Lecture notes Heterocyclic Chemistry

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Published Date:09-07-2017
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Heterocyclic Chemistry Heterocyclic Chemistry Professor J. Stephen Clark Room C4-04 Email: stephencchem.gla.ac.uk 2011–2012 1 http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.htmlRecommended 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 2Course 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 3 • Electrophilic and nucleophilic substitution quinolines and isoquinolines • General methods used for the synthesis of quinolines and isoquinolinesCourse 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 • Electrophilic substitution reactions of pyrroles, furans and thiophenes • Strategies for accomplishing regiocontrol during electrophilic substitution • Metallation of five-membered heteroaromatics and use the of directing groups Indoles • Comparison of electronic structure and reactivity of indoles to that of pyrroles • Fisher and Bischler indole syntheses • Reactions of indoles with electrophiles • Mannich reaction of indoles to give 3-substituted indoles (gramines) • Modification of Mannich products to give various 3-substituted indoles 1,2 and 1,3-Azoles • Structure and reactivity of 1,2- and 1,3-azoles • Synthesis and reactions of imidazoles, oxazoles and thiazoles • Synthesis and reactions of pyrazoles, isoxazoles and isothiazoles 4- - Introduction • Heterocycles contain one or more heteroatoms in a ring Z X X X Y Y carbocycle heterocycles X, Y, Z are usually O, N or S • Aromatic, or partially or fully saturated – this course will focus on aromatic systems • Heterocycles are important and a large proportion of natural products contain them • Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit • Heterocyclic systems are important building-blocks for new materials possessing interesting electronic, mechanical or biological properties 5Classification – Aromatic Six-Membered Isoelectronic carbocycle Heterocycles 4 4 3 5 3 5 1 2 6 2 6 N O 1 X pyridine pyrylium 4 4 4 N N 3 5 3 5 3 5 2 N 6 2 6 2 6 N N N 1 1 1 pyridazine pyrimidine pyrazine 4 5 4 5 3 6 3 6 2 7 2 N 7 N 1 8 1 8 quinoline isoquinoline 6Classification – Aromatic Five-Membered Isoelectronic carbocycle Heterocycles 3 4 3 4 3 4 2 1 5 2 5 2 5 N O S 1 1 H pyrrole furan thiophene 3 4 3 4 3 4 N N N 2 1 5 2 5 2 5 N O S 1 1 H imidazole oxazole thiazole 3 4 3 4 3 4 2 N 1 5 2 N 5 2 N 5 N O S 1 1 H pyrazole isoxazole isothiazole 4 5 3 6 2 1 N 7 7 H indoleClassification – Unsaturated / Saturated Unsaturated O O aromatic dipolar resonance form O O 4(γ γ)-pyrone γ γ N O N O N OH H H 2-pyridone Saturated O O O O N O H ethylene oxide THF 1,4-dioxan pyrrolidine dihydropyran 8- - Functional Group Chemistry Imine Formation 3 3 R R 3 O N N R NH H 2 1 2 1 2 1 2 H O R R 3 R R R R H H H H 3 H R H H 3 3 O N R N OH R N OH 2 1 2 1 2 1 2 1 2 R R R R R R R R • Removal of water is usually required to drive the reaction to completion • If a dialkylamine is used, the iminium ion that is formed can’t lose a proton and an enamine is formed 9Functional Group Chemistry Enols and Enolates O OH O B O O H 1 1 1 1 1 R R E R H R R 2 2 2 2 2 R R R R R keto form enol form enolate 2 • The enol form is favoured by a conjugating group R e.g. CO R, COR, CN, NO etc. 2 2 • Avoid confusing enols (generated under neutral/acidic conditions) with enolates (generated under basic conditions) • Enolates are nucleophilic through C or O but react with C electrophiles through C 3 3 Enol Ethers R O OR 1 R 3 R OH 3 2 R R 3 OR O acetal 1 1 R H R 2 2 R R O H O 2 enol ether 1 R 10 2 RFunctional Group Chemistry Enamines 3 3 3 3 3 3 R R R R R R N N O N H H H 1 1 1 R R H R 2 2 2 R R R iminium ion enamine (Schiff base) 3 3 3 3 R R R R N N O H O 2 E E 1 1 1 R R R E 2 2 2 R R R • Analogues of enols but are more nucleophilic and can function as enolate equivalents • Removal of water (e.g. by distillation or trapping) drives reaction to completion • Enamines react readily with carbon nucleophiles at carbon • Reaction at N is possible but usually reverses 11- - - Functional Group Chemistry Common Building-Blocks O O NH R R R OH NH NH 2 2 amides amidines carboxylic acids O NH O O O O 1 1 2 2 H N NH H N NH R R R OR 2 2 2 2 urea guanidine β-diketones β-keto esters Building-Blocks for Sulfur-Containing Heterocycles O S 1 2 P S 2 5 R R R SH S 1 2 1 2 R R R R thioketones thiols thioethers • Heterocycle synthesis requires: C O or C N bond formation using imines, enamines, acetals, enols, enol ethers C C bond formation using enols, enolates, enamines • During heterocycle synthesis, equilibrium is driven to the product side because of removal of water, crystallisation of product and product stability (aromaticity) 12- - - - - - General Strategies for Heterocycle Synthesis Ring Construction • Cyclisation – 5- and 6-membered rings are the easiest to form • C X bond formation requires a heteroatom nucleophile to react with a C electrophile Y Y δ δ δ+ δ+ conjugate addition δ+ X X X, Y = O, S, NR Manipulation of Oxidation State O O O or H H H 2 2 2 X X X X X hexahydro tetrahydro dihydro aromatic • Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation 13- - - - General Strategies for Heterocycle Synthesis Common Strategies “4+1” Strategy X X H N N NH NH 3 3 2H O 2H O 2 2 N N O O O O H H • Strategy can be adapted to incorporate more than one heteroatom “5+1” Strategy X X H NH O 3 2H O H 2 2 N N O O H 14 • 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones- - - - - - General Strategies for Heterocycle Synthesis “3+2” Strategy “3+3” Strategy or or X X X X X X Examples δ δ δ δ X H N H N O H N OH 2 2 2 O δ+ δ δ+ δ X H N O OH 2 Hal δ+ δ+ O Hal = Cl, Br, I δ+ δ+ O O E E 15 NH NH OH OH 2 2Bioactive Pyridines H N N N S NH H 2 H O O N sulphapyridine nicotine • Nicotine is pharmacologically active constituent of tobacco – toxic and addictive • Sulphapyridine is a sulfonamide anti-bacterial agent – one of the oldest antibiotics NH 2 O NH Me N N Me N isoniazide paraquat • Paraquat is one of the oldest herbicides – toxic and non-selective • Isoniazide has been an important agent to treat tuberculosis – still used, but resistance 16 is a significant and growing problem Drugs Containing a Pyridine MeO O O OMe O OMe N N S S N N H H N N Name: Nexium Name: Aciphex 2008 Sales: 4.79 billion 2008 Sales: 1.05 billion 2008 Ranking: 2 branded 2008 Ranking: 34 branded Company: AstraZeneca Company: Eisai Disease: Acid reflux Disease: Duodenal ulcers and acid reflux H N N S O N NH O N O HN N N O N Name: Actos Name: Gleevec 2008 Sales: 2.45 billion 2008 Sales: 0.45 billion 2008 Ranking: 10 branded 2008 Ranking: 87 branded Company: Eli Lilly Company: Novartis 17 Disease: Type 2 diabetes Disease: Chronic myeloid leukemia - - - Pyridines – Structure 1.40 Å 1.39 Å 2.2 D 1.17 D 1.34 Å N N N .. H • Isoelectronic with and analogous to benzene • Stable, not easily oxidised at C, undergoes substitution rather than addition • I Effect (inductive electron withdrawal) • M Effect δ+ δ+ δ+ N N N N N δ • Weakly basic – pK 5.2 in H O (lone pair is not in aromatic sextet) a 2 • Pyridinium salts are also aromatic – ring carbons are more δ+ than in parent pyridine etc. N N N 18 H H H Pyridines – Synthesis The Hantzsch synthesis (“5+1”) Ph H O O O Ph O O O H Ph O Me Me Me Me Me Me NH pH 8.5 3 Me O O Me Me O O Me Me Me aldol condensation Michael addition O O and dehydration O Ph O O O O O H Ph H Ph Me Me Me Me Me Me HNO 3 Me Me N Me oxidation Me N Me O Me H N 2 H • The reaction is useful for the synthesis of symmetrical pyridines • The 1,5-diketone intermediate can be isolated in certain circumstances • A separate oxidation reaction is required to aromatise the dihydropyridine 19- Pyridines – Synthesis From Enamines or Enamine Equivalents – the Guareschi synthesis (“3+3”) CN CN CO Et CO Et Me 2 2 CN CN O H N O H N Me 2 2 K CO K CO 2 3 2 3 Me N O Me O EtO C N Me 2 H 73% • The β-cyano amide can exist in the ‘enol’ form Using Cycloaddition Reactions (“4+2”) CO H 2 CO H CO H 2 2 H H Me Me Me + O H H O O N Diels-Alder Me N Me N Me cycloaddition CO H 2 H CO H 2 HO Me Me H O 2 Me N Me N 70% • Oxazoles are sufficiently low in aromatic character to react in the Diels-Alder reaction 20