Seven-membered Heterocycles Research Articles

A comparative study of X-ray structural analysis, supramolecular investigation by Hirshfeld surface analysis and DFT computations for tricyclic 1,4-benzodiazepines

The tricyclic 1,4-benzodiazepines - seven-membered heterocyclic compounds were synthesized derived from the three-component reaction involving o-phenylenediamine, 5,5-dimethyl-1,3-cyclohexanedione and various aromatic aldehydes under the influence of HCl. The crystal structure of 11-(3-nitrophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (NDDD) and 11-(2-chlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (CDDD) corroborated through single crystal X-ray diffraction method. The Hirshfeld surface analysis indicates crystal packing along with role of intermolecular forces in stabilizing supramolecular assembly of NDDD and CDDD. 2D fingerprint analysis is carried out to envisage to the elemental interactions in the assumption of a single crystal containing molecular fragments. DFT investigations have been carried out to understand the reactivity of NDDD and CDDD at the m062x/def2tzvp method. The obtained geometric parameters from theoretical study are well consistent with experimentally reported XRD analysis. Bonding analysis and charge transfer were examined by performing quantum theory of atoms in molecules (QTAIM) and natural bonding orbital (NBO) analysis. The synthesized NDDD and CDDD exhibit excellent electronic and nonlinear optical properties. The NLO response is justified through computed hyperpolarizability values.

The Application of Green Solvents in the Synthesis of S-Heterocyclic Compounds-A Review.

Cyclic organic compounds containing sulfur atoms constitute a large group, and they play an important role in the chemistry of heterocyclic compounds. They are valuable intermediates for the synthesis of other compounds or biologically active compounds themselves. The synthesis of heterocyclic compounds poses a major challenge for organic chemists, especially in the context of applying the principles of "green chemistry". This work is a review of the methods of synthesis of various S-heterocyclic compounds using green solvents such as water, ionic liquids, deep eutectic solvents, glycerol, ethylene glycol, polyethylene glycol, and sabinene. The syntheses of five-, six-, and seven-membered heterocyclic compounds containing a sulfur atom or atoms, as well as those with other heteroatoms and fused-ring systems, are described. It is shown that using green solvents determines the attractiveness of conditions for many reactions; for others, such use constitutes a real compromise between efficiency and mild reaction conditions.

Syntheses and medicinal chemistry of spiro heterocyclic steroids.

There is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies, spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to heterocyclic moieties containing three or more (hetero)cycles. Moreover, many compounds are accompanied by data on their biological activities, such as antiproliferative, antimalarial, antimicrobial, antifungal, steroid antagonist, and enzyme inhibition, among others, aimed at furnishing pertinent insights for the future design of more potent and selective drugs.

Phenotypic assessment of antiviral activity for spiro-annulated oxepanes and azepenes.

Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure-activity relationships for data-driven drug discovery. Here we present a primary assessment of antiviral activity of spiro-annulated derivatives of seven-membered heterocycles, oxepane and azepane, in phenotypic assays against viruses with different genomes, virion structures, and genome realization schemes: orthoflavivirus (tick-borne encephalitis virus, TBEV), enteroviruses (poliovirus, enterovirus A71, echovirus 30), adenovirus (human adenovirus C5), hantavirus (Puumala virus). Hit compounds inhibited reproduction of adenovirus C5, the only DNA virus in the studied set, in the yield reduction assay, and did not inhibit reproduction of RNA viruses.

A multicomponent reaction for modular assembly of indole-fused heterocycles.

Indoles are privileged chemical entities in natural products and drug discovery. Indole-fused heterocycles, particularly seven-membered ones, have received increasing attention due to their distinctive chemical characteristics and wide spectrum of bioactivities. However, the synthetic access to these compounds is highly limited. Herein, we report a unique multicomponent reaction (MCR) for modular assembly of indole-fused seven-membered heterocycles. In this process, indole, formaldehyde and amino hydrochloride could assemble rapidly to yield indole-fused oxadiazepines, and another addition of sodium thiosulphate would furnish indole-fused thiadiazepines. The biological evaluation disclosed the promising anticancer activity of these compounds. Furthermore, this MCR could be applicable in the late-stage and selective modifications of peptides. Therefore, this work provides a powerful strategy for indole functionalization and valuable tool for construction of seven-membered heterocycles.

Accessing five- and seven-membered phosphorus-based heterocycles via cycloaddition reactions of azophosphines.

Heterocycles containing both phosphorus and nitrogen have seen increasing use in recent years in luminescent materials, coordination chemistry and as building blocks for inorganic polymers, yet their chemistry is currently dominated by five- and six-membered derivatives. Seven-membered P/N heterocycles are comparatively scarce and lack general, high yielding syntheses. Here, we explore the synthesis and characterisation of 1,2,5-diazaphosphepines from azophosphines. The mechanism has been probed in detail with both computational and experimental studies supporting a stepwise mechanism to form a five-membered ring, and subsequent ring expansion to the diazaphosphepine. Regioselective synthesis of five- and seven-membered rings is possible using asymmetric alkynes. The Lewis acidic borane B(C6F5)3 could either catalyse the formation of the seven-membered ring (iPr derivative) or trap out a key intermediate via a frustrated Lewis pair (FLP) mechanism (tBu derivative).

Visible light-induced cascade sulfonylation/annulation of ortho-allyloxy chalcones with sodium sulfinates for the synthesis of sulfonated chromane derivatives.

A visible-light-induced radical cascade reaction for the synthesis of structurally diverse sulfonated chromanes is described. The protocol involves the addition of sulfonyl radicals to ortho-allyloxy chalcones and intramolecular Michael addition reactions in the presence of eosin Y as a photocatalyst. Additionally, this protocol shows that it is also an effective method to construct seven-membered oxygen-containing heterocycles. The method features a wide substrate scope, the use of easily accessible materials and excellent functional group tolerance with high to excellent yields. Control experiments and mechanistic studies indicate that a visible light-induced radical cascade process is involved in the transformation.

A Pd-catalyzed route to carborane-fused boron heterocycles.

Due to the expanding applications of icosahedral carboranes in medicinal and materials chemistry research, their functionalizations have become one of the central themes in boron-rich cluster chemistry. Although several strategies for incorporating nitrogen-containing nucleophiles on a single boron vertex of the icosahedral carboranes (C2B10H12) have been developed, methods for preparing clusters with vicinal B-N moieties are still lacking. The steric bulk of icosahedral carboranes and disparate electronic and steric nature of the N-containing groups have rendered the vicinal diamination challenging. In this article, we show how a developed Pd-catalyzed process is used to incorporate an array of NH-heterocycles, anilines, and heteroanilines with various electronic and steric profiles onto the vicinal boron vertices of a meta-carborane cluster via sequential or one-pot fashion. Importantly, oxidative cyclizations of the cross-coupling products with indoles and pyrroles appended to boron vertices generate a previously unknown class of all-boron-vertex bound carborane-fused six- and seven-membered ring heterocycles. Photophysical studies of the meta-carborane-fused heterocycles show that these structures can exhibit luminescence with high quantum yields and are amenable to further manipulations.

Controlled generation of ortho-quinone methides and (4+3) cyclization with 2-indolylalcohols by dual photoredox/Brønsted acid relay catalysis

Given the significance of oxacyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely construct and manipulate such ring systems in chemical research. In this area, the intermolecular, multicomponent cyclization for the synthesis of diversely substituted seven-membered ring oxacycles under simple conditions is still a challenge. Here, we report a dual photoredox/Brønsted acid relay catalytic strategy for in situ generation of ortho-quinone methides and subsequent (4 ​+ ​3) cyclization with 2-indolylalcohols. In this one-pot multicomponent reaction, two C–C and one C–O bonds are formed, providing de novo access to various biologically important indole-fused, oxygen-containing seven-membered heterocycles. By virtue of a chiral phosphoric acid, an asymmetric version can also be achieved with good to excellent levels of enantioselectivity (up to 96:4 er).

Direct Access to Quinone-Fused 5-Substituted-1,4-Benzodiazepine Scaffolds from Azidoquinones with/without [1,2]-Azide-Nitrogen Migration: Mechanistic Insights.

Seven-membered nitrogen heterocycles have a strong influence in drug discovery due to their inherent 3D character, which allows the ability to explore a vast conformational space with a biological target. Notably, the privileged 1,4-benzodiazepine scaffold is dominant in treating the central nervous system due to its binding affinity with the GABAA receptor. Herein, we report a protocol for the transformation of azidoquinones to p-quinone fused 5-substituted-1,4-benzodiazepines (p-QBZDs) from InCl3-catalyzed intermolecular tandem cycloannulation of azidoquinones with amines and aldehydes. Detailed mechanistic studies reveal that the EDA complex between azidoquinones and InCl3 is crucial in determining the reaction pathway. In the absence of EDA complex formation, the reaction proceeds via the intermediacy of 2,3-bridged-2H-azirine followed by regiospecific addition of an amine to C═N/ring opening/cyclization to deliver p-QBZD with 1,2-azide-nitrogen migration. In the case of EDA complex formation, the reaction proceeds through regioselective aza-Michael addition/nitrene insertion with aldehyde and subsequent cyclization to deliver p-QBZD and p-quinone fused imidazole as a secondary product without 1,2-azide-nitrogen migration. This protocol provides straightforward access to redox-active quinone embedded 5-substituted-1,4-benzodiazepines from azidoquinones with diverse substrate scopes that would find potential applications in medicinal chemistry and drug discovery.

Microwave-Assisted Synthesis of Five and Seven-Membered Heterocycles and Study Their Biological Activity

In this study, we synthesized one azo compound (S19) and then condensat this compound with a carbonyl compound to give a Schiff base (S20) as the key step. The next step Schiff base reacted with some Amino acids and Anhydrides by cycloaddition reaction to give five-membered (S22, S23) and seven-membered (S21, S24) heterocyclic compounds. The chemical Structure for of the synthesized compounds were confirmed by using spectroscopic techniques (IR and NMR). In addition, tested their biological activity against Staphylococcus Aureus and Escherichia Coli displayed good activity.

Regioselective synthesis, structural and bioactivity of acetylated 1,5-benzodiazepin-2-one derivatives — X-ray crystallography, DFT and molecular docking approaches

Benzodiazepines, a well-studied class of seven-membered aromatic heterocycles containing two nitrogen atoms, have shown great promise as therapeutic agents. Efficient protocols have been developed to synthesize a variety of functionalized benzodiazepines. This study focuses on the synthesis of three derivatives of 1,5-benzodiazepin-2-one through regioselective acetylation using acetyl chloride under various conditions. One of the derivatives was characterized for its molecular and crystal structure using X-ray crystallography, Hirshfeld surfaces, and density functional theory computations (at wB97X-D/aug-cc-pVTZ level). The synthesized compounds were then subjected to in vitro evaluation to assess their antibacterial and antifungal activities against multiple strains. Additionally, their antioxidant and anti-inflammatory properties were examined. The results showed different levels of inhibitory effects on the growth of microorganisms, with all compounds displaying moderate to significant biological activities. Furthermore, molecular docking simulations were conducted to investigate the binding interactions of the compounds with bacterial and fungal targets. This research enhances our understanding of the chemistry of benzodiazepine derivatives and further highlights their therapeutic potential.

Synthesis and Photophysical Properties of Carbazole-Functionalized Diazaphosphepines via Sequent P-N Chemistry.

Chemical structure tunability of organic π-conjugated molecules (OCMs) is highly appealing for fine-tuning the optoelectronic properties. Herein, we report a new series of carbazole-functionalized diazaphosphepines (DPP-CBZs) via one-pot phosphorus-nitrogen (P-N) chemistry. The one-pot synthesis harnessed the mild and selective P-N chemistry that successively installed carbazole moieties and seven-membered heterocycles at one P-center. Single-crystal structure studies revealed the tweezer-like structures for 1PO, 2PO, and 3PO that maintained the intramolecular donor-acceptor interactions between [d]-aryl moieties and carbazole. DPP-CBZs exhibited a more twisted central-diazaphosphepine ring compared with the reference molecules (1-3MO without carbazole group). DPP-CBZs with strong electron-accepting [d]-Ars generally showed lower photoluminescence quantum yields (PLQYs) than those of the reference molecules, which is probably due to the intramolecular charge transfer (ICT) from electron-donating carbazole to electron-withdrawing [d]-Ars. Upon the oxidation of the P-centers, PLQYs of DPP-CBZs increased. Furthermore, photophysical studies and theoretical studies suggested that the carbazole group had a strong impact on the structures of DPP-CBZs. As a proof of concept, we showed that grinding the mixture of 1PO as the electron-donating tweezer and benzene-1,2,4,5-tetracarbonitrile (BzCN) as the electron acceptor induced the formation of the CT complex.

Dioxepine-Peri-Annulated PMIs-Synthesis and Spectral and Sensing Properties.

New perylene monoimide (PMI) derivatives bearing a seven-membered heterocycle and 1,8-diaminosarcophagine (DiAmSar) or N,N-dimethylaminoethyl chelator fragments were synthesized, and their spectroscopic properties in the absence and presence of metal cations were determined to evaluate their potential applications as PET optical sensors for such analytes. DFT and TDDFT calculations were employed to rationalize the observed effects.

Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven-Membered Nitrogen-Containing Heterocyclic Systems.

The syntheses of several alkaloids and nitrogen-containing compounds including N-Boc-coniine (14b), pyrrolizidine (1), δ-coniceine (2), and pyrrolo[1,2a]azepine (3) are described. New C-C bonds in the α position relative to the nitrogen atom were formed by the alkylation of metalated α-aminonitriles 4 and 6a-c with alkyl iodides possessing the requisite size and functionality. In all of the reported cases, the pyrrolidine ring was formed in the aqueous medium through a favorable 5-exo-tet process involving a primary or a secondary amino group and a terminal δ-leaving group. Conversely, the azepane ring was efficiently formed in N,N-dimethylformamide (DMF), as the preferred aprotic solvent, through an unreported 7-exo-tet cyclization process involving a more nucleophilic sodium amide and a terminal mesylate borne by a saturated six carbon chain unit. In this way, we successfully synthesized pyrrolo[1,2a]azepane 3 and 2-propyl-azepane 14c in good yields from inexpensive and readily available materials without tedious separation methods.

An unexpected synthesis of azepinone derivatives through a metal-free photochemical cascade reaction

Azepinone derivatives are privileged in organic synthesis and pharmaceuticals. Synthetic approaches to these frameworks are limited to complex substrates, strong bases, high power UV light or noble metal catalysis. We herein report a mild synthesis of azepinone derivatives by a photochemical generation of 2-aryloxyaryl nitrene, [2 + 1] annulation, ring expansion/water addition cascade reaction without using any metal catalyst. Among the different nitrene precursors tested, 2-aryloxyaryl azides performed best under blue light irradiation and Brønsted acid catalysis. The reaction scope is broad and the obtained products underwent divergent transformations to afford other related compounds. A computational study suggests a pathway involving a step-wise aziridine formation, followed by a ring-expansion to the seven-membered heterocycle. Finally, water is added in a regio-selective manner, this is accelerated by the added TsOH.

Pd(0)-Catalyzed Asymmetric 7-Endo Hydroacyloxylative Cyclization of 1,6-Enyne Enabled by an Anion Ligand-Directed Strategy.

Despite diversity in reaction mechanisms, the palladium-catalyzed cyclization of 1,6-enyne generally proceeds in a 5-exo manner. Herein, we report the development of a Pd(0)-catalyzed hydroacyloxylative cyclization of 1,6-enyne in either 7-endo-trig or 6-exo-trig fashion when paired with an appropriate dihaloacetic acid reactant, such as F2HCCO2H and Cl2HCCO2H. Using the combination of Pd2(dba)3 and a chiral phosphine ligand, the hydroacyloxylative cyclization of 1,6-enyne bearing a 1,1-disubstituted alkene moiety readily gives highly enantiopure seven-membered heterocycles while the reaction of those having a 1,2-disubstituted alkene affords six-membered rings with moderate enantioselectivity. Preliminary experimental studies suggest a reaction mechanism featuring an unusual E-to-Z vinyl-Pd(II) isomerization and alkene trans-oxypalladation, which is proven to be governed by the rationally selected carboxylate.

Domino Synthesis of Thiazolo-Fused Six- and Seven-Membered Nitrogen Heterocycles via Intramolecular Heteroannulation of In-Situ-Generated 2-(Het)aryl-4-amino-5-functionalized Thiazoles.

Synthesis of novel 2-(het)aryl-substituted thiazolo-fused six- and seven-membered heterocycles, such as thiazolo[4,5-b]pyridin-5(4H)-ones, thiazolo[4,5-c]isoquinolin-5(4H)-ones, thiazolo[4,5-b]quinolin-9(4H)-ones, 4H-benzo[e]thiazolo[4,5-b]azepine-5,10-diones, have been developed in a single-pot operation via intramolecular heteroannulation of in-situ-generated 2-(het)aryl-4-amino-5-functionalized thiazoles. These 4-amino-5-functionalized thiazoles were readily obtained in a one-pot process by treatment of a range of (het)aryldithioesters with cyanamide in the presence of NaH, followed by in situ S-alkylation-intramolecular condensations of the resulting thioimidate salts with appropriate activated methylene halides. On the other hand, the corresponding 4H-benzo[b]thiazolo[4,5-e][1,4]diazepin-10(9H)-ones were synthesized in a two-step process, requiring prior isolation of 5-carboethoxy-4-(2-nitrophenyl)aminothiazoles and their subsequent reductive cyclization. The activated methylene halides employed in these reactions for the synthesis of various thiazolo-fused heterocycles were methyl bromocrotonate, ethyl 2-(bromomethyl)benzoate, 2-fluorophenacyl bromides, ethyl 2-(2-bromoacetyl)benzoate, and ethyl bromoacetate. Several of these thiazolo-fused heterocycles display yellow green to green fluorescence, and their absorption and emission spectra have also been examined.

Research Progress in Antineoplastic, Antibacterial, and Anti-inflammatory Activities of Seven-membered Heterocyclic Derivatives.

Seven-membered heterocyclic compounds are important drug scaffolds because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have been used commonly in central nervous system drugs in the past 30 years. In the past decade, many studies have been conducted on their activities, including antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which are expected to be beneficial to the development and design of novel drugs for the corresponding indications.

Preparation, characterization and biological activity of some new seven-membered heterocyclic compounds

Preparation, characterization and biological activity of some new seven-membered heterocyclic compounds