ChemInform Abstract: Synthesis and Cytotoxicity Evaluation of Aryl Triazolic Derivatives and Their Hydroxymethine Homologues Against B16 Melanoma Cell Line.

The copper‐catalyzed oxidative azide‐olefin cycloaddition (OAOC) reaction of differently substituted α,β‐unsaturated carbonyls with azides provided an efficient method for preparing biologically active 1,4,5‐trisubstituted 1,2,3‐triazoles. In this study, the cycloaddition reaction was found to be a simple and powerful method for constructing diverse mono‐ and bis‐(1,4,5‐trisubstituted 1,2,3‐triazole) functionalized heterocyclic compounds in moderate to high yields with great regioselectivity. The XRD‐analysis data of one of the bis‐triazole derivatives supported the regioselectivity as well as the conformity of the method in the construction of the triazole nucleus. The preliminary antifungal profile against C. albicans was observed with cinnamaldehyde‐based triazole derivatives demonstrating promising results.

Targeting the liver via the asialoglycoprotein-receptor : synthesis of directed small molecule libraries for the H1-CRD

Chapter 2 Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions

Halogen bond donor catalysts have been widely used in organic reactions because they are environmentally friendly, inexpensive and recyclable. The [4+2] cycloaddition reaction is a key reaction in organic synthesis because of its ease of use, fast speed, and wide range of applications. In this work, halogen bond catalysis in the [4+2] cycloaddition reaction between 2-alkenylindoles was investigated based on DFT calculations. There are two modes of I⋯π halogen bond catalysis: either on the ethenyl of 2-alkenylindole (mode A) or on the five-membered ring of 2-alkenylindole (mode B). Both modes involve two steps: the formation of carbon-carbon bonds and the formation of six-membered rings. Gibbs free energy barriers were determined to investigate the stereoselectivity of the endo pathway and exo pathway. For mode A, the exo products were more easily generated when the substituent R = H, and the N-H⋯π interaction promoted high endo selectivity in the case of the substituent R = Ph. For mode B, an increasing proportion of endo products can be obtained in the order of catalyst I2, IBr and ICl. The π⋯π interaction of the substituent R = Ph promotes the [4+2] cycloaddition reaction, which is consistent with the experimental observation that R = Ph has a higher yield than R = H. The study of different catalytic modes and stereoselectivity would provide new ideas for the further study of the [4+2] cycloaddition reaction.

In this work, the synthesis of novel triazole derivatives with barbituric motifs in good yields is described. The alkyne was prepared through the Knoevenagel reaction of barbituric derivatives with ortho and para O-propargylated hydroxybenzaldehyde. The mechanism and regioselectivity of this [3+2] cycloaddition reaction were investigated using the density functional theory at the B3LYP/6-31+G(d) level of theory. The computational studies revealed that a di-copper catalyzed stepwise mechanism, involving six-membered ring intermediate, is the preferred pathway. The regioselectivity was explained in terms of frontier molecular orbital (FMO) interactions, local and global electrophilicity and nucleophilicity indices. Accordingly, the favored interactions for di-copper acetylide are in good agreement with the observed regioselectivity, while completely opposite results were obtained for a possible uncatalysed reaction.

1,2,3-triazole have found broad uses in agrochemicals, industrial applications and drugs. Many methods of preapring N-substituted 1,2,3- triazole are reported, whereas, only a few synthesis of N-unsubstituted 1,2,3-triazole were developed. In this study, we report a high yield synthesis of N-unsubstituted triazole by cycloaddition reaction of terminal acetylene and sodium azide activated by copper(I) ion. (i). The mixture of copper(I) phenyl acetylide and sodium azide dissolved in methanol was stirred at reflux temperature of 70℃ for 3 days : the yield of 4-phenyl-1H-1,2,3-triazole (2a) is less than 10% and phenyl acetylene dimer (3a) is the major product. (ii). The mixture of copper(I) azide and phenyl acetylene dissolved in methanol was stirred at reflux temperature of 70℃ for 3 days : the yield of (2a) is 33% and the yield of (3a) is 34%. (iii). The mixture of phenyl acetylene, sodium azide and copper(I) chloride dissolved in a co-solvent (methanol : 1,4-dioxane= 1 : 2) was stirred at reflux temperature of 100℃ for 2 days under nitrogen : the yield of (2a) is 81%. The same procedure was applied to terminal alkynes carrying substituents such as aryl, alkyl, hydroxyl, ester, cycloalkyl and conjugated enyne to obtain triazoles having corresponding substitutents. The yields of these products are comparable or better then those reported in literature. This reaction isregiospecific and only 4-substituted 1H-1,2,3-triazoles were obtained. The reaction must carry out under inert gases, otherwise oxidative coupling reaction is the dominated reaction, and phenyl acetylene dimmer is the major product. Reaction temperature has to be high enough (>80℃) to allow the color change of the mixture to ensure a high yield reaction. When the rate of copper(I) chloride to phenyl acetylene is 1:1, as the reactant, the optimal yield of 81% is attained. Therefore, copper(I) chloride is not a catalyst. We also synthesize 4-phenyl-1,3-diH-1,2,3-triazolium cation and its structure determined by X-ray diffraction is described.

A simple method to synthesize propargylamines along with the highly diastereoselective synthesis of a series of 4,6,7,8,8a,9‐hexahydropyrrolo[1,2‐a][1,2,3]triazolo[1,5‐d]pyrazines has been developed. The three‐component coupling of aldehydes, amines, and alkynes (A3‐coupling), which proceeds through a C−H activation process with tin(II) chloride as the catalyst, and a metal‐free [3+2] cycloaddition reaction were used to prepare the propargylamines and fused heterocycles, respectively, without the need of a cocatalyst or activator. The coupling reaction is applicable to various aldehydes, amines, and alkynes and provides the propargylamines in good to excellent yields with excellent distereoselectivities. The cycloaddition reaction also provides various tricyclic fused triazole derivatives in excellent yields with high distereoselectivities. A mechanism is proposed for the tin(II) chloride catalyzed three‐component coupling as well as the [3+2] cycloaddition reaction.

Controlled functionalization of carbon nanotubes (CNTs) through the use of cycloaddition reactions is described. By employing various cycloaddition reactions, a wide range of molecules could be coupled onto CNTs without disruption of the structural integrity as well as with a statistical distribution of functional groups onto the surface of the CNTs. The cycloaddition reactions represent an effective and tailored approach for preparing CNT-based advanced hybrid materials that would be useful for a wide range of applications from nanobiotechnology to nanoelectronics.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) are required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3+2] reaction that utilizes C(sp3)–H activation to generate the three-carbon unit for formal cycloaddition with maleimides. We implemented a strategy where the initial C(sp3)–H activation/olefin insertion would trigger a relayed, second remote C(sp3)–H activation to complete a formal [3+2] cycloaddition. The diastereoselectivity profile of this reaction resembles that of a typical pericyclic cycloaddition reaction in that the relationships between multiple stereocenters are exquisitely controlled in a single reaction. The key to success was the use of weakly coordinating amides as the directing group, as undesired Heck or alkylation pathways were preferred with other types of directing groups. The use of the pyridine-3-sulfonic acid ligands is critical to enable C(sp3)–H activation directed by this weak coordination. The method is compatible with a wide range of amide substrates, including lactams, which lead to novel spiro-bicyclic products. The [3+2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition, also referred to as “click reaction”, has been increasingly applied in various fields of chemistry as a versatile and mild ligation method. This method allows for the synthesis of complex materials, which include bioconjugates, glycopeptides, functionalized polymers, virus particles, and therapeutics. However, due to the toxicity of the copper catalyst to both bacterial and mammalian cells applications that involve in vivo ligation are limited. In order to circumvent the use of copper ions, Bertozzi and co-workers have devised a strain-promoted [3+2] cycloaddition reaction that involves azides and a strained cyclooctyne derivative. Recent reports by Ju et al. have also shown successful applications of copper-free 1,3-dipolar cycloaddition by using either elevated temperatures or electron-deficient alkynes. We envisioned that the combination of ring strain and electron deficiency, as occurs in oxa-bridged bicyclic systems 2a and 2b, could also lead to an increased reactivity toward [3+2] cycloaddition reactions. Here, we report a spontaneous tandem [3+2] cycloaddition–retro-Diels–Alder ligation method that results in a stable 1,2,3-triazole linkage. This methodology can be applied to biomacromolecules that contain various functional groups under physiological conditions. The oxabridged bicyclic systems 2a and 2b were prepared by a Diels– Alder reaction of substituted propiolates with furan (Scheme 1). Subsequent hydrolysis provided the desired carboxylic acid derivatives 3a and 3b, in excellent yield. To compare the reactivity of Diels–Alder products 2a and b with the corresponding alkynes, [3+2] cycloaddition reactions were performed under ambient conditions by using benzyl azide, and monitored over time with H NMR spectroscopy (Figure 1). The oxanorbornadienes 2a and 2b and their respective alkynes provided identical 1,4,5-substituted triazoles to the products.

Review: 66 refs.

Novel fluorophores were synthesized, characterized, and examined with respect to their metal-binding properties. These compounds (Figure 1) consist of a heteroaromatic core substituted with two triazole rings, synthesized via copper-catalyzed azide-alkyne cycloaddition. Binding of a metal ion is achieved through coordination between two nitrogens (one in the triazole ring, and one in the heteroaromatic core). For practical purposes, these sensors must be soluble in water. This is accomplished through the use of a water-soluble side chain; in this case, one with a branched oligoethylene glycol substituent. This bulky side-chain decreases fluorescence quenching from intermolecular aggregation, resulting in metal ion sensors that are brightly fluorescent, even in water. Figure 1 Metal ion sensors. R represents tri(ethylene glycol) monomethyl ether, X represents H, F, or Cl, and Y represents O, S, or Se. These molecules are designed so that they serve as the binding receptor and the sensing element. We are then able to tune the structure of the core molecule, thereby adjusting the metal-binding activity, as well as the optical properties. In Figure 1, the series of molecules on the left is tunable through halogen substitution of the phenazine core. On the right, variation of the chalcogen heteroatom serves the same purpose. Increasing understanding of this kind of structure-property relationship is vital for the future construction of highly sensitive and selective fluorescent sensors. The results show that of the phenazine-containing compounds, those that are more electron-poor (halogen-substituted) are not able to efficiently bind metal ions in aqueous solution. A similar effect is seen with the benzochalcogendiazole compounds, with binding affinity increasing moving down the group, parallel to the decreasing electronegativity of the chalcogen atom. The heteroaromatic core also plays a significant role in the selectivity; the phenazine compound functions as a selective silver sensor, while the benzochalcogendiazole compounds respond to copper, silver, and nickel. The response to each metal is unique, and statistical analysis of the resulting data enables differentiation of these three metals with a single molecule.

Abstract1,3‐Dipolar Cycloadditions with Methyl 4‐Oxo‐ and 4‐Hydroxy‐2‐butynoates (II).

1,3-Dipolar Cycloadditions with Methyl 4-Oxo- and 4-Hydroxy-2-butynoates. Synthesis of Functionalized Pyrazoles and Triazoles

Diminutive effect on T and B-cell proliferation of non-cytotoxic α-santonin derived 1,2,3-triazoles: A report