[6830-78-0]  · C14H10N4  · 3,6-Diphenyl-1,2,4,5-tetrazine  · (MW 234.28)

(an electron-deficient heteroaromatic azadiene capable of participation in inverse electron demand cycloaddition reactions with a wide range of dienophiles1)

Alternate Name: diphenyl-s-tetrazine.

Physical Data: mp 195 °C.

Solubility: sol toluene, CH2Cl2, MeOH; insol H2O.

Form Supplied in: carmine-red needles.

Preparative Method: 2 a mixture of benzonitrile (84 mmol) and 95% hydrazine (100 mL) is heated at 100 °C for 72 h. The resulting orange-yellow solid is broken up, washed with H2O, air dried, ground to a fine powder, and added to 100 mL of 10% acetic acid. Small portions of sodium nitrite are added to this solution while warming at 100 °C for 1 h. The red solid thus produced is collected, washed with H2O, and recrystallized from EtOH.

Handling, Storage, and Precautions: stable at rt.

Cycloaddition Reactions.

3,6-Diphenyl-1,2,4,5-tetrazine (1) is one of the oldest and most extensively studied electron-deficient heteroaromatic azadienes capable of participation in inverse electron demand Diels-Alder reactions with a wide range of dienophiles and heterodienophiles including electron-rich, neutral, strained, and electron-deficient alkenes, alkynes, dienes, enol ethers, enamines, ynamines, ketene acetals, enolates, benzynes, amidines, imines, and azirines.1 These cycloaddition reactions occur exclusively across C-3/C-6 of the 1,2,4,5-tetrazine nucleus and are accompanied by a retro Diels-Alder reaction with extrusion of N2 to afford substituted 4,5-dihydro-1,2-diazines (eq 1),3 their 1,4-dihydro tautomers (when possible) (eq 2),4 or substituted 1,2-diazines (pyridazines) when the dienophiles are alkynes (eq 3)4 or contain leaving groups capable of elimination with aromatization (eqs 4 and 5).5,6 Aromatization of the dihydro-1,2-diazines may also be effected by subsequent oxidation of the alkene [4 + 2] cycloadducts for dienophiles which lack a built-in leaving group (eq 6).7

Imines and amidines often cycloadd to 3,6-diphenyl-1,2,4,5-tetrazine through their more reactive tautomeric enamine and N,N-ketene aminal forms, respectively (eqs 7 and 9).8,9 Cycloaddition of imines and amidines with (1) with reaction of the C=N double bond takes place when such tautomerization is not accessible (eqs 8 and 10).8,10 Cycloadditions with azirines result in ring-expanded products derived from [3,3]-sigmatropic rearrangement of a dihydro-1,2-diazine intermediate followed by [1,5]-hydrogen shift (eq 11).11 Ring expansion has also been observed with other strained dienophiles (eqs 12 and 13).12 In addition, the 4p participation of 3,6-diphenyl-1,2,4,5-tetrazine in [4 + 1] and [6 + 4] cycloaddition reactions has also been described.13

Despite the extensive studies with 3,6-diphenyl-1,2,4,5-tetrazine and its broad range of reactivity toward a wide spectrum of dienophiles, synthetic applications of this reagent are limited due to the presence of the phenyl substituents which are incompatible with many synthetic targets. However, a large number of 1,2,4,5-tetrazines with a range of substituents are available1b,14 and many are amenable to further synthetic manipulations for specific applications. One notable example is the development of a general approach to the preparation of substituted indoles and indolines through use of the sequential [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-1,2,4,5-tetrazine.15 The application of a 1,2,4,5-tetrazine -> 1,2-diazine -> indole synthetic strategy based on the use of 3,6-bis(methylthio)-1,2,4,5-tetrazine in the total synthesis of cis- and trans-trikentrin A (2) and (3) has been detailed (eq 14).16

Related Reagents.

Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate; 4-Methyl-1,2,3-triazine; 1,2,4-Triazine; 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; Pergamon: Oxford, 1984; Vol. 3, pp 531-572. (c) Boger, D. L. CRV 1986, 86, 784. (d) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987.
2. (a) Guither, W. D.; Coburn, M. D.; Castle, R. N. H 1979, 12, 745. (b) Abdel Rahman, M. O.; Kira, M. A.; Tolbe, M. N. TL 1968, 3871. (c) Pinner, A. CB 1893, 26, 2132.
3. Hartmann, K.-P.; Heuschmann, M. AG 1989, 101, 1288.
4. Carboni, R. A.; Lindsey, R. V., Jr. JACS 1959, 81, 4342.
5. (a) Roffey, P.; Verge, J. P. JHC 1969, 6, 497. (b) Sauer, J.; Mielert, A.; Lang, D.; Peter, D. CB 1965, 98, 1435.
6. (a) Marcelis, A. T. M.; Van der Plas, H. C. JHC 1987, 24, 545. (b) Möhrle, H.; Dwuletzki, H. CB 1986, 119, 3600.
7. De Meijere, A.; Koenig, B. HCA 1992, 75, 901.
8. Berger, U.; Dannhardt, G.; Obergrusberger, R. AP 1982, 315, 428.
9. Figeys, H. P.; Mathy, A.; Dralants, A. SC 1981, 11, 655.
10. (a) Figeys, H. P.; Mathy, A. TL 1981, 22, 1393. (b) Takahashi, M.; Hikita, Y.; Fukui, M. H 1989, 29, 1379.
11. (a) Anderson, D. J.; Hassner, A. CC 1974, 45. (b) Takahashi, M.; Suzuki, N.; Igari, Y. BCJ 1975, 48, 2605.
12. (a) Haddadin, M. J.; Agha, B. J.; Salka, M. S. TL 1984, 25, 2577. (b) Anastassiou, A. G.; Girgenti, S. J. AG 1975, 87, 842. (c) Anastassiou, A. G.; Reichmanis, E. CC 1976, 313. (d) Battiste, M. A.; Barton, T. J. TL 1967, 1227.
13. (a) Kümmell, A.; Seitz, G. TL 1991, 32, 2743. (b) Imming, P.; Mohr, R.; Müller, E.; Overheu, W.; Seitz, G. AG 1982, 94, 291. (c) Möhrle, H.; Dwuletzki, H. CZ 1987, 111, 9. (d) Sasaki, T.; Kamematsu, K.; Kataoka, T. JOC 1975, 40, 1201.
14. Neunhoeffer, H.; Wiley, P. F. Chemistry of Heterocyclic Compounds; Wiley: New York, 1978; Vol. 33, pp 1075-1109.
15. Boger, D. L.; Sakya, S. M. JOC 1988, 53, 1415.
16. Boger, D. L.; Zhang, M. JACS 1991, 113, 4230.

Dale L. Boger & Minsheng Zhang

The Scripps Research Institute, La Jolla, CA, USA

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