Michael addition and elimination

A -compounds (130) with CH2NO2 leads to the nitrocyclopropanes (131) by Michael addition and elimination of HBr. Various transformations of the la-nitromethyl-3-oxo-compounds (132) include its conversion into the la-formyl-3-oxo-compound (133), which on hydride reduction was converted into the tetra-hydrofuran (134). ... 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Acylketene dithioacetal 107 and the corresponding /3-methylthio-a,/3-enone 108 undergo self-condensation and aromatization in the presence of sodium hydride and methyl benzoates in refluxing xylene to give 2,6-bis(methylthio)-4-hydroxyacetophenone (109) and 4-hydroxyacetophenone (110), respectively, in good yields (equation 103) . The possible pathway for the formation of 109 and 110 could involve base-catalysed condensation of either 107 or 108 with methyl benzoates followed by successive inter-and intramolecular Michael additions and elimination of SMe. No reaction is observed in the absence of methyl benzoates. 

We know how stabilized carbanions such as enols and enolated enamines are key intermediates in biological isomerization reactions and in carbon-carbon bond-forming and bond-breaking events. In this chapter, we will look at two more important reaction types, called Michael additions and -eliminations, which involve stabilized carbanion species as intermediates. In a Michael addition, a nucleophile and a proton are added to the two carbons of an alkene that is conjugated to a carbonyl group. The reverse of a Michael addition is called a -elimination. 

KOMe [93% (all- )]. Notably, /-BuOK does not promote the elimination in this case. The mechanism of this process is different from that with the alkoxysulphones. The initial step is formation of a vinyl sulphone 50. Isomerization of this intermediate to the allylic sulphone 48 via 51 is effected by Michael addition and elimination of methanol. The ineffectiveness of t-BuOK is explained by this mechanism. This bulky reagent cannot abstract the proton from the a-carbon of the sulphonyl group because this is embedded in a sterically highly crowded environment. Moreover, r-BuOK does not participate in the Michael addition because of its weaker nucleophilic character. 

JV-Alditol-l-yl bases, e.g. the thymine derivative 86, were synthesized ftom the 6-0-tosyl-D-glucal derivative 84 (Scheme 8). The cu-double bond in 86 results from a Michael addition and elimination of methanol prior to reduction of the rrnns-enal 85. Reductive ring-opening of nucleosides to A-(l-deoxy-D-riho-pentitol-l-yl)purines is covoed in Chapter 20. 

In order to study the reactivity of the nitrogen atom in saccharidic OZT moieties Rollin and co-workers13,55 explored some standard reactions IV-acylation, IV-sulfonylation, IV-vinylsulfonylation by Michael addition, reductive elimination, conjugated addition and cycloaddition. 

Michael addition and intramolecular aldol condensation-elimination process to afford coumarin derivatives 523 and 524, respectively [236]. 

A surprising feature of these reactions is their apparent departure from the Michael-addition/o -elimination sequence, which is expected to lead, via alkylidenecarbenes 275, to a 2,5-disubstitution pattern in the products. This has been attributed to the initial formation of iodine(III)-sulfur(selenium) adducts 276 and their collapse by a hetero-Claisen rearrangement to the isomeric alkylidenecarbenes 277 (Scheme 78). In view... 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

The reaction is AdN2 addition to the polarized multiple bond (Adj, then p.t.). This reaction is easy to predict because the most stable product is formed under these equilibrium conditions. HSAB theory predicts that the combination of the two softest sites is favored. This conjugate addition is often called a Michael addition and forms the first step in the Robinson annotation diagramed in Figure 8.9. The later steps are an aldol addition (AdN2) to form the new ring followed by elimination by ElcB to give the bicyclic product. 

The products obtained from the reaction of (chloromethyl)trimethylsilane with organolithium reagents depend very much on the structure of the lithium compound. While lithium 2,2,6,6-tetramethylpiperidide initiates an a-elimination as described above, the treatment with sec-butyllithium leads to the formation of chloro(trimethylsilyl)methyllithium (11). This reagent cyclopropanates an electron-deficient alkene through sequential Michael addition and intramolecular ring closure (MIRC reaction), for example, the formation of cyclopropane 12. 

Nature is generally reluctant to carry out classical, central S- 2 reactions, with the exception of methylations - glycosyl- and prenyl-transfer reactions are very S Nl-like. A much preferred route for displacements of sugar substituents is oxidation by a tightly bound nicotinamide cofactor of a p-hydroxyl, elimination of the leaving group, introduction of the substituent in a Michael addition and reduction, as dealt with in Section 6.8. 

Figure 6.67 Stereoelectronics of eliminations and additions, (a) Orbital overlap favouring anti elimination/addition. (b) Cartoon of least-motion arguments favouring anti elimination. The dotted line represents the reference plane, which is perpendicular to the plane of the paper, (c) Biirgi-Dunitz-like approach in Michael additions and examples.

Substituted pyrrole-2-carboxylic esters 19 are synthesized from A-tolylsulfonyl glycine ester 17 and vinyl ketones Kenner synthesis) [42]. By Michael addition and intramolecular aldol addition, they first yield pyrrolidine-2-carboxylic esters 18. These are converted into pyrroles by succesive H2O and sulfmic acid eliminations. 

The second exanple is a new synthetic approach to the synthesis of nakadomarin A 202 rscheme 20.. 38T To this end, Wnkler and coworkers developed a tandem Pummerer-Michael process.The generation of the activated thionium ion was performed by the elimination of ethanethiol from thioacetal 198. The intermediate 199 showed double reactivity, that is, a nucleophilic position on the furan to perform the Michael addition and the usual electrophilic thionium, which was in fact trapped by the enamine carbon generating tetracyclic product 200. Winkler presented the s)mthesis of a tetracyclic model system and suggested that this reaction sequence can also be applied to the synthesis of the natural product. 

P-, and S-Heterocycles The reaction of two similar or dissimilar aryl aldehydes 250/251 with malonodi-nitrile 21 or ethyl 2-cyanoacetate 175 catalyzed by Af-hetero-cyclic carbenes (NHCs) has been demonstrated to provide fully substituted furans 252 in good to high yields (74-90%), within short reaction times up to 5 h under solvent-free conditions (Scheme 13.59) [97]. This transformation is based on the umpolung of one of the aldehydes by the NHC, while the other one undergoes a Knoevenagel condensation with the CH-acidic reaction partner. The Breslow intermediate then attacks the condensation product in fashion of a Michael addition. After elimination of the NHC, base-catalyzed cyclization provides the desired products. Five different NHCs have been tested catalyzing this reaction. 

Within a sequence of Knoevenagel condensation, Michael addition and condensation, Meldrum s acid can be used as a CHj-C(O) equivalent, through the elimination of acetone and subsequent decarboxylation (Scheme 13.86). In this sequence, other 1,3-dicarbonyl compounds within the reaction mixture serve as nucleophile in the Michael addition. By addition of a nitrogen source to this reaction... 

The steps in the formation of 5-hydroxymethyl furfural (HMF) from 1,2-enediol is shown in Formula 4.37. HMF is also used as an indicator for the heating of carbohydrate containing food, e. g., honey. The (retro-Michael addition) water elimination at C-3 and subsequently at C-4 leads to a 1,2-diulose (3,4-dideoxyosone), which after cyclization to a hemiacetal, a dihy-drofuran, releases another molecule of water, producing HMF. In the same way, e. g., furfural can be made from pentoses and 5-methylfurfural from the 6-methylpentose rhamnose. 2-Hydroxyacetylfuran, which is preferentially formed from fructose, can be obtained starting from the corresponding 2,3-enediol by water elimination at C-4, followed by C-5 (Formula 4.38). 

Primarily, Michael addition and intramolecular aldol addition gives rise to pyrrolidine-2-carboxylic esters 52, which are converted into pyrrole-2-carboxylates 53 by successive H2O and sulfinic acid eliminations. 

Thiol Substitution Reactions. Vital to the usefulness of 2-(trimethylsilyl)ethanethiol is that it behaves as a typical thiol. Base mediated reactions that proceed as expected include alkylation and nucleophilic ring openings. Moreover, addition-eliminations on unsaturated systems, Michael additions, and c -additions to triple bonds (eq 2) are all routine. To access 2-(trimethylsilyl)ethyl thioethers, a useful procedure is hydrolysis of 2-(trimethylsilyl)ethyl thiolacetate and alkylation of the thiolate in a single pot. ... 

An unusual formation of furans 155 (together with the corresponding pyrroles 156) was observed when compound 154 was treated with two equivalents of primary amine. Ratio of products depends on amine properties. Thus, if the amine acts as a base, the reaction proceeds via the intermediate enolate and an intramolecular Michael addition/fluoride elimination sequence. Further nucleophilic displacement of the ethylsulfanyl group gives 3-carboxamide furans 155. If the amine acts as a nucleophile, a Michael addition/elimination followed by an intramolecular condensation leads to the corresponding pyrrole 156 via the enaminone [112, 113]. 

Boron trifluoride etherate, is also a good catalyst for this hydride transfer to chalcone. Unlike triphenylmethyl perchlorate, however, chalcone is able to enter Michael additions with the 1,5-diketone followed by eliminations leading to unexpected products, e.g., 3-benzyl-2,4,6-triphenylpyrylium from 2-carbethoxy-l,3,5-tri-phenylpentane-l,5-dione and chalcone the benzyl group originates from chalcone, the elimination product being ethyl benzoylacetate. ... 

These amines gave, with methyl propiolate, products of Michael mono- and bis-addition. Adducts underwent further reaction leading to triazolo[4,5-/]quinolones 181, after retro Diels-Alder reaction and acetylene elimination to its methoxycar-... 

Michael addition of the enamine to the 1,3-enyne double bond (intermediate 151) and subsequent intramolecular attack of the triple bond by the amino group (intermediate 152) with the r XH elimination (formation of 2,6-isomer 148). 

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