Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor

Abstract

The participation of reactants undergoing a polarity inversion along a multicomponent reaction allows the continuation of the transformation with productive domino processes. Thus, indole aldehydes in Groebke–Blackburn–Bienaymé reactions lead to an initial adduct which spontaneously triggers a series of events leading to the discovery of novel reaction pathways together with direct access to a variety of linked, fused, and bridged polyheterocyclic scaffolds. Indole 3‐ and 4‐carbaldehydes with suitable isocyanides and aminoazines afford fused adducts through oxidative Pictet–Spengler processes, whereas indole 2‐carbaldehyde yields linked indolocarbazoles under mild conditions, and a bridged macrocycle at high temperature. These novel structures are potent activators of the human aryl hydrocarbon receptor signaling pathway.

Pseudo Natural Products—Chemical Evolution of Natural Product Structure

“…[60] Finally,p seudo-NP design and preparation are underpinned by organic synthesis.T he tools and methodologies developed for the preparation of NPs are certainly applicable in pseudo-NPs as well. However,n ew synthetic methodologies, [77] for example,p hotochemical C À Hf unctionalisations, [78,79] and creative scaffold-forming multicomponent reactions [80,81] will continue to have great impact on our ability to prepare and study further examples of these exciting and potentially highly beneficial compound classes.…”

Development of Heterocyclic Multicomponent Reactions through Guided Exploration: Direct, Reasonable and Unpredictable Processes

“…Some of the synthesized compounds are potent activators of aryl hydrocarbon receptor (AhR), a promising target in current biomedical research. 52 It is worth stating that, in our opinion, extended MCRs are not restricted to the examples presented. Thus, we firmly believe that exploring other MCR-domino combinations and their synthetic potentials is a promising research line.…”

“…The reaction led to the formation of the adduct 61, whose origin may be traced back to a GBB adduct that had suffered a domino sequence of oxidation-Pictet-Spengler cyclization-oxidation steps. 52 Tuning reaction conditions and adding auxiliary oxidants resulted in the obtention of adduct 61 as the main product. Surprisingly, the use of iodine as the external oxidant rendered a rare Pictet-Spengler (PS) reaction upon the indole C4 position, affording a novel scaffold 62 (Scheme 25a).…”

“…Moreover, indole 3-carbaldehyde was successfully swapped with similar components like, furfural, thiophene 2-carboxaldehde, electron-rich benzaldehydes, and indole 4-carbaldehyde (Scheme 25b). 52 Finally, the incorporation of indole 2-carboxaldehyde directed the reaction towards a completely unexpected direction, yielding substituted indolocarbazoles 66 through a new nonoxidative ABC 3 version of the extended GBB. Much to our surprise, the very same reaction with cyclohexyl isocyanide at high temperatures (120 °C, W), yielded a different polycyclic adduct 67 of spiranic nature and an ABC 3 composition (Scheme 26).…”

Synthesis of Spiro[chromene-imidazo[1,2-a]pyridin]-3′-imines via 6-exo-dig Cyclization Reaction

“…One of the most important isocyanide-based multicomponent reactions is the three-component Groebke–Blackburn–Bienaymé (GBB) reaction. , However, scaffold-oriented synthetic strategies involving postcondensational modifications of the GBB reaction-derived products are rather scarcely represented in the literature (apart from simple manipulation of reactive appendages). Some examples of the postcondensational buildup of molecular complexity include sequential GBB reactions, oxidative Pictet–Spengler-type transformations of indole-containing GBB adducts, and intramolecular acylations of the aminoimidazole moiety in GBB adducts . Two examples of the post-GBB reaction (containing an alkyne side chain in the aldehyde component) have been reported by Berteina-Raboin and Shen groups by using the nucleophilic attack of the secondary amine (Scheme a) and the imidazole nitrogen atom (Scheme b) to an alkyne moiety, respectively.…”