Heterocyclic Products Research Articles

DBU-Promoted Cyclizations of Cyclopentyl-Substituted Oxazapolyenes to Cyclopentapyridones and Hydroxypyrroles: Experimental and DFT Study.

1,1-Di(alkoxycarbonyl)-4-cyclopentyl-2-azabuta-1,3-dienes react with DBU to form two types of heterocyclic products: 1H-cyclopenta[c]pyrid-1-ones and 3-hydroxy-1H-pyrroles. These previously unobserved transformations proceed through the formation of 1-azapentadienyl anion which undergoes 1,6-shift of the alkoxycarbonyl group to the cyclopentyl moiety followed by 1,6-cyclization to form the cyclopentapyridone (path a) and 1,5-cyclization accompanied by 1,3-shift of the methoxy group followed by dialkyl carbonate elimination to afford the hydroxypyrrole (path b). The mechanisms of the reactions were studied using DFT calculations. Pyridones can be synthesized in one pot in three steps via Rh(II)-catalyzed isomerization of 4-cyclopentylisoxazoles to 2H-azirines and their subsequent reaction with diazomalonic esters, followed by heating of the resulting 2-azabuta-1,3-dienes with DBU.

A General and Scalable Method toward Enantioenriched C2-Substituted Azetidines Using Chiral tert-Butanesulfinamides.

Diverse ranges of chiral nitrogen-containing heterocycles serve as a molecular toolbox for modulating a wide array of biological processes, but enantioenriched production of smaller chiral heterocycles is a bottleneck. There is a lack of general approaches for the stereoselective preparation of chiral 4-membered monocyclic C2-substituted azetidines, where many routes to different substitution types are possible, but no simple and common approach exists. To bridge this gap, inexpensive and widely available chiral tert-butanesulfinamides are harnessed for chiral induction with 1,3-bis-electrophilic 3-chloropropanal, providing a three-step approach to C2-substituted azetidines with aryl, vinyl, allyl, branched alkyl, and linear alkyl substituents. Eleven azetidine products are produced, and the approach is shown to be effective on a gram-scale with a single purification of the protected azetidine product in 44% yield over three steps in an 85:15 diastereomeric ratio. In most cases, the diastereomers are separable using normal phase chromatography, often resulting in previously elusive enantiopure azetidine products. Protected azetidines were shown to undergo rapid and efficient sulfinamide cleavage, producing an azetidine hydrochloride salt that was subjected to derivatization reactions, highlighting the method's applicability to medicinal chemistry approaches.

One-Pot Transition-Metal-Free Synthesis of Alkynyl Amides.

Alkynyl amides play crucial roles in organic synthesis in the production of bioactive compounds and valuable heterocycles. Despite numerous studies on their synthesis, challenges persist due to the necessity of harsh or hazardous conditions and the use of costly or unstable reagents. Herein, we present a one-pot method for the synthesis of all three bonds of the alkyne under transition-metal free conditions. An important feature of this chemistry is the use of readily available feedstock chemicals, such as methyl esters and acetamides. This approach offers efficient access to a wide range of aryl and alkyl alkynyl amides and demonstrates excellent tolerance towards various functional groups in a sustainable and cost-effective manner.

Ru(II)-Catalyzed C-H Amination of 1,2,3-Benzotriazinones with Azide Compounds.

A Ru(II)-catalyzed directed C-H amination of 1,2,3-benzotriazinones with azide compounds has been reported. The reaction has a wide substrate scope of organic azides with good results and represents a useful pathway to the construction of versatile heterocyclic amino products. In addition, the method can be used for the phthalazinones, highlighting the synthetic practicability of the strategy.

3-Thioxo-3H-indolizinium-1-olates and Related Pseudo-Cross-Conjugated Heterocyclic Mesomeric Betaines: Synthesis and Spectral Features.

The first example of the synthesis of 3-thioxo-3H-indolizinium-1-olates, which further expands a limited class of pseudocross-conjugated heterocyclic mesomeric betaines isoconjugate to odd nonalternant hydrocarbon anion, is reported. These unique, moderately colored heterocyclic products result from a developed three-component reaction of cyclopropenones, pyridines, and sulfur. The protocol is distinguished by simple and mild reaction conditions that avoid expensive reagents or exotic catalysts, exhibiting high functional group tolerance. The broad scope of the reaction is particularly remarkable in light of the dramatic influence of pyridines' substituents on the reactivity of corresponding indolizin-1-ols, the key intermediates that proved to be highly thiophilic. In addition, an oxidative coupling of indolizin-1-ol in situ with p-tropoquinone oxime acetate is discovered. The reaction involves the C3 and C5 positions of the indolizin-1-ol and results in unusual indolizine-aminotropolone combinations. For the 3H-indolizinium-1-olate type of PCC HMBs, some general considerations concerning light absorption and NMR regularities were formulated.

Natural Occurring Terpene Cyclic Anhydrides: Biosynthetic Origin and Biological Activities.

Cyclic acid anhydride is a not very widespread structure in nature, but with a determining role in natural products possessing this functionality in their skeleton. To the best of our knowledge, no revision of terpenes containing cyclic anhydrides has been previously reported. The result was that more than 100 terpenic cyclic anhydrides and related compounds were found to be in need of being reported. This review has been systematically organized by terpene skeletons, from the smallest to largest, describing their sources and bioactivities. In addition, different biosynthetic pathways for their final oxidations, namely, routes A, B and C, leading to the formation of these heterocyclic natural products, have been proposed. We have also included the most plausible precursors of these natural products, which mostly happened to be present in the same natural source. Some molecules derived from terpene cyclic anhydrides, such as their natural imide derivatives, have also been described due to their significant biological activity. In this sense, special attention has been paid to cantharidin because of its historical relevance and its broad bioactivity. A plausible biosynthesis of cantharidin has been proposed for the first time. Finally, cyclic anhydride structures that were firstly assigned as anhydrides and later corrected have been also described.

Unusual Cascade Reactions of 8-Acetoxy-6-hydroxymethyllimonene with Salicylic Aldehydes: Diverse Oxygen Heterocycles from Common Precursors.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

Tandem Condensation-Cycloaddition of Propargylic Amines with α-Azido Ketones and β-Alkoxy-γ-Azido Enones.

α-Azido ketones and their vinylogous relatives β-alkoxy-γ-azido enones are versatile building blocks for constructing diverse heterocyclic products, but are prone to azide decomposition. Here, we report their condensation with propargylic amines and investigate the fate of the intermediate azido-enamine condensation products, both experimentally and theoretically. Efficient intramolecular cycloaddition was observed for electron-poor azide substrates, and a range of diversely substituted [1,2,3]triazolo[1,5-a]pyrazine products is reported. For electron-rich substrates, azide decomposition predominated. Computational modeling of possible pathways from the azido-enamine intermediates revealed two alternative mechanisms for azide decomposition, which were consistent with observed side products.

Synthesis of New Isoxazolidine Derivatives Utilizing the Functionality of N-Carbonylpyrazol-Linked Isoxazolidines.

Using Ni(II) as the catalyst, electron-deficient 3,5-dimethylacryloylpyrazole olefin was reacted with C,N-diarylnitrones alone for 10 min to prepare novel five-member heterocyclic products, 4-3,5-dimethylacryloylpyrazole isoxazolidines with 100% regioselectivity and up to 99% yield. And then, taking these cycloadducts as substrates, six kinds of derivatization reactions, like ring-opening, nucleophilic substitution, addition-elimination and reduction, were studied. Experimental results showed that all kinds of transformations could obtain the target products at a high conversion rate under mild conditions, a finding which provided the basic methods for organic synthesis methodology research based on an isoxazolidine skeleton.

Adventures in the Chemistry of Multicomponent and Domino Reactions

AbstractThe present personalized account summarizes various cyclization reactions, including multicomponent and domino processes, which are directed towards the synthesis of complex heterocyclic products. Domino Knoevenagel/hetero‐Diels‐Alder reactions provide a synthesis of annulated quinol‐2‐ones. The combination of Knoevenagel reactions with [3+2] cycloadditions of nitrogen ylides afford complex spiroheteriocyclic products. Domino Knoevenagel/enamine cyclization reactions result in the formation of condensed purine analogues. Formal [3+3] cyclizations of pyridinium salts allow for a rapid assembly of bridged heterocyclic systems and include the employment of thioxindoles and cyclohexane‐1,3‐diones as dinucleophilic building blocks. The formal [3+3] cyclization of thioxindoles with fluoroaroyl chlorides, such as 2‐fluorobenzoyl chlorides and 2‐chloropyridine‐3‐carboxylic chloride, give rise to the synthesis of condensed benzothiophenes. The cyclization of heterocyclic enamines with diimines and triazines afford various purine analogues by domino [4+2]/retro [4+2] reactions. The formal [3+3] cyclization of 2,4,6‐tris(trifluoromethyl)‐1,3,5‐triazine with 1,3‐bis(silyloxy)‐1,3‐butadienes afford, depending on the conditions, 2,6‐bis(trifluoromethy)pyrid‐4‐ones or triazaadamantanone derivatives. Heating of 2‐ethynylpyridines with electron‐rich dienes afforded 2‐(2‐methoxyphenyl)pyridines by a domino [4+2]/retro [4+2] process. The reaction of 2‐ethynylpyridines with enones afforded indolizines by a formal [3+3] cyclization. The reaction of trifluoromethyl‐substituted 1,3‐diketones with lithiated alkynes afforded 3‐hydroxy‐pent‐4‐yn‐1‐ones. Formal [5+1] cyclization of the latter with urea afforded trifluoromethyl‐substituted pyridines. The Pd catalyzed formal [3+2] cyclizations of 2,3‐dihalopyridines with imines afforded a series of regioisomeric 4‐ and 7‐azaindoles.

A Comprehensive Overview of Recent Trends in the Production of Nitrogen-Containing Heterocyclic Compounds Using Nanocatalysts

Abstract: Nanocatalysis is the newest invention in the area of synthetic chemistry that has changed the process of chemical transformation. The nanocatalysts have various benefits as compared to traditional catalysts, such as simple and economical methods of synthesis, high surface-to-volume ratio, large number of active sites, excellent selectivity, increased stability, rapid recovery, and recyclability. In recent years, nanomaterials have been extensively employed in the production of heterocyclic moieties. This study intends to emphasize the function of distinct nanocatalysts in the synthesis of various nitrogen-containing heterocyclic compounds. An update on the catalytic efficiency of different nanocatalysts, such as magnetic nanocatalysts, nanomixed metal oxides, core-shell nanocatalysts, nano-supported catalysts, and graphene-based nanocatalysts for the production of heterocycles has been provided in this article.

Predicting the Occurrence of Substituted and Unsubstituted, Polycyclic Aromatic Compounds in Coking Wastewater Treatment Plant Effluent using Machine Learning Regression

Organic contaminants such as polycyclic aromatic compounds (PACs) occurring in industrial effluents can not only persist in wastewater but transform into more toxic and mobile, substituted heterocyclic products during treatment. Thus, predicting the occurrence of PACs and their heterocyclic derivatives (HPACs) in coking wastewater is of utmost importance to reduce the environmental risks in water bodies that receive industrial effluents. Although HPACs can be monitored through sampling and analysis, the characterisation techniques used in their analyses are costly and time-consuming. In this study, we propose 3 distinct kernel-based machine learning (ML) models for predicting PACs including substituted HPACs and alkylated PACs occurring in coking wastewater. By using routinely measured wastewater quality data as input for our models, we predicted the occurrence of 14 HPACs in the final effluent of a coking wastewater treatment plant. Support Vector Machine based regression model (SVR) used for HPAC prediction showed the highest R2 of 0.83. Performance assessment of SVR model showed a mean absolute logarithmic error (MALE) of 0.46 and root mean square error (RMSE) of 0.073 ng/L. Comparatively, K-Nearest Neighbor and Random Forest models showed lower R2 of 0.75 and 0.76 respectively for HPAC prediction. Feature analysis attributed the superior predictability of SVR model likely to its higher weightage (81%) towards dissolved organic carbon and total ammonia as input variables. Both these variables could capture the underlying secondary PAC transformations likely occurring in the treatment plant. Partial dependence plots predicted that ammonia levels higher than 120 mg/L and DOC levels of 50–60 mg/L were likely linked to higher HPACs occurring in the final effluent. This work highlights the capability of kernel-based ML models in capturing nonlinear wastewater chemistry and offers a tool for monitoring trace organic contaminants released in coking effluents.

Enantioselective Synthesis in Continuous Flow: Polymer-Supported Isothiourea-Catalyzed Enantioselective Michael Addition-Cyclization with α-Azol-2-ylacetophenones.

A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,β-unsaturated homoanhydrides in continuous flow via an α,β-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.

Pnictogen-Rich Heterocycles Derived from a Phosphadiazonium Cation.

Heterocycles that pair main group elements and nitrogen are extremely important within the π-conjugated heterocycles research community. Compared to the vast number of boron-nitrogen heterocycles, those that include phosphorus are less common. Furthermore, the use of phosphorus-nitrogen triple bonds of any type to prepare such compounds is unprecedented. Here, we pair pyridyl hydrazonide ligands with phosphadiazonium cations and demonstrate that the chelated Mes*NP group is directly implicated in the photophysical and redox properties observed for the resulting heterocycles. In doing so, we introduce a novel building block for the production of phosphorus-containing heterocycles that could find use in small molecule activation and catalysis or as the functional component of emerging organic electronics.

Synthesis and Characterization of Heterocyclic Derivatives from 5-Aminotetrazole and Investigation of Their Biological Activities

This study included the synthesis of some new heterocyclic compounds starting with 5-aminotetrazole, which reacted with 2-hydroxy-4-methoxybenzaldehyde to get compound 1. Then, 1 was converted to a Schiff base (2) derivative by reacting 1 with 2-aminothiazole. Then, compound 2 was reacted with different compounds, namely alanine, 2-mercaptoacetic acid, 2-aminobenzoic acid, phthalic anhydride, and malic anhydride, leading to the heterocyclic products imidazolidine (3), thiazolidine (4), quinazoline (5), and oxazepane (6) derivatives, respectively. All these compounds are characterized by 13C-NMR, Fourier transform infrared spectroscopy, and 1HMNR. We also studied the biological activity of all heterocyclic derivatives toward two different kinds of bacteria and molecular docking studies.. KEYWORDS :Imidazolidine, Oxazepine, Quinazoline, Schiff bases, Thiazolidine.

Rapid access to diverse indoles by addition/SNAr with Grignard reagents and 2-fluorophenyl acetonitriles

Indoles are essential heterocycles in natural products, biological chemistry, and medicinal chemistry. Efficient approaches to their synthesis, therefore, remain in demand. Herein is reported a novel and scalable method to produce a wide variety of indoles by combining Grignard reagents and 2-fluorobenzyl cyanides (59 examples, 45%–95% yields). The Grignard reagent adds to the nitrile to give a metalated imine that undergoes SNAr with unactivated C–F bonds. This strategy installs the R group of RMgX at the indole 2-position, and it is noteworthy that a diverse array of Grignard reagents (aryl, alkyl, vinyl, and cyclopropyl) provide the desired heterocyclic products. The resulting N-magnesiated indole can be in situ functionalized at the 3-position with alkyl halides or functionalized on the nitrogen with silyl chlorides. This method enables the synthesis of indoles with functional groups at each position of the indole backbone (C4–C7), providing handles for further functionalization.

Transition-metal-free intramolecular double hydrofunctionalization of alkyne to access 6/7/5-fused heterocyclic skeletons.

We describe a novel intramolecular double hydrofunctionalization cyclization of alkyne with nitrogen and oxygen nucleophilic groups to construct valuable 6/7/5-fused heterocyclic products. This post-Groebke-Blackburn-Bienaymé (GBB) reaction introduces a new class of functionalized isocyanides. Transition-metal-free cyclization, broad substrate scope, and high atom economy were some features of the present protocol.

Palladium-catalyzed [6 + 4] cycloaddition with π-allyl all-carbon 1,6-dipole for the synthesis of ten-membered heterocycles

This work introduces a novel α,α-diester-δ-vinylvalerolactone as a dipolar precursor in a palladium-catalyzed [6 + 4] cycloaddition reaction with azadienes, resulting in the production of ten-membered heterocycles.

Recent trends for chemoselectivity modulation in one-pot organic transformations.

In organic reactions, chemoselectivity refers to the selective reactivity of one functional group in the presence of another. This can be more successful if the reagent and reaction parameters are appropriately chosen. One-pot reactions have been shown to be an effective structural variety technique for the development of novel heterocyclic or carbocyclic compounds. This review article focuses on recent efforts by researchers from around the world to synthesise novel organic molecules utilising these methodologies (2013-2024), as well as their mechanism insights. The substrate, catalyst, solvent, and temperature conditions all have a significant impact on chemoselectivity in the organic reactions described here. The manipulation of chemoselectivity in organic processes creates new potential for the production of novel heterocycles and carbocycles.

Синтез и исследование структуры иодсодержащих имидазо[2,1 b][1,3]тиазиниевых систем

Heterocyclization of S-alkenyl derivatives of 1-methylimidazole-2-thiol (1-methyl-2-prenyl-sulfanylimidazole (1), 1-methyl-2-cinnamylsulfanylimidazole (4), and 2-(3-butenyl)sulfanyl-1-methyl-imidazole (7)) has been studied for the first time under the action of iodine (iodocyclization) in various solvents (chloroform, dichloro-methane, glacial acetic acid), and at different substrate and iodine ratios (1 : 1, 1 : 2). It has been found that the interaction of compounds 1, 4, 7 with iodine proceeds regioselectively, regardless of the reaction conditions, and it is accompanied by the linear annelation of the thiazinium ring and formation of a bicyclic fused heterocyclic system. As a result, new iodine-containing imidazo[2,1 b][1,3]thiazinium systems have been synthesized – 6-iodo-1,5,5-trimethyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]hiazinium polyiodide / iodide (2, 3), 6-iodo-1-methyl-5-phenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazinium triiodide / iodide (5, 6), and 6-iodomethyl-1-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazinium iodide (9). The structure of the synthesized compounds has been studied and proved by 1H and 13C NMR spectroscopy. The evidence for heterocyclization reactions of alkenyl sulfides 1, 4, and 7 is the absence of signals for the alkenyl protons and the presence of a more complex splitting pattern of signals for the thiazinium ring protons in the 1H NMR spectra of heterocyclization products. The structures of polyiodide 2 and triiodide 5 have been unambiguously established and characterized by X-ray diffraction analysis. According to the X-ray analysis data, the cell of polyiodide 2 contains two heterocyclic cations, a triiodide anion, and an iodide anion. In the triiodide crystal 5 heterocyclic cations correspond to two types of crystallographically independent triiodide anions: one cell contains eight molecules of a heterocyclic cation and eight triiodide anions. The structural organization in the crystals is due to short contacts between atoms: I(4)∙∙∙H(3) (2.95 Å), I(4)∙∙∙I(1) (3.57 Å), H(8a)∙∙∙I(2) (3.13 Å) (in crystal 2), I(2)∙∙∙I(4) (3.95 Å), I(5)∙∙∙H(5) (3.14 Å), I(4)∙∙∙H(7a) (3.12 Å), I(4)∙∙∙H(7b) (3.17 Å) (in crystal 5).