Practical Synthetic Method Research Articles

A green, facile, and practical preparation of capsaicin derivatives with thiourea structure

Capsaicin derivatives with thiourea structure (CDTS) is highly noteworthy owing to its higher analgesic potency in rodent models and higher agonism in vitro. However, the direct synthesis of CDTS remains t one or more shortcomings. In this study, we present reported a green, facile, and practical synthetic method of capsaicin derivatives with thiourea structure is developed by using an automated synthetic system, leading to a series of capsaicin derivatives with various electronic properties and functionalities in good to excellent yields.

Stereoselective Fluorosulfonylation of Vinylboronic Acids for (E)-Vinyl Sulfonyl Fluorides with Copper Participation.

A practical synthetic method for the synthesis of vinyl sulfonyl fluorides through copper-promoted direct fluorosulfonylation has been developed. The reaction of the vinylboronic acids with DABSO and then NFSI is performed under mild reaction conditions. This transformation efficiently affords aryl or alkyl vinyl sulfonyl fluorides with good reaction yields, exclusive E-configuration, broad substrate scope, excellent compatibility, and operational simplicity.

Studies on the selective synthesis of diorganyl diselenides using potassium hydroxide and mechanistic investigations of the reaction pathway.

Methods of selectively synthesizing diorganyl diselenides (R-Se-Se-R) without using harmful reducing agents are presented. We optimized the reaction conditions for the selective formation of the diselenide dianion (Se22-) and the corresponding diorganyl diselenides using basic reagents (e.g., KOH), while suppressing the formation of side products, such as diorganyl selenides (R-Se-R) or multiselenides (R-Sen-R; n ≥ 3). Furthermore, we have suggested and examined the reaction pathways responsible for the formation of the desired diorganyl diselenides 1 and side products 2 and 3. Consequently, the selective synthesis of diverse diorganyl diselenides was achieved with modest to excellent yields (33-99%) using various organyl halides under optimized conditions. The results provide a practical and efficient synthetic method for diorganyl diselenides as a representative class of organoselenium compounds.

Practical Synthetic Method for Amino Acid-Derived Diazoketones Shelf-Stable Reagents for Organic Synthesis

Practical Synthetic Method for Amino Acid-Derived Diazoketones Shelf-Stable Reagents for Organic Synthesis

Development of a Practical Synthetic Method for Clinical Candidate 3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy} phenyl)propanoic acid (P218) and Its Hydroxylated Metabolites

Abstract3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, known as P218, has demonstrated great potency and safety in preclinical and human studies. However, the previous synthetic methods for P218 gave low yields and required hazardous reagents and challenging procedures. In this study, we have successfully developed a decagram-scale synthetic route for P218 with practical and scalable methods for large-scale production. Furthermore, this is also a first report of a novel synthetic approach for P218-OH, a hydroxylated metabolite of P218, by modification of our discovery route. Our synthetic procedures for P218 and P218-OH are a significant advancement in drug development processes, including manufacturing processes and drug metabolism studies.

A comprehensive parametric study of factors that influence synthesis of high-quality ZTC using Ca2+ exchanged zeolite Y as the template

We achieved the synthesis of an ordered 3D microporous graphene architecture via chemical vapor deposition using the faujasite type zeolite as the template, i.e., “zeolite templated carbon” (ZTC). We found that implanting Ca2+ in this zeolite effectively catalyzed the growth of ZTC and greatly lowered the growth temperature. To further improve the ZTC, we investigated the influence of various synthetic parameters on its growth: Ca2+ amount, growth temperature, growth time, growth pressure, stabilization temperature and stabilization time, and describe these in detail. High-quality ZTC samples having regions of what are likely continuous single-layer carbon structures composed of trivalently bonded carbon were grown and characterized. This effective and practical synthetic method should benefit synthesis of other ZTCs and the evaluation and exploration of the structural characterization and application of ZTCs.

Syntheses of Oxazolidinone-2,3-Fused Indoline and Azaindoline Derivatives

AbstractWe herein describe a practical synthetic method to access oxazolidinone-2,3-fused indoline and azaindoline derivatives via one-pot cyclization. These derivatives, which contain sp3-hybridized carbons, may be useful as new scaffolds in medicinal chemistry.

Practical Synthetic Method for Ogipeptin Derivatives

AbstractIn synthesizing novel derivatives of the natural cyclic peptides the ogipeptins, we established a simple and practical solid-phase peptide synthesis and macrocyclization method. By using this method, it became possible to obtain skeleton-modified ogipeptin derivatives with dehydroxylation of the β-hydroxy-α,γ-diaminobutyric acid, replacement of the (Z)-dehydrobutyrine residue, or replacement of the arginine residue.

Intertwining Olefin Thianthrenation with Kornblum/Ganem Oxidations: Ene‐type Oxidation to Furnish α,β‐Unsaturated Carbonyls

AbstractA widely applicable, practical, and scalable synthetic method for efficient ene‐type double oxidation of alkenes is reported via a two‐step alkenyl thianthrenium umpolung/Kornblum‐Ganem oxidation strategy. This chemo‐ and stereoselective procedure allows easy access to various α,β‐unsaturated carbonyls that may be otherwise difficult or cumbersome to synthesize by conventional methods. For α‐olefins, this metal‐free transformation can be tuned according to synthetic needs to produce either the elusive (Z)‐unsaturated aldehydes or their (E) counterparts. Moreover, this strategy has enabled streamlined synthesis of distinct butadienyl pheromones and kairomones.

Intertwining Olefin Thianthrenation with Kornblum/Ganem Oxidations: Ene-type Oxidation to Furnish α,β-Unsaturated Carbonyls.

A widely applicable, practical, and scalable synthetic method for efficient ene-type double oxidation of alkenes is reported via a two-step alkenyl thianthrenium umpolung/Kornblum-Ganem oxidation strategy. This chemo- and stereoselective procedure allows easy access to various α,β-unsaturated carbonyls that may be otherwise difficult or cumbersome to synthesize by conventional methods. For α-olefins, this metal-free transformation can be tuned according to synthetic needs to produce either the elusive (Z)-unsaturated aldehydes or their (E) counterparts. Moreover, this strategy has enabled streamlined synthesis of distinct butadienyl pheromones and kairomones.

Highly efficient asymmetric synthesis of α‐aminoamides via the reaction of N‐sulfonyl imines with chiral carbamoylsilane

A novel and practical asymmetric synthetic method of α‐amino amides by the reaction between N‐sulfonyl imines and N‐methyl‐N‐R‐(1‐phenyl)ethylcarbamoyl (trimethyl)silane under the induction of chiral group has been developed. The protocol tolerates various N‐sulfonyl imines bearing different groups, including aryl, double bond conjugated aryl, heteroaryl, and aliphatic group. Using carbamoylsilane with chiral group, the diastereoselectivity was very high for reactions of most N‐sulfonyl imines, and only one diastereomer was afforded in many reactions.

External electrolyte-free electrochemical one-pot cascade synthesis of 4-thiocyanato-1H-pyrazoles

A practical synthetic method for 4-thiocyanato-1 H -pyrazoles through the electrochemical cascade reaction of hydrazines, 1,3-diones and NH 4 SCN under metal-, chemical oxidant- and external electrolyte-free conditions was established. Importantly, both a gram-scale synthesis of 4-thiocyanato-1 H -pyrazoles and five one-pot sequential transformations starting from hydrazine were successfully accomplished. A practical synthetic method for 4-thiocyanato-1 H -pyrazoles through the electrochemical cascade reaction of hydrazines, 1,3-diones and NH 4 SCN under metal-, chemical oxidant- and external electrolyte-free conditions was established. Importantly, both a gram-scale synthesis of 4-thiocyanato-1 H -pyrazoles and five one-pot sequential transformations starting from hydrazine were successfully accomplished.

Simple, green and one pot new strategy for synthesis of the phthalimide derivatives

A novel, simple, green, one pot and practical synthetic method is described for the preparation of phthalimide derivatives through a condensation reaction between of 2-formylbenzoic acid and aniline in the presence of Et3N as base and S8 (Octasulfur) as oxidant in solvent free condition. This one-pot protocol provides these valuable desired compounds under mild conditions with excellent efficiency by using simple available starting materials.

Anchored Palladium Complex-Generated Clusters on Zirconia: Efficiency in Reductive N-Alkylation of Amines with Carbonyl Compounds under Hydrogen Atmosphere.

Carbon-nitrogen bond formation is an important method on both laboratory and industrial scales because it realizes the production of valuable pharmaceuticals, agrochemicals, and fine chemicals. Direct reductive N-alkylation of amines with carbonyl compounds via intermediary imine compounds, especially under catalytic hydrogenation conditions, is one of the most convenient, economical, and environmentally friendly methods for this process. Here we report a novel palladium species on zirconia having specific activity towards hydrogenation of imines but other carbonyl groups remaining intact. The present catalytic property offers a practical synthetic method of functionalized secondary amines by reductive N-alkylation under mild conditions with high atom-efficiency. Mechanistic studies revealed that the catalytically active species is the palladium cluster, which is generated in situ from molecular palladium complexes on the support by exposure to atmospheric hydrogen. These fundamental findings are expected to progress in developing novel cluster catalysts for chemical processes directed towards a sustainable society.

Clinical evaluation of [18F]pitavastatin for quantitative analysis of hepatobiliary transporter activity

It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([18F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [18F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [18F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans.

Copper-catalyzed radical cascade cyclization of 2-(allyloxy)arylaldehydes towards chroman-4-one derivatives

A copper catalyzed difluoroacetylation of 2-(allyloxy)arylaldehydes was disclosed. In the present transformation, various 2-(allyloxy)arylaldehydes and difluoro reagents were performed smoothly, and a serises of chroman-4-one derivatives were generated in moderate to good yields via radical cascade cyclization. This protocol could promise a practical and efficient synthetic method for pharmaceutically interesting chroman-4-ones.

N‐Hydroxyphthalimide‐Catalyzed Epoxidation of Inactive Aliphatic Olefins with Air at Room Temperature

AbstractMetal‐free aerobic epoxidation of aliphatic alkenes, especially terminal alkenes, remains a significant challenge. Herein, a novel and practical synthetic method with N‐hydroxyphthalimide (NHPI) as catalyst, isobutyraldehyde as sacrificial reductant and air as oxidant has been developed for the epoxidation of olefins in excellent to moderate conversions and selectivity at room temperature. Meanwhile, this synthetic methodology could efficiently convert inactive light olefins to corresponding epoxides which are highly desired in industry. Moreover, several free radicals in the reaction were identified and characterized by in situ electron paramagnetic resonance spectroscopy (in situ EPR) and high‐resolution mass spectrometry (HRMS). Mechanistic studies showed that the phthalimide N‐oxyl radical (PINO⋅) generated from NHPI would promote the homolysis of isobutyraldehyde to carbonyl carbon radical by the extraction of hydrogen atoms.

Regioselective Synthesis of 4,7,12,15‐Tetrasubstituted [2.2]Paracyclophanes: A Modular Route Involving Optical Resolution

AbstractA practical synthetic method for preparing bis‐(para)‐pseudo‐ortho and bis‐(para)‐pseudo‐meta type 4,7,12,15‐tetrasubstituted [2.2]paracyclophanes is reported. Regioselective double Rieche formylation was successfully applied to the corresponding dibromo[2.2]paracyclophanes under slightly modified conditions. Aldehydes reacted in an unknown direction with Rieche formylation agents, dichloromethyl methyl ether and titanium(IV) tetrachloride, leading to the formation of benzal chlorides. Formylated products were obtained after hydrolysis of these benzal chloride derivatives. Optical resolution was performed with the diastereomer method and (RP)‐4,12‐dibromo‐7,15‐diformyl[2.2]paracyclophane was successfully obtained in an enantiomerically pure form (99 % ee). Their synthetic utility is demonstrated with some exploratory transformations to access corresponding differently functionalized tetrasubstituted [2.2]paracyclophane derivatives.

Synthesis and applications of 3-bromo-2-hydroxy-1-tosylazaindolines

Herein we describe a practical synthetic method for 3-bromo-2-hydroxy-1-tosylazaindolines and 2-hydroxy-1-tosylazaindoline-3-triethylammonium bromides. 3-Bromo-2-hydroxy-1-tosylazaindolines were found to be stable crystals and could be stored at ambient temperature without consideration of moisture in the air. These indolines are useful reagents for the formal C3-electrophilic reactions of azaindoles with various nucleophiles. We used this method to synthesize various key intermediates of biologically active 3-substituted 7-azaindole derivatives.

Transition-Metal-Free Synthesis of Aryl Trifluoromethyl Thioethers through Indirect Trifluoromethylthiolation of Sodium Arylsulfinate with TMSCF3.

Herein, we report an indirect trifluoromethylthiolation of sodium arylsulfinates. This transition-metal-free reaction significantly provides an environmentally friendly and practical synthetic method for aryl trifluoromethyl thioethers using commercial Ruppert-Prakash reagent TMSCF3. This approach is also a potential alternative to the current industrial production method owing to facile substrates, excellent functional group compatibility, and operational simplicity.