Recent advances and applications in 1,2,4,5-tetrazine chemistry (2023)

Pyrethrum-based insecticides have remained ideal for domestic and agricultural pest control due to the efficacy and environmentally favourable qualities of the active ingredients, the natural Pyrethrins. However, the propensity of the natural Pyrethrins to degrade with heat, light and oxygen affects their long-term storage and subsequent effectiveness as an insecticide. Whilst a number of processing and storage countermeasures have been implemented, efforts have recently been made to synthetically modify the pyrethrin scaffold with particular focus on functionality that is sensitive to these degradative processes. This work describes an investigation of the Diels-Alder reactivity of pyrethrin I and II and its potential to produce stabilised pyrethrin derivatives. Initial exploration into normal electron demand Diels-Alder cycloadditions of pyrethrin I and II found that the reactions did not proceed even under forcing conditions. However, a series of pyrethrin derivatives were obtained from the inverse electron demand Diels Alder reaction employing these natural products as dienophiles and electron-deficient 1,2,4,5-tetrazines as dienes.

Despite the explosion of interest in heterocyclic azadienes, 1,2,3,5-tetrazines remain unexplored. Herein, the first general synthesis of this new class of heterocycles is disclosed. Its use in the preparation of a series of derivatives, and the first study of substituent effects on their cycloaddition reactivity, mode, and regioselectivity provide the foundation for future use. Their reactions with amidine, electron-rich, and strained dienophiles reveal unique fundamental reactivity patterns (4,6-dialkyl-1,2,3,5-tetrazines > 4,6-diaryl-1,2,3,5-tetrazines for amidines but slower with strained dienophiles), an exclusive C4/N1 mode of cycloaddition, and dominant alkyl versus aryl control on regioselectivity. An orthogonal reactivity of 1,2,3,5-tetrazines and the well-known isomeric 1,2,4,5-tetrazines is characterized, and detailed kinetic and mechanistic investigations of the remarkably fast reaction of 1,2,3,5-tetrazines with amidines, especially 4,6-dialkyl-1,2,3,5-tetrazines, established the mechanistic origins underlying the reactivity patterns and key features needed for future applications.

Herein, the first use of perfluoroalcohol H-bonding in accelerating acyclic azadiene inverse electron demand cycloaddition reactions is described, and its use in the promotion of heterocyclic azadiene cycloaddition reactions is generalized through examination of a complete range of azadienes. The scope of dienophiles was comprehensively explored; relative reactivity trends and solvent compatibilities were established with respect to the dienophile as well as azadiene; H-bonding solvent effects that lead to rate enhancements, yield improvements, and their impact on regioselectivity and mode of cycloaddition are defined; new viable diene/dienophile reaction partners in the cycloaddition reactions are disclosed; and key comparison rate constants are reported. The perfluoroalcohol effectiveness at accelerating an inverse electron demand Diels–Alder cycloaddition is directly correlated with its H-bond potential (pK_a). Not only are the reactions of electron-rich dienophiles accelerated but those of strained and even unactivated alkenes and alkynes are improved, including representative bioorthogonal click reactions.

A new nitrogen-rich energetic complex Cd(DMF)₂BTZAF (1) (DMF= N,N-Dimethylformamide, H₂BTZAF= 3, 3′-bis(1H-tetrazol-5-yl)-4, 4′-azofurazan) was first synthesized by the reaction of Cd(NO₃)₂·4H₂O with 4-amino-3-(5-tetrazolate)-furazan. The compound 1 was characterized by elemental analysis and FT-IR spectrum analysis, respectively. The crystal structure of complex 1 was determined by single-crystal X-ray diffraction. It revealed that 1 crystallizes in the monoclinic space group P2₁/c. A Cd²⁺ ion is coordinated by four N atoms and two O atoms to form a distorted octahedral structure. Among them, four nitrogen atoms are from the four BTZAF²⁻ ions and the other two oxygen atoms are from two DMF molecules. Moreover, the thermal decomposition behavior of compound 1 was studied with DSC and TG-DTG methods. The non-isothermal kinetic parameters of compound 1 was calculated by Kissinger's method and Ozawa-Doyle's method. In addition, the thermal safety performance and the impact sensitivity of complex 1 were measured and calculated, and the results showed that the synthetic compound has good insensitivity and stability.

Symmetrical and unsymmetrical 1,2,4,5-tetrazine derivatives containing 1,3,4-oxadiazole ring were obtained in high yields using commercially-available 4-cyanobenzoic acid, hydrazine hydrate and carboxylic acid chlorides. The few-step transformation involved the Pinner reaction and the subsequent mild oxidation of 1,4-dihydro-1,2,4,5-tetrazines using hydrogen peroxide at room temperature. The obtained compounds exhibited luminescent properties and large quantum yields.

The 1,2,4,5-Tetrazines, or s-tetrazines, are a particular example of small, high nitrogen content heterocycle with extremely original physico-chemical properties. In this review, we summarize the last 20 years of research on this topic, focusing more on fluorescence and related optical properties on tetrazines, and tetrazine derived materials.

Mendeleev Communications, Volume 26, Issue 1, 2016, pp. 66-68

Ecologically friendly transformation of readily accessible plant allylpolyalkoxybenzenes to hardly available aminotetraalkoxybenzenes has been developed. The efficacy of hydrogenation stage is substantially increased by the application of highly porous ceramic block Pd-catalysts featuring a large surface area, low hydraulic resistance, significant thermal and mechanical stabililty, multiple cycling and easy regeneration.

Progress in Heterocyclic Chemistry, Volume 34, 2023, pp. 469-485

This chapter covers work published in the calendar year 2021. The synthesis and reaction chemistry of six-membered heterocycles containing three or four nitrogen atoms and fused ring systems with three or more nitrogen atoms is reviewed.

European Journal of Pharmaceutical Sciences, Volume 91, 2016, pp. 1-10

Generally, heterocycles occupy a prominent place in chemistry due to their wide range of applications in the fields of drug design, photochemistry, agrochemicals, dyes and so on. Among them, indole scaffolds have been found in most of the important synthetic drug molecules and paved a faithful way to develop effective targets. Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds. Among the indole class of compounds, 2-arylindoles appear to be a most promising lead for drug development. The derivatives of 2-arylindoles exhibits antibacterial, anticancer, anti-oxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis activity, etc. This article would provide a clear knowledge on the wide-ranging biological activities of 2-arylindoles over the past two decades, which would be beneficial for the designing of more potent drug targets in order to compete with the existing drugs.

Colloids and Surfaces B: Biointerfaces, Volume 211, 2022, Article 112333

The surface chemistry of the inverse electron-demand Diels-Alder (IEDDA) reaction at the air-water interface is elucidated. Tetrazine (C18-Tz) and norbornene derivatives (C16-NCA) were used as the reactants. Langmuir monolayers of C18-Tz, C16-NCA, and their binary mixtures were prepared on aqueous substrates. The surface properties were analyzed using the surface pressure (π)-molecular area (A) and surface potential (ΔV)-A isotherms, as well as fluorescence microscopy to monitor the progress of the reaction. First, to provide comparison data to evaluate the reaction on the surface, the two components were mixed in stock solutions of organic solvents for the IEDDA reaction. The Langmuir monolayer spread from the reaction solution was characterized as a function of the reaction time. In the subsequent experiments, the Langmuir monolayers were deposited onto the surface of the substrate solutions by spreading from separate stock solutions of C18-Tz and C16-NCA. The variation of the surface behavior of the monolayers with the molecular area, surface composition of the two components, compression speed of the monolayers, and the temperature was studied. We discuss the effects of the air phase in the reaction field on the reaction efficiency by comparing the results obtained from the two methods.

Current Opinion in Chemical Biology, Volume 17, Issue 5, 2013, pp. 753-760

Discussed herein is the development and advancement of trans-cyclooctene as a tool for facilitating bioorthogonal labeling through reactions with s-tetrazines. While a number of strained alkenes have been shown to combine with tetrazines for applications in bioorthogonal labeling, trans-cyclooctene enables fastest reactivity at low concentration with rate constants in excess of k₂=10⁶M⁻¹s⁻¹. In the present article, we describe advances in computation and synthesis that have enabled applications in chemical biology and nuclear medicine.

Journal of Molecular Structure, Volume 1272, 2023, Article 134207

Novel 2-pyridyl-sym-tetrazines (1,2,4,5-tetrazines) bearing a guanidine functional group were synthetized. Their cycloaddition properties were studied in inverse electron demand [4+2] cycloaddition reactions with norbornenes and C₆₀ fullerene. Experimental results were corroborated with density functional theory calculations (DFT) with M06-2X functional. Guanidine sym-tetrazines were found to be reactive towards strained polycyclic alkenes (norbornenes), whereas reactions with C₆₀ fullerene were less successful. Estimated activation energies are in full accordance with experimental findings. Further computational studies of a series of tetrazine derivatives indicated their cycloaddition reactivity and potential synthetic utility.