Direct α‐Vinylidenation of Aldehydes and Subsequent Cascade: Gold and Amine Catalysts Work Synergistically

Carbonyl‐substituted allenes are highly important synthetic intermediates for a number of heterocycles and strained‐ring systems. However, chemistry of allenyl aldehydes has not been explored as extensively as their ketone, ester, or amide analogues because of a lack of general synthetic methods. Described herein is the first direct α‐vinylidenation of aldehydes and an α‐vinylidenation/γ‐functionalization cascade to access tri‐ and tetrasubstituted allenyl aldehydes using a combination of a gold catalyst and an secondary amine. The reactive enamine intermediate of an aldehyde reacts with the gold‐activated hypervalent silylethynyl benziodoxolone to selectively generate the corresponding trisubstituted allenyl aldehyde. The allenyl aldehyde can further react with another equivalent of the alkynylation reagent or other electrophiles to afford tetrasubstituted allenes bearing an aldehyde group, an acetylene, and a halogen functionality. This method enables rapid access to polysubstituted furans from aldehydes.     

Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

To show the synthetic utility of the catalytic C?C activation of less strained substrates, described here are the collective and concise syntheses of the natural products (?)‐microthecaline A, (?)‐leubehanol, (+)‐pseudopteroxazole, (+)‐seco‐pseudopteroxazole, pseudopterosin A–F and G—J aglycones, and (+)‐heritonin. The key step in these syntheses involve a Rh‐catalyzed C?C/C?H activation cascade of 3‐arylcyclopentanones, which provides a rapid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products. Other important features include 1) the direct C?H amination of the tetralone substrate in the synthesis of (?)‐microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C?C activation reactions, and 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.     

One‐pot Sequential Reactions Featuring a Copper‐catalyzed Amination Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines and Dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines

Tetracyclic skeletons combining an imidazo[1,2‐a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5‐b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines through one‐pot sequential reactions of commercially available or readily obtainable 2‐aminopyridines, 2‐bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step‐by‐step operations.     

Concise Synthesis of Potassium Acyltrifluoroborates from Aldehydes through Copper(I)‐Catalyzed Borylation/Oxidation

Potassium acyltrifluoroborates (KATs) were prepared through copper(I)‐catalyzed borylation of aldehydes and subsequent oxidation. This synthetic route is characterized by the wide range of aldehydes accessible, favorable step economy, mild reaction conditions, and tolerance of various functional groups, and it enables the facile generation of a range of KATs, for example, bearing halide, sulfide, acetal, or ester moieties. Moreover, this method was applied to the three‐step synthesis of various α‐amino acid analogues that bear a KAT moiety on the C‐terminus by using naturally occurring amino acids as the starting material.     

Development,Scope and Mechanisms of Multicomponent Reactions of Asymmetric Electron‐Deficient Alkynes with Amines and Formaldehyde

Based on the reactive behaviour of the substrates, two synthetic routes to polysubstituted pyrimidine derivatives are presented herein: 1) A catalyst‐free multicomponent reaction of electron‐deficient alkynes, aliphatic amines and formaldehyde and 2) Ag^I‐catalyzed synthesis of pyrimidines from electron‐deficient alkynes, anilines and formaldehyde by a domino reaction. Under optimized conditions, the multicomponent reactions were accomplished with high regioselectivity and excellent yields. A computational study was carried out by using the B3LYP density functional theory to elucidate the mechanisms of the catalyst‐free hydroamination reaction. Calculations showed the activation free energies of aliphatic amines were lower than those of anilines, which is consistent with the experimental results.     

Tandem One‐pot Synthesis of Polysubstituted 1,3‐Thiazine Derivatives

A tandem one‐pot synthesis of polysubstituted 1,3‐thiazines has been developed by reacting with cyanoacetamide and isothiocyanate derivatives to give rise to 2‐cyano‐3‐mercaptoacrylamides, which are trapped in situ by various aldehydes or diversely substituted ketones through intermolecular cyclization, providing polysubstituted 1,3‐thiazine derivatives in short reaction times with good to excellent yields. The salient features of this novel protocol are operational simplicity, accessing the desired products from the readily available starting materials and easy of product isolation and may find wide spread applications in medicinal chemistry.     

Stereodefined Acyclic Polysubstituted Silyl Ketene Aminals: Asymmetric Formation of Aldol Products with Quaternary Carbon Stereocenters

The regio‐ and stereoselective formation of stereodefined polysubstituted silyl ketene aminals is easily achieved through selective combined carbometalation–oxidation–silylation reactions. These substrates are ideal candidates for Mukaiyama aldol reactions with aliphatic aldehydes as they give the aldol products with a quaternary carbon stereocenter α to the carbonyl groups in outstanding diastereoselectivities.     

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.     

Novel syntheses of polysubstituted pyrroles and oxazoles by 1,3‐dipolar cycloaddition reactions of benzotriazole‐stabilized nitrile ylides

1,3‐Dipolar cycloadditions of benzotriazole‐stabilized nitrile ylides with benzyl α,β‐unsaturated‐carboxy‐lates and aldehydes as dipolarophiles proceeded smoothly and efficiently to give polysubstituted pyrroles and oxazoles, respectively, in good yields.     

Facile and Efficient Synthesis of Indol‐3‐yl Substituted Pyran Derivatives via One‐Pot Multicomponent Reactions under Ultrasonic Irradiation

A series of polysubstituted indol‐3‐yl substituted pyran derivatives have been synthesized via one‐pot multicomponent reactions of aldehydes, malononitrile with 3‐cyanoacetyl indoles under ultrasonic irradiation. This method has the advantages of high yield, easy operation, short‐reaction time, mild‐reaction condition, and catalyst recyclability.     

Ruthenium hydride catalyzed silylvinylation of terminal alkynes under ethylene atmosphere at 80 psi

The development of methods for the stereoselective synthesis of polysubstituted 1,3-dienes is a challenge to synthetic chemistry. Herein is reported a selective approach for the synthesis of polysubstituted 1,3-dienes using the ruthenium hydride catalyzed intramolecular silylvinylation of alkynes under 80 psi of ethylene gas. This strategy affords a single diene isomer, is applicable to substrates with aryl and alkyl substitution at the propargyl and homopropargyl positions, and has been utilized in the synthesis of 5- and 6-membered oxasilacycles.     

A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.     

Gold‐Catalyzed Synthesis of Functionalized Pyridines by Using 2H‐Azirines as Synthetic Equivalents of Alkenyl Nitrenes

2H‐Azirines are easily synthesized from the corresponding ketones and, despite possessing a C?N bond embedded in a strained three‐membered cycle, they are sufficiently stable to be isolated, stored, and manipulated. 2H‐Azirines can be regarded as valuable synthetic equivalents of alkenyl nitrenes, however, reactions capitalizing on the cyclic strain of the heterocyclic motif and involving the cleavage of the C? N single bond remain surprisingly limited. A gold‐catalyzed reaction that allows the formation of polysubstituted functionalized pyridines from easily accessible 2‐propargyl 2H‐azirine derivatives was developed. This transformation, which corresponds to an unprecedented intramolecular transfer of an alkenyl nitrene to an alkyne, proceeds with low catalyst loading, is efficient, and exhibits a high functional‐group tolerance and a wide substrate scope.     

An Effective and New Method for the Synthesis of Polysubstituted Imidazoles by the Use of CrCl3.6H2O as a Green and Reusable Catalyst: Synthasis of Some Novel Imidazole Derivatives

New, efficient and environmentally adapted synthesis of polysubstituted imidazoles in one‐pot is found. The multicomponent reaction of various aldehydes, benzil, aliphatic and aromatic primary amines and ammonium acetate under solvent‐free condition is explained. The highly efficient role of CrCl₃.6H₂O as catalyst in this synthesis was shown. By this advantage, several polysubstituted imidazoles as pharmaceutical important molecules can be prepared in high yield and high purity. This method is a very easy and a rapid reaction for the synthesis of imidazole derivatives. The crude products recrystallized to afford the crystalline pure products. Furthermore, catalyst exhibited remarkable reusable activity.     

原位生成的烯丙基磷叶立德与醛的化学反应性研究

介绍了我们小组最近有关原位生成的烯丙基磷叶立德与醛的化学反应性研究结果.在化学计量叔膦作用下,烯丙基碳酸酯或联烯酸酯经原位生成的烯丙基磷叶立德活性中间体,与醛发生高度立体选择性的三组分Wittig烯化反应和vinylogous Wittig烯化反应,该类反应为合成多取代1,3-二烯衍生物提供了简单、高效的新方法;在催化量叔膦作用下,γ-甲基联烯酸酯经烯丙基磷叶立德关键中间体与醛发生多个膦催化的环化反应,为五元、六元含氧杂环化合物的合成提供了原子经济性的方法.通过氘代实验和核磁跟踪等方法,对上述反应机理进行了初步探索.     

Synthesis of ammonium S-S bond linked dipyridinedionates via four-component reactions of cyanoacetamide, aldehyde, amine and 1,3-thiazolidinedione

An unprecedented and efficient synthetic protocol for polysubstituted ammonium S-S bond linked 2,6-pyridinedionates was developed via the novel four-component reactions of 1,3-thiazolidinedione, aromatic aldehydes, secondary amines and cyanoacetamide in acetonitrile. A feasible explanation is given based on the characteristic ring-open and recyclization properties of 1,3-thiazolidinedione.     

Carboxylic Acids as Traceless Directing Groups for the Rhodium(III)‐Catalyzed Decarboxylative C?H Arylation of Thiophenes

A rhodium(III)‐catalyzed carboxylic acid directed decarboxylative C H/C H cross‐coupling of carboxylic acids with thiophenes has been developed. With a slight adjustment of the reaction conditions based on the nature of the substrates, aryl carboxylic acids with a variety of substituents could serve as suitable coupling partners, and a broad variety of functional groups were tolerated. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which have conventionally been synthesized through lengthy synthetic sequences. An illustrative example is the one‐step gram‐scale synthesis of a biologically active 3,5‐substituted 2‐arylthiophene by way of the current method.     

Carboxylic Acids as Traceless Directing Groups for the Rhodium(III)‐Catalyzed Decarboxylative CH Arylation of Thiophenes

A rhodium(III)‐catalyzed carboxylic acid directed decarboxylative C? H/C? H cross‐coupling of carboxylic acids with thiophenes has been developed. With a slight adjustment of the reaction conditions based on the nature of the substrates, aryl carboxylic acids with a variety of substituents could serve as suitable coupling partners, and a broad variety of functional groups were tolerated. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which have conventionally been synthesized through lengthy synthetic sequences. An illustrative example is the one‐step gram‐scale synthesis of a biologically active 3,5‐substituted 2‐arylthiophene by way of the current method.     

Synthesis of Functionalized Thiophenes by Four‐component Reactions of 1,3‐Thiazolidinedione,Aromatic Aldehydes,Cyanoacetamide and Cyclic Secondary Amines

The polysubstituted thiophene derivatives were conveniently prepared by the four‐component reactions of 1,3‐thiazolidinedione, aromatic aldehydes, cyanoacetamide and cyclic secondary amines such as pyrrolidine, morpholine and piperidine. The reaction mechanism is believed to involve domino reactions of Knoevenagel condensation, Michael addition, ring‐opening and recyclization of 1,3‐thiazolidinedione.     

General Cyclopropane Assembly by Enantioselective Transfer of a Redox‐Active Carbene to Aliphatic Olefins

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. The redox‐active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect allowed the asymmetric cyclopropanation of various olefins, including unfunctionalized aliphatic alkenes, that enables the three‐step total synthesis of (?)‐dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally differentiated diazocompounds are viable and advantageous equivalents of single‐carbon chirons.