RSC Heterocyclic Group ARKIVOC 2007 (xi) 37-45
pyridines 5 in high yields.4 In this paper, we report on the extension of the TIE procedure to the preparation of pyridazines from substituted-1,2,4,5-tetrazines.
Results and Discussion
Inverse electron demand Diels-Alder reactions of 3,6-disubstituted-1,2,4,5-tetrazines have received considerable attention,1,5 although reactions with enamines derived from cycloalkanones, leading to pyridazines have been less well explored.5b,5c,5h In order to evaluate the usefulness of the TIE methodology in this area, our first objective was to compare the TIE methodology with standard Boger in situ enamine procedure (Scheme 3). Thus, when the onepot reaction of commercially available diphenyltetrazine 9 with the enamine formed from cyclohexanone and pyrrolidine was carried out, the non-aromatised adduct 10 was obtained as the sole product in 69% yield. Application of the TIE procedure, that is treatment of tetrazine 9 with N-methylethylenediamine and two equivalents of cyclohexanone, resulted in the direct formation of pyridizine 11, in a yield of 85% (Scheme 3). Further optimisation studies indicated that the molecular sieves were not required and that the use of an excess of Nmethylethylenediamine (3 equiv.) and ketone (6 equiv.) sometimes gave improved yields - -these conditions were therefore adopted as standard.
NH
NPh NPh
N
N N
N
PhN Ph
OH 9 10, 69% CHCl3, mol. sieves, ., 20 h 69%
NPh NPh
MeHN NH2 N
N CHCl3, 20 h, 85%
N
Ph N Ph PhMe, 13 h, 85%
2O
11
9
CHCl3 or PhMe mol. sieves, .
Scheme 3
Having successfully prepared pyridazine 11 in a one-step procedure, and having once again demonstrated the efficiency of the TIE procedure in the aromatisation step, we went on to explore the scope of the reaction with respect to the ketone (Table 1). It was established that tetrazine 9 reacts efficiently with a range of cyclic ketones from cyclopentanone to
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