[77202-08-5]  · C4H5N3  · 4-Methyl-1,2,3-triazine  · (MW 95.12)

(an electron-deficient heteroaromatic azadiene capable of participation in inverse electron demand Diels-Alder reactions with electron-rich dienophiles employed for preparation of substituted pyridines1)

Physical Data: mp 31 °C.

Solubility: sol CHCl3, CH2Cl2, EtOH.

Form Supplied in: plates (i-Pr2O).

Preparative Method: an ice-cold solution of 0.01 mol of N-amino-5-methylpyrazole in 30 mL of CH2Cl2 and 10 mL of H2O is treated with 0.02 mol of solid Sodium Periodate or potassium periodate with stirring. The resulting mixture is allowed to stir at 0-5 °C overnight and then extracted repeatedly with CHCl3. The CHCl3 phase is dried over Na2SO4, concentrated, and purified by recrystallization or column chromatography on silica gel.2

Handling, Storage, and Precautions: stable at room temperature and is probably hygroscopic.

Cycloaddition Reactions.

4-Methyl-1,2,3-triazine (1) is an electron-deficient heteroaromatic azadiene that has been shown to participate in inverse electron demand Diels-Alder reactions. It is capable of reacting with electron-rich dienophiles including pyrrolidine enamines and ynamines in a regioselective fashion to give, after a retro Diels-Alder reaction with loss of N2 and in situ elimination of pyrrolidine, 2,3,6-trisubstituted pyridines (eqs 1 and 2).3,4 Cycloaddition occurs across N-3/C-6 of the 1,2,3-triazine nucleus and the nucleophilic carbon of the dienophile attaches to C-6 of the 1,2,3-triazine. The utility of this reagent has been demonstrated in the total syntheses of fabianine (eq 3)5 and guaipyridine (eq 4).6 A change in the mode of cycloaddition and/or loss of regioselectivity have been observed in reactions conducted under more vigorous conditions (eqs 5 and 6).7,8

Related Reagents.

Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate; 3,6-Diphenyl-1,2,4,5-tetrazine; 1,2,4-Triazine; 1,3,5-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 369-384. (c) Boger, D. L. CRV 1986, 86, 781. (d) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987.
2. (a) Okatani, T.; Koyama, J.; Tagahara, K. H 1989, 29, 1809. (b) Ohsawa, A.; Arai, H.; Ohnishi, H.; Itoh, T.; Kaihoh, T.; Okada, M.; Igeta, H. JOC 1985, 50, 5520.
3. Sugita, T.; Koyama, J.; Tagahara, K.; Suzuta, Y. H 1985, 23, 2789.
4. Neunhoeffer, H.; Clausen, M.; Vötter, H.-D.; Ohl, H.; Krüger, C.; Angermund, K. LA 1985, 1732.
5. Sugita, T.; Koyama, J.; Tagahara, K.; Suzuta, Y. H 1986, 24, 29.
6. Okatani, T.; Koyama, J.; Tagahara, K.; Suzuta, Y. H 1987, 26, 595.
7. Okatani, T.; Koyama, J.; Suzuta, Y.; Tagahara, K. H 1988, 27, 2213.
8. Itoh, T.; Okada, M.; Nagata, K.; Yamaguchi, K.; Ohsawa, A. CPB 1990, 38, 2108.

Dale L. Boger & Minsheng Zhang

The Scripps Research Institute, La Jolla, CA, USA

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