DOCSLIB.ORG

“Design and Synthesis of Some Pyridazine Containing Compounds

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
“Design and Synthesis of Some Pyridazine Containing Compounds “Design and Synthesis of Some Pyridazine Containing Compounds of Expected Anticancer Activity” Thesis Presented By Demiana Samir Mikhail Master in Pharmaceutical Sciences (Organic Chemistry) (Faculty of Pharmacy, Cairo University) (2011) Submitted for The Degree of The Doctor of Philosophy in Pharmaceutical Sciences (Pharmaceutical Organic Chemistry) Under the supervision of Prof. Dr. Salwa El-Sayed Mohamed El-Meligie Professor of Organic Chemistry, Faculty of Pharmacy, Cairo University Dean of Faculty of Pharmacy, Sadat City University Ex-Head of Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University Prof. Dr. Eman Mohamed Ahmed Professor of Organic Chemistry Faculty of Pharmacy, Cairo University Dr. Suzan Mohamed Abuel-Maaty Dr. Sawsan Abo Bakr Zaitone Associate Professor of Organic Chemistry Associate Professor of Pharmacology & Toxicology Faculty of Pharmacy, Cairo University Faculty of Pharmacy, Suez Canal University Faculty of Pharmacy Cairo University 2017 Abstract This study comprises a brief literature survey on cancer, its causes and treatment as well as biological activities and chemistry of pyridazine and fused pyridazine derivatives. The Thesis involves design of some new pyridazine and fused pyridazine derivatives aiming to possess an anticancer activity through inhibition of VEGFR. The Schemes followed for the preparation of the designed compounds are summarized asfollows: Scheme (1) starts with the preparation of the root compound N- Carbamimidoyl-4-[(6-chloropyridazin-3-yl)amino]benzenesulphonamide (I) followed by reaction with different aromatic amines to give N-Carbamimidoyl-4- [(6-arylaminopyridazin-3-yl)amino]benzenesulphonamides IIa-f. Scheme (2) involves nucleophilic substitution reaction of compound I with meta and para phenylenediamine to give the relevant compounds IIIa, b. Furthermore, compound IIIa was reacted with each of acetyl chloride and 3- chloropropionyl chloride to give the corresponding pyridazine derivatives IVa, b respectively. Further, compounds IIIa, b were reacted with different alkyl isothiocyanates to give the corresponding thiourea compounds Va-d and VIa-d. On the other hand, Scheme (3A) involves the reaction of compound I with each of 2-aminophenol, different substituted anthranilic acids and 2-aminonicotinic acid to give the corresponding pyridazino[1,6-a]benzimidazole VII, pyridazino[6,1-b]quinazolines VIIIa,c,d and pyrido[2’, 3’,4,5]pyrimido[1,2- b]pyridazine VIIIb respectively. Scheme (3B) includes the reaction of compound I with each of substituted acetophenone phenylhydrazones, thiosemicarbazide and substituted benzoic acid hydrazides to afford the corresponding hydrazinyl derivatives IXa-c, N- Carbamimidoyl-4-[(3-amino[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino] benzenesulphonamid (X) and 3-aryl [1,2,4]triazolo[4,3-b]pyridazine derivatives XIa-c respectively. The structure elucidation of the newly synthesized compounds was supported by IR, 1HNMR, 13CNMR for some compounds, mass spectral data as well as elemental analysis. Moreover, all the synthesized compounds were subjected to in vitro cytotoxic activity on two cell lines: human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116) compared with imatinib as a reference anticancer drug. Compound VIIIb was the most potent against HCT-116 with IC50 10.42 μM while compound VIIIa was the most potent against MCF-7 with IC50 11.18 μM. In addition, the antitumor activity of some synthesized compounds was tested in vivo against Ehrlich’s ascites carcinoma (EAC) solid tumor grown in mice. The antitumor activity produced by compounds IIe, IVb and Vb was greater than that produced by imatinib, Finally, the in vitro VEGFR enzyme based inhibition assay was carried out at a single dose of 10 μM for some compounds. Percentage enzyme inhibition of IVb and Vb (89.6%, 92.0%, respectively) were more significant than that of imatinib (78.7%) against MCF-7. 1. Introduction The work in this Thesis, involves the synthesis, anticancer activity and chemistry of pyridazine containing compounds. The following is a brief survey on the synthesis of pyridazine derivatives and their biological activities as well as cancer, its causes and treatment. 1.1. Chemistry of pyridazine ring The diazines are compounds derived from benzene by the replacement of two of the ring carbon atoms by nitrogen. The three isomeric six membered ring diazines are pyridazine, pyrimidine and pyrazine having two nitrogen atoms in 1-2, 1-3 and 1-4 relationship respectively. N N N N N N Pyridazine Pyrimidine Pyrazine Pyridazine ring system does not form a part of any natural product and thus it has been less extensively investigated than other diazines. The reason for this is that pyridazine contains a potential hydrazine unit in the ring and hence, they are not readily obtainable from biochemical transformation. However, pyridazines have received much more attention from the theoretical stand point since many derivatives were found to possess potential therapeutic effect. In this Thesis, our interest was confined to pyridazine and pyridazine containing compounds. Several ways were reported to synthesize different derivatives of pyridazine. The following is a brief survey covering the methods of synthesis of this ring. 1.1.1. Synthesis of pyridazines: The first reported pyridazine derivative 2 was obtained by Fischer in 1886 through cyclization of levulinic acid phenylhydrazone (1). O C6H5 NNHC H N 6 5 -H2O N H3C CH2CH2COOH CH3 1 2 Pyridazine itself was first synthesized by Tauber through oxidation of benzo[c]cinnoline (3) to 3,4,5,6-pyridazinetetracarboxylic acid (4) which then was decarboxylated to pyridazine (5). COOH KMnO COOH 4 N 5%HCl N 200oC N COOH N N N COOH 3 5 4 In 1956, Cromwell and his associates, reported the synthesis of 2,6- diphenylpyridazin-3(2H)-one (8) via the reaction of β-benzoylacrylic acid (6) with phenylhydrazine to give the hydrazone derivative 7 which upon heating with acetic anhydride and sodium acetate afforded 2,6-diphenylpyridazin-3(2H)-one (8). C6H5 O NNHC6H5 -H2O N + C6H5NHNH2 C6H5 N C6H5 CH=CHCOOH C6H5 CHCOOH O 6 7 8 In 1989, Wermuth et al. reported the synthesis of hydroxydihydro- pyridazinone 10 by the reaction of acetophenone and pyruvic acid to yield α- methyl-β-benzoyllactic acid (9) which upon cyclocondensation with hydrazine hydrate led to pyridazinone derivative 10. O OH HO H O O N O KOH N C6H5COCH3 NH2-NH2.H2O + OH OH O C6H5 C6H5 9 10 In 1994, Moreau and his colleagues prepared pyridazinone derivative 13 via the reaction of levulinic acid (11) with benzaldehyde to produce substituted pentanoic acid 12 which when condensed with hydrazine hydrate gave pyridazinone derivative 13. H O O C O C6H5 HCl gas NH NH .H O + C H CHO H C COOH 2 2 2 NH H3C COOH 6 5 3 H3C N CHC6H5 11 12 13 On the other hand, 3-amino-6-benzoyl-5-oxopyridazines 15 were synthesized by refluxing compounds 14 with ethanolic sodium hydroxide which accomplished their cyclization to pyridazine derivatives 15. O O O O CN 20%NaOH CN C6H5 C H OH C6H5 N CN 2 5 N NH N NH2 R R 14 15 R = C H , 4-CH OC H , 4-ClC H , 4-CH C H 6 5 3 6 4 6 4 3 6 4 Furthermore, iminopyridazines 17 were successfully obtained by fusing the hydrazo derivatives 16 with malononitrile in the presence of ammonium acetate. O O O C6H5 CH COONH CN C6H5 OC2H5 + CH2(CN)2 3 4 C2H5O N N NH N NH R R 16 17 R = C H , 4-CH OC H , 4-ClC H , 4-CH C H 6 5 3 6 4 6 4 3 6 4 In addition, 6-oxo-pyridazine derivatives 18 were obtained when compounds 16 were fused with ethyl cyanoacetete. O C H O O 6 5 CN CNCH COOC H C2H5O C6H5 OC2H5 + 2 2 5 N N N O NH R R 16 18 R = C6H5, 4-CH3OC6H4, 4-ClC6H4, 4-CH3C6H4 In 2004, tetrahydropyridazin-3-one 20 was prepared via the condensation of oxobutanoic acid derivative 19 with hydrazine hydrate. O O S OH S NH O NH2NH2.H2O N O O 19 20 In 2008, Kumar et al. demonstrated the synthesis of pyridazinone derivatives 22 through Friedel-Crafts acylation of acetanilide using succinic anhydride in presence of anhydrous aluminium chloride to afford the corresponding γ-keto acids 21, which upon subsequent cyclization with various hydrazine derivatives in ethanol provided the corresponding pyridazinone derivatives 22. NHCOCH3 NHCOCH3 NHCOCH3 O O O AlCl3 NH2NHR + C2H5OH N OH O N R O O 21 22 R = C H , 4-FC H , C H N 6 5 6 4 3 6 2 Moreover, a group of investigators reported the synthesis of pyridazinones 24 via the cyclization of compounds 23 with ethyl cyanoacetate or diethyl malonate. R R CNCH2COOC2H5/C2H5ONa R R + or CH2(COOC2H5)2/C2H5ONa R1 O N NNH2 N O H 23 R = H, Br, OCH3 24 1 R = CN, COOC2H5 Aim of the work Our main objective in this Thesis was to design and synthesize new active anticancer drugs through inhibition of VEGFR. A marked increase in VEGF levels has been observed in various types of cancer including breast cancer and colon cancer. For both types of cancer significant correlations between VEGF and the extent of tumor vascularisation, tumor stages and metastasis have been reported. Blood VEGF levels are often used to estimate the degree of tumor development. Breast cancer can be propagated and metastasize under the influence of the elevated levels of VEGF, which has been indicated as a potent angiogenic factor that has an effect on tumor progression. It was reported that breast cancer is an angiogenic-dependent disease. Angiogenesis plays an essential role in breast cancer development, invasion, and metastasis. Breast cancer is potentially treatable by antiangiogenic therapy. Transfection of tumor cells with inhibitors of angiogenesis decreases growth and metastasis.
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]
  • 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]
  • 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]
  • 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]
  • Exploring Potential, Synthetic Methods and General Chemistry of Pyridazine and Pyridazinone: a Brief Introduction
    International Journal of ChemTech Research CODEN( USA): IJCRGG ISSN : 0974-4290 Vol.2, No.2, pp 1112-1128, April-June 2010 Exploring Potential, Synthetic Methods and General Chemistry of Pyridazine and Pyridazinone: A Brief Introduction Mohammad Asif1* and Anita Singh2 1Department of Pharmacy, GRD(PG)IMT 214, Rajpur road Dehradun, (UK), 248901, India 2Devsthali Vidyapeeth, College of Pharmacy Rudrapur (UK) 263148 India *Corres. Author: [email protected] ABSTRACT: Pyridazin-3-one, a saturated or unsaturated form of pyridazine with carbonyl group on third carbon, has been considered as a magic moiety (wonder nucleus) which posses almost all types of biological activities. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. Present article is sincere attempt to review chemistry, synthesis, spectral studies and applications of pyridazinone. Key words: Pyridazinone, pyridazine, biological activities. INTRODUCTION Pyridazine are diazine. The diazines are a group of compounds formally derived from benzene by the replacement of two of the ring carbon atom by nitrogen. Three isomeric diazines are possible with the nitrogen atoms in 1-2, 1-3, or 1-4 relationship, giving rise to the pyridazines (1) pyrimidine (2) & pyrazine (3) respectively. N N N N N N (1) (2) (3) Pyridazine (1,2-diazine) (1) & its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo (C) pyridazine (4) & phthalazine benzo (d) pyridazine (5) have been known since the nineteen century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds revived only during the past 35 years, when many of their derivatives found application as a result of their biological activities.
    [Show full text]
  • Heterocyclic Compounds
    Lecture note- 3 Organic Chemistry CHE 502 HETEROCYCLIC COMPOUNDS Co-Coordinator – Dr. Shalini Singh DEPARTMENT OF CHEMISTRY UTTARAKHAND OPEN UNIVERSITY UNIT 4: HETEROCYCLIC COMPOUNDS- I CONTENTS 4.1 Objectives 4.2 Introduction 4.3 Classification of heterocyclic compounds 4.4 Nomenclature of heterocyclic compounds 4.5 Molecular orbital picture 4.6 Structure and aromaticity of pyrrole, furan, thiophene and pyridine 4.7 Methods of synthesis properties and chemical reactions of Pyrrole, Furan, Thiophene and Pyridine 4.8 Comparison of basicity of Pyridine, Piperidine and Pyrrole 4.9 Summary 4.10 Terminal Question 4.1 OBJECTIVES In this unit learner will be able to • Know about the most important simple heterocyclic ring systems containing heteroatom and their systems of nomenclature and numbering. • Understand and discuss the reactivity and stability of hetero aromatic compounds. • Study the important synthetic routes and reactivity for five and six member hetero aromatic compounds. • Understand the important physical and chemical properties of five and six member hetero aromatic compounds. • Know about the applications of these hetero aromatic compounds in the synthesis of important industrial and pharmaceutical compounds 4.2 INTRODUCTION Heterocyclic compound is the class of cyclic organic compounds those having at least one hetero atom (i.e. atom other than carbon) in the cyclic ring system. The most common heteroatoms are nitrogen (N), oxygen (O) and sulphur (S). Heterocyclic compounds are frequently abundant in plants and animal products; and they are one of the important constituent of almost one half of the natural organic compounds known. Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the some important class of natural heterocyclic compounds.
    [Show full text]
  • Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry
    Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry 5 4 Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4 5 4 3 5 6 6 3 3 4 6 2 2 N 4 4 3 4 3 4 3 3 5 5 2 3 5 4 N HN 5 2 N N 7 2 7 N N 5 2 5 2 7 2 2 1 1 N NH H H 8 1 8 N 6 4 N 5 1 2 6 3 4 N 1 6 3 1 8 N 2-Pyrazoline Pyrazolidine H N 9 1 1 5 N 1 Quinazoline N 7 7 H Cinnoline 1 Pyrrolidine H 2 5 2 5 4 5 4 4 Isoindole 3H-Indole 6 Pyrazole N 3 4 Pyrimidine N pK : 11.3,44 Carbazole N 1 6 6 3 N 3 5 1 a N N 3 5 H 4 7 H pKa: 19.8, 35.9 N N pKa: 1.3 pKa: 19.9 8 3 Pyrrole 1 5 7 2 7 N 2 3 4 3 4 3 4 7 Indole 2 N 6 2 6 2 N N pK : 23.0, 39.5 2 8 1 8 1 N N a 6 pKa: 21.0, 38.1 1 1 2 5 2 5 2 5 6 N N 1 4 Pteridine 4 4 7 Phthalazine 1,2,4-Triazine 1,3,5-Triazine N 1 N 1 N 1 5 3 H N H H 3 5 pK : <0 pK : <0 3 5 Indoline H a a 3-Pyrroline 2H-Pyrrole 2-Pyrroline Indolizine 4 5 4 4 pKa: 4.9 2 6 N N 4 5 6 3 N 6 N 3 5 6 3 N 5 2 N 1 3 7 2 1 4 4 3 4 3 4 3 4 3 3 N 4 4 2 6 5 5 5 Pyrazine 7 2 6 Pyridazine 2 3 5 3 5 N 2 8 N 1 2 2 1 8 N 2 5 O 2 5 pKa: 0.6 H 1 1 N10 9 7 H pKa: 2.3 O 6 6 2 6 2 6 6 S Piperazine 1 O 1 O S 1 1 Quinoxaline 1H-Indazole 7 7 1 1 O1 7 Phenazine Furan Thiophene Benzofuran Isobenzofuran 2H-Pyran 4H-Pyran Benzo[b]thiophene Effects of Substitution on Pyridine Basicity: pKa: 35.6 pKa: 33.0 pKa: 33.2 pKa: 32.4 t 4 Me Bu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2 4 8 5 4 9 1 3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8 6 3 3 5 7 4 8 2 3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8 4 2 6 7 7 3 N2 N 1 4-position
    [Show full text]
  • Infrared Spectra of Pyrazine, Pyrimidine and Pyridazine in Solid Argon
    Journal of Molecular Structure 786 (2006) 193–206 www.elsevier.com/locate/molstruc Infrared spectra of pyrazine, pyrimidine and pyridazine in solid argon S. Breda a, I.D. Reva a, L. Lapinski a,b, M.J. Nowak b, R. Fausto a,* a Department of Chemistry, University of Coimbra, Coimbra P-3004-535, Portugal b Institute of Physics, Polish Academy of Sciences, Warsaw PL-02-668, Poland Received 17 August 2005; revised 8 September 2005; accepted 8 September 2005 Available online 25 October 2005 Abstract The vibrational spectra of monomeric diazines (pyrazine, pyrimidine and pyridazine) isolated in solid argon and of the neat crystalline phase of these compounds, at 10 K, are reported and discussed. Full assignment of the spectra is presented, providing evidence that the assignments of several bands previously undertaken for the compounds under other experimental conditions (e.g., gas phase, neat liquid or solution) shall be reconsidered. The interpretation of the experimental data is supported by extensive DFT calculations performed with the B3LYP functional and the 6-311CCG(d,p) basis set and by comparison with the anharmonic vibrational calculations reported by Boese and Martin [J.Phys.Chem. A, 108 (2004) 3085] and Berezin et al. [Russian J.Phys.Chem., 79 (2005) 425; Opt.Spectrosc., 97 (2004) 201]. Spectra/structure correlations were extracted from the data, enabling to conclude that, while the p-electron systems in both pyrazine and pyrimidine rings are strongly delocalized over all heavy-atoms, in pyridazine the canonical form with one CC and two CN double bonds strongly predominates. Finally, the UV-induced photoisomerization of matrix isolated monomeric pyrazine to pyrimidine is reported.
    [Show full text]
  • Synthesis and Evaluation of Aromaticity and Tautomerization of Pyrazolopyridazin(On)Es
    J. Chem. Sci. Vol. 129, No. 6, June 2017, pp. 741–752. © Indian Academy of Sciences. DOI 10.1007/s12039-017-1293-3 REGULAR ARTICLE Synthesis and evaluation of aromaticity and tautomerization of pyrazolopyridazin(on)es NURETTIN˙ MENGES∗ and ISHAK˙ BILD˙ IR˙ IC˙ I˙ Faculty of Pharmacy, Pharmaceutical Chemistry Section, Yuzuncu Yil University, 65090 Van, Turkey E-mail: [email protected] MS received 4 August 2016; revised 27 March 2017; accepted 24 April 2017 Abstract. Aromaticity of pyrazolopyridazin(on)es was investigated using NICS(0), NICS(1), NICSzz(1), FIPC-NICS and HOMA aromaticity indexes and it was observed that aromaticity of pyridazin(on)es was amenable to aromaticity of pyrazole and vice versa. Some tautomeric forms of pyridazinone were analyzed and the localized orbital locator maps, electron density maps, Fuzzy, Laplacian, and Mayer bond order methods showed dominant form. Different substituents, amine, chlorine, phenyl, methyl, hydrogen, substituted-phenyl, etc. on both the rings were chosen to search out the substituent effect. Aromaticity of pyrazolopyridazin(on)es was searched out in detail for the first time. Keywords. NICS; FIPC-NICS; Keto-enol tautomer; bond order; LOL map. 1. Introduction More recently, a new and widely used aromaticity index, the nucleus-independent chemical shift (NICS), has Pyrazolopyridazin(on)e is a bicyclic nitrogen-containing been proposed by Schleyer et al. 11 It has been reported structure and one of the important core of heterocyclic that the negative value of the absolute shielding was compounds (Figure 1). Their derivatives are applied as observed at a ring center or at some other interest- ligand for hedge hog signal cascade, 1 used for treatment ing points of the system.
    [Show full text]