New Cascade Reactions of Indigo to Structurally Complex Heterocycles
Creators: name: Ali, Sarfaraz
Publisher: name: University of Wollongong
Year: 2025
Subjects: classificationCode: 3405
subject: Organic chemistry
classificationCode: 3404
subject: Medicinal and biomolecular chemistry
classificationCode: 3403
subject: Macromolecular and materials chemistry
classificationCode: 3499
subject: Other chemical sciences

description: The work presented here is a contribution to the previous and parallel study to expand the understanding of indigo chemistry. The reactivity of indigo 1 was investigated with highly reactive electrophiles, namely ethyl bromoacetate 112, Michael acceptors (acryloyl chloride 170-173 and methyl acrylate 180-181), and with singlet carbene (dichlorocarbene) along with carbenoids (diazomalonate ester 196 and diazoacetylacetone 204).The optimised reactions of indigo 1 with ethyl bromoacetate 112 gave sets of new polyheterocycles via cascade process under various reaction settings. Using 5 equivalents of ethyl bromoacetate 112 in a reaction produced N,N'-dialkylated indigo 115 (6%), pyrazinodiindole derivatives 118 (2%), and 119 (3%) as the major products along with the spiro biindigoid 116 (2%) as a minor product. By increasing the amount (10 equivalents) of ethyl bromoacetate 112 in a reaction, N,N'-dialkylated indigo 115 (19%) and N-alkylated indigo 117 (5%) were isolated respectively. However, altering the reaction time (12 minutes 10 second), and reducing the reaction temperature to 80 oC gave N,N'-dialkylated indigo 115, and N-alkylated indigo 117 with increased yields of 27% and 22% respectively.Further investigation into the reactivity of ethyl bromoacetate 112 with indirubin 1a yielded mixture of new heterocycles 152-155 in a one-pot reaction under different reaction conditions. The optimised reaction of indirubin 1a with 112 at 70 oC yielded N-alkylated indirubin 151 (48%), and N,N'-dialkylated indirubin 152 (20%). Further investigation of indirubin 1a with 112 at higher temperature (110 oC) resulted in the formation of mixture of polyheterocycles; N-alkylated indirubin 151 (&lt;1%), N,N'-dialkylated indirubin 152 (25%), dihydroindolopyrroloisoquinoline-2 acetate 153 (4%), tetrahydroindolopyrroloisoquinoline-6-carboxylate 154 (2%), dihydroindolopyrroloisoquinoline-2,6-diacetate 155 (3%), and Nalkylated isatin 156 (3%), respectively. The study revealed that the compounds 153-155 possesses new class of heterocyclic system. Further investigation involved attempts to increase the yield of these polyheterocycles. Therefore, a new methodology was devised to increase the yield, which involved the reaction of N,N'-dialkylated indirubin 152 with caesium carbonate at 110 oC and resulted in the formation of compounds 153 (13%), 154 (36%), 155 (36%) in higher yield.The reactivity of indigo 1 was investigated with various α,𝛽-unsaturated electrophiles. The treatment of indigo 1 with (E)-but-2-enoyl chloride 170 resulted in the 8-methyldiazepinodiindoletrione 174 (15%) as a dark red amorphous solid. However, reaction with 3-methylbut-2-enoyl chloride 171 produced (E)-3,3'-dioxo-[2,2'-biindolinylidene]-1-carbaldehyde 175 (45%). Further investigation of indigo 1 with methyl acrylate 180 resulted in the formation of methyl-7a-hydroxytetrahydro-6H-pyridodiindole-7-carboxylate 182 (13%) as a pink solid.A new methodology was developed to explore the reactivity of indigo system with singlet carbene and carbenoids to produced polyheterocyclic frameworks. The reaction of N,N'-dimethylindigo 189 with singlet carbene (dichlorocarbene) yielded the unprecedented dibenzo-1,5-oxazocinoindole 190 (51%), the reaction N,N'-dimethylindigo 189 with diazomalonate ester 196 yielded spirofuroindoleindoline-dicarboxylate 198 (20%).The chemistry described here introduces a new approach for the indigo motif, potentially opening avenues for cascade reactions utilizing this easily accessible and affordable starting material. These methods could have broader the applications in synthesizing various new polyheterocyclic frameworks that are typically challenging to obtain through other methods.