Lewis Acid–Mediated Domino Reaction of 3-Bromomethylthiophenes with Arenes/Heteroarenes

Lewis acid–mediated domino reaction of 3-bromomethylthiophenes with various types of arenes and heteroarenes is reported.     

A DFT study of the domino inter

The molecular mechanism of the domino inter [4 + 2]/intra [3 + 2] cycloaddition reactions of nitroalkenes with enol ethers to give nitroso acetal adducts has been characterized using density functional theory methods with the B3LYP functional and the 6-31G basis set. The presence of Lewis acid catalyst and solvent effects has been taken into account to model the experimental environment. These domino processes comprise two consecutive cycloaddition reactions: the first one is an intermolecular [4 + 2] cycloaddition of the enol ether to the nitroalkene to give a nitronate intermediate, which then affords the final nitroso acetal adduct through an intramolecular [3 + 2] cycloaddition reaction. The intermolecular [4 + 2] cycloaddition can be considered as a nucleophilic attack of the enol ether to the conjugated position of the nitroalkene, with concomitant ring closure and without intervention of an intermediate. For this cycloaddition process, the presence of the Lewis acid favors the delocalization of the negative charge that is being transferred from the enol ether to the nitroalkene and decreases the activation energy of the first cycloaddition. The [4 + 2] cycloaddition presents a total regioselectivity, while the endo/exo stereoselectivity depends on the bulk of the Lewis acid used as catalyst. Thus, for small Lewis acid catalyst, modeled by BH(3), the addition presents an endo selectivity. The [3 + 2] cycloaddition reactions present an total exo selectivity, due to the constraints imposed by the tether. Inclusion of Lewis acid catalyst and solvent effects decrease clearly the barrier for the first [4 + 2] cycloaddition relative to the second [3 + 2] one. Calculations for the activation parameters along this domino reaction allow to validate the results obtained using the potential energy barriers.     

An Unprecedented Domino Double Allylsilane [3+2] Cycloaddition/Wagner–Meerwein Rearrangement/Friedel–Crafts Alkylation/Elimination Reaction Sequence Leading to a Novel Pentacyclic Ring System

A stereoselective synthesis of the disilyl derivatives 3 is achieved by the title reaction, an unprecedented Lewis acid promoted domino reaction, between the cross-conjugated dienone 1 and the allylsilanes 2 . The configurations of the five stereogenic centers of this novel ring system are established in the first step of the reaction sequence, the double [3+2] cycloaddition.     

Construction of Polyheterocyclic Compounds by Lewis Acid Mediated Intramolecular [3+2] Cycloaddition Reaction

An efficient domino approach has been developed for the synthesis of polyheterocyclic derivatives constituting pyrrole moiety. Lewis acid catalyzed reaction of 2-substituted-2-hydroxy-indane-1,3-diones and 1,4-benzoxazinone derivatives resulted in the formation of polyheterocyclic compounds under metal-free and mild conditions in good to excellent yield. The reaction is highly regioselective for C−C and C−N bond construction proceeded via intramolecular [3+2] cycloaddition reaction. The protocol is highly efficient, obviates column chromatography and the products are obtained by simple filtration followed by washing with solvent.     

α-Acyloxynitroso dienophiles in [4+2] hetero Diels-Alder cycloadditions: mechanistic insights

α-Acyloxynitroso derivatives are a class of heterodienophiles leading to valuable 3,6-dihydro-1,2-oxazines or the corresponding aminoalcohols in good yields. The discovery that a β-oxygenated moiety led to a domino [4+2] cycloaddition/σ_N-O bond cleavage in the presence of a catalytic amount of Lewis acid was investigated in detail, through kinetic profiling of the reaction both in the absence and presence of a promoter. These studies showed that the role of the Lewis acid was to accelerate the σ_N-O bond cleavage thereby promoting a highly reproducible sequence. In addition, our preliminary results on an asymmetric version of this domino sequence are reported.     

One‐Pot Three‐Component Domino Reaction for the Synthesis of Novel Spiro Indolinyl Isoxazolo[2,3‐c][1,3,5]Thiadiazepinones Catalyzed by PTSA

The synthesis of novel spiro indolinyl isoxazolo[2,3‐c] [1,3,5]thiadiazepinones has been achieved by using one‐pot three‐component domino reaction from 3‐amino‐5‐methylisoxazole, substituted isatins, and mercapto acetic acid by employing p‐toluene sulfonic acid as Lewis acid catalyst. The salient features of the present method are mild reaction conditions, cost effective, environmentally benign, high yields of products and operational simplicity.     

Bifunctional Furfuryl Cations Strategy: Three‐Component Synthesis of Enamidyl Triazoles

A new multicomponent synthesis of functionalized enamidyl triazoles starting from simple and readily available starting materials is described. A simple treatment of a dichloromethane solution of an azide, amine, and 5‐bromo‐2‐furylcarbinol with a Lewis acid provides the enamidyl triazole in good to high yield. A triple domino sequence, formal [3+2] cycloaddition/ring‐opening/amidation, is involved in this new skeleton‐generating reaction.     

Practical synthesis and Diels-Alder chemistry of [4]dendralene

Spectacular new atom efficient domino cycloaddition sequences involving [4]dendralene, the simplest cross-conjugated tetraene, are reported. Up to eight stereocenters, three new rings, and six C-C bonds are generated in one synthetic operation. The site selectivity of dienophile addition to cross-conjugated trienes and tetraenes is controlled with a simple Lewis acid.     

Control of up to five stereocenters in a cascade reaction: synthesis of highly functionalized five-membered rings

Mukaiyama-Aldol and Prins reactions have been identified as highly efficient methods in C-C bond formation since they were discovered several decades ago. Since both reactions gave the same common intermediate, oxocarbonium, we intend to combine the two reactions into a domino process, which means the formation of multiple C-C bonds and stereogenic centers in one pot without isolation of any intermediates. We envisage that the domino reactions involving the Mukaiyama-Aldol reaction of silyl enol ether and acetal treated with Lewis acid (TiBr4) will produce an oxonium intermediate which upon trapping by an alkene functionality in an intramolecular Prins cyclization will generate the cyclopentyl ring system.     

2.2]Paracyclophane derived bisphosphines for the activation of hydrogen by FLPs: application in domino hydrosilylation/hydrogenation of enones

The heterolytic splitting of hydrogen by two types of [2.2]paracyclophane derived bisphosphines (1, 2a and 2b) in combination with tris(pentafluorophenyl)borane (3) at room temperature is described. The corresponding frustrated Lewis pairs (FLPs) exhibit different behavior in the activation of hydrogen. This results from diverse steric and electronic properties of the bisphosphines. The reactivity of the frustrated Lewis pairs was exploited in the first diastereoselective domino hydrosilylation/hydrogenation reaction catalyzed by FLPs.     

Rational Design to Construct Pyridinonethiol and Its Annulated Frameworks of Expected Significant Antitumor Activity and Geometrical Optimizations

We exploited the utilization of 2‐methyl‐2‐phenyl‐1,3‐oxathiolan‐5‐one ( 1 ) that acts as activated thioglycolic acid as mercaptoacetyl transfer agent to build new pyridinonethiol derivatives via multicomponent domino reactions of 1 with different acyclic or cyclic α ,β‐unsaturated carbonyl compounds and aniline using CeCl₃∙7H₂O/KI as Lewis acid catalyst. Furthermore, the new synthesized compounds were biologically evaluated for antitumor efficiency. The geometries and normal modes of vibrations obtained from calculations are in good agreement with the experimentally observed data.     

Efficient synthesis of pyrano[2,3-c]coumarins via intramolecular domino Knoevenagel hetero-Diels-Alder reactions

The domino Knoevenagel hetero-Diels-Alder reaction of the O-propargylated salicylaldehydes and 4-hydroxycoumarin leads to pyrano[2,3-c]coumarins 3 and pyrano[2,3-c]chromones 4 in high yield in the presence of CuI as a Lewis acid. In all cases, the reaction was shown to exhibit high regioselectivity and form product 3 as main product.     

Stereoselectivity in nucleophilic additions to 3-azidoalkanals

The stereoselectivity of nucleophilic additions to 3-azidoalkanals was investigated. Non-chelating, BF(3)·OEt(2)-mediated Sakurai addition to 3-azidoalkanals afforded 1,3-anti products, whereas use of a chelating Lewis acid, TiCl(4), resulted in 1,3-syn products with moderate selectivity. A boat-like chelation structure of the 3-azidoalkanal with the Lewis acid is proposed to be consistent with the 1,3-syn selectivity of the reactions. Mukaiyama aldol addition to 3-azidohexanal generated 1,3-anti products regardless of the chelating ability of the Lewis acid.     

Synthesis of alkyl 4-(diethoxymethyl)-3-pyridin-3-ylisoxazole-5-carboxylates: useful scaffold for highly functionalised 3-(pyridin-3-yl)isoxazoles

The methyl 4-(diethoxymethyl)-3-(pyridin-3-yl)isoxazole-5-carboxylate obtained by domino 1,3-dipolar cycloaddition and elimination starting of pyridine-3-nitrile oxide and methyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoate is a convenient scaffold for the synthesis of other new highly functionalised 3-pyridin-3-ylisoxazoles-5-carboxylic acid derivatives and isoxazole-annulated heterocycles.     

ZnBr2 catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: An efficient route to polycyclic thiopyranoindol annulated [3,4-c]quinolone derivatives

Various novel polycyclic thiopyranoindol annulated [3,4-c]quinolone derivatives were synthesized via domino Knoevenagel-hetero-Diels–Alder reactions of indoline-2-thions and novel N-acrylated anthranilaldehydes in refluxing ethanol as a solvent in the presence of 20 mol% ZnBr₂ as a Lewis acid catalyst. All reactions proceed with high yields with excellent regio- and stereoselectivity.     

[4+3] Cycloadditions of some allylic dioxolanes

Four allylic dioxolanes were prepared and reacted with several dienes in the presence of Lewis acids, affording [4+3] cycloadducts. The reaction could be conducted with catalytic amounts of Lewis acid. The use of a chiral Lewis acid gave a cycloadduct with only a low enantiomeric excess.     

First synthesis of 4,5-dihydro-3(2H)-pyridazinones via Zn-mediated hydrohydrazination

The hydrohydrazination of 4-pentynoic acid with different arylhydrazines proceeds smoothly in the presence of zinc chloride. The domino amination-amidation sequence leads to aryl-substituted 4,5-dihydro-3(2H)-pyridazinones.     

Orthogonal Catalysis for an Enantioselective Domino Inverse-Electron Demand Diels−Alder/Substitution Reaction

An enantioselective domino process for the synthesis of substituted 1,2-dihydronaphthalenes has been developed by the combination of chiral amines and a bidentate Lewis acid in an orthogonal catalysis. This new method is based on an inverse electron-demand Diels−Alder and a subsequent group exchange reaction. An enamine is generated in situ from an aldehyde and a chiral secondary amine catalyst that reacts with phthalazine, activated by the coordination to a bidentate Lewis acid catalyst. The absolute configuration of the product is controlled by chiral information provided by the amine. The formed ortho-quinodimethane intermediate is then transformed via a group exchange reaction with thiols. The new method shows a broad scope and tolerates a wide range of functional groups with enantiomeric ratios up to 91 : 9. All-in-all, this enantioselective synthesis tool provides an easy access to complex 1,2-dihydronaphthalenes starting from readily available phthalazine, aldehydes and thiols in a combinatorial way.     

TiCl4/t-BuNH2-promoted hydroamination/annulation of delta-keto-acetylenes: synthesis of novel pyrrolo[1,2-a]indol-2-carbaldehydes

[reaction: see text] An original TiCl(4)/t-BuNH(2)-mediated hydroamination/annulation domino reaction of delta-keto-acetylenes is described. The synthesis of pyrrolo[1,2-a]indole-2-carbaldehydes, starting from 2-carbonyl-1-propargyl-1H-indoles runs under mild reaction conditions. A conceivable mechanism is also discussed. TiCl(4) has proved to be an effective multiactivity reagent: catalyst/Lewis acid/water scavenger. Some unpublished 2-carbonyl-1-propargyl-1H-indoles are prepared by means of Suzuki- and Negishi-type reactions.     

Novel synthesis of substituted pyrrolidines and piperidines via radical addition-ionic cyclization reaction of oxime ethers

We have developed a novel synthetic route to nitrogen-containing heterocycles via radical addition-ionic cyclization reaction. Treatment of oxime ethers carrying the tosyloxy group with Et₃B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperidines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxycarbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by the synthesis of (±)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.