Trisulfur-Radical-Anion-Triggered C(sp<sup>2</sup>)–H Amination of Electron-Deficient Alkenes

Alkenes and their derivatives are featured widely in a variety of natural products, pharmaceuticals, and advanced materials. Significant efforts have been made toward the development of new and practical methods to access this important class of compounds by selectively activating the alkenyl C(sp2)–H bonds in recent years. In this comprehensive review, we describe the state-of-the-art strategies for the direct functionalization of alkenyl sp2 C–H and C–F bonds until June 2022. Moreover, metal-free, photoredox, and electrochemical strategies are also covered. For clarity, this review has been divided into two parts; the first part focuses on currently available alkenyl sp2 C–H functionalization methods using different alkene derivatives as the starting materials, and the second part describes the alkenyl sp2 C–F bond functionalization using easily accessible gem-difluoroalkenes as the starting material. This review includes the scope, limitations, mechanistic studies, stereoselective control (using directing groups as well as metal-migration strategies), and their applications to complex molecule synthesis where appropriate. Overall, this comprehensive review aims to document the considerable advancements, current status, and emerging work by critically summarizing the contributions of researchers working in this fascinating area and is expected to stimulate novel, innovative, and broadly applicable strategies for alkenyl sp2 C–H and C–F bond functionalizations in the coming years.

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“…•-)-triggered alkenyl C−H amination of α,β-unsaturated carbonyls with simple amines (Scheme 234b). 395…”

Section: αβ-Unsaturated Ketonesmentioning

confidence: 99%

Recent Advances in Alkenyl sp² C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

et al. 2022

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“…As shown in Scheme , the trisulfur radical anion (S 3 •– ) produced by the thermal decomposition of EtOCS 2 K and the olefin undergoes free-radical addition to provide the free-radical intermediate A . Then, with the help of the trisulfur radical anion (S 3 •– ), cyclic sulfur transition state B is formed and can obtain deuterium atoms from EtOCS 2 D (derived from EtOCS 2 K and excess D 2 O) to form monodeuterated 1,2,3-trithiolane C . Then, 1,2,3-trithiolane C undergoes desulfurization to generate episulfide D .…”

mentioning

confidence: 99%

“…•− ), cyclic sulfur transition state B is formed and can obtain deuterium atoms from EtOCS 2 D (derived from EtOCS 2 K and excess D 2 O) to form monodeuterated 1,2,3-trithiolane C. 23 Then, 1,2,3-trithiolane C undergoes desulfurization to generate episulfide D. Episulfide D then generates the monodeuterated alkene E with the reaction of Z−S − through a desulfurization reaction. 16a The monodeuterated alkene E then repeats the above cyclization and desulfurization reactions to provide dideuterated episulfide G, and after a subsequent desulfurization reaction, the deuterated alkenes are generated.…”

mentioning

confidence: 99%

Synthesis of Deuterated (E)-Alkene through Xanthate-Mediated Hydrogen–Deuterium Exchange Reactions

et al. 2021

Org. Lett.

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Herein we have developed a reversible hydrogen–deuterium exchange reaction of nonactivated olefins. By using EtOCS2K as a mediator, the H/D exchange reaction was realized through repeated addition and elimination reactions, demonstrating reversible H/D exchange between ordinary olefins and deuterated olefins. Using the lowest cost D2O without precious metal catalysts and ligands, a broad spectrum of compatibility of functional groups was achieved.

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“…Hydrazine solution (35 wt.% in H 2 O; 0.06 ml; 1.92 mmol) was added dropwise to a solution of compound 3 (100 g; 0.48 mmol) in EtOH (5 ml) containing acetic acid (0.5 ml; Nguyen et al, 2020;Xu et al, 2013;Zhang et al, 2018;Zhu et al, 2017). The mixture was mechanically stirred under reflux at 100°C until the reaction reached completion.…”

Section: 5-diphenyl-1h-pyrazole (3e)mentioning

confidence: 99%

Chalcone‐inspired rA₁/A_2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure

et al. 2021

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Over the past few years, great progress has been made in the development of high-affinity adenosine A 1 and/or A 2A receptor antagonists-promising agents for the potential treatment of Parkinson's disease. Unfortunately, many of these compounds raise structure-related concerns. The present study investigated the effect of ring closures on the rA 1 /A 2A affinity of compounds containing a highly reactive α,βunsaturated carbonyl system, hence providing insight into the potential of heterocycles to address these concerns. A total of 12 heterocyclic compounds were synthesised and evaluated in silico and in vitro. The test compounds performed well upon qualitative assessment of drug-likeness and were generally found to be free from potentially problematic fragments. Most also showed low/ weak cytotoxicity. Results from radioligand binding experiments confirm that heterocycles (particularly 2-substituted 3-cyanopyridines) can replace the promiscuous α,βunsaturated ketone functional group without compromising A 1 / A 2A affinity. Structure-activity relationships highlighted the importance of hydrogen bonds in binding to the receptors of interest. Compounds 3c (rA 1 K i = 16 nM; rA 2A K i = 65 nM) and 8a (rA 1 K i = 102 nM; rA 2A K i = 37 nM), which both act as A 1 antagonists, showed significant dual A 1 /A 2A affinity and may, therefore, inspire further investigation into heterocycles as potentially safe and potent adenosine receptor antagonists.

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Trisulfur-Radical-Anion-Triggered C(sp²)–H Amination of Electron-Deficient Alkenes

Cited by 20 publications

References 74 publications

Recent Advances in Alkenyl sp² C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Recent Advances in Alkenyl sp² C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Synthesis of Deuterated (E)-Alkene through Xanthate-Mediated Hydrogen–Deuterium Exchange Reactions

Chalcone‐inspired rA₁/A_2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure

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Trisulfur-Radical-Anion-Triggered C(sp2)–H Amination of Electron-Deficient Alkenes

Cited by 20 publications

References 74 publications

Recent Advances in Alkenyl sp2 C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Recent Advances in Alkenyl sp2 C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Synthesis of Deuterated (E)-Alkene through Xanthate-Mediated Hydrogen–Deuterium Exchange Reactions

Chalcone‐inspired rA1/A2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure

Contact Info

Product

Resources

About

Trisulfur-Radical-Anion-Triggered C(sp²)–H Amination of Electron-Deficient Alkenes

Recent Advances in Alkenyl sp² C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Recent Advances in Alkenyl sp² C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

Chalcone‐inspired rA₁/A_2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure