An expedient and new synthesis of pyrrolo[1,2-b]pyridazine derivatives

The reaction of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide with tertiary butyl carbazate and subsequent condensation of the resulting carbamate derivative with a chalcone provided a facile new approach to pyrrolo[1,2-b]pyridazine derivatives.

As a part of our continued interest in the development of new synthetic methods for highly substituted pyrrole and indole derivatives [27,28], we have developed a new synthetic route to pyrrolo [1,2-b]pyridazines through a hitherto unprecedented approach from a BOC-protected 1-aminopyrrole derivative and α,β-unsaturated ketones.
To substantiate the proposed mechanism, the amine 8 was independently prepared from compound 3 by treatment with 33% hydrobromic acid in acetic acid at 30 °C followed by reaction with 4a in the presence of I 2 (0.05 equiv) in refluxing ethyl alcohol to provide alkenyl imine 9, which was characterized on the basis of its mass, 1 H and 13 C NMR, DEPT, and IR spectral data. Compound 9 was heated in toluene in the presence of p-TSA for 10-12 h and the resulting compound was found to be Scheme 2: Plausible mechanistic pathway.
identical to product 6a. Hydrolysis of the amide group and subsequent decarboxylation was carried out on pyrrole derivative 15 to afford the 2,3-diaryl pyrrole derivative 16 (Scheme 3).
With a view to extending this protocol to aliphatic systems such as α,β-unsaturated ketones, carbamate 3 was treated with crotonaldehyde under similar conditions. However, the alkenyl imine analogue 9 thus obtained did not undergo further reaction. This may be due to the +I effect of alkyl groups, whereas in the case of aryl groups (−M effect) the olefinic carbon is electron deficient and therefore cyclization is favorable.  To aromatize the pyrrolopyridazine ring system, the compound 6a was heated in the presence of p-TSA in toluene at 110 °C for 25.0 h and the resulting compound to yield 4,7-bis-(4fluorophenyl)-5-isopropyl-2,6-diphenylpyrrolo[1,2-b]pyridazine (17a, Scheme 4). Other pyrrolopyridazine derivatives 6a-j were converted into corresponding dehydro derivatives 17a-j under similar conditions (Table 2).

Conclusion
In conclusion, a facile new approach has been developed for the synthesis of pyrrolo[1,2-b]pyridazine derivatives from commercially available and environmentally friendly chemicals. This newly developed method offers quick access to building blocks for various products with pyrrolo[1,2-b]pyridazine cores.