Cycloaddition Process Research Articles

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Application of β-Phosphorylated Nitroethenes in [3+2] Cycloaddition Reactions Involving Benzonitrile N-Oxide in the Light of a DFT Computational Study

The regiochemistry of [3+2] cycloaddition (32CA) processes between benzonitrile N-oxide 1 and β-phosphorylated analogues of nitroethenes 2a–c has been studied using the Density Functional Theory (DFT) at the M062X/6-31+G(d) theory level. The obtained results of reactivity indices show that benzonitrile N-oxide 1 can be classified both as a moderate electrophile and moderate nucleophile, while β-phosphorylated analogues of nitroethenes 2a–c can be classified as strong electrophiles and marginal nucleophiles. Moreover, the analysis of CDFT shows that for [3+2] cycloadditions with the participation of β-phosphorylatednitroethene 2a and β-phosphorylated α-cyanonitroethene 2b, the more favored reaction path forms 4-nitro-substituted Δ2-isoxazolines 3a–b, while for a reaction with β-phosphorylated β-cyanonitroethene 2c, the more favored path forms 5-nitro-substituted Δ2-isoxazoline 4c. This is due to the presence of a cyano group in the alkene. The CDFT study correlates well with the analysis of the kinetic description of the considered reaction channels. Moreover, DFT calculations have proven the clearly polar nature of all analyzed [3+2] cycloaddition reactions according to the polar one-step mechanism.

Formation of a potassium coordination polymer based on a novel 2-sulfono-benzene-1,3,5-tricarboxylic acid: Synthesis, characterization, and application of the organocatalyst in CO2 cycloaddition reaction

In the present work, a new 3D potassium coordination polymer (1) was prepared by oxidation of sulfonated mesitylene. Its novel sulfono-tricarboxylic ligand, 2-sulfono-benzene-1,3,5-tricarboxylic acid (2), which acted as a structure-directing building block, was successfully synthesized by ion exchange of the potassium coordination polymer (1). The 3D coordination polymer and the sulfonate-carboxylate ligand were characterized by FT-IR and 1H and 13C NMR spectroscopies, and their molecular structures were determined by single-crystal X-ray diffraction. In addition, thermal stability and adsorption/desorption behavior of 1 was investigated by TGA-DTA and N2 adsorption/desorption techniques, respectively. The catalytic activities of the ligand, as a novel and simple organocatalyst, and the rarely explored potassium CPs were studied in the CO2 cycloaddition reaction. The results showed 2 is an efficient organocatalyst in the CO2 cycloaddition process. It is suggested that the synergetic effect among Brønsted acid COOH, Lewis base I− and free water molecules facilitate this reaction.

Synthesis of Silsesquioxanes with Substituted Triazole Ring Functionalities and Their Coordination Ability.

A synthesis of a series of mono-T8 and difunctionalized double-decker silsesquioxanes bearing substituted triazole ring(s) has been reported within this work. The catalytic protocol for their formation is based on the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) process. Diverse alkynes were in the scope of our interest—i.e., aryl, hetaryl, alkyl, silyl, or germyl—and the latter was shown to be the first example of terminal germane alkyne which is reactive in the applied process’ conditions. From the pallet of 15 compounds, three of them with pyridine-triazole and thiophenyl-triazole moiety attached to T8 or DDSQ core were verified in terms of their coordinating properties towards selected transition metals, i.e., Pd(II), Pt(II), and Rh(I). The studies resulted in the formation of four SQs based coordination compounds that were obtained in high yields up to 93% and their thorough spectroscopic characterization is presented. To our knowledge, this is the first example of the DDSQ-based molecular complex possessing bidentate pyridine-triazole ligand binding two Pd(II) ions.

On the nature of bonding in the photochemical addition of two ethylenes: C-C bond formation in the excited state?

In this work, the 2s + 2s (face-to-face) prototypical example of a photochemical reaction has been re-examined to characterize the evolution of chemical bonding. The analysis of the electron localization function (as an indirect measure of the Pauli principle) along the minimum energy path provides strong evidence supporting that CC bond formation occurs not in the excited state but in the ground electronic state after crossing the rhombohedral S1/S0 conical intersection.

Desymmetrization of Cyclopentene‐1,3‐Diones via Alkylation, Arylation, Amidation and Cycloaddition Reactions

AbstractDesymmetrization of prochiral cyclopentene‐1,3‐diones for the synthesis of various natural products and moieties of pharmaceutically active compounds, is a very challenging and competitive area of research in organic synthesis now a days. It is a very powerful strategy to provide quaternary stereocenter having different functionality, which is very difficult to install by other C−C bond‐forming methods. This review describes an elaborative discussion of desymmetrization of cyclopentene‐1,3‐diones (racemic and asymmetric) via different alkylation, arylation, amidation and cycloaddition process for the last decades.

Multisubstituted pyrazole synthesis via [3 + 2] cycloaddition/rearrangement/N[sbnd]H insertion cascade reaction of α-diazoesters and ynones

The cascade reactions of alkyl α-diazoesters and ynones using Al(OTf)3 as the catalyst are described. A series of 4-substituted pyrazoles were obtained via [3 + 2] cycloaddition, 1,5-ester shift, 1,3-H shift, and NH insertion process. Deuterium labelling experiments, kinetic studies and control experiments were carried out for the rationalization of the mechanism.

One-pot synthesis of 3-substituted-4H-[1,2,3] triazolo[5,1-c][1,4]oxazin-6(7H)-ones from propargyl alcohols, chloroacetyl chloride, and sodium azide

An efficient, one-pot synthesis of 3-substituted-4 H-[1,2,3]triazolo[5,1- c][1,4]oxazin-6(7 H)-ones is developed via sequential esterification, substitution, and 1,3-dipolar cycloaddition processes of various propargyl alcohols, chloroacetyl chloride, and sodium azide. This method provides a variety of novel 1,2,3-triazole-fused oxazinones and has several advantages including simple operation, high efficiency, and good-to-excellent product yields (80%–95%) without the need to isolate the ester and azide intermediates.

Preparation of MOF Film/Aerogel Composite Catalysts via Substrate‐Seeding Secondary‐Growth for the Oxygen Evolution Reaction and CO2 Cycloaddition

AbstractSubstrate‐supported metal–organic frameworks (MOFs) films are desired to realize their potential in practical applications. Herein, a novel substrate‐seeding secondary‐growth strategy is developed to prepare composites of uniform MOFs films on aerogel walls. Briefly, the organic ligand is “pre‐seeded” onto the aerogel walls, and then a small amount of metal‐ion solution is sprayed onto the prepared aerogel. The sprayed solution diffuses along the aerogel walls to form a continuous thin layer, which confines the nucleation reaction, promoting the formation of uniform MOFs films on the aerogel walls. The whole process is simple in operation, highly efficient, and eco‐friendly. The resulting hierarchical MOFs/aerogel composites have abundant accessible active sites and enable excellent mass transfer, which endows the composite with outstanding catalytic activity and stability in both liquid‐phase CO2 cycloaddition and electrochemical oxygen evolution reaction (OER) process.

Preparation of MOF Film/Aerogel Composite Catalysts via Substrate-Seeding Secondary-Growth for the Oxygen Evolution Reaction and CO2 Cycloaddition.

Substrate-supported metal-organic frameworks (MOFs) films are desired to realize their potential in practical applications. Herein, a novel substrate-seeding secondary-growth strategy is developed to prepare composites of uniform MOFs films on aerogel walls. Briefly, the organic ligand is "pre-seeded" onto the aerogel walls, and then a small amount of metal-ion solution is sprayed onto the prepared aerogel. The sprayed solution diffuses along the aerogel walls to form a continuous thin layer, which confines the nucleation reaction, promoting the formation of uniform MOFs films on the aerogel walls. The whole process is simple in operation, highly efficient, and eco-friendly. The resulting hierarchical MOFs/aerogel composites have abundant accessible active sites and enable excellent mass transfer, which endows the composite with outstanding catalytic activity and stability in both liquid-phase CO2 cycloaddition and electrochemical oxygen evolution reaction (OER) process.

Synthesis of a 3,4-Dihydro-1,3-oxazin-2-ones Skeleton via an Intermolecular [4 + 2] Process of N-Acyliminium Ions with Ynamides/Terminal Alkynes.

An approach to access functionalized 3,4-dihydro-1,3-oxazin-2-ones has been developed by reacting semicyclic N,O-acetals 5 and 6 with ynamides 7 or terminal alkynes 8 in a one-pot fashion. The reaction went through a formal [4 + 2] cycloaddition process to generate a number of functionalized 3,4-dihydro-1,3-oxazin-2-ones 9a-9ak and 10a-10bc in yields of 34-97%. In addition, the utility of this transformation was demonstrated by the synthesis of (±)-sedamine 13.

Pd-Catalyzed Decarboxylative Cycloaddition for the Synthesis of Highly Substituted δ-Lactones and Lactams

An efficient palladium-catalyzed decarboxylative cycloaddition process of vinyl cyclic carbonates and vinyloxazolidinones for the synthesis of highly substituted δ-lactone and δ-lactam derivatives ...

Insights into the reaction mechanism between phosphacyclopropenylidene and methyleneimine: A theoretical study

The reaction mechanism between phosphacyclopropenylidene and methyleneimine has been systematically investigated at the M06–2X/6–311++G(d,p) level of theory in order to better understand the reactivity of unsaturated cyclic phosphorus-bearing carbene. Geometry optimizations and vibrational analyses have been conducted for the stationary points on the potential energy surface of the system. Calculations show that the spiro bicyclic intermediate could be produced through the cycloaddition process between phosphacyclopropenylidene and methyleneimine initially. The reaction mechanism is illustrated with frontier molecular orbital theory. Introduction of electron-withdrawing group in phosphacyclopropenylidene will better facilitate the addition process. Through subsequent ring-expanding and hydrogen-migrating process, fuse-ring and allene compounds could be produced, respectively. Furthermore, it’s easy for spiro bicyclic intermediate and another methyleneimine to form a spiro tricyclic compound. This study is helpful to understand the reactivity of phosphacyclopropenylidene, the evolution of phosphorus-bearing molecules in space, and to offer an alternative approach to the formation of phosphorus-bearing heterocyclic compound.

Selenyl analog of the (Z)-C,N-diphenylnitrone as the TAC in [3 + 2] cycloaddition with nitroethene: A DFT computational study

The molecular mechanism of [3 + 2] cycloaddition (32CA) process between selenyl analog of the (Z)-C,N-diphenylnitrone and nitroethene was examined on the basis of the M06-2X/6-311 + G(d)(PCM) calculations. It was found that kinetic factors favor the formation of 4-nitro substituted cycloadducts in the reaction course. Additionally, the DFT computational study highlights the evidently polar nature of the title reaction. The mechanistic study also confirms the possibility of the existence of a zwitterionic intermediate in the reaction environment.

Recent Progress of Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions (CuAAC) in Sustainable Solvents: Glycerol, Deep Eutectic Solvents, and Aqueous Media.

This mini-review presents a general overview of the progress achieved during the last decade on the amalgamation of CuAAC processes (copper-catalyzed azide-alkyne cycloaddition) with the employment of sustainable solvents as reaction media. In most of the presented examples, the use of water, glycerol (Gly), or deep eutectic solvents (DESs) as non-conventional reaction media allowed not only to recycle the catalytic system (thus reducing the amount of the copper catalyst needed per mole of substrate), but also to achieve higher conversions and selectivities when compared with the reaction promoted in hazardous and volatile organic solvents (VOCs). Moreover, the use of the aforementioned green solvents also permits the improvement of the overall sustainability of the Cu-catalyzed 1,3-dipolar cycloaddition process, thus fulfilling several important principles of green chemistry.

Synthesis of pyrroloindolines through formal [3 + 2]-cycloaddition of indoles with chiral N-2-acetamidoacrylyl oxazolidinones

Chiral N-2-acetamidoacrylyl oxazolidinones were produced and reacted with indoles under Lewis acid conditions to generate hexahydropyrrolo[2,3-b]indole products in a formal [3 + 2] cycloaddition process. Optimal conditions included the use of tin(IV) chloride in methylene chloride at 0 °C. Pyrroloindoline products were obtained from various indoles with shorter reaction times (12 hr) up to 91% yield with high, >20:1 exo selectivity. A mechanism involving reversible conjugate addition followed by an enamine lone-pair-iminium capture, tautomerization, and tin-enolate protonation accounts for the selectivity. The method enables selective applications to pyrroloindoline targets and further refinement with chiral catalysts.

A density functional theory study of the stereoselectivity of Cu(OTf)2‐catalyzed [3+2] cycloaddition of trifluoromethylated N‐acylhydrazones and isoprene: A concerted asynchronous mechanism

AbstractHere we employ density functional theory calculations to systematically investigate the underlying mechanism of Cu(OTf)2‐catalyzed [3+2] cycloaddition reactions in the synthesis of CF3‐substituted pyrazolidines. About eight possible initial configurations of the [3+2] reaction is considered, and all relevant reactants, transition states, and products are optimized. Based on these structures, internal reaction coordinate paths, and wavefunction analysis results, we conclude that the Cu(OTf)2‐catalyzed [3+2] cycloaddition follows a concerted asynchronous mechanism. The CN bond forms immediately after the formation of the CC bond. Among the eight reaction paths, the energy barrier for the [3+2] reaction that leads to the CF3‐substituted syn‐pyrazolidine is the lowest, ∼5.4 kcal/mol, which might result in the diastereoselectivity that is observed in the experiment. This work not only gives the detailed mechanism of the Cu(OTf)2‐catalyzed [3+2] cycloaddition but can also be helpful for the future designation of Cu(OTf)2‐based cycloaddition processes.

New benzene dimers: an MRMP2 study

The reaction energies of one cis-fused and four new trans-fused benzene dimers have been studied with state-specific multi-reference Moller-Plesset perturbation theory of the second order (MRMP2) based on reference CASSCF(12,12) wavefunctions. The cis-fused dimer 1, the product of symmetry-allowed [4 + 2] cycloaddition process, has been previously characterized experimentally and theoretically and, in this study, was used as reference. Dimer 1 lies 45 kcal/mol above two isolated benzene molecules, and its retro-dimerization activation energy is ~ 8 kcal/mol. In contrast, the [4 + 2] formation of trans-fused dimer 2 is symmetry-forbidden with an energetic driving force (Erel) of 57.6 kcal/mol. An activation barrier for corresponding retro-dimerization calculated to be 31.0 kcal/mol. The thermal [2 + 2] formation of dimers 3 and 4 are also symmetry-forbidden. They have been calculated to be 79.0 kcal/mol and 105.1 kcal/mol higher in energy than two isolated benzene molecules, respectively. However, the activation energies of 23.2 and 20.5 kcal/mol could allow for kinetic persistence of these compounds. Dimer 5 is the only symmetry-allowed [2 + 2] cycloaddition product. With Erel of 67.5 kcal/mol and Ea for retro-dimerization reaction of 19.2 kcal/mol, it shows high similarity with the symmetry-forbidden dimers. The wave function for each of the dimers at their local minimum geometry contains greater than 80% of the configuration $$\sigma^{4} \pi^{8} \sigma^{*0} \pi^{*0}$$. The transition state for the retro-dimerization of 1 (1TS) also contains more than 80% of the closed-shell configuration $$\sigma^{4} \pi^{8} \sigma^{*0} \pi^{*0}$$. For 2TS–5TS systems, the wavefunctions exhibit significant biradical character (20%, 20%, 14% and 26%, respectively).

Copper(I)-Catalyzed Dearomative (3 + 2) Cycloaddition of 3-Nitroindoles with Propargylic Nucleophiles: An Access to Cyclopenta[b]indolines.

The copper(I)-catalyzed dearomatization of 3-nitroindoles with propargylic nucleophiles is described. In mild reaction conditions, this original dearomative (3 + 2) cycloaddition process gives access to a wide variety of cyclopenta[b]indolines in good to excellent yields, with high functional group tolerance. The proof of concept that an enantioselective version of this reaction is accessible by employing chiral phosphorous ligands was obtained. A mechanism proposal is given based on kinetic studies.

Theoretical study on the reaction between phosphacyclopropenylidene and ethylene: An alternative approach to the formation of phosphorus-bearing heterocyclic compound

The reaction mechanism between phosphacyclopropenylidene and ethylene has been systematically investigated at the B3LYP/6-311++G(d,p) level of theory in order to better understand the reactivity of unsaturated cyclic phosphorus-bearing carbene. Geometry optimizations and vibrational analyses have been performed for the stationary points on the potential energy surface of the system. Calculations show that the spiro bicyclic intermediate could be produced through the cycloaddition process between phosphacyclopropenylidene and ethylene initially. The reaction mechanism is illustrated with the frontier molecular orbital theory. Introduction of electron-withdrawing group in phosphacyclopropenylidene will better facilitate the addition process. Through subsequent ring-expanding and hydrogen-migrating process, fuse-ring and allene compounds could be produced, respectively. Furthermore, it?s easy for spiro bicyclic intermediate and another ethylene to form a spiro tricyclic compound. This study is helps to understand the reactivity of phosphacyclopropenylidene, the evolution of phosphorus-bearing molecules in space, and to offer an alternative approach to the formation of phosphorus-bearing heterocyclic compound.