Probing the hydrolytic reactivity of 2-difluoromethyl pyrroles

Melanson, Jennifer A.; Figliola, Carlotta; Smithen, Deborah A.; Kajetanowicz, Aleksandra; Thompson, Alison

doi:10.1039/c6ob01441k

Cited by 9 publications

(7 citation statements)

References 50 publications

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“…In general, we found that electron rich aryl and heteroaryldifluoroalkyl ethers were the most prone to degradation. The instability of these compounds is similar to that of 5‐membered heteroaromatic difluoromethylenes, which readily hydrolyze to the corresponding aldehyde …”

Section: Figurementioning

confidence: 99%

“…The instability of these compounds is similar to that of 5-membered heteroaromatic difluoromethylenes,which readily hydrolyze to the corresponding aldehyde. [20] From am echanistic perspective, we propose that AgF fluorination of thionoestersi nvolves coordination of Ag(I) to the thiocarbonyl, which is then activatedf or nucleophilic attack by fluoride( e.g., 46!47). As ubsequentr eactionw ith as econd equivalent of Ag(I) produces Ag 2 Sa nd an oxocarbeniumi on 48 that is then trapped by fluoride( Scheme 2).…”

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confidence: 99%

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A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

Newton

Driedger

Nodwell

et al. 2019

Chemistry A European J

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Herein we report the mild and rapid fluorodesulfurization of thionoesters using only silver(I) fluoride. This reaction demonstrates excellent functional group tolerance and complements existing strategies for difluoroalkyl ether synthesis, which rely on toxic and often dangerous reagents that demonstrate limited functional group compatibility. We additionally report the translation of this finding to the production of 18F‐labelled difluoroalkyl ethers using fluoride‐derived [18F]AgF. This new process should enable the synthesis of a wide range of difluoroalkyl ethers with applications in medicinal and materials chemistry, and radiotracer production.

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Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

Newton

Driedger

Nodwell

et al. 2019

Chemistry A European J

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“…While the CF 2 moiety is typically stable at saturated sites, haloalkyl moieties found instead at benzylic or equivalent sites in (hetero)aromatics may be more readily hydrolyzed through Reimer-Tiemann-type manifolds. 23 , 24 …”

Section: Resultsmentioning

confidence: 99%

“…We reasoned therefore that in protein chemistry, this essentially near-absent functional group (“C(O)”) might be accessed by a strategically reversed process (from “CF 2 ”: RCF 2 → RC(O) or HCF 2 → HC(O)) by appropriate positioning of gem -difluoromethylene under aqueous conditions and in an electronic environment (e.g., benzylic) that would favor hydrolysis. While the CF 2 moiety is typically stable at saturated sites, haloalkyl moieties found instead at benzylic or equivalent sites in (hetero)aromatics may be more readily hydrolyzed through Reimer-Tiemann-type manifolds. , …”

Section: Resultsmentioning

confidence: 99%

Residue-Selective Protein C-Formylation via Sequential Difluoroalkylation-Hydrolysis

Imiołek

Isenegger

et al. 2021

ACS Cent. Sci.

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The carbonyl group is now a widely useful, nonproteinogenic functional group in chemical biology, yet methods for its generation in proteins have relied upon either cotranslational incorporation of unnatural amino acids bearing carbonyls or oxidative conversion (chemical or enzymatic) of existing natural amino acids. If available, alternative strategies for directly adding the CO group through C–C bond-forming C-carbonylation, particularly at currently inaccessible amino acid sites, would provide a powerful method for adding valuable reactivity and expanding possible function in proteins. Here, following a survey of methods for HCF2· generation, we show that reductive photoredox catalysis enables mild radical-mediated difluoromethylation-hydrolysis of native protein residues as an effective method for carbonylation. Inherent selectivity of HCF2· allowed preferential modification of Trp residues. The resulting C-2-difluoromethylated Trp undergoes Reimer-Tiemann-type dehalogenation providing highly effective spontaneous hydrolytic collapse in proteins to carbonylated HC(O)-Trp (C-formyl-Trp = CfW) residues. This new, unnatural protein residue CfW not only was found to be effective in bioconjugation, ligation, and labeling reactions but also displayed strong “red-shifting” of its absorption and fluorescent emission maxima, allowing direct use of Trp sites as UV–visualized fluorophores in proteins and even cells. In this way, this method for the effective generation of masked formyl-radical “HC(O)·” equivalents enables first examples of C–C bond-forming carbonylation in proteins, thereby expanding the chemical reactivity and spectroscopic function that may be selectively and post-translationally “edited” into biology.

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“…[ 1‐7 ] For example, in small‐molecule drug discovery, CF 2 is a popular functional group because it can improve the binding affinity, physicochemical properties, and metabolic stability of molecules. [ 8‐15 ] Several top‐selling drugs contain a CF 2 group, such as Eflornithin (DFMO), Pentoprazole, Sulfentrazone and Neuropeptide Y antagonist. Among these fluoromethylated (CF 2 and CF 3 ) compounds, fluoromethylated azaindoles are useful hertercycle compounds in organic chemistry.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Base‐Promoted Formylation and N‐Difluoromethylation of Azaindoles with Ethyl Bromodifluoroacetate as a Carbon Source

Sun

Zhang

et al. 2021

Chin. J. Chem.

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Azaindoles | C1 building blocks | Difluoromethylene | Hydrolysis | Synthetic methodsWe reported for the first time that ethyl bromodifluoroacetate directly reacts with azaindole without transition metal catalysis to produce a difluoromethyl protected 5-aldehyde group product in one step. It is worth mentioning that the reacted aldehyde group is only formed at the 5 position. In addition, this method has good substrate applicability and functional group tolerance. Finally, we also carried out some mechanism auxiliary experiments, which confirmed that the aldehyde-based carbon comes from ethyl bromodifluoroacetate.

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Probing the hydrolytic reactivity of 2-difluoromethyl pyrroles

Cited by 9 publications

References 50 publications

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

Residue-Selective Protein C-Formylation via Sequential Difluoroalkylation-Hydrolysis

Base‐Promoted Formylation and N‐Difluoromethylation of Azaindoles with Ethyl Bromodifluoroacetate as a Carbon Source

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