Generation of the p -Allyl Complex
2.1.1 Via Cleavage of an Allylic C–X Bond
The generation of ap-allyl palladium complexes typically occurs through the heterolytic cleavage of a C–X allylic bond in the presence of an electron-rich palladium(0) complex, a process known as "oxidative addition" due to the increase of the metal's oxidation state by 2 This step is often termed "ionization" because the resulting reactive 3-allyl intermediate is usually ionic Various allylic substrates have been utilized in this allylation reaction, with the efficiency of turnover generally improving with better leaving groups, as illustrated in Fig 2.
In 1981, Yamamoto and colleagues demonstrated the oxidative addition of allyl acetate to a Pd(0) complex, isolating the 3-allyl(acetato)palladium intermediate The formation of the p-allyl Pd(II) complex from allyl acetate and Pd(0) is a reversible process, with the equilibrium heavily favoring the Pd(0) side Conversely, using allyl trifluoroacetate with Pd(dba)2 results in the complete formation of the corresponding p-allyl complex These findings highlight the significant impact of the leaving group's nature on the equilibrium shift and the overall substitution process.
Fig 2 Classical electrophiles used in the palladium catalyzed allylation reaction
The introduction of carbonate as a leaving group by Tsuji in 1982 marked a significant advancement in organic chemistry, as carbonate outperforms acetate by enabling reactions in nearly neutral conditions Initially, it was believed that the decarboxylation of released carbonate produced alkoxide, which could then deprotonate the pronucleophile However, this notion is contradicted by the isolation of 3-allyl palladium alkoxycarbonate complexes, which do not undergo spontaneous decarboxylation Instead, their reaction with acidic substrates yields hydrogen carbonate complexes that may decarboxylate later Recent research by Amatore, Jutand, and Moreno–Man˜as confirmed that oxidative addition from allylic carbonates is a reversible process, further supporting the idea that 3-allyl palladium alkoxycarbonates do not spontaneously decarboxylate Similarly, allyl carbamates exhibit reactivity akin to allyl carbonates, and the less common 1,3-diene monoepoxide, introduced a year prior, also reacts with nucleophiles without the need for a base While allyl phenoxides can function under neutral conditions, their limited reactivity toward oxidative addition restricts their application.
Apart from these classical substrates, allylic ammonium ions [37], sulfones [38], sulfides and selenides [39], phosphates [40], nitro groups [41, 42], halides [43], nitrates [44] have also been used asp-allyl precursors.
Allyl alcohol is a valuable substrate from an atom-economical perspective, yet its development has faced challenges due to the limited leaving ability of the hydroxyl group Despite being utilized since 1970 by Atkins, research into its potential continues to be a focus of active investigation.
Although less documented, oxidative addition of a Pd(0) complex on allenyl derivatives generates a vinyl allyl Pd(II) complex that can be trapped by a nucleo- phile (Scheme3).
In this context, phosphates [47] and acetates [48] (Scheme4) have been used successfully as leaving groups.
2.1.2 Via Cleavage of a C–X Benzylic Bond
The synthesis and isolation of benzylic p-allyl complexes from benzylic chlorides and palladium vapors were first reported in 1977 It wasn't until 1992 that Legros and Fiaud introduced the first palladium-catalyzed allylic alkylation using these benzylic p-allyl complexes.
The palladium-catalyzed allylic allenylation reaction, influenced by the formation of a 3-allylic complex, has been limited to compounds with weak aromaticity, like naphthylmethyl derivatives Kuwano demonstrated that the ligand bite angle significantly affects this reaction, as the use of larger bite angle ligands such as DPPF, DPEphos, and Xantphos enables high-yield substitution of simple benzylic carbonates This advancement in allylic alkylation has garnered considerable interest from researchers.
The use of 1,2 or 1,3 dienes as substrates can facilitate the formation of p-allyl palladium complexes through a carbopalladation process This involves the transient generation of an s-allyl complex by an organopalladium complex, which then equilibrates to the more stable p-allyl complex.
In 1970, Stevens and Shier [54] reported the isolation of a palladium p-allyl complex generated via the carbopalladation of an arylpalladium(II) onto pro- padiene, thereby giving support to such a strategy (Scheme7).
In 1984, Tsuji and Goré independently discovered the catalytic generation and trapping of p-allyl palladium complexes through allene carbopalladation, utilizing amine and malonate as nucleophiles This innovative method has seen significant advancements since those initial experiments.
[Pd(C 3 H 5 )(COD)]BF 4 (1 mol%) DPPF (1 mol%)
X = MeO or MeOCO 2 - [Pd(0)], - XK
Scheme 5 Palladium catalyzed benzylation of dimethyl malonate
Pd 2 (dba) 3 ãCHCl 3 (2.5 mol%) Ligand (7.5 mol%) n-Hex 4 NCl (5 mol%)
Cs 2 CO 3 (3 equiv.) THF, rt, 1d (1.1 equiv.)
Scheme 4 Palladium catalyzed allylic allenylation of a secondary amine
Similarly, Heck [58] has reported in 1978 the use of 1,3-dienes with amines as nucleophiles (Scheme9), whereas the use of malonates was reported by Dieck in
The reaction of a nucleophile with a PdX2-activated 1,3-diene forms an ap-allyl palladium complex This intermediate can then be selectively attacked by another nucleophile, resulting in the formation of the final product and a palladium(0) complex.
[Pd]X Scheme 6 Generation of p-allyl palladium complexes from 1,2 or 1,3 dienes
Scheme 7 Isolation of p-allyl palladium complex via carbopalladation of 1,2-propadiene
NaCH(CO 2 Et) 2 PhI [Pd(0)] cat.
Scheme 8 Generation and interception of p-allyl palladium complexes derived from allene carbopalladation
Ph-Br + Pd(PPh 3 ) 4 Ph
The generation and interception of a p-allyl palladium complex through carbopalladation of a 1,3-diene facilitate a catalytic process, necessitating the reoxidation of Pd(0) to a Pd(II) salt Notable examples in this domain include Bäckvall's methods for 1,4-diacetoxylation and 1,4-chloroacetoxylation Additionally, a comparable reactivity is observed when using allenes.
Allylic C–H bond cleavage is an efficient method for generating p-allyl complexes, involving a mechanism where Pd(II)-alkene coordination activates the cleavage in the presence of appropriate ligands or additives The resulting p-allyl complex is typically attacked by a nucleophile, leading to the release of a Pd(0) species This species is then reoxidized to Pd(II), completing the catalytic cycle.
In 1962, Parshall and Wilkinson synthesized an ap-allyl complex using mesityl oxide and palladium or platinum salts A significant advancement occurred in 1973 when Trost and Fullerton achieved the first stoichiometric allylic alkylation with a nonfunctionalized olefin Although the development of a catalytic version was sought after, challenges in compatibility among each step hindered progress Ultimately, in 2004, Chen and White successfully reported a Pd(II)-catalyzed allylic acetoxylation of terminal olefins.
[68] Success was encountered using Pd(OAc) 2 in the presence of a disulfoxide ligand and 2,6-dimethylbenzoquinone (DMBQ) as a reoxidant The same group
[69] and Shi and coworkers (see also [70]) showed in 2008 that similar conditions allow the use of “soft” carbon nucleophiles, too (Scheme12).
Palladium-catalyzed allylic C–H substitution has been further developed and allows C–O, C–N, and C–C bond formation, yet a general asymmetric version remains challenging [71,72].
Scheme 10 Generation and interception of a p-allyl palladium complex derived from nucleopal- ladation of a 1,3-diene
Scheme 11 Generation and interception of a p-allyl palladium complex derived from allylic C–H activation
Isomerism and Dynamic Equilibria of p -Allyl Palladium Complexes
2.2.1 Static Stereochemical Analysis ofh 3 -(Allyl)palladium Complexes
Cationic 3-allylpalladium complexes, represented as [3-(allyl)PdL2]+X, feature a square planar geometry where two coordination sites are occupied by an allyl fragment and the other two by Lewis-basic ligands like phosphines, amines, or halides The degree of substitution of the allyl group and the nature of the ligands can lead to the presence of zero, one, or two stereogenic elements For instance, achiral complex A lacks any stereogenic units, while chiral complexes B and C possess stereogenic characteristics at the palladium atom and the allyl plane, respectively Complex D showcases both central and planar stereogenic units, whereas achiral complex E features an alkene-type stereogenic axis Consequently, complexes B and C can exist as enantiomers (B/ent-B, C/ent-C), while complex D can manifest in four isomeric forms, comprising two diastereomers each with a pair of enantiomers (D1/ent-D1, D2/ent-D2) Additionally, complex E allows for two diastereoisomeric forms (E endo/E exo) These allyl metal complexes exhibit fluxional behavior, enabling interconversion among various isomeric forms through distinct mechanisms.
2.2.2 Dynamic Stereochemical Analysis ofh 3 -(Allyl)palladium Complexes
In the absence of a nucleophile or when the trapping step is slow, the p-allylpalladium complex can participate in four key equilibria: (a) 3 1 isomerization, (b) ligand association, (c) ligand dissociation, and (d) nucleophilic displacement by a Pd(0)L n complex The activation of these equilibria is influenced by the reaction conditions, which can lead to the exchange of the complex.
O 2 N-CH 2 -CO 2 Me DMBQ (1.5 equiv.) AcOH (0.5 equiv.) dioxane:DMSO (4:1) 45°C, 24 h
Scheme 12 illustrates the generation of a p-allyl palladium complex through allylic C–H activation, which can interact with methyl nitroacetate This interaction can occur via an allyl face complexation with the metal, either maintaining or switching the syn-anti orientation of the allylic substituents Additionally, it encompasses the formal rotation of the allyl group relative to other coordinated ligands.
A no stereogenic unit one stereogenic unit: axis one stereogenic unit: Pd atom one stereogenic unit: allyl plane two stereogenic units: Pd atom, allyl plane
Fig 3 Number and nature of stereogenic units and possible isomers associated to generic 3 - allylpalladium complexes of type [ 3 -(allyl)PdL 2 ] + X
L 1 X η 3 - η 1 ligand association ligand dissociation nucleophilic displacement
Scheme 13 Possible equilibria associated to a generic p-allylpalladium complex
Isomerization, along with C–C bond rotation and 1,3 equilibration, results in a global syn-anti exchange of the substituent pair involved in the rotation, accompanied by the exchange of the complexed allyl face This equilibrium is particularly favorable when both substituents are hydrogen (R1 = R2 = H) and typically shifts towards the syn isomer side in cases of monosubstitution.
In the case of the generic complexes [ 3 -(allyl)PdL 2 ] + X A-E, such movement may lead to regeneration of the starting molecule, enantiomerization, or diastereo- merization (Fig.4).
Szabo´ performed a DFT calculation study ofsyn-antiequilibration on a model
3 -allyl palladium complex [75] Whereas influence of the solvent during the
The 3 ! 1 process is primarily driven by electrostatic interactions, but solvent coordination significantly stabilizes the tricoordinated 1-allylpalladium species This stabilization is notably more effective in Me2O compared to CH2Cl2, with a difference of 6.8 kcal mol⁻¹ In Me2O, the energy barrier for C–C bond rotation within the resulting 1 intermediate is measured at 7.3 kcal mol⁻¹, while the restoration of the 3 coordination occurs almost without a barrier Consequently, this process is characterized by rapidity in coordinating solvents.
Scheme 14 Syn-anti isomerization of a generic p-allylpalladium complex
Fig 4 Results of the syn-anti isomerization of differently substituted generic p-allylpalladium complexes of type [ 3 -(allyl)PdL 2 ] + X
Me 2 O, whereas is less facile in noncoordinating solvents such as CH 2 Cl 2 (Scheme15).
The rate of syn-antiequilibration is significantly influenced by the type of ligand used For instance, bis(oxazoline) ligands exhibit rapid exchange, as evidenced by the coalescence of NMR spectra at 45°C, while two distinct signal sets are recorded at temperatures below 0°C In contrast, P,Pligands demonstrate lower rate constants, reaching up to 4.3 s⁻¹ at 50°C for syn-anti isomerization, and even lower rates of 3.5 s⁻¹ at 72°C are noted for P,S ligands.
The significant trans influence of the phosphorus atom leads to the cleavage of the Pd–C bond during syn-antiequilibration, resulting in rotation around the allyl terminus adjacent to phosphorus Additionally, the presence of halide ions accelerates the rate of syn-anti isomerization.
At 0°C, MOP ligands exhibit an asyn-antiisomerization rate of 2.2 s⁻¹, which can be enhanced by a smaller bite angle or the presence of electron-poor ligands These electron-poor ligands isomerize approximately 20 times faster than their electron-rich counterparts.
Trans-to-C allyl terminus has more σ -character than trans-to-P one
NMe 2 Scheme 16 Syn-anti equilibration path in a
MAP-coordinated 3 -allyl palladium complex
The energy variations in the syn-anti equilibration of a model 3-allyl palladium complex are influenced by the absence of a strong trans-influence ligand, which elevates the energy required for this process Additionally, steric hindrance between the allyl fragment and the ligands significantly contributes to these energy dynamics.
In 1,3-disubstituted p-allyl complexes, the syn,syn conformation is typically favored, with up to 80% of the p-allyl complex exhibiting this arrangement when methyl groups are the substituents For larger substituents, alternative conformers are not observed The malonate anion's attack on the p-allyl complex occurs more slowly than the anti-to-syn equilibration, resulting in consistent selectivity regardless of the starting material This regioselectivity is determined solely by the varying reactivity of the two allylic termini in the common syn,syn intermediate Additionally, the erosion of the enantiomeric ratio is minimal, as the Pd(0)-catalyzed racemization process is expected to be slower than the nucleophilic substitution reaction.
The strategic equilibration limited to a single stereochemical configuration before nucleophilic substitution has been effectively utilized in the total synthesis of the natural products pyranicin and pyragonicin This enantioconvergent process involves a mixture of (2E,4R) and (2Z,4S) allylic isomers, which are produced from a parallel reaction.
Table 1 Influence of the electronic density of ligands in the syn-anti isomerization of MOP-type coordinated 3 -allyl palladium complexes
Ph syn, syn ~65% anti, syn ~35% syn, syn > 95% anti, syn < 5%
The kinetic resolution (PKR) of a racemic precursor in 1,3-disubstituted p-allyl palladium complexes leads to the formation of a single enantiomer of the desired allyl ether, facilitated by a common 3-allyl palladium complex, as illustrated in Scheme 19.
Apparent allyl rotation (AAR) refers to the formal rotation of the allyl group around the Pd-allyl bond axis This movement can lead to the inversion of the stereogenic palladium center or the stereogenic axis, but not the stereogenic plane, which remains attached to the metal on the same side Consequently, AAR can either regenerate the original structure or result in enantiomerization or diastereomerization, depending on the substitution patterns.
P P anti-syn anti to syn equil. faster than malonate addition no significant erosion of enantiomeric ratio
[Pd(0)] dppe cat [Pd(0)] dppe cat
Scheme 18 Generation of a common enantiopure p-allyl palladium complex from different isomeric enantiopure substrates when nucleophilic substitution is the rate determining step
Scheme 19 Enantioconvergent palladium catalyzed allylic substitution starting complex (Fig 5) From the practical viewpoint, this movement is only visible when it implies the generation of two diastereoisomers.
Three potential pathways for isomerism have been proposed, with two maintaining a coordination number of three throughout the process—one following a dissociative mechanism and the other an associative mechanism The third pathway involves a sequence of 3-1 isomerization, C–Pd rotation, and 1-3 isomerization.
In complexes featuring bidentate ligands with varying donor properties such as P,N-, P,S-, and N,S-, the mechanism of apparent allyl rotation is significantly influenced by the trans effect of the ligands The more donor-like heteroatom tends to occupy the position trans to the more reactive allyl terminus This highlights the importance of the donor heteroatoms, which can be ranked based on their effectiveness in this context.
R regeneration enantiomerization regeneration epimerization D 2 diastereomerization
Fig 5 Results of apparent allyl rotation in differently substituted generic p-allylpalladium complexes of type [ 3 -(allyl)PdL 2 ] + X
Scheme 20 Possible pathways for the apparent allyl rotation according to their trans effect P~ NHC>S > N (NHCẳN-heterocyclic carbene) [89,90].
Trapping of the p -Allyl Complex
The electrophilic p-allylpalladium intermediate can react with carbon or heteronucleophiles, facilitating the creation of new C–C or C–heteroatom bonds at one allylic terminus This process simultaneously reduces palladium(II) to palladium(0), enabling the reaction to proceed catalytically.
The mechanism of nucleophilic substitution is influenced by the characteristics of the incoming nucleophile "Soft" nucleophiles, with conjugate acids having a pKa of less than 25, directly attack the allyl ligand In contrast, "hard" nucleophiles, whose conjugate acids have a pKa greater than 25, first coordinate with the palladium center before being transferred to the allyl ligand through a process known as reductive elimination.
2.3.1 Trapping ofp-Allyl Intermediates by “Soft” Nucleophiles
In palladium-catalyzed allylic substitution with a "soft" nucleophile, the ionization and nucleophilic attack occur outside the metal's coordination sphere The nucleophile targets the electrophilic p-allyl ligand from the side opposite to palladium, attacking either the C1 or C3 allylic carbon This leads to a 3-to-2 reorganization, forming a palladium(0)-olefin complex that subsequently releases the allylated product along with the active catalytic palladium(0) species.
The stereochemistry of allylation involving "soft" nucleophiles has been investigated using both cyclic and acyclic models Research by Trost and colleagues demonstrated that the reaction of cis cyclohexenyl acetate with sodium dimethylmalonate, catalyzed by palladium(0), yields a substitution product that maintains the original stereochemistry This process involves oxidative addition, leading to a transient p-allyl palladium complex through inversion, with the nucleophile attacking opposite to the palladium center.
[Pd]OAc inversion inversion overall retention
Scheme 26 Proof of the double inversion mechanism in the allylic substitution with
The Tsuji–Trost reaction is an allylic substitution process that utilizes "soft" carbon nucleophiles, typically stabilized carbanions represented by the formula RXYC In this reaction, X and Y are electron-withdrawing groups, which can include various functional groups such as esters, ketones, aldehydes, amides, imines, nitriles, nitro groups, sulfones, sulfoxides, and phosphonates.
Carbanions are typically generated by treating pronucleophiles, such as RXYCH, with a strong base like sodium hydride However, the Tsuji–Trost reaction can also occur effectively under neutral conditions through in situ deprotonation of the pronucleophile In this process, valuable electrophilic partners include allylic carbonates, allylic carbamates, vinyl epoxides, and aryl allyl ethers, as the displaced anion is sufficiently basic to form the nucleophile.
Poli and colleagues demonstrated that the common acetate leaving group can facilitate endogenous deprotonation when the pronucleophile possesses sufficient acidity Subsequent research revealed that the introduction of titanium tetraisopropoxide lowers the pKa value of the coordinated pronucleophile, expanding the variety of active methylenes that can be utilized under these mild reaction conditions.
In a novel approach to achieve neutral conditions, allylic acetates can be utilized as electrophilic partners by substituting a strong base with N,O-bis(trimethylsilyl)acetamide (BSA) alongside a catalytic amount of acetate anion This acetate anion initiates the reaction by extracting the trimethylsilyl group from BSA, resulting in the formation of N-trimethylsilylacetamide anion, which subsequently deprotonates the pronucleophile As the allylation reaction progresses, it releases an equivalent of acetate ion, which continues to react with BSA.
The Tsuji–Trost reaction facilitates the in situ generation of catalytic amounts of base, allowing for the effective application to labile compounds These mild conditions are particularly advantageous in asymmetric allylic alkylation processes.
The Tsuji–Trost reaction is a versatile method utilized in the synthesis of various natural and pharmaceutical compounds due to its adaptable nucleophilic and electrophilic partners and tolerant reaction conditions Additionally, conducting the Tsuji–Trost reaction intramolecularly enables the creation of a diverse range of compounds.
In their synthesis of α-kainic acid, Poli and colleagues utilized an intramolecular allylic alkylation to selectively generate the crucial trans pyrrolidinone Notably, they opted for a phosphonoacetamide as the nucleophilic partner, diverging from the typical choice of malonamide This strategic selection allowed for the subsequent use of the phosphonate group in a Horner–Wadsworth–Emmons olefination, enhancing the efficiency of the synthetic process.
The Tsuji–Trost reaction typically involves C–C bond formation using carbanions stabilized by two electron-withdrawing groups; however, it can also effectively utilize a range of other carbanions, including those derived from phenylacetonitrile and nitroalkanes, to produce the desired allylated products.
More synthetically important, the palladium-catalyzeda-allylation of “simple” carbonyl derivatives can be achieved via the corresponding non-stabilized enolates
[114,115] Indeed, preformed enolates of ketones, aldehydes, and esters bearing various countercations such as Li [116–118], B [119,120], Sn [121,122], Si [123],
Magnesium (Mg) and zinc (Zn) have proven effective as nucleophiles in allylic alkylation reactions Nonetheless, their practical use is limited due to challenges like low regioselectivity, the occurrence of polyalkylation, and the high basicity of the reaction environment.
Scheme 27 Mechanism of the (BSA/cat AcO ) promoted palladium catalyzed allylic substitution
(MeO) 2 OP quant (trans/cis > 95:5)
[Pd(C 3 H 5 )Cl] 2 (5 mol%) dppe (12.5 mol%) n-Bu 4 NBr (10 mol%) aq KOH
Scheme 28 Pd-catalyzed allylic alkylation reaction, used as key step in the synthesis of a -kainic acid
Palladium enolates can be generated in situ under neutral conditions using allyl β-ketoesters and allyl enol carbonates as precursors This process begins with the oxidative addition of the allyl group to palladium(0), followed by decarboxylation, resulting in the formation of a p-allylpalladium enolate Subsequently, the carbanion attacks the allyl ligand, producing the α-allylated ketone and releasing the active catalytic species This reaction exemplifies a palladium-catalyzed variant of the thermal Carroll rearrangement.
Trost and colleagues effectively utilized palladium-catalyzed decarboxylative asymmetric allylic alkylation of allyl enol carbonates to synthesize ketones with an α-tertiary center The mild reaction conditions resulted in high yields and excellent enantiomeric excess (ee), avoiding unwanted racemizations or dialkylations of the α-center.
CO 2 Scheme 29 Mechanism of the palladium catalyzed decarboxylative allylic alkylation
Pd 2 (dba) 3 ãCHCl 3 (2.5 mol%) Ligand (5.5 mol%)
Scheme 30 Example of enantioselective palladium-catalyzed decarboxylative allylation of an allyl enol carbonate
Various heteroatom-based nucleophiles have been employed in palladium- catalyzed allylic substitution reactions [132] Among them, the most studied are N-,O-,S-, andP-derivatives.
Intramolecularly Directed Regioselectivity
Efficient methods to control regioselectivity in palladium-catalyzed allylic substitution reactions have been developed using substrates that can coordinate with the metal Notably, research by Krafft and Yoshida has shown that a homoallylically located tertiary amine or thioether, along with a 2-pyridyldimethylsilyl group, can effectively direct nucleophiles to the allylic terminus near the heteroatom This selective site preference can be attributed to the trans influence of the chelated 3-allyl intermediate, where the nucleophile tends to attack the longer and more reactive Pd–C bond.
Cook and colleagues investigated the allylic substitution of chiral 5-vinyloxazolidinones with phthalimide acting as the nucleophile Their findings revealed high and consistent regio- and stereoselectivity that favored the formation of syn-configuration 1,2-diamine derivatives This selectivity can be attributed to a hydrogen bond formed between the transiently protonated amide group and the oxyanion of the deprotonated imide nucleophile.
Ligand-Directed Regioselectivity
The regioselectivity of palladium-catalyzed allylic alkylation is influenced by the interaction of steric and stereoelectronic factors associated with the nucleophile, ancillary ligand, and allyl fragment, particularly in the absence of specific directing issues in the substrate.
Two linear (E or Z) and one branched allylic precursors can oxidatively add to a Pd(0) complex to afford a syn or an anti configured monosubstituted
The 3-allylpalladium intermediate allows for nucleophilic attack at either the terminal or internal position of the allyl fragment, resulting in the formation of linear (E or Z) or branched products This unique reactivity is particularly significant for the advancement of asymmetric synthesis methods.
The linear E substrate is anticipated to produce a synallyl complex, potentially leading to the formation of either linear E or branched products Conversely, the linear Z substrate is expected to first create an anti-configured allyl complex, which may react directly with a nucleophile to yield either the Z linear or branched product.
EtO 2 C CO 2 Et (87%) 10 : 1 Y = SMe (76%) 19 : 1 Y = NMe 2
Scheme 37 Intramolecularly-directed palladium catalyzed allylic substitutions
NPhth linear : branched 20 : 1 syn : anti > 99:1
Scheme 38 illustrates that in H-bond directed palladium-catalyzed allylic substitution, both syn and anti 3-allyl intermediates can be intercepted without prior equilibration, resulting in complete stereoretention Conversely, if the rate of nucleophilic attack is slower than the anti-syn equilibration, the final product ratio will be influenced by the thermodynamically averaged intrinsic regioselectivity of the intermediates involved.
3 -allyl isomer Usually, thesyn p-allyl isomer is more stable than theanti one, and the trapping by the malonate anion is slower than equilibration (Scheme39).
The E linear isomer typically exhibits a high degree of stereoretention, while the Z isomer frequently undergoes partial anti-synequilibration before reacting Consequently, the branched allylic substrate is anticipated to yield a mixture of final products, influenced by the relative amounts and reactivity of the syn and anti p-allyl intermediates involved.
The regioselectivity of a reaction is influenced by multiple factors, including the structure and nature of the allylic fragment and ligand, the symmetry and bite angle of bicoordinating ligands, the stoichiometry of complexation for monocoordinating ligands, and the position of the rate-determining step, whether it involves ionization or nucleophilic substitution.
Under classical conditions, the structure and behavior of a transiently generated allyl complex are unaffected by the relative positioning of unsaturation and the leaving group in the substrate For instance, the same syn p-allyl complex can originate from both E-linear and branched products Typically, the branched product reacts mainly at the unsubstituted allylic terminus, with the linear-to-branched ratio generally increasing in proportion to the size of the nucleophile.
Scheme 39 Possible scenarios in the generation and reactivity of a cationic (chloride-free, see later) monosubstituted 3 -allylpalladium intermediate
A stoichiometric study on allylic alkylation with the sodium anion of methyl diethyl malonate and various bidentate ligands incorporated in a xanthene backbone demonstrated that the strong π-acceptor P,P-based ligand Xantphos, with a bite angle of 111°, primarily facilitated the formation of branched products In contrast, the use of a weak π-acceptor N,N-based ligand predominantly resulted in the production of linear products.
Enhancing the nonsymmetry of the allyl moiety or utilizing unsymmetrical bidentate P,N ligands can effectively achieve regioselectivity Research by Vitagliano and colleagues demonstrated that the allyl terminus trans to the p-accepting phosphorus atom exhibits greater electrophilicity than that trans to the nitrogen atom Subsequent computational studies have validated the "trans-to-P" effect of P,N ligands, suggesting that a shift towards earlier transition states can optimize this phenomenon This "trans-to-P" effect has proven to be widely applicable and has been successfully employed in asymmetric catalysis with symmetrical p-allyl fragments using enantiopure chiral P,N ligands.
Coming back to the alkylation of unsymmetricalp-allyl fragments, fine tuning of an appropriateP,Nligand was shown to direct the nucleophilic attack toward the branched product (Scheme40).
The use of a suitable P,N ligand with a p-acidic phosphite has successfully shifted the nucleophilic substitution mechanism from an S N 2 type to a more favorable S N 1 type Additionally, the chiral ligand can align with the chirality, facilitating effective enantioselection.
Another way of increasing the branched-to-linear ratio using bidentate P,N ligands is to increase their bite angle [200].
Achieving selectivity for the branched isomer, particularly in enantioenriched form, is typically the primary goal; however, optimizing selectivity for the linear isomer presents its own challenges This optimization was successfully achieved using PPh3 alongside a catalytic amount of lithium iodide The findings suggest a mechanism that involves substitution on an iodide-ligated allyl complex, characterized by a trans arrangement between the phosphine and the internal allylic terminus, regardless of the starting substrate Notably, "cis-to-P" attacks are less favorable when using bulkier monophosphines.
Scheme 40 Role of a P,N ligand in the regioselectivity of a palladium catalyzed allylic substitution
Monosubstituted allylic substrates lead to syn-allylpalladium intermediates that favor terminal attack, while the antiisomers, which do not convert to the syn form, exhibit a preference for internal nucleophilic substitution This distinct reactivity is particularly intriguing due to the chirality of the branched products, which can be achieved by employing specific ligands that thermodynamically promote the antiisomer.
204] or generating the anti isomer in the presence of very reactive nucleophilic partners capable of intercepting it before it equilibrates to the (usually) more stable
Scheme 41 Branched- and enantio-selective palladium catalyzed allylic substitution via a phos- phite-type P,N ligand
[Pd(C 3 H 5 )Cl] 2 cat [Pd(C 3 H 5 )Cl] 2 cat.
0 (from either linear or branched)
The Scheme 42 Iodide effect significantly influences the regioselectivity of palladium-catalyzed allylic substitutions, particularly in the formation of syn-isomers When malonate anions are employed, the process of anti-to-syn isomerization occurs rapidly compared to the nucleophilic attack, leading to a product distribution that reflects an equilibrium mixture of 3-allyl complexes, with a predominance of the syn complex Conversely, more reactive nucleophiles can effectively trap these 3-allyl complexes before they reach equilibrium, altering the outcome of the reaction.
The highly reactive zinc amino acid ester enolate A [207] can effectively intercept an anti-configured 3-allyl complex before it undergoes isomerization to the more stable syn isomer, but this requires a sufficiently fast substitution process If the reaction slows down, such as when steric bulkiness is present in the 3-allyl complex, the nucleophilic attack is preceded by anti-to-syn isomerization.
Memory Effects
In Pd-catalyzed allylic alkylations, the canonical mechanism involves a distinct bicoordinated cationic 3-allyl-Pd intermediate, regardless of the allylic precursor's structure This mechanism is characterized by variations in the positioning of the leaving group and unsaturation Additionally, electronic factors favor the nucleophile's attack at the more substituted allylic position.
RC syn product product product product profile a profile b
The qualitative energy profiles of allylic alkylations illustrate two key scenarios: (a) the rapid isomerization from anti to syn occurs faster than the nucleophilic attack, and (b) the nucleophile effectively captures the kinetically formed syn and anti 3-allyl complexes prior to their equilibration.
Metal-catalyzed allylic alkylation can yield branched products using transition metals other than palladium Although this chapter does not cover this topic in detail, it is important to note that increased steric hindrance significantly favors the formation of linear products.
Fiaud and Malleron identified a deviation from classical reaction mechanisms, termed the "memory effect," where the nucleophile interacts with the allylic carbon previously occupied by the leaving group This phenomenon has been validated by multiple studies and is notably observed when bulky mono-phosphines are present.
Various theories have been proposed to account for the differing reactivity of isomeric allylic substrates These include the participation of a tight ion pair with the leaving group, reactions involving 1-allyl intermediates, and the influence of unequal transeffects due to unsymmetrical ligation.
Recent studies have demonstrated that catalytic amounts of chloride anions significantly enhance the oxidative addition of the slow-reacting enantiomer of cyclopentenyl pivaloate in the presence of TSL These findings reveal that chloride anions can initiate a competitive reaction pathway that bypasses the traditional cationic 3-allyl intermediates The process begins with the formation of a highly reactive anionic Pd(0) phosphine complex, which then undergoes oxidative addition to the allylic substrate, resulting in a neutral chloride-coordinated 3-allyl complex This complex is subsequently attacked by a nucleophile to yield the final product.
In an allylic alkylation reaction involving linear (E or Z) and branched isomers, the presence of chloride anions creates a more complex situation, leading to the duplication of allyl intermediates The influence of phosphine, which promotes the departure of the leaving group trans to itself, allows for the preferential generation of four allyl complexes Specifically, the E and Z linear substrates yield the syn-from-E and anti-from-Z isomers, respectively.
[Pd(C 3 H 5 )Cl] 2 (2 mol%) PPh 3 (4 mol%) THF, -78°C -> rt
[Pd(C 3 H 5 )Cl] 2 (2 mol%) PPh 3 (4 mol%) THF, -78°C -> rt 84%, 82% syn, 90% Z
The generation and interception of an anti 3-allyl palladium complex can occur either before or after its equilibration to a more stable syn complex This process may lead to a mixture of syn-from-branched and anti-from-branched complexes, with their ratio influenced by the conformational population during the formation from the allyl complex Computational predictions suggest a strong preference for trans-to-P trapping in the first three complexes, while in the anti-from-Z isomer, the tendency for internal attack and the trans effect counterbalance each other Consequently, the transiently generated complexes exhibit distinct behaviors based on their formation conditions.
The immediate interception of 3-allyl complexes upon formation, particularly in the presence of chloride anions, can induce a significant memory effect, whether starting from linear or branched isomers This phenomenon relies on a slow apparent allyl rotation in relation to nucleophilic addition, which is essential for maintaining this memory effect Conversely, a rapid apparent allyl rotation would eliminate this memory, directing the reaction towards the most reactive allyl complex, in line with Curtin–Hammett conditions.
Analysis of product distribution from allylic triads reveals significant differences when comparing results with and without chloride anions Without chloride anions, the distribution from the branched substrate aligns closely with a linear interpolation of the two linear isomers However, the presence of chloride anions nearly doubles the yield of the branched product from the branched substrate compared to the linear substrates This indicates that chloride anions enhance the selectivity in branched-to-branched transformations, allowing for a clear distinction from an inherent internal memory effect.
X PPh 3 -Pd-PPh 3 Cl PPh 3 -Pd-Cl
Ph 3 P PPh 3 k 2 k 1 classical chloride-free conditions in the presence of chloride anions slow k 2 > k 1
The Pd-catalyzed allylic substitution reaction features 44 distinct 3-allylic intermediates, highlighting the differing attack preferences of chloride anions, as depicted in Scheme 46 This analysis not only elucidates the mechanisms behind branched-to-branched transformations observed in chloride-rich environments but also acknowledges the potential influence of alternative mechanisms, such as tight ion pairing with the leaving group.
Bulky ligands lead to mono-coordination with palladium, resulting in unsymmetrical 3-allyl complexes This scenario exhibits a "memory-type" behavior, transitioning from linear to linear and branched to branched structures Additionally, the presence of chloride anions significantly accelerates the isomerization rate among the isomeric 3-allyl complexes, achieving Curtin–Hammett conditions.
R Pd R' 3 P Cl anti-from-branched
Leaving group departure Nucleophilic substitution
Cl PR' 3 syn-from-branched
- X anti/syn anti/syn syn-from-E
AAR idem idem idem idem
In Scheme 45, various scenarios illustrate the generation and reactivity of a neutral monosubstituted 3-allylpalladium intermediate that contains chloride The less stable cisisomer, though more reactive, will predominantly react to yield the linear isomer as the major product, as depicted in Scheme 47.
A few representative examples are in accord with the above considerations (Table3) [80,219,220].
The formation of a neutral 3-allyl complex involves a lone coordinated P ligand positioned trans to the departing group This stereochemistry supports the idea that the oxidative addition of allylic substrates to a Pd(0)L complex is essentially the reverse of the reductive elimination step, which requires a cis arrangement of the reacting groups.
The nucleophile's preferential entry from the same side as the departing group, before any potential allyl rotation, explains the distinction between the canonical mechanism and the memory-retaining mechanism.
Scheme 46 Intrinsic versus memory-effect-assisted regioselectivity in the Pd-catalyzed allylic substitution reaction
A less stable but more reactive than B
Scheme 47 Mechanistic rationale for the regiochemical memory effect observed in the presence of particular bulky ligands
Oxidative Addition Is the Enantiodiscriminating Step
Oxidative addition serves as the enantiodiscriminating step when the substrate exhibits structural bias, particularly when the nucleophilic attack occurs rapidly compared to the interconversion of diastereomeric p-allyl complexes In such instances, the enantioselectivity is significantly influenced by the nature of the leaving group; a poorer leaving group results in a more retarded transition state with increased steric constraints, ultimately leading to enhanced enantioselectivity, as demonstrated by Fiaud and Legros.
4.1.1 Ionization of Enantiotopic Leaving Groups
Formesosubstrates featuring two enantiotopic leaving groups, or achiral substrates with geminal enantiotopic leaving groups, undergo enantiodiscrimination during the coordination and oxidative addition stages when a chiral ligand is present, resulting in the formation of chiral p-allyl complexes These complexes subsequently react with nucleophiles through a classical double inversion mechanism.
Trost and Dong successfully synthesized Agelastatin using a palladium-catalyzed AAA reaction, starting with a meso diBoc-activated cyclopentene Their approach achieved a high enantiomeric excess and yield, facilitated by the presence of the TSL.
Scheme 58 Ionization of enantiotopic leaving groups
[Pd(C 3 H 5 )Cl] 2 (1.25 mol%) Ligand (1.9 mol %)
Scheme 59 Example of ionization of enantiotopic leaving groups
In reactions involving achiral primary allylic substrates, if the p-allyl interconversion occurs slowly relative to the nucleophilic attack, the oxidative addition becomes the key enantiodiscriminating step This scenario arises when the chiral catalyst selectively targets one enantiotopic face of the alkene, steering the substitution process towards the formation of the branched product.
Trost and Asakawa demonstrated an asymmetric synthesis of Vitamin E through an intramolecular palladium-catalyzed AAA, where oxidative addition served as the enantiodiscriminating step Their findings revealed that experiments designed to enhance the trapping of the p-allyl complex, thereby reducing its racemization, resulted in an increased enantiomeric excess (ee) of the product Conversely, when racemization was accelerated by using additives or increasing the catalyst concentration, a decrease in ee was noted.
Kinetic Resolution of Secondary Allylic Substrates
The oxidative addition of certain substrates results in diastereomeric p-allyl complexes that either do not interconvert or do so slowly in comparison to nucleophilic attacks This scenario can lead to a kinetic resolution, particularly if the coordination or ionization of one enantiomer occurs more rapidly than that of the other.
-X Scheme 60 p -allyl palladium complex interconversion is slow compared to nucleophilic attack
Scheme 61 Example of slow p -allyl palladium complex interconversion compared to nucleo- philic attack
The above case study has been experimentally put into practice by Trost andToste [242], who reported an example of kinetic resolution using an oxygen-based nucleophile (Scheme63).