Amine-catalyzed synthesis of N2-sulfonyl 1,2,3-triazole in water and the tunable N2-H 1,2,3-triazole synthesis in DMSO via metal-free enamine annulation

The selective synthesis of N²-sulfonyl and N²-H 1,2,3-triazoles via organocatalytic annulation of enaminone/enaminoester with sulfonyl azide has been realized. The unconventional selectivity providing N²-sulfoyl 1,2,3-triazoles takes place in pure water, wherein the hydrogen bond effect between water and the intermediate resulting from enamine-azide corporation accounts for the novel reaction selectivity. On the other hand, the reactions conducted in DMSO specifi...     

Acidic N-dealkylation in nitrotriazolium salts

New selective synthesis of 1-alkyl-5-nitro-1,2,3-triazoles and 1-alkyl-4-nitro-1,2,3-triazoles has been developed, involving acid N-dealkylation of the relative 4-nitro-1,2,3- and 3-nitro- 5-R-1,2,4-triazolium salts. The assortment of novel 1-alkyl- 4(5)-nitro-1,2,3-triazoles has been thus essentially expanded. Treatment of relative 3-nitro-1,2,4-triazolium salts with HCl or HBr proceeds mostly as S_N^ipso-substitution of the nitro group.     

Preparation of new gem-difluoro heterocyclic-fused 1,2,3-triazole derivatives

Starting from easily accessible gem-difluoropropargylic derivatives a cascade nucleophilic substitution by N₃^–, followed by an intramolecular 1,3 dipolar cycloaddition, afforded in fair to good yields new 1,2,3-triazoles fused to pyrrolidines or piperidines. These molecules, with a gem-difluoro group vicinal to the triazoles, are fluorinated analogues of bioactive heterocycles. In parallel, a few open chain analogues have been prepared in order to evaluate the possible role of the bicyclic core on the biological properties of such molecules.     

One-pot facile synthesis,crystal structure and antifungal activity of 1,2,3-triazoles bridged with amine-amide functionalities

A library of twenty five 1,2,3-triazoles bridged with amine-amide functionalities have been synthesized from reaction of N-substituted(prop-2-yn-1-yl)amines (2a–2e), 2-bromo-N-arylacetamides (4a–4e) and sodium azide through copper(I)-catalyzed alkyne-azide cycloaddition. The synthesized compounds were characterized by using FTIR, ¹H NMR, ¹³C NMR, and HRMS techniques. The structures of synthesized 5a (CCDC 1569245) and 5h (CCDC 1569249) were also confirmed by X-ray crystallography. Antifungal evaluation of newly synthesized triazoles was carried out against – Candida albicans and Aspergillus niger. Biological screening of synthesized 1,2,3-triazoles revealed moderate to good antifungal activity against tested strains.     

Synthesis of derivatives of 5-amino-4-acyl-1,2,3-triazole, 8-azapurine,and 1,2,3-triazolo[4,5-b]pyridin-7-one using N,N-acetals of acylketenes and tosylazide

By reaction of N,N-acetals of acylketenes with tosylazide there were synthesized 5-amino-4-acyl-1,2,3-triazoles substituted at the endo(N¹)- or exocyclic nitrogen atom. Triazoles containing a free NH₂ group were used in the synthesis of the corresponding 8-azapurines and 4-acetyl-5-benzoylamino-1,2,3-triazole afforded 2-methyl-2H,4H-1,2,3-triazolo[4,5-b]pyridin-7-one.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1392–1397, June, 1990.     

Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case

Per-O-acetylated β-d-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe₃ which was then acylated to N-acyl-β-d-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(β-d-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide–alkyne cycloadditions. Deprotection of these products by the Zemplén method furnished β-d-Glc_p-NHCO-R derivatives as well as 1-(β-d-Glc_p)-4-R-1,2,3-triazoles which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides versus triazoles with the same R group displayed similar inhibition constants. X-ray crystallographic studies on the enzyme–inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compounds a different orientation of the aromatic part and changes in the conformation of the 280s loop were observed. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided.     

Design and Synthesis of New 5-aryl-4-Arylethynyl-1H-1,2,3-triazoles with Valuable Photophysical and Biological Properties

Cu-catalyzed 1,3-dipolar cycloaddition of methyl 2-azidoacetate to iodobuta-1,3-diynes and subsequent Suzuki-Miyaura cross-coupling were used to synthesize new triazoles derivatives: 5-aryl-4-arylethynyl-1H-1,2,3-triazoles. Investigation of their optical properties by using UV absorption and fluorescence emission spectroscopies revealed that all molecules possess fluorescence properties with the values of the Stokes shift more than 100 nm. The photophysical behavior of the two most promising triazoles in polar and non-polar solvents was also studied.     

Direction of glycosylation of 5-substituted 4-chloro-1,2,3-triazoles

The structures of previously obtained nucleosides of 5-substituted 4-chloro-1, 2,3-triazoles were refined by means of high-resolution mass spectrometry and ¹³C NMR spectroscopy. It is shown that fusion of 5-substituted 4-chloro,1,2,3-triazoles with tetra-0-acylribofuranoses in the presence of di(p-nitrophenyl) phosphate leads to the formation of 2-nucleosides of the corresponding triazoles. The signals of the carbon atoms in the ¹³C NMR spectra of the 4,5-di-substituted triazoles and their nucleosides were assigned.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 937–940, July, 1987.     

Alkylation of 4(5)-nitro-1,2,3-triazole with alcohols in strongly acidic media

Alkylation of 4(5)-nitro-1,2,3-triazole with alcohols in concentrated H₂SO₄ occurs at all three endocyclic N atoms, giving a mixture of isomeric N(1)-, N(2)-, and N(3)-alkyl-4-nitro-1,2,3-triazoles (alkyl is isopropyl, sec-butyl, and cyclohexyl). The selectivity of the alkylation depends on the alcohol used. The most selective alkylation is provided at the N(2) atom when isopropyl (81%) and sec-butyl alcohols are used (67%). With an increase in the reaction time, also in the order isopropyl-, sec-butyl-, and cyclohexyl-4-nitro-1,2,3-triazoles, the N(2)-isomers undergo isomerization into N(1)-alkyl-4-nitro-1,2,3-triazoles. In all the cases, the fraction of the N(3)-substitution products in the mixtures is 6–30%.     

C-(β-d-Glucopyranosyl)formamidrazones,formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study

Synthesis of O-perbenzoylated 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, precursors of potent inhibitors of glycogen phosphorylase, was studied by ring closures of N¹-acyl-carboxamidrazone type intermediates. Reactions of C-(β-d-glucopyranosyl)formimidate or C-(β-d-glucopyranosyl)formamidine with acid hydrazides as well as acylation of C-(β-d-glucopyranosyl)formamidrazone by acid chlorides unexpectedly gave the corresponding 1,3,4-oxadiazoles instead of 1,2,4-triazoles. The desired triazoles were obtained in reactions of C-(β-d-glucopyranosyl)formamidine or C-(β-d-glucopyranosyl)formyl chloride with arenecarboxamidrazones, and also in acylations of N¹-tosyl-C-(β-d-glucopyranosyl)formamidrazone with acid chlorides. Theoretical calculations (B3LYP and M06-2X DFT with the standard 6-31G(d,p) basis set) on simple model compounds with methyl and phenyl substituents to understand the bifurcation of the ring closure of N¹-acyl-carboxamidrazones indicated that in general the reaction led to 1,2,4-triazoles. However, the probability of the 1,3,4-oxadiazole forming pathway was shown to be significantly higher with N¹-benzoyl-acetamidrazones, which were closest analogues of the intermediates resulting in C-glucosyl-1,3,4-oxadiazoles. It was thereby demonstrated that the substitution pattern of the N¹-acyl-carboxamidrazones played a fundamental role in determining the direction of the ring closing reaction.     

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.     

Directed regioselective ortho,ortho′-magnesiations of aromatics and heterocycles using sBu2Mg in toluene

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base sBu₂Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several double ortho,ortho′-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes.

A toluene solution of sBu₂Mg allowed a regioselective ortho-magnesiation of aromatic and heterocyclic systems. A second ortho,ortho′-functionalization was achieved in the case of aryl oxazolines, N-aryl pyrazoles as well as N-aryl triazoles.     

Synthesis of phthalan and phenethylamine derivatives via addition of alcohols to rhodium(II)-azavinyl carbenoids

1-Sulfonyl-1,2,3-triazoles undergo inter- and intramolecular 1,3-OH insertion with rhodium(II)-azavinyl carbenoid intermediates upon treatment with a rhodium(II) catalyst. Products of this transformation contain a synthetically versatile N-(2-alkoxyvinyl)sulfonamide, enabling divergent reactivity toward several N-protected phenethylamine derivatives under various conditions. Notably, products with a phthalan framework can be accessed directly from 4-aryl-1-sulfonyl-1,2,3-triazoles bearing a pendant alcohol.     

Efficient synthesis of 5-fluoroalkylated 1H-1,2,3-triazoles and application of the bromodifluoromethylated triazole to the synthesis of novel bicyclic gem-difluorinated 1H-pyrano[3,4-d][1,2,3]-triazol-4-one compounds

A series of 5-fluoroalkylated 1H-1,2,3-triazoles were synthesized in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of (Z)-ethyl 3-fluoroalkyl-3-pyrrolidino-acrylates with aryl or benzyl azides. In the cases of benzyl azides, addition of Na₂CO₃ was crucial for a high yield of the triazoles. Tetrakis(dimethylamino)ethylene (TDAE) promoted reaction of bromodifluoro-methylated triazole with aldehydes affording a new class of β,β-difluoro-β-triazolyl alcohol derivatives, which were lactonized with catalytic amount of p-toluenesulfonic acid in toluene at 80-90°C to give a series of novel bicyclic gem-difluorinated 1H-pyrano[3,4-d][1,2,3]-triazol-4-one compounds in good yield.     

Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition

The solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of polymer-bound azides to various alkynes is reported. Polymer-bound azides were synthesized from polymer-bound halides and sodium azide and reacted with alkynes to produce polymer-bound 1,2,3-triazoles. Cleavage of the triazoles was performed with trifluoroacetic acid. A traceless synthesis of 1,2,3-triazoles was developed using 2-methoxy-substituted resin (polymer-bound 4-hydroxy-2-methoxybenzyl alcohol). In addition, a synthesis of 4-hydroxybenzyl-substituted 1,2,3-triazoles from the bromo-Wang resin (4-(bromomethyl)phenoxymethyl polystyrene) was achieved.     

Synthesis of 2(5H)-Furanone Derivatives with Symmetrical and Unsymmetrical Bis-1,2,3-triazole Structure

The interesting bioactivities of 2(5H)-furanone, 1,2,3-triazole, and amino acid derivatives have promoted their combination into one multifunctional molecule. The symmetrical bis-1,2,3-triazoles and mono-1,2,3-triazoles with one free azide group are synthesized respectively by controlling the molar ratio of reactants, N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl ester and 1,4-diazidobutane. The unsymmetrical bis-1,2,3-triazoles are afforded by the subsequent reaction of mono-1,2,3-triazoles with other terminal alkynes with good to excellent yields in a short time under the same mild “click” reaction conditions. The 32 new compounds obtained in the reactions are characterized by Fourier transform infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Because of the diversity of four or five basic units in molecule, this methodology provides easy access to different chiral 2(5H)-furanone compounds with polyheterocyclic structure, especially with unsymmetrical bis-1,2,3-triazole moiety. Importantly, a simple approach is provided for the synthesis of unsymmetrical bis-1,2,3-triazoles using common diazides.     

Identification of 4,5-unsymmetrically substituted l-amino- and 1-(N-arylacetylamino)-1,2,3-triazoles by 13C-NMR

¹³C nmr chemical shifts are used for the structural assignment of isomeric 1-amino-1,2,3-triazoles and 1-(N-arylacetylamino)-1,2,3-triazoles unsymmetrically substituted with phenyl, methyl or hydrogen in the 4,5-positions of the triazole ring. A signal at 11 ± 0.6 ppm indicates a 4-methyl triazole derivative, whereas a signal at 7.9 ± 1 ppm indicates a 5-methyl triazole. A signal at 120 ± 0.5 ppm (C-5) indicates a hydrogen in the 5-position (unsubstituted triazole).     

ZrCl4-mediated synthesis of 1,2,3-triazoles from vinyl nitrates and their biological evaluation

A ZrCl₄-mediated simple method for the conversion of vinyl nitrates to 1,2,3-triazoles in excellent yields is developed. The obtained new triazoles were evaluated for their antimicrobial activity.     

Tandem Knoevenagel-[3+2] cycloaddition-elimination reactions: one-pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles

Sodium azide has been found to catalyse Knoevenagel condensation between aromatic aldehyde and cyano compound with active methylene hydrogens and this has led to a successful route for the one pot synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles from aldehydes through Knoevenagel-[3+2]cycloaddition-elimination sequence. In the formation of 5-aryl-2H-1,2,3-triazole-4-carbonitrile derivatives, the reaction has been found to occur efficiently in water.     

DFT calculations of CH acidity of substituted triazoles and experimental study of their ability to undergo mercuration

The CH acidity of all possible N-methyl substituted nitrotriazoles as well as of some 4-substituted 1,2,3-triazoles and N-alkyl-4-nitro-1,2,3-triazoles in the gas phase and in THF and DMSO solution has been calculated with the density functional theory B3LYP method. Electronic effects of substituents on the CH acidity of 4-substituted 1,2,3-triazoles have been examined using linear free energy relationship (LFER) methodology. In order to investigate the relation between the CH acidity of the heterocycles and their ability to undergo electrophilic substitution involving C-H bond cleavage, we have studied the reaction of isomeric N-alkyl-4-nitro-1,2,3-triazoles (alkyl=methyl, ethyl, isopropyl and tert-butyl) with HgBr₂ in alkali solution. It was found that 1-isomers undergo mercuration readily, while mercuration of 2-substituted compounds do not occur under the same conditions, which is in agreement with the results of DFT calculations of the CH acidity of the compounds, showing that 2-isomers have considerably lower CH acidity than 1-isomers.