RESUMO
Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via ß-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.
Assuntos
Cloretos/química , Metano/análogos & derivados , Níquel/química , Catálise , Humanos , Metano/química , MetilaçãoRESUMO
A selective synthesis of acrylamides had been developed using the Doebner-Knoevenagel condensation. The reaction occurs under mild conditions at ambient temperatures, tolerates a wide array of functional groups, and affords the E-isomer with high selectivity. The reported method expands the scope of this classic reaction to a class of industrially important products and as well as to the use of aliphatic aldehydes. An organocatalytic mechanism has been proposed, and the ability to scale the process has been demonstrated.
RESUMO
We report a redox-neutral formylation of aryl chlorides that proceeds through selective 2-functionalization of 1,3-dioxolane through nickel and photoredox catalysis. This scalable benchtop approach provides a distinct advantage over traditional reductive carbonylation in that no carbon monoxide, pressurized gas, or stoichiometric reductant is employed. The mild conditions give unprecedented scope from abundant and complex aryl chloride starting materials.
Assuntos
Cloretos/química , Cloro/química , Radicais Livres/química , Processos Fotoquímicos , Catálise , Dioxolanos/química , Níquel/química , OxirreduçãoRESUMO
A practical one-step method has been developed to prepare α-chloroketones from readily available, inexpensive phenylacetic acid derivatives. The method utilizes the unique reactivity of an intermediate Mg-enolate dianion, which displays selectivity for the carbonyl carbon of chloromethyl carbonyl electrophiles. Decarboxylation of the intermediate occurs spontaneously during the reaction quench. The utility of the reaction products has been demonstrated through the total synthesis of the natural product cimiracemate B.
Assuntos
Acetona/análogos & derivados , Produtos Biológicos/síntese química , Fenilacetatos/química , Fenilpropionatos/síntese química , Acetona/síntese química , Acetona/química , Produtos Biológicos/química , Catálise , Fenilpropionatos/química , EstereoisomerismoRESUMO
A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.
Assuntos
Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Inibidores de Proteases/síntese química , Rutênio/química , Catálise , Ciclização , Ciclopropanos , Indóis/química , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Estrutura Molecular , Prolina/análogos & derivados , Inibidores de Proteases/química , SulfonamidasRESUMO
[structure: see text] Three stereochemically and structurally complex non-natural polyketide macrolides have been synthesized from the same simple polyol precursor. That this polyol fragment is rapidly available in quantity is key to the practicality of these syntheses and allows the targeting of more highly complex and "natural product-like" macrolides.
Assuntos
Técnicas de Química Combinatória , Macrolídeos/síntese química , Polímeros/química , Macrolídeos/química , Estrutura MolecularRESUMO
A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pironas/síntese química , Pironas/farmacologia , Aminação , Catálise , Inibidores da Dipeptidil Peptidase IV/química , Inibidores Enzimáticos , Glicina/análogos & derivados , Glicina/química , Hipoglicemiantes , Cinética , Estrutura Molecular , Oxirredução , Pironas/química , Rutênio/química , EstereoisomerismoRESUMO
The chemoselectivity of a Ru-catalyzed cycloisomerization reaction has been established. The preference for O- capture of the vinylidene intermediate allows for the synthesis of 4-aminodihydropyrans that are valuable synthetic intermediates. The synthetic utility of these structures has been demonstrated in the synthesis of l-forosamine.
Assuntos
Hexosaminas/síntese química , Piranos/síntese química , Rutênio/química , Catálise , Técnicas de Química Combinatória , Ciclização , Hexosaminas/química , Estrutura Molecular , Piranos/química , EstereoisomerismoRESUMO
The rhodium-catalyzed tandem silylformylation-crotylsilylation reaction has been extended to include internal alkynes. Tamao oxidation of the initial product leads to the production of a substituted enol, which undergoes highly diastereoselective tautomerization. The resulting one-pot procedure fashions three new stereocenters, a ketone, and a terminal alkene from a butenyl group, a propynyl group, a silyl hydride, H2O2, and CO.
Assuntos
Alcinos/química , Ródio/química , Silanos/química , OxirreduçãoRESUMO
A convenient one-step RhCl3-catalyzed deprotection of acyclic N-allyl amides is described. Preliminary mechanistic studies reveal that the key to the success of the one-step deprotection process is the dual function of RhCl3 in alcohol solvents. Reaction of RhCl3 with n-PrOH not only provides an active rhodium hydride species to catalyze isomerization of N-allyl amides to corresponding enamides but also generates a crucial catalytic amount of HCl to convert the enamides to deallylated amides through N,O-acetal exchange.
Assuntos
Amidas/química , Química Orgânica/métodos , Ródio/química , Álcoois , Catálise , Modelos Químicos , Solventes/química , Fatores de TempoRESUMO
Polyketide fragments may be rapidly and efficiently assembled in the tandem intramolecular silylformylation-crotylsilylation of alkenes and alkynes. The reactions establish up to three new stereocenters with good-to-excellent diastereoselectivity, and the use of the reaction in an iterative sense is demonstrated. In addition, a new dihydrosilane alcoholysis reaction has been developed, leading to a highly efficient sequence.