Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with nonstabilized diazo compounds, enabled by UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No transition-metal catalyst or additive was required to affect the reaction, which proceeded at room temperature in 80 min.
Pyrrole is one of the most important one-ring heterocycles because of its widespread presence in natural products and unnatural bioactive compounds and drugs in clinical use. The preparation of pyrroles by reaction between primary amines, β-dicarbonyl compounds, and α-halo ketones, known as the Hantzsch pyrrole synthesis, is reviewed here for the first time. In spite of its age and its named reaction status, this method has received little attention in the literature. Recent work involving the use of non-conventional conditions has rejuvenated this classical reaction and this is emphasized in this review. Some applications of the Hantzsch reaction in target-oriented synthesis are also discussed.1 Introduction2 The Conventional Hantzsch Pyrrole Synthesis3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions4 Applications of the Hantzsch Pyrrole Synthesis5 Conclusions
The combination of a three-component, solvent-free pyrrole synthesis performed under mechanochemical conditions with a TMSOTf-catalyzed oxonium-mediated cyclization gave general access to pyrrolo[2,1-a]isoquinoline derivatives under very mild conditions. The structural diversity generated by this method was extended by the preparation of six additional unusual polyheterocyclic frameworks.
The pseudo-five-component reaction between β-dicarbonyl compounds (2 molecules), diamines and α-iodoketones (2 molecules), prepared in situ from aryl ketones, was performed efficiently under mechanochemical conditions involving high-speed vibration milling with a single zirconium oxide ball. This reaction afforded symmetrical frameworks containing two pyrrole or fused pyrrole units joined by a spacer, which are of interest in the exploration of chemical space for drug discovery purposes. The method was also extended to the synthesis of one compound containing three identical pyrrole fragments via a pseudo-seven-component reaction. Access to compounds having a double bond in their spacer chain was achieved by a different approach involving the homodimerization of 1-allyl- or 1-homoallylpyrroles by application of cross-metathesis chemistry.
The build/couple/pair strategy was applied to the generation of 18 structurally diverse scaffolds built around pyrrole cores. The couple phase, involving the first application of a mechanochemical multicomponent reaction for this purpose, afforded pyrrole derivatives that were transformed into some unusual fused heterocyclic systems using a domino process initiated by a Cu‐catalyzed cross coupling or intramolecular furan Diels‐Alder reactions. Because of the high current importance of macrocycles in drug discovery, the synthesis of macrocyclic libraries was also investigated using a pseudo five‐component double Hantzsch pyrrole synthesis followed by ring‐closing metathesis or the one‐pot generation of two pyrrole rings.magnified image
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