Michael-Robinson reaction

Concluding this chapter a very interesting variant72 of the Robinson-annela-tion73 has to be described. In a Michael-type reaction under aprotic conditions Li-1 -cyclohexene-1-olate (83) was employed to 2-TES-l-butene-3-one (84) (Scheme 10). 

This sequential process of Michael-aldol reaction leading to a new six-membered ring is known as the Robinson annelation. It was, in fact, Robinson who invented the idea of using a Mannich product in conjugate additions because he wanted to develop this important reaction. There are now thousands of examples used to make all kinds of compounds, especially steroids (Chapter 49). 

One of the most important reactions for the construction of six-member rings (the Diels-Alder reaction is another) is based on a tandem reaction sequence a Michael addition reaction followed by an intramolecular aldol-dehydration reaction. This sequence is called the Robinson annulation (Sir Robert Robinson, Nobel Prize, 1947). " ... 

Organic reactions in the solid state, e. g. Baeyer-Villiger, Reformatsky, Luche, Glaser, Eglington, Wittig, Brown. Michael, Robinson often more efficient than in solution. 

Scheme 2.20 Three-component domino Michael-Robinson annulation-hydro-genation reaction catalysed by a combination of L-proline, a chiral diamine, TEA and HCIO4.

Working with the Concepts Using Michael and Robinson Reactions in Synthesis... 

A Michael addition reaction followed by an intramolecular aldol condensation is known as the Robinson annulation, where the term annulation means ring formation. ... 

In this section we must also mention the syntheses of cyclopentano-phenanthrene derivatives described in Scheme 88. These include, in the first place, attempts to apply the Robinson synthesis (Chapter II, Schemes 24 and 25) to the preparation of tetracyclic products with an angular methyl group at CiQ. By this method, for example, from the acetylmethylcyclo-hexene (63) and 1,5-decalindione (4) it was expected to obtain the diketone (65) through a sequence of Michael addition reactions and intramolecular crotonic condensation. However, it was found that the presence of the ce-methyl group in the acetylcyclene (63) suppressed the Michael reaction and... 

Analogously to these examples, proline-derived peptide catalysts can also efficiently promote Michael addition reactions [97-99]. Prolinamide or prolyl sulfonamide catalysts are also effective for intramolecular Michael addition reactions [100-102]. Recently, Yang and Carter reported a short-cut strategy to construct an all-carbon substituted quaternary carbon stereogenic center on a cyclohexe-none framework via Robinson-type annulation using the 17-type catalyst (Scheme 1.4) [103]. 

This sequence of Michael reaction and cyclisation is known as tile Robinson annelation since it makes a ring. 

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). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

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. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-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. 

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

Michael reaction, 894-895 acceptors in, 895 donors in, 895 mechanism of. 894-895 Robinson annulation reactions and, 899-900... 

Example Compound (21) may not look like a Robinson annelation product, but it is certainly an enone so a,B disconnection gives a 1,5-di-carbonyl compound A reverse Michael reaction disconnecting the ring from the chain gives enone (22),... 

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). 

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. 

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%). 

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). 

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