Cycloaddition Research Articles

Carbodiphosphorane-Activated Distibene and Dibismuthene Dications.

Low-valent antimony and bismuth have emerged as novel platforms for achieving reversible small-molecule activation at main-group metals. Although various examples of oxidative addition reactions at monomeric Sb(I) and Bi(I) have been reported, the chemistry of the heavy group 15 Sb(I)═Sb(I)/Bi(I)═Bi(I) double bonds toward small molecules remains largely unexplored. In this study, we present a straightforward synthesis of distibene and dibismuthene dications coordinated with a neutral carbodiphosphorane (CDP) ligand. The nonbonding interactions between the occupied p-orbital at the CDP ligand and the π-bonding orbital of the Sb═Sb/Bi═Bi bonds yield compounds with exceptionally small HOMO-LUMO gaps. In addition, the reduction of steric hindrance compared to known neutral derivatives stabilized with bulky aryl groups allows for better accessibility of the double bonds. This high reactivity is demonstrated in the oxidative addition of distibene to diphenyldisulfide as well as in [2+2] cycloadditions to alkynes. Additionally, the Sb═Sb bond reversibly adds to 2,3-dimethylbutadiene in a [4+2] cycloaddition reaction.

Repurposing Copper(II)/THPTA as A Bioorthogonal Catalyst for Thiazolidine Bond Cleavage.

Metal-mediated chemical transformations are promising approaches to manipulate and regulate proteins in fundamental biological research and therapeutic development. Nevertheless, unlike bond-forming reactions, the exploration of selective bond cleavage reactions catalyzed by metals that are fully compatible with proteins and living systems remains relatively limited. Here, it is reported that Copper(II)/tris(3-hydroxypropyltriazolylmethyl)amine (THPTA), commonly used in copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, can be repurposed as a new bioorthogonal catalyst for thiazolidine (Thz) bond cleavage. This process liberates an α-oxo-aldehyde group under physiological conditions, without requiring additional additives. To showcase the utility of this method, this simple catalyst system is coupled with genetic code expansion technology to achieve on-demand activation of genetically encoded Thz-caged α-oxo-aldehydes, enabling further functionalization of proteins. For the first time, this cell-compatible Thz uncaging reaction allows for the site-specific installation of α-oxo-aldehydes at the internal positions of proteins in phage and bacterial surface display systems, expanding the chemical space of proteins. Overall, this study expands the toolkit of bioorthogonal catalysts and paves the way for metal-promoted chemical reactions in living systems, potentially benefiting various applications in the future.

Synthesis of 5-substituted-1H-tetrazoles by lemon juice as a homogeneous and natural catalyst under green reaction conditions

Tetrazole, as a heterocyclic compound, exhibits a wide spectrum of applications in various industries. This research focuses on utilizing a natural catalyst in the synthesis of tetrazole derivatives. Leveraging the acidic nature of lemon juice (LJ), we employed it as a potential catalyst in the synthesis of 5-substituted-1H-tetrazole. LJ would act as the reaction medium as well. This synthesis involves the cycloaddition reaction (3 + 2) of sodium azide to benzonitrile under solvent-free conditions. Optimization of the reaction conditions including temperature, reaction time, and solvent type was tuned towards the highest yield considering the mild reaction time. The best product yield (97 %) was obtained at 90 °C, 40 min, in the absence of additional solvent. Various benzonitrile derivatives were examined at the optimized reaction condition.

Bypassing halide immobilization with cooperative polymers for the cycloaddition of atmospheric CO2 to epoxides

Atom-economic syntheses of cyclic organic carbonates by cycloaddition of CO2 to epoxides have risen to prominence among various approaches for CO2 fixation. In current literature, there is a general lack of recyclable fully heterogeneous organocatalytic systems which are active under mild conditions (T≤60 °C, atmospheric pressure), and that do not involve elaborated synthetic steps for the synthesis of monomers or the coimmobilization of active sites such as hydrogen bond donors (HBDs) and halide nucleophiles. From the standpoint of cost reduction and sustainability, it is also highly desirable to obtain the catalytic materials from biobased sources, especially waste materials. To address such gaps in the literature, we disclose in this work that a lignin derivative (phenolated lignin, PL) can be used as HBD in cooperation with readily available ionic polymers to form recyclable heterogeneous catalytic systems able to carry out the target cycloaddition reaction under atmospheric pressure at 60 °C. This unprecedented approach allows the upcycling of readily available biobased materials for the mild synthesis of cyclic carbonates from CO2 and bypasses the need for elaborated synthetic procedures for the synthesis of coimmobilized HBD-halide systems. PL/QPBAE (quaternized polyaminoester) emerged among various PL/ionic polymer pairs as the most active and efficient catalyst. Such a result is justified through a spectroscopic and analytical investigation as an effect of the ability of PL and QPBAE to closely interact and disperse in the reaction medium, and of the higher flexibility of QPBAE compared to other ionic polymers such as quaternized polyvinylpyridine. The resulting catalytic pair can be used as an efficient recyclable system for the cycloaddition of CO2 to several epoxides under atmospheric conditions with a catalytic performance that compared very well to that of more complex oil-based state-of-the-art polymeric organocatalysts for the same reaction.

Heteroatom‐Containing Zeolites as Solid Lewis Acid Catalysts for the Cycloaddition of CO2 to Epoxides

AbstractThe catalytic cycloaddition of CO2 to epoxides to produce valuable cyclic carbonates represents a simple and promising strategy for CO2 utilization, circumventing the ineffective CO2 reduction process. Despite current progresses, there remains an impending demand for highly‐active, cost‐effective and stable catalysts especially the ideal heterogeneous catalytic systems. Herein, we report the preparation of heteroatom‐containing zeolites through a two‐step process comprising of framework dealumination and subsequent heteroatom incorporation, and their catalytic applications in CO2 cycloaddition to epoxides. Characterization results reveal the successful incorporation of heteroatoms into framework to derive Lewis acidic M‐Beta zeolites (M = Ti, Zr or Hf). The as‐prepared M‐Beta Lewis acids show remarkable performance in the model reaction of CO2 cycloaddition to propylene oxide with the assistance of potassium iodide under solvent‐free conditions. The reaction parameters have been optimized employing Ti‐Beta catalyst and the substrate scope has been investigated. Finally, the impact of Lewis acidity on the cycloaddition reaction is discussed and the actual bifunctional Ti‐Beta/KI catalyst system is proposed, which is of important significance for the understanding of CO2 catalytic cycloaddition to epoxides.

Highly Stable Binary Cross‐Linkable Organic Nonlinear Optical Materials Using Different Acceptors Based on Huisgen Cycloaddition Reaction

Comprehensive SummaryHow to obtain organic electro‐optic materials with large electro‐optic coefficients, high glass transition temperature, and good optical transparency remains a challenge in this field. To solve this problem, we introduce groups that can undergo Huisgen cycloaddition reactions into the donor and electron bridge of chromophores with large hyperpolarizability using tetrahydroquinoline as the donor. Binary cross‐linkable chromophores TLD1‐2 with CF3‐TCF as the acceptor and chromophores TLD3‐4 with 5Fph‐TCF as the acceptor were synthesized. After poling and crosslinking, the Tg of TLD1/TLD2 and TLD3/TLD4 were raised to 152 and 174 °C, respectively. The electro‐optical coefficients of chromophores TLD1/TLD2 and TLD3/TLD4 were as high as 312 pm/V and 287 pm/V, respectively. The long‐term alignment stability test showed that after being left at 85 °C for 500 h, the cross‐linked film TLD3/TLD4 can still maintain more than 98% of the original electro‐optical coefficient value, which is higher than that of TLD1/TLD2 (93%). The chromophore TLD3‐4 exhibited much blue‐shifted maximum absorption wavelengths (~40 nm) compared to TLD1‐2 which was beneficial for reducing optical loss in the device. The combination of high electro‐optic coefficient, strong stability, and excellent optical transparency makes the TLD series of binary cross‐linked materials very promising for practical high‐performance electro‐optic devices.

Post‐Functionalization of Organoboranes by Cu‐Catalyzed Azide Alkyne [3+2]‐Cycloaddition Reaction

AbstractThe copper‐catalyzed azide alkyne [3+2]‐cycloaddition (CuAAC) reaction of organoboranes represents an attractive area of research within the field of click chemistry, with diverse applications in organic synthesis, medicinal chemistry, or materials science. Despite the potential issues caused by the copper insertion into the carbon‐boron bond, significant progress has been made to harness the reactivity of organoboron compounds in CuAAC. This review provides an overview of the catalytic methods reported for CuAAC with various organoboranes, discussing the stability of the boron group and highlighting recent advancements in this area.

4+2] Cycloaddition Mediated Stereoselective Synthesis of Tetrahydro‐1H‐Isobenzofuro Chromene Dione Derivatives: Antibacterial Evaluation and Molecular Docking Investigation

AbstractAn efficient stereoselective synthesis of tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives were achieved through a novel [4+2] cycloaddition reaction of 4‐styryl‐2H‐chromenes with cheaply available maleic anhydride. A series of new tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives 21(a–p) were synthesized in good to excellent yield under mild reaction condition with no chromatographic purification. In this reaction, the generation of four new consecutive stereogenic centers were determined by single crystal X‐ray analysis. All the synthesized compounds were investigated further in silico and in vitro for antibacterial activities using two bacterial strain of DNA gyrase. Compounds 21 b and 21 j showed excellent docking score −9.3 kCal/mol and −8.6 kCal/mol with gram negative bacterial strain Escherichia coli (E. coli) with protein data bank (PDB ID) 3G7E. Out of all the tested molecules, 21 b and 21 j displayed good results with minimum inhibitory concentration 10 μg/ml, 10 μg/ml against the bacterial strain Escherichia coli(E. coli) and 10 μg/ml, 20 μg/ml against Staphylococcus aureus (S. aureus) respectively.

Synthesis of Indole‐Fused Eight‐Membered Oxa‐Rings via Palladium‐Catalyzed Asymmetric [4+4] Cycloaddition of Indole‐2,3‐Quinodimethanes with 2‐Alkylidenetrimethylene Carbonates

Comprehensive SummaryWe report a palladium‐catalyzed asymmetric [4+4] cycloaddition reaction between 2‐alkylidenetrimethylene carbonate and electron‐deficient indole‐2,3‐quinodimethanes (IQDMs). This reaction features exclusive regioselectivity, high yield (up to 98%), excellent enantioselectivity (up to 95% ee), and easy scale‐up without any loss of efficiency, making it valuable for the synthesis of indole‐fused eight‐membered oxa‐rings.

Organocatalytic Asymmetric (4 + 3) Cycloaddition toward Optically Active Cyclohepta Fused Diindoles.

A novel asymmetric (4 + 3) cycloaddition of indole-2,3-quinodimethanes in situ generated from 3-methyl-2-indolylmethanols with 3-indolylmethanols via chiral phosphoric acid catalysis has been established. The cycloaddition reaction exhibits a broad substrate scope affording the diverse enantioenriched cyclohepta fused diindoles in high yields with good enantioselectivities. Significantly, this work represents the first application of 3-methyl-2-indolylmethanols as 4C synthons instead of the commonly reported three-atom synthons in cycloaddition reactions.

Construction of heterogeneous frustrated lewis pairs based on covalent organic frameworks stabilized boron cations and investigation of cycloaddition reaction performance

Frustrated Lewis Pairs (FLPs) catalysts have been widely designed and synthesized in current chemistry, with the key being the selection of boron-based Lewis acids. Among novel boron-based Lewis acids, boron cations with higher Lewis acidity caused by cationic charge have been proven to have special reactivity. However, the current boron cations have only been used to construct homogeneous FLPs, which would be difficult to meet the industrial process demand for FLPs catalysts, possibly due to the lack of suitable stabilizers. In this paper, we propose a strategy to construct heterogeneous FLPs using covalent organic frameworks (COFs) stabilized boron cations as Lewis acid. Firstly, heterogeneous Lewis acid COFs@[B(C6F5)2]+[Al2Cl7]- was prepared by stabilizing boron cations with CN bonds in COFs, followed by introducing tBu3P to construct heterogeneous FLPs COFs@[B(C6F5)2]+[Al2Cl7]-/tBu3P. Meanwhile, these FLPs catalysts exhibited excellent catalytic and cyclic performance in the preparation of cyclic carbonates by CO2 addition from epoxy compounds.

Trifluoromethylated 2H‐Thiete, 2,3‐Dihydrothiophenes and 3,4‐Dihydro‐2H‐thiopyranes S,S‐Dioxides in [3+2]‐Cycloaddition Reactions with Diazo Compounds and Nitrilimines

Abstract[3+2]‐Cycloaddition reactions of 3‐trifluoromethyl‐2H‐thiete 1,1‐dioxide, 4(5)‐trifluoromethyl‐2,3‐dihydrothiophene 1,1‐dioxides and 5(6)‐trifluoromethyl‐3,4‐dihydro‐2H‐thiopyrane 1,1‐dioxides with diazomethane proceed with the formation of regioisomeric mixtures of corresponding dihydropyrazole‐fused cycloadducts. Reactions of 3‐trifluoromethyl‐2H‐thiete 1,1‐dioxide with ethyl diazoacetate and in situ generated 2,2,2‐trifluorodiazoethane lead to the regioselective formation of pyrazolino‐sultine derivatives via rearrangement of initially formed pyrazoline‐fused thietane 1,1‐dioxides. Treatment of 3‐trifluoromethyl‐2H‐thiete 1,1‐dioxide and 4‐trifluoromethyl‐2,3‐dihydro‐thiophene 1,1‐dioxide with in situ generated N‐phenyl nitrilimines gives rise to dihydropyrazole‐ thietane 1,1‐dioxides and tetrahydrothiophene 1,1‐dioxides, respectively, in a regioselective fashion.

Regulating the N-functional hydrogen bond donors over magnetic nanoparticles supported imidazole tribromide zinc ionic liquid for CO2 cycloaddition

The design of catalysts for the mile production of cyclic carbonates by CO2 cycloaddition is of value. Magnetic polymer nanoparticles-supported imidazole tribromide zinc ionic liquid catalysts, incorporating N-functional hydrogen bond donors (HBD), was successfully accomplished. The correlation between the N-functional HBD and catalytic activity was thoroughly investigated through experimental studies and DFT calculations. The catalyst featuring a secondary amine group (NHM) demonstrated remarkable catalytic performance in CO2 cycloaddition reactions. Under optimized conditions, including 0.12 mol% catalyst dose, 100 °C, and nPO:nCO2 = 1:1.2 for 3 h, a complete conversion was achieved. The exceptional performance of the catalyst was attributed to the multicenter synergistic effect, arising from the appropriate electronegativity, minimal spatial site resistance, a balanced distance between the NHM and imidazolium ion, and the presence of multiple active centers (NHM, Zn2+, and Br−). The integration of a magnetic component enabled swift separation and exceptional recovery stability over 8 consecutive cycles.

Construction of bicarbonate-porous poly(ionic liquid)s for cycloaddition of CO2 and epoxides under mild conditions

The utilization of carbon dioxide (CO2) as a C1 building block to synthesize cyclic carbonates represents an environmentally and sustainably viable approach. Nevertheless, the preparation of metal- and halogen-free porous materials remains a promising avenue for the cycloaddition reaction. In this context, we have designed a bicarbonate-porous poly(ionic liquid)s (PEI/PS-HCO3) catalyst with a mesoporous structure for the construction of multiple active sites through quaterisation and ion exchange. The as-prepared PEI/PS-HCO3 catalyst exhibited excellent catalytic activity for the synthesis of cyclic carbonates, with yields of up to 93% under metal-, solvent- and halogen-free conditions. Furthermore, the catalyst exhibited excellent reusability by washing with anhydrous ethanol. The feasible reaction mechanism was proposed. The interaction of dual hydrogen bond donors (amine groups and [HCO3]− anion) with epichlorohydrin (ECH) via hydrogen bonding results in the polarisation of the epoxide C-O bond. Amine groups, also acting as Lewis base sites, captured CO₂ to produce carbamates ([NH-COO]−). The nucleophilic [HCO3]− attacked the less sterically hindered β-carbon atom of epichlorohydrin (ECH). This protocol provides a novel strategy for the preparation of halogen-free catalysts.

Total Synthesis of (+)‐Kalmanol

AbstractKalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. We have achieved the efficient total synthesis of (+)‐kalmanol in 22 steps with 2.3 % yield. The synthesis featured a Rh‐catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton.

Synthesis and Antimicrobial Activity of (E)-1-Aryl-2-(1H-tetrazol-5-yl)acrylonitrile Derivatives via [3+2] Cycloaddition Reaction Using Reusable Heterogeneous Nanocatalyst under Microwave Irradiation.

The magnetically recoverable heterogeneous Fe2O3@cellulose@Mn nanocomposite was synthesized by a stepwise fabrication of Mn nanoparticles on cellulose-modified magnetic Fe2O3 nanocomposites, and the morphology of the nanocomposite was characterized through advanced spectroscopic techniques. This nanocomposite was investigated as a heterogeneous catalyst for the synthesis of medicinally important tetrazole derivatives through Knoevenagel condensation between aromatic/heteroaromatic aldehyde and malononitrile followed by [3+2] cycloaddition reaction with sodium azide. Thirteen potent (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives are reported in this paper with very high yields (up to 98%) and with excellent purity (as crystals) in a very short period (3 min @ 120 W) using microwave irradiation. The present procedure offers several advantages over recent protocols, including minimal catalyst loading, quick reaction time, and the utilization of an eco-friendly solvent. Furthermore, the synthesized (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives (4b, 4c, and 4m) are shown to have excellent resistance against various fungal strains over bacterial strains as compared to the standard drugs Cefixime (4 μg/mL) and Fluconazole (2 μg/mL).

Catalytic Asymmetric Cycloadditions of Cyclic Sulfamidate Imines: Straightforward Access to Chiral N‐Heterocycles

AbstractChiral N‐heterocyclic compounds are key structures in natural compounds and pharmaceuticals, and they serve as essential building blocks of functional materials. Catalytic asymmetric cycloaddition reactions represent one of the most efficient synthetic strategies for constructing optically active heterocycles. Cyclic sulfamidate imines have recently come to be extensively studied and widely utilized in both organocatalytic and transition metal‐catalyzed asymmetric cycloadditions, where they have been shown to provide various N‐fused‐heterocycles and spiro‐cycles exhibiting high efficiencies with excellent stereoselectivities. This review highlights recent advancements in catalytic asymmetric cycloadditions of cyclic sulfamidate imines for the stereoselective synthesis of biologically active sulfamidate‐containing heterocycles since 2012 while focusing on the diverse reactivities of cyclic sulfamidate imines and the mechanisms of chiral induction in catalysis.

Photodimerization-Triggered Photopolymerization of Triene Coordination Polymers Enables Macroscopic Photomechanical Movements.

Controlling the packing of olefinic molecules in crystals is essential for triggering solid-state [2 + 2] photocycloaddition reactions and the synthesis of photocontrolled smart materials. Herein, we report the stepwise photodimerization-triggered photopolymerization of two triene coordination polymers (CPs), {[Zn(2-BBA)2(tpeb)]·0.5CH3CN}n (1, 2-HBBA = 2-bromobenzoic acid, tpeb = 1,3,5-tri-4-pyridyl-1,2-ethenylbenzene) and {[Zn(3-BBA)2(tpeb)]·CH3CN)}n (2, 3-HBBA = 3-bromobenzoic acid). Upon irradiation with 420 nm light, each pair of closely packed and parallel olefinic bonds in 1 undergoes a [2 + 2] cycloaddition reaction, which connects two adjacent Z-shaped chains into a ladder-like coordination chain [Zn(2-BBA)2(bpbdpvpcb)0.5]n (1a, bpbdpvpcb = 1,3-bis(4-pyridyl)-2,4-bis(3,5-di(2-(4-pyridyl)vinyl)phenyl]cyclobutene) through single-crystal to single-crystal (SCSC) transformation. After photodimerization from 1 to 1a has occurred, the olefinic bonds that were initially distant are brought in close enough proximity to meet the requirements for a subsequent [2 + 2] cycloaddition reaction. Upon further light irradiation, the neighboring bpbdpvpcb ligands in 1a experience a SCSC photopolymerization based on [2 + 2] photocycloaddition and transform into poly-3b,4,5,5a,8b,9,10a-octahydro-4,5,9,10-tetrapyridyl-2,7-di(2-(4-pyridyl)vinyl)dicyclobuta[e,l]-pyren (poly-otpdpvdcbp). 2 showed similar structural changes under UV light illumination. Under light exposure, single crystals of 1 and 2 with different morphologies exhibit bending, cracking, and jumping photomechanical motions. The composite film (1-PVA) engineered by dispersing crystalline particles of 1 in poly(vinyl alcohol) (PVA) displays interesting light-wavelength-dependent photomechanical motions and can perform photodriven swimming on a liquid surface. This work provides a useful and promising approach to enable photodimerization of those photoinactive olefin pairs embedded in CPs and opens a new route to synthesize organic polymers by using olefinic CP platforms.

Oxidation-Controlled, Strain-Promoted Tellurophene-Alkyne Cycloaddition (OSTAC): A Bioorthogonal Tellurophene-Dependent Conjugation Reaction.

Tellurophene-bearing small molecules have emerged as valuable tools for localizing cellular activities in vivo using mass cytometry. To broaden the utility of tellurophenes in chemical biology, we have developed a bioorthogonal reaction to facilitate tagging of tellurophene-bearing conjugates for downstream applications. Using TePhe, a tellurophene-based phenylalanine analogue, labeled recombinant proteins were generated for reaction development. Using these proteins, we demonstrate an oxidation-controlled, strain-promoted tellurophene-alkyne cycloaddition (OSTAC) reaction. Mild oxidation of the tellurophene ring with N-chlorosuccinimide produces a reactive Te(IV) species which undergoes rapid (k > 100 M-1 s-1) cycloaddition with bicyclo[6.1.0]nonyne (BCN) yielding a benzo-fused cyclooctane. Selective labeling of TePhe-containing proteins can be achieved in complex protein mixtures and on fixed cells. OSTAC reactions can be combined with strain-promoted azide alkyne cycloaddition (SPAAC) and copper-catalyzed azide alkyne click (CuAAC) reactions. Demonstrating the versatility of this approach, we observe the expected staining patterns for 5-ethynyl-2'-deoxyuridine (DNA synthesis-CuAAC) and immunohistochemistry targets in combination with TePhe (protein synthesis-OSTAC) in fixed cells. The favorable properties of the OSTAC reaction suggest its broad applicability in chemical biology.

A novel Eu8 cluster for efficiently catalyzing CO2 cycloaddition and Knoevenagel condensation

A novel Eu8 cluster, namely, [Eu8(acac)4(HL)4(L)2(μ3O)4 (C2H5O)4]·2C2H5OH·2CH2Cl2 (H2L = 2‑hydroxy-benzoic acid (5-hydroxymethyl-furan-2-ylmethylene)-hydrazide, Hacac = acetylacetone) (1) was assembled using a multidentate ligand H2L. X-ray diffraction analyses reveal that cluster 1 includes eight Eu(III) ions, four HL− ligands, two L2− ligands, four acac−, four μ3O and four coordinated C2H5O−. The Eu8 cluster 1 displays well thermostability. Of particular significance, cluster 1 demonstrated high efficacy in catalyzing the cycloaddition reactions between CO2 and epoxides, as well as Knoevenagel condensation reactions involving aldehydes and malononitrile. This study presents the novel finding that the Eu8 cluster, acting as a remarkable heterogeneous bifunctional catalyst, can effectively facilitate the simultaneous reactions of epoxides with CO2 and Knoevenagel condensation reactions.