INVERSE-ELECTRON-DEMAND DIELS-ALDER REACTIONS OF CONDENSED PYRIDAZINES, 5.1 1,4-BIS(TRIFLUOROMETHYL)- PYRIDAZINO[4,5-b]INDOLE AS AN AZADIENE

The pyridazino[4,5-b]indole (3), which is conveniently available from 3-methylthioindole and the tetrazine (2), undergoes thermally induced inverseelectron-demand Diels-Alder reactions with enamines to afford the cycloalkeneannelated carbazoles (7,8) or the 2-substituted carbazole (9), respectively. We have previously shown that 1,2-diazines annelated to a second π-electron-deficient aromatic ring (pyrido[3,4-d]pyridazines, pyridazino[4,5-d]pyridazines) can be successfully utilized as azadienes in inverseelectron-demand (LUMOdiene-controlled) Diels-Alder reactions.1-4 There are also reports in the literature describing similar [4+2] cycloaddition reactions of pyridazines fused with a five-membered heterocycle (imidazo[4,5-d]pyridazines, 1,2,3-triazolo[4,5-d]pyridazines).5,6 In the present paper, we wish to report a convenient synthesis of the title compound (3) and its reaction behavior on treatment with enamines as electron-rich C=C dienophiles. The isolation of 1,4-bis(trifluoromethyl)pyridazino[4,5-b]indole (3) in 26% yield as a reaction product from a cycloaddition/cycloreversion process starting from indole and 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine7 (2) has already been described by Seitz and Mohr.8 As explained by the authors, the low yield results from partial consumption of the tetrazine component as an oxidant for a dihydropyridazino[4,5-b]indole intermediate. In order to elaborate a more efficient synthesis of 3, we tried to overcome this problem by employing as a dienophile an indole derivative with an appropriate leaving group at C-3. Thus, the tetrazine (2) was reacted with an equimolar amount of readily available 3-methylthioindole9,10 (1) in refluxing toluene to afford after spontaneous elimination of molecular nitrogen and methanethiol the tricycle (3) in 58% yield (Scheme 1). As we were also interested in an access to a more electron-deficient derivative of 3, we tried to introduce a methylsulfonyl substituent at N-5. However, treatment of 3 (or its anion, respectively) with methanesulfonyl chloride under various conditions did not effect any conversion. Moreover, an attempted [4+2] cycloaddition reaction of 2 with 1-methylsulfonyl-3-methylthioindole (4) (readily prepared from 1) failed. On the other hand, we found that the tetrazine (2) slowly reacts with 1-methylsulfonylindole11 (5) in refluxing toluene. Here, the product isolated in 26% yield turned out to be the 3,4,6-trisubstituted pyridazine (6). In this case, ring-opening of the intermediate dihydro tricycle obviously is the preferred rearomatization pathway, which is in accordance with previous observations with an analogous N-methyl compound.8