Michael reactions acrylic acid derivatives

The oxazoline ring acts as an electron-withdrawing group for a substituent at the 2-position. Thus, the ot-protons of a 2-alkyloxazoline exhibit some acidity and can be abstracted by a base. A 2-alkenyloxazoline can be viewed as a masked acrylic acid derivative and is capable of undergoing Michael addition and Diels-Alder reactions. These reactions can often be carried out stereoselectively using a chiral oxazoline. Other types of chiral auxilliaries, most notably oxazolidinones, are also very effective for these types of applications. However, they are outside the scope of this chapter. The discussion in this section will focus on the new developments with oxazolines. 

Alkyl halides, alkyl tosylates or dialkyl sulfates bring about A-quatemization of pyridine to give A-alkylpyridinium salts 3, while activated haloarenes, e.g. l-chloro-2,4-dinitrobenzene, form A-arylpyri-dinium salts 4. A-Alkylation also involves the acid-induced Michael addition of pyridine to acrylic acid derivatives (e.g. to give 5, A = CN, CO2R) in the presence of HX, as well as the synthetically useful King-Ortoleva reaction (see p 309) between reactive methyl or methylene compounds and pyridine in the presence of I2, e.g. ... 

Almost all the catalysts presented up to this point have also been tested in the Michael reaction with acrylic acid derivatives, typically acrylate esters and acrylonitrile. The usual situation found is that these kinds of acceptors furnish similar results to those observed in the same reaction with vinyl ketones, although in some cases a different behavior is observed. On the other hand, there are also some catalytic systems which have been exclusively tested on acrylate-type electrophiles, as will be shown in the following. 

Scheme 5.23 Enantioselective Michael reactions glydnate imines with acrylic acid derivatives catalyzed by 103a.

The acrylic acid derivative presumably adds, via a Michael Addition Reaction, to the nucleophilic nitrogen atom of the open-ring amidoamine, thus forming an amphopropionate. No salt is formed as a by-product. This reaction was first described in 1963, assuming a cyclic product structure which contained imidazoline (32). Later, it was shown that the reaction in aqueous medium results in a linear product (33). 

It was shown that microwave irradiation accelerated the 1,4 Michael addition of primary and cyclic secondary amines to acrylic esters, leading to several /j-amino acid derivatives in good yields within short reaction times [78] (Eq. 25). 

After Michael Faraday revealed the fundamental experiments of electrolytic reactions in 1834, Kolbe carried out the electrolysis of salts of monobasic aliphatic acids producing hydrocarbons, which was the first application of the method to organic synthesis (1854). It needed another hundred years before Wilson found that some acrylic ester derivatives were polymerized at the cathode instead of being reduced in... 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

New y-ethoxycarbonyl- and ot-amino-alkyl-hydroxyphosphinic acid derivatives (366) and (367) were conveniently prepared by Michael addition or Kabachnik-Fields reaction of a new precursor, benzyloxymethyl hydrogen-phosphinate (368), with a,p-unsaturated esters or imines (Scheme 94). " Phosphinic acid inhibitors (369) of Cathepsin C were synthesized by addition of methyl acrylate to the appropriate a-amino phosphinic acid and by... 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

Amino acid derivatives have also been explored as potential chiral auxiliaries in the asymmetric aza-annulation reaction. As reported for the Michael addition to acrylate derivatives, the reaction outcome has also shown sensitivity to the special balance of complementary steric demands of the methyl and phenyl substituents. The degree of diastereoselectivity in carbon-carbon bond... 

The lithium enolate derived from angelica lactone (LDA, THF, - 78 °C) reacts as a Michael acceptor exclusively at the y-position thus the butenolide (65) is obtained from ethyl acrylate. Surprisingly, in view of this finding, reaction with methyl iodide results in mixtures of the a-methyl and aa-dimethyl derivatives. Similar results have been obtained with the enolates of 2- and 3-methylbut-2-enolides which undergo prenylation by dimethylallyl bromide at both the a- and y-positions. By contrast the tetronic acid derivative 3-methoxy-2-methylbut-2-enolide is alkylated only at the y-position to give (66) in high yields. 

Starting from nucleic acid bases, the carboxyethyl derivatives of the nucleic acid bases were prepared by a Michael type addition reaction of ethyl acrylate followed by hydrolysis. The carboxyethyl derivatives of nucleic acid bases were reacted with ( )-a-amino T-butyrolactone hydrobromide to give v-hutyrolactone derivatives of nucleic acid bases. For the coupling reactions, pentachlorophenyl ester derivatives were used with imidazole as a catalyst.22... 

Ackermann reported the second general example of oxidative alkenylation with Ru(ll) catalyst by reaction of benzoic acid derivatives with acrylonitrile or alkyl acrylates. The alkenylation this time was performed in water under mild conditions. Further oxa-Michael reaction occurred leading to lactones in good yields [(Eq. 54)] [55]. 

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