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1.
J Am Chem Soc ; 146(23): 15693-15700, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38820134

RESUMO

The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp3)-rich structural landscape. Herein, we report a general approach toward the aryl-alkylation of alkenes through a triple radical sorting mechanism. Over the course of the reaction, a high energy aryl radical, a primary radical, and a hindered alkyl radical are simultaneously formed. Through mediation by a nickel-based catalyst, the three radicals are sorted into productive bond-forming pathways toward the efficient aryl-alkylation of alkenes. A wide range of electronically and sterically differentiated alkenes and aryl radical precursors can be used to access complex scaffolds. This method was further applied to the synthesis of highly substituted semisaturated fused heterocycles.

2.
Nature ; 628(8006): 104-109, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38350601

RESUMO

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1-8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp3)-C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)-C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.


Assuntos
Alcenos , Catálise , Hidrogênio , Ácidos/química , Álcoois/química , Alcenos/química , Biomimética , Hidrogênio/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
3.
J Am Chem Soc ; 144(39): 17815-17823, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36137527

RESUMO

A neighboring boronate group in the substrate provides a dramatic rate acceleration in transmetalation to copper and thereby enables organoboronic esters to participate in unprecedented site-selective cross-couplings. This cross-coupling operates under practical experimental conditions and allows for coupling between vicinal bis(boronic esters) and allyl, alkynyl, and propargyl electrophiles as well as a simple proton. Because the reactive substrates are vicinal bis(boronic esters), the cross-coupling described herein provides an expedient new method for the construction of boron-containing reaction products from alkenes. Mechanistic experiments suggest that chelated cyclic ate complexes may play a role in the transmetalation.


Assuntos
Cobre , Ésteres , Alcenos/química , Boro/química , Ácidos Borônicos/química , Catálise , Cobre/química , Ésteres/química , Estrutura Molecular , Prótons
4.
Angew Chem Int Ed Engl ; 61(35): e202207150, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35727296

RESUMO

The rapid exploration of sp3 -enriched chemical space is facilitated by fragment-coupling technologies that utilize simple and abundant alkyl precursors, among which alcohols are a highly desirable, commercially accessible, and synthetically versatile class of substrate. Herein, we describe an operationally convenient, N-heterocyclic carbene (NHC)-mediated deoxygenative Giese-type addition of alcohol-derived alkyl radicals to electron-deficient alkenes under mild photocatalytic conditions. The fragment coupling accommodates a broad range of primary, secondary, and tertiary alcohol partners, as well as structurally varied Michael acceptors containing traditionally reactive sites, such as electrophilic or oxidizable moieties. We demonstrate the late-stage diversification of densely functionalized molecular architectures, including drugs and biomolecules, and we further telescope our protocol with metallaphotoredox cross-coupling for step-economic access to sp3 -rich complexity.


Assuntos
Álcoois , Alquilantes , Álcoois/química , Alquilação , Catálise , Oxirredução
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