A simple method for the synthesis of <i>N</i>-difluoromethylated pyridines and 4-pyridones/quinolones by using BrCF<sub>2</sub>COOEt as the difluoromethylation reagent

Gandioso, Albert; Fakiri, Mohamed El; Rovira, Anna; Marchán, Vicente

doi:10.1039/d0ra06322c

Cited by 8 publications

(3 citation statements)

References 42 publications

(14 reference statements)

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“…N -Difluoromethylation of 8 with ethyl bromodifluoroacetate in a 1:1 mixture of THF/ACN at 60 °C for 24 h afforded coumarin 3. 31 Coumarin 12 was synthesized by alkylating 8 with N-(3-azidopropyl)-2-bromoacetamide. 32 The reaction of 8 with methyl bromoacetate followed by acidic hydrolysis and HATU-mediated coupling of N-Boc-1,3-propanediamine afforded coumarin 13, which was deprotected with HCl in dioxane to provide 14.…”

Section: Resultsmentioning

confidence: 99%

“…2,2,2-Trifluoroethyl trifluoromethanesulfonate was used as the N-alkylating reagent for synthesizing 2 and 6 from 8 and 10, respectively. N -Difluoromethylation of 8 with ethyl bromodifluoroacetate in a 1:1 mixture of THF/ACN at 60 °C for 24 h afforded coumarin 3 . Coumarin 12 was synthesized by alkylating 8 with N-(3-azidopropyl)-2-bromoacetamide .…”

Section: Resultsmentioning

confidence: 99%

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COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

et al. 2021

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Photodynamic therapy (PDT) for cancer treatment has drawn increased attention over the last decades. Herein, we introduce a novel family of low-molecular-weight coumarins as potential PDT anticancer tools. Through a systematic study with a library of 15 compounds, we have established a detailed structure–activity relationship rationale, which allowed the selection of three lead compounds exhibiting effective in vitro anticancer activities upon visible-light irradiation in both normoxia and hypoxia (phototherapeutic indexes up to 71) and minimal toxicity toward normal cells. Acting as excellent theranostic agents targeting mitochondria, the mechanism of action of the photosensitizers has been investigated in detail in HeLa cells. The generation of cytotoxic reactive oxygen species, which has been found to be a major contributor of the coumarins’ phototoxicity, and the induction of apoptosis and/or autophagy have been identified as the cell death modes triggered after irradiation with low doses of visible light.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

et al. 2021

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“…As Novikov et al described by experimental and DFT investigations, there is an equilibrium between the formation and decomposition of N-difluorosubstituted pyridinium ylides. Until now, there are only a few studies on the synthesis of N -CF 2 H pyridinium salts, where only electron-donating group (such as N , N -dimethylamine or methyl) substituted pyridines were involved …”

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Metal-Free Difunctionalization of Pyridines: Selective Construction of N-CF₂H and N-CHO Dihydropyridines

et al. 2021

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The reactivity of N-difluoromethylpyridinium salts is seldom explored because of their instability and low availability. Here we present a novel nucleophilic addition of N-difluoromethylpyridinium salts with nitroalkanes to synthesize N-CF2H-dihydropyridines and N-CHO-dihydropyridines in a highly efficient and regioselective pathway. This protocol exhibits good functional group tolerance and good to excellent yields.

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Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO₂: Computational Design, Scope, and Applications

Hayashi

Takano

Katsuyama

et al. 2021

Chemistry A European J

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A three‐component reaction (3CR) for the synthesis of difluoroglycine derivatives has been achieved by using amines, difluorocarbene (generated in situ), and the abundant, inexpensive, and nontoxic C1 source CO2. Various tert‐amines and pyridine, (iso)quinoline, imidazole, thiazole, and pyrazole derivatives were incorporated, and the corresponding products were isolated in solid form without purification by column chromatography on silica gel. Detailed reaction profiles of the 3CR were obtained from computational analysis using DFT calculations, and the results critically suggest that simple ammonia is not applicable to this reaction. In addition, as strongly supported by computational predictions, a new reagent that can generate difluorocarbene at 0 °C without any additives was discovered. Finally, radical substitution reactions of the obtained difluoroglycine derivatives under photoredox conditions, as well as a synthetic application as an N‐heterocyclic carbene ligand are shown.

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A simple method for the synthesis of N-difluoromethylated pyridines and 4-pyridones/quinolones by using BrCF₂COOEt as the difluoromethylation reagent

Abstract: A simple transition-metal free method was developed for the synthesis of N-difluoromethylated pyridinium-containing compounds and 4-pyridones/quinolones.

Cited by 8 publications

References 42 publications

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

Metal-Free Difunctionalization of Pyridines: Selective Construction of N-CF₂H and N-CHO Dihydropyridines

Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO₂: Computational Design, Scope, and Applications

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A simple method for the synthesis of N-difluoromethylated pyridines and 4-pyridones/quinolones by using BrCF2COOEt as the difluoromethylation reagent

Abstract: A simple transition-metal free method was developed for the synthesis of N-difluoromethylated pyridinium-containing compounds and 4-pyridones/quinolones.

Cited by 8 publications

References 42 publications

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

Metal-Free Difunctionalization of Pyridines: Selective Construction of N-CF2H and N-CHO Dihydropyridines

Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO2: Computational Design, Scope, and Applications

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A simple method for the synthesis of N-difluoromethylated pyridines and 4-pyridones/quinolones by using BrCF₂COOEt as the difluoromethylation reagent

Metal-Free Difunctionalization of Pyridines: Selective Construction of N-CF₂H and N-CHO Dihydropyridines

Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO₂: Computational Design, Scope, and Applications