The Robinson Annelation Reaction

A recently introduced version of the Robinson annelation procedure involves the use of methyl 1-trimethylsilylvinyl ketone. The reaction follows the normal sequence of conjugate addition, aldol addition, and dehydration  

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 annelation reaction to be carried out in aprotic solvents under conditions where enolate equilibration does not take place. The annelation of unsymmetrical ketones can therefore be controlled by using specific enolates generated by the methods described in Chapter 1. 

From a mechanistic point of view, aldol reactions involving two different carbonyl compounds are feasible. To be preparatively useful, however, there must be some basis for selectivity in the reaction i.e., one component must be more likely to function as the nucleophilic reagent and the other as the carbonyl acceptor. If this requirement for selectivity is not met, a product mixture containing both self- 

One of the most important cases of mixed condensations involves the reaction of aromatic aldehydes with aliphatic ketones or aldehydes. An aromatic aldehyde cannot function as the nucleophilic species because, lacking an a-hydrogen atom, it is incapable of forming an enol or enolate. Dehydration is favored because it leads to a double bond conjugated with both the carbonyl group and the aromatic ring  

Additional insight into the factors affecting product structure was obtained by studies on the Claisen-Schmidt condensation of 2-butanone with benzaldehyde.  

2-Carbethoxycyclooctanone (40 g, 0.2 mole) dissolved in 50 ml of dry benzene is added to the stirred sodium hydride over about 30 minutes at room temperature. The mixture is stirred an additional hour at room temperature to complete the formation of the sodium salt. Methyl iodide (284 g, 2.0 mole, a 10-fold excess) is added to the stirred solution over 1 hour and the stirring at room temperature is continued for 20-24 hours. The reaction mixture is poured cautiously into 500 ml of 3 aqueous acetic acid, and the aqueous solution is extracted three times with 100-ml portions of benzene. The combined benzene extracts are washed three times with water and dried over anhydrous magnesium sulfate. Benzene and excess methyl iodide are removed under reduced pressure (rotary evaporator) and the residue is distilled. 

The ketoester is mixed in a suitable round-bottom flask with excess 6 N sulfuric acid. The flask is fitted with a condenser and a mantle, and the mixture is refluxed gently for 3-4 days. The cooled reaction mixture is extracted with ether, the ether is washed with bicarbonate solution and water, then dried, and the solvent is evaporated. On distillation, the residue affords 2-methylcyclooctanone, bp 97-98718 mm, 86712 mm, 1 4656, 

The Robinson annelation reaction has classically been employed for the building up of the six-membered ring components of the steroid nucleus (18). In the original method, the enolate is treated with the methiodide of )9-diethylaminoethyl methyl 

5 g sample of c/5-10-methyl-2-decalon-9-ol is mixed with 100 ml of 10% aqueous potassium hydroxide and steam distilled, about 1 liter of distillate being collected. The distillate is saturated with sodium chloride and extracted three times with 100-ml 

Modem Synthetic Reactions, Chaps. 7-9. Benjamin, New York, 1965. 

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Problem 17.49 The Robinson annelation reaction for synthesizing fused rings uses Michael addition followed by intramolecular aldol condensation. Illustrate with cyclohexanone and methyl vinyl ketone, CHj=CHCOCH,. <... 

WICHTERLE REACTION, Modification of the Robinson annellation reaction in which 1,3dichloro-ci,r-2-butene is used instead of methyl vinyl ketone... 

The forward synthetic reaction is a base-catalysed condensation reaction between two carbonyl compounds, the aldol condensation leading to -hydroxy-aldehydes or / -hydroxyketones followed by dehydration. This sequence is one of the most important carbon-carbon bond forming reactions, and aldol-type condensation reactions are considered in a number of other sections of the text, for example, the Doebner reaction (Section 5.18.3, p. 805), the Knoevenagel reaction (Section 5.11.6, p. 681), the Perkin reaction (Section 6.12.3, p. 1036) and the Robinson annelation reaction (Section 7.2). 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

EttdaUne sesquiterpenes. Syntheses of eudaicne-type sesquiterpenes commonly utilize the Robinson annelation reaction to construct the bicyclic ring system. However, this annelation reaction often proceeds in low yields and with stereochemical difficulties. Huffman and Mole have recently reported a new stereoselective synthesis. 8-Methoxy-tctralin-2-carboxylic acid (1) is reduced under Birch conditions followed by acid... 

Examples of intramolecular aldol reaction are legion, mainly in the context of the Robinson annelation reaction. Because this process has been the subject of recent reviews," we do not here attempt an exhaustive survey. Emphasis in this chapter is placed on representative examples, to show the scope of the reaction, and questions of regio- and stereo-selectivity. 

Dianions of /8-keto-esters can be alkylated with a-chloro-ethers to give 5-alkoxy-jS-keto-esters in ca. 70% yield. These compounds serve as useful alternatives to y5-unsaturated-/8-keto-esters in the Robinson annelation reaction.Clean nucleophilic displacement of bromine from y-bromoacetoacetates can be effected by prior protection of the keto-ester system as the sodium enolate. ... 

Several of the earlier syntheses of eremophilane sesquiterpenes have utilized the Robinson annelation reaction as a key step ". However, the synthesis of nootkatone outlined below is based on acid catalyzed rearrangement of the Diels-Alder adduct (B), directly available from a 1-methoxycyclohexa-l,4-diene (A), to a 4-substituted cyclohexenone which undergoes ring closure in formic acid to give the desired eremophilane skeleton. 

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