Making five-membered rings: 1,3-dipolar cycloadditions

 We have seen how to make four-membered rings by [2+2] cycloadditions, how to make six membered rings by [4+2] cycloadditions, and an example of making a seven-membered ring by a [4+3] cycloaddition. But what about five-membered rings? What we need is a three atom, four-electron equivalent of a ‘diene’ and we can do a Diels–Alder reaction. Such mole cules exist: they are called 1,3-dipoles and they are good reagents for [3+2] cycloadditions. The molecule containing N and O atoms labelled ‘four-electron component’ is an example. It has a nucleophilic end (O⁻) and an electrophilic end—the end of the double bond next to the central N⁺. These are 1,3-related, so it is indeed a 1,3-dipole.

This functional group is known as a nitrone. You could think of it as the N-oxide of an imine. The nitrone gets its four electrons in this way: there are two π electrons in the N=C double bond and the other two come from one of the lone pairs on the oxygen atom. The two-electron component in each of these reactions is an alkene which, in a Diels–Alder reaction, would be called a dienophile. Here it is called a dipolarophile. Simple alkenes (which are bad dienophiles) are good dipolarophiles and so are electron-deficient alkenes. The difference between dienes and 1,3-dipoles is that dienes are nucleophilic and prefer to use their HOMO in cycloadditions with electron-deficient dienophiles while 1,3-dipoles, as their name implies, are both electrophilic and nucleophilic. They can use either their HOMO or their LUMO depending on whether the dipolarophile is electron-deficient or electron-rich.

One important nitrone is a cyclic compound that has the structure in the margin and adds to dipolarophiles (essentially any alkene) in a [3+2] cycloaddition to give two five-membered rings fused together. The stereochemistry comes from the best approach with the least steric hindrance, as shown. There is no endo rule in these cycloadditions as there is no conjugating group to interact across space at the back of the dipole or dipolarophile. The product shown here is the more stable exo product. If the alkene is already joined on to the nitrone by a covalent bond, the dipolar cyclo addition is an intramolecular reaction, and one particular outcome may be dictated by the impossibility of the alternatives. In the simple case below, the product has a beautifully symmetrical cage structure. The mechanism shows the only way in which the molecule can fold up to allow a 1,3-dipolar cycloaddition to occur.

The importance of the Diels–Alder reaction is that it makes six-membered rings with control over stereochemistry. The importance of 1,3-dipolar cycloadditions is not so much in the heterocyclic products but in what can be done with them. Almost always, the first formed heterocyclic ring is broken down in some way by carefully controlled reactions. The nitrone adducts we have just seen contain a weak N–O single bond that can be selectively cleaved by reduction. Reagents such as LiAlH4 or zinc metal in various solvents (acetic acid is popular) or hydrogenation over catalysts such as nickel reduce the N–O bond to give NH and OH functionality without changing the structure or stereochemistry of the rest of the molecule. From the examples above, we get these products:

In each cycloaddition, one permanent C–C and one C–O bond (shown in brown) were made. These were retained while the N–O bond present in the original dipole was discarded. The final product is an amino-alcohol with a 1,3-relationship between the OH and NH groups.

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8 أعراض إذا شعرت بها.. اذهب للطوارئ فورا !

تعرف على أكثر 8 أماكن اتساخا في المنزل

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عودة التعاون الفضائي بين روسيا وأميركا.. وبحث ملفات "هامة"

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مواضيع ذات صلة

Non-linear Hammett plots

A complete picture of the transition state from Hammett plots

Using the Hammett ρ values to uncover mechanisms

Reactions with small Hammett ρ values

Reactions with negative Hammett ρ values

Reactions with positive Hammett ρ values

Equilibria with positive Hammett ρ values

The Hammett substituent constant σσ A

The Hammett relationship

Systematic structural variation

Crossover experiments

Labelling experiments reveal the fate of individual atoms