Michael acceptors acrylic acid derivatives

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]. 

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. 

Acrylic acid derivatives as well as a,p-unsaturated nitriles, imides, phosphonates, and sulfones have been also studied as Michael acceptors for activated methylenes. Dixon et al. have demonstrated the efficacy of bifunctional cupreidine 125 (Fig. 2.12)... 

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]. 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

The use ofTaddol as an asymmetric phase-transfer catalyst has been adopted by other research groups. For example, Jaszay has used Taddol for Michael additions to a-aminophosphonate derivative 20, as shown Scheme 8.10 [22]. A range ofTaddol derivatives was investigated, but the best results were again obtained with the same catalyst employed by Belokon and Kagan. Thus, phosphoglutamic acid derivative 21 was obtained in 95% yield and with 72% ee when tert-butyl acrylate was employed as the Michael acceptor. 

The asymmetric addition of glycine enolates to acrylates was also achieved by use of the tartaric acid-derived phase-transfer catalysts 27 and 28 (Scheme 4.9). Arai, Nishida and Tsuji [13] showed that the C2-symmetric ammonium cations 27a,b afford up to 77% ee when t-butyl acrylate is used as acceptor. The cations 28 are the most effective/selective PTC identified by broad variation of the substituents present on both the acetal moiety and nitrogen atoms [14], In this study by Shibasaki et al. enantiomeric excesses up to 82% were achieved by use of the catalyst 28a (Scheme 4.9) [14], Scheme 4.9 also shows the structure of the guanidine 29 prepared by Ma and Cheng in the absence of additional base this also catalyzes the Michael addition of the glycine derivative 22 to ethyl acrylate, albeit with modest ee of 30% [15],... 

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. 

Tartrate-derived chiral phase-transfer catalysts 175 and 176 (Fig. 2.24) have been synthesized and successfully employed in the conjugate addition of amino acid derivatives to different Michael acceptors such as acrylates and vinyl ketones [280]. 

Over the past few years, we have developed a family of NVF derivatives prepared by base catalyzed addition of the acidic amide nitrogen to acrylates and related Michael acceptors (2-3). By employing the wide range of available Michael acceptors, a broad family of materials was prepared which show some very attractive properties. The derivatives tested to date have very low toxicity. Most are not water soluble and have much lower glass transition temperatures than NVF polymers. NVF and its derivatives also show significant similarities. They are all radically co-polymerizable with major vinyl monomers, particularly acrylamides, vinyl esters, acrylates and maleates. In particular, they are conveniently photocatalytically copolymerized with widely available acrylate based radcure components. Like NVF polymers, they can be hydrolyzed, but at much slower rates and to lower extents of conversion. 

The Michael addition of methyl a-acetamidoacrylate (196) with pyrrole (1) under silica-supported Lewis acid (Si(M) Si(Zn), Si(Al) and Si(Ti)) assisted by microwave irradiation (MW) afforded the alanine derivatives 395 and 396 dependent on the reaction conditions (Scheme 81) [153]. Both MW and thermal activation for pyrrole gave only Michael product 396, whereas alanine derivatives 395, which are the a-Michael addition product, and 396 were observed with A1 and Ti-catalyst. This behavior shows that aluminium and titanium Lewis acids can form a new acceptor in an irreversible way. The Si(M) or p-TsOH catalyzed reactions of N-benzylpyrrolc 397 with the acrylate 196 under MW gave the product 398 as sole product. The reaction yield has been increased by using a catalytic amount of p-TsOH (Scheme 82). 

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