“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(8), С. 5305 - 5331

Опубликована: Апрель 4, 2023

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet beneficial effect chloro substituent has not been reviewed. The seemingly simple substitution a hydrogen atom (R = H) with chlorine Cl) can result remarkable improvements potency up to 100,000-fold lead profound effects on pharmacokinetic parameters including clearance, half-life, drug exposure vivo. Following literature terminology "magic methyl effect" term coined herein. Although reports 500-fold or 1000-fold often serendipitous discoveries that be considered "magical" rather planned, hypotheses made explain magic lessons accelerate cycle discovery.

Язык: Английский

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Pd-catalyzed regioselective activation of C(sp²)–H and C(sp³)–H bonds

Chemical Society Reviews, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Differentiating between two highly similar C-H bonds in a given molecule remains fundamental challenge synthetic organic chemistry. Directing group assisted strategies for the functionalisation of proximal has been known last few decades. However, distal bond is strenuous and requires distinctly specialised techniques. In this review, we summarise advancement Pd-catalysed C(sp

Язык: Английский

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Catalyst-Free Regio- and Stereoselective C(sp²)–H Chlorination of Enamides at Room Temperature

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 29, 2025

We disclose herein a catalyst-free, room-temperature protocol for the highly regio- and stereoselective alkenyl C(sp2)-H chlorination of diverse enamides with commercially available, inexpensive N-chlorosuccinimide (NCS) as electrophilic chlorinating reagent under exceedingly mild conditions. This operationally simple approach features remarkably broad substrate scope accommodates excellent functional group tolerance, affording range synthetically valuable geometrically defined β-chlorinated in high yields an exclusive E configuration.

Язык: Английский

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meta‐C−H Arylation of Aniline Derivatives via Palladium/ S,O‐Ligand/Norbornene Cooperative Catalysis

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(5)

Опубликована: Дек. 12, 2023

Aromatic amines are ubiquitous moieties in organic molecules and their direct functionalization is of great interest many research areas due to prevalence pharmaceuticals electronics. While several synthetic tools exist for the ortho- para-functionalization anilines, less reactive meta-position not easy achieve with current methods. To date, meta-C-H arylation aniline derivatives has been restricted either use directing groups & templates, or transformation into anilides quaternary anilinium salts. Herein, we report first general efficient meta-C-H-arylation non-directed via cooperative catalysis a palladium-S,O-ligand-norbornene system. The reaction proceeds under mild conditions wide range aryl iodides, while being operationally simple scalable. Our preliminary mechanistic investigation-including isolation palladium complexes deuterium experiments-reveal useful insights substituent-effects both aniline-substrate norbornene-mediator during activation step.

Язык: Английский

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Deciphering the Mechanistic Insights of Temporary Directing-Group-Assisted meta-Alkenylation of Complex Biaryl Systems

ACS Catalysis, Год журнала: 2023, Номер 13(16), С. 11091 - 11103

Опубликована: Авг. 7, 2023

The recently developed palladium-catalyzed C(sp2)–H olefination of 2-arylbenzaldehyde with the aid a temporary directing group (TDG) via reversible imine formation delivers selective meta-C–H functionalization and possesses significant advantages over well-established covalently attached (DG) approach. In this report, combined computational experimental investigation has been performed to elucidate detailed reaction mechanism origins such remote meta-selectivity. proceeds in three major steps: C–H activation, 1,2-migratory insertion, β-hydride elimination. While insertion olefin is found be turnover-determining step, selectivity predetermined by preceding activation step. observations have corroborated along experimentally conducted order determination studies, primary kinetic isotope effect (PKIE) study, free energy correlation Hammett plots. A DG-bound Pd complex shown competent promote meta-alkenylation. All possible Pd-catalyzed template-directed (ortho′, ortho, meta, para) olefinations 2-aryl benzaldehyde/aniline computationally investigated. density functional theory (DFT)-based computations indicated that other reactions necessitate higher barriers compared meta-olefination. Distortion-interaction analysis (DIA), noncovalent interaction (NCI) analysis, isodesmic studies were executed unravel mystery behind origin meta-regioselectivity.

Язык: Английский

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Ligand-Promoted Remote γ-C(sp³)–H Chlorination and Bromination of Alcohols

The Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

Herein, we report a Pd(II)-catalyzed protocol f-C(sp3)–H chlorination and bromination of aliphatic alcohols using NCS NBS as the halogenating reagents. The addition 2-pyridone ligand base was crucial to success reaction. method showed excellent functional group tolerance. gram-scale reaction facile removal directing demonstrated its potential application in synthesis γ-chloro or bromo containing quaternary carbon.

Язык: Английский

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Palladium Catalyzed Regioselective Distal C(sp2)-H Functionalization

Chemical Communications, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The selective functionalization of C-H bonds in arenes remains a challenging task organic synthesis. While directing group (DG)-assisted strategies for proximal activation are well-established, distal meta and para-C-H has proven more elusive attracted significant interest. Palladium-catalyzed activation, particular, emerged as promising approach achieving site-selectivity these transformations. This review provides comprehensive overview recent advances palladium-catalyzed functionalization, delving into mechanistic details the scope strategies. By summarizing successes challenges this field, we aim to illuminate potential avenues future research development synthetic methodology.

Язык: Английский

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Palladium-catalyzed remote meta-C–H olefination of cinnamates

Chemical Communications, Год журнала: 2023, Номер 59(35), С. 5249 - 5252

Опубликована: Янв. 1, 2023

Palladium-catalyzed novel remote meta -C–H olefination of geometrically challenging cinnamates using nitrile directing group derived from 2-cyanobenzoic acid has been described. A variety bioactive molecules tethered acrylates have coupled.

Язык: Английский

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meta‐C−H Arylation of Aniline Derivatives via Palladium/ S,O‐Ligand/Norbornene Cooperative Catalysis

Angewandte Chemie, Год журнала: 2023, Номер 136(5)

Опубликована: Дек. 12, 2023

Abstract Aromatic amines are ubiquitous moieties in organic molecules and their direct functionalization is of great interest many research areas due to prevalence pharmaceuticals electronics. While several synthetic tools exist for the ortho ‐ para ‐functionalization anilines, less reactive meta ‐position not easy achieve with current methods. To date, ‐C−H arylation aniline derivatives has been restricted either use directing groups & templates, or transformation into anilides quaternary anilinium salts. Herein, we report first general efficient ‐C−H‐arylation non‐directed via cooperative catalysis a palladium–S,O‐ligand–norbornene system. The reaction proceeds under mild conditions wide range aryl iodides, while being operationally simple scalable. Our preliminary mechanistic investigation–including isolation palladium complexes deuterium experiments–reveal useful insights substituent‐effects both aniline‐substrate norbornene‐mediator during activation step.

Язык: Английский

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Distal meta-C–H functionalization of α-substituted cinnamates

Chemical Science, Год журнала: 2023, Номер 14(22), С. 5880 - 5886

Опубликована: Янв. 1, 2023

Distal meta -selective C–H olefination, allylation, acetoxylation and cyanation of α-substituted cinnamates have been reported. New coupling partners such as quinones, maleimides sulfolene were utilized for the first time in -C–H activation.

Язык: Английский

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