Epoxidation & Aziridination

Introduction

It can be classified as presenting oxidation reactions of alkenes.

The formation of a three-membered ring, particularly epoxidation, is an extremely valuable transformation in organic synthesis.

Epoxides and even aziridines are present in a number of natural products and biologically active compounds.

Of crucial importance, however, is their use as building blocks in organic synthesis; their ring-opening reactions allow the formation of a wide variety of substituted alcohol- and amine-containing compounds.

1) Epoxidation

Reaction of an alkene with an oxidising agent, such as a peroxy-acid, DMDO, TFDO, leads to the formation of an epoxide ring.

Anumber of peroxy-acids can be used, although the most common is meta-chloroperoxybenzoic acid (mCPBA).

This is a fairly stable, white solid, that is commercially available.

The reaction is believed to take place by electrophilic attack of the peroxy-acid on the double bond.

In accordance with this mechanism, the rate of epoxidation is increased by electron-withdrawing groups in the peroxy-acid or electron-donating groups on the double bond.

Terminal mono-alkenes react slowly with most peroxy-acids and the rate of reaction increases with the degree of alkyl substitution.

1,2-Dimethyl-1,4-cyclohexadiene for example, reacts preferentially at the more electron-rich tetrasubstituted double bond and the diene reacts selectively at the disubstituted double bond.

On the other hand, conjugation of the alkene double bond with other unsaturated groups reduces the rate of epoxidation because of delocalization of the π-electrons.

α,β-Unsaturated acids and esters require the strong reagent trifluoroperoxyacetic acid, or mCPBA at an elevated temperature, for successful oxidation.

With α,β-unsaturated ketones, reaction is complicated by competing Baeyer–Villiger oxidation of the carbonyl.

Epoxides of α,β-unsaturated carbonyl compounds are best made by the action of nucleophilic reagents such as hydrogen peroxide or tert-butyl hydroperoxide in alkaline solution.

1.1) Stereoselectivity of Epoxide

Epoxidations with peroxy-acids are highly stereoselective and take place by cis addition to the double bond of the alkene.

For example, oleic acid gave cis-9,10-epoxystearic acid , whereas elaidic acid gave the isomeric trans-epoxide .

But in case of H2O2 forms only Trans epoxide:

Epoxide opening by acid and base:

Like unsymmetrical alkenes give the same 1,2-dibromides whichever way the bromide attacks the bromonium ion.

1) Acid catalysed epoxide opening forms more substituted:

Due stabilization of carbocation gives more substituted nucleophile

With NBS, the concentration of Br– is always low, so alcohols compete with Br– to open the epoxide even if they are not the solvent.

In the next example, the alcohol is ‘propargyl alcohol’, prop-2-yn-1-ol. It gives the expected anti-disubstituted product with cyclohexene and NBS.

If the ring bears a t-butyl substituent, ring flipping is impossible, and the diaxial product has to stay diaxial.

An example is nucleophilic attack of halide on the two epoxides.

The double bond is made into an epoxide with m-CPBA.

Epoxides react with nucleophiles, and this is the way that the four-membered ring of grandisol was formed: the nitrile still has a proton next to it, and a strong base will remove this proton as before to give an ‘enolate’.

The enolate reacts with the epoxide to give a four-membered ring.

In basic condition the Nucleophile attack on the less hindered terminal carbon atom of the epoxide gives us the less substituted product.

Epoxidation by SN2 reaction with Halogens:

Bromination in water are called bromohydrins.

They can be treated with base, which deprotonates the alcohol.

A rapid intramolecular SN2 reaction follows: bromide is expelled as a leaving group and an epoxide is formed.

This can be a useful alternative synthesis of epoxides avoiding peroxy-acids.

To make syn epoxide to the Alkyl group:

The regular epoxidation forms less hindered epoxide is as follows:

By using following way we can make epoxide syn to the Alkyl group:

Note:- The opposite stereoselectivity can be achieved by bromination in water.

The bromonium ion intermediate is formed stereoselectively on the less hindered side and the water is forced to attack stereospecifically in an SN2 reaction from the more hindered side.

Treatment of the product with base (NaOH) gives an epoxide by another SN2 reaction in which oxygen displaces bromide.

This is again stereospecific and gives the epoxide on the same side as the group R.

Two substituents on the same side of a five-membered ring combine to dictate approach from the other side by any reagent, and the two epoxides can be formed each with essentially 100% selectivity.

1.2) Hydrogen Bonding

Epoxidation of alkenes normally occurs with approach of the peroxy-acid from the less-hindered side of the double bond.

However, where there is a polar substituent, particularly in the allylic position, this may influence the direction of attack by the peroxy-acid.

Thus, whereas 2-cyclohexenyl acetate gives a mixture consisting predominantly of the trans-epoxide (as expected with attack from the less-hindered side of the double bond).

The free alcohol gives almost exclusively the cis-epoxide to the hydroxyl group under the same conditions.

The stereoselectivity and the faster rate of reaction with the hydroxy compound result from hydrogen bonding of the reactants.

1.3) Reactivity Order:

Example :

1.4) Metal catalysed epoxidation

Vanadium catalysts have found particular advantage for stereoselective epoxidations.

Thus, the acyclic allylic alcohol is oxidized with high selectivity using t-BuOOH and vanadium acetylacetonate, whereas with mCPBA a nearly equal mixture of the diastereomeric epoxides was produced.

An epoxidizing agent that has found widespread use is dimethyl dioxirane (DMDO).

The reagent is generated from acetone and Oxone®, a source of potassium peroxomonosulfate (KHSO5). Epoxidation with DMDO occurs under mild, neutral conditions, without any nucleophilic component, which is ideal for preparing sensitive epoxides

1.5) Sharpless Asymmetric epoxidation

Asymmetric epoxidation ranks as one of the most important and selective methods for the formation of single enantiomer products.

In particular, the asymmetric epoxidation of allylic alcohols with tert-butyl hydroperoxide (t-BuOOH), and a titanium(IV) metal catalyst and a tartrate ester ligand, called the Sharpless asymmetric epoxidation.

1.6) General diagram for epoxidation site on the molecule

Example:

1.7) Mechanism

A wide selection of substituted allylic alcohols are amenable to asymmetric epoxidation under these conditions.

Allylic alcohols with E-geometry or unhindered Z-allylic alcohols are excellent substrates.

However, branched Z-allylic alcohols, particularly those branched at C-4, exhibit decreased reactivity and selectivity.

Example :

1.8) Nucleophilic epoxidizing agent's

Nucleophilic oxidizing agents are well-suited for the epoxidation of α,β-unsaturated carbonyl compounds and other related electron-deficient alkenes.

Good yields of the required epoxides are obtained using alkaline solutions of hydrogen peroxide or tert-butyl hydroperoxide.

In these cases, conjugate addition of the peroxide onto the β-carbon atom of the α,β-unsaturated carbonyl compound is followed by cyclization to give the epoxide.

1.9)Stereoselectivity of Epoxide

With m-CPBA it gives stereospecific reactions to form Trans epoxide on trans double bond and syn epoxide on cis- double bond.

But in case of H2O2 forms only Trans epoxide only that is stereoselective reaction.

2) Aziridination

The aziridine ring is an important functional group.

Aziridines can be prepared from epoxides by ring-opening with azide anion and cyclization with triphenylphosphine.

This methodology provides a convenient, stereospecific way to access N-unsubstituted aziridines.

Example

Epoxidation of the alkene occurred stereoselectively to give the cis epoxid, which was converted to the aziridine via azido-alcohol with overall double inversion of stereochemistry

Direct preparation of an aziridine from an alkene is possible by reaction of the alkene with a nitrene or metal nitrenoid species.

A variety of metal catalysts can be used, with copper(II) salts being the most popular.

For example, styrene was converted to its N-tosyl aziridine by reaction with [N-(tosyl)imino]phenyliodinane (PhI=NTs) and copper(II) triflate.

2.1) Asymmetric Synthesis of Aziridines

The asymmetric synthesis of aziridines can be achieved by a number of methods.

The best alkene substrates are typically α,β-unsaturated esters, styrenes or chromenes, with aziridination by PhI=NTs and a metal–chiral ligand complex.

For example, aziridination of tert-butyl cinnamate occurs highly enantioselectively with copper(I)triflate and a bisoxazoline ligand