Palladium-catalyzed Allylic Alkylation Research Articles

Palladium-Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles.

The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)3 , have been developed. These methods enable the enantioselective synthesis of α-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue.

Palladium-catalyzed enantioselective allylic alkylation of trifluoromethyl group substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic esters with malonate anions.

We examined the palladium-catalyzed allylic alkylation of trifluoromethyl group-substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic benzoate with a malonate anion, and succeeded in obtaining an enantiomerically enriched product in high yields with high ee values through the dynamic kinetic asymmetric transformation (DYKAT). The best result was attained by the [Pd(C3H5)(cod)]BF4/(S)-tol-BINAP in the presence of BSA or DMAP as a base.

Palladium-Catalyzed Enantioselective Allylic Alkylation of Cyclopentanones

Palladium-Catalyzed Enantioselective Allylic Alkylation of Cyclopentanones

Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Lactols for De Novo Synthesis of Carbohydrate.

The control of the stereochemistry at the anomeric position is still one of the major challenges of synthetic carbohydrate chemistry. We have developed a new strategy consisting of a chiral catalyst-directed acylation followed by a palladium-catalyzed glycosidation to achieve high α- and β-stereoselectivity on the anomeric position. The former process involves a dynamic kinetic diastereoselective acylation of lactols derived from Achmatowicz rearrangement, while the latter is a stereospecific palladium-catalyzed allylic alkylation.

Modular P-Chirogenic Phosphine-Sulfide Ligands: Clear Evidence for Both Electronic Effect and P-Chirality Driving Enantioselectivity in Palladium-Catalyzed Allylations

Using the ephedrine methodology, modular stereoselective syntheses of a new class of P-chirogenic phosphines bearing a sulfur-chelating arm (P*,S-hybrid ligand) are described. A first series of syntheses based on a Fries-like rearrangement of P-chirogenic phosphinite-boranes, which are prepared from 2-bromobenzyl or 2-bromophenethyl alcohol and are mediated by metal–halide exchange, have been performed. This rearrangement affords phosphine-boranes stereospecifically with an o-hydroxyalkylphenyl substituent. The latter residue is subsequently converted into a sulfur-containing group. In a second series, the stereoselective syntheses were achieved according to a new strategy involving a reaction of a thiophenyllithium reagent with a P-chirogenic phosphinite. The X-ray structures of the P*,S ligands and their palladium complexes allow us to address the absolute configuration at both the phosphorus and sulfur centers. The P*,S ligands were used in palladium-catalyzed allylic alkylations, as tests, affording asymmetric inductions up to 96% ee. Computer modeling corroborates the regio- and enantioselectivity of the Pd-catalyzed allylations and the low influence of the substituent carried by the sulfur moiety, particularly when the chelate forms a six-membered ring with the metal.

Regio- and Stereoselective Modification of Chiral α-Amino Ketones by Pd-Catalyzed Allylic Alkylation.

Chiral α-amino ketones are excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.

Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and diastereoselective palladium-catalyzed allylic alkylations. These investigations prove (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX to be an effective and cost-efficient alternative to electronically modified PHOX ligands derived from the prohibitively expensive (R)-t-leucine.

Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation.

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds.

Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation: total synthesis of (+)-sibirinine.

A catalytic enantioselective method for the synthesis of α-quaternary Mannich-type products is reported. The two-step sequence of (1) Mannich reaction followed by (2) decarboxylative enantioselective allylic alkylation serves as a novel strategy to in effect access asymmetric Mannich-type products of “thermodynamic” enolates of substrates possessing additional enolizable positions and acidic protons. Palladium-catalyzed decarboxylative allylic alkylation enables the enantioselective synthesis of five-, six-, and seven-membered ketone, lactam, and other heterocyclic systems. The mild reaction conditions are notable given the acidic free N–H groups and high functional group tolerance in each of the substrates. The utility of this method is highlighted in the first total synthesis of (+)-sibirinine.

Asymmetric palladium-catalyzed allylic alkylation using dialkylzinc reagents: a remarkable ligand effect.

A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents, which displays broad functional group compatibility, is reported. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzincs. Owing to its mild conditions, enantioselective allylic alkylations of racemic allylic electrophiles are possible in the presence of sensitive functional groups.

Palladium-catalyzed allylic alkylation of simple ketones with allylic alcohols and its mechanistic study.

Allylic alcohols were directly used in Pd-catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20 °C by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier.

Palladium‐Catalyzed Allylic Alkylation of Simple Ketones with Allylic Alcohols and Its Mechanistic Study

AbstractAllylic alcohols were directly used in Pd‐catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20 °C by the concerted action of a Pd catalyst, a pyrrolidine co‐catalyst, and a hydrogen‐bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π‐allylpalladium complex by lowering the activation barrier.

Palladium-catalyzed allylic alkylation using chiral P,O-ligands synthesized via sulfonamide directed ortho-lithiation

An efficient approach for the synthesis of chiral P,O-ligands containing sulfonamide and phosphine moieties is designed. The introduction of the chirality is achieved through different stereogenic groups attached to the sulfonamide nitrogen. The highly effective sulfonamide directed ortho-lithiation and the subsequent reaction with ClPPh2 is the key step in the synthesis of the ligands. The prepared P,O-compounds are applied in Pd-catalyzed asymmetric allylic alkylation (AAA) under optimized conditions, to obtain high degrees of enantioselectivity.

Synthesis and application of new iminopyridine ligands in the enantioselective palladium-catalyzed allylic alkylation

A variety of iminopyridines were obtained by condensation of chiral amines with pyridine-2-carboxaldehyde and quinoline-8-carbaldehyde, or of aminoalkylpyridine derivatives with chiral ketones. These ligands were assessed in the enantioselective palladium catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate affording the product dimethyl 1,3-diphenylprop-2-enylmalonate in good yields and moderate enantioselectivities (up to 62% ee). Catalytic activity and enantioselectivity were found to be highly dependent upon the steric properties of the ligands. The best enantioselectivity (62% ee) was obtained by an iminopyridine based on a camphane skeleton.

Catalyst life in imidazolium-based ionic liquids for palladium-catalysed asymmetric allylic alkylation

A Pd/(S)-BINAP system was successfully applied to the asymmetric allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-ene () using imidazolium-based ionic liquids (ILs) attaining up to 225 h(-1) TOF and 88% ee of the (R)-product. Although the system was barely active in the recycling experiments, the catalyst life was confirmed after recharging the system with substrate/reactants resulting in an alkylated product. In the latter case, the conversion rates and enantiomeric excesses were similar or lower compared to those in the first cycle. In order to explain the observed catalyst performance in the recycling as well as in the recharging experiments, we investigated the reactivity between the catalyst precursors, substrate and reactants in ILs. We were able to identify the species involved in the catalytic reactions under various conditions by means of (31)P NMR analyses. Allylpalladium intermediates () were found to be the active and selective species at a high substrate concentration. When the substrate was consumed, competing reactions took place leading to different palladium complexes. [PdCl(NHC(Bu,Me))((S)-BINAP)]Cl (), together with [Pd((S)-BINAP)2] (), were recognised as the species responsible for the loss of activity, meanwhile, the decrease in enantioselectivity was accounted for by the formation of mixed (NHC)(monophosphine)-palladium species.

Pd-catalyzed allylic alkylation of dienyl carbonates with nitromethane with high C-5 regioselectivity

A highly regioselective palladium-catalyzed allylic alkylation of dienyl esters with nitromethane has been developed, providing selective access to the C-5 attacked products. The structures of the ligands as well as the steric effect of the substrates are important factors in determining the regiochemical outcome of the reaction.

Palladium-Catalyzed Allylic Alkylation of Allyl Dienol Carbonates: Reactivity, Regioselectivity, Enantioselectivity, and Synthetic Applications

For the past several years, the group has focused on the development of useful synthetic tools and on executing creative and efficient routes to biologically active natural products. In this context, we recently applied the palladium-catalyzed decarboxylative allylic alkylation reaction to a new class of substrates, namely allyl dienol carbonates. This method allowed a particularly straightforward access to a wide variety of heterocycles, including 2,4-disubstituted-, 2,3,4- and 2,3,5-trisubstituted-, and 2,3,4,5-tetrasubstituted furans and pyrroles, starting from simple and readily available substrates. An asymmetric version of this method was also developed and applied to the synthesis of enantiomerically enriched butenolides and butyrolactones bearing all-carbon α- and β-quaternary stereogenic centers, respectively. This asymmetric transformation was eventually used as a key step in the total synthesis of two natural products: (–)-nephrosteranic acid and (–)-roccellaric acid. This account summarizes the results of our endeavors. 1 Introduction 2 Palladium-Catalyzed Decarboxylative Allylic Alkylation of Allyl Dienol Carbonates 2.1 Synthesis of Polysubstituted Furans 2.2 Synthesis of Polysubstituted Pyrroles 3 Asymmetric Palladium-Catalyzed Decarboxylative Allylic Alkylation of Allyl Dienol Carbonates 3.1 Synthesis of Enantiomerically Enriched Butenolides 3.2 Synthesis of Enantiomerically Enriched Furanones 3.3 Synthesis of Enantiomerically Enriched Butyrolactones 3.4 Total Syntheses of (–)-Nephrosteranic Acid and (–)-Roccellaric Acid 4 Conclusion

A Regioselective Palladium-Catalyzed Allylic Alkylation Cascade with Dihydropyrans

A Regioselective Palladium-Catalyzed Allylic Alkylation Cascade with Dihydropyrans

Palladium-Catalyzed Allylic Alkylations as Versatile Tool for Amino Acid and Peptide Modifications

Palladium-catalyzed allylic alkylations are especially suitable for the introduction of γ,δ-unsaturated side chains into amino acids and even peptides. Glycine ester enolates are generally used as nucleophiles in these reactions, they react at a very low temperature (–78 °C) to give the products of isomerization-free allylation. In reactions of cis-configured allylic substrates, the olefin geometry can be transferred to the product. Because the syn position of the corresponding syn/anti π-allyl complex formed in this case is more reactive, this isomerization-free protocol also allows regioselective and stereoselective allylations. Using stannylated allylic substrates gives metalated amino acid derivatives that are ideal substrates for subsequent Stille couplings or tin–iodine exchange reactions. If peptides are deprotonated with excess­ strong base, the corresponding ester or amide enolates formed can also be subjected to allylation; in this case the stereochemical outcome can be controlled by the peptide chain.

Pd-Catalyzed Allylic Alkylation Cascade with Dihydropyrans: Regioselective Synthesis of Furo[3,2-c]pyrans

A regioselective palladium-catalyzed allylic alkylation cascade forms furo[3,2-c]pyrans from various cyclic β-dicarbonyl bis-nucleophiles and 3,6-dihydro-2H-pyran bis-electrophiles. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate allows control of the many regiochemical possibilities in this reaction. Annulation proceeds stereoconvergently to give cis-fused furopyrans from either cis- or trans-substituted starting material.