Practical Synthesis of Phosphinic Amides/Phosphoramidates through Catalytic Oxidative Coupling of Amines and P(O)−H Compounds

Herein, we report a highly efficient ZnI₂-triggered oxidative cross-coupling reaction of P(O)−H compounds and amines. This operationally simple protocol provides unprecedented generic access to phosphinic amides/phosphoramidate derivatives in good yields and short reaction time. Besides, the reaction proceeds under mild conditions, which avoids the use of hazardous reagents, and is applicable to scale-up syntheses as well as late-stage functionalization of drug molecules. The stereospecific coupling is also achieved from readily available optically enriched P(O)−H compounds.     

An efficient synthesis of varenicline

Synthesis of varenicline the antismoking drug has been achieved in six steps with 10% overall yield. A Diels-Alder reaction, oxidative cleavage of an olefin and reductive amination remain as key steps in the synthesis     

Palladium-catalyzed intramolecular C(sp(3))--H functionalization: catalyst development and synthetic applications

A novel catalytic system, based on a mixture of palladium acetate and tris(5-fluoro-2-methylphenyl)phosphane (F-TOTP), has been designed for the intramolecular C--H functionalization of alkane segments. Among other analogues of tris(2-methylphenyl)phosphane (P(o-tol)(3)), F-TOTP was shown to have the optimal metal-bonding properties for this reaction. This catalytic system operated under milder reaction conditions that allowed the regioselective production of various olefins adjacent to a quaternary benzylic carbon atom, as well as novel bi- and tricyclic molecules. A general mechanism was proposed, with the preferential formation of a six-membered palladium(II) palladacycle after oxidative addition and cyclopalladation. The regioselective C--H functionalization of alkyl groups into olefins was illustrated in the synthesis of the antihypertensive drug verapamil and an analogue. A particularly mild ruthenium-catalyzed direct hydroamidation of the intermediate olefin in this synthesis is also reported.     

羰基钴催化烯烃醛化反应中RCOCo(H)2(CO)3还原消去关键步骤的理论研究

在其催化循环过程中,RCOCo(CO)_3与H2_氧化加成生成RCOCO(H)_2(CO)_3,此中间体进一步还原消去生成醛是涉及氢在整个醛化反应催化循环中活化作用的关键步骤,文献[2]认为它是整个循环的控制步骤,由于反应的各中间物光谱无法准确测定,无法分别考察这两个步     

Oxidative C-arylation of free (NH)-heterocycles via direct (sp3) C-H bond functionalization

The development of a new chemical transformation, namely oxidative C-arylation of saturated (NH)-heterocycles, is described. This reaction combines dehydrogenation and arylation in one process, leading to cross-coupling of (NH)-heterocycles and haloarenes. Typical reaction conditions involve heating the reaction partners in anhydrous dioxane at 120-150 degrees C in the presence of RhCl(CO)[P(Fur)3]2 as the catalyst and Cs2CO3 as the base. Addition of tert-butylethylene as the hydrogen acceptor increases the chemical yield by diminishing the dehalogenation pathway. This method demonstrated a good substrate scope, allowing for cross-coupling of a variety of (NH)-heterocycles (e.g., pyrrolidine, piperidine, piperazine, morpholine) and halo(hetero)arenes to afford valuable heterocyclic products in one step. The preliminary mechanistic studies provided some insight regarding the key events in the proposed catalytic cycle, including beta-hydride elimination of an amido rhodium complex and carbometalation of the resulting imine. A large kinetic isotope effect [KIE (kC-H/kC-D) = 4.3] suggests that one or both beta-hydride elimination steps are rate determining. The central role for the phosphine ligand was established in controlling the partitioning between the oxidative C-arylation and N-arylation pathways.     

Stereoelectronic Features of a Complex Ketene Dimerization Reaction

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.     

Reactivity of Pt0 complexes toward gallium(III) halides: synthesis of a platinum gallane complex and oxidative addition of gallium halides to Pt0

The reaction of [Pt(PCy 3) 2] and GaCl 3 resulted in quantitative formation of the adduct [(Cy 3P) 2Pt-GaCl 3], the first known platinum gallane complex. Although similar reactivity with GaBr 3 and GaI 3 was expected, NMR spectroscopic data revealed a different reaction course. Crystal structure determination proved that, in the latter case, the product of the oxidative addition was formed. The resulting platinum gallyl complexes represent the first example of an oxidative addition of gallium(III) halides to low-valent transition metals.     

(±)-Palstatin的首次全合成研究

以廉价易得的5-溴香草醛和2,4,6-三羟基苯乙酮为起始原料，首次方便,高效地合成了(±)-Palstatin (1).合成的关键步骤为SeO₂促进的氧化环化和Ag₂O催化的氧化偶联反应.     

A Cu (I) catalyzed large scale synthesis of an antipsychotic drug substance Clozapine with new precursor 2-chloro benzoic acid

Development of an economic and commercial manufacturing process for an anti-psychotic drug substance clozapine with an alternative key starting material (2-chloro benzoic acid) in the place of literature reported key starting material Anthranilic acid. To avoid narcotic key starting materials usage in drug substances the author invented a commercially available raw material 2-chlorobenzoic acid, which reacts with another key starting material 4-chloro-1, 2-diamino benzene. This reaction proceeds through Ullman reaction to produce multi scale level Clozapine which quality meets the ICH requirements.     

Pulsed‐EPR Evidence of a Manganese(II) Hydroxycarbonyl Intermediate in the Electrocatalytic Reduction of Carbon Dioxide by a Manganese Bipyridyl Derivative

A key intermediate in the electroconversion of carbon dioxide to carbon monoxide, catalyzed by a manganese tris(carbonyl) complex, is characterized. Different catalytic pathways and their potential reaction mechanisms are investigated using a large range of experimental and computational techniques. Sophisticated spectroscopic methods including UV/Vis absorption and pulsed‐EPR techniques (2P‐ESEEM and HYSCORE) were combined together with DFT calculations to successfully identify a key intermediate in the catalytic cycle of CO₂ reduction. The results directly show the formation of a metal–carboxylic acid–CO₂ adduct after oxidative addition of CO₂ and H⁺ to a Mn⁰ carbonyl dimer, an unexpected intermediate.     

A Ru catalyzed divergence: oxidative cyclization vs cycloisomerization of bis-homopropargylic alcohols

During the course of investigating the development of catalytic reactions involving ruthenium vinylidene intermediates, a novel divergence of reactivity was discovered. The oxidative cyclization of bis-homopropargylic alcohols with Ru(+2) complexes as catalysts and N-hydroxysuccinimide as oxidant, which requires formation of a ruthenium vinylidene intermediate, is complicated by the simple electrophilically initiated direct attack of the hydroxyl group on a pi-complex of the alkyne and ruthenium. A catalytic system composed of CpRu[(p-CH(3)O(6)H(4))(3)P](2)Cl and excess (p-CH(3)O-C(6)H(4))(3)P directs the reaction toward the oxidative cyclization to form delta-lactones in good yields. Significantly, a simple switch of catalyst to CpRu[(p-FC(6)H(4))(3)P](2)Cl redirects the reaction to a cycloisomerization to form dihydropyrans in good yields. The synthetic utility of the oxidative cyclization is illustrated by the synthesis of oviposition attractant pheromone of the mosquito Culex pipens. The utility of the cycloisomerization to dihydropyrans is demonstrated by an iterative process leading to the antiviral agent narbosine B. A rationale for this dramatic switch by simple ligand modification is proposed.     

Amination of aromatic olefins with anilines: a new domino synthesis of quinolines

A new catalytic amination of aromatic olefins with anilines is presented. In a domino reaction, substituted quinoline derivatives are obtained in the presence of cationic rhodium complexes, such as [Rh(cod)2]BF4, and PPh3. Ethylbenzene is formed as a by-product in this new oxidative reaction. The first transition metal catalyzed anti-Markovnikov hydroamination of styrene with anilines occurs as a side reaction. Mechanistic investigations strongly support the regioselective oxidative amination of styrene as the key reaction step.     

Synthesis of methyl epijasmonate and cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one

A novel and efficient synthesis of both (±)-methyl epijasmonate and (±)-cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one is described. The key step to establish the cis-stereochemistry on the 5-membered ring is an ionic Diels–Alder reaction, which is high yielding and highly regioselective. Subsequent key steps include oxidative cleavage of the six-membered ring, Wittig coupling and for the synthesis of epijasmonate, the haloform reaction.     

Palladium‐Catalyzed C(sp3)H Activation: A Facile Method for the Synthesis of 3,4‐Dihydroquinolinone Derivatives

3,4‐Dihydroquinolinones were synthesized by the palladium‐catalyzed, oxidative‐addition‐initiated activation and arylation of inert C(sp³)? H bonds. Pd(OAc)₂ and P(o‐tol)₃ were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven‐membered palladacycle was proposed as a key intermediate of the catalytic cycle.     

Palladium‐Catalyzed C(sp3)?H Activation: A Facile Method for the Synthesis of 3,4‐Dihydroquinolinone Derivatives

3,4‐Dihydroquinolinones were synthesized by the palladium‐catalyzed, oxidative‐addition‐initiated activation and arylation of inert C(sp³) H bonds. Pd(OAc)₂ and P(o‐tol)₃ were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven‐membered palladacycle was proposed as a key intermediate of the catalytic cycle.     

天然产物Angustifolin D中间体的合成

以3,4,5-三甲氧基苯甲酸为原料,经6步反应以23％总收率完成了Angustifolin D关键中间体--6,6′-2［(Z)-2-碘代-1-丙烯基］-2,2′,3,3′,4,4′-六甲氧基-1,1′-联苯(7)的合成,其结构经¹H NMR, ¹³C NMR, IR和MS确证。其中关键步骤联苯偶连反应采用了廉价易得的铜试剂(CuBr·SMe₂)作为催化剂。     

Total synthesis of lamellarins D, H, and R and ningalin B

A concise total synthesis of lamellarins D (7 steps), H (7 steps), and R (5 steps) and ningalin B (5 steps) is achieved starting from the corresponding aldehydes and amines. The synthesis features three oxidative reactions as key steps in a biomimetic manner, involving an AgOAc-mediated oxidative coupling reaction to construct the pyrrole core, a Pb(OAc)(4)-induced oxidative cyclization to form the lactone, and Kita's oxidation reaction to form the pyrrole-arene C-C bond.     

细胞色素P450酶电化学生物传感器的构建及其药物代谢应用

药物代谢过程是药物在体内产生药效和毒性的主要过程,发展廉价、方便、快速、高通量的体外药物代谢研究方法对新药的开发和设计、给药的方法和剂量、临床药物的检测等都有重要的指导意义. 细胞色素P450酶（CYP450酶）在药物的I相反应中起到关键作用,以电极代替辅酶NADPH提供CYP450酶催化反应过程中需要的两个电子,构建CYP450酶电化学生物传感器可实现药物的初步筛选. 大量研究表明,CYP450酶在电极表面合适的固定方法与电极材料可有效提高传感器的检测性能. 本文主要综述近年来CYP450酶电化学生物传感器的构建及其在药物代谢研究方面的应用,并展望其研发前景.     

Asymmetric synthesis of ageliferin

We describe herein an asymmetric synthesis of ageliferin. A Mn(III)-mediated oxidative radical cyclization reaction was used as the key step to construct the core skeleton of this pyrrole-imidazole dimer. This approach resembles the biogenic [4 + 2] dimerization in an intramolecular fashion.     

Exploiting the oxidative coupling reaction of MBTH for indapamide determination

The oxidative coupling reaction between aromatic amines and 3-methylbenzothiazolin-2-one hydrazone (MBTH) in the presence of cerium(IV) has been extensively used with quantitative analytical purposes. Nevertheless, a literature survey reveals that different wavelengths (visible range) can be used to monitor the reaction products when using MBTH and Ce(IV) as colour developing reagents.In the present work, the oxidative coupling reaction of indapamide (an oral antihypertensive diuretic drug) with MBTH in the presence of cerium(IV) was evaluated using distinct reaction approaches and was implemented in an automated multipumping flow system. The developed methodology was applied in the spectrophotometric control of the drug in pharmaceutical formulations. The optimization of the proposed multipumping flow system was performed by using an experimental design approach, namely by exploiting a Plackett-Burman factorial design and a central cubic faces design.This work revealed the formation of products with different reaction kinetics, chemical stabilities and absorbance spectra, depending on the sequence of addition of the reagents. By exploiting a specific sequence in the addition of reagents, the proposed automatic system allowed the rapid quantification of indapamide in pharmaceutical formulations, with a determination rate of about 25 h⁻¹, and a relative deviation under 2.1% when comparing with the reference procedure. Detection limit was approximately 1 mg L⁻¹.