Catalytic metal-enabled story of isocyanides for use as “C1N1” synthons in cyclization: beyond radical chemistry

Chen, Dianpeng; Li, Jianming; Wang, Xin; Shan, Yingying; Huang, Keke; Yan, Xiaoyang; Qiu, Guanyinsheng

doi:10.1039/d2qo00753c

Cited by 13 publications

(7 citation statements)

References 69 publications

(53 reference statements)

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“…To exclude a possible radical mechanism, we performed the reaction in the presence of 2x stoichiometric amounts of the radical quencher TEMPO, and did not nd any difference in the reactivity (SI). [22][23] While running the reaction in the absence of water and direct injection in the mass spectrometer we could observe a strong peak corresponding to the bromo nitrilium ion (Fig. 7B).…”

Section: Mechanism and Chemical Spacementioning

confidence: 99%

The Isocyanide SN2 Reaction

Patil

Zheng

Kurpiewska

et al. 2023

Preprint

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The nucleophilic substitution reaction (SN2) is one of the oldest, yet very useful organic transformations and has found widespread applications for the synthesis of drugs and natural products. Typically, cyanide, oxygen, nitrogen, sulfur, or phosphorous nucleophiles replace a halogen or sulfonyl ester leaving group to form a new bond between the nucleophile and the electrophile. Isocyanides display an unusual versatile chemistry based on their C-centered lone pair s and the C-centered p* frontier orbitals leading to radical, and multicomponent reactions. Surprisingly, the nucleophilic character of isocyanides has never been explored in SN2 reactions. We discovered that isocyanides react as versatile nucleophiles in SN2 reactions with alkyl halides in a general manner to afford highly substituted secondary amides by in situ hydrolysis of the intermediate nitrilium ion. The innovative 3-component reaction has a broad scope regarding the structures of the isocyanide and electrophile components, functional group compatibility, scalability, use for late-stage modification of a drug and synthesis of highly complex compounds otherwise not easily accessible from simple precursors. The chemical space of the new reaction is not only different but nearly doubled in size compared to the classical amid coupling. Significantly, the isocyanide nucleophile comprises an unusual Umpolung amide carbanion synthon R-NHC(-)=O, useful as an alternative to the classical amide coupling.

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Section: Mechanism and Chemical Spacementioning

confidence: 99%

The Isocyanide SN2 Reaction

Patil

Zheng

Kurpiewska

et al. 2023

Preprint

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“…As a synthon with similar properties to carbene intermediate, isocyanide is often stable and has also been widely used in organic synthesis as an important source of C1 due to its unique, versatile, and useful properties . As a continuation of our interest in the synthesis of N-contain compound by isocyanide chemistry, and, moreover, in view of the importance of 3-carbamoylquinoxalinone, we reported herein an acid-promoted efficient carbamoylation of quinoxalin-2(1 H )-ones with isocyanide in water for the synthesis of 3-carbamoylquinoxalinone.…”

Section: Introductionmentioning

confidence: 99%

Acid-Promoted Direct C–H Carbamoylation at the C-3 Position of Quinoxalin-2(1H)-ones with Isocyanide in Water

Song

Tang

et al. 2022

ACS Omega

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Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

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“…2 In this field, one particularly fascinating topic is radical-mediated annulation, which continues to receive much attention benefitting from the resurgence of controllable and reliable radical chemistry over the past decade. 3 Particularly, radical annulation employing a radical reagent as a cyclization partner and unit has been extensively studied because this process expands the diversity of cyclic compounds and the functionality of radical reagents. 4…”

Section: Introductionmentioning

confidence: 99%