Enals Michael addition

From a mechanistic standpoint, ammonia serves two functions 1) it behaves as a base to catalyze an aldol reaction between 2 equivalents of 31 to generate the corresponding enal 33, and 2) it is the source of nitrogen for the resultant pyridyl ring. This occurs through formation of enamine 34 with a third equivalent of 31. The Michael addition of 34 to 33 followed by cyclization gives rise to 32. 

Michael additions. Michael addition of nitroalkanes to vinyl sulfoxides (equation 1) and to ketene diethyl dithioacetal S-monooxide (equation II) proceeds in high yield when DBU is used as base. The adducts can be converted into a,/J-enals.1... 

The best selectivity in the Michael addition of 2-carboxycyclopentanones to an enone or enal were recently achieved by Maruoka et al. [9]. As shown in Scheme 4.5, as little as 2 mol% of the binaphthyl-derived phase-transfer catalyst 10 - in the presence of 10 mol% solid potassium carbonate - enabled the highly efficient... 

The MacMillan catalysts (42, 45), the Jorgensen catalyst (51), and proline itself can promote Michael additions by iminium ion formation with the acceptor enal or enone (A, Scheme 4.22). Secondary amines can also activate a carbonyl donor by enamine formation (Scheme 4.22, B) [36, 37]. 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Prolines.1 The complex 2 undergoes base-catalyzed (CH,ONa) Michael addition to a,p-enals and -enones. Reaction of 2 with acrolein furnishes a dihydro-pyrrole-2-carboxylic acid which is reduced to (S)-proline. 

Protein cross-links may be also produced in reaction of 4-hydroxynonenal with lysine, histidine, serine, and cysteine residues, primarily via Michael addition (J5, R7, U8). These reactions occur spontaneously, but also may be catalyzed by certain glutatione 5-transferases. The glutathione transferase A4-4, which unlike other alpha-class glutathione transferases, shows high catalytic activity toward lipid peroxidation products such as 4-hydroxynon-2-enal, is the key enzyme for these reactions (B31). Products of protein coupling with aldehydes secondary to lipid peroxidation have a specific fluorescence, which can herald the protein oxidative modification process (CIO). 

Esterification of 5-hydroxyhex-2-enals with diketene is followed by a Michael addition and an aldol reaction in a one-pot stereoselective synthesis of hexahydroisocoumarins (Scheme 35). Aromatisation affords dihydroisocoumarins such as (-)-mellein <07T1074, 07T1281>. 

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Dicarbonyl compounds.4 Michael addition of a-nitro ketones to methyl vinyl ketone (la) or acrylaldehyde (lb) catalyzed by P(QH5)3 provides the adducts 2, which are reduced by Bu3SnH to 1,5-dicarbonyl compounds (3). Additions to the enal proceed more rapidly than ones to the enone. 

Another important example of the Michael addition in biochemistry and molecnlar biology is the reaction of 4-hydroxynon-2-enal with amines and snlfydryl gronps (Winter, C.K., Segall, H.J., and Haddon, W.F., Formation of cyclic addncts of deoxygnanosine with the aldehyde trans-4-hydroxy-2-hexenal and fran.y-4-hydroxy-2-nonenal in vitro. Cancer Res. 46, 5682-5686, 1986 Sayre, L.M., Arora, P.K., Iyer, R.S., and Salomon, R.G., Pyrrole formation from 4-hydroxynonenal and primary amines, Chem. Res. Toxicol. 6, 19-22, 1993 Hartley, D.P, Ruth, J.A., and Petersen,... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

However, during the addition of -keto esters onto enals, ytterbium triflate proved to be an efficient catalyst [171] as in the Michael additions of a-nitro esters [172]. Several water-soluble phosphines gave the corresponding phos-phonium salts in good yields when added to a,j9-unsaturated acids [173] or activated alkynes [174]. With alkynes, vinyl phosphine oxides or alkenes were formed depending on the pH of the aqueous solution. Significantly, the reaction of nitroalkanes with buten-2-one is considerably accelerated when going from... 

In order to broaden the scope of the amine-catalyzed Michael addition, Yamaguchi examined the system of amine and alkali metal salt [2]. Although amine did not promote the addition of malonate to enones, the LiCl04-Et3N catalyst turned out to be effective. Optically active amines, however, gave racemic adducts. As an extension, the (S)-proline rubidium salt, (S)-21, was developed, which possessed a cation and an amine moiety in the same molecule [2, 22]. The catalyst (S)-21 in chloroform promoted the asymmetric addition of malonate to a wide range of enones and enals as exemplified by the reaction of... 

In their 1977 paper Davies and Whitham [26] studied muconaldehyde and reported that the Z,Z to Z, isomerization was slower than the Z, to , isomerization. This contradicted the initial study by Nakajimaet al. [77] and all subsequent studies. Soon afterwards, Adam and Balci [32] noted that (Z,Z)-6-keto-2,4-heptadi-enal isomerized in 3 h at 135 °C to the (Z, )-isomer. This supports the view that Z, to , isomerization is much slower. These authors also noted that Z,Z to , isomerization is catalyzed by thiourea, presumably via reversible Michael addition... 

Methoxytrimethylsilane, 123 Methyl acetoacetate, 92 Methyl bromoacetate, 107 Methyl 11-hydroxyundecanoate, 58 Methyl lithium, 27,28 Methyl 10-undecenoate, 58 2-Methyl-l,3-dithiane, 81 (I I ,SS)-Methyl-3-phenyldimethyl-silyl-3-phenylpropionic acid, 53-4 2-Methyl-3-Phenylprop-2-enal, 111 2-Methyl-2-trimethylsilyl-l, 3-dithiane, 81 2-Methyl-I-(trimethylsilyloxy)cyclo-hex-I-ene, 100,109 2-Methyl-1 -trimethylsilyloxy-cyclo-hex-6-ene, 100 2-Methyl-2-trimethylsilyloxy-pentan-3-one, 133 2-Methylacetophenone, 42-3 2-Methylbutyraldehyde, 85 2-Methylcyclohexanone, 99, 100 2-Methylcyclohexenone, 132 4-Methyldec-4-ene, 67-8 Methylenation, 63 2-Methylpropen-l-ol, 132 Methyltriphenylphosphonium bromide, 27 Michael addition, 85 Monohydridosilanes, 128 Monohydroalumination, 29... 

Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon-carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolates to enones or enals. The combination Michael addition-aldol condensation provides a powerful means of synthesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the retrosynthetic analysis for compounds containing six-membered rings. 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

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