N-Aryl Lactams by Regioselective Ozonation of N-Aryl Cyclic Amines

Ozonation of N-aryl-cyclic amines in organic solvents gave N-aryl-lactams regioselectively. In particular, 4-(4-aminophenyl)-morpolin-3-one, a key intermediate in the preparation of factor Xa inhibitors, was obtained in fair yields. The method represents an alternative approach for the lactamization of tertiary N-arylic substrates and is based on a “metal-free” introduction of the carbonyl function into the heterocyclic ring. 1. Introduction N-aryl lactams are important precursors in the synthesis of alkaloids [1] and of various biologically active compounds. [2] Their chemesthetic activity has been also recently demonstrated [3]. N-aryl derivatives of azetidinone have been shown to inactivate human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) [4]. They are also used as platelet inhibitor [5]. N-aryl lactams relevance in drug development is not just limited to β-lactam exponents. For instance, 4-(4-aminophenyl)morpholin-3-one (1) is the key precursor (Figure 1) for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}methyl) thiophene-2-carboxamide (2) [6], an inhibitor of coagulation factor Xa used for prophylaxis and treatment of various thromboembolic disorders [7]. Figure 1: 4-(4-aminophenyl)morpholin-3-one ( 1)is a key intermediate for the preparation of 5-chloro- N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide ( 2). Moreover, the 4-(4-aminophenyl)morpholin-3-one moiety is present in various factor Xa inhibitors, which entered clinical and preclinical studies [8–12]. Two main approaches for the preparation of 1 are described in the literature: the reaction of 2-chloroacetate with anilinoethanol [13], and the metal-mediated selective oxidation at the morpholine ring [14]. The former is preferred on industrial scale due to the cheap reagents employed and the high reactivity exhibited under mild reaction conditions. Nevertheless, processes producing chlorinated waste should be replaced in order to comply with the recommendations of green chemistry. The latter has only an academic perspective at the present time; Markgraf and Stickney recently reported [15] a method for the preparation of N-phenyl-lactams based on the selective oxidation of cyclic tertiary amines with potassium permanganate under phase transfer catalysis conditions. The yield in N-phenyl-morpholin-3-one achieved from N-phenyl-morpholine was 45%. Different results were obtained by using manganese dioxide as oxidant (acetaldehyde and dibutyl acetal were the main products)