Structure-activity relationships for reactivity of carbonyl-containing compounds with glutathione

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 (reactGSH) 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 reactGSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized alpha,beta-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively reactGSH of the alpha,beta-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for alpha,beta-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.     

Synthetic applications of beta-fluoroalkylated alpha,beta-unsaturated carbonyl compounds

Beta-fluoroalkylated alpha,beta-unsaturated carbonyl compounds constitute efficient building blocks for the synthesis of complex fluorinated compounds. As the fluorinated moiety generally increases their reactivity, it also brings important modifications which can change the chemical behavior and selectivity. Their use has been already largely demonstrated. Nevertheless, the synthetic potential has not yet been fully explored and, consequently should play an important role in the design of new sophisticated fluorinated molecules. Nevertheless, it shall be important to develop new synthetic methods to enlarge their availability and their diversity.     

Amine-catalyzed addition of azide ion to alpha,beta-unsaturated carbonyl compounds

[formula: see text] A new protocol for the beta-azidation of alpha,beta-unsaturated carbonyl compounds is described. The method employs tertiary amines as catalysts for azide addition. The azide source is a 1:1 mixture of TMSN3 and AcOH. Tertiary amines, either in solution or bound to a solid support, are efficient catalysts for the reaction.     

Transition metal-catalysed acylation of alpha,beta-unsaturated carbonyl compounds with acylstannanes

Acylstannanes were found to add to such alpha,beta-unsaturated carbonyl compounds as enones or ynoates in the presence of a nicel or palladium catalyst to give 2-stannyl-4-oxoalk-2-enoates or 1,4-diketones, whereas the three component coupling between acylstannanes, enones and aldehydes provided 2-hydroxymethyl 1,4-diketones.     

Catalyst-free conjugated addition of thiols to alpha,beta-unsaturated carbonyl compounds in water

[reaction: see text] Catalyst-free conjugate addition of thiols to alpha,beta-unsaturated carbonyl compounds in water is reported. beta-Sulfido carbonyl compounds were formed at room temperature, in short times and with excellent chemoselectivity. Competitive dithiane/dithiolane formation, transesterification, and ester cleavage were not observed. Water played a dual role in simultaneously activating the alpha,beta-unsaturated carbonyl compound and the thiol. This new methodology constitutes an easy, highly efficient, and green synthesis of beta-sulfido carbonyl compounds.     

beta-Sulfinyl alpha,beta-unsaturated carbonyl compounds from enantiomerically pure sulfenic acids.

The addition of enantiopure sulfenic acids to oxoalkynes constitutes a new and efficient methodology for the synthesis of beta-sulfinyl alpha,beta-unsaturated carbonyl compounds. Sulfenic acids 3 and 4 were generated by thermolysis of suitable precursors and trapped in situ by oxoalkynes 5, affording (R(S),E)- and (S(S),E)-3-alkylsulfinyl-1-phenyl-2-propen-1-ones, 4-alkylsulfinyl-3-buten-2-ones, and 3-[(1S)-isoborneol-10-sulfinyl]-2-propenoates 6 and 7 in good yields and in enantiomerically pure form after simple column chromatography. (R(S),E)-3-[(1S)-isoborneol-10-sulfinyl]-1-phenyl-2-propen-1-one (6(R)a) was involved as a heterodiene in inverse-electron-demanding Diels-Alder reactions with readily available electron-rich dienophiles 14 and 15, corroborating in each case the sulfinyl auxiliary capability in controlling the stereochemical outcome of these cycloadditions. Furthermore, the addition of methylmagnesium iodide to the carbonyl moiety of 6(R)a demonstrated that the chiral sulfur atom exerts a remote stereocontrol in this reaction if assisted by the hydroxy group being part of the isoborneol substituent.     

Rhodium-catalysed 1,4-addition of diarylindium hydroxides to alpha,beta-unsaturated carbonyl compounds

Diarylindium(III) hydroxides react with alpha,beta-unsaturated carbonyl compounds in the presence of a rhodium catalyst to afford the 1,4-addition products in high yield. This reaction demonstrates the utility of diarylindium(III) hydroxide as an aryl source with rhodium catalysts.     

Mono- and beta,beta-double-Heck reactions of alpha,beta-unsaturated carbonyl compounds in aqueous media

Optimized reaction conditions for the mono- and beta,beta-diarylation of electron-deficient alkenes in aqueous media catalyzed either by a p-hydroxyacetophenone oxime-derived palladacycle or by palladium(II) acetate under phosphine-free conditions and in the presence of (dicyclohexyl)methylamine as base are described. Regioselective monoarylation of unsubstituted and substituted alpha,beta-unsaturated carbonyl compounds takes place with aryl iodides at 120 degrees C in water. Aqueous N,N-dimethylacetamide (DMA), tetra-n-butylammonium bromide (TBAB) as additive, and the palladacycle as catalyst are the most efficient conditions for the coupling with aryl bromides, good stereoselectivities being also obtained in the arylation of crotonates and itaconates, whereas cinnamic derivatives afford lower steroselectivity, with the exception of cinnamic acid and nitrile. beta,beta-Diarylation of unsubstituted alpha,beta-unsaturated carbonyl compounds can be controlled by using higher loading of the palladacycle and can be performed in refluxing water for aryl iodides, whereas DMA must be used for aryl bromides. Microwave irradiation can be used in the monoarylation of tert-butyl acrylate with aryl iodides in water or the coupling between ethyl cinnamate and aryl bromides in aqueous DMA.     

Palladium-catalyzed conjugate addition of organosiloxanes to alpha,beta-unsaturated carbonyl compounds and nitroalkenes

The addition of aryltrialkoxysilanes to alpha,beta-unsaturated carbonyl compounds (ketones, aldehydes) and nitroalkenes in the presence of SbCl(3), TBAF, AcOH, and a catalytic amount of Pd(OAc)(2), in CH(3)CN at 60 degrees C, provides the corresponding conjugate addition products in moderate to good yields. The addition of equimolar amounts of SbCl(3) and TBAF is necessary for this reaction to proceed smoothly. The arylpalladium complex, which is generated by the transmetalation from a putative hypercoordinate silicon compound, is considered to be the catalytically active species.     

Density functional theory study of electroreductive hydrocoupling of alpha,beta-unsaturated carbonyl compounds

[reaction: see text] The electroreductive hydrocoupling of methyl cinnamate, methyl crotonate, cumarin, and benzalacetone was studied by DFT (B3LYP/6-311++ G**) calculations. The computational outcomes for the transition states in the hydrocoupling of anion radicals generated by a one-electron transfer to the alpha,beta-unsaturated carbonyl compounds well agree with the diastereoselectivities in the experimental results previously reported.     

Mo-Au combo catalysis for rapid 1,3-rearrangement of propargyl alcohols into alpha,beta-unsaturated carbonyl compounds

The combination of Mo and cationic Au catalysts dramatically accelerated the rearrangement of diverse propargyl alcohols, which includes a short reaction time, mild conditions, and high product yields. A practical application to the highly challenging primary propargyl alcohols and the N-alkynyl amides is achieved.     

Triethylaluminum- or triethylborane-induced free radical reaction of alkyl iodides and alpha,beta-unsaturated compounds

A series of alpha,beta-unsaturated compounds, 1a-c, 9, 13, and 17, were used as reactants in free radical conjugate addition reactions with different radicals generated from alkyl iodides such as 3, 4, or 5 in the presence of triethylborane-oxygen in air or via the use of triethylaluminum-benzoyl peroxide as a free radical initiator. When the reactions were carried out using triethylborane-air, the products, in most cases, were clean and were easily purified. However, higher yields of the 1,4-adducts and less side reactions occurred when less reactive substrates were used as Michael acceptors in reactions with triethylaluminum-benzoyl peroxide and alkyl iodide under similar conditions. A mechanism for this is proposed in Scheme 1.     

Asymmetric Lewis acid-catalyzed Diels-Alder reactions of alpha,beta-unsaturated ketones and alpha,beta-unsaturated acid chlorides

[reaction: see text] Conformational analysis, van der Waals attractions, and transition structure calculations are combined to design an asymmetric Lewis acid-catalyzed Diels-Alder reaction for simple acyclic alpha,beta-unsaturated ketones and alpha,beta-unsaturated acid chlorides, giving up to 83 and 92% ee, respectively. The two-point-binding chiral recognition mechanism, Lewis acid-Lewis base coordination with boron and a van der Waals attraction with the naphthyl group, uses the inherent enone unit of simple alpha,beta-unsaturated carbonyl compounds, ending the need for auxiliary oxygen binding sites on the dienophile.     

Copper-catalyzed beta-Boration of alpha,beta-unsaturated carbonyl compounds: rate acceleration by alcohol additives

[reaction: see text] The efficient addition of bis(pinacolato)diboron to alpha,beta-unsaturated carbonyl compounds with a copper-diphosphine catalyst has been carried out. A dramatic rate acceleration of the reaction was realized by adding alcohol additives. With use of this procedure, a variety of alpha,beta-unsaturated carbonyl compounds including conjugated substrates at the acid oxidation level such as esters and nitriles were reacted to give to the corresponding beta-boryl carbonyl compounds in high yields.     

Conjugate reduction of alpha,beta-unsaturated carbonyl compounds catalyzed by a copper carbene complex

[reaction: see text] An N-heterocyclic carbene copper chloride (NHC-CuCl) complex (2) has been prepared and used to catalyze the conjugate reduction of alpha,beta-unsaturated carbonyl compounds. The combination of catalytic amounts of 2 and NaOt-Bu with poly(methylhydrosiloxane) (PMHS) as the stoichiometric reductant generates an active catalyst for the 1,4-reduction of tri- and tetrasubstituted alpha,beta-unsaturated esters and cyclic enones. The active catalytic species can also be generated in situ from 1,3-bis(2,6-di-isopropylphenyl)-imidazolium chloride (1) CuCl(2).2H(2)O in the presence of NaOt-Bu and PMHS.     

苯甲酸类化合物小鼠经口LD50定量构效关系的研究

采用化合物定量结构-毒性效应关系(QSTR)方法研究了39个苯甲酸类化合物的各种量化参数对小鼠经口急性毒性(LD50)的影响,并建立了毒性预测模型.为了得到更准确的毒性预测模型,各个参数的交叉项同时考虑在内,利用线性回归方法得到了苯甲酸类化合物小鼠经口急性毒性预测模型(相关系数为0.958 2).该模型具有很好的预测能力.     

Highly enantioselective michael addition of cyclic 1,3-dicarbonyl compounds to alpha,beta-unsaturated ketones

[reaction: see text] The highly enantioselective Michael addition of 1,3-cyclic dicarbonyl compounds to alpha,beta-unsaturated ketones was reported to be catalyzed by an organic primary amine derived from quinine. A chiral anticoagulant drug, (S)-warfarin, was directly prepared in 96% ee, and other related important adducts were also obtained in excellent enantioselectivity (89-99% ee).