Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp³)–C(sp³) Cross-Coupling via Radical Sorting

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(14), С. 6185 - 6192

Опубликована: Март 30, 2022

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, resulting open-shell intermediates can subsequently participate transition metal catalysis. In this report, we describe C(sp3)–C(sp3) cross-coupling of alcohols through dual combination N-heterocyclic carbene (NHC)-mediated deoxygenation hypervalent iodine-mediated decarboxylation. This mild practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array alkyl–alkyl cross-coupled products, including highly congested quaternary carbon centers from corresponding tertiary or acids. We demonstrate applications methodology alcohol C1-alkylation formal homologation, as well late-stage functionalization drugs, natural biomolecules.

Язык: Английский

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Deoxytrifluoromethylation of Alcohols

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(27), С. 11961 - 11968

Опубликована: Июль 5, 2022

Deoxy-functionalization of alcohols represents a class reactions that has had profound impact on modern medicine. In particular, deoxyfluorination is commonly employed as means to incorporate high-value fluorine atoms into drug-like molecules. Recently, the trifluoromethyl (CF3) group garnered attention from medicinal chemists due its ability markedly improve pharmaceutical properties small-molecule drug candidates. To date, however, there remains no general accomplish analogous deoxygenative trifluoromethylation alcohols. We report herein copper metallaphotoredox-mediated direct deoxytrifluoromethylation, wherein alcohol substrates are activated in situ by benzoxazolium salts for C(sp3)-CF3 bond formation.

Язык: Английский

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Exploiting the Marcus inverted region for first-row transition metal–based photoredox catalysis

Science, Год журнала: 2023, Номер 382(6667), С. 191 - 197

Опубликована: Окт. 12, 2023

Second- and third-row transition metal complexes are widely employed in photocatalysis, whereas earth-abundant first-row metals have found only limited use because of the prohibitively fast decay their excited states. We report an unforeseen reactivity mode for productive photocatalysis that uses cobalt polypyridyl as photocatalysts by exploiting Marcus inverted region behavior couples increases excited-state energies with increased lifetimes. These (III) can engage bimolecular virtue strong redox potentials sufficiently long lifetimes, catalyzing oxidative C(sp2)-N coupling aryl amides challenging sterically hindered boronic acids. More generally, results imply chromophores be designed to increase lifetimes while simultaneously increasing energies, providing a pathway relatively abundant photoredox catalysts.

Язык: Английский

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Nickel Catalysis via S_H2 Homolytic Substitution: The Double Decarboxylative Cross-Coupling of Aliphatic Acids

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(46), С. 21278 - 21286

Опубликована: Ноя. 14, 2022

Cross-coupling platforms are traditionally built around a sequence of closed-shell steps, such as oxidative addition, transmetalation, and reductive elimination. Herein, we describe dual photo/nickel catalytic manifold that performs cross-coupling via complementary involving free radical generation, sorting selective binding to Ni(II) center, bimolecular homolytic substitution (SH2) at high-valent nickel-alkyl complex. This enables the hitherto elusive diverse aliphatic carboxylic acids generate valuable C(sp3)-C(sp3)-products. Notably, powerful SH2 mechanism provides general access sterically encumbered quaternary carbon centers, addressing long-standing challenge in fragment coupling chemistry.

Язык: Английский

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Late-Stage C(sp³)–H Methylation of Drug Molecules

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(5), С. 2787 - 2793

Опубликована: Янв. 25, 2023

Methyl groups are well understood to play a critical role in pharmaceutical molecules, especially those bearing saturated heterocyclic cores. Accordingly, methods that install methyl onto complex molecules highly coveted. Late-stage C-H functionalization is particularly attractive approach, allowing chemists bypass lengthy syntheses and facilitating the expedited synthesis of drug analogues. Herein, we disclose direct introduction via C(sp3)-H broad array heterocycles, enabled by merger decatungstate photocatalysis unique nickel-mediated SH2 bond formation. To further demonstrate its synthetic utility as tool for late-stage functionalization, this method was applied range en route an methylated

Язык: Английский

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Multimetallic-Catalyzed C–C Bond-Forming Reactions: From Serendipity to Strategy

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(12), С. 6596 - 6614

Опубликована: Март 13, 2023

The use of two or more metal catalysts in a reaction is powerful synthetic strategy to access complex targets efficiently and selectively from simple starting materials. While capable uniting distinct reactivities, the principles governing multimetallic catalysis are not always intuitive, making discovery optimization new reactions challenging. Here, we outline our perspective on design elements using precedent well-documented C–C bond-forming reactions. These strategies provide insight into synergy compatibility individual components reaction. Advantages limitations discussed promote further development field.

Язык: Английский

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Rapid and Modular Access to Quaternary Carbons from Tertiary Alcohols via Bimolecular Homolytic Substitution

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(30), С. 16330 - 16336

Опубликована: Июль 20, 2023

Quaternary carbons are ubiquitous in bioactive molecules; however, synthetic methods for the construction of this motif remain underdeveloped. Here, we report synthesis quaternary from tertiary alcohols, a class structurally diverse, bench-stable feedstocks, via merger photoredox catalysis and iron-mediated SH2 bond formation. This alcohol-bromide cross-coupling is enabled by novel halogen-atom transfer (XAT) reagent, which first reductively activated XAT reagent to be reported. A wide variety sterically congested products can accessed through mild practical protocol including derived both alkylation benzylation fragments. We further demonstrate utility method expedited liver receptor agonist two-step conversion ketones esters products, enables modular control up three four substituents on center.

Язык: Английский

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Energy-transfer-induced [3+2] cycloadditions of N–N pyridinium ylides

Nature Chemistry, Год журнала: 2023, Номер 15(8), С. 1091 - 1099

Опубликована: Июнь 26, 2023

Язык: Английский

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Alcohol-alcohol cross-coupling enabled by S _H 2 radical sorting

Science, Год журнала: 2024, Номер 383(6689), С. 1350 - 1357

Опубликована: Март 21, 2024

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target maximizing exploration space, harnessing these building blocks for carbon-carbon bond-forming reactions is key goal in organic chemistry. particular, leveraging single activation mode form new C(sp

Язык: Английский

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Bismuth radical catalysis in the activation and coupling of redox-active electrophiles

Nature Chemistry, Год журнала: 2023, Номер 15(8), С. 1138 - 1145

Опубликована: Июнь 1, 2023

Radical cross-coupling reactions represent a revolutionary tool to make C(sp3)-C and C(sp3)-heteroatom bonds by means of transition metals photoredox or electrochemical approaches. However, the use main-group elements harness this type reactivity has been little explored. Here we show how low-valency bismuth complex is able undergo one-electron oxidative addition with redox-active alkyl-radical precursors, mimicking behaviour first-row metals. This paradigm for gives rise well-defined complexes, which could be fully characterized in solution solid state. The resulting Bi(III)-C(sp3) intermediates display divergent patterns depending on α-substituents alkyl fragment. Mechanistic investigations led development bismuth-catalysed C(sp3)-N reaction that operates under mild conditions accommodates synthetically relevant NH-heterocycles as coupling partners.

Язык: Английский

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