The synthesis of phosphine oxide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The phosphine oxide-linked bis(oxazoline) ligands were designed and synthesized in two ways. One is the coupling of Grignard reagent derived from 2-(2-bromophenyl)oxazoline with phenylphosphonic dichloride, another route is the condensation of bis(2-formylphenyl)(phenyl)phosphine oxide with chiral amino alcohols followed by NBS oxidation. These new bis(oxazoline) ligands were applied in Pd-catalyzed asymmetric allylic alkylation reactions and good yields and enantioselectivities were obtained with diphenyl substituted ligand (up to 95% ee).     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Preparation of indole-phosphine oxazoline (IndPHOX) ligands and their application in allylic alkylation

Two classes of indole-phosphine oxazoline ligands have been prepared from readily available starting materials in good overall yields. These modular ligands include an indole skeleton with either a phosphine moiety or an oxazoline ring at the 2- or 3-position, respectively. The utility of these ligands was demonstrated in a catalytic asymmetric reaction: the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate was performed with enantioselectivities as high as 98%.     

tert-Butanesulfinylthioether ligands: synthesis and application in palladium-catalyzed asymmetric allylic alkylation

A class of novel chiral SO-S-type bidentate ligands based on the tert-butylsulfinyl moiety as the sole chiral source were designed and synthesized through a simple and efficient pathway. These ligands are effective catalyst precursors for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate and moderate to good stereoselectivities (up to 84% ee) were obtained.     

Modular bis(oxazoline) ligands for palladium catalyzed allylic alkylation: unprecedented conformational behaviour of a bis(oxazoline) palladium eta3-1,3-diphenylallyl complex

New families of enantiopure bis(oxazolines) with 4,5-trans (5 a-g) or 4,5-cis (6 c) stereochemistry at the individual rings have been prepared in high yield. Their eta(3)-allyl palladium complexes (8 a-g, 9 c and 10) have been used as catalytic precursors in allylic alkylation reactions with excellent enantioselectivities (up to 96 %) for the trans oxazoline derivatives, while Pd/6 c system was inactive. NMR studies on palladium eta(3)-1,3-diphenylallyl intermediates (11 a, c and e) showed the presence of syn/syn- and syn/anti-allyl isomers in solution; this resembles the first example of eta(3)-eta(1)-eta(3) isomerism in Pd allylic complexes containing bis(oxazolines) derived from malonic acid.     

New dihydroxy bis(oxazoline) ligands for the palladium-catalyzed asymmetric allylic alkylation: experimental investigations of the origin of the reversal of the enantioselectivity

The origin of the reversal of the enantioselectivity in the palladium-catalyzed allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate anion using chiral dihydroxy bis(oxazoline) "BO" ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol was investigated. To determine the structural effects of the dihydroxy BO ligand on this unique phenomenon, new homochiral dihydroxy BO ligands were prepared from L-threonine and L-serine and were assessed in the transformation. The results obtained with these novel BO ligands, compared with the one obtained by using the dihydroxy BO ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, reveal that the reversal in the enantioselectivity observed with the dihydroxy BO ligand depends on the structure of the ligand. The effect of different bases used to generate the dimethyl malonate anion was also examined. The results are discussed in terms of the interaction of one hydroxy group in the intermediate pi-allyl palladium complex with the dimethyl malonate anion.     

Modification of diphenylamine-linked bis(oxazoline) ligands: Tuning of electronic effect and rigidity of ligand skeleton

The electronic effect of diphenylamine-linked bis(oxazoline) ligands was tuned through introduction of electron-withdrawing bromo and nitro substituents onto the 4 and 4′ position. The variation of the NH bond acidity was determined by the different chemical shifts of NH. The catalytic activity and enantioselectivity of the modified ligands were tested in the asymmetric Friedel-Crafts alkylation of indole with β-nitrostyrene. The effect of ligand skeleton rigidity was also investigated through the synthesis of iminodibenzyl-linked bis(oxazoline) ligands and evaluation of their catalytic activity in Friedel-Crafts alkylation.     

New homochiral amino-phosphine ligands: application in asymmetric palladium catalyzed allylic alkylation

A new series of homochiral amino-phosphine ligands was prepared. The use of these ligands in the palladium catalyzed allylic alkylation of 1,3-diphenyl-1-acetoxy-2-propene with sodium malonate gave substitution products with up to 76% e.e. The enantioselectivity was largely dependent on the nitrogen substituent.     

Stereoselective synthesis of substituted 1,2-ethylenediaziridines and their use as ligands in palladium-catalyzed asymmetric allylic alkylation

The double addition of organometallic reagents to fused oxazino-oxazines prepared from glyoxal and (S)-phenylglycinol afforded C₂- or C₁-symmetric 1,2-ethylenebis(β-aminoalcohols), depending on the nature of the organometallic reagent. This route was modified by the use of (S)-valinol and phenylglyoxal as starting materials, and by reduction of the oxazino-oxazines by diborane. Cyclization of the β-aminoalcohol moieties gave 1,2-ethylenediaziridines bearing one substituent/stereocenter on the ring carbon and one, two or no substituents/stereocenters in the ethylene tether. These bis(aziridines) were used as ligands in the Pd-catalyzed allylic alkylation of dimethyl malonate. It was established that the substituent(s) in the carbon tether and the configuration of the corresponding stereocenters have limited influence on the enantioselectivity.     

Modular synthesis of chiral pentadentate bis(oxazoline) ligands

Highly modular N,Y,Z,Y,N-ligands (Y=N, O, S; Z=N, NO, OH, OMe) have been prepared using bis(oxazoline) building blocks either as nucleophiles or as electrophiles in coupling reactions with central aromatic units. This way, a great variety of pentadentate bis(oxazoline) ligands in diastereo- and enantiomerically pure form become readily available, which are useful for the construction of helical metal complexes with predetermined chirality.     

Synthesis of a new chiral amino phosphine ligand and its application in the asymmetric allylic alkylation (AAA) reaction

This article describes the synthesis of a new chiral amino phosphine ligand based on an amino naphthol starting material, which is resolved efficiently by using l-tartaric acid. The asymmetric induction of the ligand in the Pd(0)-catalyzed allylic substitution of 1,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate was investigated. Good yields and enantiomeric excesses up to 78% of the product were obtained.     

Aminophosphine–oxazoline and phosphoramidite–oxazoline ligands and their application in asymmetric catalysis

The synthesis of a novel series of aminophosphine–oxazoline and phosphoramidite–oxazoline is described. The efficacy of these aminophosphine–oxazoline ligands was investigated in the palladium catalysed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate leading to a maximum of 38% ee at 64% conversion. Phosphoramidite–oxazoline ligands, however, gave ees of up to 87% at 71% conversion in the same reaction and also proved to be effective in the palladium catalysed asymmetric Suzuki coupling between 2-methylnaphthylboronic acid and 1-bromonaphthalene, leading to a maximum of 46% ee in 54% isolated yield at room temperature.     

Modular chiral selenium-containing oxazolines: synthesis and application in the palladium-catalyzed asymmetric allylic alkylation

A new series of modular chiral selenium-containing oxazolines has been synthesized from inexpensive and commercially available l-serine and l-aspartic acid. These new compounds were evaluated as chiral ligands in the palladium-catalyzed asymmetric allylic alkylation reaction, furnishing the product in high enantiomeric excess, using Cs₂CO₃/CH₂Cl₂ as the base/solvent system.     

N-Aryl indole-derived C–N bond axially chiral phosphine ligands: synthesis and application in palladium-catalyzed asymmetric allylic alkylation

N-Aryl indole-derived C–N bond axially chiral phosphine ligands 2a–c were obtained by DDQ oxidation of N-aryl indoline-derived phosphine oxide followed by silane reduction. Resolution of C–N bond atropisomers was achieved by chiral HPLC. The investigation of the rotation barrier for the C–N bond axial stability of phosphines and the determination of the absolute configuration of 2c are described. Finally, the ability of the chiral ligand 2c was demonstrated in a palladium-catalyzed asymmetric allylic alkylation (up to 99% ee).     

Recent advances in the application of chiral phosphine ligands in Pd-catalysed asymmetric allylic alkylation

One of the most powerful approaches for the formation of simple and complex chiral molecules is the metal-catalysed asymmetric allylic alkylation. This reaction has been broadly studied with a great variety of substrates and nucleophiles under different reaction conditions and it has promoted the synthesis of new chiral ligands to be evaluated as asymmetric inductors. Although the mechanism as well as the active species equilibria are known, the performance of the catalytic system depends on the fine tuning of factors such as type of substrate, nucleophile nature, reaction medium, catalytic precursor and type of ligand used. Particularly interesting are chiral phosphines which have proved to be effective asymmetric inductors in several such reactions. The present review covers the application of phosphine-donor ligands in Pd-catalysed asymmetric allylic alkylation in the last decade.     

Preparation of ferrocene-containing phosphinamine ligands possessing central and planar chirality and their application in palladium-catalyzed asymmetric allylic alkylation

The preparation of [2-(S(p))-[(trans-(2R,5R)-2,5-dialkylpyrrolidinyl)methyl]]ferrocenyldiphenyl phosphines, new ferrocenylphosphinamine ligands possessing one site of planar and two stereogenic centers, is described. trans-(2R,5R)-2,5-Dialkyl-1-(ferrocenylmethyl)pyrrolidines were diastereoselectively lithiated and quenched with chlorodiphenylphosphine. For the dimethyl ligand, chemical yields of up to 65% and des of up to 90% were obtained whereas the diethyl ligand afforded lower chemical yields (10%) and des of 78%. Diastereomerically pure material was obtained in both cases after a single recrystallization from ethanol. (S)-Planar chirality was confirmed by X-ray crystallographic analysis of the dimethyl ligand. The palladium complexes of the new ligands were applied in the allylic alkylation of 1,3-diphenylprop-2-enyl acetate with reasonable chemical yields and moderate ees of up to 36% and 38% when dimethyl malonate and dimethyl methyl malonate were employed as nucleophiles, respectively. Importantly, it was found that the new ligands possessing the combination of planar and central chirality gave the opposite enantiomeric alkylation products compared to ligands which possess only the central chirality of the trans-2,5-dimethylpyrrolidinyl moiety. Solution NMR studies of the 1,3-diphenylallyl palladium complex of the dimethyl ligand revealed the presence of only the exo-configured allyl diastereomer.     

Steric and electronic tuning of chiral bis(oxazoline) ligands with 3,3'-bithiophene backbone

[structure: see text] The role played by the electronic properties and the steric features of bis(oxazoline) ligands in the Cu(I)-catalyzed cyclopropanation of styrene effected with ethyl diazoacetate was investigated. Two pairs of new bis(oxazolines) displaying flexible and atropisomeric 3,3'-bithiophene backbones were synthesized and structurally and electronically characterized. For the first time, the electrochemical oxidative potential was used as a reliable index of the electronic density on the nitrogen atom of the chelating groups of new and, for comparative purposes, of already known bis(oxazolines). The Cu(I) complexes of the new ligands were prepared, and their enantioselection ability and catalytic efficiency were tested. This investigation suggests that steric factors and catalyst geometrical features are clearly more important than any consideration of the electronic properties of the chiral ligands.     

Mechanism of the cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of allylic esters

The catalytic enantioselective S(N)2' displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc](2) is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle); (b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c) secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway. These results are consistent with a novel mechanism in which chelation of the imidate nitrogen to form a cationic palladium(II) intermediate activates the alkene for attack by external carboxylate in the enantiodetermining step. Computational modeling of the transition-state structure for the acyloxy palladation step provides a model for enantioinduction.     

Resolved chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation

One-pot condensation of PhPH2, phthaloyl chloride, and the azine of 2-carboxybenzaldehyde (1) results in the new phosphine, rac-N,N'-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (rac-2), in 88% yield. Resolution via selective crystallization of the diastereomeric alpha-methylbenzylamine salts followed by coupling with amino acids and other amines provides rapid access to new collections of chiral phosphines (3). Pd-catalyzed alkylation of 1,3-dimethylallyl acetate and 1,3-diphenylallyl acetate at room temperature in the presence of 3 exhibits enantioselectivities as high as 92% ee and 97% ee, respectively, with strong sensitivity to the nature of the amino acid appendages. The presence of PF6- salts profoundly affects both the yield and the selectivity of catalytic allylic alkylation.     

Preparation of N-phenyl-(S)-prolinol-derived P,N-ligands and their application in Pd-catalyzed asymmetric allylic alkylation

Several NPN-type ligands bearing two chiral pyrrolidinyl groups derived from N-phenyl-(S)-prolinol were prepared by two synthetic methods. Their palladium-complex-catalyzed asymmetric allylic alkylation of malonates with 1,3-diphenyl 2-propenyl acetate delivered the products with good to high enantioselectivities (84–97% ee), including an optically active fluorine-containing compound.