1,2,3-Triazine 1-Oxides Are a Productive Platform for Synthetic Methodologies 

Abstract

This graphical review provides a concise overview of the synthesis and uses of 4-carboxylato-1,2,3-triazine 1-oxides in diverse syntheses, especially of heterocyclic compounds. Prepared in high yields from reactions between vinyldiazoacetates and tert-butyl nitrite, these triazines undergo nucleophilic substitution reactions, generally at the 6-position with the loss of dinitrogen or nitrous oxide, to form diverse products. Deoxygenation to 1,2,3-triazines, inverse-electron-demand Diels–Alder reactions, borohydride-induced 1,4-hydrogen addition, and syntheses of new diazo compounds are among the new processes that have been uncovered. This review serves as an indicator for future applications.

Keywords

nucleophilic addition - heterocycles - deoxygenation - cycloaddition - inverse-electron-demand Diels–Alder reaction - triazines - diazo compounds

Biosketches

Luca De Angelis received his PhD from the University of Texas at San Antonio (UTSA) under the supervision of Prof. Doyle in 2022. During his PhD years he worked on metal-catalyzed transformations with diazo compounds and on the synthesis and synthetic applications of triazine 1-oxides. In 2023, he joined the Medicinal Chemistry Core Facility of the Center for Innovative Drug Discovery at UTSA as Research Associate.

Michael P. Doyle is currently Emeritus Professor, having been the Rita and John Feik Distinguished University Chair in Medicinal Chemistry at the University of Texas at San Antonio since 2014. He is a graduate of the College of St. Thomas and Iowa State University, has had academic appointments at undergraduate institutions (Hope College and Trinity University) and graduate universities (University of Arizona and University of Maryland), as well as being Vice President, then President, of a science foundation (Research Corporation) before coming to UTSA. He is the recipient of numerous awards, the latest being the 2020 Henry J. Albert Award from International Precious Metals Institute for his research in dirhodium(II) chemistry. An early pioneer in transition-metal-catalyzed reactions of diazo compounds, his research group’s efforts uncovered effective methodologies for asymmetric catalysis and heterocyclic syntheses.

1,2,3-Triazines are versatile templates for the synthesis of heterocyclic compounds.[1] Their applications have provided convenient syntheses to other heterocyclic compounds.[2] However, convenient methods for their synthesis are limited, and available procedures severely restrict their structural diversity.[3]

1,2,3-Triazine-N-oxides are commonly obtained by peracid oxidations of 1,2,3-triazines,[4] but they suffer from low functional group tolerance, overoxidation, lack of regiocontrol, and multiple byproducts (Figure [1]). Recently, a simple and highly selective synthesis of 4-carboxylato-1,2,3-triazine 1-oxides by treatment of vinyldiazoacetates with alkyl nitrites has been reported.[5] Nitrosylation occurs at the vinylogous position of vinyldiazoacetates, and the resulting vinyldiazonium ion does not lose dinitrogen but, rather, is trapped by the nucleophilic nitrogen of the nitroso group to form the 4-carboxylate of the 1,2,3-triazine 1-oxide. These 1,2,3-triazine 1-oxides are thermally unstable above 60 °C and form isoxazoles by the extrusion of dinitrogen in very high yield and as the sole product.[5] These heterocycles are also conveniently deoxygenated to 1,2,3-triazines by trialkyl phosphites[6] (Figure [2]). This effective methodology delivers 1,2,3-triazines in high yield, and represents an alternative method to those that show structural limitations and multistep effort.[1] Triazine 1-oxides also undergo highly selective nucleophilic reactions, mainly by nucleophilic Michael addition to the 6- or 4-position that generally results in ring opening with the loss of dinitrogen or nitrous oxide to obtain highly functionalized heterocyclic and oxime compounds[7] (Figure [3]).

Like 1,2,3-triazines, 1,2,3-triazine 1-oxides undergo inverse-electron-demand Diels–Alder (IEDDA) reactions that provide access to a wide variety of heterocyclic compounds, but 1,2,3-triazine 1-oxides appear to react at a faster rate and with greater breadth of reactions than do comparable 1,2,3-triazines[7] [8] (Figure [4]). In an intriguing contrast, 1,2,3-triazine 1-oxides, in reactions with β-keto esters promoted by cesium carbonate, extrude nitrous oxide in IEDDA reactions that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reactions are performed in the presence of other alkali metal carbonates or organic bases[9] (Figure [5]). The 4-carboxylates of 1,2,3-triazine 1-oxides undergo [3+2]-cycloaddition with highly strained alkynes that, following extrusion of dinitrogen, form isoxazole-3-propenoate derivatives in high yields and diastereocontrol[10] (Figure [6]). In addition, nucleophiles from deprotonation of diazomethyl compounds having diverse electron-withdrawing groups react with 4-carboxylato-1,2,3-triazines at the 6-position to extrude dinitrogen and produce diazovinyl keto esters with five or six linear contiguous sp²-hybridized carbons, whereas these same nucleophiles react with 4-carboxylato-1,2,3-triazine 1-oxides, also at the 6-position, to form pyrazolines with the expulsion of nitrous oxide and cyanocarboxylate.[11] According to DFT calculations, the mechanism pathways between triazine 1-oxide/triazine and diazomethyl compounds diverge following nucleophilic addition at the 6-position (Figure [7]). 1,2,3-Triazine 1-oxides with an sp³-C–H bond at the 5-position also undergo base-catalyzed Dimroth-type rearrangement to form multiply substituted oximidovinyldiazoacetates in high yields at or below room temperature, and these diverse vinyldiazo compounds undergo catalytic metal carbene transformations to produce oximidovinylcyclopropanes, α-oximidovinyl-α-amino acids and α-hydroxy acids, as well as tricyclic indole derivatives in high yields and enantioselectivities[12] (Figure [8]). Overall, 1,2,3-triazine 1-oxides provide a highly productive platform for new synthetic methodologies and the design and development of heterocyclic compounds.

Figure 1 Synthesis of 1,2,3-triazine 1-oxides.

Figure 2 Deoxygenation and thermal denitrogenation of 1,2,3-triazine 1-oxides.

Figure 3 H-, N-, O-, and S-nucleophilic addtion to 1,2,3-triazine 1-oxides.

Figure 4Inverse-electron-demand Diels–Alder (IEDDA) cycloaddition with 1,2,3-triazine 1-oxides.

Figure 5Pyridine versus pyridone formation – the ‘Cesium Effect’.

Figure 6 Strain-driven [3+2] cycloaddition of triazine 1-oxides with arynes/cyclooctyne.

Figure 7Diverse outcomes from nucleophilic reactions with diazomethyl compounds.

Figure 8 1,2,3-Triazine 1-oxides undergo rearrangement to oximidovinyldiazo compounds.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 06 August 2025

Accepted after revision: 15 September 2025

Accepted Manuscript online:
13 October 2025

Article published online:
30 October 2025