2+2+2] cycloaddition reactions of macrocyclic systems catalyzed by transition metals. A review

Polyalkyne and enediyne azamacrocycles are prepared from arenesulfonamides and various alkyne and alkene derivatives either under basic or neutral conditions. The new family of macrocyclic substrates is tested in the [2+2+2] cycloaddition reaction. Several catalysts are used for the cycloisomerization reaction, and their enantioinduction is evaluated as appropriate. The effect of the structural features of the macrocycles, namely the ring size, substituents in precise positions and the number and type of unsaturations, on the [2+2+2] cycloaddition reaction has also been studied.     

[4+2]cycloaddition reactions of triarylphosphaalkene

Cycloaddition reactions of mesityl(diphenyliiifithylene)phosphine ($\text{1}$) were Investigated. With several dienes, no Diels-Alder reactions were oEserved. With azides, diphenyidiazomethane and 2,4,6-trimethylbenzonitrile oxide, the corresponding cycloadducts ($\text{4}$$\text{12}$$\text{17}$$\text{12}$were obtained. In the case of phenyl azide, a competing Staudinger reaction occurred leading to $\text{3}$.     

Intermolecular transition metal-catalyzed [4 + 2 + 2] cycloaddition reactions: a new approach to the construction of eight-membered rings

Transition metal-catalyzed cycloaddition reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a new intermolecular metal-catalyzed [4 + 2 + 2] cycloaddition of heteroatom-tethered enyne derivatives with 1,3-butadiene. This study demonstrates that excellent selectivity can be obtained for the heterocycloaddition adducts through the judicious choice of silver salt. The development of the tandem rhodium-catalyzed allylic substitution [4 + 2 + 2] cycloaddition provides a convenient three-component coupling that circumvents the prior formation of the enyne derivative. Finally, the introduction of a stereogenic center at C-2 leads to a diastereoselective cycloaddition, which provides a powerful new method for the construction of bicyclic octanoid ring systems applicable to target directed synthesis.     

Organotransition metal [3+2] cycloaddition reactions

The review, covering the literature of roughly the last three decades, describes the [3+2] cycloaddition reactions of metalla dipolarophiles M=X with organic 1,3-dipoles, and of metalla 1,3-dipoles, M---X=Y and X---M=Y, with organic dipolarophiles. The resulting 5-membered metalla heterocycles can undergo consecutive insertion and/or reductive elimination reactions to give synthetically interesting organic heterocycles. The reactivity of the organometal 1,3-dipoles is explained by extensive series of isolobal transformations to classic organic 1,3-dipoles.     

Recent advances in [2+2+2] cycloaddition reactions

The [2+2+2] cycloaddition is an elegant, atom-efficient and group tolerant process for the synthesis of carbo- and heterocycles, mostly aromatic, involving the formation of several C-C bonds in a single step. Cyclotrimerisation is catalyzed by a variety of organometallic complexes, including more than 15 different metals. The aim of this tutorial review is to point out the most recent advances in this field and to encourage the use of this reaction enroute to complex molecules. After summarizing the most common catalysts and reaction conditions generally used, we survey the mechanistic features currently accepted for this reaction. Section 4 covers the scope of the different [2+2+2] cycloaddition versions starting with the cyclotrimerisation of three triple bonds, including nitriles, with especial emphasis on asymmetric reactions that create central, axial or planar chirality. Then, reactions that use double bonds are addressed. Finally, the most outstanding examples of natural products synthesis using [2+2+2] cycloadditions as a key step reported recently are shown.     

Three-component cycloadditions: the first transition metal-catalyzed [5+2+1] cycloaddition reactions

Prompted by our studies of transition metal-catalyzed [4+4], [4+2], [5+2], and [6+2] cycloadditions and by the view that these two-component reactions could be intercepted by a third component of one or more atoms, a new three-component transition metal-catalyzed cycloaddition is described. This new [5+2+1] cycloaddition proceeds in good to excellent yield and with high or complete regioselectivity with a variety of carbonyl-substituted alkynes to give bicyclo[3.3.0]octenone adducts, resulting from transannular closure of the intermediate eight-membered-ring cycloadduct. Effects of concentration, temperature, pressure, and catalyst loading on the efficiency of the reaction are discussed. This process provides access to complex building blocks for synthesis based on simple, readily available components.     

Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.     

Recent progress in cobalt-mediated [2 + 2 + 2] cycloaddition reactions

For many years, our research group has been interested in the new developments of cobalt-mediated cyclizations. In this article, our recent achievements in the field of inter- and intramolecular [2 + 2 + 2] cyclizations are compiled.     

Catalytic enantioselective [2 + 4] and [2 + 2] cycloaddition reactions with propiolamides

We report here the catalytic and highly enantioselective [2 + 4] and [2 + 2] cycloaddition reactions of electron-rich dienes or silyl enol ethers with electron-deficient propiolamide derivatives induced by copper(II).3-(2-naphthyl)-L-alanine amide complex.     

Palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloaddition reactions

Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.     

Stereospecific [2+2] cycloaddition reactions of diphosphorus with alkenes

[2+2] Cycloaddition reactions of P₂ with alkenes were predicted to have concerted paths, that is, pseudoexcitation, distorted 2π_s+2π_s, and 2π_s+2π_a processes without any interventions of intermediates. The pseudoexcitation and/or distorted 2π_s+2π_s paths with retention of configuration of alkenes are kinetically preferred to the 2π_s+2π_a path with inversion of configuration. The reactions were predicted from the appreciable difference in the calculated enthalpies of activation to be stereospecific.     

[2+2]- AND [4+2] cycloaddition reactions of 1,3-diazabutadienes with diphenylketene

1,3-Diazabutadienes react with diphenylketene in [2+2] - and [4+2] cycloaddition reactions, depending on the substitution pattern. Spectroscopic data (IR, ¹H- and ¹³C-NMR) and results of quantummechanical model calculations (ab initio 3-21G) are presented.     

Catalytic [2+2] and [3+2] cycloaddition reactions of allenoates with cyclic ketimines

Cyclic ketimines as electrophiles for [2+2] and [3+2] cycloaddition reactions of allenoates have been developed, affording functionalized sultam-fused azetidines and dihydropyrroles, respectively, in good yields with high regioselectivities.     

A [4 + 2] cycloaddition strategy to pyridine boronic ester derivatives

Alkynylboronate cycloadditions of 1,4-oxazin-2-ones and 2-pyrazinones provide a direct and regioselective route to functionalized pyridine boronic ester derivatives.     

Functionalized cyclobutenes via multicomponent thermal [2 + 2] cycloaddition reactions

[reaction: see text] Enamine [2 + 2] cycloadditions can be achieved in useful yields simply by stirring a mixture of an aldehyde, diethylamine, a dialkyl fumarate, and potassium carbonate in acetonitrile at 25 degrees C, conditions that are compatible with the presence of a potential leaving group on the beta-position of the intermediate enamine. Methylation and elimination of the product cyclobutanes completes a mild nonphotochemical route to functionalized cyclobutenes.     

Synthesis of densely functionalised arenes using [2 + 2 + 2] cycloaddition reactions

Rh(I)-catalysed [2 + 2 + 2] cycloaddition allows the synthesis of aryl ethers and diaryl methanes containing a high degree of steric hindrance from relatively simple diyne and alkyne precursors. The diarylmethanes made in this way show no evidence in their NMR spectra, however, of rotational restriction.     

Triptycenediols by rhodium-catalyzed [2+2+2] cycloaddition

An efficient, modular synthesis of triptycene derivatives is presented, in which the triptycene ring system is constructed from readily available anthraquinone and alkyne starting materials. A rhodium-catalyzed alkyne cyclotrimerization reaction serves as the key step in this new method for the preparation of these useful unnatural products.     

Inverse electron-demand aza-[4+2] cycloaddition reactions of allenamides

An inverse electron-demand aza-[4+2] cycloaddition reaction of allenamides with 1-azadiene is described here. Effects of solvents on diastereoselectivity along with synthetic scopes and mechanistic insights are illustrated. Despite some synthetic limitations, this aza-[4+2] cycloaddition does provide a useful template for the synthesis of aza-glycoside related heterocycles.     

Preparation and synthetic applications of alkene complexes of group 9 transition metals in [2+2+2] cycloaddition reactions

The [2+2+2] cycloaddition reaction has become an invaluable tool for the synthetic chemistry in recent years, due to the increase of complexity of the accessed target molecules by this methodology. Over several decades, the members of group 9 of the periodic table have contributed significantly to the development and understanding of this particular cycloaddition reaction. On the other hand, catalyst complexes containing alkenes as ligands are widely used today as either catalysts or as precursor molecules for the facile generation of catalytically active metal species. In this tutorial review we want to describe the catalytically relevant chemistry of group 9 metal-alkene complexes and compile some recent applications in [2+2+2] cycloaddition reactions.     

Intramolecular [4+2] cycloaddition reactions of enamines and enamides

An attempt to utilize a new strategy for alkaloid synthesis which features the intramolecular [4+2] cycloaddition of enamines and enamides for the construction of the tetracyclic spiroamine skeleton characteristic of the Erythrina alkaloids was unsuccessful, unexpectedly giving a bridged cycloadduct rather than a fused one.