DOCSLIB.ORG

A One-Pot Approach to Novel Pyridazine C-Nucleosides

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A One-Pot Approach to Novel Pyridazine C-Nucleosides molecules Communication A One-Pot Approach to Novel Pyridazine C-Nucleosides Flavio Cermola 1,* , Serena Vella 2, Marina DellaGreca 1 , Angela Tuzi 1 and Maria Rosaria Iesce 1 1 Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario di M. Sant’Angelo, Via Cintia, 80126 Napoli, Italy; [email protected] (M.D.); [email protected] (A.T.); [email protected] (M.R.I.) 2 Erbagil s.r.l., Via L. Settembrini, 13, 82037 Telese Terme, Italy; [email protected] * Correspondence: [email protected] Abstract: The synthesis of glycosides and modified nucleosides represents a wide research field in organic chemistry. The classical methodology is based on coupling reactions between a glycosyl donor and an acceptor. An alternative strategy for new C-nucleosides is used in this approach, which consists of modifying a pre-existent furyl aglycone. This approach is applied to obtain novel pyridazine C-nucleosides starting with 2- and 3-(ribofuranosyl)furans. It is based on singlet oxygen [4+2] cycloaddition followed by reduction and hydrazine cyclization under neutral conditions. The mild three-step one-pot procedure leads stereoselectively to novel pyridazine C-nucleosides of pharmacological interest. The use of acetyls as protecting groups provides an elegant direct route to a deprotected new pyridazine C-nucleoside. Keywords: glycosyl furans; singlet oxygen; [4+2] cycloaddition; C-nucleosides; photooxygenation; pyridazines; reduction Citation: Cermola, F.; Vella, S.; 1. Introduction DellaGreca, M.; Tuzi, A.; Iesce, M.R. A The synthesis of nucleoside analogues has a prominent role in the field of organic One-Pot Approach to Novel chemistry and biology [1]. Among modified nucleosides, C-nucleosides represent a special Pyridazine C-Nucleosides. Molecules moiety of this compound class due to their higher stability towards enzymatic and chemical 2021, 26, 2341. https://doi.org/ hydrolysis than that of natural N-nucleosides, as well as owing to the interesting biolog- 10.3390/molecules26082341 ical and pharmacological properties of some of their derivatives [1,2]. The first natural C-nucleoside isolated was pseudouridine [3], followed by showdomycin [4], and oxazino- Academic Editor: Axel G. Griesbeck mycin [5]—all characterized by important pharmacological activities, from antitumor to antibacterial. C-nucleosides comprise a sugar moiety and a non-natural heterocyclic base Received: 1 April 2021 connected by a carbon–carbon bond. The stability of this bond and the broad structural Accepted: 13 April 2021 Published: 17 April 2021 variation in the heterocyclic base account for the high interest in this compound class [6–9]. The main synthetic approach for C-glycosides is based on coupling reactions between a Publisher’s Note: MDPI stays neutral glycosyl donor and an acceptor in the presence of a promoter [10]. Alternatively, structural with regard to jurisdictional claims in elaborations on a pre-existing aglycone are performed to afford the final C-glycoside [10]. In published maps and institutional affil- this context, the use of the furan as starting aglycone is of particular interest due to the easy iations. preparation and high versatility of this heterocycle [11]. We elaborated a green procedure based on the use of a furan aglycone as a building block and the [4+2] cycloaddition of singlet oxygen [12] by dye-sensitized photooxygenation as a strategy for providing the final desired structures. Indeed, singlet oxygen addition to furan systems offers various elegant routes to differently functionalized derivatives through structural elaborations of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the initial endoperoxides, the 2,3,7-trioxabicyclo[2.2.1]hept-5-enes [13]. Although the furan This article is an open access article endoperoxides are thermally unstable, their reactivity can be controlled and opportunely distributed under the terms and addressed by working at low temperatures. With this strategy, it is possible to synthe- conditions of the Creative Commons size novel glycosyl derivatives, such as glycals [14] and spiroketals of monosaccharides, Attribution (CC BY) license (https:// which are structural motifs of many products characterized by important and assorted creativecommons.org/licenses/by/ biological properties [15]. Pyridazine [16], pyrazoline [14], bis-epoxide [17], and spiro- 4.0/). cyclic C-nucleosides [17] were also obtained. Key intermediates are often unsaturated Molecules 2021, 26, 2341. https://doi.org/10.3390/molecules26082341 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 10 Molecules 2021, 26, 2341 2 of 10 epoxide [17], and spirocyclic C-nucleosides [17] were also obtained. Key intermediates are Zoften-1,4-enediones, unsaturated easily Z-1,4-enediones, obtained by easily photooxygenation obtained by photooxygenation and followed by in and situ followed reduction by ofin thesitu corresponding reduction of the endoperoxides corresponding [14– 17endo] atperoxides low temperatures. [14–17] at In low many temperatures. cases, the pho- In tochemicalmany cases, approach the photochemical represents approach an alternative repres toents other an methods.alternative As to an other example, methods. Maeba As describedan example, the synthesisMaeba ofdescribed 3-(20,30,50 -tri-theO -benzoyl-synthesisβ -ribofuranosyl)pyridazineof 3-(2′,3′,5′-tri-O-benzoyl- throughβ-ribo- a seriesfuranosyl)pyridazine of reactions involving through the a oxidation series of ofreactions the furan involving ring by brominethe oxidation and methanol of the furan [18]. Wering obtained by bromine an analogue and methanol 4-(20,3 0[18].,50-tri- WeO-acetyl- obtainedβ-ribofuranosyl)-3,6-dimetylpyridazine an analogue 4-(2′,3′,5′-tri-O-acetyl-β-ri- in 70%bofuranosyl)-3,6-dimetylpyridazine yield (based on starting furan) by in oxygenation, 70% yield (based followed on starting by diethyl furan) sulfide by reductionoxygena- andtion, hydrazine followed by hydrochloride diethyl sulfide cyclization reduction [ 16and]. Thehydrazine efficient hydrochloride formation of thiscyclization compound [16]. promptedThe efficient us toformation explore theof this possibility compound of extending prompted this us approach to explore to novelthe possibility furans in of order ex- totending synthesize this approach 3- and 4-(ribofuranosyl)pyridazines. to novel furans in order to synthesize The pyridazine 3- and ring4-(ribofuranosyl)pyr- is recognized as aidazines. versatile The pharmacophore. pyridazine ring Inis recognized the last years, as a particularversatile pharmacophore. attention has been In the devoted last years, to developingparticular attention novel synthetic has been approaches devoted to thisdeve system,loping novel starting synthetic with new approaches precursors to or this by utilizingsystem, starting green methodologies with new precursors [19–22]. or by utilizing green methodologies [19–22]. 2. Results and Discussion For thisthis purpose,purpose, the the suitable suitable furans furans2a ,2ab were,b were initially initially prepared prepared by the byβ the-stereoselective β-stereose- reductionlective reduction [23] of the [23] corresponding of the corresponding furyl ketoses furyl1a ketoses,b (Scheme 1a,b 1(Scheme). The latter 1). The were latter obtained were byobtained coupling by reactionscoupling betweenreactions 2,3,5-tri- betweenO -benzyl-2,3,5-tri-O-D-ribono-1,4-lactonebenzyl-D-ribono-1,4-lactone as the glycosyl as the donor, gly- andcosyl 2- donor, or 3-furyllithium, and 2- or 3-furyllithium, according to aaccord previouslying to reporteda previously procedure reported [15 procedure]. [15]. OBn O BnO O Et SiH, CH CN O BnO 3 3 BF Et O, 40 °C r.t. OH OBn O 3 2 overnight BnO OBn 1a 2a O OBn O BnO Et SiH, CH CN O BnO 3 3 BF Et O, 40 °C r.t. OH OBn 3 2 O overnight BnO OBn 1b 2b Scheme 1. Stereoselective synthesis of 2-2- andand 3-(3-(ββ-ribofuranosyl)furans 2a,,b.. The reduction times were particularly long (overnight), probably owing to the open- chain structuresstructures of of the the furyl furyl derivatives derivatives1a 1a,b,inb in equilibrium equilibrium with with very very small small amounts amounts of the of 1 correspondingthe corresponding cyclic cyclic structures, structures, as evidenced as evidenced by their by their proton proton spectra. spectra. Although Although the theH- NMR1H-NMR spectra spectra of both of both crude crude reaction reaction mixtures mixtures showed showed only the only presence the presence of products of products2a,b, a considerable2a,b, a considerable loss of loss material of material occurred occurred during during purification purification by silica by gelsilica chromatography, gel chromatog- even if performed under N , as reported in the literature for 2a [24]. Firstly, 2a was photo- raphy, even if performed under2 N2, as reported in the literature for 2a [24]. Firstly, 2a was oxygenated at −20 ◦C in dichloromethane with methylene blue as the sensitizer (Scheme2 ). photo-oxygenated at −20 °C in dichloromethane 1with methylene blue as the sensitizer When the reaction was complete (90 min, TLC or H-NMR), Et12S (1.2 equiv.) was added (Scheme 2). When the reaction was complete (90 min, TLC or H-NMR), Et2S (1.2 equiv.) − ◦ towas the added crude to mixture, the crude which mixture, was which kept atwas 20keptC at to −20 avoid °C to thermal avoid thermal rearrangement rearrangement of the intermediate endoperoxide [12–17]. of the intermediate endoperoxide [12–17]. Molecules 2021, 26, x FOR PEER REVIEW 3 of 10 Molecules 2021, 26, 2341
Load more

Recommended publications
  • [1,2,5]Thiadiazolo[3,4-D]Pyridazine As an Internal Acceptor in the DA-Π-A
    Article [1,2,5]Thiadiazolo[3,4-d]Pyridazine as an Internal Acceptor in the D-A-π-A Organic Sensitizers for Dye- Sensitized Solar Cells Timofey N. Chmovzh 1, Ekaterina A. Knyazeva 1,2, Ellie Tanaka 3, Vadim V. Popov 2, Ludmila V. Mikhalchenko 1, Neil Robertson 3,* and Oleg A. Rakitin 1,2,* 1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (O.A.R.); [email protected] (T.N.C.); [email protected] (E.A.K.); [email protected] (L.V.M.) 2 Nanotechnology Education and Research Center, South Ural State University, 454080 Chelyabinsk, Russia; [email protected] 3 EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, UK; [email protected] * Correspondence: Correspondence: [email protected] (N.R.); [email protected] (O.A.R.); Tel.: +44-131-650-4755 (N.R.); +7-499-135-5327(O.A.R.) Academic Editor: Panayiotis A. Koutentis Received: 4 April 2019; Accepted: 19 April 2019; Published: 22 April 2019 Abstract: Four new D-A-π-A metal-free organic sensitizers for dye-sensitized solar cells (DSSCs), with [1,2,5]thiadiazolo[3 ,4-d]pyridazine as internal acceptor, thiophene unit as π-spacer and cyanoacrylate as anchoring electron acceptor, have been synthesized. The donor moiety was introduced into [1,2,5]thiadiazolo[3,4-d]pyridazine by nucleophilic aromatic substitution and Suzuki cross-coupling reactions, allowing design of D-A-π-A sensitizers with the donor attached to the internal heterocyclic acceptor not only by the carbon atom, as it is in a majority of DSSCs, but by the nitrogen atom also.
    [Show full text]
  • Structure-Based Discovery and Synthesis of Potential Transketolase Inhibitors
    Supplementary Materials Structure-Based Discovery and Synthesis of Potential Transketolase Inhibitors Jingqian Huo 1,†, Bin Zhao 2,†, Zhe Zhang 1, Jihong Xing 3, Jinlin Zhang 1,*, Jingao Dong 1,3,* and Zhijin Fan 2,4,* 1 College of Plant Protection, Agricultural University of Hebei, Baoding 071001, China; [email protected] (J.H.); [email protected] (Z.Z.) 2 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China; [email protected] 3 College of life science, Agricultural University of Hebei, Baoding 071000, China; [email protected] 4 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China * Correspondence: [email protected] (J.Z.); [email protected] (J.D.); [email protected] (Z.F.) † These authors contributed equally to this work. Table of Contents Table S1. The docking affinity of the compounds with transketolase. Figure S1. The binding mode between the small molecules and transketolase. Figure S2. Molecular structure of compound 4b. The appearance, yields, melting points and spectral data of the synthesized compounds. Table S1. The docking affinity of the compounds with transketolase ZINC Affinity ZINC Affinity ZINC Affinity ZINC Affinity ZINC Affinity Compd. (kcal/mol) Compd. (kcal/mol) Compd. (kcal/mol) Compd. (kcal/mol) Compd. (kcal/mol) 12007063 -9.1 05776152 -8.7 12929396 -8.6 67603588 -8.5 41585313 -8.5 19961402 -9 72020240 -8.7 95353804 -8.6 72472311 -8.5 46127235 -8.5 12126699 -9 16283531 -8.7 95353805 -8.6 72472321 -8.5 49169766 -8.5 23186631 -8.8 08654961 -8.6 95381421 -8.6 72472332 -8.5 05175849 -8.5 12130512 -8.8 58191888 -8.6 12130884 -8.6 21941633 -8.5 19706239 -8.5 Molecules 2018, 23, 2116; doi:10.3390/molecules23092116 www.mdpi.com/journal/molecules Molecules 2018, 23, 2116 2 of 11 a b c d e f Figure S1.
    [Show full text]
  • Benzofuran Synthesis Through Iodocyclization Reactions: Recent Advances
    MOJ Bioorganic & Organic Chemistry Mini Review Open Access Benzofuran synthesis through iodocyclization reactions: recent advances Abstract Volume 1 Issue 7 - 2017 Recent advancements (2014-17) in the benzofuran synthesis through iodocyclization Saurabh Mehta have been summarized. The successful use of various iodinating agents, bases, additives Department of Applied Chemistry, Delhi Technological etc. make iodocyclization a versatile and efficient methodology. The methodology has University, India been applied for the synthesis of more complex benzofuran derivatives, and may open interesting avenues in the area of heterocyclic chemistry (Figure 1). Correspondence: Saurabh Mehta, Department of Applied O-LG Chemistry, Delhi Technological University, Bawana Road, Delhi, + O R1 I 1 2 110042 India, Tel +9188 0066 5868, R R Email [email protected], [email protected] R2 I Received: December 17, 2017 | Published: December 29, 2017 LG = H, Me or other Protecting group 1 R = H, Me, OMe, I, CO2Me, etc. R2 = H, aryl, alkyl, alkenyl, etc. Figure 1 Keywords: annulations, alkyne, benzofuran, iodocyclization, heterocycle Introduction derivatives were obtained in high yields (84%−100%) under mild conditions. The authors demonstrated that the choice of bis(2,4,6- Benzo[b]furan is a privileged heterocyclic scaffold. Several collidine)iodonium hexafluorophosphate [I(coll)2PF6] as the compounds containing this scaffold have interesting biological iodinating agent was necessary for the success of the reaction. Also, 1 activities, such as anti-cancer, anti-viral, anti-inflammatory, etc. Few the ethoxyethyl ether group acted as a protecting group as well as a 2 derivatives are even used as commercial drugs, such as Amiodarone, good leaving group.
    [Show full text]
  • A SCF MO Treatment of Some Tropone Derivatives* M
    CROATICA CHEMICA ACTA 42 (1 97 0) 1 <CCA-565 539.19:547.5 Original Scientific Paper A SCF MO Treatment of Some Tropone Derivatives* M. J. S. Dewar and N. Trinajstić** Department of Chemistry, The University of Texas, Austin, Texas 78712, U.S.A. R e c e iv e d A u g u s t 9, 1969 Recent work in these laboratories has led to the development of a semiempirical SCF MO treatment which seems to give extremely good results for ground States of conjugated molecules of ali kinds composed of carbon, hydrogen, nitrogen and oxygen. We have now applied this treatment to a problem of current interest, namely the structures of tropolone and tropone deri­ vatives. The calculations lead to the conclusion that neither of these ring systems is in itself aromatic, while tropone is now re- cognized to be polyenoid, tropolone still seems to be generally regarded as aromatic. This belief, however, arose from the behavior of tropolone derivatives in strong acid solution, where they exist as hydroxy tropylium derivatives, or in alkali where they form mesomeric anions. Calculated heats of formation, resonance ener- gies, and bond lengths are reported. INTRODU CTION Some time ago one of us1 concluded on the basis of available Chemical <evidence that stipitatic acid and colchicine must contain a novel aromatic system, tropolone (I), containing a seven-membered ring. Subsequent work not only confirmed this conclusion but also led to the synthesis of tropolone2 itself, and of the related tropone3 (II); both these compounds seemed to show stability characteristics of typical aromatic systems, and it was quickly realized that this might be due to the fact that both I and II can be regarded as deri­ vatives of the tropylium ion, C7H7+, which Hiickel4 in 1931 had predicted to be aromatic, a prediction which has been fully confirmed.5 However although an enormous amount of experimental work has been carried out since then on the synthesis and properties of numerous tropone and tropolone derivatives, very few theoretical studies seem as yet to have been reported.
    [Show full text]
  • Heterocycles 2 Daniel Palleros
    Heterocycles 2 Daniel Palleros Heterocycles 1. Structures 2. Aromaticity and Basicity 2.1 Pyrrole 2.2 Imidazole 2.3 Pyridine 2.4 Pyrimidine 2.5 Purine 3. Π-excessive and Π-deficient Heterocycles 4. Electrophilic Aromatic Substitution 5. Oxidation-Reduction 6. DNA and RNA Bases 7. Tautomers 8. H-bond Formation 9. Absorption of UV Radiation 10. Reactions and Mutations Heterocycles 3 Daniel Palleros Heterocycles Heterocycles are cyclic compounds in which one or more atoms of the ring are heteroatoms: O, N, S, P, etc. They are present in many biologically important molecules such as amino acids, nucleic acids and hormones. They are also indispensable components of pharmaceuticals and therapeutic drugs. Caffeine, sildenafil (the active ingredient in Viagra), acyclovir (an antiviral agent), clopidogrel (an antiplatelet agent) and nicotine, they all have heterocyclic systems. O CH3 N HN O O N O CH 3 N H3C N N HN N OH O S O H N N N 2 N O N N O CH3 N CH3 caffeine sildenafil acyclovir Cl S N CH3 N N H COOCH3 nicotine (S)-clopidogrel Here we will discuss the chemistry of this important group of compounds beginning with the simplest rings and continuing to more complex systems such as those present in nucleic acids. Heterocycles 4 Daniel Palleros 1. Structures Some of the most important heterocycles are shown below. Note that they have five or six-membered rings such as pyrrole and pyridine or polycyclic ring systems such as quinoline and purine. Imidazole, pyrimidine and purine play a very important role in the chemistry of nucleic acids and are highlighted.
    [Show full text]
  • An Update on Natural Occurrence and Biological Activity of Benzofurans
    Acta Scientific MEDICAL SCIENCES (ISSN: 2582-0931) Volume 4 Issue 10 October 2020 Review Article An Update on Natural Occurrence and Biological Activity of Benzofurans Kavita Khatana* and Anjali Gupta Received: June 28, 2020 Department of Chemistry, School of Basic and Applied Sciences, Galgotias Published: September 21, 2020 University, Greater Noida, UP, India © All rights are reserved by Kavita Khatana. *Corresponding Author: Kavita Khatana, Department of Chemistry, School of Basic and Applied Sciences, Galgotias University, Greater Noida, UP, India. Graphical Abstract Figure a Abstract Benzofuran and its derivatives are the major group amongst the natural collection of biologically active heterocyclic compounds. Their wide range of pharmacological activities and imaginable applications in medicinal and pharmaceutical chemistry have at- tracted various research scholars, medicinal chemists and pharmacologists. This review emphasizes the progress and development . ofKeywords: benzofuran Benzofuran; derivatives Antioxidant; in various biological Antiviral; activities Antimicrobial; with an Anticancer update of current research findings during a decade Introduction physiological and industrial world. In reference to pharmaceutical Heterocyclic ring systems have emerged as powerful scaf- industry, over 60% of the top retailing drugs contain at least one folds for many biological evaluations. Heterocyclic compounds heterocyclic motif as a part of overall topography of the compound. Benzofurans and its derivatives are important class of heterocyclic have significant role in medicinal and pharmacological chemistry, Citation: Kavita Khatana and Anjali Gupta. “An Update on Natural Occurrence and Biological Activity of Benzofurans”. Acta Scientific Medical Sciences 4.10 (2020): 114-123. An Update on Natural Occurrence and Biological Activity of Benzofurans 115 compounds, which are known to possess various biological proper- 3-(hydroxymethyl)-7-methoxy-2,3-dihydrobenzo furan-5-yl) ties.
    [Show full text]
  • How Ingredients Influence Furan and Aroma Generation in Sponge Cake Mayela Cepeda-Vázquez, Barbara Rega, Nicolas Descharles, Valérie Camel
    How ingredients influence furan and aroma generation in sponge cake Mayela Cepeda-Vázquez, Barbara Rega, Nicolas Descharles, Valérie Camel To cite this version: Mayela Cepeda-Vázquez, Barbara Rega, Nicolas Descharles, Valérie Camel. How ingredients influence furan and aroma generation in sponge cake. Food Chemistry, Elsevier, 2018, 245, pp.1025 - 1033. 10.1016/j.foodchem.2017.11.069. hal-01868629 HAL Id: hal-01868629 https://hal-agroparistech.archives-ouvertes.fr/hal-01868629 Submitted on 5 Oct 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. How ingredients influence furan and aroma generation in sponge cake AUTHORS Mayela Cepeda-Vázquez, Barbara Rega, Nicolas Descharles, Valérie Camel* UMR Ingénierie Procédés Aliments, AgroParisTech, Inra, Université Paris-Saclay, 91300 Massy, France * Corresponding author. AgroParisTech, 16 rue Claude Bernard, F-75231, Paris Cedex 05, France Tel. +33 (0) 1 44 08 17 25 email addresses: [email protected]; [email protected]; [email protected]; [email protected] * ABSTRACT A wide range of compounds can be formed during thermal processing of food, some of which are relevant for aroma (e.g. furfural), while others are of great health-concern (e.g.
    [Show full text]
  • Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-Pyridazino[3,4-B]Indoles
    molecules Article Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles Cecilia Ciccolini, Lucia De Crescentini, Fabio Mantellini, Giacomo Mari, Stefania Santeusanio and Gianfranco Favi * Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy; [email protected] (C.C.); [email protected] (L.D.C.); [email protected] (F.M.); [email protected] (G.M.); [email protected] (S.S.) * Correspondence: [email protected]; Tel.: +39-0722-303444 Academic Editor: Pascale Moreau Received: 27 August 2020; Accepted: 7 September 2020; Published: 9 September 2020 Abstract: Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles. Keywords: indole-based heterocycles; C2-C3 indole oxidation; aromatization; ring-opening/ring-closing; umpolung 1.
    [Show full text]
  • Substituent Effect on the Aromaticity of 1,3-Azole Systems
    Heterocycl. Commun., Vol. 18(1), pp. 11–16, 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hc-2011-0050 Substituent effect on the aromaticity of 1,3-azole systems Sel ç uk G ü m ü s¸ 1, * and Lemi T ü rker 2 shift (NICS) (Schleyer et al. , 1996 ), which is the computed 1 Department of Chemistry , Faculty of Sciences, value of the negative magnetic shielding at some selected Yuzuncu Yil University, 65080, Kamp ü s, Van , Turkey points in space, generally, in a ring or a cage center. Negative 2 Department of Chemistry , Faculty of Arts and Sciences, NICS values denote aromaticity (-11.5 for benzene, -11.4 for Middle East Technical University, 06531, Ankara , Turkey naphthalene) and positive NICS values denote antiaromaticity (28.8 for cyclobutadiene), whereas small NICS values indi- * Corresponding author cate non-aromaticity (-3.1 for 1,3-cyclopentadiene). NICS e-mail: [email protected] may be a useful indicator of aromaticity that usually corre- lates well with the other energetic, structural and magnetic criteria for aromaticity (Jiao and Schleyer , 1998 ; Schleyer Abstract et al. , 2000 ; Patchkovskii and Thiel , 2002 ; Quinonero et al. , 2002 ). Resonance energies and magnetic susceptibilities are The effects of substituent type and position on the aromaticity measures of the overall aromaticity of a polycyclic molecule, of certain derivatives of oxazole, imidazole and thiazole have but do not provide information about the individual rings. been theoretically investigated by using density functional However, NICS is an effective probe for local aromaticity of theory at the levels of B3LYP/6-31G(d,p) and B3LYP/6- individual rings of polycyclic systems.
    [Show full text]
  • Heterocyclic Chemistrychemistry
    HeterocyclicHeterocyclic ChemistryChemistry Professor J. Stephen Clark Room C4-04 Email: [email protected] 2011 –2012 1 http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html Recommended Reading • Heterocyclic Chemistry – J. A. Joule, K. Mills and G. F. Smith • Heterocyclic Chemistry (Oxford Primer Series) – T. Gilchrist • Aromatic Heterocyclic Chemistry – D. T. Davies 2 Course Summary Introduction • Definition of terms and classification of heterocycles • Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • Carbon–heteroatom bond formation and choice of oxidation state • Examples of commonly used strategies for heterocycle synthesis Pyridines • General properties, electronic structure • Synthesis of pyridines • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines Pyridine derivatives • Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines 3 • General methods used for the synthesis of quinolines and isoquinolines Course Summary (cont) Five-membered aromatic heterocycles • General properties, structure and reactivity of pyrroles, furans and thiophenes • Methods and strategies for the synthesis of five-membered heteroaromatics
    [Show full text]
  • Influence of Roasting Process in Six Coffee Arabica Cultivars
    295 A publication of CHEMICAL ENGINEERING TRANSACTIONS VOL. 75, 2019 The Italian Association of Chemical Engineering Online at www.cetjournal.it Guest Editors: Sauro Pierucci, Laura Piazza Copyright © 2019, AIDIC Servizi S.r.l. ISBN 978-88-95608-72-3; ISSN 2283-9216 DOI: 10.3303/CET1975050 Influence of Roasting Process in Six Coffee Arabica Cultivars: analysis of Volatile Components Profiles a a a b Fabrizio Sarghini* , Evelina Fasano , Angela De Vivo , Maria Cristina Tricarico aUniversity of Naples Federico II, Department of Agricultural Sciences, Naples, Italy b Kimbo Spa, Italy [email protected] The complex composition of coffee aroma depends on the several factors regarding green coffee such as species and variety of the beans, origin , seeds size, colour (Toci and Farah, 2014). The most important coffee varieties are known to be Coffea arabica with good organoleptic characteristics, and Coffea canephora , known as Robusta of inferior quality. Development of aroma compounds also is greatly dependent upon the degree of roasting (Lopez-Galilea et al., 2006). In the roasting process almost 840 volatile organic compounds (VOC) are evaluated (Saw et al., 2015). The aim of this work is to investigate of the aromatic profile of six Arabica cultivar from Africa, Central and South America at different roasting degrees (light, medium and dark) and to establish odordescriptor categories as indicators for the assessment of flavour differences. The three roasting degrees were obtained in laboratory considering as target the industrial products and coffee roasting intensity was evaluated by a polychromatic colorimeter. The aromatic compounds of espresso coffee were evaluated by static headspace gas mass chromatography.
    [Show full text]
  • Synthesis of Novel Fused Heterocyclic Pyrazolo- Pyridazine Derivatives As
    Alam et al, 2015 Original Article TJPS The Thai Journal of Pharmaceutical Sciences 39 (3), July-September 2015: 76-82 Synthesis of novel fused heterocyclic pyrazolo- pyridazine derivatives as antimicrobial agents M. Alam1, M. S. Zaman2, M. M. Alam2, K. Arora2, A. Ahmad3, 4 2* S. A. Khan and A. Husain 1 Department of Pharmaceutical Science, Bhagwant University, Ajmer, Rajasthan 305004, India 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India 3Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah 21589, Saudi Arabia 4Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman Abstract A series of pyrazolo-pyridazine derivatives (4a-j) were synthesized and evaluated for their antimicrobial activities with an aim to obtain promising antimicrobial agents. In the first step, 6-substituted phenyl-2,3,4,5- tetrahydropyridazin-3-one (2a,b) was prepared by reacting 4-(4-methylphenyl)-4-oxobutanoic acid (1a) and 4-(4- chlorophenyl)-4-oxobutanoic acid (1b) with hydrazine hydrate. Then, aryl-aldehydes were reacted with 2 to furnish pyridazinones (3a-j). Finally, pyridazinones (3a-j) were reacted with hydrazine hydrate to furnish the title compounds (4a-j). The newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities against six microbial strains. Compound 4i, 5-(4-Hydroxy-3-methoxyphenyl)-3-(4-chlorophenyl)- 3,3a,4,7-tetrahydro-2H-pyrazolo [3,4-c] pyridazine, was found to have significant action against Gram positive and Gram negative bacteria, whereas compound 4g, 3-(4-Bromophenyl)-5-(4-chlorophenyl)-3,3a,4,7-tetrahydro-2H- pyrazolo [3,4-c] pyridazine, exhibited potential antifungal activity.
    [Show full text]