Chapter Four - Ketenes as Privileged Synthons in the Syntheses of Heterocyclic Compounds. Part 1: Three- and Four-Membered Heterocycles

Four-membered heterocycles are the heterocyclic analogs of cyclobutane and are considered to be derived by replacing a -CH2 (methylene group) by a heteroatom (NH, O or S). The four-membered saturated heterocycles containing nitrogen, oxygen and sulfur are known as azetidines 1, oxetanes 2 and thietanes 3, respectively. Four-membered heterocyclic rings are less strained, and hence more stable than the three-membered rings and, therefore, the ring cleavage is less likely. Moreover, four-membered heterocycles are more difficult to synthesize by direct intramolecular cyclization than the three-membered heterocycles because ring forming ability falls off with the chain length. The molecules of oxetane 2 and thietane 3 are planar, but not square because of relatively larger size of the oxygen and sulfur atoms than the carbon atom. The planarity of these heterocycles 2 and 3, as compared to cyclobutane which is puckered, has been attributed to the reduction in the number of non-bonded interactions between methylene groups.

The diverse synthesis of heterocyclic compounds has always been one of the popular subjects of organic chemistry. To this end, great efforts have been devoted to developing new reagents and establishing new strategies and methods concerning efficiency, selectivity and sustainability. β-Oxodithioesters and their enol tautomers (i.e., α-enolic dithioesters), as a class of simple and readily accessible sulfur-containing synthons, have been widely applied in the construction of various five- and six-membered heterocycles (e.g., thiophenes, thiopyrans, thiazoles, pyridines and quinolines) and other useful open-chain frameworks. Due to their unique chemical structures, β-oxodithioesters bear multiple reaction sites, which enable them to participate in two-component or multicomponent reactions to construct various heterocyclic compounds. In the past decade, the application of β-oxodithioesters in the synthesis of heterocycles has made remarkable progress. Herein, an update on the recent advances in the application of β-oxodithioesters in the synthesis of heterocycles during the period from 2013 to 2023/06 is provided. According to the different types of rings concerning heteroatoms in products, this review is divided into five sections under discussion including (i) synthesis of sulfur-containing heterocycles, (ii) synthesis of sulfur and nitrogen-containing heterocycles, (iii) synthesis of nitrogen-containing heterocycles, (iv) synthesis of nitrogen and oxygen-containing heterocycles, and (v) modification to other open-chain frameworks.

Considering the very important medicinal and biological properties of heterocycles incorporated indole skeleton, synthesis of these compounds is of great interest to medicinal and organic chemists, especially researchers who are involved in the synthesis of heterocycles. The present review focuses on the recent investigation in the synthesis of heterocycles with indole moiety using indole derivatives as reactant via multi-component reaction for the period of 2012–2022. Reports were categorized based on the type of indole substitution. The main aim of this review is to provide a summary of recently reported methods in the use of indole derivatives in multicomponent synthesis of heterocyclic compounds for organic and medicinal chemists.

Fluorine-Containing Heterocycles. Part I. Synthesis by Intramolecular Cyclization

Heterocycles constitute the largest and the most diverse family of organic compounds. Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals. Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value. 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis. 2 Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand. Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry. Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools. Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years. Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others. Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc. Reviews devoted to an application of a particular type of starting materials have also been published. Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed. In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles.21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed. The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles. The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved. A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary. The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed.

A four-membered heterocycle synthesis offers a thorough exploration of these unstable organic compounds, systematically introducing the synthesis and reactions of all standard fourmembered heterocycles while showcasing various methods for creating unique variants. Due to their inherent strain, four-membered heterocyclic compounds are classified as unstable organic compounds, which makes them valuable as precursors for synthesizing a wide range of complex heterocyclic molecules. These compounds have become essential frameworks in medicinal chemistry, providing unique properties that enhance drug design and development. The incorporation of heteroatoms like nitrogen, oxygen, and sulfur into four-membered rings (such as azetidines, oxetanes, and thietanes) leads to diverse electronic, steric, and metabolic characteristics that can improve therapeutic efficacy, selectivity, and pharmacokinetics. Despite the challenges posed by their ring strain, recent advancements in chemical synthesis and functionalization techniques have made these compounds more accessible for various therapeutic applications. These strained ring structures offer increased metabolic stability, controlled lipophilicity, and the potential for advantageous binding interactions, making them suitable for multiple therapeutic uses, including oncology, infectious diseases, and CNS disorders. This review examines the key properties of four-membered heterocyclic rings, their role in drug development, recent synthetic advancements, and the potential of these compounds to yield next-generation medications with enhanced efficacy and precision.

Chapter 4 - A chapter on synthesis of various heterocyclic compounds by environmentally friendly green chemistry technologies

The Synthesis of Heterocyclic Compounds with Hypervalent Organoiodine Reagents

For Abstract see ChemInform Abstract in Full Text.

Review: 1074 refs.

Heterocyclic compounds are widely distributed in natural products, pharmaceuticals and materials, thus drawing considerable attention from the synthetic communities. Generally, alkaline earth metals are earth-abundant and environmentally friendly compared to precious metals. To date, researchers have achieved great progress in utilization of alkaline earth metals in the syntheses of various heterocyclic compounds. Herein, this review will summarize recent advances in the syntheses of heterocyclic compounds enabled by alkaline earth metals, including magnesium, calcium and strontium. In addition, the summary is also presented.

Chapter 5 - Green Solvents for Eco-friendly Synthesis of Bioactive Heterocyclic Compounds

4-Hydroxycoumarins are some of the most versatile heterocyclic scaffolds and are frequently applied in the synthesis of various organic compounds. 4-Hydroxycoumarin-based compounds are important among heterocyclic structures due to their biological and pharmaceutical activities. In this study, we provide an overview on the recent applications of 4-hydroxycoumarin in multicomponent reactions for the synthesis of various heterocyclic compounds during the time period of 2015-2018.

Nucleophilic phosphine catalysis is a practical and powerful tool for the synthesis of various heterocyclic compounds with the advantages of environmentally friendly, metal-free, and mild reaction conditions. The present report summarizes the construction of four to eight-membered heterocyclic compounds containing nitrogen, oxygen and sulphur atoms through phosphine-catalyzed intramolecular annulations and intermolecular [2+2], [3+2], [4+1], [3+1+1], [5+1], [4+2], [2+2+2], [3+3], [4+3] and [3+2+3] annulations of electron-deficient alkenes, allenes, alkynes and Morita-Baylis-Hillman carbonates.

The addition of polyhalides to multiple bonds in the synthesis of various heterocyclic compounds is discussed.