Asymmetric Heck Reaction Research Articles

Synthesis, resolution and applications of 3,3′-bis(RO)-MeO-BIPHEP derivatives

A series of optically pure 3,3′-bis(RO)-MeO-BIPHEP derivatives are prepared and used in palladium catalyzed asymmetric transformations. The phosphine oxide of (±)- 5 is prepared in four steps from p-methoxyphenol and resolved using the novel resolving reagent chloro( l-menthoxy)dimethylsilane. Subsequent conversions provide catalysts 8 and 9 . Ligands 6 , 7 and 10 are prepared in six steps from p-methoxyphenol and the phosphine oxides of 6 and 7 , and 10 are resolved using di- p-toluoyl- and dibenzoyl- l-tartaric acid, respectively. ( R)-3,3′-Bispivalate 8 is superior to the other catalysts in asymmetric Heck reaction with 2,3-dihydrofuran while ( R)-(+)-bis(tolyloxy) 10 and (+)-( R)-sugar derivative 9 are better in the Pd-catalyzed polyene cyclization; however, the absolute sense of chirality in the product from the polyene cyclization was reversed to that obtained when ( R)-(+)-BINAP and ( R)-(+)-MeO-BIPHEP were used.

The first example of atropisomeric amide-derived P,O-ligands used for an asymmetric Heck reaction

Atropisomeric N, N-diisopropyl 2-diphenylphosphino- and 2-di( tert-butyl)phosphino-1-naphthamides were used, for the first time, as bidentate P,O-ligands for intermolecular asymmetric Heck reactions of 2,3-dihydrofuran with aryl triflates. The reactions were carried out in the presence of 4 mol% Pd(OAc) 2, 8 mol% of the axially chiral ligand, and 3 equiv. of ( i-Pr) 2NEt in THF at 60 °C for 3 days. Optically active 2-aryl-2,5-dihydrofurans were obtained as the major products along with the rearranged 2-aryl-2,3-dihydrofurans. Enantioselectivity up to 55.2% ee was obtained for the major product.

Unusually Large Primary (2)H/(1)H Kinetic Isotope Effects Accompanying a syn-beta-H Elimination Reaction in a sigma-Alkyl-Palladium Complex.

The Pd-sigma-alkyl complex 5, is stable in solution for long periods in the absence of base. On addition of simple amine bases, such as 1,8-bis(dimethylamino)naphthalene (7), complex 5 rapidly generates the triene 6 via a beta-H elimination process whose stereochemistry is demonstrated to be syn. In contrast to the low primary kinetic isotope effects (kH/kD) that normally attend syn-beta-H elimination processes from sigma-alkylmetal species, large values are observed on performing inter- and intramolecular competition experiments with 5. However, the substitution of D for H has negligible effect on the absolute rate at low temperatures (-60 degrees C). A mechanism to account for this behavior is presented, and implications for asymmetric Heck reactions are noted.

Novel planar chiral diphosphines and their application in asymmetric hydrogenations and asymmetric Heck reactions

Nine planar chiral diphosphines 8a– i have been synthesised by a versatile approach: The diphosphines have been assayed in an asymmetric hydrogenation reaction and an asymmetric Heck reaction and were found to give active catalysts that generated products of moderate to good enantiopurity.

Synthesis, resolution, and application of 2,2′-bis(diphenylphosphino)-3,3′-binaphtho[b]furan (BINAPFu)

(±)-2,2′-Bis(diphenylphosphino)-3,3′-binaphtho[2,1-b]furan (BINAPFu) was synthesized from 2-naphthoxyacetic acid in a five-step sequence in 62% overall yield. A variety of reported resolution procedures for biaryl bisphosphines did not work with (±)-BINAPFu; thus, a new resolution method was developed, involving the Staudinger reaction of the aforementioned racemate of BINAPFu with an enantiopure camphor sulfonyl azide derivative. The resulting diastereomeric phosphinimines were separated by flash chromatography. Subsequent hydrolysis to the corresponding bis-phosphine oxide and trichlorosilane reduction provided enantiopure BINAPFu. The absolute stereochemical configuration of BINAPFu was established by X-ray crystallography. BINAPFu was compared with commercially available 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) in Pd(0)-catalyzed intermolecular Heck reactions. Investigation of the Heck arylation of 2,3-dihydrofuran showed BINAPFu to be more efficacious than BINAP in dioxane at 30 °C. A variety of phosphorus selenides were prepared, and the 1JP-Se coupling constants measured, to obtain a comparative scale of parent phosphine basicity. The phosphorus atoms in BINAPFu were found to be electron deficient when compared with BINAP but slightly more electron rich than trifurylphosphine. Key words: naphthofurans, atropisomers, electron-deficient phosphines, asymmetric Heck reactions, Staudinger reaction.

Sequential olefin metathesis — Intramolecular asymmetric Heck reactions in the synthesis of polycycles

Application of the intramolecular asymmetric Heck reaction in the desymmetrization of a novel class of symmetrical bicyclodienes, synthesized through a diastereoselective double ring-closing metathesis (DSRCM) reaction, was achieved with good yields (approximately 80%) and excellent enantioselectivities (up to 99% ee). Three contiguous stereocenters are established in a single desymmetrization reaction. The use of thallium carbonate as base in the asymmetric Heck reaction favours double bond migration in 13. Cationic conditions delivered products with good to excellent enantioselectivities, surpassing the results under neutral conditions.Key words: asymmetric, Heck, polycycles, metathesis, stereoselective, desymmetrization.

The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

Two new heterocyclic diphenylphosphinooxazolines derived from thiophene and benzothiophene were prepared in moderate to good yield and these, and a range of related HETPHOX ligands, were applied in the intermolecular asymmetric Heck reaction. Phenylation of 2,3-dihydrofuran with the t-butyl-substituted thiophene-oxazoline ligand gave (R)-2-phenyl-2,3-dihydrofuran highly regioselectively with excellent enantioselectivity (91-95% ee) and in good yields (70-97%). In addition, cyclohexenylation of 2,3-dihydrofuran proceeded with enantioselectivities of up to 97% ee in excellent (97%) yields, again with the t-butyl-substituted thiophene-oxazoline ligand proving optimal over a range of reaction conditions investigated.

Asymmetric Catalysis with Chiral Ferrocene Ligands

AbstractFor Abstract see ChemInform Abstract in Full Text.

Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction

The synthesis of two novel cyclisation substrates for the asymmetric intramolecular Heck reaction is reported. Their cyclisation, in addition to a known substrate for cis-decalin formation, were tested with palladium complexes of BINAP and heterobidentate oxazoline-containing ligands. In general BINAP provides a more active catalyst system for the range of substrates tested although excellent enantioselectivities of up to 85% were obtained with the P,N ligands studied. A trend was noted whereby the t-leucine-derived oxazoline ligands were more reactive and enantioselective than the valine-derived analogues. Similarly, the diphenylphosphinoferrocenyloxazoline ligands were more reactive and selective than the corresponding diphenylphosphinophenyloxazoline ligands.

A Versatile Route to Planar Chiral Diphosphines and Their Application in the Asymmetric Heck Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Heck Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective Carbon—Carbon Bond Forming Reactions Using Fluorous Chiral Catalysts.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective total synthesis of the cyclotryptamine alkaloid idiospermuline.

Stereogenic quaternary carbons present the primary challenge in the syntheses of trispyrrolidinoindoline alkaloids such as idiospermuline. In its synthesis the two contiguous quaternary centers are expediently addressed by combining the lithium dienolate of a differentially protected dihydroisoindigo with a tartrate-derived electrophile. The third quaternary stereocenter is introduced by a catalytic asymmetric Heck reaction.

Asymmetric catalysis with chiral ferrocene ligands.

Chiral ferrocene ligands have been widely used in asymmetric catalysis. The advantages of using ferrocene as a scaffold for chiral ligands are described, particularly those regarding planar chirality, rigid bulkiness, and ease of derivatization. The role of planar chirality in 1,2- and 1,1'-disubstituted ferrocene systems is discussed. By using a bulky ferrocene fragment, novel ferrocene ligands were designed, and high enantioselectivity and regioselectivity were achieved in the allylic substitution reaction of monosubstituted allyl substrates. Using the tunable electronic properties of a diphosphine-oxazoline ferrocenyl ligand, the regioselectivity of the intermolecular asymmetric Heck reaction was also examined.

A versatile route to planar chiral diphosphines and their application in the asymmetric Heck reaction

Five chiral monophosphines and nine planar chiral diphosphines have been synthesised in good yield and enantiopurity by a modular approach; the diphosphines have been reacted with Pd(OAc) 2 and screened for activity in the asymmetric Heck reaction.

Probing Electronic Effects in the Asymmetric Heck Reaction with the BIPI Ligands

Probing Electronic Effects in the Asymmetric Heck Reaction with the BIPI Ligands

A Comparative Study of Diphosphine and Phosphinamine Palladium Complexes on a New Substrate for the Intramolecular Asymmetric Heck Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Probing electronic effects in the asymmetric Heck reaction with the BIPI ligands.

[structure: see text] The new BIPI ligands are phosphinoimidazolines that can be electronically tuned in three different ligand regions to explore electronic effects in asymmetric catalysis. Their application to the asymmetric Heck reaction (AHR) in the creation of a chiral quaternary center is described. Enantioselectivity is shown for the first time to depend linearly on phosphine electron density. Changing the ligand basicity by variation of the R(2) or R(3) substituents reverses facial selectivity.

Monodentate phosphoramidites; versatile ligands in catalytic asymmetric intramolecular Heck reactions

The Pd-catalysed intramolecular asymmetric Heck reaction (AHR) of cyclohexadienone monoacetals in the presence of chiral phosphoramidite ligands is described. High enantioselectivities (up to 96% ee) are reached with monodentate ligands. The highest selectivity is observed with Taddol-based phosphoramidites containing a small amine substituent. A study of the effect of the leaving group at the aryl moiety and a number of parameters in the AHR show that this AHR most likely proceeds through a neutral pathway and that two equiv. of ligand are necessary for optimal asymmetric induction.

From 2,3-dihydrofuran to 2,2-dialkyl-2,3-dihydrofurans: new substrates for the intermolecular asymmetric Heck reaction

Palladium complexes of heterobidentate ferrocene-containing ligands were tested as catalysts in asymmetric intermolecular Heck reactions employing 2,3-dihydrofuran as the substrate and afforded a mixture of products in various ratios depending on the choice of ligand and the conditions employed. The favoured kinetic isomer was obtained in enantioselectivities of up to 99%. Dihydrofurans disubstituted at the 2-position were postulated as new substrates as they form a single regioisomeric product, thus providing a true comparative test of enantioselectivity of a range of palladium complexes. The synthesis of 2,2-dimethyl-2,3-dihydrofuran and 2,2-diethyl-2,3-dihydrofuran and their application in the intermolecular asymmetric Heck reaction with both diphosphine and phosphinamine ligands is also described. For both phenylation and cyclohexenylation of 2,3-dihydrofuran and 2,2-dimethyl-2,3-dihydrofuran the t-Bu substituted diphenylphosphinoferrocenyloxazoline ligand gave best results. The use of 2,2-diethyl-2,3-dihydrofuran as substrate demonstrated that the increased bulk at the 2-position had a deleterious effect on both the chemical yields and ees in phenylations and cyclohexenylations although enantioselectivities of 94 and 93% were obtained, respectively.