Isatoic Anhydride Research Articles

Sulfamic Acid Catalyzed One‐Pot Three‐Component Synthesis of Spiro‐Oxindole Fused Dihydroquinazolinone Derivatives in Aqueous Medium

AbstractA simple, efficient, and straightforward protocol has been developed for the synthesis of spiro‐oxindole fused dihydroquinazolinone derivatives from one‐pot three‐component reactions of isatoic anhydride, various primary anilines, and substituted isatins using a catalytic amount of sulfamic acid as an organocatalyst in water under refluxed conditions. All the synthesized compounds were formed within just 2 h and isolated pure by simple filtration with excellent yields (89%–94%). Gram scale production, use of commercially available low‐cost organocatalyst, green solvent, reusability of the medium, one‐pot three‐component reaction strategy, no column chromatography, and high atom economy are some of the major benefits of this newly developed protocol.

Discovery of a novel benzimidazole conjugated quinazolinone derivative as a promising SARS-CoV-2 3CL protease inhibitor.

This report presents the design and synthesis of quinazolinone-based derivatives as promising SARS-CoV-2 3CL protease inhibitors. Two novel series, namely, febrifugine analogues 4a-i and quinazolinone conjugated benzimidazoles 9a-c, were successfully synthesized starting from isatoic anhydride. The synthesized quinazolinone derivatives were evaluated for their cytotoxicity against cancer cell lines and SARS-CoV-2 3CL inhibitory activity. The results showed that the synthesized compounds did not have significant toxicity for the non-cancer HEK293 cell line and MCF-7, MDA-MB-231, HEPG2 and HEPG2.2.15 cancer cell lines. Notably, compound 9b exhibited anti-3CL enzymatic activity in a dose-dependent manner, with the calculated IC50 value of 10.73 ± 1.17 μM. Docking results highlighted the interaction between 9b and 3CL protease through hydrogen bonding with key amino acids, including His41, Met49, Cys145, Met165, Arg188, His164, and Glu166, at the active site of the protease. Pharmacokinetic studies and ADME analyses provide valuable insights into the potential of compound 9b as a drug candidate. These findings support the new scaffold as a candidate for 3CLpro inhibition and advanced anti-coronavirus drug research.

Highly Efficient Catalysis of Pyridinium p‐Toluenesulfonate (PPTS): Two Facile One‐Pot Protocols for the Synthesis of 2,3‐Disubstituted Quinazolinone Scaffolds

AbstractTwo different one‐pot synthetic protocols have been developed for obtaining 2,3‐disubstituted quinazolin‐4(3H)‐ones using pyridinium p‐toluenesulfonate (PPTS) as catalyst. The two‐component reaction involves isatoic anhydride and N‐acetyl amine whereas the three‐component reaction use isatoic anhydride, aryl amine and β‐diketone in Toluene under classical heating at 80–100 °C to afford 2,3‐disubstituted quinazolin‐4(3H)‐ones in good yields. The two‐component reactions are compatible with various substituted aryl/alkyl amines.

Marine-derived magnetic nanocatalyst in sustainable ultrasound-assisted synthesis of 2,3-diphenyl-2,3-Dihydroquinazolin-4(1H)-One derivatives

This research presents a sustainable approach to fabricate iron oxide nanoparticles by employing phytochemicals derived from marine grass extract as both reducing and stabilizing agents. Formation of magnetic nanoparticles (MNPs) initially confirmed by ultraviolet–visible spectroscopy (UV–vis) showing absorption peak at 370 nm. X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques unveiled magnetic iron oxide NPs with a rod shape, an average size of 21 nm, and an inverse spinel crystal structure. The participation of organic compounds in the production and stabilization of MNPs was evidenced through Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). A vibrating sample magnetometer (VSM) demonstrated the magnetic properties of iron oxide NPs showing a saturation magnetization value of 21.46 emu/g. The catalytic efficiency of these marine-assisted MNPs was evaluated in a one-pot three-component reaction involving isatoic anhydride, aromatic aldehydes, and amines under ultrasonic conditions. Under optimal conditions, a low dose of 1.5 mg of biobased magnetite nanoparticles yielded dihydroquinazolin-4(1H)-One products with up to 95 % efficiency in a brief duration of 15 min at an ultrasonic power intensity of 130 W. Different directing groups were investigated, and control experiments were carried out to enhance the understanding of the reaction mechanism. The obtained results highlight the synergistic effect of marine grass-mediated magnetic nanocatalysts combined with ultrasonic-assisted synthesis in developing sustainable green methodologies in organic synthesis.

Copper-Catalyzed Synthesis of Quinazolin-4(1H)-one from Amine-Trichloroacetonitrile Adduct and Isatoic anhydride

A rapid and direct route for the new synthesis of various quinazolines-4 (1H)-ones with appropriate yields through a three-component reaction consisting of the amine-trichloroacetonitrile adduct and isatoic anhydride is a remarkable achievement in organic chemistry. The use of CuO as the catalyst in DMF under reflux conditions at 110 °C for 4 hours offers reaction conditions, which are conducive to the formation of the desired products while maintaining good selectivity. The simplicity of the one-pot synthesis and using the available raw materials contribute to the ease of purification of the synthesized quinazolines-4 (1H)-ones, streamlining the overall synthetic process. The synthesized product is often found in drugs and other bioactive molecules.

Pentafluoropyridine (PFPy)-mediated one-pot framework for the synthesis of pharmaceutically active 2,3-dihydroquinazolin-4(1H)-ones

This article describes the employment of commercially available, cheap pentafluoropyridine (PFPy) for a simple and straightforward one-pot synthesis of 2, 3-Dihydroquinazolin-4(1H)-ones. The reported protocol involves PFPy-mediated multicomponent condensation reaction of aldehyde, amine and isatoic anhydride at elevated temperature. This research work exploited the electron-withdrawing nature of fluorine atoms in PFPy for the nucleophilic substitution at para to the N-atom to produce fluoride ions that assisted the synthesis of the 2,3-Dihydroquinazolin-4(1H)-ones in excellent yield. The broad substrate scope, easy purification, short reaction times, high yields and ease of operation enhance the versatility of the protocol.

2-Amino-N-Phenethylbenzamides for Irritable Bowel Syndrome Treatment.

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. Therefore, the current paper aimed to synthesize more effective medicines for IBS treatment. We used ring opening of isatoic anhydride for the synthesis in reaction with 2-phenylethylamine. In silico simulation predicted spasmolytic activity for 2-amino-N-phenethylbenzamides. The newly synthesized compounds demonstrated a relaxation effect similar to mebeverine but did not affect the serotonin or Ca2+-dependent signaling pathway of contractile activity (CA) in contrast. Having in mind the anti-inflammatory potential of antispasmodics, the synthesized molecules were tested in vitro and ex vivo for their anti-inflammatory effects. Four of the newly synthesized compounds demonstrated very good activity by preventing albumin denaturation compared to anti-inflammatory drugs/agents well-established in medicinal practice. The newly synthesized compounds also inhibited the expression of interleukin-1β and stimulated the expression of neuronal nitric oxide synthase (nNOS), and, consequently, nitric oxide (NO) synthesis by neurons of the myenteric plexus. This characterizes the newly synthesized compounds as biologically active relaxants, offering a cleaner and more precise application in pharmacological practice, thereby enhancing their potential therapeutic value.

Microwave-Assisted Synthesis of β-N-Aryl Glycoamphiphiles with Diverse Supramolecular Assemblies and Lectin Accessibility.

Glycoamphiphiles have attracted considerable interest in a broad range of application fields owing to their solution and bulk-state self-assembly abilities. Despite their importance, the straightforward synthesis of glycoamphiphiles consisting of a hydrophilic carbohydrate linked to a hydrophobic aglycone remains one of the major challenges in glycosciences. Here, a rapid, simple, and efficient synthetic access to chemically stable glycoamphiphiles at physiological pH, namely, N-(β-d-glycosyl)-2-alkylbenzamide, is reported. It leverages the nonreductive amination of unprotected carbohydrates with ortho-substituted aniline derivatives which could be readily obtained by reacting commercially available primary alkylamines with isatoic anhydride. This strategy avoids protection and deprotection of sugar hydroxyl groups and the use of reductive agents, which makes it advantageous in terms of atom and step economy. Moreover, in order to circumvent the cons of classical N-aryl glycosylation, we investigate the use of microwave as a heat source that provides fast, clean, and high-yield β-N-arylation of unprotected carbohydrates. Their self-assembly into water led to multiple morphologies of dynamic supramolecular glycoamphiphiles that were characterized to assess their ability to bind to lectins from pathogenic bacteria. Biophysical interactions probed by isothermal titration microcalorimetry revealed micromolar affinities for most of the synthesized glycoamphiphiles.

Photoinduced Redox Cascade Reaction of Isatins and Aliphatic Carboxylic Acids to Access 6-Hydroxyindoloquinazolinones.

A visible-light-induced cascade reaction is described for the one-pot synthesis of 6-hydroxyindoloquinazolinones using isatins (or isatins and isatoic anhydrides) and aliphatic carboxylic acids. The method provides 36 desired products in 33-96 % yield, exhibiting broad substrate scope and good functional group tolerance. This approach utilizes inexpensive and commercially available starting materials, enabling the direct construction of high-value complex structures under mild conditions without the need for photocatalyst, showcasing significant applicability and environmental friendliness.

Design, synthesis and characterization of a new series of 2,3-dihydroquinazolin-4(1H)-one (DHQZ-1) derivatives and evaluation of antitumor resistant (by Molecule Docking)

الهدف من هذا البحث هو استخدام التفاعلات متعددة المكونات لإنتاج سلسلة جديدة من مشتقات الكوينزولين والتي تعطي منتوج كثير.يحدث هذا التفاعل من خلال تكثيف بيريدين-3- كاربالديهايد مع-1,3-H1 بنزاوكزازين-2و4-ثنائي ون )أيساتويك انهيدرايد) والأمينات الأولية (7-3). وتمت اذابه المكونات باستخدام مذيب رباعي هيدروالفوران (THF ، مذيب غير بروتوني) (البروتوني). مع كبريتات الصوديوم الهيدروجينيه (NaHSO4) على شكل عامل مساعد في التفاعل وذلك لتوفيرمنتوج عالي من مشتقات 2،3- ثنائي هيدروكوينزولين -4 (1H). تم الحصول على أفضل ناتج عند درجه حراره 68 درجة مئوية. بشكل عام ، تُظهر جميع المنتجات المتسلسلة (8-12) قدرة كبيرة كمضاد فعال لسرطان الثدي باستخدام دراسة الالتحام الجزيئي للمشتقات حيث اعطى المركب 11 ، اكثر فعالية مضادة من المركبات المحضرة الاخرى. تم تقييم دراسة الالتحام الجزيئي للمشتقات باستخدام برنامج تصميم الأدوية Auto Dock 4.2 . (PDB)) ، كود البروتين M171).

Green and Convenient Synthesis of Pharmaceutically Active Mono and Bis-dihydroquinazolines via a One-pot Multicomponent Reaction Under Sulfamic Acid Catalysis

Introduction: Multicomponent reactions (MCRs) and green chemistry are essential criteria for the development of efficient chemical syntheses for valuable organic compounds. Method: The design, synthesis, and development of sustainable procedures for the production of novel biological and pharmaceutical molecules have gained high importance. Herein, an environmentally benign synthesis of mono- and bis-2,3-dihydroquinazolin-4(1H)-ones as pharmaceutically active compounds was carried out in good to high yields of 80-99% within 45-120 minutes. Result: The desired products were synthesized via three-component and pseudo five-component condensations of isatoic anhydride, a primary amine (aniline or ammonium acetate), and an aldehyde/dialdehyde using sulfamic acid (20%) as a solid acidic catalyst under the solvent-free condition at 100°C. Conclusion: The easy work-up procedure, metal-free and environmentally benign catalyst, green reaction conditions for performing MCRs, and high yields of pure products are some advantages of the presented protocol.

In situ generation of azo dyes on silk fibroin through three-step chemical modification

To enhance the efficiency and reduce the environmental footprint of silk dyeing, this study introduces a novel method that synthesizes azo dyes directly on silk fibroin (SF) using a three-step chemical modification at room temperature. Initially, SF undergoes modification with isatoic anhydride to yield aromatic primary amino-modified silk fibroin (SF–NH2). Subsequently, SF-NH2 is treated with nitrous acid to produce diazotized silk fibroin (SF–N2+). In the final step, SF-N2+ is combined with coupling components to directly form azo chromophores on the SF, culminating in the creation of coloured silk fibroin (SF–NN-CC). The efficacy of the three-step dyeing method was validated using infrared spectroscopy and colour development analysis. The modification sites on SF-NH2 were identified as the hydroxyl and amino groups of amino acid residues, confirmed through simulated reactions. SF-N2+ demonstrated excellent storage and thermal stability under dry conditions; however, its stability decreased in wet environments. Various coupling components were then reacted with SF-N2+ to synthesize in situ yellow, red, crimson, and green azo dyes on SF. The formation of covalent bonds between the dyes and SF was verified using DMF stripping methods. The dyed SF-NN-CC fabrics underwent testing for fastness, revealing wet fastness rating above grade 4. These findings demonstrate that the three-step modification process represents an innovative, energy-efficient, and fast-reacting dyeing method for SF.

Pd(II)‐Catalyzed Aerobic Alcohol Oxidation for Multicomponent Synthesis of 2,3‐Dihydroquinazolin‐4(1H)‐ones in Water

AbstractWe describe a multicomponent reaction between isatoic anhydrides, alkylamines and benzylic alcohols using Pd(II)/TPPMS catalyst with cocatalytic Cu(II) salt in water. This cascade reaction involves the catalytic dehydrogenation of benzyl alcohol to benzaldehyde under aerobic conditions, followed by cyclocondensation with in situ generated 2‐aminobenzamides, allowing rapid access to 2,3‐dihydroquinazolin‐4(1H)‐ones (DHQs). This practical method enables direct access to a series of DHQs without strong bases and hazardous oxidants. Mechanistic studies reveal that the multicomponent reaction is first order with respect to the concentrations of benzyl alcohol and catalysts, and proceeds independently of the concentration of the 2‐aminobenzamide intermediate.

Sulfonated magnetic spirulina nanobiomaterial as a novel and environmentally friendly catalyst for the synthesis of dihydroquinazolin-4(1H)-ones in aqueous medium

Spirulina algae is an excellent candidate for catalyst preparation due to its reactive functional groups, cost-effectiveness, widespread commercial accessibility, and biodegradability. In this study, magnetized Spirulina was used for the synthesis of dihydroquinazolin-4(1H)-ones (DHQZs) as catalyst. Magnetized Spirulina was produced by CoFe2O4 and sulfonation method using chlorosulfonic acid to create the catalyst [CoFe2O4-Sp-SO3H]. It was affirmed by various techniques, including Fourier transform infrared (FT-IR), Vibrating sample magnetometry (VSM), Powder X-ray diffraction (XRD), Energy-dispersive X-ray spectroscopy (EDS), Thermogravimetric analysis (TGA), Transmission electron microscopy (TEM), Field emission scanning electron microscopy (FE-SEM), and elemental mapping techniques. DHQZs synthesis was accomplished through a concise one-pot, three-component reaction involving a range of diverse aldehydes, isatoic anhydride, and primary aromatic amine, within an aqueous medium. The method offers several advantages, including using green conditions, the generation of several new 2-furan-quinazolinone derivatives, chromatography-free purification, short reaction times, appropriate yield of product (75–96%), and catalyst recyclability. The proposed catalyst and water as solvent demonstrated a strong synergistic effect, leading to the prosperous synthesis of various novel dihydroquinazolinones at 60 °C. These numerous benefits make our approach highly attractive for academic research and industrial applications.

Diversity oriented total synthesis (DOTS) of pyridoquinazolinone alkaloids and their analogues

A short diversity oriented total synthesis (DOTS) of substituted rutaecarpines, homo-luotonins, homo-vasicinone, homo-isaindigotones and homo-vasnetine has been achieved from the key tricyclic intermediate. The [6,6,6] tricyclic ketone, the mackinazolindione, was accessed from simple substrates i.e., quinazolinone diester obtained from the disubstituted anthranilamide which in turn was prepared from the coupling of amino acid ester and ethyl oxalyl chloride with isatoic anhydride and Dieckmann condensation chemistry.

Isatoic anhydride as a masked directing group and internal oxidant for Rh(III)-catalyzed decarbonylative annulation through C-H activation: insights from DFT calculations.

Density functional theory calculations uncovered a new mechanism for the rhodium-catalyzed decarbonylative annulation of isatoic anhydride with alkynes, in which the acyloxy group formed from the N-H deprotonation and C-O bond cleavage of isatoic anhydride acts as the directing group to assist the ortho C-H activation. From the generated five-membered rhodacycle intermediate, the final aminoisocoumarin product could be formed by subsequent steps of alkyne insertion, reductive elimination, decarbonylation, and protonation. The isocyanate moiety contained in the annulation intermediate was uncovered as a novel internal oxidant for the reaction, which oxidizes the Rh(I) to Rh(III) by decarbonylation.

TMSOTf‐Promoted Synthesis of Quinazolin‐4(3H)‐one Utilizing DMSO as a Carbon Source

AbstractAn efficient TMSOTf‐promoted multicomponent reaction has been developed for the one‐pot synthesis of quinazolin‐4 (3H)‐ones. Using the TMSOTf as a Lewis acid promoter and DMSO as a carbon source, the reaction of isatoic anhydride, primary amines yielded a variety of quinazolines‐4 (3H)‐ones. Additionally, TMSOTf promoted the reaction of 2‐amino‐N‐substituted benzamide with DMSO yielding the same scaffolds in high yields. However, the use of DMSO‐d6 as a solvent in the reaction enabled the incorporation of the −CD moiety in quinazolines‐4 (3H)‐one skeleton. This proves that DMSO plays a twin role as a C1 source and solvent. Various functional groups containing a wide range of quinazolin‐4 (3H)‐ones and other heterocycles were developed employing this methodology. Also, the synthetic methodology has been extended for the synthesis of 3‐(2‐carboxyphenyl)‐4‐(3H)‐quinazolinone, as an anti‐endotoxic drug.

Modification of Hydroxysodalite Nanoparticles by (3-aminopropyl)trimethoxysilane and Isatoic Anhydride as a Novel Composite for Efficient Sorption of Cu(II) Ions from Aqueous Media

Modification of Hydroxysodalite Nanoparticles by (3-aminopropyl)trimethoxysilane and Isatoic Anhydride as a Novel Composite for Efficient Sorption of Cu(II) Ions from Aqueous Media

Total and Diverted Total Synthesis of Pyrrolo‐Quinazolinone Alkaloids and Their Analogues

AbstractA short and expeditious total and diverted total synthesis of luotonin, vasicinone, and their analogues has been achieved from the key tricyclic quinazolinone intermediate which was accessed from simple substituted anthranilamide obtained from the coupling of β‐alanate with isatoic anhydride followed by Dieckmann condensation chemistry of the resulting diester. The tricyclic ketone exhibited interesting chemical properties, e. g. keto‐enol tautomerism. Friedlander condensation and Fischer‐Indolization were employed for further annulations to access polycyclic alkaloids and their analogues.

DNA-Compatible Benzotriazinone Formation through Aryl Diazonium Intermediates.

The incorporation of N-containing heterocycles with potential bioactivity into DNA-encoded chemical libraries (DELs) represents an important approach to synthesizing medicinally useful compound collections for high-throughput screening. Herein, we reported a synthetic methodology to afford a benzotriazinone core as a drug-like scaffold in a DNA-compatible manner through aryl diazonium intermediates. Starting from DNA-conjugated amines, anthranilic acid or isatoic anhydride building blocks were coupled to form chemically diversified anthranilamides, which were subsequently transformed into 1,2,3-benzotriazin-4(3H)-one via tert-butyl nitrite-triggered cyclization. This methodology features DEL synthesis compatibility through a mild diazonium intermediate mechanism, allowing late-stage decoration of the bioactive benzotriazinone cap on DNA-conjugated amines. The broad substrate scope and high conversion render this methodology a promising approach to diversifying and decorating DNA-encoded combinatorial peptide-like libraries with medicinally relevant heterocyclic moieties.