Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides DOI
K. Benjamin,

Samantha Gavin,

Benjamin N. Ahern

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(14), P. 11087 - 11100

Published: July 9, 2024

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules recent years due to enhanced biological properties fluorinated compared their non-fluorinated analogues. Despite potential advantages conferred by incorporating difluoromethyl group organic compounds, industrial adoption difluoromethylation methods lags behind fluorination trifluoromethylation. This is part challenges applying common sources towards applications. We report here nickel-catalyzed cross-electrophile coupling (hetero)aryl bromides with 2-pyridyl sulfone, sustainably sourced, crystalline reagent. The scope this reaction demonstrated 24 examples (67 ± 16% average yield) including diverse array heteroaryl precursors difluoromethyl-containing preclinical pharmaceuticals. can be applied small-scale parallel synthesis benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles coupling, mechanism process was investigated. Studies confirmed formation •CF2H instead difluorocarbene. A series modified sulfones revealed that reactivity does not correlate exclusively reduction coordination cations or nickel pyridyl essential reactivity, setting out parameters for matching coupling.

Language: Английский

Late-stage difluoromethylation: concepts, developments and perspective DOI Creative Commons
Jeroen B. I. Sap, Claudio F. Meyer, Natan J. W. Straathof

et al.

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(14), P. 8214 - 8247

Published: Jan. 1, 2021

This review describes the conceptual advances that have led to multiple difluoromethylation processes making use of well-defined CF2H sources.

Language: Английский

Citations

286
Contemporary synthetic strategies in organofluorine chemistry DOI
Robert Britton, Véronique Gouverneur, Jin‐Hong Lin

et al.

Nature Reviews Methods Primers, Journal Year: 2021, Volume and Issue: 1(1)

Published: July 8, 2021

Language: Английский

Citations

215
Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis DOI Creative Commons
Wei Zhang, Xinxin Xiang, Junyi Chen

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Jan. 31, 2020

Abstract The discovery of modern medicine relies on the sustainable development synthetic methodologies to meet needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class organofluoro molecules potential applications in pharmaceutical, agricultural and material science. Herein, we developed organophotocatalytic direct difluoromethylation heterocycles using O 2 as a green oxidant. C–H oxidative obviates need for pre-functionalization substrates, metals additives. operationally straightforward method enriches efficient synthesis many difluoromethylated moderate excellent yields. pharmaceutical moleculars demonstrates practicability this methodology late-stage development. Moreover, 2′-deoxy-5-difluoromethyluridine (F TDR) exhibits promising activity against some cancer cell lines, indicating that might provide assistance discovery.

Language: Английский

Citations

152
Scalable decarboxylative trifluoromethylation by ion-shielding heterogeneous photoelectrocatalysis DOI
Yixin Chen, Yuchen He, Yong Gao

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6696), P. 670 - 676

Published: May 9, 2024

Electrochemistry offers a sustainable synthesis route to value-added fine chemicals but is often constrained by competing electron transfer between the electrode and redox-sensitive functionalities distinct from target site. Here, we describe an ion-shielding heterogeneous photoelectrocatalysis strategy impose mass-transfer limitations that invert thermodynamically determined order of transfer. This showcased enable decarboxylative trifluoromethylation sensitive (hetero)arenes using trifluoroacetate, inexpensive yet relatively inert trifluoromethyl group (CF

Language: Английский

Citations

26
Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid DOI
Claudio F. Meyer, Sandrine M. Hell,

Antonio Misale

et al.

Angewandte Chemie International Edition, Journal Year: 2019, Volume and Issue: 58(26), P. 8829 - 8833

Published: April 25, 2019

Abstract A facile method for the regioselective hydrodifluoromethylation of alkenes is reported using difluoroacetic acid and phenyliodine(III) diacetate in tetrahydrofuran under visible‐light activation. This metal‐free approach stands out as it uses inexpensive reagents, does not require a photocatalyst, displays broad functional group tolerance. The procedure also operationally simple scalable, provides access one step to high‐value building blocks application medicinal chemistry.

Language: Английский

Citations

135
Electrochemical fluoromethylation triggered lactonizations of alkenes under semi-aqueous conditions DOI Creative Commons
Sheng Zhang, Lijun Li, Jinjin Zhang

et al.

Chemical Science, Journal Year: 2019, Volume and Issue: 10(11), P. 3181 - 3185

Published: Jan. 1, 2019

Electrochemical fluoromethylation triggered lactonizations of alkenes were achieved under chemical oxidant-, catalyst- and additional supporting electrolyte-free conditions.

Language: Английский

Citations

131
Direct and Regioselective C–H Oxidative Difluoromethylation of Heteroarenes DOI
Shengqing Zhu,

Yin-Li Liu,

Huan Li

et al.

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 140(37), P. 11613 - 11617

Published: Sept. 4, 2018

The difluoromethyl group (CF2H) is of great interest in the area medicinal chemistry. However, investigation molecular scaffolds containing this has been hampered by limitation synthetic methods for introduction CF2H into heteroarenes. Herein we disclose a new strategy direct heteroarenes via copper-mediated C–H oxidative difluoromethylation with TMSCF2H. This mild and regioselective method enables convenient synthesis range difluoromethylated high yields. usage 9,10-phenanthrenequinone (PQ) as an oxidant critical to success reaction.

Language: Английский

Citations

108
Transition-metal-free decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-ones with α,α-difluoroarylacetic acids DOI

Hong Guangfeng,

Jinwei Yuan, Jun‐Hao Fu

et al.

Organic Chemistry Frontiers, Journal Year: 2019, Volume and Issue: 6(8), P. 1173 - 1182

Published: Jan. 1, 2019

A facile and efficient transition-metal-free decarboxylative radical coupling reaction of α,α-difluoroarylacetic acids with quinoxalin-2(1H)-ones has been developed under mild conditions.

Language: Английский

Citations

105
Copper-Catalyzed, Chloroamide-Directed Benzylic C–H Difluoromethylation DOI

Xiaojun Zeng,

Wenhao Yan,

Matthew Paeth

et al.

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(50), P. 19941 - 19949

Published: Nov. 22, 2019

We report herein the first catalytic strategy to harness amidyl radicals derived from N-chloroamides for C–C bond formation, allowing discovery of benzylic C–H difluoromethylation. Under copper-catalyzed conditions, a wide variety N-chlorocarboxamides and N-chlorocarbamates direct selective difluoromethylation with nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits broad substrate scope functional group tolerance, enabling late-stage bioactive molecules. copper-catalyzed, chloroamide-directed has also been extended pentafluoroethylation trifluoromethylation. Mechanistic studies on reactions support that involve formation via intramolecular activation, followed by copper-mediated transfer groups radicals.

Language: Английский

Citations

97
Transition-Metal-Free Decarboxylation of 3,3,3-Trifluoro-2,2-dimethylpropanoic Acid for the Preparation of C(CF3)Me2-Containing Heteroarenes DOI
Shuai Liu, Yangen Huang, Feng‐Ling Qing

et al.

Organic Letters, Journal Year: 2018, Volume and Issue: 20(17), P. 5497 - 5501

Published: Aug. 27, 2018

The direct synthesis of C(CF3)Me2-substituted heteroarenes by decarboxylative 1,1-dimethyltrifluoroethylation with 3,3,3-trifluoro-2,2-dimethylpropanoic acid is reported. This method does not need the transition-metal catalyst, and base crucial for this reaction. A series previously unknown C(CF3)Me2-containing were obtained in high yields have potential applications drug discovery process.

Language: Английский

Citations

93