Conjugate addition multiple

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

Annexin V-functionalized crosslinked iron oxide (CLIO) was designed as a contrast agent for MRI, which was additionally labeled with Cy5.5 to allow colocalization with optical imaging techniques [98]. Alternatively, conjugation of multiple Gd-DTPA molecules or SPIO particles to the C2 domain of synaptotagmin I was shown to allow the detection of apoptotic cells in vitro [99]. Zhao et al. [100] were the first to apply a C2 domain-functionalized SPIO and showed very promising results for future in vivo applications of MR contrast agents for the detection of apoptotic sites. 

The term carbometallation was most probably coined only about a quarter of a century ago.1 However, the history of those reactions that can be classified as carbometallation reactions is much older. If one includes not only the Ziegler-Natta-type organometallic alkene polymerization reactions2 but also various types of organometallic conjugate addition reactions,3 carbometallation collectively is easily more than a century old. In its broadest definition, carbometallation may be defined as a process of addition of a carbon-metal bond to a carbon-carbon multiple bond. As such, it may represent either a starting material-product relationship irrespective of mechanistic details or an actual mechanistic microstep of carbon-metal bond addition to a carbon-carbon metal multiple bond irrespective of the structure of the product eventually formed. 

Multiple conjugate additions anionic polymerization and superglue... 

We have seen a number of reactions in which alkene derivatives can be polymerized. Radical polymerization (see Section 9.4.2) is the usual process by which industrial polymers are produced, but we also saw the implications of cationic polymerization (see Section 8.3). Here we see how an anionic process can lead to polymerization, and that this is really an example of multiple conjugate additions. 

Addition reactions to carbon-carbon multiple bonds (see also Conjugate addition reactions, Cycloaddition, Cy-clopropanation, Epoxidation, Halolac-tamization, Hydrometallation, Reduction reactions)... 

ANNULATIONS AND MULTIPLE CONJUGATE ADDITIONS (TANDEM MICHAEL REACTIONS) 121... 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

Multiple-component difunctionalization reactions of a,/ -unsaturated carbonyl systems have been achieved by catalytic conjugate addition/aldol sequences. As Scheme 8.13 illustrates, an efficient method reported by Montgomery [46] allows regioselective addition of an aryl iodide to the /i-position of an unsaturated ester under nickel catalysis and subsequent trapping with an aldehyde to give / -hydroxyesters (e.g. 33). Significantly, premature termination of the sequence by the /Miydride elimination process that is usually observed in Pd-catalyzed Heck reactions does not occur here. 

Scheme 12.4. Multiple metal variant of the conjugate addition/ enolate trapping 3CR on cyclopentenones, by Lipshutz and Wood [13]. THF = tetrahydrofuran, TBS = t-butyldimethylsilyl.

Nitromethane readily undergoes multiple conjugate additions under more forcing conditions with excess ester. 

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. 

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