CHI552 Heterocyclic Chemistry - Lecture Slides

3A-CHI552 Organisation of the cours 4 lessons in 5 lessons in advanced advanced organometallic heterocyclic chemistry chemistry Dr. Sophie Carenco Dr. Samir Messaoudi...

3A-CHI552 Organisation of the cours 4 lessons in 5 lessons in advanced advanced organometallic heterocyclic chemistry chemistry Dr. Sophie Carenco Dr. Samir Messaoudi 1  3A-CHI552 Heterocyclic Chemistry Course Objectives Knowledges on the most important heterocyclic families, their preparation and reactivity ✔ Naming heterocycles ✔ Reactivity trends in aromatic heterocycles ✔ Focus on synthetic approaches ✔ Medicinal and agrochemical applications 2  3A-CHI552 Heterocyclic Chemistry Organization of the courses: 4 lessons of 2 h 4x2 h exercices Evaluation at the end Knowledges: basic organic chemistry (CHI421) 3  3A-CHI552 Heterocyclic Chemistry 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 4  3A-CHI552 Heterocyclic Chemistry Course Summary I. Introduction Why are heterocycles so important? Definition of terms and classification of heterocycles (monocyclic and fused heterocycles, aromatics and non-aromatics, saturated and unsaturated…etc) II. Pyridines and derivatives III. Pyrroles, furans and thiophens IV. Indoles (and azaindoles) Associated documents :  Courses (oral and slides)  PC (exercices and corrections) 5  3A-CHI552 Heterocyclic Chemistry Course Summary I. Introduction Why are heterocycles so important? Definition of terms and classification of heterocycles (monocyclic and fused heterocycles, aromatics and non-aromatics, saturated and unsaturated…etc) II. Pyridines and derivatives III. Pyrroles, furans and thiophens IV. Indoles (and azaindoles) 6  Introduct Classification and naming ion Aromatic Five- Membered Aromatic Six- Membered Fused heterocycles 7  Introduct Classification and naming ion Aromatic Five- Membered Aromatic Six- Membered Fused heterocycles 8  Introduct Classification and naming ion Aromatic Five- Membered Aromatic Six- Membered Fused heterocycles H N O H N O Non aromatics N N H H O (saturated) 9  Introduct Classification and naming ion Aromatic Five- Membered Aromatic Six- Membered Fused heterocycles H N O H N O N N H H O Non aromatics Pyrrolidine Piperidine ethylene oxide Pepirazine tetrahydropyran Chroman (saturated) 10  Introduct Classification and naming ion R=H A >> B Unsaturated R = Cl B > A non polar solvent 1,2-oxazol-5-one A >> B,C 11  Introduct Classification and naming ion R=H A >> B R = Cl B > A non polar solvent Unsaturated Non aromatics (saturated) 12  Introduct Why are heterocycles so important? ion Medecine and crop protection: Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit ▪ relatively stable compounds (towards acid and enzymatic hydrolysis- compatible with the gastrointestinal track) ▪ pharmacokinetic: use of acido-basic couples ( AH +/A ) to optimise drug distribution ▪ Interaction with the receptors (H bonds…) ▪ structure close to products involved in many natural biological pathways (indoles, pyrimidine…) ▪ Easy preparation and low cost Heterocyclic systems are important building-blocks for new materials possessing interesting electronic propreties 13  Introduct Why are heterocycles so important? ion Living systems: nucleic acids contain pyrimidines (T, U, C) and purines (A,G) heterocycles 14  Introduct Why are heterocycles so important? ion Nucleic acids: DNA (DeoxyriboNucleic Acid ) double strand: (A, T, C, G) heterocycles + ribose (sugar heterocycle) 15  Introduct Why are heterocycles so important? ion Nucleic acids: RNA Vaccine 16  Introduct Why are heterocycles so important? ion Nucleic acids: RNA Vaccine 17  Introduct Why are heterocycles so important? ion Nucleic acids: RNA Vaccine The strategy for active RNA vaccine Uridine to pseudouridine 18  Introduct Why are heterocycles so important? ion Tryptophan and histidine in proteins prote Tryptoph in Histidi an ne 19 Drugs containing Top Drugs by retail sales in 2022 heterocycles 20 Naming heterocycles: Hantzsch and Widman system for monocyclic structures Proposed by Hantzsch (1887) and Widman (1888) for N cycles with 5 et 6 atoms, extended in 1940 (Patterson and Campbell) and finally adopted by IUPAC (1957). Prefix + suffix Nature of Size of the the ring heteroato ms 1°) Find the right prefix with the priority order of the table: Oxygen Sulphur Selenium Nitrogen Phosphorus Silicium Bore Oxa Thia Selena Aza Suppress Phosphathe final Sila "a" when the prefix is followed by a vowel Bora Use priorities to number position of heteroatoms in the cycle 21 Naming heterocycles: Hantzsch and Widman system for monocyclic structures 2°) Suffix according to length of the cycle and degree of saturation: * replaced by "ane" if immediatly after: ox, thi, selen ou tellur Aza + iridine 1,3- = dioxolane aziridine 22 Naming heterocycles: Hantzsch and Widman system for monocyclic structures 3°) Partially saturated heterocycles and structural isomeres - From the unsaturated systems (usual name or HW) indicate double bonds by using dihydro, tetrahydro. - Remaining H are numbered in order to differentiate structural isomeres : ? Oxa (1)-aza (3) ine = 1,3-Oxazine (rotation choosen to minimize the substituents position numbers) 2H-1,3-Oxazine 2H-1,3-Oxazine 5,6-dihydro-2H-1,3- oxazine 23 Naming heterocycles: Hantzsch and Widman system for monocyclic structures 4) aromatic ring tethered to heterocycles -Place before the name of the heterocycle the prefix benzo followed by a letter eg [x] to indicate the bond belonging to both cycles: 2H-1,3- 2H-1,3- oxazine benz[e]oxazine -Numbering: write the structure on an horizontal line with the heterocycle on the right. The first upper side atom of the heterocyclique next to the benzene ring is numbered 1. 1,2- Benzo[c]thiazepi 24 ne Aromatic Heterocycles: Huckel 25  Aromatic Heterocycles: Huckel - Many tautomeric forms: 2-pyridone: 26  Aromatic Heterocycles: Huckel - Many tautomeric forms: 2-pyridone: 27  Aromatic Heterocycles: Huckel - Many tautomeric forms: 2-pyridone: 28  Aromatic Heterocycles: Reactivity and regiochemistry Less reactive than benzene towards electrophiles Much more reactive than benzene Nitration ( 300°C) at position 3 with HNO 3/H2SO4 Diazonium salts addition at rt. at position 2 - Uses of mesomeric forms often limited to understand the reactivity: Attack at 3 Attack at 2 29  Aromatic Heterocycles : Pyrrole Molecular Orbital Diagram Pi orbitals Pyrrole Benzene Energie a Y3 = a + 0.6b (-8.2 eV) NH Y2 = Y3 = a + b (-9.2 eV) Y2 = a + 1.1b 1.090 1.087 N Y1 =a + 2b H 1.647 Y1 = a + 2.4b p electron density Electron rich heterocycle (reactivity close to dimethoxybenzenes) α: energy of an electron in the 2p AO β: energy of resonance integral (corresponds to the stabilization resulting from overlap and bonding, covalent pi bonding). 30  Aromatic heterocycles : Pyridine Molecular Orbital Diagram Pyridin Pi orbitals Benzene e Energie a N Y3 a+b a + 1.2b 0.976 a + 1.4b 1.004 0.988 N a + 2b 1.048 a + 2.1b p electron density Electron poor heterocycle (reactivity close to nitrobenzene) 31  Aromatic heterocycles : Pyridine Molecular Orbital Diagram Pyridin Pi orbitals Benzene e Electron poor heterocycle (reactivity close to nitrobenzene) 32  Aromatic heterocycles : electron pairs on N Pyridine: the electron pair is not shared with the π system Pyrrole: the electron pair is conjugated and poorly available Basicity and dipolar strenght: Interaction of the N electron pair of pyridine with electrophiles (M+, C+…) Reactivity of pyridines towards nucleophiles raised 1 Debye = 3,335 64 × 10−30 C m (Colomb meter) 33  Aromatic heterocycles : general trends Heterocycles with more than one heteroatom? 34  Aromatic heterocycles : Aromaticity? How much are the aromatic heterocycles stabilized ?: The bonding energies, E, at 25°C of compounds CmHnOP are evaluated using the heats of A classic scale: - Dewar resonance energy (DRE) formulation of gaseous carbon, hydrogen, and oxygen atoms, and the AHf, of the compound: E = m ΔHf (C.) + n ΔHf (H.) + p ΔHf (O) - ΔHf (CmHnOP) Ref. N. C. Baird, Canadian J. Chem, 1969 , 47 If cyclic systems with zero DRE are defined as non-aromatic, then a positive DRE value for a molecule indicates that it is aromatic, and a negative DRE indicates that it is anti-aromatic. 35  Aromatiques heterocycles : Aromaticity General trends: Pyridine: electron poor but highly stabilized: ex no reaction with NaBH4 (Cf pyridinium) Thiophene, pyrrole and most of all furan limited stability, easy electrophiles additions, Easy loss of aromaticity in furan reations. Stability of benzothiophene, indole and benzofuran linked to the benzo cycle, Nucleophilic behavior close to enamines, enols, thioethers… Pyrazoles, imidazoles…very stable. 36  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 Manipulation of Oxidation State Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation 37  General Strategies for Heterocycle Synthesis Common Strategies “4+1” Strategy Strategy can be adapted to incorporate more than one heteroatom “5+1” Strategy Unsa1,5-Dicarbonyl compounds can be prepared by Michael addition of enones 38  General Strategies for Heterocycle Synthesis “3+2” Strategy “3+3” Strategy selected examples 39  Aromatic Heterocycles : Metallation Het-Br (Het-I) + R-M Het-M : M = Li, Mg, Zn… Het-H + R-M (M =Li) Generally more acidic H for 5-membered ring aromatic cycles ( similar to orthometallation effect in all carbon aromatic systems) Arroyo, Tetrahedron Lett., 2002, 43, 9129 40  Aromatic heterocycles : Metallation Application: indoles formation: 1,3-heterocycles: Benzothiazole as analogue of a formyl group: Beware of the acidity of alkyl groups at 2 position: Evans, Org. Lett., 1999, 1, 87 41  Aromatic Heterocycles : Metallation Metallation of electron poor heterocycles : - Less usefull and more difficult to control - Addition onto the heterocycle/deprotonation - LDA/nBuLi - Low temperatures to avoid homocoupling Use of superbases LD A (nBuLi+ROLi): nBuLi/Et2N(CH2)2OLi Rodriguez, Tet.Asymm., 2001, 2631 Easier formation with metal/halogen exchange or use of a strong ortho directing group: Guéguiner, Tetrahedron, 2002, 2743 42 Aromatic Heterocycles : Palladium Couplings (Heck, Suzuki, Stille, Sonogashira…) Very useful access to functionalised heterocycles: Two traditional approaches 1) Direct metallation with RLi followed by transmetallation... 2) Use of iodo, bromo heterocycles (by metallationor or else) followed by transmetallation More recent approaches 3) CH activation processes: a Pd(II) activation of a CH bond followed by Heck type addition or Arylation, 43 ( Cooxydant necessary)  Palladium Cross Coupling Reactions Tamejiro Ei-ichi Hiyama Suzuki Richard Victor Heck Sniekus Robert Makoto Corriu Kumada John Stille Stephan John F. 44 Buchwald Hartwig Palladium Cross Coupling Reactions 45  Traditional Cross Coupling Reaction Limitation: organometallics R-M in a stochiometric amount 46 Traditional Cross Coupling Reaction 47  Traditional Cross Coupling Reaction Concerted Metalation-Deprotonation (CMD) Mechanism 48  3A-CHI552 Heterocyclic Chemistry Course Summary I. Introduction Why are heterocycles so important? Definition of terms and classification of heterocycles (monocyclic and fused heterocycles, aromatics and non-aromatics, saturated and unsaturated…etc) II. Pyridines, quinoline, isoquinolines and derivatives III. Pyrroles, furans and thiophens IV. Indoles 49  PYRIDINES, QUINOLINES: Biological interest Many FDA approved drugs used in pharma et agro Isoniazide has been an important agent to treat tuberculosis – still used, but resistance is a significant and growing problem Actos, diabetes type 2, Eli Gleevec, Leukemia, Lilly Novartis 50  PYRIDINES, QUINOLINES: Biological interest Many FDA approved drugs used in pharma et agro Isoniazide has been an important agent Paraquat is one of the oldest to treat tuberculosis – still used, but herbicides resistance toxic and non-selective is a significant and growing problem Many natural compounds : Nicotine is pharmacologically active constituent of tobacco-toxic and addictive 51  PYRIDINES: biological activity NAD+/NADH Redox type Coenzymes (ternary complex formation) : - Oxydation by P450 cytochrome (metabolism) - Reduction of pyruvic acid to (L)-lactic acid, acetaldehyde to ethanol… 52 Most important heterocyclic synthesis: pyridines How to synthesize pyridines? 53 Most important heterocyclic synthesis: pyridines Hantzsc h (1882) 54 Most important heterocyclic synthesis: pyridines Hantzsc h (1882) 55 Most important heterocyclic synthesis: pyridines / Hantzsc h (1882) 56 Most important heterocyclic synthesis: pyridines Hantzsc h (1882) 57  Most important heterocyclic synthesis: pyridines Conversion of Aryl Azides to Aminopyridines J. Am. Chem. Soc. 2022, 144, 17797 58  Most important heterocyclic synthesis: pyridines Conversion of Aryl Azides to Aminopyridines J. Am. Chem. Soc. 2022, 144, 17797 59  Most important heterocyclic synthesis: pyridines Conversion of Aryl Azides to Aminopyridines: Ipso-Selective Nitrene Internalization Mark Levin et all, Science. 2023, 381(6665), 1474-1479.7 60  PYRIDINES: Reactivity Electrophilic Reactions Regiochemical Outcome of Electrophilic Substitution of Pyridines - Resonance forms with a positive charge on N (i.e. 6 electrons) are very unfavourable - The β-substituted intermediate, and the transition state leading to this product, have more stable resonance forms than the intermediates/transition states leading to the α /γ products 61  PYRIDINES: Reactivity Electrophilic Reactions Regiochemical Outcome of Electrophilic Substitution of Pyridinium salts Regiochemical control is even more pronounced in the case of pyridinium ions In both pyridine and pyridinium systems, β substitution is favoured but the reaction is slower than that of benzene Reaction will usually proceed through the small amount of the free pyridine available 62  PYRIDINES: Reactivity Electrophilic Reactions N- Substitution Reaction at C (C Substitution) is usually difficult and slow, requiring forcing conditions Friedel-Crafts reactions are not usually possible on free pyridines 63  PYRIDINES: Reactivity Electrophilic Reactions Nitration Multiple electron-donating groups Multiple electron-donating groups Multiple electron-donating groups accelerate the reaction Both reactions proceed at similar rates which indicates that the protonation at N occurs prior to nitration in the first case 64  PYRIDINES: Reactivity Electrophilic Reactions Halogenation Forcing reaction conditions are required for direct halogenation 65  PYRIDINES: Reactivity Electrophilic Reactions Halogenation Forcing reaction conditions are required for direct halogenation 66  PYRIDINES: Reactivity Electrophilic Reactions Reduction Birch reduction? Full or Partial Reduction of Pyridines Full or partial reduction of the ring is usually easier than in the case of benzene 67  PYRIDINES: Reactivity Nucleophilic Reactions Regiochemical Outcome of Nucleophilic Addition to Pyridines ? Mechanism: addition-elimination 68  PYRIDINES: Reactivity Nucleophilic Reactions Regiochemical Outcome of Nucleophilic Addition to Pyridines Nitrogen acts as an electron sink b Substitution is less favoured because there are no stable resonance forms with the negative charge on N Aromaticity will is regained by loss of hydride or a leaving group, or by oxidation 69  PYRIDINES: Reactivity Nucleophilic Reactions Nucleophilic Substitution Favoured by electron-withdrawing substituents that are also good leaving groups The position of the leaving group influences reaction rate (γ > α >> β) 70  PYRIDINES: Reactivity Nucleophilic Reactions Nucleophilic Substitution Favored by electron-withdrawing substituents that are also good leaving groups The position of the leaving group influences reaction rate (γ > α >> β) 71  PYRIDINES: Reactivity Nucleophilic Reactions: pyridine versus pyridinium Nucleophilic Substitution Conversion of a pyridine into the pyridinium salt greatly accelerates substitution Substituent effects remain the same (γ, α >> β) but now (α > γ) 72  PYRIDINES: Reactivity Nucleophilic Reactions: via a Pyridyne Intermediate When very basic nucleophiles are used, a pyridyne intermediate intervenes Pyridynes are similar to benzynes and are very reactive (not isolable) Pyridy ne 73  PYRIDINES: Reactivity Nucleophilic Reactions: with a Hydride transfert A hydride acceptor or oxidizing agent is required to regenerate aromaticity Amination a of Py Chichibabin reaction 74  PYRIDINES: Reactivity Metal-Halogen Exchange Direct Exchange of Metal and a Halogen Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl lithium or alkyl magnesium reagents Metallated pyridines behave like conventional Grignard reagents 75  PYRIDINES: Reactivity Direct metallation Use of Directing Groups Directing groups allow direct lithiation at an adjacent position Directing Groups A Lewis basic group is required to complex the Lewis acidic metal of the base 76  PYRIDINES: Reactivity Oxy-amino-Pyridines: new reactivity? Subject to tautomerism The α, γ systems differ from the b systems in terms of reactivity and structure In the α case, the equilibrium is highly solvent dependent, but the keto form is favored in polar solvents 77 Amino pyridines are polarized in the opposite direction to oxy-pyridines  PYRIDINES: Reactivity Oxy-Pyridines: new reactivity? Electrophilic Substitution Reactions such as halogenation, nitration, sulfonation etc. are possible N is much less basic than that in a simple pyridine Substitution occurs ortho or para to the oxygen substituent (cf. phenols) 78  PYRIDINES: Reactivity Oxy-Pyridines: new reactivity? Nucleophilic Substitution Replacement of the oxygen substituent is possible The driving force of the reaction is the formation of the very strong P=O bond Appel Reaction (Rolf Appel) 79  PYRIDINES: Reactivity Alkyl-Pyridines: new reactivity? Deprotonation with a Strong Base Deprotonation of a and g alkyl groups proceeds at a similar rate, but b alkyl groups are much more difficult to deprotonate 80  PYRIDINES: Reactivity N-Oxide-Pyridines: new reactivity? Formation m- CPBA The reactivity N-oxides differs considerably from that of pyridines or pyridinium salts A variety of peracids can be used to oxidize N but m-CPBA is used most commonly N-Oxide formation can be used to temporarily activate the pyridine ring to both nucleophilic and electrophilic attack 81  PYRIDINES: Reactivity N-Oxide-Pyridines: reactivity m- CPBA The N-oxide is activated to attack by electrophiles at both the α and γ positions Nitration of an N-oxide is easier than nitration of the parent pyridine Reactivity is similar to that of a pyridinium salt in many cases e.g. nucleophilic attack, deprotonation of alkyl groups etc. 82  PYRIDINES: Reactivity N-Oxide-Pyridines: Reactivity The reactivity N-oxides differs considerably from that of pyridines or pyridinium salts A variety of peracids can be used to oxidize N but m-CPBA is used most commonly N-Oxide formation can be used to temporarily activate the pyridine ring to both nucleophilic and electrophilic attack Removal of O (reduction with phosphines) 83  PYRIDINES: Reactivity N-Oxide-Pyridines: Reactivity Adv. Synth. Catal.2014, 84 356, 2375  3A-CHI552 Heterocyclic Chemistry Course Summary I. Introduction Why are heterocycles so important? Definition of terms and classification of heterocycles (monocyclic and fused heterocycles, aromatics and non-aromatics, saturated and unsaturated…etc) II. Pyridines, quinoline, isoquinolines derivatives III. Pyrroles, furans and thiophens IV. Indoles 85 Why quinolines? 86  Drugs Containing a Quinoline/Isoquinoline Anticancers, Leukemia, Quinoline-based organic light-emitting diodes (OLEDs) Hydroxychloroquine -((sales 74 million 2008 ), Malaria, rheumatoid arthritis, …etc an opium alkaloid antispasmodic drug (visceral spasms and vasospasms) 8 Opium 7 Quinoline/Isoquinoline How to synthesize a quinoline heterocycle? 88  Quinoline/Isoquinoline Structur e N N H pKa values 4.9 and 5.4 5.25 0.4 8 9  Quinoline: methods of synthesis Structur e N N H pKa values 4.9 and 5.4 5.25 0.4 Combes Synthesis 6 3 5 2 4 1 (3+3) strategy 9 0  Quinoline: methods of synthesis Conrad-Limpach-Knorr Synthesis (“3+3”) Very similar to the Combes synthesis by a b-keto ester is used instead of a b-diketone Altering the reaction conditions can completely alter the regiochemical 9 outcome 1  Quinoline: methods of synthesis Skraup Synthesis (“3+3”) OH Acrolein can be H H H generated in situ by H O O treatment of glycerol with conc. sulfuric 130 °C, H2SO4 acid NH2 N N H H H OH [O] (e.g. I2) -H2O N N N 85% H H A mild oxidant is required to form the fully aromatic system from the 1. O Me dihydroquinoline Me Me Me ZnCl2 or FeCl3, NH2 EtOH, reflux N 2. [O] 65% 9 2  Quinoline: methods of synthesis Friedlander Synthesis (“4+2”) Ph Ph Ph O H Me O Me Me O Me -H2O c-H2SO4, AcOH NH2 heat N Me N Me 88% Acidic and basic H The starting acyl conditions deliver aniline can be difficult regioisomeric to prepare products in good yields Ph Ph Ph O Me O O Me -H2O KOH aq., EtOH 0 °C N NH2 N 71% Me Me OH H 9 3  N Isoquinoline: methods of synthesis Pomeranz-Fritsch Synthesis (“3+3”) EtO OEt OEt H2N OEt H , EtOH O H2O N N H 9 4  Isoquinoline: methods of synthesis Pomeranz-Fritsch Synthesis (“3+3”) EtO OEt OEt H2N OEt H , EtOH O H2O N N H Bischler-Napieralski Synthesis (“5+1”) MeCOCl P4O10, heat Pd-C, 190 °C NH2 NH N N O Me Me Me 93% “5+1” Strategy Cyclisation can be Oxidation of the accomplished dihydroisoquinoline using POCl3 or PCl5 can be performed using a mild oxidant 9 5  Isoquinoline: methods of synthesis Pictet Spengler Synthesis (“5+1”) An electron- MeO MeO MeO donating HCHO 20% aq. 20% HCl substituent on the heat aq. 100 NH2 N N carboaromatic ring °C H is required MeO MeO MeO [O] N NH NH 80% H A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the fully aromatic isoquinoline 9 6  Quinolines and Isoquinolines: Reactivity Electrophilic Reactions * Regiochemist ry N N H Under strongly acidic H conditions, reaction occurs via the ammonium salt Attack occurs at the benzo- rather than hetero-ring Reactions are faster than those of pyridine but slower than those of naphthalene NO2 Nitratio n fuming HNO3, N cH2SO4, 0 °C N N 72% 8% NO2 In the case of isoquinoline, 5- and 8-isomers are produced 9 7  Quinolines and Isoquinolines: Reactivity Electrophilic Reactions Sulfonatio n HO3S 30% oleum3, > 250 °C 90 N °C N N SO3H 54% thermodynamic product To be noted: Halogenation is also possible but product distribution is highly dependent on conditions It is possible to introduce halogens into the hetero-ring under the correct conditions Friedel-Crafts alkylation/acylation is not usually possible 9 8  Quinolines and Isoquinolines: Reactivity Nucleophilic Reactions Regiochemist ry N N They are enerally more reactive Attack occurs at than pyridines to nucleophilic hetero- rather than attack benzo-ring 2-MeOC6H4Li H2O Et2O, rt H H N N OMe N OMe Li H Carbon Nucleophiles [O] N 56 MeO 9 9  Quinolines and Isoquinolines: Reactivity Nucleophilic Reactions n-BuLi H2O [O] N benzene, rt N NH N Li H n-Bu H n-Bu n-Bu Oxidation is required to regenerate aromaticity Aminatio H NH2 n KNH2, NH3 (l) >-45 °C -65 H N °C N N KMnO4, -65 °C K NH2 K KMnO4, -40 °C NH2 N NH2 N 50% 60% thermodynamic 1 0 product 0  Quinolines and Isoquinolines: Reactivity Nucleophilic Reactions Displacement of Halogen NaOEt, EtOH reflux Cl N Cl N N OEt OEt OMe Cl OMe NaOMe, Cl MeOH N DMSO 100 N N °C 87% 10 1  Quinolines and Isoquinolines: Reactivity Nucleophilic Reactions The proton adjacent to the cyano group is extremely acidic The reaction works best with highly reactive alkyl halides 10 2  Quinoline/Isoquinoline Synthesis of Papaverine O O MeO MeO O MeO NaOEt, EtOH, rt N NH2 MeO Me Me2CH(CH2)2ONO,MeO ZnCl2, HCl, rt OH MeO 75% O Cl KOH aq., rt H O OMe OH MeO MeO MeO OMe P4H10, Na-Hg, H2O, 50 °C N xylene, heat NH NH O O MeO MeO MeO 30% 60% OMe OMe OMe MeO MeO MeO Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler- Napieralski reaction 1 0