The azaphilic addition of organometallic reagents on tetrazines: scope and limitations q Ja ´nos Farago ´, a Zolta ´n Nova ´k, a Gitta Schlosser, b Antal Csa ´mpai a and Andra ´s Kotschy a, * a Department of General and Inorganic Chemistry, Eo ¨tvo ¨s Lora ´nd University, Pa ´zma ´ny Pe ´ter s. 1/A, Budapest H-1117, Hungary b Chemical Research Center, Hungarian Academy of Sciences, PO Box 32, H-1525 Budapest, Hungary Received 23 October 2003; revised 4 December 2003; accepted 8 January 2004 Abstract—A series of tetrazines were reacted with organometallic reagents. Depending on the nature of the metal azaphilic addition, reduction of the tetrazine or simple complex formation was the predominant transformation and usually high selectivity was observed. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction The chemistry of tetrazines has gained increased attention in the last few decades, 1 due mostly to their applications in organic synthesis, 2 crop protection 3,4 and materials science. 5 Their basic structural feature, the electron- deficient heterocyclic core, is the key to their most extensively utilized transformation, the ‘inverse electron- demand’ Diels – Alder reaction, that provides an attractive route to pyridazines, 6–8 pyrroles, 9 and other condensed 10,11 and strained heterocyclic ring systems. 12 Another charac- teristic feature of the electron deficient aromatic ring is its reactivity towards nucleophiles that has been utilized in the preparation of non-symmetrically substituted tetrazines through their addition onto the ring 13 or substitution of leaving groups, such as chloro, 14,15 methylthio 16,17 or dimethylpyrazolyl 15,18,19 with nitrogen, oxygen or sulfur nucleophiles. The analogous reactions introducing carbon nucleophiles would also be of synthetic importance, but there are only a few know examples utilizing potassium cyanide 15 or malonates. 20,21 The cross-coupling reactions on tetrazines, also recently reported have only a limited scope. 22 The use of reactive carbon nucleophiles, such as organo- lithium or Grignard reagents in an attempt to substitute 3,6- bis(methylthio)tetrazine led to the addition of the organic group onto a ring nitrogen atom. 23 The transformation, coined ‘azaphilic addition’ is quite unprecedented for other heterocycles, but had been reported previously for 3,6- diphenyltetrazine too. 24 – 27 A common feature of the published reactions is that they utilize either organolithium or Grignard reagents, and apparently no rationalization has been provided so far for this unusual transformation. To explore the generality of this reaction we decided to react a series of tetrazines with organometallic reagents. In the light of the fact that on the same tetrazine soft carbanions can initiate nucleophilic substitution, 20,21 while hard carbanions give azaphilic addition selectively, 23 we also wanted to explore the territory between this two ‘extremes’. We planed to achieve this aim by reacting a series of organometallic reagents containing different metal residues with a tetrazine that is capable of undergoing nucleophilic substitution. 2. Results and discussion The first tetrazine selected to test the generality of the azaphilic route was 3,6-bis(3 0 ,5 0 -dimethylpyrazolyl)-tetra- zine (1). The choice of 1 was based on two facts: the ease and economy of its preparation 28 and its well documented reactivity towards nitrogen and oxygen nucleophiles. 5,14,18,19 The first experiments, including the reaction of butyl- lithium, phenyllithium and phenylmagnesium chloride (Table 1, entries 1–3) with 1, led to the formation of 1-butyl-1,4-dihydro-3,6-bis(dimethylpyrazolyl)tetrazine (6a) or 1-phenyl-1,4-dihydro-3,6-bis(dimethylpyrazolyl)- tetrazine (6b) in good yield, if the reaction mixtures were quenched at 278 8C, supporting the generality of the azaphilic pathway. On prolonged standing of the reaction mixture on air or letting it warm to room temperature, the yield of 6a decreased considerably, especially when organolithium reagents were used. In entry 1, the formation 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.01.013 Tetrahedron 60 (2004) 1991–1996 q Supplementary data associated with this article can be found in the online version, at doi: 10.1016/j.tet.2004.01.013 Keywords: Tetrazines; Azaphilic addition; Aromatic nucleophilic substitution; Reduction. * Corresponding author. Tel.: þ36-1-209-0555; fax: þ36-1-209-0602; e-mail address: kotschy@para.chem.elte.hu