Reactivity and Synthetic Applications of 4,5-Dicyanopyridazine: An Overview

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.

Four Mechanisms in the Reactions of 3-Aminopyrrole with 1,3,5-Triazines: Inverse Electron Demand Diels–Alder Cycloadditions vs SNAr Reactions via Uncatalyzed and Acid-Catalyzed Pathways

“…An analogous S N Ar reaction was observed in the reaction of 1-substituted-2-aminopyrroles with 2,4,5,6-tetrachloropyrimidine; reactions took place at the 3-amino group or at C 2 or C 5 of the pyrrole ring depending on the size of the 1-substituent . In the reaction of pyrrole and 1-methylpyrrole with 4,5-dicyanopyridiazine a S N Ar reaction competed with cycloadditionhere the leaving group was cyanide ion . Reactions of 1 equiv of 2,4,6-trifluoro- or 2,4,6-trichloro-1,3,5-triazine with 3-aminopyrrole ( 1 ) to give 6 , took about the same time (60–90 min) using either method (Table ).…”

“…24 In the reaction of pyrrole and 1-methylpyrrole with 4,5-dicyanopyridiazine a S N Ar reaction competed with cycloadditionhere the leaving group was cyanide ion. 39 Reactions of 1 equiv of 2,4,6-trifluoro-or 2,4,6-trichloro-1,3,5triazine with 3-aminopyrrole (1) to give 6, took about the same time (60−90 min) using either method (Table 1). There did not appear to be an element effect.…”

Synergistic–cooperative combination of enamine catalysis with transition metal catalysis

“…74 Asymmetric inverse-electron-demand hetero-Diels-Alder reactions of an electron-rich alkene with an electron-deficient a,b-unsaturated ketone (enone) offer a convenient and valuable entry to the synthesis of dihydropyran and tetrahydropyran derivatives, which constitute important structural motifs in natural products and in a variety of biologically important compounds. [75][76][77][78][79] Organoamine catalysts were only able to catalyze IED-HDA of enolizable aldehydes with an enone. 77,[80][81][82] Ketones are much less reactive due to both electronic and steric reasons.…”

Untitled

“…Alkenes and alkynes also could act as typical dienophile counterparts for chemical reactions with dienes like dicyanocyclohexa-1,3-dienes and substituted phthalonitriles resulting in the synthesis of a broad class of heterocyclic derivatives like dicyano-indoles, and -carbazoles 93 .…”