And Michael reactions

Acrolein reacts slowly in water to form 3-hydroxypropionaldehyde and then other condensation products from aldol and Michael reactions. Water dissolved in acrolein does not present a hazard. The reaction of acrolein with water is exothermic and the reaction proceeds slowly in dilute aqueous solution. This will be hazardous in a two-phase adiabatic system in which acrolein is suppHed from the upper layer to replenish that consumed in the lower, aqueous, layer. The rate at which these reactions occur will depend on the nature of the impurities in the water, the volume of the water layer, and the rate... 

Heck reactions can also be combined with anion capture processes, animations, metatheses, aldol and Michael reactions, and isomerizations. The anion capture process has also been widely used with other Pd-catalyzed transformations. Outstanding examples of many different combinations have been developed by Grigg and coworkers, though not all of them match the requirements of a domino process. All of these reactions will be detailed here, despite the fact the nature of these intermediate transformations would also have permitted their discussion in Chapter 2. 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

In the very recent past, metal complex catalysis has been used with advantage for the stereo- and enantio selective syntheses based on the Henry and Michael reactions with SENAs (454-458). The characteristic features of these transformations can be exemplified by catalysis of the reactions of SENAs (327) with functionalized imides (328) by ligated trivalent scandium complexes or mono-and divalent copper complexes (454) (Scheme 3.192). Apparently, the catalyst initially forms a complex with imide (328), which reacts with nitronate (327) to give the key intermediate A. Evidently, diastereo- and enantioselectivity of the process are associated with preferable transformations of this intermediate. 

Carbanions derived from diazeniumdiolates can also undergo the Knoevenagel [169] (Scheme 3.19, Eq. (1)) and Michael reactions [170] (Scheme 3.19, Eq. (2)). Under suitable conditions, (1-substiluted diazeniumdiolates can undergo elimination to yield products derived from the olefin [171] and, in a related reaction, bis (diazeniumdiolates) can undergo elimination of one N202R group to produce olefins [172],... 

These retro-Aldol and -Michael reactions can, obviously, follow an isomerization of the aldose to the corresponding ketose, leading thereby to different Aldol fragments or retro-Michael products. Keto-enol exchange as well as the retro-... 

Fig. 2.3 Key reactions in carbohydrate conversion (the arrows represent the retro-Aldol and Michael reactions).

Aldol and -Michael reactions can also proceed on the reaction products of retro-Aldol and -Michael reactions. The reverse (direct) Aldol and Michael reaction can also proceed on various intermediates. Hence, these few reactions can already form a very large variety of possible products. They, indeed, account for most of the reactivity of carbohydrates discussed below, being under pyrolysis, hydrolysis or fermentation conditions. 

Samarium and other lanthanide iodides have been used to promote a range of Mukaiyama aldol and Michael reactions. The syntheses show promise as enantio-selective transformations, but the precise mechanistic role of the lanthanide has yet to be elucidated. 

Figure 17. Test reactions of Knoevenagel and Michael reactions [35].

NUCLEOPHILIC ADDIHON TO CONJUGATED SYSTEMS CONJUGATE ADDITION AND MICHAEL REACTIONS... 

Le Roux C, Gaspard-Iloughmane H, Dubac J, Jaud J, Vignaux P (1993) New effective catalysts for Mukaiyama-aldol and -Michael reactions bismuth trichloride-metallic iodide systems. J Org Chem 58 1835-1839... 

Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substimtions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. 

Crtm-aldol and Michael reactions. CsF is an effective catalyst in reactions of ullyl cool i-lhri s with aldehydes and keloncs lo form i./l-unsaluratcd ketones. 

Another highly useful heterobimetallic catalyst is the aluminum-lithium-BINOL complex (ALB) prepared from LiAlH4 and 2 equiv. of (/ )-BINOL. The ALB catalyst (10 mol %) is also effective in the Michael reaction of enones with various malonates, giving Michael products generally with excellent enantioselectivity (91-99% ee) and in excellent yields [23]. These results ate summarized in Table 8D.3. Although LLB and LSB complement each other in their ability to catalyze asymmetric nitroaldol and Michael reactions, respectively, the Al-M-(/ )-BINOL complexes (M = Li, Na, K, and Ba) are commonly useful for the catalytic asymmetric Michael reaction. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

In a different approach, one may synthesize molecular scaffolds that have not been found in nature. These templates are often also called new chemotypes, expressing the hope of finding interesting and unexpected biological activities. For example, cycloadditions, imine formation, and Michael reactions are used to generate such novel backbones (34,35). 

Combining aldol and Michael reactions in one sequence is very powerful, particularly if one of the reactions is a cyclisation. The Robinson annelation9 makes new rings in compounds like 73 that were needed to synthesise steroids. Disconnection of the enone reveals triketone 74 having 1,3- and 1,5-dicarbonyl relationships. The 1,3-disconnection would not remove any carbon atoms but the 1,5-disconnection at the branchpoint gives a symmetrical 3-diketone that should be good at conjugate addition. 

Aldol and Michael reactions of nitriles.3 Activated nitriles such as ethyl cy-anoacetate react with aldehydes or ketones in the presence of this ruthenium catalyst... 

Stereoselective formation of carbon carbon and carbon heteroatom bonds remains an important goal in synthetic chemistry. Very recently lanthanide alkoxides were successfully utilized in enantioselective C-C bond forming reactions. Catalysis of aldol, cyanosilylation, nitroaldol and Michael reactions has been ascribed to the basic character of lanthanide alkoxides [158, 250, 251]. Ln3(OfBu)9 was successfully employed in test runs and subsequently optically active bidentate ligands were used (Fig. 35) [250a]. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

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