7-Membered unsaturated heterocycles

What are 7-membered unsaturated heterocycles?

The 7-membered unsaturated heterocycles with a nitrogen, oxygen and sulfur atom are systematically named azepines, oxepines and thiepines, respectively.

fig-00

Only thiepines with bulky substituents are known but both oxepine and 1H-azepine have been synthesized.

1H-azepine and the oxepine are not flat and there is no evidence that they are delocalized.

In addition, (I)-oxepines exist in equilibrium with (II)-valent tautomers.

fig-01

Interconversion is a six-electron electrocyclic disrotatory reaction.

Oxepine exists as an inseparable mixture with benzene oxide at room temperature, as the activation energies of the direct or reverse reactions are very low (9.1 and 7.2 kcal·mol-1, respectively).

Arene oxides are formed as intermediates in the enzymatic oxidation of aromatic hydrocarbons which has stimulated much research into oxepine-arene oxide equilibria.

However, research into the synthesis and properties of 7-membered heterocycles has taken place for the biological activity of benzodiazepines and dibenzozepines.

fig-02

These 7-membered heterocycles are used as drugs to control anxiety and as antidepressants.

Azepines

Azepines substituted at the N1 position have been prepared from aziridines.

fig-03

These in turn are obtained by reacting iodine isocyanate with 1,4-hexadiene.

fig-04

It is followed by alkylation, bromination and dehydrobromination reactions.

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The 1H-azepines, unlike the azepines show little tendency to isomerize to give bicylic structures, but it can occur in the protonated 1H-azepines, because it is possible to convert them irreversibly to benzene derivatives.

fig-06

The polyene character of the π-electron system is manifested in the reaction between the C2 and C5 of ethyl 1-azepin carboxylate with activated dienophiles. As for example diethyl azo-dicarboxylate.

fig-07

3H-azepines can be formed by irradiating phenyl azides in primary or secondary aliphatic amines.

fig-08

Oxepines

Oxepines can be prepared from 1,4-cyclohexadiene by bromine addition, epoxidation and dehydrobromination.

fig-09

Oxepine is in equilibrium with its bicyclic tautomer and at room temperature both tautomers are present.

fig-10

Benzene oxide (II) is the lowest energy system (ΔHº = 1.7 kcal·mol-1), but the entropy gain associated with ring opening shifts the equilibrium slightly in favor of oxepine at room temperature.

This equilibrium favors benzene oxide at low temperature and in polar solvents.

The position of the benzene oxide—oxepine equilibrium, in substituted oxepines, depends largely on the nature and position of the substituents.

Substitution at the C2 position, especially with electron-attracting conjugating groups, favors the oxepine form. However, substitution at the C3 position of these groups favors the benzene oxide form.

This difference can be explained by stabilization of the different tautomeric forms by resonance.

For example, in 2-acetyloxepine there is a possible conjugative interaction with the oxygen atom of the ring. This interaction cannot occur in the case of the valency (II) tautomer.

fig-11

However, in 3-acetyloxepine, the conjugative interaction the benzene oxide tautomer is also stabilized by resonance.

fig-12

The same applies to the benzofused analogs. For example, naphthalene 1,2-oxide exists in the bicyclic form. This can be prepared as a pure enantiomer, with no tendency to racemize via the 7-membered valence tautomer. Whereas naphthalene 2,3-oxide exists entirely in benzoxepine.

fig-13

However, all monocyclic oxepines can be reacted by their bicyclic tautomers even though these are the least favored structures.

For example, oxepine easily undergoes Diels-Alder reaction through its bicyclic valence tautomer and with maleic anhydride.

2-Acetyl-oxepine, for which the bicyclic tautomer cannot be detected by NMR, nevertheless gives an analogous cycloadduct with the same maleic anhydride.

fig-14

Oxepines are easily transformed to give phenols in acidic media, via their valence tautomers.

fig-15

The transposition may involve a 1,2-hydride shift that has been established by deuterium labeling experiments.

The mechanism of biological hydroxylation of aromatic compounds is analogous, in that arene oxides are involved as intermediates and their transposition involves a 1,2-hydride shift that is often referred to as the "NIH shift" after the National Institutes of Health where it was first discovered.

The oxirane ring of the bicyclic tautomers, too, can be opened by reaction with azide ions and other mild nucleophiles attacking at C2.

Thiepines

Single thiepines are thermally unstable because they readily expel sulfur from the bicyclic tautomer. If the tautomerism is sterically inhibited, it is possible to isolate the thiepines. For example, in the case of 2,7-di-tert-butylthiazepine. It is thermally stable because the bulky substituents prevent its isomerization to the corresponding benzene sulfide.

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Diazepines

There are three groups of noncyclic diazepines, with nitrogen atoms in positions N1-N2, N1-N3 and N1-N4.

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Of the three structures, the 1,2-diazepines are the most studied. In addition, the 4 possible tautomers (1H, 3H, 4H and 5H) of the 1,2-diazepines are shown below.

fig-18

Several 1H-1,2-diazepines with electron-attracting substituents at the N1 position have been prepared by irradiation () of pyrilium imides. Disrotatory electrocyclization occurs when they are irradiated with ultraviolet light.

However, they revert to pyridinium N-imides above 150 °C and open with bases that extract the activated proton at the C3 position.

fig-19

3H-1,2-diazepines have been prepared by thermal cyclization of unsaturated diazocompounds.

fig-20

However, the 5H-1,2-diazepines show a marked preference for adopting the structure of valence (II) tautomers.

fig-20

This allows the molecule to exist as conjugated azines, rather than azo compounds.

Benzodiazepines

Derivatives of the 1,4-diazepine system were of great relevance in the late 1970s. Thousands of these compounds had been synthesized as potential drugs.

They can be prepared from suitable 1,2-disubstituted benzenes.

For example, the synthesis of clonazepam, a commercial drug, is carried out as follows.

fig-21

Another drug librium (chlorodiazepoxide) is synthesized by a less direct route.

It is prepared by reaction of an oxime with chloroacetyl chloride.

fig-22