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David A Nicewicz - One of the best experts on this subject based on the ideXlab platform.
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Nucleophilic Aromatic Substitution of Unactivated Fluoroarenes Enabled by Organic Photoredox Catalysis.
Journal of the American Chemical Society, 2020Co-Authors: Vincent A. Pistritto, Megan E. Schutzbach-horton, David A NicewiczAbstract:Nucleophilic Aromatic Substitution (SNAr) is a classical reaction with well-known reactivity toward electron-poor fluoroarenes. However, electron-neutral and electron-rich fluoro(hetero)arenes are considerably underrepresented. Herein, we present a method for the Nucleophilic defluorination of unactivated fluoroarenes enabled by cation radical-accelerated Nucleophilic Aromatic Substitution. The use of organic photoredox catalysis renders this method operationally simple under mild conditions and is amenable to various nucleophile classes, including azoles, amines, and carboxylic acids. Select fluorinated heterocycles can be functionalized using this method. In addition, the late-stage functionalization of pharmaceuticals is also presented. Computational studies demonstrate that the site selectivity of the reaction is dictated by arene electronics.
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19f and 18f arene deoxyfluorination via organic photoredox catalysed polarity reversed Nucleophilic Aromatic Substitution
Nature Catalysis, 2020Co-Authors: Nicholas E S Tay, Vincent A. Pistritto, Wei Chen, Alison Levens, Zeng Huang, David A NicewiczAbstract:Nucleophilic Aromatic Substitution (SNAr) is routinely used to install 19F- and 18F- in Aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C-F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated Nucleophilic Aromatic Substitution (CRA-SNAr) enables the fluorination of electron-rich arenes with 19F- and 18F- under mild conditions, thus complementing the traditional arene polarity requirements necessary for SNAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [18F]5-fluorouracil ([18F]FU). Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical SNAr strategies, with the potential for use in the synthesis and discovery of PET radiopharmaceuticals.
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Cation Radical-Accelerated Nucleophilic Aromatic Substitution for Amination of Alkoxyarenes
Organic letters, 2020Co-Authors: Nicholas J. Venditto, David A NicewiczAbstract:Nucleophilic Aromatic Substitution (SNAr) is a common method for arene functionalization; however, reactions of this type are typically limited to electron-deficient Aromatic halides. Herein, we describe a mild, metal-free, cation-radical accelerated Nucleophilic Aromatic Substitution (CRA-SNAr) using a potent, highly oxidizing acridinium photoredox catalyst. Selective Substitution of arene C-O bonds on a wide array of aryl ether substrates was shown with a variety of primary amine nucleophiles. Mechanistic evidence is also presented that supports the proposed CRA-SNAr pathway.
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arene cyanation via cation radical accelerated Nucleophilic Aromatic Substitution
Organic Letters, 2019Co-Authors: Natalie Holmbergdouglas, David A NicewiczAbstract:Herein we describe a cation radical-accelerated-Nucleophilic Aromatic Substitution (CRA-SNAr) of alkoxy arenes utilizing a highly oxidizing acridinium photoredox catalyst and acetone cyanohydrin, a...
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cation radical accelerated Nucleophilic Aromatic Substitution via organic photoredox catalysis
Journal of the American Chemical Society, 2017Co-Authors: David A NicewiczAbstract:Nucleophilic Aromatic Substitution (SNAr) is a direct method for arene functionalization; however, it can be hampered by low reactivity of arene substrates and their availability. Herein we describe a cation radical-accelerated Nucleophilic Aromatic Substitution using methoxy- and benzyloxy-groups as nucleofuges. In particular, lignin-derived Aromatics containing guaiacol and veratrole motifs were competent substrates for functionalization. We also demonstrate an example of site-selective substitutive oxygenation with trifluoroethanol to afford the desired trifluoromethylaryl ether.
Piotr Kaszynski - One of the best experts on this subject based on the ideXlab platform.
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azo group assisted Nucleophilic Aromatic Substitutions in haloarene derivatives preparation of substituted 1 iodo 2 6 bispropylthiobenzenes
Journal of Organic Chemistry, 2004Co-Authors: Jason Manka, Virginia C Mckenzie, Piotr KaszynskiAbstract:Aryldiazo substituents were used in Nucleophilic Aromatic Substitution reactions of halogens. The Ph-NN− group activates ortho fluorine atoms toward alkylthiolation under mild conditions. In contra...
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azo group assisted Nucleophilic Aromatic Substitutions in haloarene derivatives preparation of substituted 1 iodo 2 6 bispropylthiobenzenes
Journal of Organic Chemistry, 2004Co-Authors: Jason Manka, Virginia C Mckenzie, Piotr KaszynskiAbstract:Aryldiazo substituents were used in Nucleophilic Aromatic Substitution reactions of halogens. The Ph-NN− group activates ortho fluorine atoms toward alkylthiolation under mild conditions. In contrast, the Me2N-C6H4-NN− group has virtually no activation effect in Nucleophilic Aromatic Substitution, and serves as a “neutral” mask for the amino group. The Ph-NN− group was efficiently introduced by diazo coupling of aryllithium with dry PhN2+BF4- salt.
Miroslaw Tomaszewski - One of the best experts on this subject based on the ideXlab platform.
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rapid access to pyrido 1 2 5 triazepin 4 ones through intramolecular Nucleophilic Aromatic Substitution
ChemInform, 2012Co-Authors: Shujuan Jin, Olivier Stjean, Sandra I Baltatu, V Santhakumar, Miroslaw TomaszewskiAbstract:The condensation of ketoamides (I) and (IV) with methyl hydrazine produces hydrazones which undergo intramolecular Nucleophilic Aromatic Substitution to yield the title compounds (III) and their benzo analogues (V).
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rapid access to pyrido 1 2 5 triazepin 4 ones through intramolecular Nucleophilic Aromatic Substitution
Tetrahedron Letters, 2012Co-Authors: Shujuan Jin, Olivier Stjean, Sandra I Baltatu, V Santhakumar, Miroslaw TomaszewskiAbstract:Abstract Several 3-substituted pyrido[1,2,5]triazepin-4-ones and their benzo counterparts have been prepared in three steps from commercial starting materials. The key step involves S N Ar-type intramolecular Nucleophilic Aromatic Substitution of the appropriate hydrazone substrates.
Yin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Nucleophilic Aromatic Substitution of unactivated aryl fluorides with primary aliphatic amines via organic photoredox catalysis
Chemistry: A European Journal, 2020Co-Authors: Shaolin Zhou, Fengqian Zhao, Fang Liang, Jingjie Zhang, Yin ZhangAbstract:Here, we report a mild and transition-metal-free approach for the Nucleophilic Aromatic Substitution (S N Ar) of unactivated fluoroarenes with primary aliphatic amines to form Aromatic amines. This reaction is facilitated by the formation of cationic fluoroarene radical intermediates in the presence of an acridinium-based organic photocatalyst under blue light irradiation. Various electron-rich and electron-neutral fluoroarenes are competent electrophiles for this transformation. A wide range of primary aliphatic amines, including amino acid esters, dipeptides, and linear and branched amines are suitable nucleophiles. The synthetic utility of this protocol is demonstrated by the late-stage functionalization of several complex drug molecules.
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Nucleophilic Aromatic Substitution of unactivated aryl fluorides with primary aliphatic amines via organic photoredox catalysis
Chemistry: A European Journal, 2020Co-Authors: Shaolin Zhou, Fengqian Zhao, Fang Liang, Jingjie Zhang, Weimin Shi, Wei Wei, Yin ZhangAbstract:In this work, a mild and transition-metal-free approach for the Nucleophilic Aromatic Substitution (SN Ar) of unactivated fluoroarenes with primary aliphatic amines to form Aromatic amines is reported. This reaction is facilitated by the formation of cationic fluoroarene radical intermediates in the presence of an acridinium-based organic photocatalyst under blue-light irradiation. Various electron-rich and electron-neutral fluoroarenes are competent electrophiles for this transformation. A wide range of primary aliphatic amines, including amino acid esters, dipeptides, and linear and branched amines are suitable nucleophiles. The synthetic utility of this protocol is demonstrated by the late-stage functionalization of several complex drug molecules.
Zachary R Woydziak - One of the best experts on this subject based on the ideXlab platform.
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a general method for Nucleophilic Aromatic Substitution of aryl fluorides and chlorides with dimethylamine using hydroxide assisted decomposition of n n dimethylforamide
Synthetic Communications, 2016Co-Authors: Juana Garcia, Jacob Sorrentino, Emily J Diller, Daniel Chapman, Zachary R WoydziakAbstract:A practical and convenient procedure for the Nucleophilic Aromatic Substitution of aryl fluorides and chlorides with dimethylamine was developed using a hydroxide-assisted thermal decomposition of ...
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General method for Nucleophilic Aromatic Substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide
2016Co-Authors: Juana Garcia, Jacob Sorrentino, Emily J Diller, Daniel Chapman, Zachary R WoydziakAbstract:A practical and convenient procedure for the Nucleophilic Aromatic Substitution of aryl fluorides and chlorides with dimethylamine was developed using a hydroxide-assisted thermal decomposition of N,N-dimethylforamide. These conditions are tolerant of nitro, nitrile, aldehyde, ketone, and amide groups but will undergo acyl Substitution to form amides for methyl esters and acyl chlorides. Isolated yields of the products range from 44% to 98%, with the majority being greater than 70% for 17 examples.
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synthesis of fluorinated benzophenones xanthones acridones and thioxanthones by iterative Nucleophilic Aromatic Substitution
Journal of Organic Chemistry, 2012Co-Authors: Zachary R Woydziak, Liqiang Fu, Blake R. PetersonAbstract:Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential Nucleophilic Aromatic Substitution reactions, first at one or both of the more reactive 4,4′-fluorines, and second by cyclization through Substitution of the less reactive 2,2′-fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies reveal...
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synthesis of fluorinated benzophenones xanthones acridones and thioxanthones by iterative Nucleophilic Aromatic Substitution
Journal of Organic Chemistry, 2012Co-Authors: Zachary R Woydziak, Blake R. PetersonAbstract:Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic prop- erties. To facilitate access to fluorinated fluorophores, bis- (2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential Nucleophilic Aromatic Substitution reactions, first at one or both of the more reactive 4,4!-fluorines, and second by cyclization through Substitution of the less reactive 2,2!-fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds.
