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. Főszerkesztő: Erdey-Grúz Tibor Akadémiai Kiadó, Budapest, 1966 Szabó László: Szerves kémia előadások - heterociklusos vegyületek Semmelweis OTE Budapest, 1978-1996 Three-, four- and five-membered heterocycles with one heteroatom and their derivatives Three-membered heterocycles with one heteroatom and their derivatives Nomenclature 1 1 H O S N 1 3 2 3 2 3 2 Hantzsch-Widman name oxirane thiirane aziridine Radicofunctional name ethylene oxide ethylene sulfide ethylene imine Replacement name oxacyclopropane thiacyclopropane azacyclopropane 1 1 H O O N 1 diazomethane 2 2 2 3 O 3 NH 3 NH H2C N N dioxirane oxaziridine diaziridine structural isomers H 1 1 1 N O S N N 3 2 2 3 2 3 N H H oxirene thiirene 1H-azirine 2H-azirine 3H-diazirine 2-azirine 1-azirine Preparation [2+1] intermolecular ring closure With contribution of atoms from olefin [2] and peracid [1] O R CO3H R CH CH2 R Br2 / CCl4 R: oxirane derivatives Cl Cl2 / H2O perbenzoic acid m-chloroperbenzoic acid KOH HCl Br OH R CH CH2 R CH CH2 Br Cl +HCl halohydrin Ethylene oxide is used for gas sterilisation. It must be diluted with carbon dioxide, otherwise explosive mixture would be formed with air. Peracids are explosive, toxic compounds! Br OH R CH CH2 R CH CH2 Br Cl halohydrin OH Cl H2S NH3 SOCl2 R CH CH2 R CH CH2 aminoalcohol NH2 haloamine NH2 SH KOH S R CH CH2 HBr KOH +HCl HCl Br +HBr R halothiol H thiirane derivative N 2 R CH2 3 1 aziridine derivative N C N carbene Aziridines are carcinogen compounds. benzonitrile 2H-azirine derivative Only singlet carbene (not triplet) e.g., CH2N2 is suitable for the reaction. Epoxidation with peracid without catalyst O C C O H H CH (CH ) 3 2 7 (CH2)7COOH H H CH3COOH C C enantiomers ° H H CH3(CH2)7 (CH2)7COOH 20 C, 3 h 1:1 one-step C C CH (CH ) (CH ) COOH oleic acid syn-addition 3 2 7 O 2 7 O C C O CH3(CH2)7 H H (CH2)7COOH CH3(CH2)7 H CH3COOH C C enantiomers H (CH ) COOH 20 °C, 3 h 2 7 CH3(CH2)7 H 1:1 one-step C C elaidinic acid syn-addition H (CH ) COOH O 2 7 Asymmetric oxidation of alkenes Sharpless epoxidation Knowles, Noyori, Sharpless 2001 Nobel-prize, Chemistry, chiral catalysis A) diastereo(enantio-)selective EtOOC OH Ti[OCH(CH ) ] O H 3 2 4 O H + O HO (CH3)3C O OH H COOEt CH OH O H CH Cl 2 2 2 H O CH2OH diethyl tartrate enantiomers H EtOOC H Ti[OCH(CH ) ] O OH 3 2 4 H allyl alcohol + O derivative H (CH3)3C O OH HO COOEt CH OH CH Cl 2 2 2 H O B) O HO H OEt OEt H HO S O OH (2S,3S)-(-)-Diethyltartrate 2 R R R O 1 R2 R i R (CH3)3C-O-O-H / Ti(O Pr)4 molecular sieve R Z 1 R OH R2 HO O S O R R1 H HO OEt OEt 1 2 HO R < R < R H O (2R,3R)-(+)-Diethyltartrate O HO H OEt OEt H HO S O OH (2S,3S)-(-)-Diethyltartrate 2 R R1 S O R2 R i R1 (CH3)3C-O-O-H / Ti(O Pr)4 molecular sieve R E R 2 OH R HO O R 1 O R R H HO OEt OEt 1 2 HO R < R < R H O (2R,3R)-(+)-Diethyltartrate Chemical properties 2,2'-iminodiethanol 2,2'-[(hydroxymethyl)imino]diethanol 2-[(2-hydroxyethyl)amino]ethan-1-ol 2-[bis(2-hydroxyethyl)amino]ethan-1-ol O O CH2CH2OH CH2CH2OH HN N CH2CH2OH CH CH OH CH CH OH O δ 2 2 2 2 NH3 OH NH2 diethanolamine triethanolamine CH2 CH2 δ In ointment, lacquer KOH H N SOCl2 Cl NH2 KOH CH2 CH2 aziridine Baeyer strain is greater for 3-membered rings than for 4-membered ones. As a consequence of this ring opening, reactions are easier for the former ones. Ring opening – it may occur with acid or with base Different regiochemistry: with acid: SN1-like mechanism (alkyl cation of higher order is more stable) with base: SN2 mechanism (for sterical reasons, the nucleophile attacks the carbon of lower order) H H H O O O O H Y Y OH R CH CH2 R R R R Nu O Nu OH Nu H R CH CH2 R CH CH2 OH CH2 CH3 LiAlH4 OH OR RO CH2 CH2 O OH HO CH2 CH2 OH RMgBr MgBr O R NH4Cl OH R CH2 CH2 CH2 CH2 O 1 2 HO / H2O H2S HO CH2CH2 SH 2-sulfanylethanol RO / ROH 2 1 O S RO CH2CH2 SH SCN 2-alkoxyethanethiol HCl Cl CH CH SH thiirane R1 2 2 2-chloroethanethiol NH R1 R2 N CH2CH2 SH R2 2-dialkylaminoethanethiol Some important derivatives O CH3 O (CH3CO)2O + N CH3 HOCH2CH2N(CH3)3 H3C COCH2CH2N(CH3)3 CH3 Cl Cl HCl choline chloride acetylcholine chloride Acetylcholine: neurotransmitter of parasympathic nervous system (it can be found in the parasympathic part of the vegetative nervous system and in the central nervous system) b) pathway Ar OH competing reaction O O OH Cl b) pathway HO Ar OH + Ar O CH2 CH CH2 a) pathway HCl CH2 Cl Ar O CH2 a) pathway (main pathway) epichlorohydrin RNH2 steric reason OH NHR prototypes: RNH2 Ar O CH2 CH CH2 Ar R name β-adrenoceptor blocker CH3 CH propranolol CH3 CH3 CH pindolol N H CH3 Four-membered heterocycles with one heteroatom and their derivatives Nomenclature 1 2 O S HN 4 3 Hantzsch-Widman name oxetane thietane azetidine Radicofunctional name trimethylene oxide trimethylene sulfide trimethylene imine Replacement name oxacyclobutane thiacyclobutane azacyclobutane 1 2 1 2 1 2 1 2 O S N HN N 4 3 4 3 4 3 4 3 oxet(ene) thiet(ene) 1-azetine 2-azetine azet 1 2 1 2 S S HN NH 4 3 4 3 1,2-dithiet 1,2-dihydro-1,2-diazet Preparation By intramolecular ring closure O OCCH3 Cl HS Cl O Cl H2S Cl KOH S HO AlCl3 HCl H3C SO2NH2 Br Ts Br Ts NH2 N LiAlH4 HN ether Chemical properties RMgX R CH2CH2CH2OH LiAlH4 CH3CH2CH2OH O HBr Br CH2CH2CH2 Br RNH2 RNHCH2CH2CH2OH HO O O propano-3-lactone OH O 1 β-propiolactone H O 2 β α cyclic ester β α 3 2 EtO O O propano-3-lactam NH2 NH ether β-propiolactam EtOH cyclic amide β α β α (antibiotics) O O S propano-3-thiolactone [2+2] S C β-propiothiolactone cycloaddition cyclic thioester C C H3C Ph H3C Ph Ph Ph Ph Ph HY O O Nu O Nu Y YH Nu H Nu H Some important derivatives β-Lactam antibiotics • Penicillins • Cephalosporins Antibiotics: natural compounds produced either by microorganisms (e.g., fungi), or by a higher organism against other microorganisms (e.g., bacteria) to block the life and reproduction of the bacteria. Antibiotics are efficient in low concentration. β-lactame ring of penicillins is sensitive to acids, bases, or penicillinase enzyme. Nowadays penicillins with broad therapeutic range also exist (see microbiology). Cephalosporins (1948) makes the other main group of the β-lactame antibiotics. These are resistent to penicillinase enzyme. The bacterium produces penicillinase/cephalosporinase enzyme in order to be resistent against the given penicillin/cephalosporin derivative. Thus, newer and newer penicil- lin/cephalosporin derivatives must be synthesized. Their total synthesis is possible, but it would be too expensive, thus new derivatives are produced by semisynthetic me- thods. The fermentation processes are combined by chemical methods (beginning of biotechnology). Clavulanic acid: inhibitor of the β-lactamase with low antibiotic effect. Clavulanic acid is produced by Streptomyces clavurigeus (the same fungus also produces penicillin as well as cephamycin). Augmentin® contains amoxycillin and potassium clavulanate. β -Lactam antibiotics Basic skeletons azetidine + thiazolidine azetidine + [1,3]thiazidine 1 1 6 5 7 6 S 2 S 2 7 8 N 3 N 3 4 5 O O 4 penam cepham lactam lactam Penicillium notatum Cefalosporium acremonium 6-aminopenicillinic acid 7-aminocephalosporinic acid H H 1 H H 1 H2N 2 H2N 5 S CH3 6-APS 7-ACS 6 S 2 6 6-APA 7-ACA 7 CH3 7 penicillinase enzyme cephalosporinase enzyme 8 N OH N O CH3 4 3 5 3 O cleaves cleaves O 4 O O penicillins "-cillin" cephalosporins "ceph(a)-" O OH O NH2 O H H H H CH2 C N CH C N 3 6 7 CH3 benzylpenicillin cephalexin G-penicillin O O H H H H S N N O CH3 3 7 N 6 O CH O oxacillin 3 cephalotin O N OH H O RNH COOH RNHX S Y CH3 Clavulanic acid N CH3 N Z O COOH O Penicillins COOH Cephalosporins (X=H, Y=S) NH Cephamycins (X=OCH3, Y=S) OH O β -Lactam skeleton H3C Y Z RNH N OH O O COOH N P O K H C Y O Penems (Y=S) 3 OCH NHR 3 Carbapenems (Y=CH2) N S 2-Azetidinon-1-phosphonate O COOH Thienamycin (R=H) RNHX N SO2O K O Monobactams Five-membered heterocycles with one heteroatom and their derivatives with condensed ring systems I/ Furan and its derivatives Nomenclature CH O O O O O C furan α-furyl- β-furyl- α-furfurylidene- α-furoyl- Preparation 1/ By Paal-Knorr synthesis from