A mild,catalytic, and highly selective method for the oxidation of alpha,beta-enones to 1,4-enediones

A new and simple method is described for the one-step oxidation of alpha,beta-enones to 1,4-enediones in good yields (generally 80-90%) using t-butylhydroperoxide as stoichiometric oxidant and 20% Pd(OH)2 on carbon (5 mol %) as catalyst in CH2Cl2 solution. The same reagents have been used to convert ethylene ketals of alpha,beta-enones to the corresponding monoethylene ketals of 1,4-enediones. Seven representative examples are presented in Table 1. All of the available evidence on these oxidations points to a radical-chain mechanism initiated by the tert-butylperoxy radical (see Scheme 1). gamma-tert-Butylperoxy ethers are formed as major products in the oxidation of alpha,beta-enones possessing only a single gamma-hydrogen.     

Nucleophilic fluoroalkylation of alpha,beta-enones, arynes, and activated alkynes with fluorinated sulfones: probing the hard/soft nature of fluorinated carbanions

We have successfully accomplished the nucleophilic fluoroalkylation of alpha,beta-enones, arynes, and activated alkynes with fluorinated sulfones. It was found that for acylic alpha,beta-enones, although the reaction medium and the structure of the enones can all influence the regioselectivity of the nucleophilic alkylation reactions, the hard/soft nature of the carbanions played a major role. By using the 1,4- and 1,2-addition product ratio as a probe to determine the hard/soft nature of the above-mentioned four halogenated carbanions, the order of the softness of these carbanions can be given as follows: [(PhSO2)2CF(-)] (20) approximately = PhSO2CCl2(-) (32) > PhSO2CHF(-) (31) > PhSO2CF2(-) (30). In the case of fluoroalkylation of aryne (35 as the precursor) and alpha,beta-acetylenic ketones 46 with fluorobis(phenylsulfonyl)methane (21), fluorobis(phenylsulfonyl)methylated arenes 36 and beta-fluorobis(phenylsulfonyl)methylated alpha,beta-enones 47 were obtained as the corresponding products in good yields. During the reaction between 2-fluoro-2-(phenylsulfonyl)acetophenone (34) and arynes or activated alkynes 46, an intramolecular tandem reaction process leads to the formation of acyl-fluoroalkylated arenes 43 or alpha-acyl-beta-fluoroalkylated alpha,beta-enones 48. It turned out that the softness of a fluorine-bearing carbanion (such as 20 or 33 derived from 21 or 34) plays a crucial role for the success of the nucleophilic fluoroalkylation reactions with arynes and some activated alkynes (alpha,beta-acetylenic ketones).     

Cationic rhodium(I)/BINAP complex-catalyzed isomerization of secondary propargylic alcohols to alpha,beta-enones

We have developed a cationic rhodium(I)/BINAP complex-catalyzed isomerization of secondary propargylic alcohols to alpha,beta-enones. The asymmetric variant of this reaction, a kinetic resolution of secondary propargylic alcohols, was also developed with good selectivity. The mechanistic study revealed that the isomerization proceeds through intramolecular 1,3- and 1,2-hydrogen migration pathways. [reaction: see text]     

Highly enantioselective dimerization of alpha,beta-enones catalyzed by a rigid quaternary ammonium salt

[reaction: see text] The chiral quaternary ammonium salt 1 served as a phase-transfer catalyst for the enantioselective dimerization of alpha,beta-enones, providing a route for the asymmetric syntheses of chiral 1,5-dicarbonyl compounds and alpha-alkylated gamma-keto acids.     

Chelation-assisted hydrative dimerization of 1-alkyne forming alpha,beta-enones by an Rh(I) catalyst

The intermolecular hydrative dimerization of 1-alkyne was developed through the chelation-assisted catalytic system with Rh(I)/2-amino-3-picoline. This novel transformation afforded branched and linear alpha,beta-enones directly from two 1-alkyne molecules and H2O. The results demonstrate that a branch/linear ratio can be controlled by the alkyl substituent of 1-alkyne.     

One-pot three-component reaction for the synthesis of alpha-(aminoethyl)-alpha,beta-enones

[reaction: see text] The synthesis of alpha-substituted alpha,beta-enones by a new metal iodide-promoted one-pot three-component reaction involving commercially available cyclopropyl ketones, aldehydes, and secondary amines followed by base treatment is described.     

Gold-catalyzed reactions of 2-alkynyl-phenylamines with alpha,beta-enones

[reaction: see text] The gold-catalyzed reaction of 2-alkynyl-phenylamines with alpha,beta-enones represents a new general one-pot entry into C-3-alkyl-indoles by sequential reactions. Gold-catalyzed sequential cyclization/alkylation, N-alkylation/cyclization, or N-alkylation/cyclization/alkylation reactions leading to different indoles can be directed by changing the 2-alkynyl-phenylamine 1/alpha,beta-enone 3 ratio and the reaction temperature. Unusual gold-catalyzed rearrangement reaction of indoles are observed at 140 degrees C. New gold-catalyzed formation of propargyl-alkyl ether under mild conditions and the hydration reaction of N-acetyl-2-ethynyl-phenylamine are reported.     

4-Substituted-alpha,alpha-diaryl-prolinols improve the enantioselective catalytic epoxidation of alpha,beta-enones

To seek novel metal-free organic catalysts for epoxidation with high stereoselectivity, a series of 4-substituted-alpha,alpha-diaryl-prolinols were synthesized in four steps from trans-4-hydroxyl-L-proline. These prolinol derivatives catalyzed the asymmetric epoxidation of alpha,beta-enones to give the corresponding chiral epoxides in good yields and high enantioselectivities under mild reaction conditions. Studies of substituent effects on enantioselectivity revealed that steric bulk and electronic effect promoted higher enantioselectivity, and prolinol 8a was found to be the best catalyst until now.     

Substituent effects on dynamics at conical intersections: alpha,beta-enones

Femtosecond time-resolved photoelectron spectroscopy and high-level theoretical calculations were used to study the effects of methyl substitution on the electronic dynamics of the alpha,beta-enones acrolein (2-propenal), crotonaldehyde (2-butenal), methylvinylketone (3-buten-2-one), and methacrolein (2-methyl-2-propenal) following excitation to the S2(pipi*) state at 209 and 200 nm. We determine that following excitation the molecules move rapidly away from the Franck-Condon region, reaching a conical intersection promoting relaxation to the S1(npi*) state. Once on the S1 surface, the trajectories access another conical intersection, leading them to the ground state. Only small variations between molecules are seen in their S2 decay times. However, the position of methyl group substitution greatly affects the relaxation rate from the S1 surface and the branching ratios to the products. Ab initio calculations used to compare the geometries, energies, and topographies of the S1/S0 conical intersections of the molecules are not able to satisfactorily explain the variations in relaxation behavior. We propose that the S1 lifetime differences are caused by specific dynamical factors that affect the efficiency of passage through the S1/S0 conical intersection.     

Mechanism and conditions for highly enantioselective epoxidation of alpha,beta-enones using charge-accelerated catalysis by a rigid quaternary ammonium salt

[formula: see text] Highly enantioselective (up to 130:1) epoxidation of a variety of alpha,beta-enones to form alpha,beta-epoxy ketones is described along with a rational analysis of the mechanistic basis for this strong absolute stereochemical control by the chiral catalyst 2.     

Enantioselective, organocatalytic oxy-michael addition to gamma/delta-hydroxy-alpha,beta-enones: boronate-amine complexes as chiral hydroxide synthons

An organocatalytic, enantioselective oxy-Michael addition to achiral gamma- and delta-hydroxy-alpha,beta-enones was developed. The key transformation is an unprecedented, asymmetric conjugate addition triggered by complexation between an in situ generated boronic acid hemiester and a chiral amine catalyst. Functionally, the intermediate amine-boronate complex acts as a chiral hydroxide surrogate or synthon. The resultant chiral beta-hydroxy-ketones are obtained in good to excellent yields and high ee following mild oxidative removal of the cyclic boronate. Natural products (R,12Z,15Z)-2-hydroxy-4-oxohenicosa-12,15-dienyl acetate and (+)-(S)-streptenol A were synthesized to demonstrate the utility of this reaction.     

Pd(0)-catalyzed conjugate addition of benzylzinc chlorides to alpha,beta-enones in an atmosphere of carbon monoxide: preparation of 1,4-diketones

Pd(0)-catalyzed conjugate addition of benzylzinc chloride to methyl vinyl ketone in the presence of chlorotrimethylsilane and lithium chloride in an atmosphere of carbon monoxide at room temperature afforded 1-phenyl-2,5-hexanedione monosilyl enol ether. In this catalytic carbonylation, four components are connected in one reaction. Successive acidic workup generated a variety of 1,4-diketones from substituted benzylzinc chlorides or related compounds and alpha,beta-enones. Some products were converted to cyclopentenones or five-membered heterocyclic compounds containing an N, O, or S atom.     

Nickel-Catalyzed Tandem Coupling of alpha,beta-Enones, Alkynes, and Alkynyltins for the Regio- and Stereoselective Synthesis of Conjugated Enynes

The nickel-catalyzed reaction of alpha,beta-enones 2 with alkynes 1, alkynyltins 6, and Me(3)SiCl was carried out by the successive construction of two carbon-carbon bonds to give enol silyl ethers 5, which were then hydrolyzed to conjugated enynes 7, with high regio- and stereoselectivities (isomeric purities: 92-98%).     

Intramolecular tandem Michael-type addition/aldol cyclization induced by TiCl(4)-R(4)NX combinations

[reaction: see text] Treatment of formyl alpha,beta-enones with a TiCl(4)-R(4)NX combination induces an intramolecular aldol cyclization to furnish 2-acyl-3-halocyclohexanol with three controlled consecutive stereogenic centers. The reaction of bis-alpha,beta-enones with the combination provides cyclic diketones with high stereoselectivity via an intramolecular Michael addition reaction.     

Enantioselective synthesis of bridged- or fused-ring bicyclic ketones by a catalytic asymmetric Michael addition pathway

Efficient methodology has been developed for the conjugate addition of ketene acetals to cyclic alpha,beta-enones. The chiral adducts allow access to fused- or bridged-ring structures such as those shown.     

Oxovanadium(V)-induced vicinal dialkylation of cyclic enones with organozinc compounds

Oxovanadium(V) compounds induce nucleophilic alpha,beta-vicinal dialkylation of cyclic alpha,beta-enones with dialkylzinc reagents. Alkylzinc enolates generated from cyclic enones and lithium trialkylzincates were also oxidized by VO(OEt)Cl(2), giving 2, 3-dialkylcycloalkanones.     

Broad-spectrum enantioselective diels-alder catalysis by chiral,cationic oxazaborolidines

The cationic chiral Lewis acids 1 and 2, generated by triflic acid protonation of the corresponding neutral oxazaborolidines, serve as excellent catalysts for Diels-Alder addition of cyclopentadiene to a wide variety of dienophiles. Adducts have been obtained in excellent yield and enantioselectivity from alpha,beta-unsaturated esters, lactones, and cyclic ketones. The absolute facial selectivity for each of these substrates follows a common pattern which differs from that observed with alpha,beta-enals. The different reaction channels can be understood in terms of pathways via complexes 3 (for alpha,beta-enals) and 4 (for alpha,beta-enones and esters).     

Highly enantioselective Friedel-Crafts alkylations of indoles with simple enones catalyzed by zirconium(IV)-BINOL complexes

Complexes of BINOL-based ligands with Zr(OtBu)4 catalyze the Friedel-Crafts alkylation reaction of indoles and pyrrole with nonchelating beta-substituted alpha,beta-enones at room temperature affording the expected products with good yields and ee above 95% in most of the studied examples.     

Synthesis of six epoxyketooctadecenoic acid (EKODE) isomers, their generation from nonenzymatic oxidation of linoleic acid, and their reactivity with imidazole nucleophiles

As a class of linoleic acid oxidation products, epoxyketooctadecenoic acids (EKODEs), are formed in vivo and in vitro by a free radical mechanism initiated by either enzymatic or nonenzymatic pathways. They have so far been made available in small-scale quantities, often as isomeric mixtures, from reductive decomposition of linoleic acid-derived hydroperoxides. There is major interest in these compounds owing to their highly potent biological activities and their ability to covalently modify proteins. The synthesis of six EKODE regio- and stereoisomers, two trans alpha',beta'-epoxy-alpha,beta-enones, and two trans and the two cis gamma,delta,-epoxy-alpha,beta-enones was accomplished, with the key steps being Wittig-type reactions and aldol condensations. All six EKODE isomers were confirmed by HPLC to be generated in the autoxidation of linoleic acid promoted by Fe(II)/ascorbic acid through spiking in of authentic samples. On the basis of evidence for EKODE modification of protein His residues, the reactions of Nalpha-benzoyl-L-histidine with autoxidizing linoleic acid and with the individual EKODE isomers were compared, as were the kinetics of the various EKODE reactions with imidazole nucleophiles. The structures of His-EKODE-(E)-I adducts were confirmed to reflect conjugate addition (epoxide ring remains intact) through an NMR study of the reaction of imidazole with a generic EKODE-(E)-I analog. The synthesis of the EKODE isomers makes these important molecules available for further chemical and biological evaluation.     

A novel nucleophilic substitution of in situ generated 3-tert-butyldimethyl- silyloxyalk-2-enylsulfonium salts with allylindium reagents

[reaction: see text] In situ generated 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salts derived from the reaction of alpha,beta-enones with dimethyl sulfide in the presence of TBSOTf undergo a novel nucleophilic substitution with in situ generated allylindium reagents from indium and allyl halides to give silyl enol ethers of delta,epsilon-unsaturated ketones, which correspond to Michael addition products, in good yields.