Synthesis and reactions of Seven membered heterocycle-Azepines

This presentation outlines the synthesis and reactions of Azepines

1. Synthesis and reactivity of Azepines Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University

2. Replacement of the sp 3 hybridized carbon atom in cycloheptatriene by a nitrogen leads to an Azacyclohepatriene known as Azepines . These are class of nitrogen containing seven membered heterocycles with molecular formula C 6 H 7 N.. Azepine is planar and cyclic with 8 π electrons. Hence, they obey 4n π electron system. Therefore azepine is anti-aromatic compound.

3. Due to instability in planar form and to gain stability azepine exist in non planar conformation (Chair and Boat). Hence azepine is non aromatic compound.

4. Azepine exhibits valence tautomerism and four tautomeric forms are possible 1H-azepine 2H-azepine 3H-azepine 4H-azepine

5. 2, 3 and 4H-azepines the lone pair out of conjugation removing the destabilizing contribution. The relative stability 3 > 4 corresponds to torsional difference in boat conformation and conjugated enamines offer greater stabilization than conjugated imines. The stability of 1H-azepine is enhanced by electron withdrawing substituents at 1-position. The order of stability is 3H > 4H > 2H > 1H

6. Nitrene Insertion Synthesis The most frequently used synthetic method for azepine is the insertion of a stabilized singlet nitrene into benzene ring by a concerted cycloaddition mechanism gives 1-azanorcaradiene which changes to azepine .

7. Phenylazide undergoes thermal or photolytic decomposition to yield nitrene. This nitrene react with arenes to afford azanorcaradiene which rearrange to give stable azepines .

8. Nitrobenzene / Nitrosobenzene undergoes deoxygenation in presence of tributylphosphine to yield nitrene. This nitrene react with arenes to afford azanorcaradiene which rearrange to give stable azepines .

9. From Heterocycles 2H-Aziridine react with cyclopentadienones in [4+2] cycloaddition reaction to give polysubstituted 3H-azepines by loss of carbon monoxide.

10. Pyrrole react with acetylene- dicarboxylate in [4+2] cycloaddition reaction adduct which undergoes photochemical [2+2] addition to give azaquadricyclanes finally leads to formation of 4, 5-disubstituted 1H-azepines.

11. Reactions Aromatization Heating of 2-methyl derivative of azepine at 200 o C converts to aromatic urethane via aziridinobenzne valence tautomer .

12. Pericyclic reactions Non planar polyene nature of azepines allow them to take part in a wide variety of intra and intermolecular pericycli c process. Irradiation of 2-methyl-1H-azepine selectively gives a 4, 7-ring closure product. Irradiation of 3-methyl-1H-azepine gives two four membered product in 1:1 ratio.

13. Cycloaddition reaction Azepines can participate in cycloaddition reactions as 2 π , 4 π (or) 6 π components. Cycloaddition reactions of N-substituted azepines with various dienophiles have been studied. Azepines undergo [4+2] Diels-Alder reaction with dienophiles at the C2-C5 positions.

14. Reaction with Metal carbonyl complexes Tricarbonyl chromium, molybdenum and tungsten complexes of azepine-1-carboxylate have been prepared by treating azepine-1-carboxylate with the metal carbonyl tris acetonitrile complex in THF.

15. The seven membered lactam ( caprolactam or hexahydroazepin-2-one) has been isolated from natural source and has biological properties such as growth inhibitng activity and allelopathy . The most relevent use is as an intermediate in th e synthesis of nylon 6 through polymerization process. Uses