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 sp3 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 C6H7N..
Azepine is planar and cyclic with 8π electrons. Hence, they obey 4nπ electron system.
Therefore azepine is anti-aromatic compound.
N
H
1
2
3
45
6
7

3. H
N
NH
NH HN
Boat Conformation
Chair Conformation
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
(1) 1H-azepine
(2) 2H-azepine
(3) 3H-azepine
(4) 4H-azepine
N
H
1
2
3
45
6
7
N
1
2
3
45
6
7
N
1
2
3
45
6
7
N
1
2
3
45
6
7
H
H
1H-azepine 2H-azepine
3H-azepine 4H-azepine
H
H
H
H

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.
N
C C
N
H
H H
H
3H-azepine 4H-azepine1H-azepine
H
N
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.
N CO2Et
N N N CO2Et
h 
N CO2Et N CO2Et
Azanorcaradiene

7. h

N
N
H
N3 N
NuH
N
Nu
H
NuN Nu
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.
N
N
H
N
NuH
N
Nu
H
NuN Nu
NO2
Bu3P
N
O O
Bu3PN
O
Bu3P
N
O
Bu3P

9. From Heterocycles
2H-Aziridine react with cyclopentadienones in [4+2] cycloaddition reaction to give
polysubstituted 3H-azepines by loss of carbon monoxide.
N
R4
N
R1
R2O
R3
Ph
Ph
R4
N
O
Ph
Ph
R4
R3
R2
R1
R2
R1
R3 Ph
Ph
CO
[4+2]

10. N R
CO2Me
CO2Me N
CO2Me
CO2Me
R
N
CO2Me
CO2Me
R
N
R
MeO2C CO2Me
h
R = -Ac, -Ts
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 200oC converts to aromatic urethane via
aziridinobenzne valence tautomer.
N
CO2Me
CH3
N
CO2Me
CH3
NHCO2Me
CH3
200o
C
H

12. Pericyclic reactions
Non planar polyene nature of azepines allow them to take part in a wide variety of
intra and intermolecular pericyclic process.
Irradiation of 2-methyl-1H-azepine selectively gives a 4, 7-ring closure product.
N
CO2Me
h
Me
N
Me
CO2Me
7
6
5 4
3
2
1
N
CO2Me
h
N
CO2Me
7
6
5 4
3
2
1
Me
Me
N
CO2Me
Me
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 2π, 4π (or) 6π 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.
N
R
N
R
[4+2]
2
5

14. N
R
N R
[2+2]
N
R
[4+2]
N
R
N
R
[6+2] [2+2]
[6+6]
N
R
N
R

15. 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.
N
R
M(CO)3 (CH3CN)3
N R
OC
M
CO
CO
M = Cr, Mo, W

16. 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 the synthesis of nylon 6 through
polymerization process.
N
H
O
Uses