RESUMO
Due to the lower LUMO energy level at the ß-position of α,ß-unsaturated-ß-trifluoromethyl enone than that of its non-fluorinated counterpart, there is a challenge to activate the sp2 C-H bond of aromatic rings. Herein, we have reported iridium(III)-catalyzed ß-trifluoromethyl enone carbonyl-directed regioselective aromatic C(sp2)-H olefination with acrylates under oxidative conditions. Furthermore, coupling with natural product-derived acrylates, scale-up and product diversification have also been performed.
RESUMO
Chemodivergent reactions are more advantageous in organic synthesis that yield diversely functionalized scaffolds from common starting materials. Herein, we report an efficient metal-free chemodivergent protocol for the synthesis of 1-substituted 9H-pyrrolo[1,2-a]indole derivatives in the presence of catalytic amounts of Lewis acid/Brønsted acid conditions using 3-substituted indoles and ß-trifluoromethyl-α,ß-unsaturated ketones. Fine-tuning of the catalyst and solvent system in the reaction conditions deliver the trifluoromethyl, trifluoroethylcarboxylate, or carboxylic acid substituents on the C1-position of 9H-pyrrolo[1,2-a]indole derivatives in situ. It is postulated that the solvent and LA/BA catalyst interaction was found to be crucial for the catalytic C-F activation in these transformations.
RESUMO
Pyridine is a crucial heterocyclic scaffold that is widely found in organic chemistry, medicines, natural products, and functional materials. In spite of the discovery of several methods for the synthesis of functionalized pyridines or their integration into an organic molecule, new methodologies for the direct functionalization of pyridine scaffolds have been developed during the past two decades. In addition, transition-metal-catalyzed C-H functionalization and rare earth metal-catalyzed reactions have flourished over the past two decades in the development of functionalized organic molecules of concern. In this review, we discuss recent achievements in the transition-metal and rare earth metal-catalyzed C-H bond functionalization of pyridine and look into the mechanisms involved.
RESUMO
RATIONALE: Metabolite profiling is an integral part of the drug development process for selecting candidates with high therapeutic efficacy and low risk. Baricitinib (BARI) was approved in 2018 by the US Food and Drug Administration to treat rheumatoid arthritis. According to the available literature, no systematic study has been reported on the metabolite profiling of BARI. The biotransformation pathway of the drug has also not been established until recently. This study aims to identify BARI metabolites generated in in vitro matrices. METHODS: The in vitro metabolism study was carried out using rat liver microsome, human liver microsomes, and human S9 fraction. Ultra high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (U-HPLC-Q/TOF) and ultra-high-performance liquid chromatography/linear ion trap-Orbitrap mass spectrometry (U-HPLC/LTQ-Orbitrap-MS/MS) were used to identify and characterize the metabolites of BARI. The in silico toxicity of BARI and its metabolite was studied using ProTox-II toxicity predictor software. RESULTS: A total of five new metabolites have been identified amongst which two (M1 and M2) were detected on both U-HPLC/LTQ-Orbitrap-MS/MS and U-HPLC-Q/TOF and two additional metabolites (M4 and M5) were detected on U-HPLC/LTQ-Orbitrap-MS/MS. Moreover, one metabolite (M3) was only detected on LC-QTOF. CONCLUSIONS: The major metabolic changes were found to be N-dealkylation, demethylation, hydroxylation, and hydrolysis. Metabolites M3 and M4 were found to have the potential for carcinogenicity. The novelty of the study can be justified by the unavailability of any previous research on in vitro metabolite profiling of BARI. Furthermore, this is the first time the biotransformation pathway of BARI and the toxicity potential of its metabolites have been reported.
Assuntos
Microssomos Hepáticos , Espectrometria de Massas em Tandem , Animais , Azetidinas , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Microssomos Hepáticos/metabolismo , Protoporfirinogênio Oxidase/metabolismo , Purinas , Pirazóis , Ratos , Sulfonamidas , Espectrometria de Massas em Tandem/métodosRESUMO
The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the ß-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.
Assuntos
Alcenos/química , Antineoplásicos/farmacologia , Iminas/química , Isoindóis/farmacologia , Nitrilas/química , Ródio/química , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoindóis/síntese química , Isoindóis/química , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin.
Assuntos
Antineoplásicos/farmacologia , Cromonas/síntese química , Naftoquinonas/síntese química , Ródio/química , Succinimidas/análise , Xantonas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Cromonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Naftoquinonas/química , Naftoquinonas/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Xantonas/química , Xantonas/farmacologiaRESUMO
The rhodium(III)-catalyzed direct C-H functionalization of various indolines with 1,4,2-dioxazol-5-ones as new amidating agents is described. This transformation provides efficient preparation of C7-amidated indolines known to display potent anticancer activity. The synthetic compounds were evaluated for in vitro anticancer activity against human prostate adenocarcinoma cells (LNCaP), human endometrial adenocarcinoma cells (Ishikawa), and human ovarian carcinoma cells (SKOV3). Compound 4f was found to be highly cytotoxic, with activity competitive with that of anticancer agent doxorubicin.
Assuntos
Amidas/química , Indicadores e Reagentes/química , Indóis/química , Ródio/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/farmacologia , Masculino , Análise Espectral/métodosRESUMO
The rhodium(III)-catalyzed mild and site-selective C-H allylation of enol carbamates with 4-vinyl-1,3-dioxolan-2-one and allylic carbonates affords allylic alcohols and terminal allylated products, respectively. The assistance of the carbamoyl directing group provides a straightforward preparation of biologically and synthetically important allylated enol carbamates.
RESUMO
The rhodium(III)-catalyzed γ-trifluoromethylallylation of various heterocyclic C-H bonds with CF3-substituted allylic carbonates is described. These reactions provide direct access to linear CF3-containing allyl frameworks with complete trans-selectivity via C-H bond activation followed by a formal SN-type reaction pathway.
RESUMO
The rhodium(III)-catalyzed site-selective C-H alkylation of various N-heterocycles, such as indolines, carbazoles, and pyrroles with readily available allylic alcohols is described. This protocol allows the generation of a heterocyclic scaffold containing a ß-aryl carbonyl moiety, which is known to be a crucial structural unit of biologically active compounds.
RESUMO
The rhodium(III)-catalyzed ortho-C-H amidation of azobenzenes with arylsulfonyl and aryl and alkyl isocyanates is described. The N-sulfonyl amidation reaction using arylsulfonyl isocyanates is first reported in the C-H activation strategy. These transformations provide the facile and efficient construction of a range of amide moieties into azobenzenes.
Assuntos
Amidas/síntese química , Compostos Azo/síntese química , Compostos Organometálicos/química , Ródio/química , Ácidos Sulfônicos/síntese química , Amidas/química , Compostos Azo/química , Catálise , Estrutura Molecular , Ácidos Sulfônicos/químicaRESUMO
The rhodium(III)-catalyzed direct amidation of indoles and pyrroles with aryl and alkyl isocyanates is described. These transformations provide a facile and efficient construction of C2-amidated N-heterocyclic scaffolds.
Assuntos
Amidas/química , Compostos Heterocíclicos/síntese química , Indóis/química , Isocianatos/química , Pirróis/química , Catálise , Compostos Heterocíclicos/química , Estrutura Molecular , Ródio/químicaRESUMO
The rhodium(III)-catalyzed direct allylation of indolines with allylic carbonates at room temperature is described. These transformations provide the facile and efficient construction of C7-allylated indolic scaffold.
Assuntos
Compostos Alílicos/química , Carbonatos/química , Indóis/química , Ródio/química , Catálise , Estereoisomerismo , TemperaturaRESUMO
A ketone-assisted ruthenium-catalyzed selective amination of xanthones and chromones C-H bonds with sulfonyl azides is described. The reactions proceed efficiently with a broad range of substrates with excellent functional group compatibility. This protocol provides direct access to 1-aminoxanthones, 5-aminochromones, and 5-aminoflavonoid derivatives known to exhibit potent anticancer activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azidas/síntese química , Azidas/farmacologia , Cromonas/síntese química , Cromonas/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Rutênio/química , Xantonas/síntese química , Xantonas/farmacologia , Aminação , Antineoplásicos/química , Azidas/química , Catálise , Cromonas/química , Flavonoides/química , Estrutura Molecular , Xantonas/químicaRESUMO
A palladium-catalyzed oxidative coupling of arene C-H bonds with benzylic ethers via C-H bond activation is described. The reaction proceeds efficiently with a broad range of substrates bearing conventional directing groups with excellent functional group compatibility. This protocol potentially provides opportunities to use dibenzyl ethers as new acyl equivalents for catalytic acylation reactions.
Assuntos
Éteres/química , Paládio/química , Catálise , Ligação de Hidrogênio , Acoplamento OxidativoRESUMO
A copper-catalyzed oxidative coupling of 2-carbonyl-substituted phenols and 1,3-dicarbonyl compounds with a wide range of dibenzyl or dialkyl ethers is described. This protocol provides an efficient preparation of phenol esters and enol esters in good yields with high chemoselectivity. This method represents an alternative protocol for classical esterification reactions.
Assuntos
Compostos de Benzil/química , Cobre/química , Éteres/química , Éteres/síntese química , Fenóis/química , Fenóis/síntese química , Catálise , Esterificação , Ésteres , Estrutura Molecular , OxirreduçãoRESUMO
The rhodium-catalyzed oxidative C2-olefination of indoles and pyrroles containing N-arylcarboxamide directing groups with a range of alkenes and subsequent cleavage of directing groups is described. This method provides direct and efficient access to C2-functionalized free (NH)-heterocycles.
Assuntos
Carbono/química , Hepatócitos/citologia , Indóis/química , Pirróis/química , Ródio/química , Catálise , OxirreduçãoRESUMO
A palladium-catalyzed ortho-acylation of N-benzyltriflamides from the alcohol oxidation level via C-H bond activation is described. These transformations have been applied to a wide range of substrates, and typically proceed with excellent levels of chemoselectivity and with high functional group tolerance.
Assuntos
Álcoois/química , Amidas/química , Cetonas/síntese química , Catálise , Cetonas/química , Estrutura Molecular , Oxirredução , Paládio/químicaRESUMO
A palladium(II)-catalyzed direct acylation of acetophenone N-Boc hydrazones with aldehydes via C-H bond activation is described. This protocol provides direct access to a range of 1,2-diacylbenzenes, which are useful precursors to construct biologically interesting and pharmaceutically important compounds.
Assuntos
Aldeídos/química , Benzofenonas/síntese química , Hidrazonas/química , Compostos Organometálicos/química , Paládio/química , Acilação , Benzofenonas/química , Catálise , Estrutura MolecularRESUMO
Tandem rhodium-catalyzed oxidative allylation and annulation of acetanilides with allyl acetate to afford the corresponding indoles are described. In addition, the site-selective C2 allylation, crotylation and prenylation of indoles using allylic acetates under rhodium catalysis are reported.