Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate1

[2166-14-5]  · C6H6N4O4  · Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate  · (MW 198.138)

(reactive heteroaromatic azadiene for inverse electron demand Diels-Alder reactions with a wide range of dienophiles and heterodienophiles; used to prepare substituted 1,2-diazines, 1,2,4-triazines, pyrroles, pyridines, indolines, and related condensed heterocycles)

Alternate Name: bis(methoxycarbonyl)-s-tetrazine.

Physical Data: mp 175-177 °C.

Solubility: sol dioxane, CH2Cl2, THF, C6H6; insol H2O.

Form Supplied in: bright red crystalline solid.

Preparative Method: Ethyl Diazoacetate (0.90 mol) is added dropwise to a stirred solution of NaOH (4.0 mol) in 250 mL of H2O at such a rate so as to maintain the temperature of the reaction between 60 and 80 °C. After cooling to 25 °C, the reaction slurry is poured onto 1 L of 95% EtOH, mixed well, and the liquid decanted. This washing procedure is repeated 5 times before the precipitate is collected by filtration, washed with absolute EtOH (0.5 L) and Et2O (0.5 L) sequentially, and air-dried to afford disodium dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate (2) (85-97%).

A stirred slurry of (2) (0.39 mol) in 200 mL of ice-water at 0 °C is treated dropwise with 1.95 equiv of concentrated HCl. The yellow solid formed is immediately collected by suction filtration, washed with cold H2O (50 mL) and Et2O (50 mL) sequentially, and dried at 60 °C overnight to afford dihydro-1,2,4,5-tetrazine-3,6-dicarboxylic acid (3) (72-74%).

The solid (3) (0.16 mol) is added in small portions over 20 min to a stirred solution of SOCl2 (27.5 mL) in dry MeOH (375 mL) at -30 °C. After completion of the addition, the reaction mixture is allowed to warm to 25 °C over 2 h, and then concentrated under reduced pressure. Extraction of the residue with CH2Cl2 (400 mL × 5) from H2O (400 mL) followed by removal of the solvent from the organic phase in vacuo affords dimethyl dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate (4) (44-51%).

Nitrous gases generated by dropwise addition of a 6 N NaNO2 solution (200 mL) to 125 mL of concentrated HCl are bubbled into a stirred slurry of (4) (0.1 mol) in CH2Cl2 (800 mL) at 0 °C using a N2 stream until the addition of NaNO2 solution is complete. The solvent and excess nitrous gases are removed in vacuo to afford dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1) (99%).2

Handling, Storage, and Precautions: dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate is a very reactive diene which is unstable to acid, base, H2O, or protic solvents and should be stored moisture-free and refrigerated.

Cycloaddition Reactions.

Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1) is one of the most reactive heteroaromatic azadienes examined to date and it reacts with a wide range of dienophiles and heterodienophiles including electron-rich, neutral, strained, or electron-deficient alkenes, alkynes, dienes, enol ethers and acetates, enamines, ynamines, ketene acetals, enolates, benzynes, selected aromatics and heteroaromatics, imidates, thioimidates, aldehyde N,N-dimethylhydrazones, imines, azirines, and cyanamides. Extensive reviews have summarized1 and compiled1a the results of such studies. Cycloaddition reactions occur exclusively across C-3/C-6 of the 1,2,4,5-tetrazine nucleus and is accompanied by a retro Diels-Alder reaction with extrusion of N2 to afford substituted dihydro-1,2-diazines (dihydropyridazines) (eq 1),3 or substituted 1,2-diazines (pyridazines) when the dienophiles are alkynes (eq 2),4 or contain leaving groups capable of elimination with aromatization (eqs 3, 4 and 8).3,5 Imines, imidates, and thioimidates prefer to react through their more reactive tautomeric enamine and ketene acetal forms, respectively (eq 5),6 although cycloaddition of the C=N double bond may take place when such tautomerization is blocked (eq 6).7 In selected instances, a preference for C&tbond;N triple bond addition over C=N double bond has been observed (eq 7).8 Recent studies have illustrated the use of selenophene, oxazole, N-methylpyrazole,9 2-vinylindoles,10 and naphthalenes11 as dienophiles and an extensive and complete compilation of relative dienophile reactivities toward dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (Table 1)12 has been described.

Indoline Synthesis.

The 1,2-diazine (pyridazine) products obtained from the Diels-Alder reactions of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1) are poor dienes for further Diels-Alder reactions.13 However, the entropic assistance provided in intramolecular reactions has been utilized to promote their participation in Diels-Alder reactions with unactivated alkynes.14 Thus a general 1,2,4,5-tetrazine -> 1,2-diazine -> indoline strategy based on sequential inverse electron demand Diels-Alder reactions of (1) has been developed and applied to the total synthesis of PDE-I and PDE-II (eq 9),15,16 (+)-CC-1065 (5),17 and related agents.18

Pyrrole Synthesis.

A novel reductive ring contraction reaction of dimethyl 1,2-diazine-3,6-dicarboxylates to provide dimethyl pyrrole-2,5-dicarboxylates19 has been developed and provides an attractive 1,2,4,5-tetrazine -> 1,2-diazine -> pyrrole synthetic strategy (eq 10).20 Successful applications of this strategy in the total syntheses of octamethylporphyrin (6),20 prodigiosin (7) (eq 11),21 and isochrysohermidin (8) (eq 12)22 have been reported.

Pyridine Synthesis.

The triazine products derived from the [4 + 2] cycloaddition reactions of (1) with aryl imidates or aryl thioimidates are themselves electron-deficient heteroaromatic azadienes capable of participation in further regioselective inverse electron demand Diels-Alder reactions. Such triazines have proven useful in the preparation of substituted pyridines (see also Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate and 1,2,4-Triazine). Consequently, a 1,2,4,5-tetrazine -> 1,2,4-triazine -> pyridine synthetic strategy has been developed based on two consecutive [4 + 2] cycloaddition reactions and successfully applied in the total synthesis of streptonigrin (9) (eq 13).23

1. (a) Boger, D. L. T 1983, 39, 2869. (b) Neunhoeffer, H. 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. (e) Boger, D. L. BSB 1990, 99, 599.
2. (a) Boger, D. L.; Panek, J. S.; Patel, M. OS 1991, 70, 79. (b) Boger, D. L.; Coleman, R. S.; Panek, J. S.; Huber, F. X.; Sauer, J. JOC 1985, 50, 5377.
3. (a) Sauer, J.; Mielert, A.; Lang, D.; Peter, D. CB 1965, 98, 1435. (b) Spencer, G. H., Jr.; Cross, P. C.; Wiberg, K. B. JCP 1961, 35, 1939.
4. Neunhoeffer, H.; Werner, G. LA 1973, 437.
5. Gnichtel, H.; Gumprecht, C. LA 1985, 628.
6. (a) Overheu, W.; Seitz, G.; Wassmuth, H. CZ 1989, 113, 188. (b) Seitz, G.; Overheu, W. AP 1977, 310, 963. (c) Berger, U.; Dannhardt, G.; Obergrusberger, R. AP 1982, 315, 428.
7. (a) Boger, D. L.; Panek, J. S. TL 1983, 24, 4511. (b) Roffey, P.; Verge, J. P. JHC 1969, 6, 497.
8. Seitz, G.; Wassmuth, H. CZ 1988, 112, 281.
9. Seitz, G.; Mohr, R.; Hoferichter, R. CZ 1988, 112, 17.
10. (a) Pindur, U.; Kim, M.-H. TL 1988, 29, 3927. (b) Pindur, U.; Pfeuffer, L.; Kim, M.-H. HCA 1989, 72, 65.
11. Seitz, G.; Hoferichter, R. AP 1988, 321, 889.
12. (a) Thalhammer, F.; Wallfahrer, U.; Sauer, J. TL 1990, 31, 6851. (b) Meier, A.; Sauer, J. TL 1990, 31, 6855.
13. (a) Neunhoffer, H.; Werner, G. LA 1973, 1955. (b) Neunhoeffer, H.; Werner, G. LA 1973, 437.
14. Boger, D. L.; Coleman, R. S. JOC 1984, 49, 2240.
15. Boger, D. L.; Coleman, R. S. JACS 1987, 109, 2717.
16. Boger, D. L.; Coleman, R. S. JOC 1986, 51, 3250.
17. (a) Boger, D. L.; Coleman, R. S. JACS 1988, 110, 1321. (b) Boger, D. L.; Coleman, R. S. JACS 1988, 110, 4796.
18. (a) Boger, D. L.; Coleman, R. S. JOC 1988, 53, 695. (b) Boger, D. L.; Coleman, R. S. In Studies in Natural Products Chemistry; Atta-ur-Rahman; Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 301-389. (c) Boger, D. L.; Coleman, R. S.; Invergo, B. J. JOC 1987, 52, 1521. (d) Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. JACS 1989, 111, 6461. (e) Boger, D. L.; Coleman, R. S.; Invergo, B. J.; Sakya, S. M.; Ishizaki, T.; Munk, S. A.; Zarrinmayeh, H.; Kitos, P. A.; Thompson, S. C. JACS 1990, 112, 4623. (f) Boger, D. L.; Wysocki, R. J., Jr.; Ishizaki, T. JACS 1990, 112, 5230.
19. Bach, N. J.; Kornfeld, E. C.; Jones, N. D.; Chaney, M. O.; Dorman, D. E.; Paschal, J. W.; Clemens, J. A.; Smalstig, E. B. JMC 1980, 23, 481.
20. Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D. JOC 1984, 49, 4405.
21. (a) Boger, D. L.; Patel, M. TL 1987, 28, 2499. (b) Boger, D. L.; Patel, M. JOC 1988, 53, 1405.
22. (a) Boger, D. L.; Baldino, C. M. JACS 1993, 115, 11418. (b) Wasserman, H. H.; DeSimone, R. W.; Boger, D. L.; Baldino, C. M. JACS 1993, 115, 8457.
23. (a) Boger, D. L.; Panek, J. S. JACS 1985, 107, 5745. (b) Boger, D. L.; Panek, J. S. JOC 1983, 48, 621.

Dale L. Boger & Minsheng Zhang

The Scripps Research Institute, La Jolla, CA, USA

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