RESUMO
Here we report an efficient access to high-value N-polyfluoroalkyl anilines, primary polyfluoroalkylamines and N,N-bis(polyfluoroalkyl)amines, via N-polyfluoroalkylation of sulfonamides and phthalimide derivatives using sulfuryl fluoride (SO2 F2 ). The inâ situ formation of polyfluoroalkyl fluorosulfonates from commercially available fluorinated alcohols and economical sulfuryl fluoride is highly advantageous given that some polyfluoroalkyl halides are ozone-depleting substances (ODS) regulated by the Montreal protocol. This general method is applied to the polyfluoroalkylation of a variety of sulfonamides, N-sulfonyl carbamates and phthalimide with a wide tolerance of functional groups. The process thus provides viable access for industry to N-(polyfluoroalkyl)anilines as well as primary and secondary N-(polyfluoroalkyl)amines, which are very valuable but not easily accessible building blocks for life science applications.
Assuntos
Aminas , Compostos de Nitrogênio , Compostos de Anilina , Sulfonamidas , NitrogênioRESUMO
The N-alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of nontoxic, economic, and commercially available alcohol derivatives on exposure to SO2F2 gas. The use of electron-withdrawing groups and DMAc as solvent affords a (Z)- and N-endocyclic selectivity for the easy introduction of a variety of alkyl and polyfluoroalkyl chains.
Assuntos
AlquilaçãoRESUMO
In the context of new scaffolds obtained by photochemical reactions, Paternò-Büchi reactions between heteroaromatic, trifluoromethylphenyl ketone and electron rich alkenes to give oxetanes are described. A comprehensive study has then been carried out on the reaction of aromatic ketones with fluorinated alkenes. Depending on the substitution pattern at the oxetane ring, a metathesis reaction is described as a minor side process to give mono fluorinated alkenes. Overall, this last reaction corresponds to a photo-Wittig reaction and yield amid isosteres. In order to explain the uncommon regioselectivity of the Paternò-Büchi reaction with these alkenes, electrostatic-potential derived charges (ESP) have been determined. In a second computational study, the relative stabilities of the typical 1,4-diradical intermediates of the Paternò-Büchi reaction have been determined. The results well explain the regioselectivity. Further transformations of the oxetanes or previous functionalization of the fluoroalkenes open perspectives for oxetanes as core structures for biologically active compounds.
Assuntos
Alcenos , Cetonas , EstereoisomerismoRESUMO
Several approaches were developed for the preparation of phosphorus-substituted 5- and 6-membered benzophostams. Carbodiimide-promoted cyclization of zwitterionic aminophosphinates derived from a nitrobenzene precursor accomplished the cyclization in good yields. Alternatively, a novel copper-catalyzed cross-coupling between a phosphonamide and a bromobenzene precursor produced the heterocycles in moderate to good yields. Three different methods are compared for the synthesis of the P-ethoxy-substituted 5-membered benzophostam.
RESUMO
The synthesis of glycopyranosyl nucleosides modified in the sugar moiety has been less frequently explored, notably because of the lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.
Assuntos
NucleosídeosRESUMO
New phosphorous-containing lead structures against drought stress in crops interacting with RCAR/(PYR/PYL) receptor proteins were identified starting from in-depth SAR studies of related sulfonamide lead structures and protein docking studies. A converging 6-step synthesis via phosphinic chlorides and phosphono chloridates as key intermediates afforded envisaged tetrahydroquinolinyl phosphinamidates and phosphonamidates. Whilst tetrahydroquinolinyl phosphonamidates 13a,b exhibited low to moderate target affinities, the corresponding tetrahydroquinolinyl phosphinamidates 12a,b revealed confirmed strong affinities for RCAR/ (PYR/PYL) receptor proteins in Arabidopsis thaliana on the same level as essential plant hormone abscisic acid (ABA) combined with promising efficacy against drought stress in vivo (broad-acre crops wheat and canola).
Assuntos
Amidas/farmacologia , Produtos Agrícolas/efeitos dos fármacos , Secas , Compostos Organofosforados/farmacologia , Proteínas de Plantas/química , Quinolinas/farmacologia , Ácido Abscísico/metabolismo , Amidas/química , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Produtos Agrícolas/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organofosforados/química , Proteínas de Plantas/metabolismo , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
A new strategy was developed using fluorinated acetoacetates, malononitrile, and fluoroalkyl amino reagents (FARs) to access unprecedented 4,6-bis(fluoroalkyl)pyrimidine-5-carboxylates, their carboxylic acid analogues, and 4-amino-6-(fluoroalkyl)pyrimidine-5-carbonitriles. An efficient cyclization step using suitable amidines was developed under microwave irradiation, providing the desired pyrimidines rapidly and efficiently. Standard saponification conditions were applied from carboxylate derivatives to access to the corresponding carboxylic acids. These new valuable building blocks, bearing either a single or two emergent fluorinated substituents, hold strong potential for medicinal and agrochemical research.
RESUMO
Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)-a class of chemicals that was slightly forgotten over the last decades-has emerged again recently and proved to be a powerful tool for the introduction of various fluorinated groups onto (hetero)aromatic derivatives.
Assuntos
Halogenação , Compostos Heterocíclicos/síntese química , Hidrocarbonetos Fluorados/síntese química , Flúor/química , Compostos Heterocíclicos/química , Hidrocarbonetos Fluorados/química , EstereoisomerismoRESUMO
A novel approach towards highly functionalized fluoroalkyl pyrazoles was developed by using fluoroalkyl amino reagents in combination with a variety of fluorinated ketimines. Tuneable introduction of fluoroalkyl groups in the 3- and 5-positions was possible by using vinamidinium intermediates or the corresponding enamino ketones after hydrolysis. These high-value building blocks can give rise to a large number of analogues for bioactivity screening and discovering new heterocyclic bioactive ingredients in various life science fields.
RESUMO
A range of valuable 1-indanols and 1-indanamines containing a tertiary C1 atom were synthesized by intramolecular palladium(0)-catalyzed C(sp(3))-H arylation, despite unfavorable steric interactions. The efficiency of the reaction was found to correlate with the degree of substitution at C2, as expected from the Thorpe-Ingold effect. Additionally, the nature of the heteroatomic substituent at C1 had a marked influence on the diastereoselectivity at C1 and C2; indeed, 1-indanols and 1-indanamines were obtained with the opposite relative configuration. Analysis of the X-ray and DFT-optimized structures of the corresponding reactive intermediates provided useful insights into the subtle conformational effects induced by these substituents.
RESUMO
A new general access to A-ring aromatic strigolactones, a new class of plant hormones, has been developed. The key transformations include in sequence ring-closing metathesis, enzymatic kinetic resolution and a radical cyclization with atom transfer to install the tricyclic ABC-ring system. The activity as plant hormones for the inhibition of shoot branching in pea of various analogues synthesized by this strategy is reported.
Assuntos
Lactonas/síntese química , Pisum sativum/química , Reguladores de Crescimento de Plantas/síntese química , Lactonas/química , Lactonas/metabolismo , Estrutura Molecular , Pisum sativum/metabolismo , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/metabolismo , Relação Estrutura-AtividadeRESUMO
In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon-fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of -CFH2, -CF2H, -C n F2 n +1 and -SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.
RESUMO
A synthesis to access rarely described 3-amino-5-fluoroalkylfurans has been developed by cyclization of easily accessible fluorovinamides. This method is rapid and simple and affords the desired furans as hydrochloride salts in quantitative or nearly quantitative yields. It is compatible with four different fluorinated groups (-CF3, -CF2CF3, -CHF2, and -CF2Cl) and a wide range of substituents on the amine.
RESUMO
The functionalization of 3-(difluoromethyl)pyridine has been developed via direct deprotonation of -CHF2 with a lithiated base and subsequent trapping with various electrophiles in THF. In situ quenching gives access to 3-pyridyl-CF2-SiMe2Ph as a new silylated compound, which can be postfunctionalized with a fluoride source to obtain a larger library of 3-(difluoroalkyl)pyridines that could not be accessed via direct deprotonation.
RESUMO
Avenues to bi- and tricyclic building blocks for the elaboration of sordaricin and its analogues are described. The target molecules were obtained through inter- and intramolecular Diels-Alder reactions of a number of previously unknown cyclopentadienes. Unusual properties of 3-cyanoenones and 1-cyanocyclopentadienes have been unveiled and circumvented.
Assuntos
Indenos/síntese química , Inibidores da Síntese de Proteínas/síntese química , Terpenos/química , Ácidos Carboxílicos/química , Ciclopentanos/química , Indenos/química , Nitrilas/química , Oxigênio/química , Inibidores da Síntese de Proteínas/química , EstereoisomerismoRESUMO
After nitrogen, fluorine is probably the next most favorite hetero-atom for incorporation into small molecules in life science-oriented research. This review focuses on a particular fluorinated substituent, the trifluoromethoxy group, which is finding increased utility as a substituent in bioactives, but it is still perhaps the least well understood fluorine substituent in currency. The present review will give an overview of the synthesis, properties and reactivity of this important substituent.
RESUMO
The xanthate-mediated addition of tertiary alkyl radicals to heteroarenes enabled the easy functionalization of heteroaromatic rings as well as more decorated structures, such as marketed drugs or agrochemicals. This work provides a synthetic tool for efficiently exploring the chemical space by allowing late-stage diversification with a high tolerance toward functional groups.
RESUMO
3,5-Dihalogeno-4-methoxy-N-methylpyridin-2(1H)-ones have been shown to undergo single Suzuki coupling reactions in a site-selective fashion. Monoarylations occur at the C-5 position preferentially, thus leaving the remaining C-3 halide free for further functionalization, to finally access differentially 3,5-disubstituted 2-pyridones. This two-step strategy has been applied to the elaboration of the 3-acyl-5-aryl-4-oxy-2-pyridone subunit that is prevalent in numerous bioactive natural products. [reaction: see text].
Assuntos
Acetatos/química , Paládio/química , Piridonas/síntese química , Catálise , Estrutura Molecular , Piridonas/química , EstereoisomerismoRESUMO
We describe a synthesis of ketones 3 (X = O-R or CN; Y = H or alkyl), which are useful building blocks for the preparation of analogs of the potent antifungal agent sordarin, 1. Congeners of 1 constructed from 3 should permit detailed SAR investigations of the terpenoid core of the natural product.
Assuntos
Antifúngicos/síntese química , Indenos/síntese química , Terpenos/química , Antifúngicos/química , Antifúngicos/farmacologia , Indenos/química , Indenos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Terpenos/síntese químicaRESUMO
Fluoroalkyl amino reagents 1a and 2a have been developed from commercially available trifluoromethyl trifluorovinyl ether via a hydroamination reaction with diethylamine or dimethylamine. These reagents can be activated by treatment with a Lewis acid and subsequently used as a mono- or dielectrophile for the introduction of the fluoro(trifluoromethoxy)methyl group, either in Vilsmeier-type acylations of aromatic substrates or in the synthesis of fluorinated pyrazoles from CH-acidic substrates and of bis-fluorinated pyrazoles, all being important building blocks for medicinal and agricultural chemistry.