The Robinson Annulation Reaction

Because the Michael addition step involves the thermodynamic enolate, Robinson annulation reactions are regioselective with unsymmetrical ketones. As entry 4 illustrates, the methyl group of 2-methylcyclohexanone appears at the ring junction in the annulated product. In order to achieve the opposite regioselectivity in annulation, recourse is taken to enamine methodology. Since the more stable pyrrolidine enamine of 2-methylcyclohexanone is the less substituted one (as discussed in Chapter 1, Section 1.9), annulation via the enamine occurs away from a 2-alkyl group. Entries 4 and 5 illustrate the complementary nature of annulation using enolates and enamines. 

An alternative version of the Robinson annulation procedure involves the use of methyl 1-trimethylsilylvinyl ketone. The reaction follows the normal sequence of conjugate addition, aldol addition, and dehydration  

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

The role of the trimethylsilyl group is to stabilize the intermediate carbanion formed by conjugate addition. The silyl group is removed under conditions similar to those required for the dehydration the removal occurs by nucleophilic attack on silicon resulting in displacement of the ketone. The advantage of the substituted methyl vinyl ketone is that it permits the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration does not take place. The annulation of unsymmetrical ketones can therefore be controlled by using specific enolates generated by the methods described in Chapter 1. 

There is a pronounced preference for the formation of trans double bonds in the Claisen-Schmidt condensation of methyl ketones. This stereoselectivity arises in the dehydration step. In the transition state for elimination to a cis double bond, an unfavorable interaction between the ketone substituent (R) and the phenyl group occurs. This unfavorable interaction is absent in the transition state for elimination to a trans double bond. 

Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for the synthesis of polycyclic molecules. The word annulation comes from the Latin annulus, meaning ring, so an annulation reaction builds a new ring onto a molecule. 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a j8-keto ester, an enamine, or a )8-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

In this example, the )3-diketone 2-methyl-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,)3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

What product would you expect from a Robinson annulation reaction of2-methyl-1,3-cyclo-pentanedione with 3-buten-2-one  

How would you prepare the following compound using a Robinson annulation reaction between a 8-diketone and an o ,j8-unsaturated ketone Draw the structures of both reactants and the intermediate Michael addition product. 

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Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

An alternate means of forming 96 arises from reaction of imine 97 with methylvinylketone in a variant of the Robinson annulation reaction. This... 

A procedure using a phase-transfer catalyst is employed to prevent the rapid polymerisation of crotonaldehyde dining the Robinson annulation reaction. 

The Robinson annulation reaction of 7-methoxy-l-methyl-2-tetralone with methyl vinyl ketone in the presence of A,-(4-trifluoromethylbenzyl)cinchonidinium bromide produces the S-isomer of the tricyclic compound (Scheme 12.10) with an 81% conversion (81% ee) [8]. 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

Show the intermediate aldol product in the Robinson annulation reaction of ethyl 2-oxocyclohexanecarboxylate with 1 -penten-3-one. 

Show syntheses of these compounds using the Robinson annulation reaction ... 

The Robinson annulation reaction combines a Michael reaction with an intramolecular aldol condensation to synthesize substituted ring systems. 

Carbonyl Condensnlion Reactions in Synthesis The Robinson Annulation Reaction 9 0... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson annulation reaction, which leads to the formation of substituted cyclohexanones. Treatment of a i dikotone or -keto ester u-itb an o,fi-unsaturated ketone leads first tu a Mie nael addition, which is followed by intramolecular aldol cycUaatinn. Condensation reactions are also used widely in nature for the bionyntbesis of such molecules as fats and steroids. 

The intramolecular aidol condensation is a powerful tool for obtaining five- and six-member rings. This is an important step in the Robinson annulation reaction (see Section 7.9). 

Kuo, F., Fuchs, P. L. Bruceantin support studies. II. Use of 1-penten-3-one-4-phosphonate as a kinetic ethyl vinyl ketone equivalent in the Robinson annulation reaction. Synth. Commun. 1986, 16,1745-1759. 

Kim, S., Emeric, G., Fuchs, P. L. Use of 3-silylethyl vinyl ketone as a 3-hydroxyethyl vinyl ketone synthon in the Robinson annulation reaction. J. Org. Chem. 1992, 57, 7362-7364. 

When an a,P-unsaturated carbonyl compound is treated with a carbanion, particularly one that is stabilised by a carbonyl group as well, the resultant 1,4-addition with the formation of a new carbon/carbon bond is called the Michael reaction. Like the Claisen condensation, it is possible for this reaction to occur in an intramolecular manner with a suitably substituted compound. This reaction leads to the formation of a new ring and is called the Robinson annulation reaction. Write down the complete reaction sequence for the reaction between cyclohexanone and but-l-en-3-one. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

The following reaction illustrates the Robinson annulation reaction (Section 19.7A). Provide a mechanism. 

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