A DFT study on the 1,3-dipolar cycloaddition reactions of C-(methoxycarbonyl)-N-methyl nitrone with methyl acrylate and vinyl acetate

In the 1,3-dipolar cycloaddition of glyoxylic nitrones with electron-poor and electron-rich alkenes, the configurational instability of the nitrone leads to parallel models when regio- and stereoselectivities are rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations, leading to a total of sixteen transition structures for each dipolarophile, the regio- and stereochemical preferences of the reaction are discussed.     

A DFT study on the 1,3-dipolar cycloaddition reactions of C-(hetaryl) nitrones with methyl acrylate and vinyl acetate

The 1,3-dipolar cycloaddition of C-(hetaryl) nitrones with electron-poor and electron-rich alkenes is rationalized. The energetics of the cycloaddition reactions have been investigated through molecular orbital calculations at the B3LYP/6-31-G(d) theory level. By studying different reaction channels and reagent conformations the regio- and stereochemical preferences of the reaction are discussed.     

1,2,3-Triazol-5-ylidene-palladium complex catalyzed Mizoroki-Heck and Sonogashira coupling reactions

The bis-1,4-dimesityl-1,2,3-triazol-5-ylidene-palladium complex (1a) successfully catalyzes the Mizoroki-Heck and Sonogashira coupling reactions with aryl bromides to give the corresponding alkenes and alkynes, respectively, in good to excellent yields. In the Mizoroki-Heck reaction, electron-rich, electron-poor, and functionalized aryl bromides and alkenes are tolerated, while the substrates are limited to electron-poor aryl halides in the Sonogashira coupling reaction. The palladium complex also catalyzes cross-coupling reactions with aryl chlorides to give higher yields of products than does the bis-IMes-Pd complex analogue (2), under specific conditions.     

A density functional theory study of the chemoselectivity and regioselectivity of the domino cycloaddition reactions of nitroalkenes with substituted alkenes

The chemoselectivity and regioselectivity of the domino intermolecular [4 + 2]/[3 + 2] cycloaddition reactions of nitroalkenes with substituted alkenes, vinyl ethers as electron-rich alkenes and vinyl ketones as electron-poor alkenes, have been studied using density functional theory (DFT) methods with the B3LYP functional and the 6-31G^* basis set. These domino processes comprise two consecutive cycloaddition reactions: the first one is an intermolecular [4 + 2] cycloaddition of the vinyl ether to the nitroalkene to give a nitronate intermediate, which then affords the final nitroso acetal adduct through an intermolecular [3 + 2] cycloaddition reaction with the vinyl ketone. The two consecutive cycloadditions present total chemoselectivity and ortho regioselectivity. While first [4 + 2] cycloaddition reaction takes place along the attack of the electron-rich alkene to nitroalkene, the [3 + 2] one takes place along the attack of the electron-poor alkene to the corresponding nitronate intermediate. This DFT study is in complete agreement with the experimental results. Received: 16 September 1999 / Accepted: 3 February 2000 / Published online: 2 May 2000     

Concurrent cyclopropanation by carbenes and carbanions

The generation of phenylhalocarbenes in the presence of varying quantities of halide ions and electron-poor alkenes affords concurrent cyclopropanation of the alkenes by an equilibrating mixture of phenylhalocarbenes and phenylhalomethide carbanions, which permits the smooth modulation of selectivity between electron-poor alkenes and electron-rich alkenes, a feature of potential synthetic utility.     

Copper (I)-BOX Catalyzed Asymmetric 3-Component Reaction for the Synthesis of Trifluoromethylated Propargylic Ethers and Anilines**

An asymmetric 3-component reaction between EthynylBenziodoXoles (EBXs), 2,2,2-trifluorodiazoethane and nucleophiles catalyzed by a Cu^I-BOX (Bisoxazoline) catalyst is described. This protocol gives access to chiral trifluoromethylated propargyl ethers and anilines, which are valuable building blocks in synthetic and medicinal chemistry. The reaction proceeds with high enantioselectivity and yield with different nucleophiles such as primary, secondary and tertiary alcohols, as well as both electron-rich and electron-poor anilines. Aryl-, alkyl- and silyl-substituted alkynes can be successfully introduced as electrophiles. In case of chiral substrates, high catalyst control was observed, leading to good diastereoselectivity.     

Cobalt(I)-mediated preparation of polyborylated cyclohexadienes: scope, limitations, and mechanistic insight

A series of 1,3- and 1,4-diboryl-1,3-cyclohexadienes have been prepared by intermolecular CoCp-mediated [2+2+2] cocyclizations of alkynylboronic pinacolate esters with alkenes, followed by oxidative demetallation with iron(III) chloride. The effect of substitution at the borylated alkyne on chemo- and regioselectivities has been studied, suggesting steric control. The proper choice of substituents allowed the preparation of 1,3-diborylated cyclohexadienes in a highly selective manner. Alternatively, 1,4-diborylated cyclohexadienes could be prepared from diborylated diynes. The scope of this reaction has been examined and found to include electron-poor, electron-rich, linear, and cyclic alkenes. The diborylated cyclohexadienes were submitted to single or double Suzuki-Miyaura cross-coupling reactions with haloarenes to afford polyarylated systems. The mechanism of the title reaction, including the regioselectivity of the cycloaddition steps, has been analyzed by means of DFT computations.     

Intermolecular migratory insertion of unactivated olefins into palladium-nitrogen bonds. Steric and electronic effects on the rate of migratory insertion

We report a detailed examination of the effect of the steric and electronic properties of the ancillary ligand and the alkene reactant on the rate of migratory insertion of unactivated alkenes into the palladium-nitrogen bond of isolated palladium amido complexes. A series of THF-bound and THF-free amidopalladium complexes ligated by cyclometalated benzylphosphine ligands possessing varied steric and electronic properties were synthesized. The THF-free complexes react with ethylene at -50 °C to form olefin-amido complexes that were observed directly and that undergo migratory insertion, followed by β-hydride elimination to generate enamine products. The effect of the steric properties of the ancillary ligand on the binding of the alkene and the rate of migratory insertion were evaluated individually. The relative binding affinity of ethylene vs THF is larger for the less sterically hindered complex than for the more hindered complex, but the less hindered complex undergoes the insertion of ethylene more slowly than does the more hindered complex. These two changes in relative equilibrium and rate constants cause the rates of reaction of ethylene with the two THF-ligated species having different steric properties to be similar to each other. Reactions of the complexes containing electronically varied ancillary ligands showed that the more electron-poor complexes underwent the migratory insertion step faster than the more electron-rich complexes. Reactions of a THF-ligated palladium-amide with substituted vinylarenes showed that electron-poor vinylarenes reacted with the amido complex slightly faster than electron-rich vinylarenes. Separation of the energetics of binding and insertion indicate that the complex of an electron-rich vinylarene is more stable in this system than the complex of a more electron-poor vinylarene but that the insertion step of the bound, electron-rich vinylarene is slower than the insertion step with the bound, electron-poor vinylarene.     

Origins of the Reactivity in 1,3-Dipolar Cycloadditions of Acyl Isocyanide Ylides

1,3-Dipolar cycloadditions are the preferred method to generate five-membered heterocyclic rings. Surprisingly, cycloadditions based on acyl-isocyanide ylides have remained underexplored by the chemical community. Acyl-isocyanide ylides readily react with dipolarophiles, such as substituted alkenes, to yield Δ¹-pyrroline derivatives. As an explanation for the observed reactivity of this reaction is lacking, extensive density functional theory calculations were performed to scrutinize the mechanistic features of the transformation. Herein we explain the experimental outcome of the reaction using a variety of reactivity theories and predict opposed regioselectivity for electron-poor and electron-rich dipolarophiles. With the insights obtained, we hope to incentivize the design of new cycloaddition reactions based on the acyl-isocyanide ylides motif.     

Chelation-controlled intermolecular alkene and alkyne hydroacylation: the utility of beta-thioacetal aldehydes

[reaction: see text]. Beta-thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO4 as a catalyst and are proposed to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or reduced to alkanes in good yields.     

Rhodium-catalyzed anti-Markovnikov hydroamination of vinylarenes

The transition metal-catalyzed anti-Markovnikov hydroamination of unactivated vinylarenes with a rhodium complex of DPEphos is reported. The reaction of electron-neutral or electron-rich vinylarenes with a variety of secondary amines in the presence of catalyst forms the products from anti-Markovnikov hydroamination in high yields. Reactions of morpholine, N-phenylpiperazine, N-Boc-piperazine, piperidine, 2,5-dimethylmorpholine, and perhydroisoquinoline reacted with styrene to form the amine product in 51-71% yield. Reactions of a variety of vinylarenes with morpholine generated amine as the major product. Reactions of morpholine with electron-poor vinylarenes gave lower amine:enamine ratios than reactions of electron-rich vinylarenes at the same concentration of vinylarene, but conditions were developed with lower concentrations of electron-poor vinylarene to maintain formation of the amine as the major product. Reactions of dimethylamine with vinylarenes were fast and formed amine as the major product. Mechanistic studies on the hydroamination process showed that the amine:enamine ratio was lower for reactions conducted with higher concentrations of vinylarene and that one vinylarene influences the selectivity for reaction of another. A mechanism proceeding through a metallacyclic intermediate that opens in the presence of a second vinylarene accounts for these and other mechanistic observations.     

Palladium-catalyzed desulfitative Mizoroki-Heck couplings of sulfonyl chlorides with mono- and disubstituted olefins: rhodium-catalyzed desulfitative heck-type reactions under phosphine- and base-free conditions

New conditions have been found for the desulfitative Mizoroki-Heck arylation and trifluoromethylation of mono- and disubustituted olefins with arenesulfonyl and trifluoromethanesulfonyl chlorides. Thus (E)-1,2-disubstituted alkenes with high stereoselectivity and 1,1,2-disubstituted alkenes with 12:1 to 21:1 E/Z steroselectivity can be obtained. Herrmann's palladacycle at 0.1 mol % is sufficient to catalyze these reactions, for which electron-rich or electron-poor sulfonyl chlorides and alkenes are suitable. If phosphine- and base-free conditions are required, 1 mol % [RhCl(C(2)H(4))(2)] catalyzes the desulfitative cross-coupling reactions. Contrary to results reported for [RuCl(2)(PPh(3))(2)]-catalyzed coupling reactions with sulfonyl chlorides, the palladium and rhodium desulfitative Mizoroki-Heck coupling reactions are not inhibited by radical scavenging agents. Possible sulfones arising from the sulfonylation of alkenes at 60 degrees C are not desulfitated at higher temperatures in the presence of the Pd or Rh catalysts.     

Asymmetric Wacker-Type Oxyallenylation and Azaallenylation of Cyclic Alkenes

Palladium-catalyzed three-component carboetherification of cyclic alkenes proceeded to give trans adducts exclusively with excellent enantioselectivity through a Wacker-type pathway. The reaction is also applicable to other oxygen nucleophiles, such as water, phenols, and carboxylic acids, as well as some electron-poor aryl amines.     

Layered double hydroxide supported nanopalladium catalyst for Heck-, Suzuki-, Sonogashira-, and Stille-type coupling reactions of chloroarenes

Layered double hydroxide and Merrifield resin supported nanopalladium(0) catalysts are prepared by an exchange of PdCl(4)(2-) followed by reduction and well characterized for the first time. The ligand-free heterogeneous layered double hydroxide supported nanopalladium (LDH-Pd(0)) catalyst using the basic LDH in place of basic ligands indeed exhibits higher activity and selectivity in the Heck olefination of electron-poor and electron-rich chloroarenes in nonaqueous ionic liquids (NAIL) over the homogeneous PdCl(2) system. Using microwave irradiation, the rate of the Heck olefination reaction is accelerated, manifold with the highest turnover frequency ever recorded in the case of both electron-poor and electron-rich chloroarenes. The basic LDH-Pd(0) shows a superior activity over a range of supported catalysts, from acidic to weakly basic Pd/C, Pd/SiO(2,) Pd/Al(2)O(3), and resin-PdCl(4)(2-) in the Heck olefination of deactivated electron-rich 4-chloroanisole. The use of LDH-Pd(0) is extended to the Suzuki-, Sonogashira-, and Stille-type coupling reactions of chloroarenes in an effort to understand the scope and utility of the reaction. The catalyst is quantitatively recovered from the reaction by a simple filtration and reused for a number of cycles with almost consistent activity in all the coupling reactions. The heterogeneity studies provide an insight into mechanistic aspects of the Heck olefination reaction and evidence that the reaction proceeds on the surface of the nanopalladium particles of the heterogeneous catalyst. TEM images of the fresh and used catalyst indeed show that the nanostructured palladium supported on LDH remains unchanged at the end of the reaction, while the XPS and evolved gas detection by TGA-MS of the used catalyst identify ArPdX species on the heterogeneous surface. Thus, the ligand-free nanopalladium supported on LDH, synthesized by the simple protocol, displays superior activity over the other heterogeneous catalysts inclusive of nanopalladium in the C-C coupling reactions of chloroarenes.     

DABCO-mediated aza-Michael addition of 4-aryl-1H-1,2,3-triazoles to cycloalkenones. Regioselective synthesis of disubstituted 1,2,3-triazoles

Aza-Michael addition of 4-aryl-1H-1,2,3-triazoles to 2-cycloalken-1-ones has been studied in the presence of DABCO as organic base. The reactions were carried out in acetonitrile at room temperature to provide 2,4-disubstituted 2H-1,2,3-triazoles as major adducts and 1,4-disubstituted 1H-1,2,3-triazoles as minor adducts. Though the reaction times are longer (4–8 days), the two regioisomers were separated by using column chromatography and the adducts were obtained in very good to excellent combined chemical yields. The electron-rich and electron-poor substituents on aryl moiety of 4-aryl-triazoles could tolerate the reaction conditions to afford the title adducts.     

Characteristics of the two frontier orbital interactions in the Diels-Alder cycloaddition

Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the roles played by the two frontier orbital interactions emerged. It was demonstrated that in the case of normal Diels-Alder cycloadditions, the FMO theory could predict the relative reactivities between dienophiles, while in the case of inverse-electron demand Diels-Alder reactions, it could not. It was shown that the dissymmetry in electron-rich dienophiles increases their reactivities.     

Rhodium-catalyzed intermolecular chelation controlled alkene and alkyne hydroacylation: synthetic scope of beta-S-substituted aldehyde substrates

The use of beta-S-substituted aldehydes in rhodium-catalyzed intermolecular hydroacylation reactions is reported. Aldehydes substituted with either sulfide or thioacetal groups undergo efficient hydroacylation with a variety of electron-poor alkenes, such as enoates, in Stetter-like processes and with both electron-poor and neutral alkynes. In general, the reactions with electron-poor alkenes demonstrate good selectivity for the linear regioisomer, and the reactions with alkynes provide enone products with excellent selectivity for the E-isomers. The scope of the process was shown to be broad, tolerating a variety of substitution patterns and functional groups on both reaction components. A novel CN-directing effect was shown to be responsible for reversing the regioselectivity in a number of alkyne hydroacylation reactions. Catalyst loadings as low as 0.1 mol % were achievable.     

Phosphonyl, phosphonothioyl, phosphonodithioyl, and phosphonotrithioyl radicals: generation and study of their addition onto alkenes

The treatment of benzyl dialkyl phosphites and dithiophosphites with benzeneselanyl chloride generates an Arbuzov-type transformation leading to the dialkyl selenophosphates 19a and 19b and to selenophosphorodithioates 21a and 21b. Interaction of these substrates with Lawesson's reagent yields the corresponding selenophosphorothioates 20a and 20b and the selenophosphorotrithioates 22a and 22b. When treated with a radical initiator in the presence of a hydrogen donor and an alkene, all eight phosphorus(V) precursors undergo homolytic cleavage of the P-Se bond to generate the phosphonyl, phosphonothioyl, phosphonodithioyl, or phosphonotrithioyl radicals. Most of these are shown to add onto electron-rich and electron-poor alkenes to deliver the expected adducts in fair to excellent yields. Cyclic precursor 19b displays peculiar behavior and, under the reaction conditions, produces only the corresponding cyclic phosphite. Application of this radical chain process is carried out on furanosyl 3-exo-methylene derivative 37 to diastereoselectively furnish five new 3-phosphonomethyl-, 3-phosphonothiomethyl-, and 3-phosphonodithiomethyl-3-deoxofuranoses 38a-c and 38f,g. The possibility of conducting tandem processes is also discussed through experiments involving (1R)-(+)-alpha-pinene (39) and diallylamine 41.     

Lewis acid-promoted carbon-carbon bond cleavage of aziridines: divergent cycloaddition pathways of the derived ylides

Lewis acids are shown to cleave the carbon-carbon bond of activated aziridines at ambient temperature. The derived metal-coordinated azomethine ylides undergo cycloaddition reactions with electron-rich alkenes. Cyclic alkenes afford products that are formally [4+2] adducts most likely derived from a Mannich-type addition to the ylide, followed by intramolecular Friedel-Crafts alkylation. Alternatively, acyclic alkenes undergo [3+2] cycloaddition to give new pyrrolidine products.     

On the reaction of 2-chloroethylisothiocyanate with aromatic amines

The reaction of aromatic amines with 2-chloroethylisothiocyanate 2 to give 2-arylaminothiazolines 1 was investigated. The course of this reaction was found to depend on the electronic nature of the amine and the reaction conditions. With arylamines that are relatively electron-rich, good yields of the thiazolines 1 were obtained. With electron-poor amines, adducts 4 , in which two equivalents of 2 reacted with the amine, accompanied 1. The relative amounts of 2:1 adducts increased as the arylamine became progressively more electron deficient. With 3,4-dichloroaniline, the yields of the 2:1 adducts were promoted by the presence of triethylamine.