Recent synthetic strategies for the functionalization of fused bicyclic heteroaromatics using organo-Li, -Mg and -Zn reagents.

This review highlights the use of functionalized organo-Li, -Mg and -Zn reagents for the construction and selective functionalization of 5- and 6-membered fused bicyclic heteroaromatics. Special attention is given to the discussion of advanced syntheses for the preparation of highly functionalized heteroaromatic scaffolds, including quinolines, naphthyridines, indoles, benzofurans, benzothiophenes, benzoxazoles, benzothiazoles, benzopyrimidines, anthranils, thienothiophenes, purine coumarins, chromones, quinolones and phthalazines and their fused heterocyclic derivatives. The organometallic reagents used for the desired functionalizations of these scaffolds are generally prepared in situ using the following methods: (i) through directed selective metalation reactions (DoM), (ii) by means of halogen/metal exchange reactions, (iii) through oxidative metal insertions (Li, Mg, Zn), and (iv) by transmetalation reactions (organo-Li and Mg transmetalations with ZnCl2 or ZnO(Piv)2). The resulting reactive organometallic reagents allow a wide range of C-C, C-N and C-X cross-coupling reactions with different electrophiles, employing in particular Kumada or Negishi protocols among other transition metal (Pd, Ni, Co, Cu, Cr, Fe, etc.)-catalyzed processes. In addition, key developments concerning selective metalation techniques will be presented, which rely on the use of RLi, LDA and TMP metal bases. These methods are now widely employed in organic synthetic chemistry and have proven to be particularly valuable for drug development programs in the pharmaceutical industry. New and improved protocols have resulted in many Li, Mg and Zn organyls now being compatible with functionalized aryl, heteroaryl, alkenyl, alkynyl and alkyl compounds even in the presence of labile functional groups, making these reagents well-suited for C(sp2)-C(sp2), C(sp2)-C(sp) and C(sp2)-C(sp3) cross-coupling reactions with fused heteroaryl halides. In addition, the use of some transition metal-catalyzed processes occasionally allows a reversed role of the reactants in cross-coupling reactions, providing alternative synthetic routes for the preparation of fused heteroaromatic-based bioactive drugs and natural products. In line with this, this article points to novel methods for the functionalization of bicyclic heteroaromatic scaffolds by organometallic reagents that have been published in the period 2010-2023.

Metal-free oxidative coupling of aryl acetylene with elemental sulphur and amines: facile access to α-ketothioamides.

A simple and efficient oxidative coupling of aromatic alkynes with elemental sulphur and secondary amines has been reported. The iodine/DMSO system easily promoted the transformations, affording thioglyoxamides via C-S, C-O, and C-N bond formations. In this context, acetylenic C-H bond oxidation has occurred through iodination, leading to the desired products. Moreover, this metal-free, one-pot protocol is accomplished by using readily available starting materials, without external oxidants, and under aerobic conditions, providing a variety of α-ketothioamide compounds in moderate to good yields.

Metal-free efficient synthesis of aryl sulfonamides from N-hydroxy sulfonamide and amines.

A simple and novel approach has been developed for the synthesis of sulfonamides from N-hydroxy sulfonamide. Notably, the iodine-tert-butyl hydroperoxide (TBHP) system efficiently promoted the sulfonylation reactions of N-hydroxy sulfonamides and amines via the oxidative cleavage of an S-N bond. A variety of aryl sulfonamides were prepared in moderate to good yields using readily available starting materials and the biomass-derived 2-MeTHF solvent. The present method has the advantages of using metal-free reagents, an eco-friendly medium, cost-effective reagents, wide substrate scope, and mild conditions.

Synthetic Strategies of N-Heterocyclic Olefin (NHOs) and Their Recent Application of Organocatalytic Reactions and Beyond.

N-heterocyclic olefin (NHO) derivatives have an electron-rich as well as highly polarized carabon-carbon (C=C) double bond because of the electron-donating nature of nitrogen and sulphur atoms. While NHOs have been developing as novel organocatalysts and ligands for transition-metal complexes in various organic compound syntheses, different research groups are currently interested in preparing imidazole and triazolium-based chiral NHO catalysts. Some of them have been used for enantioselective organic transformations, but were still elusive. N-heterocyclic olefins, the alkylidene derivatives of N-heterocyclic carbenes (NHC), have shown promising results as effective promoters for numerous organic syntheses such as asymmetric catalysis, hydroborylation, hydrosilylation, reduction, CO2 sequestration, alkylation, cycloaddition, polymerization and the ring-opening reaction of aziridine and epoxides, esterification, C-F bond functionalization, amine coupling, trifluoromethyl thiolation, amination etc. NHOs catalysts with suitable structures can serve as a novel class of Lewis/Bronsted bases with strong basicity and high nucleophilicity properties.These facts strongly suggest their enormous chemical potential as sustainable catalysts for a wide variety of reactions in synthetic chemistry. The synthesis of NHOs and their properties are briefly reviewed in this article, along with a summary of the imidazole and triazole core of NHOs' most recent catalytic uses.

N-Heterocyclic Carbene Triazolium Salts Containing Brominated Aromatic Motifs: Features and Synthetic Protocol.

In this work, we provide a brief overview of the role of N-aryl substituents on triazolium N-heterocyclic carbene (NHC) catalysis. This synopsis provides context for the disclosed synthetic protocol for new chiral N-heterocyclic carbene (NHC) triazolium salts with brominated aromatic motifs. Incorporating brominated aryl rings into NHC structures is challenging, probably due to the substantial steric and electronic influence these substituents exert throughout the synthetic protocol. However, these exact characteristics make it an interesting N-aryl substituent, because the electronic and steric diversity it offers could find broad use in organometallic- and organo-catalysis. Following the synthetic reaction by NMR guided the extensive modification of a known protocol to enable the preparation of these challenging NHC pre-catalysts.

Polyfunctional Lithium, Magnesium, and Zinc Alkenyl Reagents as Building Blocks for the Synthesis of Complex Heterocycles.

New conjunctive ß-silylated organometallic reagents of Li, Mg, and Zn have been prepared and used for an expeditive construction of various polyfunctionalized 5-, 6-, and 7-membered heterocycles, such as furans, pyrroles, quinolines, benzo[b]thieno-[2,3-b]pyridine, naphthyridines, fused pyrazoles, and 2,3-dihydro-benzo[c]azepines. The latent silyl group has been converted into various carbon-carbon bonds in most heterocycle types.

A Review on Functionalization of Benzo-5,6-Fused Bicyclic Heteroaromatic Compounds.

Over the decades, functionalized heteroaromatic compounds and their scaffolds have drawn significant attention in synthetic organic chemistry as well as in interdisciplinary sciences due to their prevalence in natural products, hormones, vitamins, and their applications in pharmaceuticals, agrochemicals, veterinary products, dyes and pigments, bio-imaging, semiconductors, and optoelectronics, etc. This review explores various synthetic strategies for functionalization of numerous 5,6 benzo-fused heteroaromatic derivatives such as indole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole and benzotriazole through various methods including C-H activation, cross-coupling, metal catalysis, photo-catalysis, electrocatalysis and organocatalysis in recent years (2019-2023). Highly functionalized heterocyclic scaffolds are the important precursors for synthesizing many bioactive drugs like fenbendazole, viozan, griseofulvin, zileuton, flunoxaprofen, natural products, and optoelectronic materials, etc.

Recent synthetic strategies for the construction of functionalized carbazoles and their heterocyclic motifs enabled by Lewis acids.

This article demonstrates recent innovative cascade annulation methods for preparing functionalized carbazoles and their related polyaromatic heterocyclic compounds enabled by Lewis acid catalysts. Highly substituted carbazole scaffolds were synthesized via Lewis acid mediated Friedel-Crafts arylation, electrocyclization, intramolecular cyclization, cycloaddition, C-N bond-formations, aromatization and cascade domino reactions, metal-catalyzed, iodine catalyzed reactions and multi-component reactions. This review article mainly focuses on Lewis acid-mediated recent synthetic methods to access a variety of electron-rich and electron-poor functional groups substituted carbazole frameworks in one-pot reactions. Polyaromatic carbazole and their related nitrogen-based heterocyclic compounds were found in several synthetic applications in pharma industries, energy devices, and materials sciences. Moreover, the review paper briefly summarised new synthetic strategies of carbazole preparation approaches will assist academic and pharma industries in identifying innovative protocols for producing poly-functionalized carbazoles and related highly complex heterocyclic compounds and discovering active pharmaceutical drugs or carbazole-based alkaloids and natural products.

Recent Advances in the Practical Synthesis of C1 Deuterated Aromatic Aldehydes Enabled by Catalysis and Beyond.

C1 -selective deuteration of aromatic aldehydes is of great importance for isotopic labeling and for improving the characteristics of drug molecules. Due to the recent increase in the use of deuterated pharmacological drugs, there is a pressing need for synthetic procedures that are efficient to produce deuterated aromatic aldehyde analouges. Deuterium labeling approaches are typically used as an effective tool for researching pharmaceutical absorption, distribution, metabolism, and excretion (ADME). Furthermore, deuterium-labeled pharmaceuticals are intended to increase therapeutic effectiveness and reduce side effects by extending the half-life of drug response. In the last few years, several catalytic or non-catalytic methods have been developed to synthesize deuterated aromatic aldehydes. In this concern, we offer a brief overview of the various synthetic strategies and practical methods for the formyl-selective deuterium labeling of aromatic aldehydes using different deuterium sources.

Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere.

Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.

Synthesis of polyfunctional secondary amines by the addition of functionalized zinc reagents to nitrosoarenes.

Addition of functionalized aryl, heteroaryl or adamantyl zinc reagents to various nitroso-arenes in the presence of magnesium salts and LiCl in THF produces after a reductive work-up with FeCl2 and NaBH4 in ethanol the corresponding polyfunctional secondary amines in high yields.

Synthesis of substituted adamantylzinc reagents using a Mg-insertion in the presence of ZnCl2 and further functionalizations.

The LiCl-mediated Mg-insertion in the presence of ZnCl2 allows an efficient synthesis of adamantylzinc reagents starting from the corresponding functionalized tertiary bromides. The highly reactive adamantylzinc species readily undergo a broad variety of functionalizations such as Negishi cross-couplings, Cu(I)-catalyzed acylations and allylations, and 1,4-addition reactions leading to the expected products in excellent yields. Furthermore, the adamantyl moiety could be introduced as α-substituent in terthiophene, increasing its solubility due to the higher lipophilicity and the prevention of π-stacking.

Synthesis of 2-substituted 17ß-hydroxy/17-methylene estratrienes and their in vitro cytotoxicity in human cancer cell cultures.

Synthesis of various types of 2-(alkylaminomethyl) and 2-(aroyl) 17ß-estradiol analogs are reported. The synthesis of similar types of 2-substituted 17-methylene estratriene analogs was also achieved. Synthesis of chalcone derivatives of 17ß-estradiol and 17-methylene estratriene were also realized. All these 2-substituted estratrienes were tested for their antiproliferative activity by using four different cell lines from colon, lung, glioma and breast cancers. Among the various 2-substituted estratrienes, the compounds 10d, 14a-h and 17e were found to have in vitro antiproliferative activity comparable to that of parent analogs 1-4. Comparison of the SAR pattern of these 2-susbtituted estratriene derivatives confirmed that relatively, 17-methylene estratrienes are more active than that of 17ß-estradiol analogs.