Michael-Robinson

Michael Robinson (10) Division of Mathematics, School of Science and Mathematics, Sheffield Hallam University, FIK Gunnar Rosen (10, 12) Department of Work Organisation Research, National Institute for Working Life, Solna S 171 84, Sweden Sakari Sainio (16) Espoo-Vantaa Institute of Technology, Espoo, Finland Esa Sandberg (8) Satakunta Polytechnic, Pori FIN-28600, Finland... 

Submitted by John M. Cassady, Gary A. Howie, J. Michael Robinson, and Ioannis K. Stamos1... 

J. Michael Robinson, The University of Texas of the Permian Basin Suzanne Ruder, Virginia Commonwealth University... 

Submitted by John M Cassady, Gary A Howie, J Michael Robinson, and lOANNis K Stamos ... 

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

August Strindberg edited by Michael Robinson Jonathan Swift edited by Christopher Fox /. M. Synge edited by P. J. Mathews Tacitus edited by A. J. Woodman... 

August Strindberg ited by Michael Robinson Jonathan Swift ited by Christopher Fox J.M. Synge edit by P.J. Mathews Tacitus edited by A.J. Woodman Henry David Thoreau edited by Joel Myerson... 

August Strindberg, Miss Julie and Other Plays, trans. Michael Robinson (Oxford University Press, 1998), p. 176 translation modified. 

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.

J. Michael Robinson, Caroline E. Burgess , Melissa A. Bently, Chris D. Brasher, Bruce O. Horne Danny M. Lillard ... 

Shelley edited by Timothy Morton Mary Shelley edited by Esther Schor Sam Shepard edited by Matthew C. Roudane Spenser ited by Andrew Hadheld Laurence Sterne edited by Thomas Keymer Wallace Stevens edited by John N. Serio Tom Stoppard edited by Katherine E. Kelly Harriet Beecher Stowe edited by Cindy Weinstein August Strindberg edited by Michael Robinson Jonathan Swift edited by Christopher Fox /. M. Synge edited by P. J. Mathews Tacitus edited by A. J. Woodman Henry David Thoreau edited by Joel Myerson Tolstoy lited by Donna Tussing Orwin... 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

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

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)... 

Robinson annotation (Section 18 13) The combination of a Michael addition and an intramolecular aldol condensation used as a synthetic method for nng formation... 

Me02C xb Robinson Annulation (Aldol + Michael) MeOjC O Me ... 

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... 

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. 

Two-Group Disconnections III 1,5-Difunctionalised Compounds Michael Addition and Robinson Annelation... 

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%). 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

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