Cyclization Research Articles

Process of Preparing 3-methyl-6-nitro-1H-indazole by Scale of 180 g/batch as an Important Intermediate for the Preparation of Pazopanib

Pazopanib hydrochloride, marketed worldwide under the brand name Votrient, is an anti-cancer medication manufactured by Novartis. It is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). In previous studies, we presented initial results regarding the synthesis of 3-methyl-5-nitro-2H-indazole (3) as an important indazole component on a laboratory scale (approximately 10 g/batch). In this study, we have successfully synthesized this compound (3) at a scale of 200 g/batch, achieving an overall process yield of 79.6 % from the starting material ethylaniline. This yield is higher than that reported in previous publications. Some of the technical conditions that have been improved include optimizing the amount of sulfuric acid in the nitration reaction, the amount of acetic acid, sodium hydroxide in the diazotization reaction for ring closure, reaction temperature, and the feed method to control the reaction safely and achieve high efficiency at a scale of 200 g/batch.

Palladium-Catalyzed Aminoalkylative Cyclization Enables Modular Synthesis of Exocyclic 1,3-Dienes.

A novel and efficient palladium-catalyzed regioselective and stereodivergent ring-closing reaction of aminoenynes with aldehydes and boronic acids or hydrosilane is developed. This three-component reaction allows for the modular synthesis of a series of exocyclic 1,3-dienes bearing 5- to 8-membered saturated N-heterocycles. The reactions utilize a simple Pd-catalyst and work with broad range of aminoenynes, aldehydes and organometallic reagents under mild reaction conditions. The products represent useful intermediates for chemical synthesis due to the versatility of the conjugated diene. Preliminary mechanistic details of the method are also revealed.

Disruption of the rice 4-DEOXYOROBANCHOL HYDROXYLASE unravels specific functions of canonical strigolactones

Strigolactones (SLs) regulate many developmental processes, including shoot-branching/tillering, and mediate rhizospheric interactions. SLs originate from carlactone (CL) and are structurally diverse, divided into a canonical and a noncanonical subfamily. Rice contains two canonical SLs, 4-deoxyorobanchol (4DO) and orobanchol (Oro), which are common in different plant species. The cytochrome P450 OsMAX1-900 forms 4DO from CL through repeated oxygenation and ring closure, while the homologous enzyme OsMAX1-1400 hydroxylates 4DO into Oro. To better understand the biological function of 4DO and Oro, we generated CRISPR/Cas9 mutants disrupted in OsMAX1-1400 or in both OsMAX1-900 and OsMAX1-1400. The loss of OsMAX1-1400 activity led to a complete lack of Oro and an accumulation of its precursor 4DO. Moreover, Os1400 mutants showed shorter plant height, panicle and panicle base length, but no tillering phenotype. Hormone quantification and transcriptome analysis of Os1400 mutants revealed elevated auxin levels and changes in the expression of auxin-related, as well as of SL biosynthetic genes. Interestingly, the Os900/1400 double mutant lacking both Oro and 4DO did not show the observed Os1400 architectural phenotypes, indicating their being a result of 4DO accumulation. Treatment of wild-type plants with 4DO confirmed this assumption. A comparison of the Striga seed germinating activity and the mycorrhization of Os900, Os900/1400, and Os1400 loss-of-function mutants demonstrated that the germination activity positively correlates with 4DO content while disrupting OsMAX1-1400 has a negative impact on mycorrhizal symbiosis. Taken together, our paper deciphers the biological function of canonical SLs in rice and reveals their particular contributions to establishing architecture and rhizospheric communications.

Rhodamine-Based Cyclic Hydroxamate as Fluorescent pH Probe for Imaging of Lysosomes.

Monitoring the microenvironment within specific cellular regions is crucial for a comprehensive understanding of life events. Fluorescent probes working in different ranges of pH regions have been developed for the local imaging of different pH environments. Especially, rhodamine-based fluorescent pH probes have been of great interest due to their ON/OFF fluorescence depending on the spirolactam ring's opening/closure. By introducing the N-alkyl-hydroxamic acid instead of the alkyl amines in the spirolactam of rhodamine, we were able to tune the pH range where the ring opening and closing of the spirolactam occurs. This six-membered cyclic hydroxamate spirolactam ring of rhodamine B proved to be highly fluorescent in acidic pH environments. In addition, we could monitor pH changes of lysosomes in live cells and zebrafish.

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis**

AbstractTerpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC‐like enzymes are known but are very rare. In this study, we genome‐mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A−C (1–3), that possess a 6/7/5‐fused tricyclic scaffold. In vivo and in vitro experiments systematically established a noncanonical two‐step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10‐fused bicyclic cis‐eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5‐fused tricyclic scaffold through C2−C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring closure is shown to be a viable mechanism for AriF‐mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

Design, synthesis, docking studies and biological screening of 2-pyrimidinyl-2, 3-dihydro-1H-naphtho [1, 2-e][1, 3] oxazines as potent tubulin polymerization inhibitors

A series of novel substituted 2-pyrimidinyl-2,3-dihydro-1H-naphtho[1,2-e][1, 3]oxazine analogs have been designed and synthesized based on structure-activity relationships from 2-naphthol, substituted pyrimidinyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were evaluated for their in vitro cytotoxicity, cell cycle assay and their inhibitory effect on tubulin polymerization. From the MTT assay, it is clear that most of the synthesized compounds displayed potent cytotoxic activities on HeLa (cervical cancer) and B16F10 (melanoma) cancerous cell lines. The compounds 6b and 6k were found to be more effective against HeLa cell lines and exhibited significant cytotoxicity (with IC50 values 1.26 ± 0.12 µM and 1.16 ± 0.27 µM respectively), accumulation of HeLa cells in G2/M phase and exhibiting induced apoptosis. The immunohistochemistry and fluorescence assays showed that these compounds 6b and 6k inhibited the microtubule assembly in human cervical cancer cells (HeLa) at 2 µM concentration. Furthermore, molecular docking studies of these molecules revealed their better-fit potential as anticancer molecules and have a high affinity for colchicine binding site, indicating more inhibitory potential at the cellular level. Our studies suggest that the newly synthesized compounds may become promising leads for the development of new anti-cancer agents. Communicated by Ramaswamy H. Sarma

One Pot Synthesis, Crystal Structure, Hirshfeld Studies, Docking Simulation and Antimicrobial Efficacy Assay of New Fused/Substituted Pyrazolinyl–Thiazolidinyl–Indolone Triheterocyclic Hybrid Scaffolds

In this present investigation, a new series of functionalized hybrid compounds containing three bioactive triheterocyclic templates, pyrazolines, thiazolidinones, and indolones are designed and synthesized via multicomponent, one-pot reaction of 3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide with various substituted isatin derivatives and chloroacetic acid in the presence of fused sodium acetate and glacial acetic acid viz ring closure mechanism followed by dehydration. The formation of new scaffolds 4–7(a–c) is evidenced by analytical and spectral studies. The single-crystal X-ray diffraction study supported the molecular structure of compound 4a as a triclinic crystal system with a P space group and Z = 2. Interestingly, the compound is crystallized with two molecules (A/B) and one water molecule in the asymmetric unit, and the crystal packing is stabilized by intra and intermolecular hydrogen bonds. To quantify the percentage of intermolecular contacts and electrostatic potential distribution in crystal packing, Hirshfeld surface analysis was performed. All the compounds were screened for their preliminary antimicrobial activity against a panel of bacterial and fungal strains. The newly synthesized compounds exhibited fairly encouraging in vitro antibacterial activity, so the validation of the potent compound was done by docking against the antibacterial target Escherichia coli FabH (PDB: 5BNS). The virtual screening is focused on ADME and drug-likeliness properties to identify their putative ligand-protein interactions using Schrödinger software.

Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors.

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure-activity relationship (SAR) points for delivery of potent ACC inhibitors.

Fe(CO)5-catalyzed oxidative photolytic cyclization of ferrocenated en-yne-aldehydes: Synthesis of ferrocene appended furans

En-yne-aldehydes are important organic motifs due to having a high synthetic potential of cyclization. Herein, the ferrocenated en-yne-aldehydes were successfully transformed into ferrocene appended furans by oxidative, photolytic exo-cyclic ring closure reaction in the presence of an earth-abundant metal catalyst, i.e., iron pentacarbonyl. Along with the formation of the furan ring, the carbon adjacent to furan gets oxidized into a carbonyl group. The transformation takes just 30 min to accomplish the desired product. The formation of these unusual ferrocene appended furan products were confirmed by single crystal X-Ray diffraction studies, FTIR, 1H & 13C NMR, and HRMS spectrometry. The general scope of the reaction was established and a library of 11 new ferrocene-appended furan products were developed. Here, the established reaction protocol was found to be active for aryl, alkyl, cycloalkyl, and ferrocenyl-substituted ene-yne-aldehydes and produced good to significant yield of the respective furan products. To the best of our minds, this report serves as the first example of iron-catalyzed photolytic oxidative cyclization of ferrocenated en-yne-aldehydes, and the products are first time reported in this report.

6-Endo-dig cyclization: Flexible enforce to develop synthetic route in organic syntheses

The organic ring closure reaction of diverse acyclic compounds is governed mostly by the Baldwin rule. The ring closure compounds shows emergent application. In recent years, ring closure reactions that are favoured by the Baldwin rules have received a lot of attention. In particular, the Baldwin rule favours the usage of sp- geometrical (diagonal) molecules in the cyclization reaction. The endo-dig cyclization help for synthesis of bulky compound in simple manner via radical coupling. The radical coupling method help for synthesis of various cyclized compounds, also heterocyclic compounds like, three – eight memebered ring compounds. Also, the endo dig cyclization used for synthesis of C-C, C-N, C-O, C-S bond forming compounds. From the all ring closing reaction, 6-endo dig cyclization has great important for synthesis of highly active 6, 7, 8 membered ring compounds. The formed 6-endo dig cyclized product has selective activity against various field cosmetics, medicinal, dye, agrochemical. There are come list of organic compounds are synthesis via 6-endo-dig cyclization like, carbazole, fused benzimidazole, fused pyrimidine, oxazole, chromenos, pyridine, quinoline etc., analogues. The 6-endo-dig cyclization reaction proceed presence of transition metal catalyst and with out catalyst. The 6-endo-dig cyclization processes can be used to synthesise a wide range of 6 membered heterocycles and carbocycles. This review compiles the significant uses of 6-endo-dig cyclization in organic synthesis from a variety of perspectives.

Anionic Polymerization of Polar Conjugated Diene Monomers with Phosphine as the Initiator and Subsequent Ring Closure without Highly Dilute Conditions

Anionic Polymerization of Polar Conjugated Diene Monomers with Phosphine as the Initiator and Subsequent Ring Closure without Highly Dilute Conditions

Synthesis of New Coumarin Scaffold Bearing 2-Iminochromene Moiety

Coumarin is classified as one of interesting therapeutic starting research points to obtain remarkable compounds with high efficacy. So, during this research, new 2-iminochromene derivatives bearing coumarin moiety were synthesized. At first, cyanoacetohydrazone of 3-acetylcoumarin was prepared and used as the starting material. The 2-iminochromene derivatives were synthesized through the ring closure of cyanoacetohydrazone derivative with 4-hydroxysalicylaldehyde, 5-aryldiazosalicylaldehydes, 2-hydroxynaphthaldehyde and 7-hydroxychromone-6-carboxaldehyde derivative. All of the newly synthesized coumarin derivatives were obtained in excellent yields; so, the new synthesized coumarin derivatives will participate in the enrichment of the chemical libraries.

Design of Synthetic Surrogates for the Macrolactone Linker Motif in Coibamide A.

A marine cyanobacterial cyclic depsipeptide, coibamide A (CbA), inhibits the mammalian protein secretory pathway by blocking the Sec61 translocon, which is an emerging drug target for cancer and other chronic diseases. In our previous structure-activity relationship study of CbA, the macrolactone ester linker was replaced with alkyl/alkenyl surrogates to provide synthetically accessible macrocyclic scaffolds. To optimize the cellular bioactivity profile of CbA analogues, novel lysine mimetics having β- and ε-methyl groups have now been designed and synthesized by a stereoselective route. A significant increase in cytotoxicity was observed upon introduction of these two methyl groups, corresponding to the d-MeAla α-methyl and MeThr β-methyl of CbA. All synthetic products retained the ability to inhibit secretion of a model Sec61 substrate. Tandem evaluation of secretory function inhibition in living cells and cytotoxicity was an effective strategy to assess the impact of structural modifications to the linker for ring closure.

Synthesis of New 2-Pyridinone and 2-Iminochromene Derivatives Bearing Biologically Active Pyrrole Moiety as Expected Antibacterial and Antifungal Agents

In an attempt to discover new antimicrobial drugs, new 2-pyridinone and 2-iminochromene derivatives bearing biologically active pyrrole nucleus were designed and synthesized. The pyridin-2-one derivatives were synthesized via ring closure of 2-cyano-N'-((1-methyl-1H-pyrrol-2-yl)methylene)acetohydrazide by acetylacetone or 2-arylidenemalononitriles. The 2-iminochromene derivatives were obtained in high yields through the cyclocondensation reaction of 2-cyano-N'-((1-methyl-1H-pyrrol-2-yl)methylene)acetohydrazide with o-hydroxy aldehyde derivatives (salicyaldehyde derivatives, 2-hydroxy-1-naphthaldehyde and 7-hydroxy-chromone-6-carboxaldehyde derivative). The antibacterial and antifungal properties of all synthesized compounds were evaluated. All tested compounds displayed weak activities toward the G + ve bacteria (S. aureus) and G –ve bacteria (E. coli and P. vulgaris). The polycyclic benzo[f]chromene derivative 7 showed weak activity toward both G + ve and G –ve bacteria.

Enantioselective Total Syntheses of (-)-Silicine and (-)-20-Episilicine.

The enantioselective total syntheses of (-)-silicine and (-)-20-episilicine, which contain a chiral piperidine with three contiguous chiral centers (D-ring) and a strained seven-membered ring (C-ring) attached to an indole, were achieved. The key steps of these syntheses included a chiral secondary amine-catalyzed formal aza-[3 + 3] cycloaddition reaction and Lewis acid-mediated irreversible ring-closing reaction. In addition, the stereochemistry at C20 was controlled at a later stage in the syntheses.

Stereoselective Synthesis of Pyrrolo/Pyrido[2,1-a]isoindoles via Alkyne Iminium Ion Cyclization of Vinylogous Carbamates.

An efficient, acid-mediated, intramolecular alkyne iminium ion cyclization of oxoisoindolidene for the diastereoselective synthesis of pyrrolo/pyridoisoindole is described. This protocol features broad substrate scope and easy scalability. An unusualNtoC-1,3-alkyl shift is observed with substrates bearing strong electron donating group at the phenyl ring attached to alkyne with concomitant hydration of alkyne to the ketone.

DFT Insight into the Kinetics and Mechanism of OH⋅‐Initiated Atmospheric Oxidation of Catechol: Addition of 3∑g− O2 and Isomerization of Peroxy Radicals

AbstractAtmospheric oxidation mechanism of predominant catechol‐OH adduct [C6H6O2−OH]⋅ (AD2) by oxygen molecule in its triplet electronic ground state and isomerization processes of catechol peroxy radicals [C6H6O2−OH]⋅−O2 into bicyclic peroxy radicals have been studied at the M06‐2X/aug‐cc‐pVTZ level in conjugation with the RRKM theory. The first step begins via the complexation of [C6H6O2−OH]⋅ with oxygen molecule and formation of two pre‐reactive van der Waals complexes in syn and anti modes. Syn mode addition of O2 is more favorable over the anti mode due to the formation of intramolecular hydrogen bond. Kinetically and thermodynamically, addition of O2 at the C5 position in syn mode, namely peroxy radical AD2‐5OO‐syn, is the most efficient process with bimolecular RRKM rate coefficient 2.80×10−16 cm3 molecule−1 s−1 at ambient conditions. Isomerization (cyclization) of peroxy radical AD2‐5OO‐syn into bicyclic peroxy radicals via the formation of −OO− bridge are strongly endothermic and nonspontaneous processes with high activation energies. Ring closure into the bicyclic peroxy radical AD2‐5,6OO‐syn is the most favorable process with unimolecular RRKM rate coefficient 1.41×10−8 s−1 at ambient conditions.

Synthesis of New Oxopyrimidine and Cyanopyridine Derivatives Containing the Pyrimidine Benzothiazole Moiety with the Evaluating their Colon Anticancer Bioactivity

In this contribution, new derivatives of bicyclic fused rings with bridgehead nitrogen of 3-substituted imidazo/pyrimidine derivatives A1-A3 were synthesized by reacting 2-aminobenzothiazol, acetyl acetone, and different substituted aldehydes in a one-pot reaction. These compounds A1-A3 were then condensed with 4-bromobenzaldehyde and 4-(N,N-dimethylamino)benzaldehyde to form new chalcone derivatives A4-A9. Ring closure of these compounds A4-A9 with urea and malononitrile afforded new oxopyrimidine derivatives A10-A15 and cyanopyridine derivatives A16-A21, respectively. These compounds were characterized by FT-IR, 1H NMR, and 13C NMR spectroscopy. The second part of this work included some of the important applications conducted for these compounds to evaluate their biological activities against colon cancer, which showed excellent results against this disease.

Ring-Closing Reactions of Porphyrins on Noble Metal Surfaces

On-surface chemistry protocols provide elegant routes to individual molecular complexes, oligomers, and hybrid structures at confining interfaces, yielding distinct chemical, physical, and structural properties [1]. In this context, porphyrins and other tetrapyrroles represent versatile precursors that can undergo metalation, ring-opening, and ring-closing reactions. Furthermore, they are often used as functional tectons for self-assembled molecular films, metal-organic coordination networks, and covalent architectures at interfaces [2].We will report on temperature-induced ring-closing reactions of porphyrins on single crystalline Ag and Au surfaces in an ultrahigh vacuum environment. Examples covered include dehydrogenative homocoupling as well as intramolecular ring-closing. Specifically, distinct oligomers including square-type porphyrin tetramers featuring a planar, central antiaromatic cyclooctatetraene (COT) moiety were achieved on a Ag(100) support by employing unsubstituted Zn- and free-base porphines (see Figure) as precursors [3]. Low-temperature scanning tunnelling microscopy (STM), spectroscopy (STS), and bond-resolved atomic force microscopy (AFM) supported by complementary theoretical modelling were used to comprehensively characterize chemical structure and electronic properties of the square-type tetramers with sub-molecular resolution. Furthermore, the synthesis of π-extended oxygen-embedded porphyrins via O-annulation on Au(111) will be discussed. This surface chemical approach yields high selectivity and yield for planar porphyrin products with distinct symmetries and oxygen content that is not achieved by solution chemistry. The bond-resolved AFM characterization is complemented by X-ray photoelectron spectroscopy measurements. These studies thus give access, and insights, to novel porphyrinoids with distinct properties on noble metal supports.

(Invited) Interplay Between π–Conjugation and Exchange Magnetism in One-Dimensional Porphyrinoid Polymers

The field of carbon magnetism has gained an increased attention in view of the recent progress made in the synthesis and characterization of open-shell polycyclic aromatic hydrocarbons following a bottom-up synthetic approach[1,2]. Under this scenario, the comprehensive fabrication of magnetic porphyrinoid-based polymers emerges as a highly appealing field of research. However, the vast majority of the porphyrinoid species and polymers studied to date exhibit a closed-shell ground state[3].In this work, we introduce an exemplary approach toward the bottom-up fabrication of unprecedented magnetic porphyrinoid-based polymers homocoupled via surface-catalyzed [3 + 3] cycloaromatization of isopropyl substituents studied on Au(111) under ultra-high vacuum (UHV) conditions. The chemical structure of the polymer, formed by thermal-activated intra- and intermolecular oxidative ring closure reactions followed by controlled tip-induced hydrogen dissociation from the porphyrinoid units, have been clearly elucidated by scanning tunneling microscopy (STM) and non-contact atomic force microscopy (nc-AFM). Scanning tunneling spectroscopy (STS), complemented by computational investigations reveals the open-shell character, i.e. antiferromagnetic singlet ground state (S=0) of the formed polymers, which display singlet−triplet inelastic excitations observed between spins of adjacent porphyrinoid units only along a specific π-conjugation pathway, thus revealing the interplay between π-conjugation and magnetic exchange. We envision that our approach can be a highly relevant step towards the on-surface synthesis of covalently linked 1D magnetic organic polymers with prospects in nanoscale spintronic devices.