Nucleophiles conjugate addition reactions

The compounds that we are now calling dienophiles were the stars of Chapters 10, 23, and 29 where we called them Michael acceptors as they were the electrophilic partners in conjugate addition reactions. Nucleophiles always add to the (3 carbon atoms of these alkenes because the product is then a stable enolate. Ordinary alkenes do not react with nucleophiles. 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

It will be recalled that one of the key operations in the synthesis of IJK ring system 86 is the intramolecular conjugate addition reaction (see 90—>89, Scheme 17b) to form ring J. In the context of compound 90, the electrophilic a,/ -unsaturated ester moiety and the potentially nucleophilic tertiary hydroxyl group reside in proximal regions of space, a circumstance that would seem to favor the desired cyclization evept (see Scheme 19). Indeed, exposure of a solution of 90 in THFto sodium hydride (1 equiv.) for one hour at 25 °C results in the formation of compound 89 in 92% yield. In... 

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. 

There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. 

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. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. The pK of HCN is 9.3, so addition in hydroxylic solvents is feasible. An alcoholic solution of potassium or sodium cyanide is suitable for simple compounds. 

In a, P-unsaturated carbonyl compounds and related electron-deficient alkenes and alkynes, there exist two electrophilic sites and both are prone to be attacked by nucleophiles. However, the conjugated site is considerably softer compared with the unconjugated site, based on the Frontier Molecular Orbital analysis.27 Consequently, softer nucleophiles predominantly react with a, (i-unsaturated carbonyl compounds through conjugate addition (or Michael addition). Water is a hard solvent. This property of water has two significant implications for conjugate addition reactions (1) Such reactions can tolerate water since the nucleophiles and the electrophiles are softer whereas water is hard and (2) water will not compete with nucleophiles significantly in such... 

Li and co-workers also reported a highly efficient conjugate addition reaction with arylsilanes as nucleophilic reagents. The reaction of 2-cyclohexenone with 4 equiv. of either diphenyldichlorosilane or phenylmethyldichlorosilane in water generated the conjugate addition product in 97% and 95% yields, respectively (Scheme 55).143 An excess of sodium fluoride additive was important in this 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. 

Pyrrole is very reactive towards electrophiles charge distribution from the nitrogen makes either C-2 (or C-3) electron rich. Thus, a second porphobilinogen acts as the nucleophile towards the methylidene pyrrolium cation in a conjugate addition reaction. It is now possible to see that two further identical steps will give us the required linear tetrapyrrole, and that one more time will then achieve ring formation. 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

The resonance hybrid and its contributing resonance structures resulting from nucleophilic attack in a conjugate addition reaction. 

Oxazoline-directed conjugate addition of nucleophiles to a naphthalene nucleus is one of the most useful methods to prepare dihydronaphthalenes. Since Meyers last comprehensive review, the focus has been directed to stereoselective synthesis of these important compounds. Meyers laboratory has continued their preeminence in this field and has expanded the scope and applications of this reaction. 

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