Nucleophilic reactions conjugates

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

Anions derived from nitriles can act as nucleophiles in conjugate addition reactions. A range of substituted phenylacetonitriles undergoes conjugate addition to 4-phenylbut-3-en-2-one. 

The Mannich reaction can be used for the immobilization of certain drugs, steroidal compounds, dyes, or other organic molecules that do not possess the typical nucleophilic groups able to participate in traditional coupling reactions (Hermanson et al., 1992). It also can be used to conjugate hapten molecules to carrier proteins when the hapten contains no convenient nucleophile for conjugation (Chapter 19, Section 6.2). In this case, the carrier protein contains the primary amines and the hapten contains at least one sufficiently active hydrogen to participate in the condensation reaction. 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

Many of these reactions support a measure of thermodynamic control in nucleophilic capture Conjugated radicals or products formed with release of ring strain are favored. For example, the addition of ethanol to radical cation 110 + is regiospecific, forming the more stable (benzylic) intermediate 111 + the capture of 112 + likewise forms a benzylic radical (113 ). Radical cation 48 + generates a... 

Most main group organometallic compounds undergo nucleophilic reactions with carbonyl groups, whereas 1,4-conjugate addition to enones... 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

A review has examined the use of radical anions in elucidation of the role of electron transfer in nucleophilic reactions through the determination of rates of electron-transfer reactions or obtaining reduction potentials of short-lived radical species.203 The control of conjugation and high-spin formation of radical anions of linear and ladder-type n-... 

Perbenzoic acid reacts with organic disilanes by oxidation to the corresponding disiloxanes488) in a second-order reaction. A substitution on the phenyl group of the phenylpentamethyl-disilanes increases the nucleophilic reaction rate of the Si-Si oxidation and increases pw— d conjugation from the phenyl-group to the silicon. 

Amines are good nucleophiles for conjugate addition reactions, and give products that we can term [3- ami no carbonyl compounds (the new amino group is [3 to the carbonyl group). Dimethyl amine is a gas at room temperature, and this reaction has to be carried out in a sealed system to give the ketone product. 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

The synthesis will be successful only if (1) the right reagent enolizes and (2) the nucleophile undergoes conjugate (and not direct 1,2-) addition to the unsaturated carbonyl compound (Chapter 29). Malonate derivatives enolize easily and do Michael additions and are therefore a good choice for this type of reaction. 

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