Nucleophilic addition to a, p-unsaturated aldehydes and

FIGURE 18 7 Nucleophilic addition to a p unsaturated aldehydes and ketones may take place either in a 1 2 or 1 4 manner Direct addition (1 2) occurs faster than conjugate addition (1 4) but gives a less stable product The product of 1 4 addition retains the carbon-oxygen double bond which is in general stronger than a carbon-carbon double bond... 

Conjugate Nucleophilic Addition to a,p-Unsaturated Aldehydes and Ketones 786... 

In this chapter cover the most important processes for nucleophilic addition to a,P-unsaturated aldehydes and ketones based on organocatalysis. 

The p-carbon atom of an a,p-unsaturated carbonyl compound is electrophilic nucleophiles, especially weakly basic ones, yield the products of conjugate addition to a,p-unsaturated aldehydes and ketones. 

Then, the hydride ion is selectively transferred to the f-olefin from the least sterically hindered face to produce the corresponding isomer of the product. Furthermore, although a kinetic preference for (he (Z)-iminium ion formation has been demonstrated, the ( )-iminium ion intermediates, which dominate the equilibrium ratio, react with nucleophiles faster than the ( -isomers when diarylprolinol and imidazohnone-based chiral catalysts are anployed in conjugate additions to a,P-unsaturated aldehydes [20]. 

As described by Cordova et al., the strategy of combining transition metal-catalysed nucleophilic activation with chiral amine-catalysed iminium activation allows the enantioselective conjugate silyl addition to a,p-unsaturated aldehydes [115]. The reaction proceeds with good 1,4-selectivity and moderate enantio-selectivity when p,p-disubstituted unsaturated aldehydes are used as substrates, as exemplified in Scheme 77. The silylated products are versatile adducts that can be easily converted to protected 1,3-diols and p-functionalised esters. 

Iminium catalysis is another key catalyhcconceptinaminocatalysis. Initial workwas disclosed by MacMillan for the Diels-Alder reaction of cyclopentadiene and a,(i-unsaturated aldehydes [12], butitwas rapidly extended to Michael additions (including Friedel-Crafts reachons). Now iminium catalysis has been established as a general mode for nucleophilic addition to a,P-unsaturated carbonyl compounds. 

J0rgensen [111] and Vicario [112] independently described the conjugate addition of both triazole and tetrazole based nucleophiles to a,P-unsaturated aldehyde substrates as an alternative method for C-N bond formation. These reactions were catalysed by the diarylprolinol and imidazolidinone scaffolds with equal efficiency showing the complementarity and efficacy of both these catalyst architectures. In addition, Jprgensen has also shown succinimide to be an effective Michael donor (see Sect. 2.3.5 Scheme 49 for further details) [113]. 

As the text continues to develop the chemistry of aldehydes and ketones, you will now see how the carbon adjacent to a carbonyl group can become nucleophilic. First, reactions of these new nucleophiles with common electrophiles like haloalkanes will be covered alkylation reactions. More important are reactions of the nucleophilic a-carbons of one carbonyl compound with electrophilic carbonyl carbons of another. They are generically termed carbonyl condensation reactions. You see them here for aldehydes and ketones the aldol condensation. (In a later chapter you will be introduced to the analogous reaction of carboxylic esters the Claisen condensation.) The products of aldol condensations are a, P-unsaturated aldehydes and ketones, which contain additional sites of electrophilic and potential nucleophilic character. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Heteroaromatic compounds are also suitable nucleophiles in the Michael additions to enals catalysed by prolinol silyl ethers. Hayashi and coworkers demonstrated that oxazolinones can add effectively to enals (Scheme S.lSa)." Indole also added effectively to a,p-unsaturated aldehydes (Scheme 8.13b). Also, enantioselective Michael addition of simple 3(2H)-furanones to a,(3-unsaturated aldehydes has been described (Scheme 8.13c). ... 

The asymmetric conjugate addition of activated methylenes to a, P-unsaturated aldehydes has been studied with a wide variety of nucleophiles such as malonates, 1,3-diketones, P-ketoesters, malononitriles, benzylic methylenes, and suhbnyl nucleophiles. 

In 2005, J0rgensen et al. extended the conjugate addition of sulfur nucleophiles to a,P-unsaturated aldehydes under iminium catalysis with trimethylsilyl ether 56 (10 mol%) as catalyst [385]. Very high enantioselectivities (89-97% ee) were reported for the addition of aliphatic thiols to different aromatic and aliphatic enals at low temperatures (-24°C) where the employment of an acid cocatalyst (PhCOjH, 10 mol%) was mandatory in order to improve the reaction rate. This methodology has been incorporated into domino reactions by the same group and others to successfully prepare optically active sulfur-containing heterocyclic compounds [385, 386],... 

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