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.     

Rational tuning of the rigidity of a ligand scaffold: synthesis of diphenylsulfide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The scaffold rigidity of bis(oxazoline) ligands was rationally tuned on the basis of literature information. Diphenylsulfide-linked bis(oxazoline) ligands with a flexible scaffold were efficiently synthesized to test our hypothesis. The improved enantioselectivity in palladium-catalyzed asymmetric allylic alkylation reaction was achieved as we expected.     

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.     

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.     

Synthesis and application of chiral cyclopropane-based ligands in palladium-catalyzed allylic alkylation

A series of chiral, cyclopropane-based phosphorus/sulfur ligands have been synthesized and evaluated in the palladium-catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate with dimethyl malonate. Variation of the ligand substituents at phosphorus, sulfur, and the carbon backbone revealed 24d to have the optimal configuration for this reaction, giving the product in high yield and with good enantioselectivity (93%). A model for the observed enantioselectivity is discussed within the context of existing models, using X-ray crystallographic data, solution-phase NMR studies, and the absolute stereochemistry of the products. Selected ligands were also evaluated in the palladium-catalyzed intermolecular Heck reaction and the rhodium-catalyzed hydrogenation of a dehydroamino acid.     

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.     

Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic alkylations

First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained were assessed in palladium-catalyzed allylic alkylations. The first type of ligands exhibited enantioselectivity similar to that of a benzoyl ester derivative, whereas the latter type of ligands afforded products with higher selectivity than the analogous benzoyl ester. The activity of the dendritic catalysts decreased with increasing generation.     

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.     

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.     

新型双膦配体及钯催化的烯丙基烷基化反应用于构筑季碳手 性中心

从二茂铁恶唑啉膦化合物(Sp)-1出发,合成了严平面手性二茂铁修饰的口袋型双膦配体(R,R,Sp,Sp)-4和(S,S,Sp,Sp)-4。这类配体在前手性亲核试剂的不对称烯丙基化构筑手性季碳中心的反应中,显示了较好的反应活性及对映选择性。当利用亚胺的氨基酸酯衍生物时,可以得到一些非天然的季碳氨基酸衍生物,ee值最高可以达到75.3%。一些简单的酮的烯醇负离子也可用作亲核试剂,产物为α-位双取代的具有季碳中心的酮,ee值可高达95%。     

Preparation of planar‐chiral multidonor phosphanylferrocene carboxamides and their application as ligands for palladium‐catalysed asymmetric allylic alkylation

Amide coupling of (S_p)‐2‐(diphenylphosphanyl)ferrocene‐1‐carboxylic acid with appropriate terminal amines mediated by 1‐hydroxybenzotriazole and a carbodiimide affords multi‐donor amides terminally functionalized with planar‐chiral (S_p)‐2‐(diphenylphosphanyl)ferrocen‐1‐yl moieties in good to excellent yields. Palladium catalysts based on these ligands efficiently promote asymmetric allylic alkylation of 1,3‐diphenylallyl acetate with in situ generated dimethyl malonate anion to give the C‐alkylated product with ees up to 93% at room temperature. Copyright © 2010 John Wiley & Sons, Ltd.     

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.     

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.     

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.     

Palladium-catalyzed allylic alkylation using chiral hydrazones as ligands

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (4) with a dimethyl malonate-BSA-LiOAc system and its derivatives has been successfully carried out in the presence of a new chiral hydrazone ligands such as 2-(diphenylphosphino)benzaldehyde SAMP hydrazone (DPPBA-SAMP) (3a) in high yields with high enantioselectives.     

Preparation of quarternary ammonium salt-tagged ferrocenylphosphine-imine ligands and their application to palladium-catalyzed asymmetric allylic substitution

A series of novel quarternary ammonium salt-modified chiral ferrocenylphosphine-imine ligands have been synthesized and the molecular structure of BIT5 has been determined by single-crystal X-ray diffraction. The applicability of these ligands in asymmetric C1–C and C1–N bond formation was demonstrated. High enantioselectivity was obtained in the Pd-catalyzed asymmetric substitution of 1,3-diphenyl-2-propenyl acetate, with dimethyl malonate (up to 94.6% ee) and benzylamine (up to 92.6% ee).     

Palladium-catalyzed asymmetric allylic alkylation using chiral aminophosphine ligands

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate 18 with a dimethyl malonate–BSA–LiOAc system has been successfully carried out in the presence of new chiral aminophosphine ligands 1–5 in good yields with good enantioselectivities (up to 85% e.e.).     

Camphane-based aminophosphine ligands for Pd-catalyzed asymmetric allylic alkylation

A practical synthesis of new chiral aminophosphine ligands based on the camphane scaffold bearing alkoxy groups was accomplished. The application of these ligands in the Pd-catalyzed allylic alkylation of (E)-1,3-diphenyl-2-propenyl acetate proceeded with excellent conversions and ee’s of up to 91%. Variation of the alkoxy substituents did not substantially influence the catalytic performance.     

Chiral S,S-donor ligands in palladium-catalysed allylic alkylation

Chiral dithioether ligands have been tested in the model Pd-catalysed allylic alkylation reaction of (±)-3-acetoxy-1,3-diphenyl-1-propene with dimethyl malonate, giving high enantioselectivity (up to 81% e.e.) for the first time in this type of system. Pd(II)-allylic intermediates, [Pd(η³-1,3-Ph₂-C₃H₃)(dithioether)]PF₆ were prepared and characterised both in solution by NMR spectroscopy and solid state. The X-ray structure for [Pd(η³-1,3-Ph₂-C₃H₃)(L)]PF₆ (L=(R,R)-7,8-O-isopropylidene-1,5-dithia-cyclononane) was determined.