Addition reactions of ROPHy/SOPHy oxime ethers: asymmetric synthesis of nitrogen containing compounds

Oxime ethers prepared from (R)- or (S)-O-(1-phenylbutyl)hydroxylamine (ROPHy or SOPHy) are versatile intermediates for the asymmetric synthesis of a range of nitrogen containing compounds including simple amines, 1,2-aminoalcohols, alpha- and beta-amino acids, heterocyclic building blocks of natural products, piperidine alkaloids, lactams, 5- to 8-membered ring nitrogen heterocycles, imino-sugars, and chiral ferrocene based receptors.     

3,5-Dioxopimelates as new synthetic building blocks. Cyclocondensation with 1,2-, 1,3- and 1,4-dinucleophiles

Cyclocondensation reactions of 3,5-dioxopimelates, new and versatile synthetic building blocks, with hydrazines, urea, thiourea and phenylene-1,2-diamines allow for a convenient synthesis of various heterocycles containing two ester-substituted side-chains.     

Syntheses and Synthetic Applications of Functionalized Propargylic and Allylic Fluorides

This account presents the synthesis and application of propargylic and allylic fluorides containing hydroxy or carbonyl functional groups. In particular, the Barbier-type reaction of difluoropropargyl bromides with aldehydes or chloroformates provides versatile propargylic fluorides, and the organocatalytic fluorination of dienamine intermediates has been demonstrated as an effective method to obtain allylic fluorides stereoselectively. Additionally, mechanistic insights into such reactions are discussed with the aid of density functional theory calculations. The report also describes the preparation of fluorinated 1,7-diyne or 1,7-enyne derivatives of these compounds. These propargylic and allylic fluorides can be used as building blocks for fluorinated heterocycles, such as fluorinated furans, tetrahydrofurans, and lactams. Additionally, fluorinated bi- or tri-heterocyclic compounds can be synthesized via transition-metal-catalyzed reactions with fluorinated 1,7-diyne or 1,7-enyne derivatives.     

Direct C−H Bond Borylation of (Hetero)Arenes: Evolution from Noble Metal to Metal Free

Organoboron compounds are among the most versatile and useful building blocks in modern synthetic chemistry. The past decades have seen impressive developments in the direct C?H bond borylation of (hetero)arenes in which the applied catalysts are shifting from noble metals to metal‐free systems. This Highlight gives a brief summary on this evolution and focuses on recent elegant work in this field.     

Ynamides: Versatile Tools in Organic Synthesis

Ynamides display an exceptionally fine balance between stability and reactivity. They also offer unique and multiple opportunities for the inclusion of nitrogen‐based functionalities into organic molecules, and are emerging as especially useful and versatile building blocks for organic synthesis. Recent breakthroughs in the preparation of these substrates have revitalized interest in nitrogen‐substituted alkynes, and the beginning of the 21st century has witnessed an ever‐increasing number of publications reporting the development of new reactions or synthetic sequences starting from ynamides. This Review highlights major developments in this area.     

Conjugated pyrrole/aminoenone and pyrrole/aminoacrylonitrile ensembles: new motives in heterocyclic chemistry

Methods for the preparation of two highly flexible synthetic building blocks, namely pyrrole/aminoenone and pyrrole/aminoacrylonitrile ensembles, on the basis of available starting materials such as 2-acylethynylpyrroles or pyrrole-2-carbodithioates, are summarized. The presence of several reactive centers in their molecules (pyrrole ring, enamine and carbonyl or nitrile moieties) ensures their multiple reactivity and application as versatile intermediates in the synthesis of heterocyclic ensembles such as pyrrolyl pyridines, bipyrroles, pyrrolyl-isoxazoles and condensed compounds, such as pyrrolo[3,2-a]pyrazines, pyrrolizines, which have high potential for use in medical chemistry and materials science.     

Synthesis of methoxy and hydroxy containing tetralones: versatile intermediates for the preparation of biologically relevant molecules

The synthesis of 5-hydroxy-6-methoxy-1-tetralone and the 7-hydroxy regioisomer along with the corresponding 5,7-dihydroxy analog has been achieved using an efficient directed metallation procedure followed by a regioselective methylene oxidation. This methodology represents a general synthetic route for the preparation of highly oxygenated tetralone analogs which are versatile building blocks for the construction of molecules of biological interest.     

Advances in 2H-azirine chemistry: A seven-year update

2H-Azirines are versatile building blocks for the preparation of various nitrogen-containing heterocycles. Seven years ago the comprehensive review on azirine chemistry was published in Tetrahedron. Since then, there had been an explosion of research activities in the field of these strained molecules. This renaissance is primarily associated with the discovery of new reactivity of azirines and in particular new catalytic and light-induced reactions, which made possible unusual transformations of this three-membered N-heterocycle into azole and azine derivatives as well as polyheterocyclic systems. The second reason for the progress of azirine chemistry is the development of methods for the preparation of new azirine derivatives. The third reason is the discovery of new synthetic equivalents of azirines, which permitted avoiding the use of unstable azirines in some modern catalytic procedures. In the present comprehensive review, we have placed particular emphasis on discussing the new developments in the synthesis and reactivity of azirines for the period from 2012 until the end of 2018.     

α- and β-Mercaptoalkanoic Acids: Versatile Synthons in the Syntheses of Thiasteroid Analogues and Selenathiadiazoles

This review describes the reactions of α/β-mercaptoalkanoic acids as building blocks for the synthesis of heterosteroids, polyfunctional heterocycles with pharmacological interest. Annelated heterocycles have been prepared by the cyclocondensation reaction of α- and β-mercaptoalkanoic acids with carbonyl compounds. This reaction takes place by nucleophilic addition, followed by cyclization with elimination of water. The main objective of this survey is to provide a comprehensive account of this reaction type in building various heterocycles, and examining their potential in developing better chemotherapeutic agents.     

含氟内酯化合物的合成方法研究进展

内酯化合物广泛存在于天然产物和具有生理活性的物质中, 因此, 内酯化合物的合成一直是人们非常关心的一个研究领域, 不仅作为天然产物的重要合成砌块, 也用来合成一些精细化工产品和医药中间体. 将氟原子或含氟基团引入到内酯化合物分子中, 可使其生理活性发生改变. 就含氟内酯化合物合成方法的研究进展进行了综述.     

Intramolecular cross-dehydrogenative coupling of benzaldehyde derivatives: A novel and efficient route to benzocyclic ketones

Benzocyclic ketones are not only found throughout many natural products and synthetic pharmaceutically active compounds but also used as versatile building blocks in organic synthesis. In view of their importance, many researchers have been working to explore novel and efficient synthetic routes for this class of carbonyl compounds. Recently, cross-dehydrogenative coupling reactions have emerged as one of the most versatile and powerful synthetic strategies to construct various carbon-carbon and carbon-heteroatom bonds. In this regard, direct acylation of (hetero)arenes with aldehydes through C(sp²)-H activation opened up a new page on the synthesis of the titled compounds. In this focus-review, we discuss the most representative and important reports on the synthesis of cyclic diaryl ketones through intramolecular cross-dehydrogenative coupling reactions of corresponding benzaldehydes with emphasis on the mechanistic aspects of the reactions.     

A convenient method for the synthesis of six-membered heterocyclic enaminones

Enaminones are widely employed in the synthesis of heterocycles, however heterocyclic enaminones and their use in the synthesis of more complex systems have been less studied. The reaction between 4-chloroacetylacetate and aliphatic or aromatic 1,2-aminoalcohols, 1,2-aminothiols or 1,2-diamines, yields in one pot a six-membered 1,4-heterocyclic system containing the enaminone moiety.     

Isocyanides in the synthesis of nitrogen heterocycles

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition-metal-catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.     

Glycosyl β-Bromo-α-ketonitriles: Useful Intermediates for a Rapid Conversion of Dialdoses into Glycoamidoesters and Glycothioesters

Glycosyl β-bromo-α-ketonitriles can be conveniently accessed through a versatile reaction of easily available dialdoses with potassium dibromoacetonitrile anion in isopropanol. They proved to be very useful intermediates in the direct preparation of new glycoamidoesters and glycothioesters. The synthesis of the title compounds involves coupling of glycosyl β-bromo-α-ketonitrile intermediates with suitably protected amino acid esters and 1-propanethiol, respectively. The coupling reaction proceeded smoothly at rt affording the targeted products in good yields and with moderate diastereoselectivities. The route presented here constitutes an important synthetic potential for the rapid preparation of new glycoamidoesters and glycothioesters that can find application as useful building blocks in the construction of more complex glycopeptides.     

Synthesis of Heterocycles by Formal Cycloadditions of Isocyanides

Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one‐pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.     

‐Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis

Due to their numerous reactivity modes, α‐aminonitriles represent versatile and valuable building blocks in organic total synthesis. Since their discovery by Adolph Strecker in 1850, this compound class has seen a wide dissemination in synthetic applications from laboratory to million‐ton industrial scale and was extensively used in the syntheses of various classes of natural products. As these compounds provide a multitude of reactivity options, we feel that a broad overview of their multiple reaction modes may reveal less familiar opportunities for successful total synthesis planning. This personal account article will thus focus on α‐aminonitriles used as key intermediates in selected natural product synthesis sequences which have been reported in the two decades since Enders’ and Shilvock's seminal review. Natural α‐aminonitriles will also briefly be treated.     

Aldo‐X Bifunctional Building Blocks for the Synthesis of Heterocycles

Compounds containing oxygen, nitrogen, or sulfur atoms inside the rings are attracting much attention and interest due to their biological importance. In recent years, several methods for the synthesis of such molecules have been reported by using aldo‐X bifunctional building blocks (AXB3 s) as substrates; these are a wide class of organic molecules that contain at least two reactive sites, among them, one aldehyde, acetal, or semiacetal group was involved. Because of the multiple reactivities, AXB3 s are widely used in the one‐pot synthesis of biologically important heterocycles. This review summarizes the synthesis of important heterocycles by using AXB3 s as pivotal components in establishing multicomponent reactions, tandem reactions, and so forth. In many cases, the established reaction systems with AXB3 s were characterized by some green properties, such as easy access to the substrate, mild and environmentally benign conditions, and wide scope of the substrate.     

Review of synthesis and various biological activities of spiro heterocyclic compounds comprising oxindole and pyrrolidine moities

Spirocyclic compounds isolated from plant and animal origins have important applications in medicinal chemistry. Spiro compounds having cyclic structures fused at a central carbon are of recent interest because of their interesting conformational features and their structural implications for biological systems. Spiro heterocycles like spiropyrrolidines and oxindole moieties have been found to play fundamental roles in biological processes and have exhibited diversified biological activity and pharmacological and therapeutical properties. In view of these facts we decided to present a representative synthetic scheme and various biological activities of the heterocycles like spiropyrrolidines and oxindole moieties derivatives, especially in relation to microbial infections like cancer and tubercular, viral, HIV, bacterial, and fungal infections.     

Design of Trifluoroalkenyl Iodonium Salts for a Hypervalency‐Aided Alkenylation–Cyclization Strategy: Metal‐Free Construction of Aziridine Rings

The synthesis of fluorinated compounds and their use as pharmaceutical ingredients or synthetic building blocks have been in the focus of chemical and medicinal research. However, the efficient synthesis of trifluoromethylated nitrogen heterocycles is sometimes challenging. Herein, we disclose a simple aziridination process that relies on the use of amines and novel alkenyl iodonium reagents for the synthesis of strained, trifluoromethylated heterocycles. With the utilization of a newly designed and bench‐stable but highly reactive hypervalent alkenyl iodonium species, these three‐membered‐ring heterocyclic compounds can be efficiently constructed from simple amines under mild conditions in the absence of transition‐metal catalysts. The special reactivity of the new trifluoropropenyl synthon towards nucleophilic centers could be exploited in more general cyclization and alkenylation reactions in the future.     

Fluorinated Imines in Tandem and Cycloaddition Reactions

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.