Catalyzed synthesis of β-amino acids esters

Abstract

β-Aminoalcohols, β-amino acids, and their esters exhibit a wide range of biological action antitumor, immunostimulating, antiphlogistic). They are used as peptidomimetics and are precursors of many synthetic and natural compounds, in particular, of β-lactams [1– 4]. For instance, bestatin, [(2S,3R)-3-amino-2-hydroxy4-phenylbutanoyl]-L-leucine, is a specific inhibitor of the chemotoxic activity of the aminopeptidase possessing a low toxicity; it is used in medical practice as immunomodulator and antitumor drug [1]. The intense studies on the development of new methods for preparation the mentioned compounds are going on, and the substances as a rule are obtained by the nucleophilic Michael addition of primary or secondary amines to the activated C=C bond [5, 6]. The reaction is commonly performed in polar solvents (alcohols or carboxylic acids), the process is carried out in the presence of catalysts, Lewis acids (AlCl3, TiCl4, SnCl4) that accelerate Michael reaction [2, 5–10]. Recently as catalysts triflates of lanthanides were suggested [6]. However even at the use of new more efficient catalysts the reaction often proceeds nonselectively and requires several hours at 50–100°C and the presence of organic solvents. Therefore the development of catalytic methods free of the mentioned drawbacks is an urgent task. We report here on the new convenient catalytic procedure for one-stage preparation of β-amino acids esters by the reaction of esters of conjugated unsaturated acid with a series of primary and secondary amines in the presence of Kuganak montmorillonite Al2O3 . 4SiO2 . 2H2O that contains relatively high amount of TiO2. As esters of α,β-unsaturated acids we used methyl acrylate (Ia), allyl acrylate (Ib), methyl methacrylate (Ic), and dimethyl maleate (Id), and as amines, isopropylamine (IIa), butylamine (IIb), benzylamine (IIc), monoethanolamine (IId), diethylamine (IIe), and morpholine (IIf). The experiments were carried out at 20°C over 0.5 and 1.5 h at molar ratio of the α,β-un-saturated acid–amine 2 : 3.