Ethylene in organic synthesis: a new route to anticholenergic pyrrolidinoindolines, and other molecules with all carbon-quaternary centers via asymmetric hydrovinylation

The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans.     

Palladium-catalyzed asymmetric hydrovinylation under mild conditions using monodentate chiral spiro phosphoramidite and phosphite ligands

Palladium complexes of chiral spiro phosphoramidite and phosphite ligands are effective catalysts in the asymmetric hydrovinylation of vinylarenes with ethylene. The hydrovinylation products were obtained in modest selectivity with enantioselectivities up to 92% ee. The structures of the palladium catalysts have been analyzed by X-ray diffraction. The active catalyst contained one monodentate ligand. A kinetic resolution accompanied the isomerization of the hydrovinylation product in the reaction.     

Ruthenium-catalyzed hydrovinylation of N-acetylenamines leading to amines with a quaternary carbon center

A catalytic hydrovinylation of N-acetylenamines with ethylene is reported. This new hydrovinylation reaction is catalyzed by a ruthenium hydride complex, RuHCl(CO)(PCy(3))(2), providing a series of N-acetylamines with a quaternary carbon center with up to 99% yield.     

Tunable ligands for asymmetric catalysis: readily available carbohydrate-derived diarylphosphinites induce high selectivity in the hydrovinylation of styrene derivatives

Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphonites prepared from readily available carbohydrates in conjunction with a highly dissociated counterion ([3,5-(CF3)2-C6H3)4B]- or SbF6-) effect the hydrovinylation of 4-bromostyrene or 4-isobutylstyrene under ambient pressure of ethylene with the best overall selectivities reported to date for these important substrates. In a prototypical synthesis of a 2-arylpropionic acid, 3-(4-bromophenyl)-1-butene (prepared in 98% isolated yield and 89% ee from 4-bromostyrene) has been transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, ozonolysis, and subsequent oxidation of the resulting aldehyde.     

The mechanism of the phosphine-free palladium-catalyzed hydroarylation of alkynes

The mechanism of the Pd-catalyzed hydroarylation and hydrovinylation reaction of alkynes has been studied by a combination of experimental and theoretical methods (B3LYP), with an emphasis on the phosphine-free version. The regioselectivity of the hydroarylation and hydrovinylation shows unexpected differences, which could be attributed mainly to the higher steric demand of the cyclohexenyl group as compared to the phenyl group. Hydroarylation of alpha,beta-acetylenic carbonyl substrates yields a very unusual anti-Michael selectivity, which is shown to result from reaction of the nonconjugated double bond, leaving the conjugation intact. In all cases were the regioselectivities reproduced by the calculations.     

Hydrovinylation of norbornene. Ligand-dependent selectivity and asymmetric variations

[reaction: see text] Norbornene undergoes Ni-catalyzed (1-2 mol% allylnickel bromide/phosphine/NaBARF or AgSbF(6), 1 bar ethylene, -50 degrees C) hydrovinylation (>97% yield), giving either a 1:1 or a 2:1 (norbornene/ethylene) adduct depending on the size of the phosphine. Use of binaphthol-derived phosphoramidite ligand results in up to 80% ee for the 1:1 adduct. The course of the reaction is highly dependent on the ligand (size and configuration of the appendages) and the counteranion present.     

Annulation of Alkynyl Aryl Ethers with Allyl Pivalates To Give 2,3‐Bismethylenechromanes through Double C−H Bond Cleavage

The treatment of silylethynyloxyarenes with allylic pivalates in the presence of a palladium catalyst led to efficient C?H bond cleavage in both substrates and a novel annulation reaction to give 2,3‐bismethylenechromanes. When ortho‐allylated silylethynyloxybenzenes were used as the substrates, the same products were obtained. This result shows that site‐selective intramolecular hydrovinylation is involved in the annulation reaction. The synthetic utility of the products was demonstrated by the construction of condensed polycycles.     

Syntheses and applications of 2-phosphino-2'-alkoxy-1,1'-binaphthyl ligands. Development of a working model for asymmetric induction in hydrovinylation reactions

Among the handful of monophosphine ligands that effect asymmetric hydrovinylation of vinylarenes, 2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl (MOP) is among the most accessible. Addition of a methyl group at the 3'-position of this ligand significantly improves the enantioselectivity of hydrovinylation of prototypical alkenes. Introduction of a chiral phospholane at the C2 position of this scaffolding has no effect on the enantioselectivity. These results are consistent with a model proposed for the asymmetric induction for this exacting reaction.     

Tunable phosphinite, phosphite and phosphoramidite ligands for the asymmetric hydrovinylation reactions

Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphinites, carrying β-acylamino groups prepared from readily available carbohydrates, in conjunction with highly dissociated counteranions {[(3,5-(CF₃)₂C₆H₃]₄B⁻ or SbF₆⁻}, effect the hydrovinylation of vinylarenes under ambient pressure of ethylene with high enantioselectivity. Nitrogen substituents such as -COCF₃ and COPh groups lead to isomerization of the primary products (3-arylbutenes) to Z- and E-2-aryl-2-butenes. In a prototypical synthesis of a 2-arylproionic acid, (S)-3-(4-bromophenyl)-1-butene (89% ee) has be transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, followed by oxidation of the double bond with NaIO₄ and KMnO₄. Asymmetric codimerization of norbonene and ethylene using binaphthol-derived phosphoramidites as ligands gives 1:1, 2:1 or polymeric adducts depending on the relative configurations and nature of the BINAP and amine moieties. With one of the phosphoramidite-Ni complexes, counteranions BAr₄⁻ [Ar=3,5-(CF₃)₂C₆H₃] and SbF₆⁻, which had been used interchangeably in other reactions, give either a 1:1 adduct or a 2:1 adduct, respectively.     

Highly selective cobalt-catalyzed hydrovinylation of styrene

The hydrovinylation reaction is a codimerization of a 1,3-diene or vinyl arene and ethene with great potential for fine chemicals and pharmaceuticals. For the first time, enantioselective cobalt-catalyzed hydrovinylations of styrene were achieved with a cobalt-based system bearing a chiral bis(phosphine)amide ligand.     

Nickel-catalyzed enantioselective hydrovinylation of silyl-protected allylic alcohols: An efficient access to homoallylic alcohols with a chiral quaternary center

Asymmetric hydrovinylation of silyl-protected allylic alcohols catalyzed by nickel complexes of chiral spiro phosphoramidite ligands was developed. A series of homoallylic alcohols with a chiral quaternary center were produced in high yields (up to 97%) and high enantioselectivities (up to 95% ee). The reaction provides an efficient method for preparing bifunctional compounds with a chiral quaternary carbon center.     

Low‐Pressure Cobalt‐Catalyzed Enantioselective Hydrovinylation of Vinylarenes

An efficient and practical protocol for the enantioselective cobalt‐catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L₂CoCl₂] complexes are employed that are activated in situ with Et₂AlCl. A modular chiral TADDOL‐derived phosphine–phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH₂, CN, and CO₂R, are tolerated.     

Fine-tuning monophosphine ligands for enhanced enantioselectivity. Influence of chiral hemilabile pendant groups

[reaction: see text] C(2)-Symmetric P-(2-X-aryl)-2,5-dialkylphospholanes (X = dioxolan-2-yl or dioxan-2-yl), designed on the basis of a working model for asymmetric induction, are effective ligands for the Ni(II)-catalyzed asymmetric hydrovinylation of styrenes. Excellent yields (>99%), selectivities for the desired 3-arylbutenes (>99%), high S/C ratios (>1200), and ee's (up to 91%) have been realized for a number of prototypical vinylarenes. In the dioxolane series, the selectivity depends on the configuration of the C(4) and C(5)() carbons.     

Asymmetric hydrovinylation of vinylindoles. A facile route to cyclopenta[g]indole natural products (+)-cis-trikentrin A and (+)-cis-trikentrin B

Vinylindoles undergo Ni(II)-catalyzed asymmetric hydrovinylation under very mild conditions (-78 °C, 1 atm ethylene, 4 mol % catalyst) to give the corresponding 2-but-3-enyl derivatives in excellent yields and enantioselectivities. Hydroboration of the alkene and oxidation to an acid, followed by Friedel-Crafts annulation, gives an indole-annulated cyclopentanone that is a suitable precursor for the syntheses of cis-trikentrins and all known herbindoles. For example, the cyclopentanone from 4-ethyl-7-vinylindole is converted into (+)-cis-trikentin A in four steps (Wittig reaction, alkene isomerization, diastereoselective hydrogenation, and nitrogen deprotection). The previous synthesis of this molecule from (S)-(-)-malic acid involved more than 20 steps and a preparative HPLC separation of diastereomeric intermediates.     

Enantioselective hydrovinylation via asymmetric counteranion-directed ruthenium catalysis

The first Ru-catalyzed enantioselective hydrovinylation has been realized by using an asymmetric counteranion-directed catalysis strategy. Styrene derivatives react with ethylene in excellent yields and promising enantioselectivity using this approach.     

Highly enantioselective nickel-catalyzed hydrovinylation with chiral phosphoramidite ligands

Readily available chiral phosphoramidites are a promising class of ligands for nickel-catalyzed asymmetric hydrovinylation of vinyl arenes. Cooperative effects are operative when ligands with more than one element of chirality are used. Choosing the proper stereochemistry in each part of the modular ligand system leads to high chemoselectivities and excellent enantioselectivities up to 94%. Moreover, the catalysts derived from these ligands proved extremely efficient and remarkably robust performing up to 8300 catalytic turnovers at an initial turnover frequency beyond 1000 h-1. The large potential for structural variation and their straightforward synthesis make the phosphoramidites currently the best lead structure for catalyst development in this field.     

Ethylene in organic synthesis. Repetitive hydrovinylation of alkenes for highly enantioselective syntheses of pseudopterosins

In this report we highlight the significant potential of ethylene as a reagent for the introduction of a vinyl group with excellent stereoselectivity at three different stages in the synthesis of a broad class of natural products, best exemplified by syntheses of pseudopterosins. The late-stage applications of the asymmetric hydrovinylation reaction further illustrate the compatibility of the catalyst with complex functional groups. We also show that, depending on the choice of the catalyst, it is possible to either enhance or even completely reverse the inherent diastereoselectivity in the reactions of advanced chiral intermediates. This should enable the synthesis of diastereomeric analogs of several classes of medicinally relevant compounds that are not readily accessible by the existing methods, which depend on 'substrate control' for the installation of many of the chiral centers, especially in molecules of this class.     

Coordinated olefins as incipient carbocations: catalytic codimerization of ethylene and internal olefins by a dicationic Pt(II)-ethylene complex

The coordinated ethylene molecule in the dicationic complex [(PNP)Pt(CH2=CH2)](BF4)2 (PNP = 2,6-bis(diphenylphosphinomethyl)pyridine) undergoes nucleophilic attack by free internal alkenes, giving the isolable complexes [(PNP)Pt(CH2=CHCH(Me)CMeRR'](BF4)2 (R, R' = H, Me) and providing a new effective pathway for a chemo- and regio-selective catalytic hydrovinylation reaction.     

Highly enantioselective hydrovinylation of alpha-alkyl vinylarenes. an approach to the construction of all-carbon quaternary stereocenters

The highly enantioselective hydrovinylation of alpha-alkyl vinylarenes was realized by using nickel complexes of chiral spiro phosphoramidite ligands. The method provided a new approach to the construction of chiral all-carbon quaternary centers.     

Ligand tuning in asymmetric hydrovinylation of 1,3-dienes: a stereoselective route to either steroid-C20 (S) or -C20 (R) derivatives

1,3-Dienes derived from steroidal D-ring C 17-ketones undergo Ni(II)-catalyzed hydrovinylation to give 1,2- or 1,4-addition of ethylene. Using finely tuned phosphoramidite ligands, it is possible to synthesize either the C 20 ( R)- or ( S)-derivatives without mutual contamination. The proportion of the 1,4-adduct, which is also formed stereoselectively, can be minimized by optimizing the reaction conditions. Because the two alkenes in the resultant dienes have differing steric demands for many potential reactions, and are ideally juxtaposed for further D-ring functionalization, these intermediates could be useful for the preparation of biologically important compounds such as vitamin D analogs and various antitumor steroidal glycosides.