Synthetic utility of glycosyl triazoles in carbohydrate chemistry

We report herein a study of the synthetic utility of the glucosyl triazole moiety in carbohydrate chemistry. A model glucosyl triazole was prepared by a modified Huisgen 1,3-dipolar cycloaddition reaction. The relative rate of cycloaddition was investigated using a variety of alcohol co-solvents and reaction temperatures. It was found that the reaction proceeded with similar efficiency irrespective of co-solvent, however mildly elevated temperatures (40 °C cf. rt) increased the speed of reaction significantly (2 h cf. 8 h). The robustness of the triazole moiety was then interrogated under conditions typically encountered in carbohydrate chemistry reaction sequences—alcohol group protection/deprotection, nucleophilic displacement, and O-glycosylation. The triazole integrity was retained in all cases studied as evidenced from full compound characterization. Finally, a diverse set of triazole-linked glycoconjugates was synthesized. Collectively, our results demonstrated that the glucosyl triazole moiety was indeed a robust entity for carbohydrate chemistry.     

Functionalization of 2-(S)-isopropyl-5-iodo-pyrimidin-4-ones through Cu(I)-mediated 1,3-dipolar azide-alkyne cycloadditions

A series of 2-(S)-isopropyl-pyrimidinones functionalized at C5 with triazole rings, in which the substituents are found at N-1′ of the triazole ring, were synthesized. Through the azide-acetylene cycloaddition reaction, using CuI as a copper source and ultrasonic waves as an energy source it was possible to obtain products with yields ranging from 79% to 89% within 5 min or less. A preliminary study to gain further insight into the reaction was performed using in situ ReactIR technology.     

Efficient synthesis of 1,4-disubstituted triazolyl N-carboxamides via a simple and convenient MCR using basic alumina as solid support

A microwave assisted green protocol for the synthesis of 1,4-disubstituted triazolyl N-carboxamides was explored using basic alumina as solid support. The method allows domino Ullmann-type reaction, Click reaction and formation of ester or amide linkages in a single reaction vessel using Cu(phen)(PPh₃)Br and CMPA as catalyst and basic alumina as solid support in high yield. The protocol did not require addition of any external ligands or base. The method was also found to be equally good for the synthesis of bis triazole adducts.     

Reaction of N-phenylbenzamidrazone with cis-1,2-cyclohexanedicarboxylic anhydride

An analysis of the products of the reaction of N³-phenylbenzamidrazone with cis-1,2-cyclohexanedicarboxylic anhydride at various temperatures is presented. The identification of the reaction products is carried on with the support of computational techniques. The most stable conformers of the isoindole and triazole derivatives are found within the DFT approach. The theoretical calculations reveal the possible structure of a triazole derivative not available experimentally because of the presence of two diastereoisomers of equal energy.     

Catalyst-free 1,3-dipolar cycloaddition of 3-nitrochromen with sodium azide: a facile method for the synthesis of 4-aryl-1,4-dihydrochromeno[4,3-d][1,2,3]triazole derivatives

1,3-Dipolar cycloaddition of 3-nitrochromen with sodium azide under catalyst-free conditions afforded 4-aryl-1,4-dihydrochromeno[4,3-d][1,2,3]triazole derivatives at 80 °C in DMSO is described. The generality of this reaction was demonstrated by synthesizing an array of 4-aryl-1,4-dihydrochromeno[4,3-d][1,2,3]triazole derivatives. Clean reaction conditions, easy isolation, and good yields of the triazoles are the salient features of the methodology.     

Regioselective alkylation of 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole

Alkylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole using different alkylating agents leads regioselectively to 1-N-alkylated products. The hydrolysis-decarboxylation of 1,6-dimethyl-7-ethoxycarbonyl-pyrazolo[5,1-c][1,2,4]triazole yields a compound identical with that obtained by the direct methylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole. The 1-N-alkylation is confirmed by NMR spectroscopy and mass spectrometry.     

Boric acid in aqueous micellar medium: an effective and recyclable catalytic system for the synthesis of aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitriles

A simple, green, and efficient protocol is reported for the preparation of aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]-pyrimidine-6-carbonitriles through one-pot multi component reaction using substituted aromatic aldehydes, malononitrile, and 3-amino[1,2,4]triazole. The reaction is catalyzed by boric acid in aqueous micellar condition. Present protocol incorporates environmentally non-hazardous reaction condition, easy work-up, and use of recyclable catalytic system with associated benefits like excellent yield (84–96%) and shorter reaction time (20 min). Proposed methodology offers rapid access to substituted aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitriles with high atom-economy and catalytic efficiency.     

A regioselective and convenient one-pot multicomponent synthesis of 9-amino-3,5-diaryl-4,9-dihydro-5H-[1,2,4]triazolo[5,1-c][1,2,4]triazepine-8-thiol

An efficient and environment-friendly procedure for the synthesis of a new series of nitrogen bridge-head [1,2,4]triazolo[5,1-c][1,2,4]triazepine derivatives through one-pot three-component reaction of polyfunctional triazole with aromatic aldehydes and acetophenone derivatives using alcoholic sodium hydroxide solution. The same new products were prepared in classical route through reaction of triazole with the corresponding chalcones under the same conditions.     

A new modular and flexible approach to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines

A new synthetic route for the access to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines and other derivatives is described. This strategy is based on the cycloaddition of 2-oxoalkylidenephosphoranes to o-functionalized aryl azides followed by the reaction of the corresponding triazole intermediate with amines. This new approach presents unique properties such as regioselectivity, modularity, mild reaction conditions, and high yields.     

Synthesis of new tetrazole and triazole substituted pyroglutamic acid and proline derivatives

Racemic 4-(substituted-1H-1,2,3-triazol-1-yl), 4-aryl and 4-(arylmethyl)tetrazolyl-pyroglutamic and proline derivatives were synthesized from dimethyl-2,4-dibromoglutaryle 1 in good yield using mild reaction conditions. The key step for the preparation of the triazole substituted molecule was the 1,3-dipolar cycloaddition of an acetylenic compound with an azido derivative. The tetrazole derivatives were prepared by the selective N2-alkylation of 5-substituted tetrazoles with 1.     

Regioselective synthesis of thiophene fused sultam derivatives via iodocyclization approach and their application towards triazole linker

An efficient regioselective synthesis of 4-iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide derivatives via iodocyclization approach using iodine under mild reaction condition described herein. This coupling–iodocyclization strategy tolerated a variety of functional groups such as alkyl, cycloalkyl, phenyl producing the six-membered heterocyclic ring selectively. The resulting 4-iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide was coupled with a variety of boronic acids (Suzuki coupling) and activated alkenes (Heck coupling). The iodo group was utilized for Sonogashira coupling followed by efficient transformation to azido precursor, which was used for the synthesis of various thieno-sultam linked with triazole.     

Design,synthesis, and in vitro antifungal evaluation of novel triazole derivatives bearing alkynyl side chains

In order to explore novel antifungal agents, twenty-seven triazole derivatives featuring an alkyne linker in the side chain were designed and synthesized by the Sonogashira reaction. Most of the target compounds exhibited good antifungal activity against eight human pathogenic fungi, especially excellent activity against Candida and Cryptococcus species, comparing with the reference drugs fluconazole, voriconazole and ravuconazole. Compounds A2 and A3 exhibited in vitro activity against all the tested fungi with MIC₈₀ values ranging from 0.0156 μg/mL to 0.5 μg/mL, which are superior to ravuconazole and fluconazole. SAR and molecular docking study give a clear conclusion that para-fluoro, para-chloro, and para-cyano substituted phenylalkynyl or pyridinylalkynyl side chains may promote triazole antifungal activity.     

Lithiation-Functionalisation of Triazoles Bearing Electron-Withdrawing N-Substituents: Challenges and Solutions**

The regioselective lithiation of 1,2,3-triazoles provides an opportunity to introduce additional functionality, however this simple functionalisation strategy using triazoles bearing electron-withdrawing N-substituents has not been investigated until now. Herein, we demonstrate that the lithiated triazole intermediates can readily decompose, even at −78 °C. In addition, lithiation-deuteration studies reveal lithiation can take place competitively on both the triazole and the electron-withdrawn aryl ring. Careful control of reaction conditions is therefore required to i) minimise decomposition pathways; and ii) facilitate regioselective functionalisation of the triazole.     

Chemoselective preparation of disymmetric bistriazoles from bisalkynes

Best of both worlds, molecules bearing two alkyne groups, activated and unactivated, can selectively react on the activated one in a copper-free version of Huisgen’s reaction to form a first triazole ring, with a good selectivity toward the 1,4-isomer, which is solely isolated by a simple trituration procedure. The other alkyne function is then submitted to the selective reaction using a polymer-supported copper(I) catalyst to form a second triazole ring. This gave access to disymmetric bistriazoles without the need of protection using simple, easy, and fast procedures.     

Anaerobic conditions to reduce oxidation of proteins and to accelerate the copper-catalyzed "Click" reaction with a water-soluble bis(triazole) ligand

Oxidation of protein (bovine albumin serum) by air still occurred under the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction conditions even in the presence of a Cu(I)-stabilizing tris(triazole) ligand. Anaerobic conditions not only avoided the oxidation of the protein, but also greatly accelerated the CuAAC reaction using a water-soluble bis(triazole) Cu(I) ligand.     

Synthesis of 1,2,3-triazolo-nucleosides via the post-triazole N-alkylation

2-Substituted-2H-1,2,3-triazolo-nucleosides with 3-phosphonopropyl, 2-hydroxyethyl, 2-cyanoethyl, carbamoylmethyl, or 1-deoxy-2,5-anhydro-d-mannitol-1-yl on the triazole N-2 nitrogen atom were obtained via the DBU-promoted N-alkylation of 3-(pivaloyloxymethyl)-1-[(NH-1,2,3-triazol-4-yl)methyl]thymine with diethyl 3-bromopropylphoshonate, 2-bromoethanol, acrylonitrile, methyl bromoacetate, or 3,4,6-tris(O-benzoyl)-2,5-anhydro-d-mannitol 1-tosylate. The N-2/N-1 regioselectivity of the alkylation varied from 57/43 (methyl bromoacetate) to 97/3 (diethyl 3-bromopropylphoshonate). The 1-substituted-1H-1,2,3-triazoles, when formed in the appreciated amount in the alkylation reaction, were converted into the corresponding 1-substituted-1H-1,2,3-triazolo-nucleosides. The substitution pattern of 2-substituted-2H-1,2,3-triazolo-nucleosides was confirmed by ¹H–¹⁵N HMBC NMR spectra; the triazole nitrogen atoms were identified through their correlations with the triazole exo-cyclic protons.     

An Efficient Protocol for the Synthesis of Novel 1,2,3‐Triazole Substituted 4H‐Chromene Derivatives

A facile and an efficient protocol has been developed for the synthesis of novel 1,2,3‐triazole substituted 4H‐chromene derivatives 4 in single pot by multicomponent reaction of 1,3‐cyclohexanedione, malononitrile and 1‐substituted 1,2,3‐triazole‐5‐aldehyde using potassium carbonate as catalyst.     

Synthesis and DSSC application of novel dendrimers with benzothiazole and triazole units

Synthesis of novel dendrimers with benzothiazole as surface group and triazole as branching unit is achieved through click chemistry. The presence of more number of benzothiazole and triazole units increases the molar absorption coefficient and alters the fluorescence as well as electrochemical behaviors in the dendrimers. Dye-sensitized solar cell (DSSC) studies reveal that dendrimers with more number of benzothiazole and triazole groups exhibit better current generating capacity than the dendrimers with lesser number of benzothiazole and triazole groups. Dendrimer 2b shows the maximum current conversion efficiency (η) of 7.1%.     

Novel triazolopeptides: chirospecific synthesis and conformational studies of proline derived analogs

Replacing the backbone amide function by a heterocyclic bioisostere, [3+2] azide-alkyne cycloaddition has been applied for the construction of biologically relevant peptidomimetics. Starting from aminoalkynoates, triazole formation was accomplished by addition of hydrazoic acid. NMR studies displayed that the newly developed 4,5-triazolopeptides, which incorporate a biomimetic triazole NH-function as polar constraint element, showed a substantially higher tendency to form a cis-prolyl-geometry than a comparable native peptide sequence.     

A fluorescent sensor for Hg and Ag functions as a molecular switch based on click-generated triazole moiety

The novel (S)-BINOL-based sensor 1 incorporating triazole moieties could be obtained by click reaction. The results show that 1 can exhibit excellent fluorescence response behaviors toward Hg²⁺ (selective switching-off) and Ag⁺ (selective switching-on) without interference from other metal ions, which functions as a molecular switch. This work can expand the application of click reaction in design and synthesis of the novel fluorescence sensor molecules.