J . Org. Chem. 1994,59,8284-8287
8284
A Simple Route to Unsymmetrically Substituted 1,2,4,S-Tetrazines Stephen C. Fields,",?Marshall H. Parker,* and W. Randal Ericksono Departments of Weed Management, Crop Disease Management, and Process Research, Discovery Research, DowElanco, Dow Venture Center, 9330 Zionsville Road, Indianapolis, Indiana 46268-1054 Received August 8, 1994
"here is interest in the synthesis of 3,6-(disubstituted)1,2,4,54etrazines 1 because they can be readily converted to triazines, pyridazines, and other heterocycles via a [4 21 cycloaddition with the appropriate dienophile followed by expulsion of molecular nitrogen (cycloreversion) and re-aromatization.' Our interest in tetrazines similarly stemmed from a desire to use them to access substituted pyridazines. We required a 6-tert-alkyl-3amino-1,2,4,5-tetrazine(2)as our precursor. While there
Me) gave 1%6and 3%' yields from readily available starting materials. We report herein a simple procedure for preparing multigram quantities of the title compounds, including 2a,in 15-33% yield. In most syntheses of 1,2,4,5-tetrazinesdescribed in the literature, ring formation proceeds through an intermediate such as 3,4,and/or 5. In such cases, when R is a sterically demanding substituent, the hydrazide carbon becomes less accessible and side reactions dominate. Specifically, when Y and/or Z is capable of nucleophilic attack (e.g. SH, OH, NHR), this atom initiates B-membered ring formation to give 6.394 If X is sufficiently electron-donating, however, N-aminotriazoles 7 can result.4
+
R q = Y F X
R
:~:=y+~
N-N
~2
N-N
are many preparations of symmetrically substituted tetrazines,2 few general preparations exist for unsymmetrically substituted (Rf X in 1)t e t r a z i n e ~ . ~ -Of l ~the preparations that exist, we could find no synthetically useful methods for preparing 6-alkyl-3-heteroatom substituted tetrazines when the alkyl substituent was tertiary. For example, the only reported preparations of 3-amino-6-tert-butyl-1,2,4,5-tetrazine 2a (R = R' = R2 = +
6 a: Y-S b: Y - 0 C: Y-NH
2
1
Department of Weed Management.
7
Werbel and co-workers circumvented formation of 7 by employing S-methylisothiocarbonohydrazide salt 9 as a bis-aminoguanidine equivalent in the preparation of 6-aryl-3-aminotetrazines12 from the dithiobenzoate esters 8 (eq l h 3 In this case, the methylthio group served to deactivate the internal latent guanidine nitrogens for cyclization4as well as to provide a handle for subsequent amination.**
*8 Department of Crop Disease Management. Department of Process Research.
(1)For a review, see: Boger, D. L. Tetrahedron 1985, 39, 2869. Hetero Diels-Alder Methodology in Organic Synthesis; Boger , D., Weinreb, S., Eds.; Academic Press, Inc.: New York, 1987. (2) For example: (a)Cohen, V. I. J.Heterocycl. Chem. 1978,15,1113 and references cited therein. (b) Boger, D.; Coleman, R.; Panek, J. J. Org. Chem. 1985,50, 5377. (3)For an excellent overview of the varied approaches and side reactions in synthesis of 6-alkyl- or 6-aryl-3-(methylthio)-1,2,4,5tetrazines, see: Werbel, L.; McNamara, J.; Colbry, N.; Johnson, J.; Degnan, M.; Whitney, B. J. Heterocycl. Chem. 1979, 16, 881 and references cited therein. (4) Dithiolbenzoate esters 8 react with S-methylisothiocarbonohydrazide hydroiodide (9) to form dihydrotetrazines 10 followed by oxidation to (methy1thio)tetrazines11: Esmail, R.; Kurzer, F. J. Chem. Soc., Perkin Trans. I1975, 1787. (5) Takimoto, H. H.; Denault, G. C. Tetrahedron Lett. 1966, 5369. (6)Application of the Takimoto and Denault method5 to the t e e butyl case found in ref 4 experimental. (7) Counotte-Potman, A.; van der Plas, H. C. J.Heterocycl. Chem. 1981, 18, 123. (8) 3-Aminotetrazines via amination of 3,6-bis(methylthio)-1,2,4,5tetrazine: (a) Mangia, A.; Bortesi, F.; Amendola, U. J. Heterocycl. Chem. 1977, 14, 587. (b) Johnson, J.; Whitney, B.; Werbel, L. J. Heterocycl. Chem. 1980, 17, 501. (9) 3-Alkyl-6-aryltetrazines: (a) Demus, D.; Krucke, B.; Kuschel, F.; Nothnick, H. U.; Pelzl, G.; Zaschke, H. Mol. Cryst. Liq. Cryst. 1980, 56,115. (b) Lang, S. A.; Johnson, B. V.; Cohen, E. J.Heterocycl. Chem. 1975,12, 1143. (10) 6-Aryl-3-halotetrazines:Grakauskas, V.; Tomasewski, A.; Horwitz, J. J.Am. Chem. SOC.1958,80, 3155. (11)3,6-Diaryltetrazines: Brooker, P.; Parsons, J.; Reid, J.; West, P. Pestic. Sci. 1987, 18, 179. (12) Imidate esters have been reacted with (a) formamidine acetate Foster-Verner, P. and hydrazine to give 3-aryltetrazines [Meresz, 0.; A. J. Chem. Soc., Chem. Commun. 1972, 9511 and (b) with Smethylisothiocarbonohydrazide salts to give 6-aryl and secondary 6-alkyl-3-methylthiotetrazines [Just, M.; Thalmann, F. German (East) Patent, DD290011 A5910516; Chem. Abstr. 1982,115, 185. (13)Scott, E. S.; Audrieth, L. F. J . Org. Chem. 1964,19, 1231.
12
11
However, significant quantities of thiadiazole 6a were still produced from the alternative competitive cyclization of Y or Z = SH in the presumed intermediate 4a or Sa (X= SMe). For our studies, we surmised that reaction of a tert-alkyl dithiocarboxylic ester would promote even more formation of 6a at the expense of formation of dihydrotetrazine owing to the increased steric encumbrance at the thiocarbonyl carbon. Thus, we sought to remove the potential for this competitive cyclization by starting with a carboxylic acid equivalent (13)such that Y and 2 in an intermediate like 5a is alkylated and cannot initiate deleterious cyclizations to give byproducts such as 6 (eq 2). r
1
v,i
x, = OR', SR', NW2
0022-3263/94/1959-8284$04.5QIQ0 1994 American Chemical Society
14
J. Org. Chem., Vol. 59, No. 26, 1994 8286
Notes Preliminary success was obtained using triethyl orthoformate (16a), triethyl orthoacetate (16b) and dimethylformamide dimethyl acetal (16a). Oxidation was performed in situ by either bubbling air through the reaction vessel (only in the case of R = H)or by adding HzOz, Brz, or NaN02/CF&OzH. Column chromatography afforded a modest yield of tetrazines 17a,b, whose bright red color is characteristic of this class of tetrazines (eq 3). OMe
Rk;;: or
OMe k O M e R NMe2
1) 9 EtOH EtsN,A
2) IO1
15
R
