RESUMEN
Dihydrobenzofuran is an important skeleton for bioactive compounds and natural products. Hydroquinones can be easily modified into substituted hydroquinones, which effectively undergo oxidation to produce the corresponding benzoquinone derivatives. Benzoquinones are reactive electrophiles that are frequently utilized in coupling with olefins to dihydrobenzofurans. Herein, we report the one-pot oxidative coupling of hydroquinones bearing an electron-withdrawing group at the C2 position with olefins to dihydrobenzofurans in the presence of the Lewis acidic FeCl3 and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidant. Furthermore, this method was applied to the oxidative coupling of N-electron-withdrawing group-substituted 4-aminophenol.
Asunto(s)
Alquenos , Benzofuranos , Hidroquinonas , Hidroquinonas/química , Hidroquinonas/síntesis química , Benzofuranos/química , Benzofuranos/síntesis química , Alquenos/química , Estructura Molecular , Acoplamiento Oxidativo , Compuestos Férricos/química , Oxidación-Reducción , Cloruros/química , Benzoquinonas/química , Benzoquinonas/síntesis químicaRESUMEN
The first atroposelective Chan-Lam coupling for the synthesis of C-N axial enantiomers is reported with good yields and ee. MnO2 additive is crucial for the success of the coupling. The longstanding problem of the lack of enantioselective synthesis to make chiral C-N linked atropisomers is solved.
RESUMEN
Although deuterium incorporation into pharmaceutical drugs is an attractive way to expand drug modalities, their physicochemical properties have not been sufficiently examined. This study focuses on examining the changes in physicochemical properties between flurbiprofen (FP) and flurbiprofen-d8 (FP-d8), which was successfully prepared by direct and multiple H/D exchange reactions at the eight aromatic C-H bonds of FP. Although the effect of deuterium incorporation was not observed between the crystal structures of FP and FP-d8, the melting point and heat of fusion of FP-d8 were lower than those of FP. Additionally, the solubility of FP-d8 increased by 2-fold compared to that of FP. Calculation of the interaction energy between FP/FP-d8 and water molecules using the multi-component density functional theory method resulted in increased solubility of FP-d8. These novel and valuable findings regarding the changes in physicochemical properties triggered by deuterium incorporation can contribute to the further development of deuterated drugs.
RESUMEN
Catechols possessing electron-withdrawing groups at the C3 position effectively underwent oxidative functionalization at the C4 position in the presence of phenyliodine(III) diacetate (PIDA) and heteroarene nucleophiles (e.g., indole, indazole, and benzotriazole) to produce the corresponding biaryl products. The PIDA-mediated oxidation of catechol derivatives afforded the ortho-benzoquinone intermediate, which subsequently underwent regioselective nucleophilic addition to the α,ß-unsaturated carbonyl moiety of ortho-benzoquinone using indole, indazole, and benzotriazole to give 4-substituted catechol derivatives in a one-pot manner. Notably, the nucleophilic substitution positions of indazole and benzotriazole were perfectly controlled. Additionally, the reaction using N-methylaniline as the nucleophile afforded a tertiary amine product.
Asunto(s)
Catecoles , Electrones , Benzoquinonas , Estrés OxidativoRESUMEN
All aromatic C-H bonds of triphenylphosphine (PPh3) were efficiently replaced by C-D bonds using Ru/C and Ir/C co-catalysts in 2-PrOH and D2O, an inexpensive deuterium source. Furthermore, non-radioactive and safe deuterium-incorporated Mito-Q (drug candidate) was prepared from deuterated PPh3 and used for the live-cell Raman imaging to evaluate the mitochondrial uptake.
RESUMEN
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them-ADTK1, with an AD ring and 23,24-triple bond-shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells-a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy.
Asunto(s)
Colecalciferol , Vitamina D , Humanos , Vitamina D/farmacología , Colecalciferol/farmacología , Regulación de la Expresión Génica , Diferenciación CelularRESUMEN
The synthesis of polycyclic aromatic compounds generally requires stoichiometric oxidants or homogeneous metal catalysts, however, the risk of contamination of inorganic residues can affect their properties. Here we present a microwave (MW)-assisted platinum on beaded activated carbon (Pt/CB)-catalyzed C-C bond formation of diarylacetylenes and aromatic hydrocarbons under continuous-flow conditions. Various fused aromatic compounds were continuously synthesized via dehydrogenative C(sp2)-C(sp2) and C(sp2)-C(sp3) bond formation with yields of up to 87% without the use of oxidants and bases. An activated, local reaction site on Pt/CB in the flow reaction channel reaching temperatures of more than three hundred degrees Celsius was generated in the catalyst cartridge by selective microwave absorption in CB with an absorption efficiency of > 90%. Mechanistic experiments of the transformation reaction indicated that a constant hydrogen gas supply was essential for activating Pt. This is an ideal reaction with minimal input energy and no waste production.
RESUMEN
3-Methoxycarbonylcatechol effectively underwent two-way regiocontrolled coupling with indoles via an ortho-benzoquinone intermediate, resulting from phenyliodine(III) diacetate oxidation, to generate 4-adducts or 5-adducts with or without BF3·Et2O in a one-pot manner. DFT calculations confirmed the obtained regioselectivities.
Asunto(s)
Indoles , Estrés Oxidativo , Oxidación-ReducciónRESUMEN
Deuterium oxide (D2O) is a special variety of water that serves as a crucial resource in a range of applications, but it is a costly and unusual resource. We therefore developed a new D2O concentration system that combines a polymer electrolyte water electrolyzer and a catalytic combustor for recycling used D2O. In this study, 1.6 L of used D2O, with a concentration of 93.1%, was electrolyzed for 13.6 h to obtain 0.62 L of D2O, with a concentration of 99.3%. In addition, the recombined water obtained by burning electrolytic gas using the catalytic combustor was also electrolyzed for 8.8 h to obtain 0.22 L of D2O, with a concentration of 99.0%. The estimated separation factor of this electrolyzer at 25 °C was 3.6, which is very close to the equilibrium constant of the water/hydrogen isotope exchange reaction. Recycled D2O was used as a deuterium source for the deuteration reaction of sodium octanoate, and 93.6% deuterated sodium octanoate was obtained. It is concluded that there were no impurities in the recycled D2O that interfered with the deuteration reaction. These results can lead to the development of a cost-effective deuteration method for these materials.
RESUMEN
A wide range of aryl boronic 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] were readily synthesized. Purifying aryl boronic esters by conventional silica gel chromatography is generally challenging; however, these introduced derivatives are easily purified on silica gel and isolated in excellent yields. We subjected the purified ArB(Epin) to Suzuki-Miyaura couplings, which provided higher yields of the desired biaryl products than those obtained using the corresponding aryl boronic acids or pinacol esters.
RESUMEN
Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)-H and activated C(sp3)-H bonds while the unactivated C(sp3)-H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)-H and unactivated benzylic C(sp3)-H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)-H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C-H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)-H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.
RESUMEN
Flow reaction methods have been developed to selectively synthesize tertiary, secondary, and primary amines depending on heterogeneous platinum-group metal species under catalytic hydrogenation conditions using nitriles as starting materials. A 10 % Pd/C-packed catalyst cartridge affords symmetrically substituted tertiary amines in good to excellent yields. A 10 % Rh/C-packed catalyst cartridge enables the divergent synthesis of secondary and primary amines, with either cyclohexane or acetic acid as a solvent, respectively. Reaction parameters, such as the metal catalyst, solvent, and reaction temperature, and continuous-flow conditions, such as flow direction and second support of the catalyst in a catalyst cartridge, are quite important for controlling the reaction between the hydrogenation of nitriles and nucleophilic attack of inâ situ-generated amines to imine intermediates. A wide variety of aliphatic and aromatic nitriles could be highly selectively transformed into the corresponding tertiary, secondary, and primary amines by simply changing the metal species of the catalyst or flow parameters. Furthermore, the selective continuous-flow methodologies are applied over at least 72â h to afford three different types of amines in 80-99 % yield without decrease in catalytic activities.
Asunto(s)
Aminas , Nitrilos , Catálisis , Hidrogenación , IminasRESUMEN
A protocol for the ruthenium-on-carbon (Ru/C)-catalyzed solvent-free oxidation of alcohols, which proceeds efficiently under solid-solid (liquid)-gas conditions, was developed. Various primary and secondary alcohols were transformed to corresponding aldehydes and ketones in moderate to excellent isolated yields by simply stirring in the presence of 10% Ru/C under air or oxygen conditions. The solvent-free oxidation reactions proceeded efficiently regardless of the solid or liquid state of the substrates and reagents and could be applied to gram-scale synthesis without loss of the reaction efficiency. Furthermore, the catalytic activity of Ru/C was maintained after five reuse cycles.
Asunto(s)
Alcoholes/química , Aldehídos/síntesis química , Carbono/química , Cetonas/síntesis química , Rutenio/química , Aldehídos/química , Catálisis , Cetonas/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
A tandem oxidative coupling reaction of ß-ketoallenes and arenes was developed, which leads to the formation of 2-furylmethylarenes using AuCl3 and phenyliodine diacetate. The AuIII salt catalyzed the cyclization of ß-ketoallenes to form a 2-furylmethyl gold intermediate, and the subsequent C-H functionalization of arenes proceeded smoothly. During the oxidative coupling, nucleophilic additions occurred at the center and terminal carbon atoms of the allene moiety to form C-O and C-C bonds.
RESUMEN
Facilitated by the dual role of Ceric Ammonium Nitrate (CAN), herein we report a cost-effective approach for the cyanation of aryl iodides/bromides with CAN-DMF as an addition to the existing pool of combined cyanation sources. In addition to being an oxidant, CAN acts as a source of nitrogen in our protocol. The reaction is catalyzed by a readily available Cu(ii) salt and the ability of CAN to generate ammonia in the reaction medium is utilized to eliminate the additional requirement of a nitrogen source, ligand, additive or toxic reagents. The mechanistic study suggests an evolution of CN- leading to the synthesis of a variety of aryl nitriles in moderate to good yields. The proposed mechanism is supported by a series of control reactions and labeling experiments.
RESUMEN
Skeletal reorganization is a type of intriguing processes because of their interesting mechanism, high atom-economy and synthetic versatility. Herein, we describe an unusual, divergent skeletal reorganization of N-sulfonyl ynamides. Upon treatment with lithium diisopropylamine (LDA), N-sulfonyl ynamides undergo a skeletal reorganization to deliver thiete sulfones, while the additional use of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU) shifts the process to furnish propargyl sulfonamides. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistically, experimental and computational studies reveal that these processes may initiate from a lithiation/4-exo-dig cyclization cascade, and the following ligand-dependent 1,3-sulfonyl migration or ß-elimination would control the chemodivergence. This protocol additionally provides a facile access to a variety of privileged molecules from easily accessible ynamides.
RESUMEN
The N-O bond cleavage of 2-oxa-3-azabicyclo substrates, which are readily prepared by the hetero Diels-Alder reaction between nitroso dienophiles and cyclic 1,3-dienes, was effectively catalyzed by heterogeneous copper-on-carbon (Cu/C) under aqueous conditions to give the corresponding cyclic cis-1,4-amino alcohol derivatives. The present method was applied to the direct incorporation of the hydroxy and amino groups derived from a nitroso substrate into cyclic 1,3-dienes with cis-selectivity by the combination of the inâ situ formation of 2-oxa-3-azabicyclo compounds and following Cu/C-catalyzed N-O bond cleavage. The obtained cis-4-aminocyclohexenols, derived from cyclohexadiene as a cyclic 1,3-diene, could be selectively oxidized by using the ruthenium-on-carbon (Ru/C) catalyst under oxygen atmosphere to the corresponding 4-aminocyclohexenones at 50-65 °C or para-iminoquinones at 100-110 °C as useful reactive synthetic precursors.
RESUMEN
A Knoevenagel condensation of various aldehydes with malononitrile effectively proceeded in the presence of hydroquinone/benzoquinone mixed catalysts at room temperature in H2O. Furthermore, γ-deuterium-labeled α,ß-unsaturated nitrile derivatives were also constructed via a deuteration of an aliphatic aldehyde in D2O using a basic resin and the subsequent Knoevenagel condensation.
RESUMEN
3-Arylindoles were easily constructed from indoles and cyclohexanone derivatives using a combination of catalytic niobic acid-on-carbon (Nb2O5/C) and palladium-on-carbon (Pd/C) under heating conditions without any oxidants. The Lewis acidic Nb2O5/C promoted the nucleophilic addition of indoles to the cyclohexanones, and the subsequent dehydration and Pd/C-catalyzed dehydrogenation produced the 3-arylindoles. The additive 2,3-dimethyl-1,3-butadiene worked as a hydrogen acceptor to facilitate the dehydrogenation step.
RESUMEN
An efficient gold-catalyzed cyclization of 2-alkynylaldehyde cyclic acetals has been developed for the synthesis of indenone derivatives. A wide variety of functionalized indenone derivatives can be obtained in good-to-excellent yields. HMBC and NOESY NMR analyses and mechanistic elucidation experiments revealed that the cyclization occurs via a 1,5-H shift. The cyclic acetal group promoted the 1,5-H shift by activating the benzylic C-H bond and preventing the migration of the alkoxy group by tethering both alkoxy groups.