Abstract
Despite the poor reputation of electron-deficient pyridazines in intermolecular Hetero Diels-Alder (HDA) reactions, 4,5-dicyanopyridazine (DCP) showed a surprising reactivity as a heterocyclic azadiene in inverse electron-demand HDA processes with different dienophiles. The use of alkenes, alkynes and enamines as 2π electron counterparts afforded dicyanocyclohexa-1,3-dienes and substituted phthalonitriles, respectively, while the use of suitable bis-dienophiles provides a general strategy for the one-pot synthesis of polycyclic carbo- and hetero-cage systems through pericyclic three-step homodomino processes. HDA reactions with heterocyclic dienophiles allowed direct benzoannelation: in particular, pyrrole and indole derivatives were converted to dicyano-indoles and -carbazoles. In addition an unprecedented reactivity of DCP as a very reactive heterocyclic electrophile at the C-4 carbon was also evidenced: by changing the experimental conditions, cyanopyrrolyl- and cyanoindolyl-pyridazines were obtained through reactions of pyrrole and indole systems as carbon nucleophiles in formal SNAr2 processes where a CN group of DCP acts as leaving group. Thus, careful control of the reaction conditions allows exploitation of both pathways for the synthesis of different classes of heterocyclic derivatives.
Highlights
Pyridazine and its benzo derivatives have been known since the nineteenth century, but interest in these compounds was quite limited compared to other nitrogen heterocycles, like for instance the pyrimidines, because only a few examples of naturally occurring 1,2-diazines have been reported
According with the most significant aspects of reactivity of DCP, namely as heterocyclic electron-poor azadiene in inverse electron-demand Hetero Diels-Alder (HDA) reactions and heterocyclic electrophile in formal nucleophilic aromatic substitutions SNAr2, this review is organized into four parts concerning the synthesis of DCP (Section 2), Hetero Diels-Alder reactions (Section 3), nucleophilic aromatic substitutions (Section 4), and synthetic applications (Section 5)
Phthalonitriles, key building blocks for the synthesis of phthalocyanines whose importance is associated to manifold applications in different fields of material science, are generally obtained by multistage elaboration of aromatic precursors
Summary
Pyridazine and its benzo derivatives have been known since the nineteenth century, but interest in these compounds was quite limited compared to other nitrogen heterocycles, like for instance the pyrimidines, because only a few examples of naturally occurring 1,2-diazines have been reported. Analogous domino processes of DCP with different bis-dienophiles have been exploited for direct access to polyfunctionalized carbo- and hetero-cage compounds, often isolated in high yields as sole reaction products (Table 1, entries 1–8) [28,29]. Allowed evaluation of the higher reactivity of DCP as an azadiene in inverse electron-demand HDA reactions with respect to other electron-poor 1,2-diazines: a previous study concerning different pyridazine derivatives reported that only the highly activated tetramethyl pyridazine-3,4,5,6tetracarboxylate was able to react with COD, in more drastic conditions (150 °C), affording the corresponding cage system in only 19% yield [17]. Isolated yields. c Phthalonitrile, formed by competitive elimination of methacrylic acid from the corresponding cyclohexadiene intermediate, was recovered in 39% yield. d Reaction performed at 70 °C for 6 days to isolate the cyclohexadiene intermediate converted into the cage system by heating at 110 °C for 9 days. e Competitive aromatization of the corresponding cyclohexadiene intermediates afforded minor amounts of substituted phthalonitriles. f Reactions performed with 1.1 equiv. of reagent to reduce the formation of by-products
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