Anions Annulation, Robinson

Robinson annulation (Section 18.13) A combination of conjugate addition of an enolate anion to an a,p-unsaturated ketone with subsequent intramolecular aldol condensation. 

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

A rather nice example of enolate anion chemistry involving the Michael reaction and the aldol reaction is provided by the Robinson annulation, a ring-forming sequence used in the synthesis of steroidal systems (Latin annulus, ring). 

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

It is well known that the tricarbonylchromium-complexed benzylic anions and cations are stabilized due to overlapping between d-orbital of the chromium and p-orbital of the benzylic carbon [1]. Tricarbonylchromium complexes of a-te-tralone and a-indanone having a carbonyl group at the side chain underwent a deprotonation of the exo-benzylic protons by treatment with base to give the stereo-controlled tricyclic compounds (Eqs. 1 and 2) [2]. In these cases, Robinson annulation products were formed in less than 10% yield. Also, base treatment of benzyl ether chromium complex having a chlorine at the side chain 3 gave cyclization product as a diastereomeric mixture (Eq. 3) [3]. 

Section 23-3 reinforces the fact that anions of (i-dicarbonyl compounds are still enolates. Thus, you will find that they do 1,4-additions to a, (3-unsaturated carbonyl compounds (Michael additions). Furthermore, these additions can be followed by Robinson annulations. thereby resulting in six-membered rings. 

This reaction has been extended to the Michael Addition on a,)0-unsaturated nitrile by temporarily chelating the Grignard reagent to y-hydroxy unsaturated nitrile. An alternative route involving a free-radical )0-alkylation of nonactivated carbon atoms and subsequent anionic cyclization has been developed as a complementary route of the Robinson annulation. In addition, this reaction has been modified to occur under antibody catalysis" or with the combination of a lithium enolate with aluminum tris(2,6-diphenylphenoxide). Further modifications include the Robinson annulation in supercritical C02, the reaction promoted by K2CO3 under ultrasound,and the solid-supported reaction under microwave irradiation. ... 

A classical reaction of an enolate anion with a conjugated carbonyl leads to a bicyclic derivative. When cyclohexanone (58) is heated with methyl vinyl ketone (10) in the presence of ethanoUc KOH, the final product (after hydrolysis) is bicyclic ketone 64. This process is called the Robinson annulation, after Sir Robert Robinson (England 1886-1975). It begins with the reaction of 58 with KOH to form the enolate anion (59). Under these conditions, Michael addition to 10 is faster than self-condensation of the ketone (see Chapter 22, Section 22.2), and the product is enolate anion 60. 

Scheme 8.63. A representation of the Robinson annulation process. The initial addition of the enolate anion to the a,P-imsaturated ketone represents a Michael reaction. Subsequent cyclization with loss of water is an aldol reaction.

Scheme 9.85. The Robinson annulation.The reaction of cyclohexanone with l-bntene-3-one in the presence of ethoxide anion to produce the corresponding bicyclo[4.4.0]-A -decene-2-one. See Rapson, W. S. Robinson, R. /. Chem. Soc., 1935,1285.

The conjugate addition of enolate anions to activated 3-trimethylsilyl-3-buten-2-one helped solve another long-standing problem in organic synthesis by permitting the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration is avoided. The annulation of thermodynamically unstable lithium enolates with MVK, where equilibration to the more stable enolate occurs prior to Michael addition, often yields a mixture of stractmal isomers. For exan le, Boeckman successfully employed 3-trimethylsilyl-3-buten-2-one in a Robinson annulation sequence (eq 2). Thus treatment of cyclohexenone with lithium dimethylcuprate in diethyl ether and then with 3-trimethylsilyl-3-buten-2-one gives the desired Michael adduct, which is converted into the functionalized octalone in 52% overall yield. ... 

A final note You may have recognized that the allylic anion discussed above is also benzylic and hence enjoys additional resonance stabilization by conjugation with the benzene ring. Benzylic resonance will be discussed in detail in Section 22-1. For more practice with Robinson annulations, go to Problems 59, 63, and 64. 

In Summary -Dicarbonyl anions, like ordinary enolate anions, undergo Michael additions to a,/8-unsaturated carbonyl componnds. Addition of a /8-ketoester to an enone gives a diketone, which can generate six-membered rings by intramolecular aldol condensation (Robinson annulation). 

The Robinson annulation (or annelation) is a powerful synthesis of six-membered rings involving conjugate addition of an enolate, followed by an aldol condensation. A simple example is shown in Figure 17.72. The diketone is readily converted completely into the enolate anion and then attacks the enone, to give, after reketonization, a 1,5-dicarbonyl compound. This diketone undergoes an... 

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