Robinson Annulation

The Robinson annulation is a ring forming chemical process utilised in organic chemistry. Robert Robinson found it in 1935 as a way to make a six-membered ring by generating three new C–C bonds. A Michael addition followed by an aldol condensation is used to generate a -unsaturated ketone in a cyclohexane ring using a methyl vinyl ketone and a ketone. One of the most important plan for forming fused ring systems is to employ this procedure.

The synthesis of numerous natural products and other interesting chemical molecules, such as steroids and antibiotics, requires the formation of cyclohexenone and its derivatives. The Robinson annulation is used to complete the synthesis of cortisone in particular.

While Rapson was studying at Oxford with professor Robinson, William Rapson and Robert Robinson wrote the first work on the Robinson annulation. The,-unsaturated ketone component was not used in cyclohexenone synthesis prior to their work.

The methyl vinyl ketone was initially combined with a naphthol to produce a naphtholoxide. This process was inadequate to produce the desired cyclohexenone. This was due to the reaction's insufficient settings.

In 1935, Rapson and Robinson discovered that the reaction of cyclohexanone with a,-unsaturated ketone produces the required cyclohexenone. It is one of the most critical ways for making six-membered ring compounds. Because of its widespread application, many elements of the reaction have been studied, including substrate changes and reaction conditions.

Mechanism of action

In the presence of base sodium ethoxide, arrow pushing for the Robinson annulation between 2-methylcyclohexan-1-one and but-2-en-3-one. The Robinson annulation's original technique starts with the nucleophilic assault of a ketone in a Michael reaction on a vinyl ketone. It resulted in the intermediate Michael adduct. The keto alcohol is produced as a result of the subsequent aldol type ring closure, followed by dehydration to create the annulation product

The ketone is deprotonated by a base, forming an enolate nucleophile. It attacks the electron acceptor in the Michael process. An,-unsaturated ketone is the most common acceptor, but aldehydes, acid derivatives, and other related molecules can also be used. The creation of the thermodynamic enolate dictates regioselectivity in the outline.

Alternatively, because deprotonation at the carbon flanked by the carbonyl groups is significantly favoured, regioselectivity is commonly controlled by utilising a -diketone or -ketoester as the enolate component. The six-membered ring is then installed as a result of the intramolecular aldol condensation. The four-carbon bridge of the newly installed ring is made up of the three carbon atoms of the,-unsaturated system and the carbon to its carbonyl group in the by-product.

To avoid a reaction between the original enolate and the cyclohexenone product, the first Michael adduct is frequently separated first, followed by cyclization to yield the desired octalone. The production of hydroxy ketones in the Robinson annulation reaction scheme has been studied in stereochemistry. In kinetically regulated processes, the trans compound is preferred due to antiperiplanar effects of the final aldol condensation. However, it has also been discovered that cyclization can occur in a synclinal orientation. The three probable stereochemical paths are depicted in the diagram below, assuming a chair transition state.

The discrepancy in the production of these transition states and their related products is caused by solvent interactions. Scanio discovered that altering the reaction's solvent from dioxane to DMSO results in variable stereochemistry. This shows that different transition phases come up when aprotic or protic solvents are present.

Classification based on mechanisms

Robinson annulation is a well-known example of a larger class of chemical transformations known as Tandem Michael-aldol reactions. They combine the aldol reaction and Michael addition in one step. Michael addition normally occurs first to bind the two reactants together. Then the aldol reaction occurs intramolecularly to produce the ring system in the result, as with Robinson annulation. Rings with five or six members are most common.

Conditions of reaction

Although the Robinson annulation is usually carried out in basic conditions, reactions have been carried out in a number of ways. Ellis and Heathcock report similar results to the sulfuric acid-catalyzed and base-catalyzed technique. The Michael reaction can occur in the presence of an enamine under neutral circumstances. The Michael adduct can be made by heating a Mannich base in the presence of a ketone. The Robinson annulation procedures have been used to prepare chemicals successfully.