The Robinson Annulation

If the preference for formation of a six-membered ring were not so great, what other cyclic product would be formed from the intramolecular aldol addition of 

Draw the product of the reaction of each of the following compounds with a base  

We have seen that Michael reactions and aldol additions both form new carbon-carbon bonds. The Robinson annulation is a reaction that puts these two carbon-carbon bond-forming reactions together in order to form an a,j8-unsaturated cychc ketone. Annulation comes from annulus, Latin for ring, so an annulation reaction is a ring-forming reaction. The Robinson annulation makes it possible to synthesize many complicated organic molecules. 

Notice that a Robinson annulation results in a product that has a 2-cyclohexenone ring. 

Draw the product obtained by heating each pair of ketones in a basic solution. 

The word annulation comes from the Greek word annulus for ring. The Robinson annulation is named for English chemist Sir Robert Robinson, who was awarded the 1947 Nobei Prize in Chemistry. 

The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction. Like the other reactions in Chapter 24, it involves enolates and it forms carbon-carbon bonds. The two starting materials for a Robinson annulation are an a,P-unsaturated carbonyl compound and an enolate. 

The Robinson annulation forms a six-membered ring and three new carbon-carbon bonds—two a bonds and one 7t bond. The product contains an a,P-unsaturated ketone in a cyclohexane ring—that is, a 2-cyclohexenone ring. To generate the enolate component of the Robinson annulation, OH in H2O and OEt in EtOH are typically used. 

The mechanism of the Robinson annulation consists of two parts a Michael addition to the a,P-unsaturated carbonyl compound to form a 1,5-dicarbonyl compound, followed by an intramolecular aldol reaction to form the six-membered ring. The mechanism is written out in two parts (Mechanisms 24.7 and 24.8) for Reaction [2] between methyl vinyl ketone and 2-methyl-l,3-cyclohexanedione. 

Mechanism 24.7 The Robinson Annulation—Part [A] Michael Addition to Form a 1,5-Dicarbonyl Compound 

The Robinson annulation forms a six-membered ring and three new carbon-carbon 

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The 5-oxohexanal 27 is prepared by the following three-step procedure (1) 1,2-addition of allylmagnesium bromide to an a, / -unsaturated aldehyde to give the 3-hydroxy-1,5-diene 25, (2) oxy-Cope rearrangement of 25 to give 26, and (3) palladium catalyzed oxidation to afford 27. The method was applied to the synthesis of A -2-octalone (28), which is difficult to prepare by the Robinson annulation[25]. 

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

FUJIMOTO - BELLEAU Cyclohexenone Synthesis Synthesis of fused cyclohexenones from lactones (an alternative to the Robinson annulation). 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

From a stereochemical point of view the Robinson annulation can be a highly complex reaction, since the configuration at five stereogenic sp -carbon centers... 

Since an annulated six-membered carbocycle is a common structural element of natural products, the Robinson annulation is an important reaction in organic synthesis. 

Scheme 5.1-33 The Knoevenagel condensation and the Robinson annulation in [HMIM][PFg],...

The Robinson annulation of ethyl acetoacetate and trans-chalcone proceeded smoothly to give 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone in 48 % yield. The product was separated from the ionic liquid by solvent extraction with toluene. In both these reactions, the ionic liquid [HMIM][PF6] was recycled and reused with no reduction in the product yield. 

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 tire 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 /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

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. 

Conditions for kinetic control of enolate formation can be applied to the Robinson annulation to control the regiochemistry of the reaction. Entries 5 and 6 of Scheme 2.11 are cases in which the reaction is carried out on a preformed enolate. Kinetic... 

The Robinson annulation is a valuable method for preparing bicyclic and tricyclic structures that can serve as starting materials for the preparation of steroids and terpenes.175 Reaction with 2-methylcyclohexan-l,3-dione gives a compound called the Wieland-Miescher ketone. 

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. 

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. 

While this example of the Robinson annulation is clearly not enantioselec-tive, the same antibody converts the mero-ketone [120] into the Wieland-Miescher (WM) decalenedione product kcM = 0.086 min-1 and Km = 2.34 mM at 25°C, parameters that give an impressive ER of 3.6 x 106. Good evidence suggests that the mechanism of the reaction involves the formation of a ketimine with the e-amino group of a buried lysine residue in the antibody, as shown in Fig. 39. Most significantly, the reaction delivers the ( )-(+)-WM product in 96% ee (by polarimetry) and in 95% ee by nmr and hplc analysis for a 100 mg scale reaction. A recent report tells that this antibody is to be made commercially available at a cost of 100 for 10 mg. The realization of that objective would mark the start of a new era of application of abzymes to organic stereoselective synthesis. 

Why does this pathway occur instead of the Robinson annulation when the seemingly trivial change of increasing the concentration of NaOH is made Good question. It is not clear. It seems likely that the Robinson annulation does occur first (because quick quenching helps to increase the quantity of Robinson product), but the Elcb elimination at the end of the annulation mechanism is reversible in the presence of NaOH as base. It seems likely, then, that if NaOEt were used as base instead, only the Robinson product would be observed regardless of the quantity of catalyst. 

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]. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

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]. 

Scheme 7.25. Annulation methodology a) Hajosh-Parrish version of the Robinson annulation, b) catalytic enantioselective annulation with functionalised organozinc reagents.

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

A variant of the Robinson annulation, where bulky amines such as pyrrolidine are used, making the conjugate addition to methyl vinyl ketone (MVK) take place at the less hindered side of two possible enamines. 

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). 

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