1,2-dinitrogen-containing heterocycles22were synthesized in 77%–98% yields with >20/1dr.δ-Vinylvalerolactones20with aryl,2-naphthyl,thienyl and methyl-substituted all displayed well reactivity,affording the corresponding products.

Scheme 9.Pd-catalyzed [6+3] cycloadditions of δ-vinylvalerolactone.

In 2022,Chen and coworkers designed novelπ-allylpalladium dipolar 10π-cycloaddends derived from 2-methylene-1-indanols23viaoxidative addition under Pd(0) catalysis and deprotonation(Scheme 10) [63].Thus,an asymmetric [10+2] cycloaddition reaction of23with diverse activated alkenes was developed under double activation of Pd(0) and phosphoric acid.By employing a newly designed chiral phosphoramidite ligandL10,various polycyclic frameworks embedding an indene core were obtained in moderate to excellent yields with high enantioselectivities.Notably,introducing an electron-withdrawing group at the indane ring is required to enhance the acidity of the benzylic C-H.The addition of phosphoric acid as a co-catalyst may be beneficial for the oxidative addition of Pd(0) to allyl alcohol and may also facilitate enantiomeric control.Besides,apart fromα-cyano chalcones24and barbiturate-derived alkenes25,other types of activated alkenes can also be employed to construct polycyclic frameworks with more structural diversity through asymmetric [10+8] and[10+4] cycloaddition reactions.

Scheme 10.Pd-catalyzed [10+n] cycloadditions of 2-methylene-1-indanols.

3.Pd-π-allyl zwitterions bearing an O-centered anion

Novel Pd-π-allyl zwitterions bearing anO-centered anion have also been rapidly developed and can be used as versatile multiatomic synthons depending on the reaction conditions and the variation of dipolarophiles (Scheme 11),however,the control of the reaction site as well as the stereoselectivity is difficult.Nevertheless,with the continuous efforts of chemists,numerous carbon-or heterocycles compounds have been successfully furnished.

Scheme 11.Pd-π-allyl zwitterions bearing an O-centered anion.

3.1.Pd-π-oxyallyl 1,3-zwitterions

Pd-oxyallyl intermediates have attracted the attention of researchers since the 1990s [64–66].They were generated from different precursors and were all found to react only with norbornene type strained alkenes to yield unexpected cyclopropanation products.However,it was not until very recently that a catalytic Pdoxyallyl-mediated [3+2] cycloaddition was achieved by Trost and coworkers in 2018 [67].The key to success was the introduction of an additional electron-withdrawing group (EWG) on the Pdoxyallyl intermediate,which could drive the equilibrium toward[3+2] cycloaddition products (Scheme 12).The Pd-oxyallyl intermediatedinsitugenerated by the reaction of Pd(0) with precursor29acted as an electrophile,which differed from the analogous Pd-TMM intermediates that are nucleophiles.Subsequently,the new Pd-allyl zwitterionic intermediate28would be generated by the addition of Pd-oxyallyl to the conjugated diene,and this Pd-allyl transfer process would be followed by C-O or C-C reductive elimination to form the five-membered rings31or32,respectively.In addition,it was found that the kinetic products31would be converted to thermodynamic products32viathe intermediate28.

Scheme 12.General reaction process of Pd-catalyzed cycloadditions via Pd-oxyallyl intermediates.

In this work,a tailored bifunctional precursor29and 1,3-dienes30including cyclohexadienes and linear dienes were chosen as substrates (Scheme 13).A wide variety of tetrahydrofurans31containing an exocyclic double bond were delivered in good to high yields,which was quite different from those obtainedviathe[3+2] cycloadditions of vinyl three-membered cycles with olefins[68–71].

Scheme 13.Pd-catalyzed [3+2] cycloadditions via Pd-oxyallyl intermediates.

In addition,the heterocycles31could smoothly be converted to the thermodynamically more stable carbocyclic cyclopentanones32in 62%-73% yields by using CpPd(cinnamyl)/1,2-bis(diphenylphosphino)ethane (dppe) as the catalyst under elevated temperature that can facilitate the irreversible C–C bond reductive elimination (Scheme 14).Subsequently,to rationalize the regioselectivity of these reactions,Houketal.performed density functional theory (DFT) calculations,which revealed that the CO reductive elimination step is kinetically favorable [72].The DFT calculations also revealed that the electron-withdrawing ester substituent was crucial as it could decrease the LUMO energy of the Pd-oxyallyl species,leading to a more favorable energy match with the HOMO of the dienes.

Scheme 14.Pd-catalyzed conversion of tetrahydrofurans to cyclopentanones.

Despite the aforementioned successes,because C-O bond formation is kinetically favored,the [3+2] cycloadditions directly involving C-O reductive elimination are more general.In contrast,catalytic cycloaddition reactions of Pd-oxyallyl species directly through C-C reductive elimination to provide cyclic ketones remain challenging.In 2021,Zi and coworkers developed a method of lithium triflate-promoted [3+2] cycloaddition reactions of Pd-oxyallyl intermediates with 1,3-dienes (Scheme 15)[73].The key to the success of this method was the coordination of the lithium ion with the alkoxide moiety,and this coordination disrupted the C-O reductive elimination pathway and promoted to form the metalenolate tethered Pd-π-allyl intermediateIIthat then could undergo intramolecular allylic attack by the enolate moiety to form the carbocyclic products35or36.Methylene ethylene carbonates (MECs)34were chosen as the precursors for the Pd-oxoallyl intermediate because they can be easily prepared by a one-step gold-catalyzed cyclization reaction [74].The corresponding five-membered carbocycles35were delivered in good to high yields with high regioselectivities through [3+2] cycloadditions.Furthermore,the competitive [4+3] cycloaddition reactions were also accomplished by tuning the steric properties of the ligands.A larger sterically hindered ligandL12facilitated delivery of [4+3] products36.Importantly,DFT calculations indicated that whenL12was used as the ligand,the activation energies of the [3+2] and [4+3] cycloadditions differed in the intramolecular allylic substitution step.The former is higher than the latter.Therefore,the [4+3] cycloaddition reaction was favored over the [3+2] cycloaddition,which was consistent with experimental observations.

Scheme 15.Pd-catalyzed cycloadditions of MECs.

In 2022,Zhang and coworkers developed asymmetric [3+2] cycloaddition reactions of Pd-oxyallyl specie precursors29or34with cyclic or acyclic 1,3-dienes to provide various tetrahydrofuran rings in high yields and selectivities,with 10 examples in yields up to 91% andeevalues up to 98% [75].In this process,a rationally designed chiral sulfinamide phosphine (Sadphos) type ligand was employed to improve the reaction efficiency and enantioselectivity.

With the development of heterocycles decarboxylative process,Guo’s or Zi’s groups respectively designed new cyclic carbonates vinyl methylene cyclic carbonates (VMCCs) that can provide carbon-carbon zwitterion species under palladium catalysis in 2021 [76,77].

Guo and coworkers [76] designed a series of vinyl methylene cyclic carbonates37as substrates that could be used as 1,3-or 1,5-zwitterion intermediates under palladium catalysis (Scheme 16).The general process of the reaction is briefly described.The VMCCs could react with Pd(0) to form vinyl-substituted Pd-oxyallyl speciesAwith the loss of one molecular CO2.The charge delocalization led to the equilibrium betweenAand Pd-oxypentadienyl speciesB.The C1 position ofBhad some nucleophilicity,allowing for the realization of an inverse electron demanding cycloaddition,which was quiet unlike the above electrophilicity of Pd-oxoallyl intermediate shown in Scheme 12.The five-membered carbocycles38were delivered through a [3+2] cycloaddition reaction in the presence of Pd(PPh3)4catalyst with good to high yields and high diastereoselectivity and regioselectivity at 60°C.Interestingly,by adding the ligandL3and increasing the temperature,the regioselectivity was completely reversed to [5+2] cycloadditon,yielding the seven-membered products39.In addition,in order to broaden the applicability of this reaction,the asymmetric examples were also explored,but the results were not satisfactory.

Scheme 16.Pd-catalyzed [3+2]/[5+2] cycloadditions of VMCCs.

Almost at the same time,Zi and coworkers [77] realized an asymmetric [3+2] cycloaddition reaction of VMCCs37as precursors of vinyl-oxyallyl-Pd species (Scheme 17).In this case,Pdoxoallyl was predicted by DFT calculations to be a highly electrophilic intermediate,and previously only electron-rich olefins could be available as cycloaddition partners.In contrast,the vinyloxoallyl-Pd species exhibited nucleophilicity,and its application would expand the range of olefins.Thus,the first enantioselective [3+2] cycloaddition reactions of vinyl-oxoallyl-Pd with electron-deficient nitroalkenes40were realized.Different ligands,including Binap,iPr-PhOX,Phosferrox,and DACH-PhTrost ligand,failed to enable the desired [3+2] cycloaddition.Only using phosphoramidite-type ligands can provide the cycloaddition product41in 40% yield with >20:1drand 40%ee.Inspired by the application of noncovalent interactions in asymmetric transitionmetal catalysis [78–80],a new type of hydrogen-bond-donating phosphine ligandL13containing a tethered urea moiety was designed.LigandL13can form hydrogen bonds with the electron-rich oxygen of Pd-oxyallyl,and this interaction has the potential to enhance chiral induction.Cyclopentanones41containing three contiguous stereocerters witheevalues up to 99% anddr>20/1 were obtained by employing rationally designed FeUrPhosL13.The R group of37could be aryl,benzyl,alkyl,terminal alkenyl.In addition,not only variousβ-aryl nitroethylenes40but alsoα-methyl nitroethylenes40were well employed.

Scheme 17.Pd-catalyzed enantioselective [3+2] cycloadditions of VMCCs.

Recently,Liu and coworkers realized another [3+2] cycloaddition reaction of VMCCs37with [60]fullerenes in the presence of Pd(PPh3)4[81].In this process,VMCCs also participated in the cycloadditions as 1,3-C,C-zwitterion intermediates,which further demonstrated the reaction versatility and broad substrate applicability of VMCCs37as dipolar precursors.

In 2022,inspired by the above works,by using chiral H8-BINOLderived bis-phosphite ligandL14,Cao and coworkers [82] developed Pd-catalyzed enantioselective [3+2] cycloaddition reactions of vinyl-substituted oxyallyl carbonates42with activated carbonyl compounds trifluoromethyl aryl ketones43or isocyanates44,delivering 1,3-dioxolanes45with up to 98%eeand 94/6drvalue or oxazolidinones46with up to 98%ee,respectively.In addition,an aminoketone47withα-chiral tetrasubstituted carbon was produced through ring-opening hydrolysis of46under basic conditions in 70% yield and 91%ee(Scheme 18).

Scheme 18.Pd-catalyzed enantioselective [3+2] cycloadditions of VMCCs with aryl ketones or isocyanates.

3.2.Pd-π-oxyallyl 1,4-zwitterions

Since the discovery of newly designed vinyl methylene cyclic carbonates (VMCCs),Guo and coworkers has achieved several Pdcatalyzed decarboxylative cyclizations to construct carbon-or heterocycles.During the process,they unexpectedly discovered the formation of pyrrole products when the reactions proceeded in the presence of amine nucleophile reagents [83].The synthesis of a series of polysubstituted pyrroles49was then achieved under Pd catalysis (Scheme 19a).This decarboxylative protocol generated only CO2and H2O as byproducts and operated at room temperature in air.Mechanistic investigations suggested that the stereoselective formation of the (Z)-configuredγ-amino ketone intermediateAwas crucial for the success of the reaction.The (E)-Awas stable and isolatable.In contrast,the intramolecular nucleophilic attack of (Z)-Areadily occurred to give intermediateB,which was subsequently dehydrated to give the corresponding pyrrole compounds49.

Scheme 19.Pd-catalyzed [4+1] cycloadditions of VMCCs.

In the same year,Guo and coworkers reported a watermediated catalytic decarboxylation process to form a series of polysubstituted furans50(Scheme 19b) [84].This protocol also utilized VMCCs48as reaction substrates with broad functional group tolerance in the presence of Pd(TFA)2andL16in a mixed solvent of acetone and H2O.

3.3.Pd-π-oxyallyl 1,5-zwitterions

In addition to acting as three-atom synthons,VMCCs can also serve as five-atom synthons for [5+2] cycloadditions.Guo and coworkers obtained the [5+2] cycloaddition products53from the reaction of VMCCs37and activated alkenes54with high selectivity and good to high yields under Pd(PPh3)4and ligandL3cocatalysis (Scheme 20a) [76].When the reaction substrates were switched from olefins51to triazines52,non-fusedN-aryl azepane derivatives54were obtainedvia[5+2] cycloaddition reactions promoted by Pd catalysis and AgOTf [85].In this process,in order to gain insights into the reaction pathways,DFT calculations showed that the origin of the exclusive [5+2] rather than the[3+2] cycloaddition process was due to a much lower barrier for the formation of azepanes54(Scheme 20b).Besides,the same group [86] found that two molecules of vinyl Pd-oxyallyl species could dimerize regiospecifically to form highly functionalized nonbridged cyclooctanoids55.This methodology demonstrated the vinyl Pd-oxyallyl species possessing both electrophilic and nucleophilic properties (Scheme 20c).

Scheme 20.Pd-catalyzed [5+n] cycloadditions of VMCCs.

Guo and coworkers also reported ligand-controlled Pd-catalyzed decarboxylative [5+4] and [5+2] cycloadditions by utilizing VMCCs37as C5-synthons [87].When using a diphosphine ligandL16,only the thermodynamically favorable [5+2] cycloaddition products57were given (Scheme 21a).The utilization of a monophosphine ligandL15could switch the regioselectivity,prompting the challenging nine-membered compounds58to be the major productsviathe [5+4] cycloadditions (Scheme 21b).A reaction mechanism was proposed.First,cyclic carbonate37underwent decarboxylation in the presence of a palladium catalyst to give the zwitterionic Pd-π-allyl enolate intermediateI.Followed by nucleophilic attack on dienes56,the new zwitterionic intermediateIIwas generated.The regio-divergent nucleophilic cyclization under kinetic(path a) or thermodynamic control (path b) generated the corresponding nine-or seven-membered carbocycles,respectively,with the regeneration of the palladium catalyst.

Scheme 21.Pd-catalyzed [5+n] cycloadditions of VMCCs and allylidenemalononitriles.

3.4.Pd-π-allyl 1,4-zwitterions derived from vinyl oxetanes and their analogues

Since Alper and coworkers reported the Pd-catalyzed allylic cycloaddition of vinyloxetanes59with isocyanates/carbodiimides to provide compounds 1,3-oxazines in a racemic form in 1999 [88],which was the first report on the oxa-1,4-dipoles (Scheme 22).In addition to cycloaddition reactions,vinyloxetanes59also delivered acyclic products [89,90] and dihydropyrans [91]viaring-opening allylic substitution and ring-expansion reactions.However,metalcatalyzed asymmetric cycloaddition reactions of vinyloxetanes remained to be unknown for a long time.

Scheme 22.General Pd-catalyzed reactions of vinyl oxetanes.

In 2019,Zhang and coworkers [92] achieved an asymmetric [4+2] cycloaddition of vinyloxetanes59with an abundant feedstock formaldehyde in the presence of Pd2(dba)3·CHCl3and phosphoramidite ligandL18under mild conditions to provide 4-substituted 4-vinyl-1,3-dioxanes60in high yields with good to excellent enantioselectivities (Scheme 23a).Vinylpropylene carbonate (VPC)61a,which was synthesized from the corresponding 1,3-diol [93],was also tested instead of vinyl oxetanes59for this cycloaddition reactions.As shown in Scheme 23b,the same reaction conditions were effective for the cycloaddition of VPC61awith formaldehyde to furnish 1,3-dioxane60ain 60% yield with high enantioselectivity (95%ee).

Scheme 23.Pd-catalyzed [4+2] cycloadditions of vinyl oxetanes.

Almost at the same time,Hou and coworkers [94] paid attention to the oxa-1,4-dipoles and developed the first asymmetric[4+2] cycloaddition reaction of VPCs62with singly activated electron deficient alkenes63catalyzed by a combination of Pd and the newly developed benzyl-substituted P,N-ligandL19(Scheme 24).A range of tetrahydropyrans64containing three continuous chiral centers were obtained in high yields with high diastereo-and enantioselectivities.Reactions using commercial P,N-ligandsL20produced64in high yields with varied enantioselectivities,but with very low diastereoselectivities.Excitingly,if benzylic substituted P,N-ligand (S,S)-L19with isopropyl as a substituent at the benzylic position was used,both the yields and diastereo-and enantioselectivities were significantly improved.This class of benzylic substituted P,N-ligands was further applied in the palladiumcatalyzed asymmetric [3+2] cycloadditions of vinyl epoxides with alkynyl esters as well [95].

Scheme 24.Pd-catalyzed [4+2] cycloadditions of vinylpropylene carbonates(VPCs).

3.5.Pd-π-allyl 1,6-zwitterions derived from vinyl oxetanes and their analogues

Vinyl oxetanes59are commonly used as 1,4-zwitterionic precursors to achieve Pd-catalyzed [4+2] cycloaddition reactions [96].Until 2018,Zhao and coworkers reported the first Pd-SIPHOXL21complex-catalyzed enantioselective [6+4] cycloaddition reactions of vinyl oxetanes59with azadienes65(Scheme 25) [97].Various benzofuran-as well as indole-fused heterocycles66could be accessed in excellent yields and enantioselectivities.In this context,vinyl oxetanes were involved in the reaction as oxa-1,6-dipole precursorsviaoxidative addition of Pd(0).Then,the alkoxide moiety of oxa-1,6-dipoles underwent Michael addition with azadienes65to give intermediateA.Finally,the [6+4] cycloaddition products were obtained through intramolecularN-allylic substitution.In fact,the preparation of ten-membered rings by cycloaddition reactions remains scarce in organic synthesis.This reaction provided a fast and efficient method to construct of chiral 10-membered rings.

Scheme 25.Pd-catalyzed [6+4] cycloadditions of vinyl oxetanes.

In 2020,Shibata and co-workers reported another reaction on the use of vinyl oxetanes59as 1,6-dipolesviaPd catalysis (Scheme 26) [98].In this case,a non-decarboxylated Pdcatalyzed [6+6] cycloaddition of six-membered trifluoromethyl benzo[d][1,3]oxazinones67with vinyl oxetanes59was developed,which was an efficient way for the synthesis of trifluoromethylated 12-membered heterocycles68.The possible reaction mechanism was shown in Scheme 26.First,the oxa-1,6-dipoles were generatedinsituby the reaction of Pd with vinyl oxetanes59.Then,nucleophilic attack on the carbonyl moiety of67by the oxygen anion of the oxa-1,6-dipoles induced ring openingviaC-N bond breakage of67,which led to the formation of the Pd complex intermediateAthat was confirmed by LC-MS analysis (m/z=940.0,M+Na).Finally,the reductive elimination of the Pd complexAprovided [6+6] cycloaddition products68.In addition,the reaction of vinyl oxetane59awith (S)-67aunder standard conditions afforded the chiral trifluoromethyl-substituted 12-membered heterocycle (S)-68ain 77% yield and 99%eewithout any loss of the enantiopurity compared to the starting material (S)-67a.

Scheme 26.Pd-catalyzed [6+6] cycloadditions of vinyl oxetanes.

In the same year,Shibata and co-workers [99] altered sixmembered trifluoromethyl benzo[d][1,3]oxazinones67into difluorooxindoles,isatins or their analogs in reaction system,thus producing functionalized 11-membered heterocycles70in good to high yields by Pd-catalyzed [6+5] cycloadditions (Scheme 27a).In this process,vinyl oxetanes59smoothlyinsitugenerated oxa-1,6-dipoles in the present of Pd2(dba)3and dppe.The reaction mechanism was similar to the catalytic cycle of Scheme 26.

Scheme 27.Pd-catalyzed [6+5]/[6+3] cycloadditions of vinyl oxetanes.

Recently,Huang and coworkers achieved a palladium-catalyzed selective [6+3] cycloaddition reaction of 2-vinyl oxetanes59andN-iminoisoquinolinium ylides71to deliver 9-memberedN,N,Oheterocycles72in moderate to high yields (Scheme 27b) [100].A range of 2-aryl-2-vinyl oxetanes59were examined,while 2-methyl-2-vinyl oxetanes failed to provide the corresponding heterocycle,possibly owing to the poor stability of the generated zwitterionic allylpalladium intermediates.

VPCs can also act as 1,6-dipole precursors,which is similar to vinyl oxetanes.VPCs could undergo oxidative addition catalyzed by palladium catalysis followed by spontaneous decarboxylation to produce oxa-1,6-dipoles.In 2021,Lee and coworkers [101] reported a novel Pd(0)/Rh(II) dual catalytic strategy to enable [6+3]cycloadditions between VPCs61andN-sulfonyl-1,2,3-triazoles73to provide nine-membered 1,4-oxazonines74in moderate to high yields (Scheme 28).The plausible reaction pathway was depicted.First,the Pd(0) and Rh(II) catalysts selectively activated61and73,respectively,to generate 1,6-dipoleIand 1,3-dipole equivalentα-imino rhodium(II) carbenoid intermediateII.Then,the oxygen anion of intermediateIcould be added nucleophilically to the electrophilic carbenoid carbon of intermediateIIto deliver the Pd/Rh-bimetalated intermediateIII.Finally,nine-membered oxazonines74were formed through intramolecular cyclization pathways.Moreover,the nine-membered oxazonines74could be further converted to the correspondingcis-fused bicyclic hexahydropyranopyrroles75in moderate to good yields through the transannular Alder-ene rearrangement in one pot.

Scheme 28.Pd-catalyzed [6+3] cycloadditions of vinylpropylene carbonates.

3.6.Pd-π-allyl zwitterions derived from alkylidenetrimethylene carbonates (ADTMCs)

In addition to VPCs,2-alkylidenetrimethylene carbonates(ADTMCs),first reported by Tsuji and coworkers [102] in 1984,were also applied to Pd-catalyzed cycloaddition reactions with isocyanates by Hayashi and co-workers in 2011 (Scheme 29) [103].The application of ADTMCs has developed rapidly in recent years.Interestingly,compared to VPCs or vinyl oxetanes,ADTMCs were used only as 1,4-dipole species for Pd-catalyzed intermolecular cycloadditions with different dipolarophiles,and the cycloaddition products contained an exocyclic double bond.

Scheme 29.General Pd-catalyzed cycloaddition of alkylidenetrimethylene carbonates (ADTMCs).

In 2019,Liu and coworkers [104] explored a Pd-catalyzed [4+2]cycloaddition between ADTMCs76and fullerene77to afford fullerene-fused tetrahydropyrans78in medium to good yields(Scheme 30).Although there were only 5 examples,this methodology revealed the application of ADTMCs as oxa-1,4-dipolar precursors under palladium catalysis.

Scheme 30.Pd-catalyzed [4+2] cycloadditions of ADTMCs and fullerene.

In 2020,Guo and co-workers [105] realized palladium-catalyzed asymmetric [4+2] cycloadditions of ADTMCs76awith olefins derived from pyrazolones79,indandiones80or barbiturates25to provide pharmacologically interesting chiral tetrahydropyrane-fuse spirocyclic scaffolds81-83in good to excellent yields and high enantioselectivities (Scheme 31).The chiral diphosphine ligandL23was proved to be the best choice.In this process,ADTMCs were designed to generate oxa-1,4-dipolesviapalladium-catalyzed oxidative addition followed by spontaneous decarboxylation.

Scheme 31.Pd-catalyzed [4+2] cycloadditions of ADTMCs and alkenes.

In the same year,Shibata and coworkers [99] applied76ain the Pd-catalyzed [4+5] cycloaddition reactions with isatins and their analogs to access 9-membered heterocycles84in good to excellent yields (Scheme 32).The highly electron withdrawing nature of the Z group in combination with the nucleophilic attack of thein-situgenerated 1,4-dipole species induced the C-N bond breakage of substrates69.The desired products84were obtained by subsequent intramolecular cyclization.

Scheme 32.Pd-catalyzed [4+5] cycloadditions of ADTMCs.

In 2021,Lu and co-workers successfully completed the Pdcatalyzed,visible-light-induced asymmetric [4+2] cycloaddition reaction of ADTMCs76withα-adiazoketones85(Scheme 33)[106].The proposed mechanism began with the generation of oxa-1,4-dipole intermediatesIfrom the reaction of ADTMCs and Pd(0)catalyst.Meanwhile,ketenesIIwere readily generated fromαdiazoketones85viaa photo-Wolff rearrangement under blue LEDs.Then,intermolecular nucleophilic addition/intramolecular asymmetric allylic alkylation sequence produced 6-membered lactones86bearing exocyclic olefin.The chiral phosphoramidite ligandL24proved to be efficient and provided chiral products86in 50%-95%yields with high selectivities.The reaction had a wide range of substrate applicability,allowing the use ofα-diazoketones containing Me,Et,nBu,i-Bu,Bn and so on.Aryl substituted ADTMCs with different electrical properties could be employed.Moreover,unsubstituted ADTMCs also reacted smoothly;whereas alkyl-substituted ADTMCs failed to produce the desired lactone products under the standard conditions.

Scheme 33.Pd-catalyzed [4+2] cycloadditions of ADTMCs and ketenes.

Chen and coworkers [107] achieved that the isatin-derived Morita-Baylis-Hillman (MBH) carbonates87couldinsituform zwitterionic allylic ylidesIIunder the catalysis of Lewis bases(LBs),such as DABCO,DMAP or PPh3(Scheme 34).ADTMCs76aor VPCs61bwould readily generate zwitterionic Pd-π-allyl intermediates upon Pd-catalyzed CO2dissociation.Therefore,an asymmetric [4+3] cycloaddition reaction between isatin-derived MBH carbonates87and oxygen-containing 1,4-dipoles through the process of intermolecular allyl substitution/intramolecular cyclization was realized (Scheme 34) [108].A range of spirooxindoles incorporating an oxepane frameworks88or89were smoothly constructed in moderate to good yields with high stereocontrol.Phosphine ligands bearing hydrogen bonding motifs were suitable,such asL25,L26,which could be readily obtained from chiral 1,2-aminoalcohol or 1,2-diol,respectively [77,109].In this process,the hydrogen bonding interactions played a pivotal role in enhancing reactivity and enantiocontrol.

Scheme 34.Pd-catalyzed [4+3] cycloadditions via Pd-1,4-oxa-dipoles.

3.7.Pd-π-allyl zwitterions derived from 3-hydroxy-2-methylenepropyl carbonates

Analogous to ADTMCs,3-hydroxy-2-methylenepropyl carbonates could be transformedinsituinto the same oxa-1,4-dipole intermediate under palladium catalysis (Scheme 35).The 3-hydroxy-2-methylenepropyl methyl carbonate90a,first reported by Pátek and co-workers in 1996 [110],was synthesis in one step.The allyl carbonates bearing a nucleophilic alcohol side chain have been applied in Pd-catalyzed [4+2] cycloadditions with indoles91orpara-quinone methides93by You’s [111] or Yao’s groups [112] in 2016 and 2017,respectively (Schemes 36a and b).Since then,the application of 3-hydroxy-2-methylenepropyl carbonates with a nucleophilic alcohol side chain in cycloadditon reactions has been opened.

Scheme 35.The formation of oxa-1,4-dipole from ADTMC and 3-hydroxy-2-methylenepropyl methyl carbonate.

In 2020,3-hydroxy-2-methylenepropyl carbonate90bwas further used to deliver an array of 3-methylenetetrahydropyrans96in good to excellent yieldsvia[4+2] cycloadditon reactions with 2-alkenylbenzothiazoles95by Ni and coworkers (Scheme 36c)[113].When asymmetric syntheses were attempted,Trost ligands or monodentate phosphoramidite ligands were tested.Unfortunately,neither was able to yield the product of the [4+2] cycloaddition reaction.Chiral bidentate ligands were also tested,and only axially chiral bisphosphine ligandL30realized the enantioselectivity and gave96ain 95% yield and 37%ee.

Subsequently,Lin and coworkers [114] developed the ligandcontrolled asymmetric [4+2] or [4+4] cycloaddition reactions oftert-butyl[2-(hydroxymethyl)allyl]carbonate90cwith benzofuranderived azadienes65aby palladium catalysis (Scheme 37).Using chiral P,P-ligand (S)-ClMeO-BIPHEPL31,the tetrahydropyranfused spirocyclic compounds97with good to high enantio-and diastereoselectivities were obtained in good yieldsviathe [4+2]cycloaddition reactions of intermediateI(Scheme 37).When taking advantage of chiral P,N-ligand (S,Rp)-PPFAL32,the chemoand regio-selectivities were switched to synthesize a variety of benzofuro[2,3-c][1,5] oxazocines98in good yields with excellent enantioselectivitiesviathe [4+4] cycloaddition reactions of intermediateII.The C-or N-nucleophilic sites could be specifically discriminated during the subsequent intramolecular allylic substitution processes after initial oxo-Michael addition due to the inherent steric and electronic effects of two different chiral ligands.

Scheme 37.Pd-catalyzed [4+2] and [4+4] cycloadditions of tert-butyl[2-(hydroxymethyl)allyl] carbonate.

Almost simultaneously,Archambeau and coworkers [115] also realized a similar [4+4] cycloadditon reaction using dppe as the ligand between benzofuran-derived azadienes65awithtertbutyl[2-(hydroxymethyl)allyl] carbonate90c.In contrast to the above work,the difference was the absence of asymmetric examples.Noticeably,linear azadienes were also involved and yielded monocyclic eight-membered heterocycles with complete regioselectivity.

In 2022,Guo and coworkers [116] achieved the construction of tetrahydropyran derivatives101-105in moderate to high yields with excellentdrvalues (>20:1dr)viapalladium-catalyzed[4+2] cycloaddition reactions of hydroxy-tethered allyl carbonate99with five electron-deficient alkenes,including indandionebased alkene80,1,1-dicyanoalkenes2,barbiturate-derived alkenes25,pyrazolone-derived alkenes79,and acyl-substituted alkene100(Scheme 38).Interestingly,compared with the previous 3-hydroxy-2-methylenepropyl carbonates,theα-position of oxygen atom in the dipole precursors has one extra substituent in99,and therefore theα-position of the oxygen atom in the corresponding tetrahydropyran products also has an additional chiral center.The possible mechanism is described using99and indandione-based alkenes80as substrates.First,the oxa-1,4-dipole intermediateAis produced by palladium-catalyzed decarboxylation/deprotonation of substrate99to release of CO2andt-BuOH.The intermediateAsubsequently attacks indandione-based alkenes80to give the intermediateB.The two aryl groups in the six-membered ring transition state ofBare located at equatorial positions,so that thecisisomer serves as the major product when undergoing intramolecular cyclization.

Scheme 38.Pd-catalyzed [4+2] cycloadditions of hydroxy-tethered allyl carbonate.

Very recently,Yuan and coworkers also developed the [4+2]cycloaddition reaction of 2-alkylidenetrimethylene carbonates76or 2-(hydroxymethyl)-3-arylallyl carbonates90with 3-nitroindoles to deliver a wide range of indoline-fused tetrahydropyrans in good yields with excellent diastereoselectivities [117].That was due to the formation of the same oxa-1,4-dipole intermediate catalyzed by palladium using different dipole precursors.Unexpectedly,Liu and coworkers also involved 2-alkylidene-trimethyl carbonates (ADTMCs) as 1,3-all-carbon dipoles in the [3+2] cycloaddition reactions with [60]fullerenes [81].

3.8.Miscellaneous

In 2018,Rios and coworkers [118] successfully reported the first ring contraction/formal [6+2] cycloaddition of pyrazolone derivatives106withα,β-unsaturated aldehydes107in synergistic Pd(0)/chiral secondary amine catalysis to obtain [5,5]-spiropyrazolone derivatives108in excellent yields and stereoselectivities (Scheme 39).The reaction mechanism started with the coordination of palladium to the double bond of substrates106.Palladium not only interacted with the C=C double bond,but also coordinated with one molecule of acetonitrile to form complexI.ComplexIrearranged to form intermediateII.Meanwhile,iminium intermediateIIIwas formedviacondensation of enal107with a chiral secondary amine,which underwent conjugate addition with intermediateIIto give complexIV.The desired products108were afforded after intramolecular allylic substitution and hydrolysis of iminium.In addition,the protonated form of the key palladiumactivated intermediateIIcan be detected by mass spectrometry and its structure was characterized by infrared spectroscopy and DFT calculations.

Scheme 39.Pd-catalyzed ring contraction/formal cycloadditions with pyrazolone derivatives.

In 2021,Vesely and coworkers [119] also developed similar cycloadditions between thiazole derivatives109andα,β-unsaturated aldehydes107.The reactions were catalyzed by the cooperative achiral Pd(0) complex and a chiral secondary amine to deliver the corresponding chiral spirothiazolones110in yields up to 98%,as well as 12/1drand 99%eevalues (Scheme 40).The process proceeded by forming the transient zwitterionicπ-allyl palladium intermediatesIand chiralα,β-unsaturated iminium ionsII.Next,iminium intermediateIIunderwent conjugate addition to intermediateI,affording enamineIII.After intramolecular 5-exo-trigcyclization and hydrolysis of iminium,spirocycles110were formed and Pd(0) was returned to the catalytic cycle.

Scheme 40.Pd-catalyzed ring contraction/formal cycloadditions with thiazole derivatives.

The development of 1,8-dipoles has lagged significantly compared to Pd-π-allyl 1,4-or 1,6-dipoles.In 2020,Lu and coworkers[120] developed Pd-catalyzed [8+2] cycloaddition reactions withα-diazoketones85using carbamates111as non-decarboxylated Pd-containing 1,8-dipolesIrather than decarboxylated intermediateIIto provide various 10-membered monocyclic products112bearing chiral quaternary stereocenters in the presence of chiral ligandL33under mild conditions (Scheme 41).Decarboxylation occurred in most dipole cycloaddition reactions based on the palladium-catalyzed reactions involving carbamate substrates,producing active Pd-π-allyl zwitterionics by releasing CO2[44].Interestingly,in this process,the carbonate anions of dipolesIcould attack the ketenesIIIvianucleophilic addition to produce intermediatesIV,and subsequently intramolecular allylation of the enolate intermediatesIVwould yield 10-membered monocyclic products112.Moreover,the electronic effect of the amine played a key role in the stability of the reaction intermediates.Under the same conditions,tosyl (Ts)-and 4-MeO-benzyl (PMB)-substituted vinyl carbamates gave very different results (Scheme 41bvs.41a).The former reaction provided an inseparable mixture of 6-and 8-membered cycloadducts113and114,neither of which retained the CO2unit (Scheme 41b).While the latter reaction did delivere the desired 10-membered monocyclic compound112a(as racemate) in a good yield (Scheme 41a).These results are similar to that ofγ-methylidene-δ-valerolactones,where the electron-richα-substituted ofγ-methylidene-δ-valerolactones could act as 1,6-dipoles by inhibiting the decarboxylative process [56].

Scheme 41.Pd-catalyzed [8+2] cycloadditions of vinyl carbamates.

4.Pd-π-allyl zwitterions bearing a N-centered anion

N-Heterocycles have received widespread attention due to their bioactivities and pharmaceutical applications [121–123].Therefore,it is necessary to develop facile and efficient dipolar cycloaddition reactions for the selective and diverse construction of variousNheterocycles.In addition to the well-known vinyl aziridines as azadipole precursors,in 2006,Tunge and coworkers [124] observed for the first time aza-1,4-zwitterionic Pd complexes generated by palladium catalyzed decarboxylation of 6-vinyl-1,3-oxazinanones,undergoing [4+2] cycloaddition with electron-deficient olefins.On the basis of those preliminary studies,several new 1,n-C,N-dipoles have been recently developed (Scheme 42).

Scheme 42.Pd-π-allyl zwitterions bearing a N-centered anion.

In 2016,Harrity and coworkers [125] established a short and scalable synthetic route to carbamate115,which was able to adapt the sequence developed by Suzuki [126].Then,the [4+2] cycloaddition reactions of carbamate115that was used as a precursor of 1,4-C,N-dipole intermediate,with 1,3-dicarbonyl substrates116or118were realized by using a catalyst system comprising Pd(dba)2and phosphoramidite ligands (Scheme 43).When achiral phosphoramidite ligandL35was employed,a range of piperidines117were constructed in good to high yields (Scheme 43b).When using chiral ligandent-L18,increasing the steric encumbrance of R group of ketoesters118had varying effects on the selectivity,where the isopropyl group produced the best enantiomeric excess.The corresponding piperidines119were obtained in high yields and enantioselectivities (Scheme 43c).

Scheme 43.Pd-catalyzed [4+2] cycloadditions of carbamate 115.

In 2021,the same group [127] achieved another [4+2] cycloaddition between carbamate115andα-fluoroβ-ketoesters120orα-SCF3-substituted ketones121to construct 3-fluoro-or trifluoromethylthio-piperidines123and125with imine,ester,and alkene functional groups in good to high yieldsvia122or124intermediates,respectively (Scheme 44).This method is a new and efficient way to introduce 3-trifluoromethylthio-group into piperidines,providing a general approach for these important scaffolds.

Scheme 44.Pd-catalyzed [4+2] cycloadditions of carbamate 115 with α-fluoro βketoesters or α-SCF3-substituted ketones.

In 2019,acyclic allylic carbonates126-128can be readily obtained in a one-step synthesis.A Pd-catalyzed asymmetric [3+2]cycloaddition reaction of nitrogen-containing allylic carbonate126with isocyanates44was first reported by Zhang and coworkers (Scheme 45a) [128].A practical and efficient method for obtaining imidazolidinones129in high yields and enantioselectivities in the presence of chiral binol-derived phosphoramidite ligandL18and palladium co-catalysis was developed.Allylic carbonate126could afford stable 1,3-zwitterionic allylpalladium intermediate similar to 5-vinyloxazolidin-2-ones or vinylaziridine [20,129].In addition,a Pd-catalyzed asymmetric [4+2] cycloaddition of nitrogen-containing allylic carbonate127with isocyanates44was also developed (Scheme 45b) [128].Allylic carbonate127could provide stable 1,4-zwitterionic allylpalladium intermediate similar to 6-vinyl-1,3-oxazinanones under palladium catalysis.A series of chiral tetrahydropyrimidinones130could be obtained in up to 87% yield and 99%eeunder ligandL36and palladium co-catalysis.When the reaction of allyl carbonate128with benzyl isocyanate44aunder the same reaction conditions as that of126was investigated,only pyrrolidine131was obtained in 72% yield and 43%ee.No cycloadduct132was observed (Scheme 45c).This result suggested that allyl carbonate128underwent intramolecular cyclization to produce pyrrolidine131through the generation of 1,5-zwitterionic allylpalladium intermediate.

Scheme 45.Pd-catalyzed [n+2] cycloadditions of acyclic allylic carbonates.

In 2019,Trost and coworkers designed a new Pd-aminoallyl precursors133and applied them to the [3+2] cycloaddition reactions with dienes (Scheme 46a) [130].Compared with their previous reports,an electron withdrawing group on the Pd-oxyallyl precursors was essential for the smooth [3+2] cycloaddition with conjugated dienes [67].Thus,the electron-withdrawing ester motif was also indispensable for the [3+2] cycloaddition involving the Pdaminoallyl precursors.A variety of pyrrolidines134were produced in moderate to high yields via the C-N reductive elimination.The Pd-aminoallyl precursors133were prepared from commercially available substrates in a single step by Tamaru and coworkers in 1994 [131].Notably,similar to Pd-oxyallyl intermediate,the heterocycle adducts134can be readily isomerized to thermodynamically more stable carbocycles135viaintermediate136in the present of bidentate dppe ligand and CpPd(cinnamyl) (Scheme 46b).Thus,the five-membered carbocyclic135could be formed by palladiumcatalyzed [1,3] N-to-C rearrangement.

Scheme 46.Pd-catalyzed [3+2] cycloadditions via Pd-aminoallyl intermediates.

Additionally,Zhang and co-workers achieved highly substituted or fused pyrrolidines in asymmetric cycloaddition reactions of Pdaminoallyl intermediates with 1,3-dienes in 2022 (Scheme 47) [75].The cyclic or acyclic 1,3-dienes reactions with Pd-aminoallyl intermediates were catalyzed using chiral ligands SadphosL37orL38respectively,in which aminoallyl precursors had a large range of ester groups,including Et,Me,nBu,iBu,Ph and Bn.Control experiments indicated that the apparent matched/mismatched effect of substrates was influenced bycis/trans-configuration of aminoallyl precursor and dienes.The cycloaddition products could not be obtained forE-133andZ-33a.The asymmetric version required the aminoallyl precursor133with exclusiveZ-geometry since it could reduce the activation entropy of the transition state generated by Pd/Sadphos-aminoallyl zwitterion.Moreover,a Pdcatalyzed [1,3] N-to-C rearrangement with the achiral ligand could also be achieved.

Scheme 47.Pd-catalyzed asymmetric [3+2] cycloadditions via Pd-aminoallyl intermediates.

In 2020,Shi and coworkers [45] continued to expand the application of vinyl indoloxazolidones1,which could be convert to Pd-π-allyl zwitterion intermediateAspecifically used as a nitrogen-carbon-carbon building block (Scheme 48).Thus,palladium-catalyzed decarboxylative [3+2] cycloaddition reactions were achieved by reaction with isocyanates44.Nevertheless,different chiral ligands (including chiral phosphoramidites and chiral bidentate phosphine ligands) could hardly control the enantioselectivity (<8%ee) of the [3+2] cycloaddition reaction.Furthermore,when the electron-deficient olefin benzylidene malononitrile2was used as a dipolarophile for the reaction with oxazoloindol-3-one1under palladium catalysis,the product140was produced in 94% yield with a diastereoselectivity of 56/44.

Scheme 48.Pd-catalyzed [3+2] cycloadditions of vinyl indoloxazolidones.

Interestingly,in 2021,Chen and coworkers disclosed the first use of pyrrolidines141[132,133] for the palladium-catalyzed[5+2] cycloaddition reactions with azlactones or butenolides to produce seven-membered azepines143(Scheme 49) [134].A wide range of substrate scope was suitable.R3on142could be aryl,vinyl,alkyl.Moreover,the substituent on the nitrogen atom of substrates141could contain PMB,cyanide,phthalimide,or ester groups.A possible reaction pathway was depicted.Firstly,with the assistance of B(OH)3,the palladium catalyst underwent oxidative addition with 3-alkylidenepyrrolidines141to yieldN-zwitterionic intermediateIthrough an inert C-N bond cleavage.The substrates142acted as a two-atom synthon to capture intermediateIto give intermediateII.Subsequently,1,1-disubstituted alkene on intermediateIImay isomerized to form conjugated azlactone intermediateIII.The final azepines143were generated by an intramolecular lactamization step.

Scheme 49.Pd-catalyzed [5+2] cycloadditions of 3-alkylidenepyrrolidine.

5.Summary and outlook

As described in this review,the palladium-catalyzed intermolecular cycloaddition reactions of 1,n-dipoles with different dipolarophiles in the present of ligands can be an effective and practical strategy for constructing structurally diverse 5-to 12-membered cyclic compounds,which are widely found in many natural products and pharmaceutical molecules and have received significant attention from synthetic chemists.We mainly summarize the progress of Pd-π-allyl zwitterions in the past 5 years,including newly designed Pd-π-allyl zwitterionics and several zwitterionics that have received renewed attention,which have also been designed and applied to diverse reaction partners to achieve new cyclic compounds that may be difficult to construct by other conventional methods.

Despite these great achievements allow for the rapid and convenient construction of complex polycyclics or medium-sized cycles exclusively with relatively simple substrates under mild conditions.There are several areas still need improvement.First of all,such transformations are often plagued by competitive reaction pathways and low levels of site-and stereoselectivity,and improvements in new catalytic systems may depend heavily on the design and discovery of new dipoles and chiral ligands.Secondly,the corresponding precursors of these key species are far from adequate,especially for 1,6-or 1,8-zwitterionicπ-allyl palladium species,and their applications are still rare.Moreover,studies on the direct application of cycloaddition reactionsviaPd-π-allyl zwitterion intermediates to the total synthesis of natural products,bioactive molecules,and pharmaceuticals are still scarce [135,136],even though this aspect is of great importance.Therefore,the design and discovery of novel zwitterionicπ-allyl palladium species will be crucial to the continuous advancement of this field and the direct application of this reaction strategy to the synthesis of drugcontaining or active molecules.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We acknowledge the financial support from the National Natural Science Foundation of China (Nos.22071143 and 21772215),Start-up Funding for Scientific Research of Nanning Normal University (No.86612345) and “BAGUI Scholar” Program of Guangxi Province of China.