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 C6H6O / C6H6S.
O
1
2
3
45
6
7
S
1
2
3
45
6
7
These heterocycles has 8 π electron and obey 4nπ electron rule. Hence, anti aromatic
in nature.

3. Oxepine and thiepine exist in non planar conformation and are non aromatic
compound.
X
X
X X
Boat Conformation
Chair Conformation
X = O, S
X = O, S
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.
O
O
Oxepine Benzene-oxide
O
O
Oxepine Benzene-oxide
O
Benzene-oxide
OCOPh
OCOPh OCOPh
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.
Oxepine Benzene-oxide
O
O
O
O
Low temperature
Less polar solvent

6. Substitution at C-3 favor benzene-oxide tautomer while substitution at C-2 and C-4
favor oxepine form.
O
O
C-3 substituentR
R
Oxepine Benzene-oxide
O
O
C-2 & C-4 substituent
R
R
R
R

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. (COCl)2
DMSO/Et3N
OH
R1R2
R4
R3
O
R1R2
R4
R3
O
R4
R2
R3
R1
[3, 3] rearrangement
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.
O
O
115o
C
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.
O
O
Epoxidation
O
Bromination
O
Br
Br
Dehydrohalogenation
H
H
Six membered carbocycle

11. O
OO O
Br
Br
Base
H
H
R
RCO3H
R
Br2
R R
R
2-substituted oxepine
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. O
OO
Base
R
RCO3H Br2
4-substituted oxepine
R
O
Br
Br
R
R
R
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.
O
O
h
O
Heat
Several di-, tri-, and tetra-substituted oxepines have been prepared using the same
approach.
Photochemical and thermal reaction

14. O
O
h
O
Heat
O
R2
R1
R4
R3
[4+2]
R2 R1 R4
R3
R2
R1 R4
R3
R4
R3
R2
R1
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
O
O
N
N
CO2Me
MeO2C
OO
O
O
O
OO
O
N
N
CO2Me
CO2Me

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.
O
O
X R1
R2
R2
R1
X
H+
OH
R2
R1
XOH
R2 R1
OHR2
X
OH
R2 R1
OH
R2 R1
X
-R1, 3-shift
1, 6-shift -X
X

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 NH3, NH2
- and RNH2 but reacts with azide ion.
O
O
N3
-
N3
OH

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.
S
S
Heat
H H
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.
SBut t
Bu S
But
t
Bu
NC CN
CNNC
60o
C
CNNC
NC CN
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