Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

Practical Methylation Procedure for (1H)‐1,2,4‐Triazole

Conversion of (1H)‐1,2,4‐triazole to its sodium salt with methanolic sodium methoxide is followed by reaction with iodomethane. A scalable approach that overcomes problems associated with water‐soluble starting material and water‐soluble product combined continuous extraction (chloroform/water) with a final short‐path distillation under a controlled vacuum to obtain spectroscopically pure 1‐methyl‐1,2,4‐triazole in 63% yield. Adaptation to microwave synthesis conditions, while providing a faster reaction time, offers no product yield or purification advantages over the conventional approach described. Conversions of this product to related derivatives such as 1,4‐dimethyl‐1,2,4‐triazolium iodide and 1‐methyl‐1,2,4‐triazolium hydrochloride are readily achieved.     

A One‐Pot Tandem Ugi Multicomponent Reaction (MCR)/Click Reaction as an Efficient Protecting‐Group‐Free Route to 1H‐1,2,3‐Triazole‐Modified α‐Amino Acid Derivatives and Peptidomimetics

By a one‐pot tandem Ugi multicomponent reaction (MCR)/click reaction sequence not requiring protecting groups, 1H‐1,2,3‐triazole‐modified Ugi‐reaction products 6a – 6n (Scheme 1 and Table 2), 7a – 7b (Table 4), and 8 (Scheme 2) were synthesized successfully. i.e., terminal, side‐chain, or both side‐chain and terminal triazole‐modified Ugi‐reaction products as potential amino acid units for peptide syntheses. Different catalyst systems for the click reaction were examined to find the optimal reaction conditions (Table 1, Scheme 1). Finally, an efficient Ugi MCR+Ugi MCR/click reaction strategy was elaborated in which two Ugi‐reaction products were coupled by a click reaction, thus incorporating the triazole fragment into the center of peptidomimetics (Scheme 3). Thus, the Ugi MCR/click reaction sequence is a convenient and simple approach to different 1H‐1,2,3‐triazole‐modified amino acid derivatives and peptidomimetics.     

A Metal‐Free Three‐Component Reaction for the Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

A metal‐free three‐component reaction to synthesize 1,4,5‐trisubstituted 1,2,3‐triazoles from readily available building blocks, such as aldehydes, nitroalkanes, and organic azides, is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound, which is followed by the 1,3‐dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope, and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.     

Novel Hyperbranched Poly([1,2,3]‐triazole)s Derived from AB2 Monomers by a 1,3‐Dipolar Cycloaddition

Summary: Novel hyperbranched poly([1,2,3]‐triazole)s were synthesized from several AB₂ monomers by a 1,3‐dipolar cycloaddition reaction. The compound 3,5‐bis(propargyloxy)benzyl azide was polymerized thermally at room temperature leading to 1,4‐ and 1,5‐disubstituted poly([1,2,3]‐triazole) and catalytically leading only to the 1,4‐disubstituted poly([1,2,3]‐triazole). Only the thermal reaction led to fully soluble products. The AB₂ monomers containing an internal alkyne A unit could be autopolymerized thermally under mild reaction conditions leading to soluble, high‐molecular‐weight hyperbranched poly([1,2,3] triazole)s. All products were characterized by detailed NMR investigations.

Synthesis route for polymers 8a and 8b .     

Click To Bind: Metal Sensors

The copper‐catalyzed azide–alkyne “click” cycloaddition reaction is an efficient coupling reaction that results in the formation of a triazole ring. The wide range of applicable substrates for this reaction allows the construction of a variety of conjugated systems. The additional function of triazoles as metal‐ion ligands has led to the click reaction being used for the construction of optical sensors for metal ions. The triazoles are integral binding elements, which are formed in an efficient modular synthesis. Herein, we review recent examples of triazoles as a metal‐binding element in conjugated metal‐ion sensors.     

Stabilization of the Cysteine‐Rich Conotoxin MrIA by Using a 1,2,3‐Triazole as a Disulfide Bond Mimetic

The design of disulfide bond mimetics is an important strategy for optimising cysteine‐rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4‐disubstituted‐1,2,3‐triazole bridge, are described. Sequential copper‐catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.     

One‐Pot Consecutive Catalysis by Integrating Organometallic Catalysis with Organocatalysis

The present study integrates two types of catalysis, namely, organometallic catalysis and organocatalysis in one reaction pot. In this process, the product of the first catalytic cycle acts as catalytic component for next catalytic cycle. The abnormal N‐heterocyclic carbene–copper‐based organometallic catalyst acts as an efficient catalyst for a click reaction to provide triazole, which, in turn, acts as an efficient organocatalyst for different organic transformations, for example, aza‐Michael addition and multicomponent reactions, in a consecutive fashion in the same reaction pot.     

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.     

Nucleophilic Iron Complexes in Proton‐Transfer Catalysis: An Iron‐Catalyzed Dimroth Cyclocondensation

The nucleophilic iron complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) is an active catalyst in C?H‐amination but also in proton‐transfer catalysis. Herein, we describe the successful use of this complex as a proton‐transfer catalyst in the cyclocondensation reaction between azides and ketones to the corresponding 1,2,3‐triazoles. Cross‐experiments indicate that the proton‐transfer catalysis is significantly faster than the nitrene‐transfer catalysis, which would lead to the C?H amination product. An example of a successful sequential Dimroth triazole–indoline synthesis to the corresponding triazole‐substituted indolines is presented.     

Supported benzimidazole‐salen Cu(II) complex: An efficient,versatile and highly reusable nanocatalyst for one‐pot synthesis of hybrid molecules

A novel and efficient nanocatalyst consisting of benzimidazole‐salen Cu(II) complex on surface‐modified silica (BS‐Cu(II)@SiO₂) was prepared. The heterogeneous nanocatalyst was characterized by FESEM, TEM, EDX, FT‐IR, XRD, ICP, and TGA. The nanocatalyst was used for the one‐pot synthesis of some target hybrid molecules. An efficient four component C–H bond activation/[3 + 2] cycloaddition and condensation/cyclization/aromatization sequence toward triazole‐benzimidazole derivatives is disclosed. This methodology provides a general and rapid synthetic route to some new triazole‐benzimidazole hybrids under mild reaction conditions. In addition, the heterogeneous nanocatalyst can be easily separated from the reaction mixture and used several times without noticeable leaching or loss of its catalytic activity. We believe this interesting one‐pot reaction as well as benzimidazole‐salen Cu(II) complex pave the way to the design and synthesis of other new hybrid molecules and metal catalysts, respectively.     

An Efficient Synthesis of Some New Isolated and Fused Triazole Derivatives

A facile and efficient route to 5‐hydrazinyl‐3‐phenyl‐3H‐[1,2,4]triazole 2 from the reaction of triazol‐3‐one 1 and hydrazine hydrate is described. In addition, the formation of isolated and fused triazole derivatives was prepared via reaction of 2 with some selected electrophilic reagents in basic medium.     

Mercury(II) Chloride‐Mediated Desulphurization of Amidinothioureas: Synthesis and Antimicrobial Activity of 3‐Amino‐1,2,4‐triazole Derivatives

The synthesis of 3‐amino‐1,2,4‐triazole via mercury(II) chloride‐mediated cyclization of amidinothiourea is described. This procedure offers a general and efficient route to synthesize the title compound by 3 + 2 annulation reaction. On the basis of the literature precedence, the mechanism for the formation of 3‐amino‐1,2,4‐triazole is proposed. When the synthesized compounds were tested for their antimicrobial activity showed promising inhibition against tested microbes.     

Acid Catalyzed tert‐Butylation and Tritylation of 4‐Nitro‐1,2,3‐triazole: Selective Synthesis of 1‐Methyl‐5‐nitro‐1,2,3‐triazole via 1‐tert‐Butyl‐4‐nitro‐1,2,3‐triazole

4‐Nitro‐1,2,3‐triazole was found to react with tert‐butanol in concentrated sulfuric acid to yield 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole as the only reaction product, whereas tert‐butylation and tritylation of 4‐nitro‐1,2,3‐triazole in presence of catalytic amount of sulfuric acid in benzene was found to provide mixtures of isomeric 1‐ and 2‐alkyl‐4‐nitro‐1,2,3‐triazoles with predominance of N2‐alkylated products. A new methodology for preparation of 1‐alkyl‐5‐nitro‐1,2,3‐triazoles from 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole via exhaustive alkylation followed by removal of tert‐butyl group from intermediate triazolium salts was demonstrated by the example of preparation of 1‐methyl‐5‐nitro‐1,2,3‐triazole.     

Iron‐Catalyzed C(sp2)H and C(sp3)H Arylation by Triazole Assistance

Modular 1,2,3‐triazoles enabled iron‐catalyzed C? H arylations with broad scope. The novel triazole‐based bidentate auxiliary is easily accessible in a highly modular fashion and allowed for user‐friendly iron‐catalyzed C(sp²)? H functionalizations of arenes and alkenes with excellent chemo‐ and diastereoselectivities. The versatile iron catalyst also proved applicable for challenging C(sp³)? H functionalizations, and proceeds by an organometallic mode of action. The triazole‐assisted C? H activation strategy occurred under remarkably mild reaction conditions, and the auxiliary was easily removed in a traceless fashion. Intriguingly, the triazole group proved superior to previously used auxiliaries.     

Efficient Synthesis of Some New 1,3,4‐Thiadiazoles and 1,2,4‐Triazoles Linked to Pyrazolylcoumarin Ring System as Potent 5α‐Reductase Inhibitors

The current study in this article concerned with construction of five‐membered heterocycles with multiple heteroatoms as nitrogen and sulfur from readily available starting materials and reagents. Treatment of 1‐(2‐oxo‐2H‐chromene‐3‐carbonyl)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one with each of phenylisothiocyanate in alcoholic potassium hydroxide and carbon disulfide in basic medium gave rise to a thioanilide and methylthio derivatives, respectively. Treatment of the latter compounds with a variety of hydrazonoyl halides resulted in construction of thiadiazole moiety linked to pyrazole ring. Furthermore, triazole derivatives were synthesized from the thioanilide derivative through its reaction with methyl iodide followed by reaction with hydrazonoyl halides. 5α‐Reductase inhibition activity for the prepared compounds was investigated against the reference drug anastrozole, and the results showed that the inhibition activity of compounds 5g and 11g is more potent than anastrozole. Also compounds bearing triazole moiety is more potent than compounds bearing thiadiazole one. Moreover, the anti‐prostate cancer screening anti‐androgenic bioassay in human prostate cancer cells for the tested compounds was evaluated, and the results showed great inhibition growth and potential antiandrogens.     

On the Mechanism of Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition

The copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4‐disubstituted‐1,2,3‐triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring‐formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pK_a values and an inclination to engage in π‐backbonding with copper(I), azides with ancillary copper‐binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne‐involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.     

Hydrazononitriles as Precursors for 4‐aminotriazoles and 3‐aminoisoxazoles: One Pot Synthesis of triazolo[1,5‐a]quinazoline Derivatives

The reaction of various hydrazononitriles with hydroxylamine hydrochloride yielded various products, namely, 3‐aminoisoxazolone, 3‐amino‐1,2,4‐triazole and 4‐amino‐1,2,3‐triazole derivatives depending on the nature of substituents.     

A Dual‐Response [2]Rotaxane Based on a 1,2,3‐Triazole Ring as a Novel Recognition Station

Two novel multilevel switchable [2]rotaxanes containing an ammonium and a triazole station have been constructed by a Cu^I‐catalyzed azide–alkyne cycloaddition reaction. The macrocycle of [2]rotaxane containing a C6‐chain bridge between the two hydrogen bonding stations exhibits high selectivity for the ammonium cation in the protonated form. Interestingly, the macrocycle is able to interact with the two recognition stations when the bridge between them is shortened. Upon deprotonation of both [2]rotaxanes, the macrocycle moves towards the triazole recognition site due to the hydrogen‐bond interaction between the triazole nitrogen atoms and the amide groups in the macrocycle. Upon addition of chloride anion, the conformation of [2]rotaxane is changed because of the cooperative recognition of the chloride anion by a favorable hydrogen‐bond donor from both the macrocycle isophthalamide and thread triazole CH proton.