B.Sc. Semester-IV Core Course-IX (CC-IX) Organic Chemistry-III III. Heterocyclic Compounds 21. Furan, Pyrrole and Thiophene : Methods For Synthesis Dr. Rajeev Ranjan University Department of Chemistry Dr. Shyama Prasad Mukherjee University, Ranchi Heterocyclic Compounds 22 Lectures Classification and nomenclature, Structure, aromaticity in 5-numbered and 6-membered rings containing one heteroatom; Synthesis, reactions and mechanism of substitution reactions of: Furan, Pyrrole (Paal-Knorr synthesis, Knorr pyrrole synthesis, Hantzsch synthesis), Thiophene, Pyridine (Hantzsch synthesis), Pyrimidine, Structure elucidation of indole, Fischer indole synthesis and Madelung synthesis), Structure elucidation of quinoline and isoquinoline, Skraup synthesis, Friedlander’s synthesis, Knorr quinoline synthesis, Doebner- Miller synthesis, Bischler-Napieralski reaction, Pictet-Spengler reaction, Pomeranz-Fritsch reaction Derivatives of furan: Furfural and furoic acid. Coverage: 1. Furan, Pyrrole and Thiophene : Methods For Synthesis 2 Furans, Pyrroles and Thiophenes – Structure Structure X O N S .. H • 6 electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion Resonance Structures etc. X X X X .. + • Electron donation into the ring by resonance but inductive electron withdrawal 1.44 Å 1.43 Å 1.42 Å 1.35 Å 1.37 Å 1.37 Å 0.71 D 1.55 D 0.52 D 1.37 Å O 1.38 Å N 1.71 Å S H 1.68 D 1.57 D 1.87 D O N S H • O and S are more electronegative than N and so inductive effects dominate Dr. Rajeev Ranjan 3 Furans – Synthesis Paal Knorr Synthesis R1 R2 R1 R2 R1 R2 O O O O O OH H H H H heat H H R1 R2 R1 R2 R1 R2 O O O OH2 • The reaction is usually reversible and can be used to convert furans into 1,4-diketones • A trace of acid is required – usually TsOH (p-MeC6H4SO3H) Dr. Rajeev Ranjan 4 Furans – Synthesis Feist-Benary Synthesis (“3+2”) Me O EtO2C O + Me EtO2C O Me EtO2C + Cl Me O Cl Me O Cl Me O NaOH aq., rt OH Me OH Me EtO2C Me EtO2C H OH EtO2C Cl H2O Me Me O O Me O isolable • The product prior to dehydration can be isolated under certain circumstances • Reaction can be tuned by changing the reaction conditions Dr. Rajeev Ranjan 5 Furans – Synthesis Modified Feist-Benary I EtO2C O + Me EtO2C Me EtO2C Me + O O Me O Cl Me O Me O I NaI, NaOEt, EtOH EtO EtO2C EtO2C H EtO2C Me H2O Me O Me Me Me O O OH Me O • Iodide is a better leaving group than Cl and the carbon becomes more electrophilic • The Paal Knorr sequence is followed from the 1,4-diketone onwards • The regiochemical outcome of the reaction is completely altered by addition of iodide Dr. Rajeev Ranjan 6 Thiophenes – Synthesis Synthesis of Thiophenes by Paal Knorr type reaction (“4+1”) Me Me Me Me Ph P4S10 S O Me Ph Me Me Ph O O S Me Ph O S • Reaction might occur via the 1,4-bis-thioketone Dr. Rajeev Ranjan 7 Thiophenes – Synthesis Paal Knorr Synthesis (“4+1”) Me Me Me Me Me Me O O O HN O H2N NH3, C6H6, heat H H Me Me R1 R2 R1 R2 N N N H H OH H • Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole Dr. Rajeev Ranjan 8 Pyrroles – Synthesis Knorr Pyrrole Synthesis (“3+2”) EtO2C Me EtO2C O Me KOH aq. HO2C MeO2C O NH2 N H 53% H2N O Me Me N Me O NH2 N Me • Use of a free amino ketone is problematic – dimerisation gives a dihydropyrazine HO Me EtO2C Me EtO2C O Me EtO2C EtO2C O Me NaOH aq. via or NH2 EtO2C EtO2C O NH3 Cl N EtO2 C O EtO2C N H H • Problem can be overcome by storing amino carbonyl compound in a protected form • Reactive methylene partner required so that pyrrole formation occurs more rapidly than dimer formation Dr. Rajeev Ranjan 9 Pyrroles – Synthesis Liberation of an Amino Ketone in situ by Oxime Reduction EtO2C Me EtO2C O Me Zn, AcOH or Na S O aq. 2 2 4 Me Me O N (sodium dithionite) N H OH Preparation of -Keto Oximes from -Dicarbonyl Compounds H O O O O NaNO2, H (HNO2) OEt OEt H2O N O O O O O H OEt OEt N N OH O Dr. Rajeev Ranjan 10 Pyrroles – Synthesis One-Pot Oxime Reduction and Pyrrole Formation O O O CO2Et EtO2C CO2Et OEt Zn, AcOH EtO C 2 N N H OH CO2Et Hantzsch Synthesis of Pyrroles (“3+2”) Cl H EtO2C O + Me EtO2C Me EtO2C Me + O O Me O Cl Me NH2 Me NH NH3 aq. rt to 60 °C EtO2C EtO2C EtO2C Me H2O Me Me Me Me O N N OH Me NH2 H H 41% • A modified version of the Feist-Benary synthesis and using the same starting materials: an -halo carbonyl compound and a -keto ester Dr. Rajeev Ranjan Thank You 11.