DOCSLIB.ORG

A Review on Synthetic Protocols of Pyridazine and Pyridazone Analogues

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Review on Synthetic Protocols of Pyridazine and Pyridazone Analogues Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 INDO GLOBAL JOURNAL OF PHARMACEUTICAL SCIENCES ISSN 2249- 1023 A Review on Synthetic Protocols of Pyridazine and Pyridazone Analogues Vikas Jakhmola 1,2, Sunil Jawla 1, Prianshu Tangri 1,2, Ravinesh Mishra 3* 1 Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Saharanpur-247341, Uttar Pradesh, India 2 Department of Pharmacy, GRD (PG) IMT, Dehradun-248001, Uttarakhand, India 3 School of Pharmacy and Emerging Sciences, Baddi University of Emerging Sciences and Technology, Baddi (Solan)-173205, Himachal Pradesh, India Address for Correspondance ABSTRACT: Several methods for syntheses are available in literatures which involve conventional Ravinesh Mihra, synthesis methods. Most synthesis of pyridazine is based on the addition of hydrazine or its derivative to an [email protected] appropriately 1,4-disubstituted carbon chain. As part of our program aimed at utilizing β-aroylpropionic acid om derivatives containing the different aromatic moiety as starting materials react with different hydrazine Keywords derivatives for the synthesis of pyridazine and pyridazinone derivatives, these reports of interesting biological Pyridazine; 4,5- activities prompted us to synthesize a new series of pyridazinones containing different other moieties to give Dihydropyridazin the corresponding pyridazinone. © 2015 iGlobal Research and Publishing Foundation. All rights reserved. -3(2H)-one; Synthetic Methods. Pyridazines have not been investigated as thoroughly as the INTRODUCTION other isomeric diazines especially pyrimidine because they are not known to occur in nature and are not easily produced by nitrogen biochemical transformation. Since, some pyridazines The diazines are six membered ring containing two nitrogen have been found useful as growth inhibitors or medicinal atoms. Three isomeric diazines are theoretically possible and compounds; the literature has been expanding day by day. all of them are known. Pyridazine has been assumed to be a planar molecule for N N N which two Kekule structures are given as mentioned. N Pyridazine is a resonance hybrid in which the greater N N contribution is made by the structure containing = N- 3 1,2-Diazine 1,3-Diazine 1,4-Diazine N=configuration . The 1,2 diazine systems that contain a carbonyl group in the ring are called pyridazinone. (Pyridazine) (Pyrimidine) (Pyrazine) O 1 Knorr Coined the term pyridazine for 1,2 diazine ring system , N N however Fischer first prepared substituted pyridazines in 1886 H 2 & later on by Tauber in 1895. 4,5-Dihydropyridazin-3(2H)-one 65 Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 During last two decade numbers of pyridazines have been (A) Ring closure of acyclic compounds, synthesized due to variety of biological activities specially (B) Alteration and or Fusion with Other Heterocyclic Ring related to cardiovascular system. System, and (C) Substitution and Displacement on Pyridazinone System Properties of Pyridazine (A) Ring Closure of Acyclic Compounds Pyridazine being a pie electron deficient heteroaromatic i) 1,2-Dicarbonyl compounds: Compounds containing compound is a colorless liquid at room temperature with carboxylic group and an active methylene group on pyridine like odour & melting point of -8°C. condensation with 1,2-dicarbonyl group containing compounds in presence of hydrazine give substituted 7 Pyridazine is a weak base with boiling point 208°C. This pyridazinones . unusually high boiling point compared to benzene (80°C) indicates the involvement of some type of intermolecular R4 association and is attributed to the polariseability of N-N unit, O O OR R4 O N 4 which results in extensive dipolar association in the liquid . + + O N NH R3 H N R 2 R R1 R Pyridazine forms pyridazinium mono-cation with acids. It 1 2 3 R2 undergoes nucleophilic substitution with great difficulty; but Scheme 1 conversion into 1-oxide gives a means of preparing various Method 1 pyridazine substitution products5. O O ii) Most of the compounds having 6-(alkylaminophenyl)-6- N + N + N N N PhCOOH N H2SO4 N N dimethylaminophenyl, and 6-(o-substituted phenyl) HNO3 constituents are prepared by treatment of appropriate --keto 8 NH acid or --keto ester with hydrazine (Method 2). NO2 2 R'' R' H N N R'' N Facile elimination of nitrogen can be used in conjugation with CO C CH2COOZ + O H NH Diels-Alder addition to construct aromatic rings. Pyridazine- 2 R R 3,6-dicarboxylate ester reacts with electron rich alkene to give R' Scheme 2 adducts that undergo subsequent elimination of nitrogen6. + ZOH Method 2 COOMe COOMe iii) Pyridazinone derivatives are also synthesized from Claisen condensation of levulinic acid with benzaldehyde followed by OMe MeO N N reaction with hydrazine hydrate9 (Method 3). + H C Me N 2 2 R1 R (R ) N N 2 4 2 NMe Piperidine 2 + CH -CO-CH-C-COOH 3 Toluene COOMe COOMe COOMe CHO p-(Substituted) (Substiuted)-B-methyl NMe benzaldehyde levulinic acid 2 R -MeOH 2 COOH R R2 4 - N R4 2 NH2NH2 H O O (R4)2 2 R1 O N N COOMe H R1 R2 R4 Methods of Preparation of Pyridazines/Pyridazinones MnO2 R1 THF, O N N The methods for the preparing pyridazine and pyridazinones H can be grouped into three main categories: Scheme 3 Method 3 66 Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 iv) The reaction between diarylglyoxal monohydrazone (1), vii) Synthesis of new series of 4,5-dihydro-3(2H)- isocyanides (2), aldehydes (3), affords a series of 3(2H)- pyridazinones has been carried out according to Method 7. pyridazinones10 in very simple manner (Mehod 4). The Ring closure of the requisite -keto acid is readily intermediate Ugi-four component condensation products are accomplished in high yield with hydrazine in refluxing never observed due to their tendency to cyclize when the less ethanol13. reactive cyclopentanone is used instead of aldehyde. Ph-NCO MeOOC R + MeOOC NO2 R Satisfactory yield is obtained for 3(2H)-pyridazinone with the TEA 4 5 N O preformed azine. 6 HOOC R O OH O R' 10% NaOH C/Pd Ph NNH 2 X C HOOC R o-C6H11CN (2) N H CO N O 10% NaOH 8 R'-CHO (3) N HN 7 Ph O Ph Ph 1 O NH2NH2 R N N X = CN, COOC2H5 H Scheme 4 OH Method 4 9 SchemeMethod 7 7 Intermediate (8) is obtained through a two step sequence v) 6-Aryl-2,3,4,5-tetrahydro-3-pyridazinones can also be involving a 1,3-dipolar cycloaddition reaction between the obtained by dehydrocyclisation of various hydrazides formed nitric oxide generated from 4-nitrobutyric acid methyl ester by the reaction of appropriate methyl -aroyl propionate and (4) and the appropriate alkene (5) followed by reductive ring 11 hydrazine hydrate in presence of sodium acetate (Method 5). opening of the formed cycloproduct. viii) A number of 4,6-disubstituted pyridazinone analogues14 Appropriate (CH2CO)2O Aromatic R OH AlCl have been synthesized since the original synthesis of Compound 3 O O Minaprine (psychotropic drug with pyridazine nucleus) is Dimethyl sulphate applicable to a great number of such types of analogues, which R O R NHNH starts with the use of acetophenone (Method 8). The first step 1 2 R OMe N N O O of the synthesis involves a ketolization reaction between R1 R = Aryl acetophenone (10) and pyruvic acid (11) to give -methyl-- R = H, Ph Scheme 5 1 Method 5 benzollactic acid (12). The cyclocondensation of the - ketoacids with hydrazine gives the vi) Pyridazinone ring system fused with benzoselenazine hydroxydihydropyridazinones (13). Tertiary alcoholic group is moiety is synthesized from aminophenyl-3-methyl then easily dehydrated in an acidic medium giving oxybutyrate12. It is treated with potassium selenocyanate in pyridazinone (14). acetic acid and bromine. The resultant cyanate is hydrolyzed O CH3 O with sodium sulfide to give aminoselenol; which is then O OH OH KOH cyclised to the selenazine with chloroacetyl chloride. Reaction + CH3 HO O with alcoholic hydrazine gives the desired compound (Method O CH3 12 6). 10 11 NH NH COOEt COOEt 2 2 CH OH H C H3C 3 3 CH + 3 HSe H KSeCN, Br2 O O ClCH2COCl O O N N N N H N H N 2 2 H H COOEt H3C O 14 13 H C 3 Se NH Scheme 8 N Method 8 Se NH2NH2 O O N H ix) Saturated 1,4-diketones have also been used for the O N H 1,4-Benzoselenazinyl pyridazine synthesis. The intermediate dihydro compound 15 Scheme 6 pyridazinone may be oxidized by chromium trioxide in acetic acid Method 6 (Method 9). 67 Indo Global Journal of Pharmaceutical Sciences, 2016; 6(2): 65-71 iii) Pyridazinone can be synthesized in an unusual way from 18 R O R N R N the reaction of glyoxalic acid and tetralone as illustrated in O NH [O] N + NH NH 2 2 Method 13. R R R Method 9 Glyoxalic acid Zn x) Bis-pyridazinone derivatives can be synthesized through the OH- Acetic acid 16 formation of Mannich bases . 1,4-diacetyl benzene on O O COOH treatment with formaldehyde and dimethylamine gets Tetralone converted to Mannich bases. These undergo elimination- NH NH addition with cyanide to give the dinitrile derivative; which on 2 2 hydrolysis gives corresponding diacid. Cyclocondensation of O COOH N diacid with hydrazine hydrate gives bis-pyridazinone N O H compound. m-Nitrobenzene NHCH3 CN sulphonate O O COCH N 3 N O H NHMe2 KCN Scheme 10 HCHO MeOH Method 13 COCH 3 O O iv) Pyridazinone derivatives can also be synthesized by NHCH3 CN Friedel Crafts acylation of substituted benzene with dimethyl O maleic anhydride which gives lactol19. Reduction of olefinic COOH NH center in lactol is accomplished with zinc and acetic acid.
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]
  • Heterocyclic Compounds with Biological Meaning
    Heterocyclic compounds with biological meaning 1 Heterocyclic compounds Cyclic, organic compounds which besides carbon atoms have one or more heteroatom (other elements than C). Heterocyclic atoms: – nitrogen, N – sulphur, S – oxygen, O – phosphorus, P – barium, Ba – zinc, Zn – silicon, Si. 2 Heterocyclic compounds From the biological point of view, the most important are heterocyclic compounds with 5- and 6-membered rings, containing: S, N, O. Most of the heterocyclic compounds have their common names. Substituent’s position in the ring is described by : – number – position of heteroatom – no. 1 – Greek letter – describes carbon atom the closest to heteroatom as a, then β and γ, respectively. 3 Heterocyclic compounds Heterocyclic compounds are: • widespread in nature • biologically active • some of them are toxic (e.g. coniine, coumarin and derivatives). Occurrence in: • natural dyes - heme, chlorophyll • alkaloids – atropine and nicotine • amino acids such as tryptophan and histidine • enzymes, nucleoproteins, antibiotics • vitamins • many synthetic pharmaceuticals. 4 Heterocyclic compounds Aromatic character of heteroatom-containing ring comes from aromatic sextet which consists of: • „not bound” electron pairs of heteroatoms • four electrons π from carbon atoms Pyrrole Furane Thiophen 5 5- membered ring heterocyclic compounds with one heteroatom 5-membered rings: • contain mostly oxygen, sulphur and nitrogen • are flat • are aromatic 6 5- membered ring heterocyclic compounds with two heteroatoms oxazole imidazole thiazole pyrazole 7 5- membered ring heterocyclic compounds With one heteroatom With two heteroatoms Condensation products with benzene 8 Pyrrole and derivatives • Pyrrole derivatives: • pyrroline • pyrrolidone • proline, • Hydroksyproline. • Condensation’s products of pyrrole with benzene: – indole, – tryptophan, – serotonin. • Condensation’s products of pyrrole with formaldehyde: – heme – hemoglobin – billirubin – porphyrins – Biliverdin.
    [Show full text]
  • Heterocyclic Compounds
    Gábor Krajsovszky Heterocyclic compounds ISBN: 978-615-5722-01-1 © Gábor Krajsovszky Responsible editor: Gábor Krajsovszky Publisher’s reader: István Mándity Translated by Péter Tétényi Department of Organic Chemistry Pharmaceutical Faculty Semmelweis University Budapest, 2018 Acknowledgements The editor wants to express many thanks to Dr. István Mándity, who is Associate Professor and Director of Department of Organic Chemistry, for the careful proofreading service of the current manuscript, as well as to Dr. Péter Tétényi, who is Assistant Professor, for the translation to English language. Moreover, the editor renders many thanks to Mrs. Ferenc Juhász and Ms. Nikoletta Zlatzky laboratory assistants for drawing material of the figures. Dr. Gábor Krajsovszky Associate Professor Department of Organic Chemistry Literature used Alan R. Katritzky, Charles W. Rees: Comprehensive Heterocyclic Chemistry Parts 2-3, 4-6, 7 Pergamon Press 1984 Oxford • New York • Toronto • Sydney • Paris • Frankfurt T. Eicher, S. Hauptmann, A. Speicher: The Chemistry of Heterocycles Structure, Reactions, Syntheses, and Applications Wiley-VCH GmbH 2003 Weinheim E. Breitmaier, G. Jung: Organische Chemie Grundlagen, Stoffklassen, Reaktionen, Konzepte, Molekülstruktur Georg Thieme Verlag 1978, 2005 Stuttgart • New York Clauder Ottó: Szerves kémia II/2. Egyetemi jegyzet Semmelweis OTE Budapest, 1980 Bruckner Győző: Szerves kémia III−1. Tankönyvkiadó, Budapest, 1964 Természettudományi Lexikon − Harmadik kötet Clauder Ottó: 'Heterociklusos vegyületek' címszó, 155-161.
    [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]
  • 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]
  • Tetrazinebox: a Structurally Transformative Toolbox Qing-Hui Guo, Jiawang Zhou, Haochuan Mao, Yunyan Qiu, Minh T
    pubs.acs.org/JACS Article TetrazineBox: A Structurally Transformative Toolbox Qing-Hui Guo, Jiawang Zhou, Haochuan Mao, Yunyan Qiu, Minh T. Nguyen, Yuanning Feng, Jiaqi Liang, Dengke Shen, Penghao Li, Zhichang Liu, Michael R. Wasielewski, and J. Fraser Stoddart* Cite This: J. Am. Chem. Soc. 2020, 142, 5419−5428 Read Online ACCESS Metrics & More Article Recommendations *sı Supporting Information ABSTRACT: Synthetic macrocycles capable of undergoing allosteric regulation by responding to versatile external stimuli are the subject of increasing attention in supramolecular science. Herein, we report a structurally transformative tetracationic cyclophane containing two 3,6-bis(4-pyridyl)-l,2,4,5-tetrazine (4-bptz) units, which are linked together by two p-xylylene bridges. The cyclophane, which possesses modular redox states and structural post-modifications, can undergo two reversibly consecutive two-electron reductions, affording first its bisradical dicationic counterpart, and then subsequently the fully reduced species. Furthermore, one single-parent cyclophane can afford effectively three other new analogs through box- to-box cascade transformations, taking advantage of either reductions or an inverse electron-demand Diels−Alder (IEDDA) reaction. While all four new tetracationic cyclophanes adopt rigid and symmetric box-like conformations, their geometries in relation to size, shape, electronic properties, and binding affinities toward polycyclic aromatic hydrocarbons can be readily regulated. This structurally transformative tetracationic cyclophane performs a variety of new tasks as a result of structural post-modifications, thus serving as a toolbox for probing the radical properties and generating rapidly a range of structurally diverse cyclophanes by efficient divergent syntheses. This research lays a solid foundation for the introduction of the structurally transformative tetracationic cyclophane into the realm of mechanically interlocked molecules and will provide a toolbox to construct and operate intelligent molecular machines.
    [Show full text]
  • Non-Empirical Calculations on the Electronic Structure of Olefins and Aromatics
    NON-EMPIRICAL CALCULATIONS ON THE ELECTRONIC STRUCTURE OF OLEFINS AND AROMATICS by Robert H. Findlay, B.Sc. Thesis presented for the Degree of Doctor of philosophy University of Edinburgh December 1973 U N /),, cb CIV 3 ACKNOWLEDGEMENTS I Wish to express my gratitude to Dr. M.H. Palmer for his advice and encouragement during this period of study. I should also like to thank Professor J.I.G. Cadogan and Professor N. Campbell for the provision of facilities, and the Carnegie Institute for the Universities of Scotland for a Research Scholarship. SUMMARY Non-empirical, self-consistent field, molecular orbital calculations, with the atomic orbitals represented by linear combinations of Gaussian-type functions have been carried out on the ground state electronic structures of some nitrogen-, oxygen-, sulphur- and phosphorus-containing heterocycles. Some olefins and olefin derivatives have also been studied. Calculated values of properties have been compared with the appropriate experimental quantities, and in most cases the agreement is good, with linear relationships being established; these are found to have very small standard deviations. Extensions to molecules for which there is no experimental data have been made. In many cases it has been iôtrnd possible to relate the molecular orbitals to the simplest member of a series, or to the hydrocarbon analogue. Predictions of the preferred geometry of selected molecules have been made; these have been used to predict inversion barriers and reaction mechanisms. / / The extent of d-orbital participation in molecules containing second row atoms has been investigated and found to be of trivial importance except in molecules containing high valence states of the second row atoms.
    [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]
  • Heterocyclic Chemistry at a Glance Other Titles Available in the Chemistry at a Glance Series
    Heterocyclic Chemistry at a Glance Other Titles Available in the Chemistry at a Glance series: Steroid Chemistry at a Glance Daniel Lednicer ISBN: 978-0-470-66084-3 Chemical Thermodynamics at a Glance H. Donald Brooke Jenkins ISBN: 978-1-4051-3997-7 Environmental Chemistry at a Glance Ian Pulford, Hugh Flowers ISBN: 978-1-4051-3532-0 Natural Product Chemistry at a Glance Stephen P. Stanforth ISBN: 978-1-4051-4562-6 The Periodic Table at a Glance Mike Beckett, Andy Platt ISBN: 978-1-4051-3299-2 Chemical Calculations at a Glance Paul Yates ISBN: 978-1-4051-1871-2 Organic Chemistry at a Glance Laurence M. Harwood, John E. McKendrick, Roger Whitehead ISBN: 978-0-86542-782-2 Stereochemistry at a Glance Jason Eames, Josephine M Peach ISBN: 978-0-632-05375-9 Reaction Mechanisms at a Glance: A Stepwise Approach to Problem-Solving in Organic Chemistry Mark G. Moloney ISBN: 978-0-632-05002-4 Heterocyclic Chemistry at a Glance Second Edition JOHN A. JOULE The School of Chemistry, The University of Manchester, UK KEITH MILLS Independent Consultant, UK This edition fi rst published 2013 © 2013 John Wiley & Sons, Ltd Registered offi ce John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offi ces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identifi ed as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.
    [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]
  • Haloselectivity of Heterocycles Will Gutekunst
    Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Background SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure Polysubstituted heterocycles represent some of the most important compounds in the realm of pharmaceutical and material sciences. New and more efficient ways to selectively produce these Br Br molecules are of great importance and one approach is though the use of polyhalo heterocycles. Br NaNH2 N N Consider: Ar N 3 Ar2 NH3(l), 90% NH2 3 Halogenations H NH2 H N CO2Me Ar H 3 Suzuki Couplings 1 N CO2Me - Br H Ar 3 Ar2 1 Triple Halogenation NH2 NH CO Me N N 2 Ar1 H 1 Triple Suzuki Coupling N CO2Me N NH H NH2 Ar H 3 Ar2 1 Triple C-H activation? CO Me N 2 Ar1 H N CO2Me Cross Coupling H Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions: Nucleophilic Substitution Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc. SNAr or SN(AE) In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity determining steps and is frequently considered to be irreversible. This addition highly resembles a nucleophilic substitution and it frequently follows similar regioselectivities in traditional S Ar reactions. Nu N The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's Nu of the corresponding C-X bonds. N X N X N Nu 2nd 2nd Meisenheimer Complex 1st Br Br 88.9 83.2 S (EA) Br 88.9 N 87.3 Br O O via: st OMe 1 Br NaNH , t-BuONa 2 N N pyrrolidine + Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling N N THF, 40ºC N reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of N the LUMO of the heterocycle to the HOMO of the Pd species.
    [Show full text]
  • Dual Kinase Targeting in Leukemia
    cancers Review Dual Kinase Targeting in Leukemia Luca Mologni 1, Giovanni Marzaro 2 , Sara Redaelli 1 and Alfonso Zambon 3,* 1 Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; [email protected] (L.M.); [email protected] (S.R.) 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, I-35131 Padova, Italy; [email protected] 3 Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy * Correspondence: [email protected]; Tel.: +39-059-2058-640 Simple Summary: A new option to treat cancer is based on the use of so-called multi-targeting drugs. This strategy can replace the standard treatment based on the co-administration of several drugs. An increased and uncontrolled activity of kinases (enzymes devoted to the regulation of several cell pathways) is often seen in hematological malignancies. The development of multi-kinase inhibitors is having a great impact on the treatment of this kind of cancer. Here, we review the most recent findings on this novel class of drugs. Abstract: Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and lymphoid tumors, giving details on preclinical studies as well as ongoing clinical trials.
    [Show full text]