[290-38-0]  · C3H3N3  · 1,2,4-Triazine  · (MW 81.09)

(electron-deficient heteroaromatic azadiene capable of participation in inverse electron demand Diels-Alder reactions with electron-rich dienophiles1)

Alternate Names: as-triazine; a-triazine; isotriazine.

Physical Data: mp 16-17.5 °C; bp 158 °C; n25D 1.5150.

Solubility: sol CHCl3, THF, dioxane, DMSO.

Form Supplied in: pale yellow oil.

Preparative Methods: 2 a cooled (-75 °C) solution of monomeric Glyoxal (90.0 mmol) in absolute MeOH (200 mL) is added to a solution of formamidrazone hydrochloride (40 mmol) in absolute MeOH (300 mL) at -50 °C. Et3N (200 mmol) is added and the resulting reaction mixture is allowed to stand at 25 °C for 24 h. The MeOH is removed in vacuo at 20 °C and the residue extracted with Et2O (peroxide free, 5×). Vacuum distillation of the residue after evaporation of the Et2O affords 1,2,4-triazine (bp 25-28 °C/0.5 mmHg). Alternative preparations of 1,2,4-triazine have been detailed.2

Handling, Storage, and Precautions: best stored at 0 °C or below. It is stable to acid, less stable to base, and is hygroscopic; should be stored under anhydrous conditions since it reacts slowly with water and protic solvents.

Cycloaddition Reactions.

1,2,4-Triazine (1) is the parent agent representative of a class of synthetically accessible, substituted, electron-deficient 1,2,4-triazines capable of diene 4p participation in inverse electron demand Diels-Alder reactions with electron-rich dienophiles.1 Cycloaddition reactions between 1,2,4-triazine and enamines have been shown to be general and regioselective, and occur with [4 + 2] addition exclusively across C-3/C-6 of the 1,2,4-triazine nucleus with the more nucleophilic carbon of the dienophile attaching to C-3. This cycloaddition reaction is followed by in situ retro-Diels-Alder reaction with loss of N2 and in situ elimination of pyrrolidine to afford 3,4-disubstituted pyridines (eq 1).3 A general pyridine annulation based on a catalytic Diels-Alder reaction has been developed (eq 2),4 and its application in the synthesis of rigid norbornylogous spacers for long-range electron transfer studies has been described (eq 3).5 [4 + 2] Cycloaddition reactions of 1,2,4-triazine with N,O-ketene acetals (eq 4)6 and ynamines (eq 5)7 have also been detailed. However, the cycloaddition reaction of (1) with ynamines generally proceeds through a C-5/N-2 cycloaddition process with subsequent loss of a nitrile to afford substituted pyrimidines (eq 5).1,7

Less nucleophilic alkenes, including b-enamino ketones, b-alkoxy enones, trimethylsilyl enol ethers, and tri-n-butylstannyl enol ethers, are not sufficiently reactive to participate in a Diels-Alder reaction with the parent 1,2,4-triazine.3 Complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus increases its rate of participation in inverse electron demand Diels-Alder reactions (eqs 6-9),8,9 influences the mode of [4 + 2] cycloaddition,1 and controls the observed regioselectivity (eqs 6, 8, and 9)8 (see also Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate).

Related Reagents.

3,6-Diphenyl-1,2,4,5-tetrazine; 1,3,5-Triazine; Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate.

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) Neunhoeffer, H.; Hennig, H. CB 1968, 101, 3592. For an alternative, though indirect preparation, see: (b) Krass, D.; Paudler, W. W. S 1974, 351. (c) Paudler, W. W.; Chen, T.-K. JHC 1970, 7, 767. (d) Paudler, W. W.; Barton, J. M. JOC 1966, 31, 1720.
3. Boger, D. L.; Panek, J. S. JOC 1981, 46, 2179.
4. Boger, D. L.; Panek, J. S.; Meier, M. M. JOC 1982, 47, 895.
5. Golka, A.; Keyte, P. J.; Paddon-Row, M. N. T 1992, 48, 7663.
6. Neunhoeffer, H.; Frühauf, H.-W. LA 1972, 758, 120.
7. Neunhoeffer, H.; Frühauf, H.-W. LA 1972, 758, 125.
8. Burg, B.; Dittmar, W.; Reim, H.; Steigel, A.; Sauer, J. TL 1975, 2897.
9. Barlow, M. G.; Haszeldine, R. N.; Simpkin, D. J. CC 1979, 658.

Dale L. Boger & Minsheng Zhang

The Scripps Research Institute, La Jolla, CA, USA

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