Conjugate additions aldehyde olefinations

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

In general, the zinc promoted condensation of alkyl halides with aliphatic aldehydes and ketones gives only poor results.2 In contrast good results are obtained when one of the reactants is unsaturated. Thus the addition of an allylic group to a carbonyl compound, or the conjugate addition of an alkyl moiety to an activated olefin, occur in excellent yields. Some corrections to this schematic view will be given in the following discussion. 

The synthesis of the C1-C7 fragment, which corresponds to the lactone, starts with the homoallylic alcohol 2 which was prepared from 1. The existing stereocenter and the conjugate addition method of Evans [21] allow the control of the C5 stereocenter. The homoallylic alcohol 2 was oxidatively cleaved and homologated to the trans enoate 3 by a Wittig olefination. Treatment of 3 with benzaldehyde and a catalytic amount of KHMDS provided acetal 4. The internal Michael addition of the hemiacetal intermediate proceeds with complete stereoselectivity [22]. After deprotection and oxidation, the corresponding aldehyde was treated with Amberlyst-15 and then with camphor sulfonic acid (CSA), to yield pyrane 5 as a mixture of (3- and a-anomers (1.8/1). This compound was converted to the thiophenyl acetal 6 (4 steps) as this compound can be hydrolyzed later under mild conditions (Hg +) with subsequent oxidation of the lactol to the desired lactone. Compound 6 represents the C1-C7 fragment of discodermolide (Scheme 1). 

The behavior of a-keto-a,p-unsaturated esters is slightly different. The Michael reaction between aldehydes and these kinds of doubly activated olefins proceeded smoothly in the presence of 31a as catalyst but the conjugate addition products underwent spontaneous intramolecular hemiacetalization via the corresponding enol form of the a-ketoester moiety. Consequently, this reactivity was exploited for setting up a very efficient and simple protocol for the enantioselective synthesis of highly substituted dihydropyrones by carrying out the in situ oxidation of these Michael adducts (Scheme 2.30). ° The final heterocyclic derivatives were obtained in excellent overall yield and outstanding enantioselectivity. Moreover, the reaction could also be carried out in water as solvent. 

The application of this ability of A -heterocyclic carbenes to activate aldehydes (or ketones) for their participation as nucleophiles in polar reactions to the conjugate addition reaction was discovered by Stetter in 1975, when he found that aldehydes underwent 1,4-addition to electron-deficient olefins in the presence of a carbene generated in situ from a thiazolium salt in the presence of a base (also known as the Stetter reaction). Many attempts have been made since then to develop enantioselective variants of this reaction, although it has to be pointed out that the most important advances have been reported quite recently, as will be shown in this section. 

The direct asymmetric conjugate addition of simple aldehydes to electrophiles is crucial in organic reactions. Barbas et al. developed the first example of a highly stereoselective direct Michael reaction that involved adding unmodified aldehydes to nitro-olefins. After various p3Trolidine-diamines were screened, (S)-2-(morpholinomethyl)pyrrolidine Ic was determined to be the ideal catalyst for obtaining satisfactory stereoselectivity in the reaction. These reactions afforded various 2,3-disubstituted y-formyl nitroalkanes with satisfactory yields and moderate to good enantioselectivity (Scheme 9.12). ... 

S)-Pyrrolidine trifluoromethanesulfonamide 3a is a highly active catalyst for the asymmetric conjugate addition of aldehydes and ketones to nitroalkenes. The use of catalyst 3a (20 mol%) in i-PrOH at 0 °C, afforded a,a-dialkyl aldehydes with good to high yields and high to excellent levels of diastereo- and enantioselectivity (Scheme 9.20). In addition, the reactions of various cyclic and acyclic ketones with aromatic nitro-olefins indicated the usefulness of the catalyst. " Computational results corresponded with the observed stereoselectivities of 3a-catalysed Michael reactions. 

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]. 

The conventional preparation of the zinc-copper couple is long and tedious Sonication of copper (I) iodide with zinc powder in THF or in alcoholic solvents makes it much easier, and a black suspension is produced in a few minutes The method tolerates up to 40% of water in the organic solvents. Besides the applications for conjugate additions to activated olefins (p. 225), this sonochemically prepared couple was used for the carbonylation of iodoalkanes to aldehydes.52 The zinc-nickel couple prepared from nickel salts and zinc is an excellent catalyst for the hydrogenation of olefinic bonds (p. 187).53 Cementation of cobalt on zinc is achieved in water under sonication.54 The temperature must be adjusted to avoid the reduction of water. 

The procedure involves copper(I)-catalysed conjugate addition of MeMgBr to an a,p-unsaturated thioester 4, followed by reduction to the corresponding aldehyde and subsequent olefination to elongate the chain. This yields anew a,p-unsaturated thioester 6, which, in turn, can be subjected to the next catalytic reaction (Scheme 5). 

Hagiwara, H. N. Komatsubara H. Ono T. Okabe T. Hoshi T. Suzuki M. Ando and M. Kato (2001). "Diethylamino(trimethyl)silane-mediated direct 1,4-addition of naked aldehydes to electron-defident olefins." Journal of the Chemical Society-Perkin Transactions 1, No.3, (Jan 11,2001), pp. 316-322, ISSN 1472-7781 Hagiwara, H. T. Okabe K Hakoda T. Hoshi H. Ono V. P. Kamat T. Suzuki and M. Ando (2001). "Catalytic enamine readion an expedient 1,4-conjugate addition of naked... 

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