Novel chiral P,N-ferrocene ligands in palladium-catalyzed asymmetric allylic alkylations

Novel chiral P,N-ferrocene ligands, 1-diphenylphosphino-1′-oxazolinylferrocenes, were prepared from ferrocene via 1,1′-bis(tributylstannyl)ferrocene and 1-diphenylphosphino-1′-methoxycarbonylferrocene as intermediates, and with this new kind of ligand up to 91% ee with 99% chemical yield was afforded for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethylmalonate anion. The complexation behavior of this kind of ligand with dichlorobis(acetonitrile)palladium and bis(μ-chloro)(1,3-diphenyl-η³-allyl)dipalladium was investigated.     

Chiral sulfideoxathiane ligands for palladium-catalyzed asymmetric allylic alkylation

Easily prepared, chiral sulfideoxathiane ligands are described, which give excellent enantioselectivities (up to 99% ee) in the Pd-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with a range of alkyl malonate nucleophiles.     

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.     

Strategy for employing unstabilized nucleophiles in palladium-catalyzed asymmetric allylic alkylations

We report a strategy for the employment of highly unstabilized anions in palladium-catalyzed asymmetric allylic alkylations (AAA). The "hard" 2-methylpyridyl nucleophiles studied are first reacted in situ with BF3.OEt2; subsequent deprotonation of the resulting complexes with LiHMDS affords "soft" anions that are competent nucleophiles in AAA reactions. The reaction is selective for the 2-position of methylpyridines and tolerates bulky aryl and alkyl substitution at the 3-, 4-, and 5-positions. Investigations into the reaction mechanism demonstrate that the configuration of the allylic stereocenter is retained, consistent with the canonical outer sphere mechanism invoked for palladium-catalyzed allylic substitution processes of stabilized anions.     

Modular multidentate phosphine ligands: application to palladium-catalyzed allylic alkylations

Multidentate phosphines were readily obtained by reaction of chiral multidentate amines, prepared via ring opening of (S)-N-tosyl-2-isopropylaziridine with ammonia, primary, and secondary amines, with achiral phosphorus containing building blocks. The phosphines were used in palladium-catalyzed alkylation of rac-3-cyclohexenyl and cyclopentenyl carbonates. The enantioselectivity and reactivity were largely dependent on the structure of the amine core of the ligands. Up to 88% ee was observed in reactions with the six-membered substrate.     

Chiral phenylselenyl derivatives of pyrrolidine and Cinchona alkaloids: nitrogen–selenium donating ligands in palladium-catalyzed asymmetric allylic alkylation

Enantiomeric pyrrolidine alcohols and Cinchona alkaloids reacted with PhSeCN/Bu₃P in toluene at 0–25 °C to give the corresponding phenyl selenides with complete inversion of configuration at the substitution centers. Thus, the chiral selenoethers obtained were tested in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenyl-2-propenyl acetate. When chiral selenium pyrrolidine derivatives were applied, the enantioselectivity observed was improved versus the respective sulfur pyrrolidine derivatives up to over 98% ee. The results suggest that the pyrrolidine selenoethers served as the effective N(sp³), Se-donating chiral ligands. The selenoethers obtained from Cinchona alkaloids also gave the allylic alkylation product with a higher ee over those for the corresponding thioethers. The results are in agreement with nucleophilic attack directed at the allylic carbon located trans to the chalcogen atom in the intermediate η³-allylpalladium complex.     

Preparation of a new FerroPHOS derivative for palladium-catalyzed asymmetric allylic alkylations

A new C₂-symmetric only cylindrically chiral FerroPHOS derivative possessing (1-methoxy-1-methyl)ethyl substituents was prepared and applied to the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-en-1-yl acetate. Both high catalytic activity (up to 500 turnovers) and enantioselectivity (e.e.'s of up to 96.3%) were attained in reactions using the new diphosphine ligand.     

Chiral pyridylmethyl- and quinolinyl-oxazolines as ligands for enantioselective palladium-catalyzed allylic alkylation

Chiral pyridylmethyl- and quinolinyl-oxazolines were prepared and assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselectivities up to 77% were obtained.     

Synthesis of novel carbohydrate-based iminophosphinite ligands in Pd-catalyzed asymmetric allylic alkylations

A series of novel carbohydrate-based iminophosphinite ligands have been synthesized for the first time and successfully applied in Pd-catalyzed asymmetric allylic alkylation. The substituent effects on the catalytic reaction were also investigated, and 92% ee was achieved when the p-nitro-substituted ligand 10d was used.     

Novel and efficient chiral sulfideoxathiane ligands for palladium-catalyzed asymmetric allylic alkylation

Easily prepared, chiral sulfideoxathiane ligands are described which give excellent enantioselectivity (up to 99% ee) in the Pd-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with a range of alkyl malonate nucleophiles.     

Modification of optically active ferrocenylphosphine ligands for palladium-catalyzed asymmetric allylic alkylation

Optically active ferrocenylphosphines containing a functional group on the side chain were effective as ligands for the palladium—catalyzed asymmetric allylic alkylation of 1,3-disubstituted allyl acetates such as l,3-diphenyl-3-acetoxy-l-propene with sodium acetylacetonate and related soft carbon nucleophiles to give the alkylation products of up to 92% ee.     

Highly effective chiral phosphorus amidite-olefin ligands for palladium-catalyzed asymmetric allylic substitutions

This paper describes the development of a type of novel P-olefin hybrid ligand by the incorporation of terminal olefins onto phosphorus amidite ligands for palladium-catalyzed asymmetric allylic alkylations of indoles and substitutions with amines to give the desired products in 70-97% yield with 91-98% ee.     

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.     

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.     

Sulfoxides derived from Cinchona alkaloids—chiral ligands in palladium-catalyzed asymmetric allylic alkylation

Phenyl sulfides derived from Cinchona alkaloids, 9-PhS-epi-CD, 9-PhS-epi-QN, 9-PhS-epi-QD, and 9-PhS-QN were oxidized into the corresponding sulfoxides. Regardless of the oxidation system used (NaIO₄, TEMPO/NaOCl, VO(acac)₂/chiral Schiff base/H₂O₂) a similar stereochemical outcome of the oxidation was observed. Four pure epimers of sulfoxides 9-PhSO-epi-CD and 9-PhSO-epi-QN were isolated and fully characterized (X-ray, CD, ¹H NMR-pattern). The chiral sulfoxides as well as the corresponding sulfides and sulfones were tested in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenyl-2-propenyl acetate. The sulfoxides obtained from Cinchona alkaloids bearing the additional stereogenic center gave the main product of configuration dependent on the chirality of alkaloid framework only. Similar ees (up to 60%) but significantly higher yields (90%) were obtained as compared to the reaction with the corresponding thioethers. The results were in agreement with nucleophilic attack directed at the allylic carbon located trans to the sulfur atom in the M-shaped intermediate η³-allylpalladium complex.     

Aromatic spiroketal bisphosphine ligands: palladium-catalyzed asymmetric allylic amination of racemic morita-baylis-hillman adducts

Showing a backbone: The spiroketal backbone of the bis(phosphine) ligand 1 led to good regio- and enantioselectivity in the palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts with aromatic amines. The methodology provides a facile and efficient synthesis of precursors for optically active β-lactam derivatives, including the cholesterol drug Ezetimibe.     

Aziridine-derived iminophosphine ligands in palladium-catalyzed allylic substitution

New iminophosphines have been synthesized from (R,R)-1-amino-2-diphenylphosphino cyclohexane (R.R)-1 in good to excellent yields. The catalysts obtained from iminophosphines 3a-g and [Pd(C₃H₅)Cl]₂ promote the enantioselective allylic substitution of 1,3-diphenyl-2-propenyl acetate (6) with diethyl malonate with good enantioselectivity. The air-stable complex PdCl₂[κ²-P,N-(R,R)-2-Ph₂PC₆H₁₀NCHPh] (4) has been prepared and structurally characterized by X-ray crystallography.     

Unexpected reversal of the enantioselectivity using chiral quinolylmethyl- and acridininyloxazolines as ligands for asymmetric palladium-catalyzed allylic alkylation

New chiral quinolylmethyloxazolines and acridininyloxazolines were prepared and assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. The introduction of a benzo-fused substituent on the pyridine ring not containing the chiral backbone resulted in the switch of the expected chiral sense of enantioselection of the reaction. Enantiomeric excesses up to 78% were obtained.