Seven membered heterocycles-Oxepines & thiepines

This presentation discuss the stability, synthesis and reaction sof seven membered heterocycles - Oxepines and thiepines

1. Oxepines and Thiepines Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University

2. The structure related to 1H-azepine that bear an oxygen atom is known as Oxepine while sulfur atom is known as Thiepine . These are class of oxygen / sulfur containing seven membered heterocycles with molecular formula C 6 H 6 O / C 6 H 6 S. These heterocycles has 8 π electron and obey 4n π electron rule. Hence, anti aromatic in nature.

3. Oxepine and thiepine exist in non planar conformation and are non aromatic compound. Oxepine is much more stable than thiepine and has been synthesised , isolated and characterised at room temperature while thiepine has not been detected.

4. Due to instability of most monocyclic oxepine does not have any commercial application, but they do play a remarkable role as intermediate in biosynthesis and metabolism of natural products and xenobiotics . Oxepine at room temperature exists in rapid equilibrium with its valence tautomer benzene oxide. Monosubstituted oxepines supports the existance of two enantiomers in equilibrium with the oxepine . Oxepine

5. The oxepine -benzene oxide ratio depends on temperature, solvent and substitution. Oxepine form favored in less polar solvent while at low temperature the benzene oxide is preferred form.

6. Substitution at C-3 favor benzene-oxide tautomer while substitution at C-2 and C-4 favor oxepine form.

7. From cyclic compounds Synthesis Three, four and six membered carbocycles have been employed as starting material for the construction of oxepine ring system. Most synthetically useful method involve cyclopropance and cyclohexenes as starting material. The most efficient method for synthesis of dihydro and tetrahydrooxepine involves ring expansion of alkenylcyclopropyl carbinols .

8. Three membered carbocycle

9. The method Bicyclo [2.2.0]hexa-2,5-diene undergoes epoxidation followed by rearrangement of the resulting tricycle leads to the formation in low yield of oxepine . Four membered carbocycle

10. The formation of the oxepine ring from six-membered carbocycles is one of the most useful routes to monocyclic oxepines . The method is based on the epoxidation and bromination of 1,4-cyclohexadienes. The dibromoepoxides , when subjected to dehydrohalogenation conditions, afford the corresponding oxepine –benzene oxides and these tautomerize to oxepines . Six membered carbocycle

11. The electronic nature of the substituents in the cyclohexadiene ring determines which of the two possible substituted oxepines is formed and this depends on which of the two double bonds are initially involved in the epoxidation. If substituent is electron donating then it leads to formation of 2-substituted oxepine .

12. If substituent is electron withdrawing then it leads to formation of 4-substituted oxepine .

13. The parent oxepine can be prepared by a short and efficient route starting from 7-oxanorbornadiene as the five -membered heterocycle . Isomerization of this bicyclic compound into the monocyclic oxepine is promoted photochemically and this is followed by thermal rearrangement. Several di -, tri-, and tetra-substituted oxepines have been prepared using the same approach. Photochemical and thermal reaction

14. Diels–Alder reaction of substituted furans with alkynes via corresponding 7-oxonorbornadienes .

15. The existence of a rapid oxepine –benzene oxide equilibration does not allow oxepines to be treated as separate entities and some reactions may involve the benzene oxide tautomer . Reactions

16. Oxepines undergo cycloaddition reactions with unsaturated molecules due to their cyclic polyenic character and can behave as an ene , diene , and triene according to the kind of dienophile and considering the oxepine –benzene oxide system . Oxepine reacts with maleic anhydride to from [4+2] cycloadduct while benzene-oxide reacts with DMAD via [4+2] cycloaddition to form corresponding product. Cycloaddition reactions

17. Reactions with Electrophiles The protonation of oxepine –benzene oxides takes place at the ring oxygen atom and generally results in C-O ring cleavage with the formation of carbocation before conversion into phenol.

18. Reactions with Nucleophiles The arene oxide valence tautomer of oxepines could react with nucleophiles as a simple epoxide . However, the oxepine –benzene oxide is quite unreactive towards nitrogen nucleophiles like NH 3 , NH 2 - and RNH 2 but reacts with azide ion.

19. Theoretical studies at a high level of theory dealing with the stability of thiepine and its valence tautomer have shown a significant preference for the valence tautomer benzene sulfide , which was more stable than the parent thiepine . A remarkable difference with azepines or oxepines is that valence isomers in simple thiepines are prone to extrude the sulfur atom in an irreversible process. Thiepine

20. Thermal rearrangement of cis-1,2-divinylthiirane leads to the formation of corresponding 4, 5-dihydrothiepine. Thiepine thus appears to exist exclusively in this valence isomer. The stability of thiepines is enhanced by the presence of bulky substituents at the C2 and/or C7 positions and electrondonating or -withdrawing groups. Additional stability is achieved in the transformation to S,S-dioxides ( sulfones ) and thiepinium salts. Synthesis

21. The cycloaddition of 2,7-di-tertbutylthiepine with tetracyanoethylene (TCNE) produced only the cycloadduct . Reactions Cycloaddition reactions

22. The most common thermal reaction of thiepines is the extrusion of a sulfur atom. A similar reaction occurs with thiepine 1-oxide and 1,1-dioxide, which lose sulfur monoxide and sulfur dioxide, respectively. Thermal reaction