Fransan, pyrunas omeclare of organic compounds.pptx

Fransan and pyrunas molecular nomeclature

1. Bioactive Furans, Pyrroles and Thiophenes N O 2 Me 2 N S O N ranitidine H N HMe • Ranitidine (Zantac®, GSK) is one of the biggest selling drugs in history. It is an H 2 -receptor antagonist and lowers stomach acid levels - used to treat stomach ulcers O N Ph ketorolac C O 2 H • Ketorolac (Toradol®, Roche) is an analgesic and anti-inflammatory drug Me N S banminth N • Pyrantel (Banminth®, Phibro) is an anthelminthic agent and is used to treat worms in livestock 61

2. Drugs Containing a Furan/Thiophene/Pyrrole Me O 2 C N S Cl O 2 N O N N N H O O Name: Plavix 2008 Sales: $3.80 billion 2008 Ranking: 3 branded Company: Bristol-Myers Squibb Disease: Stroke and heart attack risk N H O Name: Nitrofurantoin 2008 Sales: $92 + 72 million 2008 Ranking: 119 and 149 generic Company: N/A Disease: Antibiotic for urinary tract infections F H O 2 C Ph S Name: Cymbalta 2008 Sales: $2.17 billion 2008 Ranking: 14 branded Company: Eli Lilly Disease: Depression H O H O N Name: Lipitor 2008 Sales: $5.88 billion 2008 Ranking: 1 branded Company: Pfizer Disease: Lowers LDL levels N HPh O 62

3. Furans, Pyrroles and Thiophenes - Structure Structure β α X O N H • 6 π electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion Resonance Structures δ− δ− etc. δ− δ− X X X X δ + • 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 S 63

4. Furans - Synthesis Paal Knorr Synthesis R 1 R 1 O O H heat O R 2 R 1 2 R R 1 O O H H H H O R 2 R 2 R 1 R 1 O O H H O O H 2 R 2 R 2 • 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 -MeC 6 H 4 SO 3 H) 64

5. Furans - Synthesis Feist-Benary Synthesis (“3+2”) Et O 2 C O δ + Me δ + Me O Cl NaOH aq., rt Et O Me Et O 2 C O Me Et O 2 C Me O Cl Me O H Et O 2 C Me Me O Cl O Me O H H 2 C Me − H 2 O O Me O H Et O 2 C Cl O Me O isolable • The product prior to dehydration can be isolated under certain circumstances • Reaction can be tuned by changing the reaction conditions 65

6. Furans - Synthesis Modified Feist-Benary I Et O 2 C O Me O NaI, NaOEt, EtOH Et O 2 C Me δ + Me Et O 2 C δ + Cl Me I Et O 2 C − H 2 O Me Me Me Et O 2 C O O Me Et O Et O 2 C Me O O H O Me Me O O O H 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 66

7. Thiophenes - Synthesis Synthesis of Thiophenes by Paal Knorr type reaction (“4+1”) Me Me Me Ph O O Me P 4 S 10 Me Me Me Ph S O Me Ph O S S Ph • Reaction might occur via the 1,4- bis -thioketone 67

8. Pyrroles - Synthesis Paal Knorr Synthesis (“4+1”) Me Me O O NH 3 , C 6 H 6 , heat Me Me Me O H N H H 1 R Me Me Me O H 2 N R 2 R 1 R 2 N N N H H O H H • Ammonia or a primary amine can be used to give the pyrrole or N -alkyl pyrrole 68

9. Pyrroles - Synthesis Knorr Pyrrole Synthesis (“3+2”) Et O 2 C O Me Me O 2 C O N H 2 H 2 N O Me Me O N H 2 Et O 2 KOH aq. H O 2 C Me C Me N H 53% N N Me • Use of a free amino ketone is problematic - dimerisation gives a dihydropyrazine H O Me Et O C Me Et O 2 C O Me Et O 2 C O N H 3 Cl 2 NaOH aq. Et O 2 C Et O 2 C via N Et O 2 C H Et O 2 C O Me or N H 2 O Et O 2 C N 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 69

10. Pyrroles - Synthesis Liberation of an Amino Ketone in situ by Oxime Reduction Et O 2 C O Me Me O N O H Zn, AcOH or Na 2 S 2 O 4 aq. (sodium dithionite) Et O 2 C Me Me N H Preparation of α-Keto Oximes from β-Dicarbonyl Compounds H O O O Et O O O Et N O H NaNO 2 , H (HNO 2 ) O O O Et H 2 O N O O O H O Et N O 70

11. Pyrroles - Synthesis One-Pot Oxime Reduction and Pyrrole Formation O O O Et O 2 C O Et C O 2 Et C O 2 Et Zn, AcOH N O H Hantzsch Synthesis of Pyrroles (“3+2”) Cl Et O 2 C O δ + Me Et O 2 C δ + Me O Cl Me N H 2 NH 3 aq. rt to 60 °C Et O 2 C Et O 2 C − H 2 O Me Me Me Et O 2 C Me O Me N H C O 2 Et H Et O 2 C Me O Me N H Et O 2 C Me O N N O H Me N H 2 H H 41% • A modified version of the Feist-Benary synthesis and using the same starting materials: an α-halo carbonyl compound and a β-keto ester 71

12. Furans, Pyrroles Thiophenes - Electrophilic Substitution Electrophilic Substitution - Regioselectivity − H α X β X E E E X H X E H X X E H X E H − H X E E H X E • Pyrrole > furan > thiophene > benzene • Thiophene is the most aromatic in character and undergoes the slowest reaction • Pyrrole and furan react under very mild conditions • α-Substitution favoured over β-substitution more resonance forms for intermediate and so the charge is less localised (also applies to the transition state) • Some β-substitution usually observed - depends on X and substituents N O 2 AcONO 2 X N O 2 X X = N H 4:1 X = O 6:1 X 72

13. Furans - Electrophilic Substitution Nitration of Furans AcONO 2 , <0 °C O (Ac 2 O, HNO 3 ) N O 2 N O 2 Ac O O H H Ac O O isolable N O 2 H N pyridine, heat − AcOH N O 2 O H • Nitration can occur by an addition-elimination process N O 2 O • When NO 2 BF 4 is used as a nitrating agent, the reaction follows usual mechanism Bromination of Furans Br 2 , dioxan, 0 °C O Br Br Br Br O H Br − HBr Br H O H O 80% Br • Furan reacts vigorously with Br 2 or Cl 2 at room temp. to give polyhalogenated products 73 • It is possible to obtain 2-bromofuran by careful control of temperature

14. Furans - Electrophilic Substitution Friedel-Crafts Acylation of Furan O Me Ac 2 O, SnCl 4 , Ac 2 O, SnCl 4 , O H 3 PO 4 cat., 20 °C 150 °C Me O O α : β 6800:1 Me Me O Me O 77% Me • Blocking groups at the α positions and high temperatures required to give β acylation Vilsmeier Formylation of Furan O Mannich Reaction of Furans CH 2 O, Me 2 NH.HCl O O Me Me 2 NCO, POCl 3 , 0 to 100 °C O 76% CH 2 N Me 2 O Me O H H N Me 2 O 66% N Me 2 74

15. Thiophenes - Electrophilic Substitution Nitration of Thiophenes N O 2 AcONO 2 S S N O 2 S • Reagent AcONO 2 generated in situ from c-HNO 3 and Ac 2 O Halogenation of Thiophenes Br S Br Br 2 , Et 2 O, 48% HBr, − 10 → 10 °C S Br 2 , Et 2 O, 48% HBr, − 25 → − 5 °C S Br • Occurs readily at room temperature and even at −30 °C • Careful control or reaction conditions is required to ensure mono-bromination 75

16. Pyrroles - Electrophilic Substitution Nitration of Pyrroles AcONO 2 AcOH, − 10 °C N N H H 51% N O 2 N O 2 N H 13% • Mild conditions are required (c-HNO 3 and c-H 2 SO 4 gives decomposition) Vilsmeier Formylation of Pyrroles N Cl H H Me O N Me H Me N Me POCl 3 N H Me O P Cl 2 N Me H H Cl N Me 2 N H Me Cl N Me H K 2 CO 3 aq. H N Me 2 N H 83% 76 H O

17. Pyrroles - Porphyrin Formation O H 2 N R 1 R N H H H N N N H H H R 1 O H N R 2 H N N H H R 1 O H 2 R 2 R 2 N R 1 R 2 R 1 R 2 R 1 , R 2 = H N H H N N H H N N H H N N H H N R 1 N H N N H N H no extended aromaticity 18 π-electron system • The extended aromatic 18 π-electron system is more stable than that having four isolated aromatic pyrroles 77

18. Porphyrin Natural Products C O 2 H N N H O 2 C Fe N N H 2 N N H N N Mg N N porphobilinogen H O 2 C C O 2 H haem Me O 2 C O O O C 20 H 39 chlorophyll- a • The pigment haem is found in the oxygen carrier haemoglobin • Chlorophyll- a is responsible for photosynthesis in plants • Both haem and chlorophyll- a are synthesised in cells from porphobilinogen 78

19. Furans, Pyrroles Thiophenes - Deprotonation Metallation n -BuLi X Bu Deprotonation of Pyrroles R M H H X = O pK a (THF) 35.6 X = N R pK a (THF) 39.5 X = S pK a (THF) 33.0 M X α >> β Li M N H pK a (THF) 39.5 N N N pK a (THF) 17.5 M • Free pyrroles can undergo N or C deprotonation • Large cations and polar solvents favour N substitution • A temporary blocking group on N can be used to obtain the C-substituted compound 79

20. Furans, Pyrroles Thiophenes - Directed Metallation Control of Regioselectivity in Deprotonation Y n -BuLi X X Y Li Bu H Y Li X Common directing groups: C O 2 H( Li ), CH 2 O Me, C O N R 2 , CH( O R) 2 Synthesis of α,α’-Disubstituted Systems Y n -BuLi E 1 X X Use of a Trialkylsilyl Blocking Group Y Y n -BuLi n -BuLi Me 3 SiCl E Y 1 E n -BuLi E 2 Y 2 E F X Y E 1 Y X X Si Me 3 E X Si Me 3 E X 80

21. Furans - Synthesis of a Drug Preparation of Ranitidine (Zantac®) Using a Mannich Reaction Me 2 NH.HCl, Me 2 N CH 2 O, rt O O furfural Me 2 N S O N ranitidine H O N O 2 N HMe O H N O 2 Me S N HMe Me 2 N O O H HS(CH 2 ) 2 NH 2 , c-HCl, heat S O N H 2 • Furfural is produced very cheaply from waste vegetable matter and can be reduced to give the commercially available compound furfuryl alcohol • The second chain is introduced using a Mannich reaction which allows selective substitution at the 5-position • The final step involves conjugate addition of the amine to the α,β-unsaturated nitro compound and then elimination of methane thiol 81

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