Acrolein conjugate additions

Acrolein (H2C=CHCH=0) undergoes conjugate addition with sodium azide in aqueous solution to give N3CH2CH2CH=0 Propanal is not an a 3 unsaturated carbonyl compound and cannot undergo conjugate addition... 

V,7V-dimethylaminopyridme provides l-(2-methoxycarbonyl)ethoxy- (40,69%) and l-(2-methoxycarbonyl-l-methyl)ethoxytryptamine (41, 72%), respectively (Scheme 4). The conjugate addition to mesityl oxide proceeds successfully as well, giving iVb-acetyl-1-(1, l-dimethyl-3-oxo)butoxytryptamine (42,49%), while the reaction with methyl 3-methylcrotonate affords 43 in a miserable yield (1.6%). Addition to acrolein results in failure, and 44 is not yet obtained. 

The formation of the quinoline is formulated to involve a conjugate addition of the primary aromatic amine to the acrolein 6, to give a /3-arylaminoaldehyde 3 as an intermediate ... 

Brown proposed a mechanism where the enolate radical resulting from the radical addition reacts with the trialkylborane to give a boron enolate and a new alkyl radical that can propagate the chain (Scheme 24) [61]. The formation of the intermediate boron enolate was confirmed by H NMR spectroscopy [66,67]. The role of water present in the system is to hydrolyze the boron enolate and to prevent its degradation by undesired free-radical processes. This hydrolysis step is essential when alkynones [68] and acrylonitrile [58] are used as radical traps since the resulting allenes or keteneimines respectively, react readily with radical species. Maillard and Walton have shown by nB NMR, ll NMR und IR spectroscopy, that tri-ethylborane does complex methyl vinyl ketone, acrolein and 3-methylbut-3-en-2-one. They proposed that the reaction of triethylborane with these traps involves complexation of the trap by the Lewis acidic borane prior to conjugate addition [69]. 

The reaction pathways of conjugate addition of Me2CuLi and Me2CuLi LiCl have been studied for acrolein [79] and cydohexenone [80] with the aid of density functional methods, and fit favorably with the NMR properties of intermediates, kinetic isotope effects [81], and the diastereofacial selectivity. A similar mechanism also operates in this reaction, as summarized in Scheme 10.5. The rate-determining step of the reaction (TScc) is the C-C bond formation caused by reductive elimination from Cu " to give Cu. ... 

The conjugate addition of a thiol, methanethiol, to the a,(5-unsaturated aldehyde acrolein may be used in the synthesis of the amino acid methionine. Under basic conditions, the nucleophile will be the thiolate anion, and 1,4-addition leads to the thia-aldehyde. Methionine may then be obtained via... 

MacMillan reported a short and effective synthesis of spiculisporic acid which elegantly exemplified his Mukaiyama-Michael addition of silyloxyfurans to a,P-unsatu-rated aldehydes [88], Robichaud and Tremblay augmented this in a formal synthesis of compactin [224], Within this report it was shown that low enantioselectivities were obtained in the conjugate addition to aCTolein. Use of p-silyl acrolein 177 circumvented this and gave butenohde 178 in 95% yield and 82% ee. Conversion of adduct 178 to the decaUn (179) in eight steps resulted in a formal synthesis (Scheme 71). 

The conjugate addition of nitroalkanes to a,P-unsaturated aldehydes (Sect. 2.2.2) has been investigated by Uggerud, who compared the uncatalysed, proton catalysed and iminium ion catalysed additions [232]. The results suggested that protonated acrolein was more activated towards addition than the iminium ion catalysed process and also indicated that an intermediate oxazolidin structure 183, unobserved experimentally, may be involved in the reaction pathway (Fig. 17) with the transition state resembling that of a [3+2] cycloaddition process. 

The relationship between the molecular formula of acrolein (C3H40) and the product (C3H5N30) corresponds to the addition of HN3 to acrolein. Because propanal (CH3CH2CH=0) does not react under these conditions, the carbon-carbon, not the carbon-oxygen, double bond of acrolein is the reactive site. Conjugate addition is the reaction that occurs. 

Since 35 is a symmetrical ketone we can use the strategy, introduced in chapter 19, of adding an ester group and disconnecting to two identical molecules, here the aldehydoester 37 still having the 1,5-diCO relationship, and we can use a malonate to make sure we get conjugate addition to acrolein. 

To the extent that the enolate resulting from conjugate addition at the (3-carbon can be stabilized, the rate of this reaction pathway is enhanced. For example, (3-Michael additions are observed for MVK, acrolein, and acetylenic electrophiles even without the presence of a Lewis acid. Furthermore, MVK reacts with the 2,5-dimethylpyrrole complex (22) to form a considerable amount of (3-alkylation product, whereas only cycloaddition is observed for methyl acrylate. The use of a Lewis acid or protic solvent further enhances the reactivity at the (3-position relative to cycloaddition. While methyl acrylate forms a cycloadduct with the 2,5-dimethylpyrrole complex (22) in the absence of external Lewis acids, the addition of TBSOTf to the reaction mixture results in exclusive conjugate addition (Tables 3 and 4). 

Serotonin (8) mimics have been used effectively as treatments for a variety of psychiatric illnesses [199-201]. Homotryptamines could be constructed by multistep routes. One-pot synthesis of homotryptamines 277a-k was achieved by the conjugate addition of indoles with acrolein in the presence of the MacMillan organocatalysts (118a, 274) followed by reductive amination (Scheme 60) [201]. 

The thermodynamic control of conjugate addition allows even enals that are very electrophilic at the carbonyl carbon to participate successfully. Any aldol reaction, which must surely occur, is reversible and 1,4-addition eventually wins out Acrolein combines with this five-membered diketone under very mild conditions to give a quantitative yield of product, The mechanism is analogous to that shown above,... 

However, the catalysts 64 were found to be ineffective for the a-substituted-a-cyanoacetate donors 72 (up to 48% ee). The same authors overcame this problem by introducing the new 6 -OH cinchona alkaloid catalyst 71 that afforded excellent yields (90-100%) and a synthetically useful level of enantioselectivities (80-95% ee) for conjugate addition to acrolein with the a-cyanoacetates 72 bearing a range of a-aryl and a-heteroaryl groups (Scheme 9.24). 

The addition of trialkyl phosphites to acrolein was first investigated in dioxane solution. However, despite a rather effective control of the conditions, isolation of a pure product was difficult. The reaction generally furnishes the conjugated addition product in low yields in the enol ether form. Among a number of factors that may affect the completion of such a conjugate addition reaction, the dealkylation of the zwitterionic adduct is crucial to the success of the reaction to exclude the inter- and intramolecular competition that can lead to production of mixtures of products, including acetals, enol ethers, and simple carbonyl compounds. - ... 

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