The Cascade Reactions of Indigo with Propargyl Substrates for Heterocyclic and Photophysical Diversity.

The synthesis of structurally diverse heterocycles for chemical space exploration was achieved via the cascade reactions of indigo with propargylic electrophiles. New pyrazinodiindolodione, naphthyridinedione, azepinodiindolone, oxazinoindolone and pyrrolodione products were prepared in one pot reactions by varying the leaving group (-Cl, -Br, -OMs, -OTs) or propargyl terminal functionality (-H, -Me, -Ph, -Ar). Mechanistic and density functional theory studies revealed that the unsaturated propargyl moiety can behave as an electrophile when aromatic terminal substitutions are made, and therefore competes with leaving group substitution for new outcomes. Selected products from the cascade reactions were investigated for their absorption and fluorescence properties, including transient absorption spectroscopy. This revealed polarity dependent excited state relaxation pathways, fluorescence, and triplet formation, thus highlighting these reactions as a means to access diverse functional materials rapidly.

Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo.

Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2'-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.

Rapid cascade synthesis of poly-heterocyclic architectures from indigo.

The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a']diindole, pyrido[1,2-a:3,4-b']diindole and benzo[b]indolo[1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring B-homologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through single-crystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means.