Conjugate addition base catalysis

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

Scheme 4.13 (a) Two different types of xanthone-based oxyanion hole receptors developed by Simon and co-workers and (b) possible mode of catalysis of a conjugate addition reaction between pyrrolidine and a, 5-unsaturated valerolactam by one of the receptors. 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

An alternative route to nitriles of high enantiomeric excess, based on the conjugate addition of Me,Si-CN to an activated amide 7, has been reported (J. Am. Chem. Soc. 2004,126,9928) by Eric Jacobsen of Harvard University. The key to success in this case was dual catalysis, with a chiral AI complex and a chiral Er complex. 

In the discussion of the general base catalyzed addition step above (p. 120) the objection was raised that it was difficult to believe that general base catalysis would be necessary for the addition of water to so reactive a species as a protonated ester. An answer to this objection is implicit in the discussion above of the mechanism of hydrolysis of orthoesters. It appears that the protonated orthoester, which would be the initial product of the simple addition of a molecule of water to a protonated ester, is too reactive a species to exist in aqueous solution, and that carbon-oxygen bond-cleavage is concerted with the transfer of the proton to the orthoester. The formation of a protortated orthoester by the addition of a molecule of water to the conjugate acid of an ester will be even less likely, and it seems entirely reasonable, therefore, that the formation of the neutral orthoester, by a general base catalyzed process, should be the favoured mechanism. 

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. 

A few cases of enantioselective conjugate addition of O-nucleophiles to electron-deficient alkenes are also known. They are all based on enzymatic catalysis and are summarized in Section 4.7.2. 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

Other fates are possible for the enolate formed in the initial conjugate addition and an obvious possibility is an aldol reaction. With an asymmetric catalyst, the combination of three simple molecules leads to one enantiomer of one diastereoisomer of the tandem Michael-aldol product14 83. The catalyst 84 is based on a BINOL A1 complex (see chapters 25, 26). It can be drawn either as a lithium salt with an aluminium cation or, better, as a lithium aryloxide with a Lewis-acidic aluminium atom. This is better because both basic ArCT and Lewis acidity are necessary for catalysis. 

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