Michael reaction Robinson annulation reactions

Problem 23.22 How would you prepare the following compound using a Robinson annulation reaction between a jS-diketone and an, /3-unsaturated ketone Draw the structures of both reactants and the intermediate Michael addition product. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by Entry 6. Entry 7 shows a annulation using silyl enol ether as the enolate equivalent. These reactions are called Mukaiyama-Michael reactions (see Section 2.6.3). 

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent Robinson annulation reactions of isophorone with chalcones were performed efficiently in a solvent-free PTC system under the action of MW irradiation. Compared with conventional heating substantial rate enhancements were observed, within very short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far better than those achieved by the classical method (NaOEt in EtOH under reflux for 24 h 40-56%). 

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... 

Fig. 13.71. Tandem reaction I, consisting of a Michael addition and an aldol condensation Robinson annulation reaction for the synthesis of six-membered rings that are condensed to an existing ring.

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

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 cyclohexenones. Treatment of a /8-diketone or fi-keto ester with an a,p-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Progesterone, a female sex hormone, has been prepared by total synthesis and by modifications of other steroids. Using established methodologies, such as Diels-Alder cycloadditions, Michael additions, Robinson annulations, aldol reactions, and ring contraction reactions, propose a total synthesis of progesterone. Discuss the merits of your approach in comparison with the total synthesis reported by Woodward, R. B., Sondheimer, R, Taub, D., Heusler, K., McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223. 

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. 

Robinson annulation reactions involve two steps Michael addition and aldol condensation. Assume that Michael addition leads to the following intermediate. What would be produced when this intermediate undergoes aldol condensation ... 

Annulation. 3-Trimethylsilyl-3-buten-2-one has been employed as a methyl vinyl ketone homolog in an improved method for the annulation of ketones. Based on work by Stork and Ganem, who employed 3-triethylsilyl-3-buten-2-one as a Michael acceptor in the Robinson annulation reaction, Suzuki and co-workers prepared a functionalized bicyclic ketone via a silyl enol ether as shown in eq 1. In general, the annulation of 2-alkylcycloketones with methyl vinyl ketone and its homologs produces rather poor yields of the desired cyclized products. 

The alcohol adducts from Q -(trimethylsilyl)vinyllithium and aldehydes have found many uses in organic synthesis. The ketones obtained by oxidation (eq 4) are especially good Michael acceptors and have been used in a modified Robinson annulation reaction for the construction of cyclohexenones. Cyclopropana-tion leads to cyclopropylsilane adducts, which can be converted into a variety of cyclopentenes (eq 5). Halogenation followed by stannylation gives synthons (eq 6) useful for making substituted vinylsilanes through radical reactions. ... 

As we saw in Chapter 1, Michael additions to a,jS-unsaturated ketones occur best when the nucleophile is only weakly basic. In entries 1 and 2 of Scheme 2.2, we note examples of Robinson annulation reactions in which the nucleophiles are derived by deprotonation of a /3-diketone and a /3-keto ester, respectively. The Michael acceptor is methyl vinyl ketone in entry 1 and is ethyl vinyl ketone in... 

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. 

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. 

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

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." ... 

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). 

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