The preparation of highly substituted pyridazines via a tethered imine-enamine (TIE) procedure

1,2,4,5-Tetrazines can be converted directly into cyclo-annelated pyridazines via an inverse electron demand Diels-Alder procedure incorporating tethered imine-enamine (TIE) methodology. This methodology provides an improved one-pot preparation of such compounds, eliminating the need for either the preformation of the enamine or a separate aromatisation step, and has been applied to 4 tetrazines producing 11 pyridazines.


Introduction
2][3][4][5] This procedure was greatly improved by Boger et al. who developed modifications which enabled the enamine 2 to be prepared in situ. 2 With more substituted examples, however, the final elimination/aromatisation step of intermediate 4 can prove problematic and a separate oxidation/Cope elimination may be required to complete the sequence.2b,3,4 To overcome this problem, we developed the tethered-imine-enamine (TIE) procedure shown in Scheme 2. 4 Thus, N-methylethylenediamine on treatment with two equivalents of a ketone in situ produces imine-enamine 7 which, after reaction with 1,2,4-triazine 1 and subsequent retro-Diels-Alder reaction, generates the tethered imine 8a.We envisage the imine acting as a tethered base to facilitate conversion into the corresponding pyridine 5 by promoting an E1cb mechanism or epimerising adjacent to the amine leaving group to enable an antielimination to take place.We also conjectured that the zwitterionic species 8a' could be present to some extent thus enhancing the basic nature of the tethered imine (and mimicking the N-oxide intermediate in the Cope elimination).† Richard Taylor was Chairman of the RSC Heterocyclic Group during the period 1999-2001 Retro-Diels-Alder Elimination Toluene, ∆, 4Å mol.sieves

Scheme 2
Whatever the validity of the mechanistic speculation shown in Scheme 2, the TIE procedure was successfully utilised to prepare a wide range tri-, tetra-and penta-substituted pyridines 5 in high yields. 4In 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.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 cyclooctanone giving the corresponding pyridazines 11-14 in high yields (85-97%, entries i-iv) under TIE conditions, a considerable improvement over the published 5h,6 procedure in terms of both operational simplicity and yields.Tetrazine 9 also underwent reaction with 3-coumaranone to give pyridazine 15 in 95% yield by a one-pot process (entry v): the reported 5c procedure for the preparation of 15, not only requires preformation of the enamine (derived from pyrrolidine and 3-coumaranone), but also requires a second aromatisation step, giving 15 in a 60% overall yield.
Table 1.Reactions of 3,6-diphenyl-1,2,4,5-tetrazine ( 9) with ketones (6.0 equiv.)and Nmethylethylenediamine (3.0 equiv.) in refluxing toluene Having successfully demonstrated the TIE procedure to be an improved method for the direct conversion of tetrazine 9 into highly substituted pyridazines, we went on to explore the scope of the reaction in terms of the tetrazine (Table 2).Atfah has reported the reaction of commercially available 3,6-di-2-pyridyl-1,2,4,5-tetrazine (16) with the enamines derived from cyclohexanone, cycloheptanone and cycloctanone but utilising a three-step synthesis (enamine formation, cycloaddition and aromatisation).5h The requirement for a discrete aromatisation step provided an opportunity to apply our TIE procedure to this more challenging substrate.As can be seen (entries i-iii), pyridazines 17-19 were obtained in yields of 41%, 71% and 30%, respectively, via the one-pot process using refluxing xylene as solvent (the yields in toluene were considerably lower).The reaction of tetrazine 16 with cyclopentanone and Nmethylethylenediamine, failed to give corresponding pyridazine product.
Table 2. Reactions of tetrazines with carbonyl compounds (6.0 equiv.)and Nmethylethylenediamine (3.0 equiv.)Finally, we went on to extend the TIE procedure to the one-pot preparation of pyridazines 20, 22 and 24 from tetrazines 16, 21 7 and 23 8 and phenylacetaldehyde (Table 2, entries iv-vi).In these examples, the reactions were complete in 3-5 minutes on being heated in toluene.In the case of tetrazine 21 (entry v), pyridazine 22 was obtained with complete regioselectivity (as indicated by 1 H NMR spectroscopy [δ 8.00 ppm (1 H, d, J = 2.0 Hz) and 9.42 ppm (1 H, d, J = 2.0 Hz)]. 10 In summary, we have successfully extended the TIE methodology to prepare di-, tri-and tetra-substituted pyridazines, some annelated, from the corresponding 1,2,4,5-tetrazines in a onepot process.This procedure does not require the use of pre-formed enamines, or a separate aromatisation step, and in many examples gives almost quantitative yields of the pyridazine products.

Experimental Section
General Procedures.Tetrazines 21 7 and 23 8 were prepared according to literature procedures.All other reagents and solvents were of commercial grade.NMR spectra were recorded on Jeol EX270 or Jeol ECX400 instruments and were recorded in CDCl 3 .Melting points were determined on a Gallenkamp melting point apparatus.