Trisubstituted Triazoles Research Articles

3‐Hydroxypyridinyl‐Substituted‐1,2,4‐Triazoles as New ESIPT Based Fluorescent Dyes: Synthesis and Structure–Fluorescence Properties Correlations

AbstractThis report presents the design, synthesis, and photophysical study of two new series of promising fluorescent trisubstituted triazoles, 3‐hydroxypyridinyl substituted‐1,2,4‐triazoles (PyOHTr) and 2‐pyridonyl substituted‐1,2,4‐triazoles (PyCOTr). An excited state intramolecular proton transfer (ESIPT) fluorescence mechanism is evidenced for PyOHTr molecules by ab initio theoretical calculations. These fluorescent dyes possess unique optical properties such as large Stokes shifts, dual emission, solvatochromism, solid‐state emission and, for one of them, a white light emission, rendering them particularly attractive for future applications in both medicinal chemistry and materials science.

Topochemical Cycloaddition Reaction between an Azide and an Internal Alkyne

AbstractHere we report the synthesis of a trisubstituted‐1,2,3‐triazole‐linked polymer using a topochemical azide‐alkyne cycloaddition (TAAC) reaction. A cyclitol‐derived monomer having an azide and an internal alkyne group was designed. The four hydroxy groups present in this monomer dictate its crystal packing such that the monomer molecules are arranged head‐to‐tail, thereby placing the internal alkyne and the azide units of adjacent molecules proximally. Although the alignment of the reactive groups in the monomer crystal is not favourable for a topochemical reaction, a reactive orientation can be achieved by the rotation of the reactive groups. Upon heating the crystals, the monomer underwent topochemical polymerization to yield the trisubstituted‐1,2,3‐triazole‐linked‐polycyclitol. This study demonstrates a new synthetic strategy for cycloaddition reaction between non‐polarized internal alkynes and azides to yield trisubstituted triazoles.

Topochemical Cycloaddition Reaction between an Azide and an Internal Alkyne.

Here we report the synthesis of a trisubstituted-1,2,3-triazole-linked polymer using a topochemical azide-alkyne cycloaddition (TAAC) reaction. A cyclitol-derived monomer having an azide and an internal alkyne group was designed. The four hydroxy groups present in this monomer dictate its crystal packing such that the monomer molecules are arranged head-to-tail, thereby placing the internal alkyne and the azide units of adjacent molecules proximally. Although the alignment of the reactive groups in the monomer crystal is not favourable for a topochemical reaction, a reactive orientation can be achieved by the rotation of the reactive groups. Upon heating the crystals, the monomer underwent topochemical polymerization to yield the trisubstituted-1,2,3-triazole-linked-polycyclitol. This study demonstrates a new synthetic strategy for cycloaddition reaction between non-polarized internal alkynes and azides to yield trisubstituted triazoles.

Some 3,4,5-Trisubstituted-1,2,4-triazole Synthesis, Antimicrobial Activity, and Molecular Docking Studies

Methyl 4-aminopicolinate 1 interacted with hydrazine hydrate and subsequently with carbon disulfide to produce a triazole thiol derivative, which then reacted with different aldehydes to produce the appropriate Schiff base products. 4a-c. The reaction of Schiff base products 4a-c with benzoyl chloride resulted in the formation of trisubstituted triazoles 5a-c. The spectroscopic studies of the produced chemicals helped to clarify their structures. The antibacterial activity of the produced compounds against various bacterial and fungal strains was tested. Molecular docking studies of newly synthesized 1,2,4-triazoles were also conducted.

Regioselective Synthesis of 1,4,5‐Trisubstituted‐1,2,3‐Triazoles from Aryl Azides and Enaminones

A total regioselective synthesis of 1,4,5‐trisubstituted‐1,2,3‐triazoles from aryl azides and enaminones is reported. The use of an ionic liquid in the presence of water and trimethylamine is crucial for the progress of the reaction. The process, consisting of a cascade starting with a water‐promoted 1,3‐dipolar cycloaddition (in agreement with DFT calculations) followed by a base‐promoted retro‐aza‐Michael reaction, shows a completely different reactivity to previously reported base‐promoted reactions between enaminones and sulfonyl azides only leading to disubstituted triazoles. Such reactivity, reported herein, allows preparation of trisubstituted triazoles in a complete regioselective way.

Effective and Transition‐Metal‐Free Construction of Disubstituted, Trisubstituted 1,2,3‐NH‐Triazoles and Triazolo Pyridazine via Intermolecular 1,3‐Dipolar Cycloaddition Reaction

AbstractAn interesting approach for synthesis of disubstituted‐1,2,3‐(NH) triazoles from easily available raw materials and reagents like substituted acetophenones, iodine, DMSO and NaN3 via intermolecular 1,3‐dipolar cycloaddition reaction. Trisubstituted triazoles and its corresponding triazolo pyridazine could be made easily using this method. These are key intermediates for poly benzodithiophene triazole (PBnDT‐TAZ) for solar cells and 1‐benzyl‐1H‐4,5‐dibenzoyl‐1,2,3‐triazole (BDBT) for corrosion inhibition.

Tri-Substituted Triazole-Enabled C–H Activation of Benzyl and Aryl Amines by Iron Catalysis

The design of trisubstituted triazoles set the stage for proximity-induced iron-catalyzed C-H activation of benzyl and aryl amines with ample scope. Thereby, C-H alkylations and C-H arylations proved viable with high levels of chemo and positional selectivities by means of racemization-free iron catalysis with the reusable triazole being removed in a traceless fashion.

ChemInform Abstract: Regioselective Synthesis of Triazoles via Base‐Promoted Oxidative Cycloaddition of Chalcones with Azides in Aqueous Solution.

A base-promoted oxidative cycloaddition of chalcones with azides in aqueous solution has been developed under transition-metal-free conditions, which provides a green method for the regioselective synthesis of trisubstituted triazoles in good yields.

Cu/Pd-Catalyzed, Three-Component Click Reaction of Azide, Alkyne, and Aryl Halide: One-Pot Strategy toward Trisubstituted Triazoles.

A Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide has been developed. By using this Cu/Pd transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-triazoles were quickly assembled in one step in high yields with complete regioselectivity, just like assembling Lego bricks. Notably, different from the well-established CuAAC click reactions only working on terminal alkynes, this reaction offers an alternative solution for the problem of the click reaction of internal alkynes.

Regioselective synthesis of triazoles via base-promoted oxidative cycloaddition of chalcones with azides in aqueous solution

A base-promoted oxidative cycloaddition of chalcones with azides was developed for the regioselective synthesis of trisubstituted triazoles under transition-metal-free conditions.

ChemInform Abstract: One‐Flask Synthesis of 1,3,5‐Trisubstituted 1,2,4‐Triazoles from Nitriles and Hydrazonoyl Chlorides via 1,3‐Dipolar Cycloaddition.

AbstractThe synthesis of trisubstituted triazoles involves the conversion of nitriles into imidate intermediates followed by 1,3‐dipolar cycloaddition with in situ generated nitrilimines.

Abstract 1626: Novel trisubstituted triazoles modeled from naltrindole inhibit the proliferation of human multiple myeloma cells

Abstract Multiple myeloma (MM) is an invasive plasma cell neoplasm of malignant cells that proliferate in the bone marrow. This incurable cancer is responsible for 10% of all hematological malignancies. The American Cancer Society estimated that in 2011, 11,400 men and 9,120 women were diagnosed with MM in the United States, and 5,770 men and 4,840 women died of the disease. MM is characterized by monoclonal gammopathy, destructive bone disease, renal failure, hypercalcemia, and hematological dysfunction. The molecular pathogenesis of MM is complex. Gene expression profiling and deep genome sequencing has revealed that in many cases, chromosome translocations result in overexpression of growth regulatory genes via their juxtaposition to the immunoglobulin heavy chain locus, activation of the NF-kB pathway, activation of MYC, FGFR3, KRAS, NRAS, and loss of function mutations in the histone H3K27 demethylase gene UTX. Despite the development of new treatment agents in the last decade, including lenalidomide (an immunomodulatory drug) and bortezomib (a proteasome inhibitor), the five-year relative survival rate for MM is approximately 40%. Obviously, there is a great need for additional treatment options. Naltrindole (Nti) is a synthetic alkaloid with the pharmacological profile of a selective delta opioid receptor antagonist. Nti has also been reported to be a potent immunosuppressant. Nti suppresses the allogeneic mixed lymphocyte reaction in vitro and inhibits renal graft rejection in vivo. Subsequently, it was reported that Nti retains its immunosuppressive activity in triple mu/delta/kappa opioid receptor knockout mice, revealing a non-opioid receptor target for the immunosuppressant activity of Nti (Gaveriaux-Ruff et al., 2001). We reported previously (Mundra et al., J. Pharmacol. Exp. Ther. 342: 273-287, 2012), that Nti inhibited human MM cell proliferation in vitro and in a murine xenograft model in vivo, by interaction with a non-opioid receptor target. In the present study, we describe a novel series of triazole-based ligands derived from Nti by rational design (see Peng et al., Bioorgan. & Med. Chem. 17: 6442-6450, 2009) that competed for specific 3H-Nti binding to human U266 MM cells and inhibited MM cell proliferation in vitro. To date, 17 trisubstituted triazoles have been evaluated for their ability to inhibit MM cell proliferation. Following incubation with U266 MM cells for 72 h, the majority of MM triazoles exhibited EC50's in the 10-60 micromolar range. However, 3 of the triazoles displayed EC50's of 300-400 nM. It is hoped that further modification of these lead compounds will yield drugs with even greater efficacy. This study provides a rationale basis for further evaluation of this series of triazoles as anti-MM therapeutic agents. Citation Format: William J. Welsh, Youyi Peng, Jyoti Joshi Mundra, Julianne F. Avrutik, Thomas C. Yoon, Andrew M. Meillier, Richard D. Howells. Novel trisubstituted triazoles modeled from naltrindole inhibit the proliferation of human multiple myeloma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1626. doi:10.1158/1538-7445.AM2014-1626

Enantiopure 1,4,5-trisubstituted 1,2,3-triazoles from carbohydrates: applications of organoselenium chemistry.

A wide range of stable vinyl selenone-modified furanosides has been synthesized for the first time. These 2π-partners undergo 1,3-dipolar cycloaddition reactions with a wide range of organic azides to afford enantiopure trisubstituted triazoles. Furanosyl rings opened up during triazole synthesis to generate polyfunctionalized molecules, ready to undergo further transformations. This strategy is one of the most convenient methods for the synthesis of enantiopure 1,4,5-trisubstituted 1,2,3-triazoles where the chiral components are attached to C-4 or C-5 position of triazole ring. These triazoles are formed in a regioselective manner, and several pairs of regioisomeric triazoles have also been synthesized. The approach affords densely functionalized triazoles, which are amenable to further modifications because of the presence of aldehyde and hydroxyl groups. This powerful and practical route adds to the arsenals of chemists and biologists interested in the synthesis and applications of triazoles.

Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles Amicable for Automation

A three-component 3+2 cycloaddition reaction followed by Suzuki coupling reaction was carried out to synthesize a library of compounds using automation (parallel synthesizer). Scaffolds that are unexplored in literature were used for the synthesis of library. The iodo-triazoles formed by 3+2 cycloaddition reaction were coupled with boronic acids to get tri-substituted triazoles.

Synthesis, characterization, and antioxidant activities of new trisubstituted triazoles

A series of new 4-(3,4dimethoxyphenethyl)-3,5-akyl/aryl-4H- 1,2,4-triazoles (3a-g) were obtained by reaction of ethyl N'-(alkylidene/arylidene)hydrazonate (1) and 2-(3,4-dimethoxy phenyl)ethanamine (2). Compounds 4d, e, and g were synthesized from the reaction of corresponding compounds 3d, e, and g with BBr_3, respectively. The 10 new compounds synthesized were characterized by elemental analyses, IR, ^1H-NMR, and ^{13}C-NMR spectral data. The structure of compound 3g was inferred through IR, ^1H-, ^{13}C-NMR, elemental analyses, and X-ray spectral techniques. In addition, the newly synthesized chemicals were screened for their antioxidant properties. Among the chemicals tested, 4d, e, and g exhibited the highest degree of antioxidant activity.

Microwave‐Assisted Palladium‐Catalyzed Direct Arylation of 1,4‐Disubstituted 1,2,3‐Triazoles with Aryl Chlorides

Treatment of 1,4-disubstituted 1,2,3-triazoles with aryl chlorides in the presence of potassium carbonate under palladium catalysis and microwave irradiation at 250 degrees C for 15 min leads to arylation of the triazole at the 5-position. A variety of functional groups, including ester and hydroxy groups, are compatible. The procedure is suitable for the regioselective preparation of trisubstituted triazoles. Microwave irradiation accelerates the reaction, thus allowing the rapid synthesis of trisubstituted triazoles, which are difficult to synthesize selectively.

Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase

A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.