Conjugate addition reactions Robinson annulation reaction

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. 

A popular and useful application of the conjugate addition reaction is the combined conjugate addition-intramolecular aldol strategy, commonly known as the Robinson annulation. When the Michael donor is a ketone and the Michael acceptor an a,p-unsaturated ketone, the product is a 1,5-diketone which can readily undergo cyclization to a six-membered ring. Typical Michael donor substrates are 2-substituted cyclohexanones, which condense with alkyl vinyl ketones to give the intermediate conjugate addition products 42 (1.52). The subsequent intramolecular... 

Conjugate addition reactions, including the Robinson annulation, which make use of reactive Michael acceptors such as methyl vinyl ketone, can suffer from low yields of the desired adduct. The basic conditions required for enolate formation can cause polymerization of the vinyl ketone. Further difficulties arise from the fact that the Michael adduct 42 and the original cyclohexanone have similar acidities and reactivities, such that competitive reaction of the product with the vinyl ketone can ensue. These problems can be minimized by the use of acidic conditions. Sulfuric acid is known to promote the conjugate addition and intramolecular aldol reaction of 2-methylcyclohexanone and methyl vinyl ketone in 55% yield. Alternatively, a silyl enol ether can be prepared from the ketone and treated with methyl vinyl ketone in the presence of a Lewis acid such as a lanthanide triflate" or boron tri fluoride etherate (BF3 OEt2) and a proton source to effect the conjugate addition (followed by base-promoted aldol closure). 

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 ... 

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). 

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... 

These ,(i-unsaLurated ketones and aldehydes are used as reactants in conjugate additions (Section 2.6), Robinson annulations (Section 2.1.4), and in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.12 illustrate... 

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

The sequence that follows illustrates how a conjugate aldol addition (Michael addition) followed by a simple aldol condensation may be used to build one ring onto another. This procedure is known as the Robinson annulation (ring forming) reaction (after the English chemist Sir Robert Robinson, who won the Nobel Prize in Chemistry in 1947 for his research on naturally occurring compounds). 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

The Michael reaction in combination with an aldol condensation provides a useful method for the construction of six-membered rings in a process termed the Robinson annulation. In the following example a tertiary amine is used as the base to catalyze the conjugate addition. Then, treatment with sodium hydroxide causes an intramolecular aldol condensation to occur. 

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... 

Q Predict the products of conjugate (Michael) additions, and show how to use these reactions in syntheses. Show the general mechanism of the Robinson annulation, and use it to form cyclohexenone ring systems. 

In an a,P-unsaturated carbonyl system, the addition could be either 1,2 or 1,4, i.e. simple or conjugate. With Grignard reagents, the nucleophilic addition can be either 1,2 or 1,4, and often depends upon any steric factors that are present in the substrate. When an a,P-unsaturated carbonyl compound is treated with a carbanion, particularly one that is stabilised by a carbonyl group, the resultant 1,4-addition with the formation of a new carbon/carbon bond is called the Michael reaction. If the reaction occurs intramolecularly, it is called the Robinson annulation reaction. 

One problem with the Robinson annulation is the reversible nature of the initial Michael addition. One solution is to use a conjugated system that is particularly prone to Michael addition and forms the product, essentially irreversibly. a-Silyl vinyl ketones have been shown to be powerful Michael acceptors.The lithium enolate of cyclohexanone reacted with conjugated ketone 559 to produce the Michael product. 560.304b jn this case, the initially formed Michael adduct was stabilized by the presence of the silyl group at the a-position, driving the reaction toward the product. Hydrolysis produced 561, which was converted to the Robinson product (562) in 80% overall yield by treatment with NaOMe/MeOH under the requisite thermodynamic conditions.304b Pq,. this sequential process is justified when compared with normal treatment... 

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. 

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. ... 

In Summary The Michael addition results in the conjugate addition of an enolate ion to give dicarbonyl compounds. The Robinson annulation reaction combines a Michael addition with a subsequent intramolecular aldol condensation to produce new cyclic enones. 

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