Iridium‐Catalysed C−H Borylation of Heteroarenes: Balancing Steric and Electronic Regiocontrol

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 60(6), P. 2796 - 2821

Published: March 23, 2020

The iridium-catalysed borylation of aromatic C−H bonds has become the preferred method for synthesis organoboron compounds. reaction is highly efficient, tolerant a broad range substituents and can be applied to both carbocyclic heterocyclic substrates. regioselectivity activation dominated by steric considerations there have been considerable efforts develop more selective processes less constrained However, most these focused on benzenoid-type substrates in contrast, heteroarenes remain much desired but challenging with position and/or nature heteroatom(s) significantly affecting reactivity regioselectivity. This review will survey heteroarenes, focusing influence electronic effects regiochemical outcome and, linking current mechanistic understandings, provide insights what currently possible where further developments are required.

Language: Английский

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Remarkably Efficient Iridium Catalysts for Directed C(sp²)–H and C(sp³)–H Borylation of Diverse Classes of Substrates

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(13), P. 5022 - 5037

Published: March 30, 2021

Here we describe the discovery of a new class C–H borylation catalysts and their use for regioselective aromatic, heteroaromatic, aliphatic systems. The have Ir–C(thienyl) or Ir–C(furyl) anionic ligands instead diamine-type neutral chelating used in standard conditions. It is reported that employment these newly discovered show excellent reactivity ortho-selectivity diverse classes aromatic substrates with high isolated yields. Moreover, proved to be efficient wide number selective C(sp3)–H bond borylations. Heterocyclic molecules are selectively borylated using inherently elevated bonds. A late-stage functionalization been described same catalysts. Furthermore, one could even open air C(sp2)–H borylations enabling method more general. Preliminary mechanistic studies suggest active catalytic intermediate Ir(bis)boryl complex, attached ligand acts as bidentate ligand. Collectively, this study underlines should find application context chemistry.

Language: Английский

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Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Science, Journal Year: 2022, Volume and Issue: 378(6621), P. 779 - 785

Published: Nov. 17, 2022

Carbon-hydrogen (C−H) functionalization of pyridines is a powerful tool for the rapid construction and derivatization many agrochemicals, pharmaceuticals, materials. Because inherent electronic properties pyridines, selective meta -C−H challenging. Here, we present protocol highly regioselective trifluoromethylation, perfluoroalkylation, chlorination, bromination, iodination, nitration, sulfanylation, selenylation through redox-neutral dearomatization-rearomatization process. The introduced dearomative activation mode provides diversification platform meta-selective reactions on other azaarenes radical as well ionic pathways. broad scope high selectivity these catalyst-free render processes applicable late-stage drugs.

Language: Английский

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Halogenation of the 3-position of pyridines through Zincke imine intermediates

Science, Journal Year: 2022, Volume and Issue: 378(6621), P. 773 - 779

Published: Nov. 17, 2022

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required drug and agrochemical development. However, despite more than a century synthetic endeavors, processes that selectively functionalize carbon-hydrogen bond in 3-position broad range pyridine precursors remain largely elusive. We report reaction sequence pyridyl ring opening, halogenation, closing whereby acyclic Zincke imine intermediates undergo highly regioselective under mild conditions. Experimental computational mechanistic studies indicate nature halogen electrophile can modify selectivity-determining step. Using this method, we produced diverse set 3-halopyridines demonstrated late-stage complex pharmaceuticals agrochemicals.

Language: Английский

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Transition-Metal-Catalyzed Silylation and Borylation of C–H Bonds for the Synthesis and Functionalization of Complex Molecules

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(19), P. 11619 - 11663

Published: Sept. 26, 2023

The functionalization of C–H bonds in organic molecules containing functional groups has been one the holy grails catalysis. One synthetically important approach to diverse is catalytic silylation or borylation bonds, which enables a broad array downstream transformations afford structures. Advances both undirected and directed methods for transition-metal-catalyzed have led their rapid adoption early-, mid-, late-stage synthesis complex molecules. In this Review, we review application bioactive molecules, materials, ligands. Overall, aim provide picture state art as applied modification architectures that will spur further development these reactions.

Language: Английский

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meta‐Selective C−H Functionalization of Pyridines

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(42)

Published: April 4, 2023

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization C-H bonds in pyridines straightforward approach to access valuable substituted pyridines. Compared the direct ortho- para-functionalization, meta-selective far more challenging due inherent electronic properties entity. This review summarizes currently available methods meta-C-H using directing group, non-directed metalation, temporary dearomatization strategies. Recent advances ligand control are highlighted. We analyze advantages as well limitations current techniques hope inspire further developments this area.

Language: Английский

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Enzyme‐like Supramolecular Iridium Catalysis Enabling C−H Bond Borylation of Pyridines with meta‐Selectivity

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(33), P. 18006 - 18013

Published: March 11, 2021

Abstract The use of secondary interactions between substrates and catalysts is a promising strategy to discover selective transition metal for atom‐economy C−H bond functionalization. most powerful are found via trial‐and‐error screening due the low association constants substrate catalyst in which small stereo‐electronic modifications within them can lead very different reactivities. To circumvent these limitations increase level reactivity prediction important reactions, we report herein supramolecular harnessing Zn⋅⋅⋅N that binds pyridine‐like as tight it be some enzymes. distance spatial geometry active site binding ideal target unprecedented meta‐selective iridium‐catalyzed borylations with enzymatic Michaelis–Menten kinetics, besides unique selectivity dormant patterns.

Language: Английский

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Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning

Nature Chemistry, Journal Year: 2023, Volume and Issue: 16(2), P. 239 - 248

Published: Nov. 23, 2023

Abstract Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, chemical complexity molecules often makes late-stage diversification challenging. To address this problem, a platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as critical step in functionalization, computational model predicted yields for diverse conditions with mean absolute error margin 4–5%, while reactivity novel reactions known unknown substrates classified balanced accuracy 92% 67%, respectively. The regioselectivity major products accurately captured classifier F -score 67%. When applied 23 commercial molecules, successfully identified numerous opportunities structural diversification. influence steric electronic information performance quantified, comprehensive simple user-friendly format introduced that proved be key enabler seamlessly integrating experimentation functionalization.

Language: Английский

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Asymmetric C3-Allylation of Pyridines

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: unknown

Published: May 17, 2023

Asymmetric intermolecular C–H functionalization of pyridines at C3 is unprecedented. Herein, we report the first examples such transformations: specifically, C3-allylation via tandem borane and iridium catalysis. First, borane-catalyzed pyridine hydroboration generates nucleophilic dihydropyridines; then, dihydropyridine undergoes enantioselective iridium-catalyzed allylation; finally, oxidative aromatization with air as oxidant gives C3-allylated pyridine. This protocol provides direct access to excellent enantioselectivity (up >99% ee) suitable for late-stage pyridine-containing drugs.

Language: Английский

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Hybrid Machine Learning Approach to Predict the Site Selectivity of Iridium-Catalyzed Arene Borylation

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(31), P. 17367 - 17376

Published: July 31, 2023

The borylation of aryl and heteroaryl C–H bonds is valuable for the site-selective functionalization in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze bond that most acidic least sterically hindered an arene, but predicting site molecules containing multiple arenes difficult. To address this challenge, we report a hybrid computational model predicts Site Borylation (SoBo) SoBo combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, machine learning to predict selectivity extrapolate these predictions new chemical space. Experimental validation showed major pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating will be useful guide experiments specific C(sp2)–H during development.

Language: Английский

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