Late-Stage C–H Functionalization of Azines

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7655 - 7691

Опубликована: Май 3, 2023

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite physiochemical properties that match key criteria in drug design is tunable by varying their substituents. Developments synthetic chemistry, therefore, directly impact these efforts, methods can install various groups azine C–H bonds particularly valuable. Furthermore, there growing interest late-stage functionalization (LSF) reactions focus on advanced candidate compounds often complex structures with multiple heterocycles, functional groups, reactive sites. Because factors electron-deficient nature the effects Lewis basic N atom, distinct arene counterparts, application LSF contexts difficult. However, have been many significant advances reactions, this review will describe progress, much which has occurred over past decade. It possible to categorize radical addition processes, metal-catalyzed activation transformations occurring via dearomatized intermediates. Substantial variation reaction within each category indicates both rich reactivity heterocycles creativity approaches involved.

Язык: Английский

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Borane-Catalyzed C3-Alkylation of Pyridines with Imines, Aldehydes, or Ketones as Electrophiles

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(11), С. 4810 - 4818

Опубликована: Март 8, 2022

Achieving C3-selective pyridine functionalization is a longstanding challenge in organic chemistry. The existing methods, including electrophilic aromatic substitution and C–H activation, often require harsh reaction conditions excess generate multiple regioisomers. Herein, we report method for borane-catalyzed tandem reactions that result exclusively alkylation of pyridines. These consist hydroboration, nucleophilic addition the resulting dihydropyridine to an imine, aldehyde, or ketone, subsequent oxidative aromatization. Because limiting reactant are mild, this constitutes practical tool late-stage structurally complex pharmaceuticals bearing moiety.

Язык: Английский

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Practical and Regioselective Synthesis of C-4-Alkylated Pyridines

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(31), С. 11927 - 11933

Опубликована: Июль 28, 2021

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this addressed using prefunctionalized materials to avoid overalkylation and mixtures regioisomers. This study reports the invention simple maleate-derived blocking group for that enables exquisite control Minisci-type decarboxylative at allows inexpensive access these valuable building blocks. method is employed on variety different carboxylic acid alkyl donors, operationally scalable, applied known structures rapid fashion. Finally, work points an interesting strategic departure use Minisci chemistry earliest possible stage (native pyridine) rather than current dogma almost exclusively employs as late-stage functionalization technique.

Язык: Английский

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C3-Selective Trifluoromethylthiolation and Difluoromethylthiolation of Pyridines and Pyridine Drugs via Dihydropyridine Intermediates

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(32), С. 14463 - 14470

Опубликована: Авг. 1, 2022

Herein, we report a method for C3-selective C–H tri- and difluoromethylthiolation of pyridines. The relies on borane-catalyzed pyridine hydroboration generation nucleophilic dihydropyridines; these intermediates react with trifluoromethylthio difluoromethylthio electrophiles to form functionalized dihydropyridines, which then undergo oxidative aromatization. can be used late-stage functionalization drugs the new drug candidates.

Язык: Английский

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Organocatalytic DYKAT of Si-Stereogenic Silanes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(9), С. 4994 - 5000

Опубликована: Фев. 24, 2023

Chiral organosilanes do not exist in nature and are therefore absent from the "chiral pool". As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, utilization racemic silanes dynamic kinetic transformation (DYKAT) or resolution (DKR) would significantly expand breadth accessible Si-stereogenic compounds. We now report DYKAT allyl enabled by strong confined imidodiphosphorimidate (IDPi) catalysts, providing access to silyl ethers. The products this reaction easily converted into useful monohydrosilanes. propose spectroscopically experimentally supported mechanism involving epimerization catalyst-bound intermediate.

Язык: Английский

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C–H functionalization of pyridines

Organic & Biomolecular Chemistry, Год журнала: 2023, Номер 21(28), С. 5671 - 5690

Опубликована: Янв. 1, 2023

This review discusses known approaches for selective pyridine C–H editing, focusing on recent discoveries uniquely suited to pyridines.

Язык: Английский

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C3‐Cyanation of Pyridines: Constraints on Electrophiles and Determinants of Regioselectivity

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(6)

Опубликована: Дек. 15, 2022

Methods for C-H cyanation of pyridines are rare. Here, we report a method C3-selective by tandem process with the reaction an in situ generated dihydropyridine cyano electrophile as key step. The is suitable late-stage functionalization pyridine drugs. low reduction potential and effective transfer nitrile group were found to be essential success this method. We studied mechanism detail means control experiments theoretical calculations that combination electronic steric factors determined regioselectivity reactions involving C2-substituted pyridines.

Язык: Английский

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Regioselective synthesis of 4-functionalized pyridines

Chem, Год журнала: 2023, Номер 10(2), С. 628 - 643

Опубликована: Ноя. 21, 2023

Язык: Английский

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Organocatalytic, Stereoselective, Cationic Reversible Addition–Fragmentation Chain-Transfer Polymerization of Vinyl Ethers

Journal of the American Chemical Society, Год журнала: 2021, Номер 144(2), С. 679 - 684

Опубликована: Дек. 30, 2021

Tacticity is a crucial factor affecting the properties of synthetic polymer materials. Here, we introduce type chiral organic Brønsted acid catalyst, 1,1'-bi-2-naphthol-derived N,N'-bis(triflyl)phosphoramidimidates (PADIs), for cationic polymerization vinyl ethers, which enables development first organocatalytic, highly stereoselective, reversible addition-fragmentation chain-transfer (RAFT) ethers with trithiocarbonate agent. This metal-free RAFT process could afford isotactic poly(vinyl ethers) high stereoselectivity, controllable molecular mass, and narrow dispersity at low catalyst loadings (as as 200 ppm). Moreover, chain-end allows chain extension to synthesize diblock copolymers comprising an ether) block, by mechanistic switching from stereoselective visible-light-regulated radical polymerization.

Язык: Английский

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Regiodivergent Arylation of Pyridines via Zincke Intermediates

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(8)

Опубликована: Ноя. 21, 2023

Abstract An arylation protocol for pyridines is described, via the ring‐opened Zincke intermediate. Treatment of with triflic anhydride and a secondary amine produces an azahexatriene species, which undergoes regioselective Pd‐catalyzed at putative C4 position. Recyclization then provides pyridine products. Alternatively, metal‐free diaryliodonium salt selective meta ‐position, affording regiodivergent approach to biaryls from common

Язык: Английский

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