Skeletal editing through direct nitrogen deletion of secondary amines

Kennedy, Sean H.; Dherange, Balu D.; Berger, Kathleen J.; Levin, Mark D.

doi:10.1038/s41586-021-03448-9

Cited by 211 publications

(127 citation statements)

References 38 publications

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“…In this vein, “single-atom” manipulations of ring systems (i.e., targeted insertions or deletions) are of particular interest, in part due to their retrosynthetic simplicity. 11 − 14 Such reactions are known for a limited subset of molecules, including venerable carbonyl rearrangements such as the Bayer–Villiger, Beckmann, and Wolff rearrangements. 15 − 18 However, the practical attractiveness of these classic reactions varies greatly from case to case by virtue of their conditions and limitations.…”

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confidence: 99%

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

et al. 2021

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Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.

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Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

et al. 2021

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“…This method rapidly and reliably achieves skeletal diversity by modifying the core framework. 4 However, the skeletal remodeling of aromatic pyridine cores remains underdeveloped, because their high resonance stabilization energy needs to be overcome first to dearomatize the aromatic ring. In addition, dearomatized rings contain unstrained six-membered rings that are very difficult to dissociate.…”

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Skeletal remodeling of chalcone-based pyridinium salts to access isoindoline polycycles and their bridged derivatives

Wang

Han

et al. 2021

Chem. Sci.

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“…Byproducts such as the alkene resulting from β-fragmentation and a small quantity of stereoinverted cyclobutanes were also identified. In 2021, Levin’s group disclosed the nitrogen deletion of secondary amines using an N -anomeric amide, 24 postulating the concept of skeletal editing of organic molecules. 25 , 26 An N -anomeric amide acts as a nitrogen transfer reagent to a secondary amine to produce a 1,1-diazene, which generates a biradical via nitrogen extrusion, affording cyclobutane.…”

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Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

et al. 2021

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Here we report a contractive synthesis of multisubstituted cyclobutanes containing multiple stereocenters from readily accessible pyrrolidines using iodonitrene chemistry. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsymmetrical spirocyclobutanes were prepared successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported.

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Skeletal editing through direct nitrogen deletion of secondary amines

Cited by 211 publications

References 38 publications

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines

Skeletal remodeling of chalcone-based pyridinium salts to access isoindoline polycycles and their bridged derivatives

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

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