Michael addition, -, 1,2-double

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

In a related example, reaction of N-hydroxy-N-methylthiophene-2-carboximidamide 56 with DMAD gave a double Michael addition product 57, which when heated at reflux in xylenes, afforded hydroxypyrimidinone 60 in 57% overall yield (Scheme 6.21) [9f]. The mechanism invoked was opening of the oxa-diazole 57 to 58, followed by a [3,3]-Claisen-type rearrangement to 59, which, after tautomerization and cyclization, afforded 60. 

Scheme 2.2. Double Michael addition leading to bicyclo[2.2.2]octane 2-4.

Double Michael additions of nitro compounds bearing tethered acidic carbons to 3-butyn-2-one under NaH catalysis give nitrocyclohexanes with high stereoselectivity. The products are transformed into traws-fused bicyclic compounds via the Dickmann reaction on treatment with base. (Eq.4.129).176... 

Barco and coworkers have reported a more elegant synthesis of the nitrocyclohexanone via the double Michael addition of nitromethane with enones. (Eq. 4.130).178... 

Sodium sulfide or hydrosulfide can be used in double Michael additions thus the bridged thiopyran (11) is formed from 2,7-cyclooctadienone (12),12 and dihydrodithiin oxides (13) and related compounds are similarly produced from unsaturated sulfoxides (14).13... 

The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. 

An acid-catalyzed double-Michael addition of water to the bridged bis-dioxine moiety in a larger macrocyclic framework has been described by the Kollenz group (Scheme 6.134) [269]. While conventional reaction conditions failed to provide any of the desired functionalized 2,4,6,8-tetraoxaadamantane product, microwave heating of the hydrophobic macrocyclic bisdioxine in a 1 1 mixture of 1,2-dichloroethane and acetic acid containing excess concentrated hydrochloric acid at 170 °C for 40 min provided a 35% isolated yield of the desired oxaadamantane compound. 

A dodecakis(NCN-Pdn) catalyst, synthesized in the group of Van Koten (Figure 4.24), was applied in the a continuous double Michael addition reaction between methyl vinyl ketone (MVK) and ethyl a-cyanoacetate.[34] The reaction was performed in the deadend reactor discussed in paragraph 4.2.1. Two catalytic runs were performed differing in the amount of catalyst and in the applied flow (both increased by a factor 2.5). Both runs showed high productivity for more than 24 h (Figure 4.25). 

Figure 4.25. Continuous double Michael addition. (Reprinted with permission from ref. 34. Copyright 2003...

A new three-component approach to the highly substituted 2,5-dihydro-l,2,4-oxadiazoles 359 has been reported from the reaction of nitriles 354 under mild conditions with iV-alkylhydroxylamines 355 in the presence of electron-deficient alkynes 356 (Scheme 60) <20050L1391>. This synthesis is proposed to proceed via the initial formation of the alkyl or arylamidoximes 357, which then undergo a sequential double Michael addition to the electron deficient alkyne. The intermediate alkyl or arylamidoximes 357 can be isolated and then reacted with the alkyne to produce the product. The initial Michael adduct 358 is stable in cases where R2 is H. 

By using diamines, the 2-alkyl-(benzo)imidazolines 581 and 582 were formed by a double Michael addition reaction and subsequent elimination of MeCN [266, 267]. 

Secondary nitro compounds can be converted into carbanions in similar fashion. Interesting highly functionalized adducts (46) were prepared by addition to levoglucosene (45) (equation 17)59. Mixtures of diastereomeric adducts were generally formed60. The adduct from nitromethane undergoes double Michael addition followed by aldol condensation to afford the novel adduct 47. 

Most aryl alkyl sulphones react with electron-deficient alkenes in the expected manner [e.g. 4-8] and a-(arenesulphonyl)acetic esters undergo a catalysed one-pot double Michael addition with Michael acceptors (Scheme 6.24) [8], The two Michael acceptors can be either identical or different. 

One-pot single and double Michael addition reactions (Table 6.18)... 

Scheme 62 Double Michael addition of electrogenerated to a divinylketone.

The same hyperbranched polyglycerol modified with hydrophobic palmitoyl groups was used for a noncovalent encapsulation of hydrophilic platinum Pincer [77]. In a double Michael addition of ethyl cyanoacetate with methyl vinyl ketone, these polymer supports indicated high conversion (81 to 59%) at room temperature in dichloromethane as a solvent. The activity was stiU lower compared with the noncomplexed Pt catalyst. Product catalyst separation was performed by dialysis allowing the recovery of 97% of catalytic material. This is therefore an illustrative example for the possible apphcation of such a polymer/catalyst system in continuous membrane reactors. 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

Scheme 6.59 Typical 4-nitrocyclohexanone derivatives prepared from the thiourea 12/TMC-catalyzed enantio- and diastereoselective double Michael addition of y,5-unsaturated P-ketoesters to frans-P-nitrostyrene.

Scheme 6.62 Double Michael addition of a y,5-unsaturated P-ketoester to trarrs-P-nitrostyrene catalyzed by PEG-bound thiourea 62.

The aprotic double Michael addition was discovered by R. A. Lee and to synthesize functionalized bicyclo[2.2.2]octanes which may serve as starting materials in natural products syntheses (Table I). These ljicyclo[2,2.2]octanes can also be obtained by a Diels-Alder cycloaddition of 2-trimethyl5iloxy-substituted cyclohexadienes and dienophiles H... 

But there are many cases known where the (4+2) cycloaddition fails even with siloxy-activated dienes, e.g., methyl (E)-crotonate does not react with diene 1 at normal pressure and elevated temperature llO C), whereas the aprotic double Michael addition does give the desired bicyclo[2.2.2]octane in high yield. This reaction gives mainly (92%) bicyclic esters with the endo configuration. 

EXAMPLES OF CARBOCYCLIC ESTERS PREPARED BY THE APROTIC DOUBLE MICHAEL ADDITION... 

APROTIC DOUBLE MICHAEL ADDITION PREPARATION OF 1,3-DIMETHYL-5-OXOBICYCLO[2.2.2]OCTANE-2-CAR80XYLIC ACID... 

Bicyclic bridged phosphorinane derivatives can be synthesized by different methods. When phenylphosphine is heated with cycloocta-2,7-dienone to 135 °C in the presence of polymerization inhibitors, e.g. hydroquinone, and the double Michael addition product is oxidized, the two crystalline syn and anti isomers (total yield 48-59%) are isolated. Separation by crystallization gives the pure compounds which can in turn be transformed at the carbonyl or the phosphorus group (equation 10) (75T33,76JOC589). 

Much milder conditions are used in the double Michael addition approach, in which a divinyl ketone is condensed with hydrogen sulfide in mildly basic medium (equation 77) (77JOC2777). Enol acetates (R1 = MeCC>2) may be used, and the product obtained then contains a 2-mercapto function (R1 = SH see also equation 82) (59% yield). Although this is a very versatile synthesis, its biggest drawback is the lability of simple divinyl ketones, and phenyl substitution at position 2 is frequently used to overcome this. 

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