Heterocyclic ring ( MPHARM,BPHARM,MSC,BSC,BIOCHEM,ORAGANIC CHEMISTRY)

STATERGIES FOR SYNTHESIS THREE ,FOUR,FIVE,SIX,MEMBERED RINGS

1. jjjAT Presented by : Souparnika T Ist M.Pharm Pharmaceutical Chemistry STRATERGIES FOR SYNTHESIS THREE ,FOUR,FIVE AND SIX MEMBERED RINGS

2. CONTENTS: Introduction 3 membered ring 4 membered ring 5 membered ring 6 membered ring Conclusion Reference 1

3. CLASSIFICATION OF ORGANIC COMPOUND ORAGNIC COMPOUND CYCLIC COMPOUNDS OPEN CHAIN COMPOUNDS HOMOCYCLIC HETEROCYCLIC STRAIGHT CHAIN BRANCHED COMPOUND COMPOUND COMPOUND COMPOUND 2

4. HETEROCYCLIC COMPOUND Greek word ‘heteros’ means different. Heterocyclic compounds are those where one or more atoms of the ring are heteroatoms,for eg.N,O,S,P,As,Se,B, and so on. More than half of the known organic compounds are heterocyclic compounds. For eg.nucleic acid bases, hemoglobin, chlorophyll, vitamins,amino acids,alkaloids, carbohydrates etc. 3

5. STRUCTURES OF SOME HETEROCYCLES AZIRIDINE PYRROLE PYRIDINE OXETENE OXAZOLE PYRIMIDINE 4

6. INTRODUCTION Ring formation reaction are significant in retrosynthesis. intramolecular reaction are favoured over intermolecular reaction . Both reactive components are present in same molecule. 3,5 and 6 membered rings are formed easily. 6 membered ring can be flipped and can be projected into boat and chair form . 6 membered ring are more stable in chair form . 4 and more than 6 membered ring are formed with some difficulties. 3 and 4 membered rings are strained and less stable as compared to 5 and 6 membered ring 5

7. N E E Nu Nu E 6

8. THREE MEMBERED HETEROCYCLES Formally derived from cyclopropane bt replacing a carbon atom with a hetero atom.Such a change widely affects the physical and chemical properties of the resulting heterocyclic rings. Three membered saturated heterocyclic compounds containing a N,O and S as the hetero atom are known as aziridine,oxirane, and thirane respectively. chemically they are most stable than cyclopropane derivatives. These ring formation is kinetically favourable but thermodynamically unfavourable so these are often destroyed under condition of their formation. 7

9. RING SYNTHESIS OF OXYGEN: ex 1; Epoxides are usually made from alkenes. both C-O bonds disconnected at once, Reagent is per acid. 8

10. Eg .1 9

11. RING SYNTHESIS OF NITROGEN: Aziridine can be prepared by cyclization reaction similar to that involved in epoxide formation. 10

12. Eg.2 Disconnection 11

13. 4 MEMBERED RING Heterocyclic analogues of cyclobutene. Relatively less strained than the three membered hetero cylic rings. 4 membered heterocycles are rarely and uniquely difficult to make and very easy to break. The normal cyclization approach often gives poor results. Azitidine Thietane Oxetane 2-Azetine Azete 12

14. RING SYNTHESIS OF NITROGEN C-N Disconnection of cyclic amine suggest 1,3- dibromide as a starting material which can be made from the lactone. 13

15. EX 1: C-N + NH 2 SYNTHESIS Br 2 MeOH NH 2 MeCN 14

16. RING SYNTHESIS OF OXYGEN: Oxetane can be prepared by cyclization reaction. Four membered compound is taken as target molecule. 15

17. DISCONNECTION APPROACH SYNTHESIS TS C-O TS Base 16

18. 5 MEMBERED RING: The simplest of the five- membered heterocyclic compounds are pyrrole, furan, and thiophene.   Characterized by high degree of reactivity substitution by electrophilic reagents rather than addition.    From molecular orbital standpoint these molecules are described as consisting of planar pentagon with sp2 hybridized carbon atom.   . 17

19. PYRROLE FURAN THIOPHENE OXAZOLE 1H-IMIDAZOLE 18

20. RING SYNTHESIS OF NITROGEN 19

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22. RING SYNTHESIS OF SULPHUR: H 2 S 21

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24. RING SYNTHESIS OF OXYGEN 23

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26. 6 MEMBERED RING : The methane (-CH-) group in a benzene ring can be replaced by a heteroatom to generate six membered heterocyclic compounds. The departure from perfectly regular hexagonal geometry caused by the presence of the heteroatom. A strong permanent dipole, traceable to the greater electronegativity of nitrogen compared with carbon. 6 Membered ring is favorable for both thermodynamic and kinetic factors. They are stable compared to other ring systems. 25

27. Easily disconnected Easily disconnected

28. PYRIDINE PYRRONE THIOPYRAN PYRAZINE PYRIMIDINE 26

29. DISCONNECTION APPROACH 27

30. SYNTHETIC APPROACH 28

31. DISCONNECTION APPROACH 29

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34. CONCLUSION: The goal of retrosynthesis analysis is structural simplification. Often, a synthesis will have more than one possible synthetic route. Retrosynthesis is well suited for discovering different synthetic routes and comparing them in a logical and straight forward fashion. 31

35. Reference: Warren S. Organic synthesis: the disconnection approach. John Wiley & Sons; 2007 page no:217-279. Structures in ChemSketch Image source- Google 32