Successful Cycloaddition Research Articles

Copper-catalyzed Z-selective synthesis of acrylamides and polyacrylamides via alkylidene ketenimines

It remains very important to discover and study new fundamental intermediates consisting of carbon and nitrogen as the abundant elements of organic molecules. The unique alkylidene ketenimine could be formed in situ under mild conditions by an unexpected copper-catalyzed three-component reaction of alkyne, azide and water involving a successive cycloaddition, N2 extrusion and carbene-assisted rearrangement. Only Z-α,β-unsaturated amides instead of E-α,β-unsaturated amides or triazoles were acquired from alkylidene ketenimines with excellent selectivities and stereospecificities. In addition, a series of “approximate” alternating copolymers (poly (triazole-alt-Z-acrylamides)) with high Mns and yields were efficiently afforded by multicomponent polymerization through a very simple operation basing on this multicomponent reaction.

Front Cover: Reactivity of Terminal Iron Borylenes and Bis(borylenes) with Carbodiimides: Cycloaddition, Metathesis, Insertion and C−H Activation Pathways (Eur. J. Inorg. Chem. 45/2021)

The Front Cover shows the wide variety of novel (metalla)heterocycles obtained from the reactions of iron mono- and bis(borylene) complexes with carbodiimides. These result from complex branching and interwoven reaction pathways involving successive cycloaddition, metathesis, insertion, and C−H activation steps, dependent on the sterics of the carbodiimide substituents (Graphic design: Dr. Merle Arrowsmith; background image from NASA′s Earth Observatory). More information can be found in the Full Paper by H. Braunschweig and co-workers.

Small-Molecule Investigation of Diels-Alder Complexes for Thermoreversible Crosslinking in Polymeric Applications.

Combinations of dienes and dienophiles were examined in order to elicit possible combinations for thermoreversible crosslinking units. Comparison of experimental results and quantum calculations indicated that reaction kinetics and activation energy were much better prediction factors than change in enthalpy for the prediction of successful cycloaddition. Further testing on diene-dienophile pairs that underwent successful cycloaddition determined the feasibility of thermoreversibility/retro-reaction of each of the Diels-Alder compounds. Heating and testing of the compounds in the presence of a trapping agent allowed for experimental determination of reverse kinetics and activation energy for the retro-reaction. The experimental values were in good agreement with quantum calculations. The combination of chemical calculations with experimental results provided a strong insight into the structure-property relationships and how quantum calculations can be used to examine the feasibility of the thermoreversibility of new Diels-Alder complexes in potential polymer systems or to fine-tune thermoreversible Diels-Alder systems already in use.

DFT study on the mechanism of bimetallic Pd-Zn-catalyzed cycloaddition of alkynyl aryl ethers with internal alkynes.

The reaction mechanism of bimetallic Pd-Zn-catalyzed cycloaddition of alkynyl aryl ethers with internal alkynes has been studied theoretically. Besides cycloaddition reaction, the dimerization of alkynyl aryl ethers was also considered. Both C6H5OC[triple bond, length as m-dash]CSiiPr3 and C6H5OC[triple bond, length as m-dash]CSiMe3 were chosen as the substrates. The reactions involve C-H activation of the substrate, acetic acid rotation, H transformation, MeC[triple bond, length as m-dash]CMe or substrate insertion into the Pd-phenyl bond and reductive elimination steps. It is found that cycloaddition is favored for C6H5OC[triple bond, length as m-dash]CSiiPr3, while dimerization is preferred for C6H5OC[triple bond, length as m-dash]CSiMe3, because the steric repulsion between two bulky SiiPr3 groups is relatively large and the steric repulsion between two small SiMe3 groups is relatively small. In addition, besides C6H5OC[triple bond, length as m-dash]CSiiPr3, four other substrates C6H5CH2C[triple bond, length as m-dash]CSiiPr3, C6H5C(O)C[triple bond, length as m-dash]CSiiPr3, C6H5SC[triple bond, length as m-dash]CSiiPr3 and C6H5N(H)C[triple bond, length as m-dash]CSiiPr3 have been calculated as the substrates for cycloaddition reaction with MeC[triple bond, length as m-dash]CMe. Among the five substrates, C6H5OC[triple bond, length as m-dash]CSiiPr3 has the lowest energy barrier (29.9 kcal mol-1), consistent with the experimental observation that C6H5OC[triple bond, length as m-dash]CSiiPr3 is the appropriate substrate for successful cycloaddition.

Star-Shaped Polycyclic Aromatic Ketones via 3-Fold Cycloadditions of Isobenzofuran Trimer Equivalent.

Three-directional annulations of isobenzofuran trimer equivalent are developed. Importantly, the successive cycloadditions could be controlled under suitable conditions, selectively affording the dual or triple cycloadduct, which leads to the alternative preparation of the symmetrical and unsymmetrical star-shaped polycyclic aromatic ketones. 1H NMR analysis of the star-shaped aromatic ketone indicated the π-π interactions through the aggregation in solution.

Preparative successive generation of dehydrobenzene intermediate from 2,5-Bis(trimethylsilyl)-1,4-phenylene bis(trifluoromethanesulfonate) and its cycloaddition reactions

Open image in new window A method of preparative successive cycloaddition to synthetic equivalent of bis(dehydrobenzene) was found. Monoaddition products were isolated and characterized.

The 1,3-Dipolar Cycloaddition of Nitrile Oxide to Vinylacetic Acid: Computational Study of Transition States Selectivity, Solvent Effects, and Bicyclo Formation

The 1,3-dipolar cycloaddition reaction is a powerful tool for the cycloaddition of nitrile oxides to olefins, and this reaction is of considerable interest to obtain isoxazolines. Density functional theory (DFT) was used to study the 1,3-dipolar cycloaddition reaction mechanism that initially occurs between benzonitrile oxide and vinylacetic acid to yield a bicyclo, from successive cycloadditions. PBE1PBE, B3LYP and CAM-B3LYP functionals were used together with 6-311+G(2d,p) basis set. CCSD(T)/6-311+G(2d,p) calculations were done to compare the DFT energy barriers. The solvent effects were included using polarizable continuum model (PCM), with three different solvents. In the first cycloaddition, only the 3,5-regioisomer is expected. In the gas phase, the β face attack, that originates the trans-bicyclo, is slightly favored, but the cis-bicyclo is considerably more stable. However, the α face attack was favored with solvent effects. The PBE1PBE functional gives the closest activation energies and reaction energies to CCSD(T). The inclusion of solvent effects changes the preferential rotamer in each cycloaddition.

A Two-Photon Excitation Based Fluorogenic Probe for Sialome Imaging in Living Systems.

Taking advantage of the fluorescence property of alkyne-modified naphthalimide, the two-photon excited fluorogenic probe Naph-yne is used for azide-tagged mannosyl glycoprotein imaging both at the cellular level and for vertebrate model organisms.

Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes.

We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.

Regiocomplementary Cycloaddition Reactions of Boryl- and Silylbenzynes with 1,3-Dipoles: Selective Synthesis of Benzo-Fused Azole Derivatives

Benzo-fused nitrogen-containing heterocycles are abundant in biologically active compounds. One of the most important methods for preparing such heterocycles is the (3 + 2) cycloaddition reaction of benzynes with 1,3-dipolar compounds. However, the reactions of unsymmetrically substituted benzynes generally show low selectivity and hence yield mixtures of two regioisomers. In this paper, we describe the synthesis of both regioisomers of multisubstituted benzo-fused azole derivatives such as benzotriazoles, 1H-indazoles, and benzo[d]isoxazoles through the regiocomplementary (3 + 2) cycloaddition reactions of 3-boryl- and 3-silylbenzynes with 1,3-dipoles. The improved generation of 3-borylbenzynes from new precursors was one of the most important results of this work, which produced the successful (3 + 2) cycloaddition reactions with exclusive and proximal selectivities. On the other hand, similar reactions of 3-silylbenzynes selectively afforded distal cycloadducts. Analysis of the reaction pathways of these amazing regioselectivities by density functional theory calculations revealed that the (3 + 2) cycloadditions of borylbenzynes are controlled by the electrostatic effect of the boryl group, while those of silylbenzynes are controlled mainly by the steric effect of the bulky silyl groups that produced electrostatically unfavorable adducts via anomalous transition states.

Enantioselective Construction of Pyrrolidines by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethane with Imines

A protocol for the enantioselective [3 + 2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complementary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters.

Cycloaddition reactivity studies of first-row transition metal–azide complexes and alkynes: an inorganic click reaction for metalloenzyme inhibitor synthesis

The studies described herein focus on the 1,3-dipolar cycloaddition reaction between first-row transition metal-azide complexes and alkyne reagents, i.e. an inorganic variant of the extensively used "click reaction". The reaction between the azide complexes of biologically-relevant metals (e.g., Fe, Co and Ni) found in metalloenzyme active sites and alkyne reagents has been investigated as a proof-of-principle for a novel method of developing metalloenzyme triazole-based inhibitors. Six Fe, Co and Ni mono-azide complexes employing salen- and cyclam-type ligands have been synthesized and characterized. The scope of the targeted inorganic azide-alkyne click reaction was investigated using the electron-deficient alkyne dimethyl acetylenedicarboxylate. Of the six metal-azide complexes tested, the Co and Ni complexes of the 1,4,8,11-tetrametyl-1,4,8,11-tetraazacyclotetradecane (Me(4)cyclam) ligand showed a successful cycloaddition reaction and formation of the corresponding metal-triazolate products, which were crystallographically characterized. Moreover, use of less electron deficient alkynes resulted in a loss of cycloaddition reactivity. Analysis of the structural parameters of the investigated metal-azide complexes suggests that a more symmetric structure and charge distribution within the azide moiety is needed for the formation of a metal-triazolate product. Overall, these results suggest that a successful cycloaddition reaction between a metal-azide complex and an alkyne substrate is dependent both on the ligand and metal oxidation state, that determine the electronic properties of the bound azide, as well as the electron deficient nature of the alkyne employed.

ChemInform Abstract: Progress Towards Viridin: Synthesis of the Pentacyclic Furanosteroid Ring System via o-Benzoquinonoid Cycloadditions.

The pentacyclic ring system of viridin is synthesised in nine steps from 4-methylguaicol by means of successive cycloadditions involving o-benzoquinonoid intermediates generated in situ.

Phthalocyanine–C60 Fused Conjugates Exhibiting Molecular Orbital Interactions Depending on the Solvent Polarity

New covalently C60-connected zinc phthalocyanine (ZnPc) derivatives have been synthesized by utilizing successive cycloaddition reactions of C60 with a ZnPc derivative containing a pyridazine moiety employing Komatsu's method in reaction of C60 with phthalazine. The UV/Vis absorption spectrum of the fused conjugate (5) shows red shifts from the corresponding absorption of ZnPc derivative (8), indicating interactions between the ZnPc and C60 moieties. The DFT calculations under non-polar medium predict that the HOMO and LUMO of 5 localize on the ZnPc moiety, whereas LUMO+1 localizes on the C60 moiety, which reasonably explain the magnetic circular dichroism (MCD) and absorption spectra in toluene. Electrochemical redox potentials of 5 in polar solvents indicate the first-oxidation potential arises from the ZnPc moiety, whereas the first reduction potential is associated with the C60 moiety, suggesting the LUMO localizes on the C60 moiety in polar solvent. This reversal of the LUMO is supported by the ZnPc-fluorescence quenching with a nearby C60 moiety in benzonitrile, which leads to the charge-separation via the excited singlet state of the ZnPc moiety. In toluene on the other hand, such a ZnPc-fluorescence quenching owing to the photoinduced charge separation is not observed as predicted by the DFT-calculated LUMO on the ZnPc moiety.

Diels–Alder reaction of α-tropolone and electron-deficient dienophiles prompted by Et 3N or silica gel: a new synthetic method of highly functionalized homobarrelenone derivatives

A Diels–Alder reaction of α-tropolone and electron-deficient dienophiles prompted by Et 3N or silica gel was performed. Reaction with the highly reactive dienophile, N-methylmaleimide, proceeded smoothly in the presence of Et 3N or silica gel to yield adducts as a mixture of endo and exo isomers. Both catalysts accelerated endo/ exo isomerization of the product, and detailed examination of the reaction using hinokitiol and N-methylmaleimide revealed that isomerization proceeds via an intramolecular path without retro Diels–Alder reaction. Successful cycloaddition reactions were established with six other dienophiles: acrylonitrile, methyl acrylate, ethyl vinyl ketone, dimethyl fumalate, dimethyl malate, and dimethyl acetylenedicarboxylate, and the corresponding adducts were obtained in good to moderate yields.

Diene-modified nucleotides for the Diels–Alder-mediated functional tagging of DNA

We explore the potential of the Diels–Alder cycloaddition for the functional tagging of DNA strands. A deoxyuridine triphosphate derivative carrying a diene at position 5 of the pyrimidine base was synthesized using a two-step procedure. The derivative was efficiently accepted as substrate in enzymatic polymerization assays. Diene carrying strands underwent successful cycloaddition with maleimide-terminated fluorescence dyes and a polymeric reagent. Furthermore, a nucleotide carrying a peptide via a Diels–Alder cyclohexene linkage was prepared and sequence-specifically incorporated into DNA. The Diels–Alder reaction presents a number of positive attributes such as good chemoselectivity, water compatibility, high-yield under mild conditions and no additional reagents apart from a diene and a dienophile. Furthermore, suitable dienophiles are commercially available in the form of maleimide-derivatives of fluorescent dyes and bioaffinity tags. Based on these advantages, diene- and cyclohexene-based nucleotide triphosphates are expected to find wider use in the area of nucleic acid chemistry.

Effect of Substitution on the Intramolecular 1,3-Dipolar Cycloaddition of Alkene Tethered Münchnones

A sequence of chemoselective activation of N-acylaminoacids, münchnone generation, intramolecular 1,3-dipolar cycloaddition, and ring opening efficiently generated functionalized polycyclic structures such as cyclopenta[b]pyrroles or zwitterionic bicyclo[4.3.0]nonane or bicyclo[3.3.0]octanes in one operation is given. These zwitterionic species were isolated for the first time and were subsequently reduced to bicyclic aminoalcohols. The effect of the substitution of both the dipolarophile and the münchnone on the intramolecular cycloaddition outcome was examined. It was found that either nonactivated or electron-poor alkenes can react with the münchnone if these alkenes are tethered at position 4 on the münchnone (2, R2 = alkene tether), whereas only an electron-poor alkene at position 2 (2, R3 = alkene tether) could undergo successful cycloaddition. Also, münchnones substituted at position 2 with a phenyl (2, R3 = Ph) showed a dramatic increase in reactivity, whereas a phenyl at position 4 (2, R2 = Ph) had a very limited effect.

Synthesis of Complex Condensed Heterocycles by Diels-Alder Reactions

(E)-3-(2-Alkoxyvinyl)-benzofurans, -furopyridines and -indoles undergo rapid [4+2] cycloaddition reactions with even poorly reactive dienophiles under thermal and pressurized conditions to afford condensed dibenzofurans, dibenzofuro[2,3-c]pyridines, carbazoles, 2-azacyclopenta[c]fluorenes, furo[2,3-c]isochromenes, among other complex ring systems. Interesting temperature and pressure dependence on stereoselectivity was observed: endo products are derived by pressure-mediated reactions while exo isomers result under thermal conditions. For successful cycloaddition to give the [4.4.0] condensed isochromene and isoquinolinone systems, activated dienophiles such as maleic anhydride were required.

Titanium‐Mediated [2 + 2 + 2] Coupling of Diynes with Homoallylic Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Successive Cycloadditions between 4‐Fluoro‐5‐trifluoromethyl‐1,2‐dithiole‐3‐thione and Dimethyl Acetylenedicarboxylate: New Fluorinated Thiaheterocycles through New Reaction Mechanisms

AbstractThe cycloaddition reaction between dimethyl 2‐(1‐fluoro‐2‐trifluoromethyl‐2‐thioxoethylidene)‐1,3‐dithiole‐4,5‐dicarboxylate and dimethyl acetylenedicarboxylate proceeds efficiently under irradiation conditions in air. A study of the reaction conditions resulted in the proposal of a chain mechanism initiated by a photochemically induced single‐electron transfer to oxygen. On the other hand, the cycloadduct can be transformed into a rearranged hydroxylated product by filtration through silica gel. Either the cycloadduct or its rearranged product can be obtained selectively in a one‐pot process from the parent 1,2‐dithiole‐3‐thione. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)