Four-membered heterocycles

Four-membered heterocycles show less ring strain than the 3-membered rings and therefore have fewer applications as synthetic intermediates.

These heterocycles are less frequent due to the difficulty of preparing 4-membered rings. They exhibit different properties from the major and minor rings.

fig-01

The three compounds in the figure (oxetane, azetidine and thiethane) are more stable than their 3-membered counterparts. Therefore, more vigorous conditions are required to cause breakage of the 4-membered ring.

The chemistry of azetidin-2-one (β-lactam) is highly developed due to the use of its derivatives as antibacterial agents.

fig-02

Since penicillin was shown to have a β-lactam ring in 1945, β-lactam antibiotics with a broad spectrum of activity have been synthesized.

fig-03

 

There is another relevant natural structure with a four-membered heterocyclic ring, which is cephalosporin.

fig-04

 

In addition, many current semisynthetic antibiotics are derived from the cephalosporin structure.

Synthesis

In some favorable cases 4-membered rings are formed due to direct chain closure. However, the yields obtained are generally very low.

fig-05

 

Another method to generate 4-membered heterocyclic compounds is the joining of two double bonds. That is, a [2 + 2] cycloaddition reaction.

fig-06

 

These reactions are not analogous in their mechanisms to the Diels-Alder reactions of benzenoid systems. On the contrary, these cycloadditions comprise stepwise mechanisms, as shown in the following examples:

fig-07

Reactivity

The 4-membered heterocycles undergo many of the characteristic transformations of the 3-membered ones but generally exhibit a lower degree of reactivity, because there is less stress on the 4-membered ring.

They can react with electrophiles to give ring opening:

fig-08

The breaking direction of asymmetrically substituted oxetane rings cannot always be predicted since the process is not strictly an SN1 reaction.

Mechanisms occur in which fully developed carbonium ions (carbocations) are not always generated.

Examples

The 2-methyloxetane reacts with hydrogen chloride via an intermediate oxonium ion which is subsequently attacked on carbon with less hindrance.

fig-09

However, 2-phenyloxetane gives only a product resulting from the generation of a benzyl carbonium ion (carbocation).

fig-09

 

The β-lactones, as expected, hydrolyze rapidly to β-hydroxy acids, in aqueous media.

fig-10

 

In addition, certain β-lactones are exothermically converted to substituted acrylic acids with concentrated sulfuric acid (H2SO4) or boron trifluoride (BF3).

Nucleophilic ring opening

The 4-membered rings react much more slowly with nucleophiles compared to 3-membered rings.

For example, oxetane breaks down, in the presence of hydroxide ions, at a rate 1000 times slower than ethylene oxide.

fig-11

with other reagents gives the following:

 

fig-12

 

Azetidines and thiethanes are quite resistant to the action of bases and nucleophiles.

Some functionalized thiethanes have been treated with nucleophilic reagents without ring opening:

fig-13

 

Unsaturated 4-membered rings

In general, they are very unstable compounds, unless they are highly substituted. This is partly due to their tendency to undergo electrocyclic ring opening to give heterodienes.

 

Examples

fig-14

 

The 2,3-dihydroazete transposes only in the gas phase, and some derivatives are stable at room temperature such as dimethyl 1,2-dihydrodiazete-1,2-dicarboxylate.

fig-15