Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate1

[74476-38-3]  · C12H15N3O6  · Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate  · (MW 297.30)

(electron-deficient heteroaromatic azadiene capable of participation in inverse electron demand Diels-Alder reactions employed for the preparation of substituted pyridines)

Physical Data: bp 168-169 °C/1 mmHg, 173 °C/3 mmHg; n26D = 1.4949.

Solubility: sol CHCl3, EtOAc, Et2O; insol H2O.

Form Supplied in: viscous, yellow oil.

Preparative Methods: a solution of ethyl oxalamidrazonate (88 mmol) in absolute EtOH (350 mL) is added dropwise to a stirring solution of diethyl dioxosuccinate (114 mmol) in absolute EtOH (86 mL) at 25 °C under N2. After addition is complete, the stirring is allowed to continue at 25 °C for 16 h before the solution is warmed at reflux for 2 h. The reaction mixture is cooled and the solvent is removed under reduced pressure. Chromatography (SiO2, 10-40% Et2O-hexane gradient elution) affords the pure reagent.2

Handling, Storage, and Precautions: can be stored at 25 °C but is hygroscopic and reacts with protic solvents; should be stored under anhydrous conditions.

Cycloaddition Reactions.

Triethyl 1,2,4-triazine-3,5,6-tricarboxylate (1) is a highly electron-deficient heteroaromatic azadiene capable of participation in inverse electron demand Diels-Alder reactions with a variety of electron-rich dienophiles1 including enamines (eq 1),3 ketene-N,O-acetals (eq 2),4 alkynes (eq 3),5 benzynes,6 benzocyclopropenes (eq 4),7 and indoles (eq 5).8 The reaction is regioselective with the cycloaddition occurring across C-3/C-6 of the 1,2,4-triazine nucleus with the more nucleophilic carbon of the electron-rich dienophile preferentially attaching to C-3 of 1,2,4-triazine (eqs 1 and 2).3,4 A decrease or loss of regioselectivity is observed when the reacting sites in the dienophile become electronically and sterically less distinguishable (eqs 3 and 5).5-8 The reaction is accompanied by a retro Diels-Alder reaction with loss of N2 and in situ aromatization, constituting a general approach to the preparation of substituted pyridines (eqs 1-5). The methodology has been successfully applied (eq 6) in the total syntheses of streptonigrin (2),9 and lavendamycin (3).10

Related Reagents.

Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate; 3,6-Diphenyl-1,2,4,5-tetrazine; 1,3,5-Triazine; 1,2,4-Triazine.


1. (a) Boger, D. L. T 1983, 39, 2869. (b) Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3, pp 385-456. (c) Boger, D. L. CRV 1986, 86, 781. (d) Boger, D. L. BSB 1990, 99, 599. (e) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987.
2. (a) Boger, D. L.; Panek, J. S.; Yasuda, M. OS 1987, 66, 142. (b) Ratz, R.; Schroeder, H. JOC 1958, 23, 1931.
3. Boger, D. L.; Panek, J. S. JOC 1982, 47, 3763.
4. (a) Möhrle, H.; Dwuletzki, H. CB 1986, 119, 3600. (b) Möhrle, H.; Dwuletzki, H. ZN(B) 1987, 42b, 1032.
5. Maggiora, L.; Mertes, M. P. JOC 1986, 51, 950.
6. Gonsalves, A. M. D. R.; Pinho e Melo, M. V. D.; Gilchrist, T. L. T 1992, 48, 6821.
7. (a) Martin, J. C.; Muchowski, J. M. JOC 1984, 49, 1040. (b) Maddox, M. L.; Martin, J. C.; Muchowski, J. M. TL 1980, 21, 7.
8. Benson, S. C.; Gross, J. L.; Snyder, J. K. JOC 1990, 55, 3257.
9. Boger, D. L.; Panek, J. S. JACS 1985, 107, 5745.
10. (a) Boger, D. L.; Panek, J. S. TL 1984, 25, 3175. (b) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. JOC 1985, 50, 5782. (c) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. JOC 1985, 50, 5790.

Dale L. Boger & Minsheng Zhang

The Scripps Research Institute, La Jolla, CA, USA



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