Simplifying Nitration Chemistry with Bench-stable Organic Nitrating Reagents

Nitro compounds play a crucial role in academia and industries, serving as building blocks for the synthesis of drugs, agrochemicals, and materials. Nitration, a fundamental process in organic synthesis, has undergone significant evolution since the 19th century. While electrophilic nitration dominates historically, recent decades have seen a focus on new reagents and their reactivity modes for achieving mild and robust synthesis of nitro compounds. Our group has a longstanding interest in developing cost-effective, readily available, recyclable nitrating reagents derived from organic scaffolds. These reagents serve as a controllable source of nitryl radical and nitronium ion species, enabling mild and practical nitration of hydrocarbons with exceptional functional group tolerance. This account details the development of nitrating reagents and their diverse applications in catalytic nitration across various classes of organic molecules

Asymmetric Pd-NHC*-catalyzed coupling reactions

Very high asymmetric inductions result in the Pd-catalyzed intramolecular arylation of amides to give 3,3-disubstituted oxindoles when new in situ-generated chiral N-heterocyclic carbene (NHC*) ligands are employed. Structural studies show that conformational locking to minimize allylic strain is the key to understanding the function of these ligands. New applications of these ligands in the frontier area of asymmetric coupling reactions involving C(sp3)-H bonds are detailed. Highly enantioenriched fused indolines are accessible using either preformed- or in situ-generated Pd-NHC* catalysts. Remarkably, this occurs at high temperature (140-160 °C) via excellent asymmetric recognition of an enantiotopic C-H bond in an unactivated methylene uni

Chiral N-heterocyclic carbene (NHC) ligands in Pd-catalyzed cross-coupling reactions

New chiral N-heterocyclic carbene (NHC) ligands have been developed and applied in the asymmetric Pd-catalyzed intramolecular a-arylation of amides producing 3,3-disubstituted-, spiro-, and aza-spirooxindoles in high yields (up to 99%) and excellent enantioselectivities (up to 97% ee). For the first time a palladacycle intermediates were isolated and fully characterized including X-ray crystal structure determinations. Analysis of these solid state structures demonstrates the importance of both the bulky tert-butyl groups and ortho-substituted aryl rings at the stereogenic centers of the ligand. Additionally, an extraordinarily efficient palladium-NHC catalyzed synthesis of highly enantioenriched 2,3-trans-fused indolines via asymmetric C(sp3)-H activation of an unactivated methylene unit was developed. It is noteworthy that this C-C coupling delivers the products with enantioselectivities of up to 95% ee despite the high temperature required. The initial results were extended to the synthesis of 2- and 2,3-disubstituted indolines. Racemic substrates reacted via highly asymmetric regiodivergent reactions

Catalytic Enantioselective Synthesis of a 3-Aryl-3-benzyloxindole (=3-Aryl-3-benzyl-1,3-dihydro-2H-indol-2-one) Exhibiting Antitumor Activity

A palladium-catalyzed intramolecular α-arylation of an amide in the presence of a bulky chiral N-heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)-6-chloro-3-(3-chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one ((R)-5). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)-5 was obtained with an overall yield of 45% and with 96% enantioselectivity

Facile access to nitroarenes and nitroheteroarenes using N-nitrosaccharin

Nitroaromatics and nitroheteroaromatics serve as key building blocks and intermediates in synthesis, and form the core scaffold of a vast number of materials, dyes, explosives, agrochemicals and pharmaceuticals. However, their synthesis relies on harsh methodologies involving excess mineral acids, which present a number of critical drawbacks in terms of functional group compatibility and environmental impact. Modern, alternative strategies still suffer from significant limitations in terms of practicality, and a general protocol amenable to the direct C-H functionalization of a broad range of aromatics has remained elusive. Herein we introduce a bench-stable, inexpensive, easy to synthesize and recyclable nitrating reagent based on saccharin. This reagent acts as a controllable source of the nitronium ion, allowing mild and practical nitration of both arenes and heteroarenes displaying an exceptional functional group tolerance.ISSN:2041-172

Synthesis of 3-hydroxyoxindoles by Pd-catalysed intramolecular nucleophilic addition of aryl halides to α-ketoamides

Pd/PtBu3-catalysed intramolecular nucleophilic addition of aryl halides to α-ketoamides in the presence of nBuOH and base has been realized with high yields, providing a new, direct, and efficient synthetic strategy to obtain 3-hydroxyoxindoles