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.     

Regiocontrolled Gold‐Catalyzed [2+2+2] Cycloadditions of Ynamides with Two Discrete Nitriles to Construct 4‐Aminopyrimidine Cores

Reported herein is the novel gold‐catalyzed intermolecular [2+2+2] cycloaddition of ynamides with two discrete nitriles to form monomeric 4‐aminopyrimidines, which are pharmaceutically important structural motifs. The utility of this new cycloaddition is demonstrated by the excellent regioselectivity obtained using a variety of ynamides and nitriles.     

Metal‐Free [2+2+2] Cycloaddition of Ynamides and Nitriles: Mild and Regioselective Synthesis of Fully Substituted Pyridines

A metal‐free trimolecular [2+2+2] cycloaddition of internal ynamides and nitriles for de novo synthesis of fully substituted pyridines is disclosed. With the versatile Brønsted acid catalyst HNTf₂, the mild intermolecular cyclotrimerization process proceeds with complementary chemoselectivity and excellent regioselectivity.     

Synthesis of substituted imidazolines via [3+2]-cycloaddition of aziridines with nitriles

An efficient synthesis of 2,4-disubstituted 1H-imidazolines from aziridines and nitriles in the presence of BF₃-Et₂O or triethyloxonium tetrafluoroborate has been described. The reaction proceeds via a [3+2]-cycloaddition reaction. Most of the nitriles successfully underwent cycloaddition reactions with aziridines even at room temperature in a very short time.     

Synthesis of Functionalized Tetrahydropyridines by SnCl4-Mediated [4+2] Cycloaddition between Donor–Acceptor Cyclobutanes and Nitriles

Cycloadditions of strained carbocycles promoted by Lewis acids are powerful methods to construct heterocyclic frameworks. In fact, the formal [3+2] cycloadditions of donor–acceptor (DA) cyclopropanes with nitriles has seen particular success in synthesis. In this work, we report on the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis acid activation. Tetrahydropyridine derivatives were obtained in up to 91 % yield from various aryl-activated cyclobutane diesters and aliphatic or aromatic nitriles.     

Synthesis of aminopyridines and aminopyridones by cobalt-catalyzed [2+2+2] cycloadditions involving yne-ynamides: scope, limitations, and mechanistic insights

An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.     

Formal [3 + 2] cycloadditions of donor-acceptor cyclopropanes and nitriles

Donor-acceptor cyclopropanes activated with Me3SiOTf cleave to reactive intermediates that can be efficiently intercepted by nitriles in a formal [3 + 2] dipolar cycloaddition reaction. Aliphatic, aromatic, and alpha,beta-unsaturated nitriles are excellent reaction partners, giving synthetically useful 2H-3,4-dihydropyrrole cycloaddition products in high yield.     

The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions

Cycloaddition reactions compose one of the most important classes of reactions when it comes to the simultaneous formation of several bonds in one reaction step. The de novo construction of carbocyclic aromatic systems from acetylenes was also found as an excellent possibility for the assembly of heteroaromatic systems. The transition metal-catalysed [2 + 2 + 2] cycloaddition reaction constitutes a fascinating tool for the synthesis of pyridines from nitriles and the most recent developments demonstrate the ability to control the substitution pattern as well as the possibility of introducing chirality by the use of achiral substrates and a chiral catalyst under mild conditions. In this tutorial review we are focusing on the de novo construction of pyridine ring systems by the transition metal-catalysed [2 + 2 + 2] cycloaddition reaction. After surveying the mechanistic features and intermediates of the reaction depending on the different metal complexes used, we depict the preparation of achiral pyridine derivatives. The last section describes the advances in the synthesis of chiral pyridines and biaryls using the cyclotrimerization method. The various possibilities of introducing chirality by catalytic means are presented and illustrated by instructive examples. This review will be of interest for people active in: Organic Chemistry, Organometallic Chemistry, Transition Metal Chemistry, Stereoselective Synthesis, Heterocyclic Chemistry.     

Metal Free Access to Polysubstituted Pyrimidines via Nitrile Activation and [2+2+2] Cycloaddition

Tf₂O mediated intermolecular / intramolecular [2+2+2] cycloaddition between alkynes and nitriles has been developed for efficient construction of polysubstituted pyrimidines and bicyclopyrimidines. In presence of Tf₂O, aza-allene species were generated in situ through nitrile activation and subsequently participated in the [2+2+2] cycloaddition, which was fully supported by deuteration experiments. The reaction had good substrate extensibility with moderate to excellent yield including trimethylsilylalkynes. The method was utilized as a synthetic tool in the preparation of a luminescent metal complex.     

Synthesis of Aminopyridines and Aminopyridones by Cobalt‐Catalyzed [2+2+2] Cycloadditions Involving Yne‐Ynamides: Scope,Limitations, and Mechanistic Insights

An in‐depth study of the cobalt‐catalyzed [2+2+2] cycloaddition between yne‐ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal‐catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron‐deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne‐ynamide allows the regioselectivity to be switched toward 3‐ or 4‐aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne‐ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines arise from an insertion pathway.     

Copper-catalyzed synthesis of 5-substituted 1H-tetrazoles via the [3+2] cycloaddition of nitriles and trimethylsilyl azide

The [3+2] cycloaddition between various nitriles and trimethylsilyl azide proceeds smoothly in the presence of a Cu^I catalyst in DMF/MeOH, to give the corresponding 5-substituted 1H-tetrazoles in good to high yields. The reaction most probably proceeds through the in situ formation of a copper azide species, followed by a successive [3+2] cycloaddition with the nitriles.     

Nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes with nitriles

Pyridines, which comprise one of the most important classes of the six-membered heterocyclic compounds, are widely distributed in nature, and the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction of two alkynes and a nitrile is one of the most powerful methods for preparing versatile, highly substituted pyridine derivatives. However, the lack of chemo- and regioselectivity is still a crucial issue associated with fully intermolecular [2 + 2 + 2] cycloaddition. The present study developed the Ni(0)-catalyzed intermolecular dehydrogenative [4 + 2] cycloaddition reaction of 1,3-butadienes with nitriles to give a variety of pyridines regioselectively.     

2-aryl-N-tosylazetidines as formal 1,4-dipoles for [4 + 2] cycloaddition reactions with nitriles: an easy access to the tetrahydropyrimidine derivatives

[reaction: see text] A new synthetic route to 2-aryl-N-tosyl azetidines has been developed starting from N-tosylarylaldimines in two steps in an overall yield of 63-70%. A formal [4 + 2] cycloaddition of these 2-aryl-N-tosylazetidines with nitriles in the presence of BF3.OEt2 has been described for the synthesis of substituted tetrahydropyrimidines. It is proposed that the reaction proceeds in Ritter fashion.     

Regioselective preparation of 2-substituted 3,4-diaryl pyrroles: a concise total synthesis of ningalin B

Methylisocyanoacetate undergoes a 2 + 3 cycloaddition with alpha,beta-unsaturated nitriles to provide a regioselective synthesis of 2-substituted 3,4-diaryl pyrroles. The ease of preparation of alpha,beta-unsaturated nitriles allows the rapid synthesis of pyrroles with varied substituents. Using this method, a key intermediate (1) for the synthesis of the marine natural products lukianol A, lamellarin O, and lamellarin Q was prepared in two steps. A total synthesis of ningalin B (11) was also accomplished utilizing this methodology.     

Formal [4+2] cycloaddition of 3-phenylcyclobutanones with nitriles

Various 3-phenylcyclobutanones reacted with aliphatic and aromatic nitriles in the presence of Me₃SiOTf to afford dihydropyridones by formal [4+2] cycloaddition.     

AgNO3 catalyzed synthesis of 5-substituted-1H-tetrazole via [3+2] cycloaddition of nitriles and sodium azide

An efficient one-pot, convenient catalysis for the synthesis of 5-substituted-1H-tetrazoles is reported. The [3+2] cycloaddition involves various nitriles, sodium azide in refluxing DMF and AgNO₃ as catalyst to give corresponding 5-substituted-1H-tetrazoles in good to excellent yields. It is expected that the reaction proceeds via in situ formation of a silver azide species, which participates in coordination of nitrile moiety followed by cycloaddition of azide ion to give tetrazole.     

Zeolite and sulfated zirconia as catalysts for the synthesis of 5-substituted 1H-tetrazoles via [2+3] cycloaddition of nitriles and sodium azide

The [2+3] cycloaddition between various nitriles and sodium azide proceeds smoothly in the presence of zeolite and sulfated zirconia as effective catalysts, in water and DMF/MeOH, to give the corresponding 5-substituted 1H-tetrazoles in good to high yields. The reaction most probably proceeds through the in situ formation of catalyst azide species, followed by a successive [2+3] cycloaddition with the nitriles. This method has the advantages of high yields, simple methodology and easy work-up. The catalyst can be recovered by simple filtration and reused with good yields.     

过渡金属催化[2 + 2 + 2]环加成反应合成吡啶衍生物

环加成反应可以一步同时构建多个化学键,是目前国内外研究最为活跃的领域之一。相比于传统方法,过渡金属催化的[2+2+2]环加成反应是合成吡啶衍生物的有效手段。本文从反应机理、非手性吡啶化合物合成和手性吡啶化合物合成三个方面阐述了近年来吡啶衍生物的研究情况,涉及Co、Rh、Ru、Fe、Ni、Ti等金属催化体系。     

Fine‐Tuning the Reactivity and Stability by Systematic Ligand Variations in CpCoI Complexes as Catalysts for [2+2+2] Cycloaddition Reactions

CpCo^I‐olefin‐phosphite and CpCo^I‐bisphosphite complexes were systematically prepared and their reactivity in [2+2+2] cycloaddition reactions compared with highly active [CpCo(H₂C?CHSiMe₃)₂] ( 1 ). Whereas 1 is an excellent precursor for the synthesis of [CpCo(olefin)(phosphite)] complexes ( 2 a – f ), [CpCo(phosphite)₂] complexes ( 3 a – e ) were prepared photochemically from [CpCo(cod)]. The complexes were evaluated in the cyclotrimerization reaction of diynes with nitriles yielding pyridines. For [CpCo(olefin)(phosphite)], as well as some of the [CpCo(phosphite)₂] complexes, reaction temperatures as low as 50 °C were sufficient to perform the cycloaddition reaction. A direct comparison showed that the order of reactivity for the complex ligands was olefin₂>olefin/phosphite>phosphites₂. The complexes with mixed ligands favorably combine reactivity and stability. Calculations on the ligand dissociation from [CpCo(olefin)(phosphite)] proved that the phosphite is dissociating before the olefin. [CpCo(H₂C?CHSiMe₃){P(OPh)₃}] ( 2 a ) was investigated for the co‐cyclization of diynes and nitriles and found to be an efficient catalyst at rather mild temperatures.     

Rhodium catalysed [2+2+2] cycloadditions- an efficient regiospecific route to calomelanolactone

A short regiospecific synthesis of calomelanolactone has been devised in which the key step is a [2+2+2] cycloaddition.