New synthetic methods for α,β -unsaturated ketones,aldehydes, esters and lactones by the palladium-catalyzed reactions of silyl enol ethers,ketene silyl acetals,and enol acetates with allyl carbonates

Silyl enol ethers and ketene silyl acetals derived from ketones, aldehydes, esters and lactones are converted into α,β-unsaturated ketones, aldehydes, esters and lactones by treatment with allyl carbonates in high yields using the palladium—bis(diphenylphosphino)ethane (dppe) complex as catalyst. Phosphine-free palladium catalyst instead of the palladium—phosphine complex gives a higher selectivity for the preparation of cyclopentenone, cyclooctenone, dienones, α,β-unsaturated esters and lactones. As a solvent, the use of nitriles such as acetonitrile is essential. In other solvents, allylation takes place. Enol acetates derived from ketones are converted into α,β-unsaturated ketones by reaction with allyl carbonate in acetonitrile using the palladium complex and tributyltin methoxide as bimetallic catalysts.     

Enantioselective Michael reaction of α-alkyl-β-keto esters and enones under multifunctional catalysis

An efficient approach for the enantioselective Michael additions of β-alkyl-β-keto esters to β-substituted α,β-unsaturated ketones has been developed. The Michael products could be obtained in good to excellent yields (75-98%) with excellent diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 96% ee) and could easily be transformed into a synthetically useful hexahydrophenanthrene structure under mild conditions in good yield.     

Metal-free catalytic C-Si bond formation in an aqueous medium. Enantioselective NHC-catalyzed silyl conjugate additions to cyclic and acyclic α,β-unsaturated carbonyls

A metal-free method for enantioselective conjugate addition of a dimethylphenylsilyl group to α,β-unsaturated carbonyls is reported. Transformations are catalyzed by a chiral N-heterocyclic carbene (NHC), performed in an aqueous solution (3:1 mixture of water and tetrahydrofuran) and are operationally simpler to perform than the NHC-Cu-catalyzed variant. The chiral catalyst is generated from an enantiomerically pure imidazolinium salt (prepared in three steps) and a common organic amine base (dbu). NHC-catalyzed processes proceed with 5.0-12.5 mol % catalyst loading at 22 °C within 1-12 h, affording the desired β-silyl carbonyls in 85:15 to >98:2 enantiomeric ratio and in 50% to >98% yield. Cyclic enones or lactones and acyclic α,β-unsaturated ketones, esters, and aldehydes can be used as substrates.     

A novel route for the synthesis of α,β-unsaturated esters,ketones and nitriles using dibutyl telluride

In the presence of dibutyl telluride, α-halo-ester, nitrile, and ketone were found to condense easily with aromatic aldehydes to afford α,β-unsaturated esters, nitriles and ketones in high yields as one-pot reaction. A possible reaction machanism was proposed.     

1,4-Addition of tetraethyl fluoromethylenebisphosphonate to α,β-unsaturated compounds

Tetraethyl fluoromethylenebisphosphonate in the presence of cesium carbonate in DMF undergoes efficient 1,4-addition to Michael acceptors having terminal double bond such as α,β-unsaturated ketones, esters, sulfones, sulfoxides, and phosphonates to yield the corresponding adducts (α-alkyl-α-fluoromethylenebisphosphonates) in good to excellent yields.     

Catalytic carbon-sulfur bond formation by amphoteric vanadyl triflate: exploring with thia-Michael addition, thioacetalization, and transthioacetalization reactions

A series of thiols have been examined as protic nucleophiles for Michael-type additions to α,β-unsaturated carbonyls as well as double nucleophilic condensations with aldehydes, ketones, and acetals catalyzed by amphoteric, water-tolerant vanadyl triflate under mild and neutral conditions. The newly developed C-S bond formation protocols were carried out smoothly in good to high yields in a highly chemoselective manner.     

Trends in structure–toxicity relationships for carbonyl-containing α,β-unsaturated compounds

Using toxicity data for 30 aliphatic polarized α,β-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure–toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of α,β-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within α,β-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between α,β-unsaturated carbonyl compounds with the carbon–carbon double bond on the end of the molecule (vinyl ketones) and those with carbon–oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of α,β-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between α,β-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.     

Tandem olefin metathesis-elimination reactions. A new route to doubly unsaturated carbonyl derivatives

Cross-metathesis between an activated olefin and an ethereal derivative of homoallylic alcohols leads to products that are subject to facile elimination resulting in α,β,γ,δ-unsaturated esters, ketones, acids, and aldehydes in high yields.     

Ionic liquid as catalyst and solvent: the remarkable effect of a basic ionic liquid, [bmIm]OH on Michael addition and alkylation of active methylene compounds

A basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide, [bmIm]OH, catalyzes the Michael addition of active methylene compounds to conjugated ketones, carboxylic esters and nitriles. It further catalyzes the addition of thiols to α,β-acetylenic ketones and alkylation of 1,3-dicarbonyl and -dicyano compounds. The Michael addition to α,β-unsaturated ketones proceeds in the usual way, giving the monoaddition products, whereas addition to α,β-unsaturated esters and nitriles leads exclusively to the bis-addition products. The α,β-acetylenic ketones undergo double conjugate addition with thiols producing β-keto 1,3-dithio-derivatives. In the alkylation reaction the acyclic 1,3-diketones are monoalkylated, whereas cyclic ketones undergo dialkylation under identical conditions. All these reactions were carried out without any organic solvent. The ionic liquid can also be recycled.     

Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral δ-keto nitroalkanes and δ-keto esters.     

Barbier coupling in water: SnCl2-mediated and Co(acac)2-catalyzed allylation of carbonyls

Co(acac)₂·2H₂O efficiently catalyzes SnCl₂-mediated Barbier coupling in water between carbonyls, including aromatic, aliphatic and α,β-unsaturated aldehydes, ketones, sugars and allyl bromide to afford the corresponding homoallylic alcohols in high yields. The catalyst was reused for several cycles with consistent activity.     

Lewis acid-catalyzed Meyer-Schuster reactions: methodology for the olefination of aldehydes and ketones

In principle, the most efficient and atom-economical means of converting an aldehyde or ketone into the homologated α,β-unsaturated ester is through addition/rearrangement sequences involving acetylenic π-bonds (Scheme 1). Implementation of such a strategy for the synthesis of α,β-unsaturated esters is presented: addition of ethoxyacetylene followed by scandium(III) triflate-catalyzed Meyer-Schuster rearrangement reaction. Stereoselectivities range from good to excellent in the formation of disubstituted α,β-unsaturated esters from aldehydes (Table 3). The two-stage olefination of even the most hindered ketones proceeds with near perfect efficiency (Table 4).     

Chloracylierung und Bromacylierung von Carbonylverbindungen: Eine in Vergessenheit geratene Carbonylreaktion. I. Präparative Anwendungsbreite

Chloroacylation and bromoacylation of carbonyl compounds: A forgotten carbonyl reaction. I. Scope of the reaction Aliphatic, α,β-unsaturated and aromatic aldehydes as well as aliphatic ketones react with acyl halides to (α-haloalkyl)esters. These bifunctional derivates contain two leaving groups of different reactivity. The scope of this scarcely of this scarcely known carbonyl reaction is discussed.     

Referees for Volumes 1–2

For toxicological-based structure–activity relationships to advance, will require a better understanding of molecular reactivity. A rapid and inexpensive spectrophotometric assay for determining the reactive to glutathione (GSH) was developed and used to determine GSH reactivity (react_GSH) data for 21 aliphatic derivatives of esters, ketones and aldehydes. From these data, a series of structure–activity relationships were evaluated. The structure feature associated with react_GSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized α,β-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively react_GSH of the α,β-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for α,β-unsaturated carbonyl compounds: (1) the acetylenic-substituted derivatives were more reactive than the corresponding olefinic-substituted ones; (2) terminal vinyl-substituted derivatives was more reactive than the internal vinylene-substituted ones; (3) methyl substitution on the vinyl carbon atoms diminishes reactivity and methyl-substitution on the carbon atom farthest from the carbonyl group causes a larger reduction; (4) derivatives with carbon–carbon double bond on the end of the molecule (i.e. vinyl ketone) were more reactive than one with the carbon–oxygen bond at the end of the molecule (i.e. aldehyde) and (5) the ester with an additional unsaturated vinyl groups were more reactive than the derivative having an unsaturated ethyl group.     

Synthesis of β-carbolines from aldehydes and ketones via the α-siloxy α,β-unsaturated esters

We report an efficient method for the synthesis of β-carbolines from α-siloxy α,β-unsaturated esters, which are accessible from a variety of aldehydes and ketones.     

A ruthenium-catalyzed one-pot method for α-alkylation of ketones with aldehydes

Ketones react with an array of aldehydes in dioxane at 80 °C in the presence of a catalytic amount of RuCl₂(PPh₃)₃ along with KOH to give the corresponding α-alkylated ketones in moderate to good yields. A reaction pathway involving base-catalyzed cross-aldol reaction between ketones and aldehydes to form α,β-unsaturated ketones and regioselective reduction of carbon-carbon double bond of α,β-unsaturated ketones is proposed for this catalytic process.     

Reactivity of α-chloro-aldimines

A series of secondary N-1-(2-chloroalkylidene)amines has been prepared by condensation of disubstituted acetaldehydes with primary amines followed by chlorination with N-chlorosuccinimide in carbontetrachloride. A study of the reactivity of these N-homologues of α-chloroaldehydes is described. Treatment of the title compounds with sodium methoxide in methanol gave high yields of α,β-unsaturated aldimines. However, N-1-(2-chloro-2-methylpropylidene)amines afforded a mixture of elimination and rearrangement products, which proceeded via an aziridine intermediate. On the other hand, α-phenyl-substituted α-chloro aldimines on treatment with methoxide in methanol underwent α-substitution, consistent with an S_N1 mechanism. Powerful nucleophiles such as sodium thiophenolate in methanol and sodium azide in acetone caused α-substitution. Reaction of α-chloro aldimines with Grignard reagents produced coupling of two aldimine units or α-alkylation. Finally the reactivity of α-chloro aldimines was compared with the reactivity of the corresponding oxygen-analogues, i.e. α-chloro aldehydes.     

Réaction du diméthylcuprate de lithium avec les dérivés carbonylés α,β-insaturés α-fluorés et α-chlorés

Depending on the nature of the halogen, α-fluoro- and α-chloro-α,β-unsaturated carbonyl compounds (whose reduction potentials are greater than ? 2.4V) react in different ways with lithium dimethylcuprate. With α-fluoro derivatives, both 1,2- and 1,4-addition is observed, their ratios depend on the steric hindrance of the β-position. 1,4-Addition products are obtained from aldehydes and β-monosubstituted α-chloro-α,β-ethylenic ketones and esters. β,β-Disubstituted α-chloro ketones and esters give only reduction of halogen via halogen-metal exchange.     

Direct synthesis of 2,4,5-trisubstituted imidazoles and di/tri-substituted pyrimidines via cycloadditions of α,β-unsaturated ketones/aldehydes and N′-hydroxyl imidamides

An efficient route for the synthesis of 5-acetylimidazoles and di/trisubstituted pyrimidines via iron-catalyzed cross-dehydrogenative coupling (CDC), with excellent tolerance and yields, has been developed. In this report, α,β-unsaturated aldehydes/ketones and N′-hydroxyl imidamides undergo [3+2] and [3+3] cycloadditions in two processes, involving iron-mediated Michael reaction, Robinson Annulation and 1,5-electrocyclization.     

Quantification of the electrophilic reactivities of aldehydes, imines, and enones

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.