Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C−H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxysubstituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C−H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric s...

Rhodium and Iridium Mediated C-H and O-H Bond Activation of Two Schiff Base Ligands: Synthesis, Characterization and Catalytic Properties of the Organometallic Complexes

“…Metal center in complexes having ability to undergo two-electron transfer reaction should, in principle, be capable of serving as catalyst for bringing about C-C cross coupling reactions. Palladium complexes are familiar examples of such catalysts ( Corbet and Mignani, 2006 ; Gu et al, 2019 ; Sebastian and Morales, 2019 ; Dickmu and Smoliakova, 2020 ; Lutz and Morandi, 2021 ). Rhodium and iridium centers in the present group of complexes may also be expected to display such catalytic property, as they can also undergo two-electron transfer reactions.…”

“…In our earlier studies we experienced the ability of these two complexes in bringing about C-H bond activation of organic ligands (Dutta et al, 2000b;Dutta et al, 2002;Acharyya et al, 2004b;Acharyya et al, 2005;Basu et al, 2006;Baksi et al, 2007a;Paul and Bhattacharya, 2012;Paul et al, 2014). It is relevant to mention here that metal-mediated C-H bond activation is of significant interest, with particular reference to synthesis of targeted organic molecules (Kumar et al, 2017;Zhu and Zhou, 2017;Cheng et al, 2019;Woźniak et al, 2020;Dongbang et al, 2021;Rej et al, 2021). Reaction of the rhodium and iridium starting materials with the two selected Schiff base ligands has indeed afforded organorhodium and organoiridium complexes.…”

Recent advances in transition metal-catalyzed heteroannulative difunctionalization of alkenes via C–H activation for the synthesis of heterocycles

“…2 Among them, transition metal-catalyzed annulation of alkynes has emerged as one of the most convenient and efficient procedures to construct carbon–carbon and carbon–heteroatom bonds for the rapid access of useful heterocyclic moieties from simple starting materials. 3 On the other hand, alkenes are also important synthetic building blocks for the synthesis of heterocycles.…”

Synthesis and Characterization of Related Substances of Torasemide

“…4 In the synthesis of related substances and relevant analogues of APIs, key intermediates containing synthetic building blocks and privilege scaffolds usually play a significant role. 5,6 Moreover, some related substances might be discovered to exhibit other biological activities and pharmacological actions based on the drug repositioning strategy. Therefore, the research on the synthesis of the related substances is of great importance.…”