Acrolein 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... 

The ratio of the two diastereomeric products 190 and 191 was found to depend on the reaction temperature and reaction time. The addition of acrolein or methyl vinyl ketone proceeded smoothly, but in the case of methylacrylate or acrylonitrile the reaction did not proceed under the same conditions (EtsN THF 30°C). An accompanying AMI calculation of these Q ,/3-unsaturated compounds [LUMOs for acrolein, -0.13877 for methyl vinyl ketone, -0.06805 (s-trans) for methyl acrylate, -0.01413 (s-tmns) for acrylonitrile, 0.04971] suggested the low reactivity of methyl acrylate and acrylonitrile toward the Michael reaction (99H1321). 

FIGURE 8.12 Michael reaction of glutathione with acrolein and acrolein-like reactive metabolites of felbamate, terbinaflne, as well as the formation of a Michael acceptor metabolite of abacavir. 

Crossed reactions of the two aldehydes under phase-transfer catalytic conditions with the intermediate thioacetates, which can be isolated under controlled reaction conditions [14], leads to the formation of three products [13], as result of retro-Michael reactions (Scheme 4.18). In the case of the reactions involving crotonaldehyde, the major product results from the reaction of the aldehyde with the released thiolacetic acid, with lesser amounts of the expected crossed reaction products (Table 4.23). In contrast, the reaction of acrolein with the thioacetate derived from crotonaldehyde produces, as the major product, the crossed cycloadduct. These observations reflect the relative stabilities of the thioacetates and the relative susceptibilities of acrolein and crotonaldehyde to the Michael reaction. 

The Michael reaction of nitroalkanes with acrolein, catalyzed by tributylphosphine, followed by acet-alization of the resultant adduct, led to l,l-ethanediyldioxy-4-nitroalkane (202), which is oxidized by an electrolytic procedure to 4-oxoalkanal 1-acetal, the protected form of the expected 4-oxoalkanal (203 Scheme 47). 

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. 

Addition (See also Michael reaction. Thiele reaction.) Acrolein. Cuprous chloride. Cuprous iodide. Diethylaluminum cyanide. Difluoramine. Dimethylcopper lithium. Methyl(tri-K-butylphosphine)copper complex. Methyl vinyl ketone. Rhodium trichloride. Sulfur dichloride. 

Regiospecific alkylation of dimethylhydrazone anions with the masked acrolein equivalent, 3-bromo-propionaldehyde dimethyl acetal, has brcn used as an alternative to a conventional Michael reaction in Corey s total synthesis of picrotoxinin (c/. equation 13). Azaallyllithium reagents derived from aldehyde and ketone hydrazones, unlike enolates, yield monoalkylation products with control of both regio-chemistry and stereochemistry. In appropriate cases, alkylation followed by deprotection to form a dicarbonyl product can be a very effective synthetic strategy. 

These products can be used as synthetic equivalents of a,/3-unsaturated aldehydes in Michael reactions. Thus C6HsSCH=CHCH2Cl can be used as the equivalent of acrolein, CH2 =CHCHO, which normally undergoes 1,2- rather than 1,4-addition with organometallic reagents. An interesting example is the preparation of an intermediate (1) to the pyridine annelation reagent of Danishefsky and Cain. ... 

Thus, if the amino acid (Figure 8.23) is alanine (R3 = -CH3), widely represented in must and wine, the corresponding aldehyde is ethanal. If the amino acid is methionine (R4 = CH3-S-CH2-CH2-), which is certainly only present in small quantities but is reputed to be highly reactive with carbonylated compounds, then methional, or -methyl-S-propanal, is produced. This compound is thermally unstable and evolves rapidly, via a Retro-Michael reaction, into acrolein and methanethiol (Figure 8.28). These smell of cooked cauliflower, wet dog, etc. In wine, part of the methional returns to methionol via catalyzed reduction by alcohol dehydrogenase with NADH. 

The conjugate addition of oxygen nucleophiles to acceptor-substituted olefins is the oxa-Michael reaction (Scheme 15). The term is derived from heteroatom replacement nomenclature, meaning that oxygen takes the place of a CH2 unit (RCH2 RO ). Oxa-Michael reactions have been known for many years and are often catalyzed by bases or acids [7]. Catalysis by metals has been reported sporadically in the older literature, e.g. for the case of alcohol addition to vinyl ketones with a Nieuwland catalyst (HgO, BF3-OEt2, ROH) [75-77]. A patent describes a PdCl2-catalyzed addition of alcohols to acrolein or methacrolein [78]. 

It may be possible that the anthrone undergoes the Michael Reaction with acrolein, and the cyclized product is then oxidized by anthraquinone and the latter is reduced to anthrone, as shown by the partial illustration of the mechanism. This route is consistent with the relatively low yield of 50-60% ... 

A vinylogous Michael reaction has also been reported using enolizable doubly activated alkylidenes as Michael donors and acrolein as Michael acceptor (Scheme 4.39). In this case, the reaction furnished regioselectively the corresponding a-addition products, the unsaturation remaining in the final adduct at the p-position. After optimizing the reaction conditions, modified... 

A first approach described the use of catalyst 106a in the Michael reaction of a cyclic p-ketoester with acrolein (Scheme 5.28). ° The reaction proceeded satisfactorily, furnishing quantitatively the desired conjugate addition product in excellent enantioselectivity, requiring the in situ protection of the formyl moiety as the corresponding cyclic acetal derivative. However, the authors reported the need of a 9-fluorenyl ester Michael donor and the reaction was not studied further, with no data reported about the scope and limitations of the methodology. 

Scheme 5.28 Enantioselective Michael reaction of a cyclic P-ketoester with acrolein catalyzed by 106a.

Scheme 5.30 Enantioselective 105-catalyzed Michael reaction of cyclic P-ketoesters with acrolein.

In the total synthesis of (+)-Greek tobacco lactone (14SL1888), the authors utilized the previously reported asymmetric Mukaiyama—Michael reaction of acrolein with a 2-siloxyfuran to prepare the key aldehyde intermediate in one step (14CEJ5983). This process was catalyzed by tmns-2,5-diphenylpyrrolidine via an iminium intermediate, with high enantioselectivity. The natural product was obtained from the aldehyde intermediate in a remarkable 34% overall yield in only four steps. 

Again, using the phosphine-free catalyst 4, the pyrrole derivative 202 could be used in a diastereoselective domino CM/aza-Michael reaction with acrolein, resulting in the formation of the heterocyclic products 203 and 204 without adding... 

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

Later, Sasai et al. [204] developed another example of domino reaction initiated by the aza-Morita-Bayhs-HiUman reaction followed successively by an aza-Michael reaction, an aldol reaction, and a dehydration. This novel process, induced by a chiral acid-base organocatalyst (20mol%), involved acrolein and various N-tosylarylimines as the substrates, leading to the corresponding highly functionahzed tetrahydropyridines in moderate yields (40-60%) and good enantioselectivities of 80-88% ee. Attempts to extend the scope of the reaction to other activated alkenes such as methylvinylketone failed. 

Remaining in the field of hetero-Michael reaction, Gong et al. disclosed a four-component quadruple cascade reaction activation initiated by oxa-Michael addition of alcohol to acroleins providing an easy and direct access to highly functionalized chiral trisubstituted cyclohexene derivatives 170 (Scheme 2.54) [81]. 

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