Unusual Intramolecular Cyclization of Tris(β-oximinoalkyl)amines. The First Synthesis of 1,4,6,10-Tetraazaadamantanes

Abstract

An unusual intramolecular cyclization of tris(beta-oximinoalkyl)amines 1 into 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes 2 was discovered. Compounds 2 are related to a previously unknown type of heteroadamantanes that contain the cage isomeric to urotropin. A simple three-step synthesis of tetraazaadamantanes 2 and their N-substituted derivatives 3 and 4 from ammonia and aliphatic nitro compounds via the intermediacy of available tris-oximes 1 was developed.

Synthesis of Unsymmetrically Substituted 4,6,10-Trihydroxy-1,4,6,10-tetra­azaadamantanes via Intramolecular Cyclization of Tris(β-oximinoalkyl)amines

“…Tris-oximes 1, possessing two (see Table 1, entry 8) or three (see Scheme 1 and Semakin et al 2 ) CO 2 Et groups did not cyclize to tetraazaadamantanes 2 using either procedure 1 or 2. This fact may be explained in terms of Brønsted acid catalysis of the oxime cyclotrimerization reaction between 1 and 2 (Scheme 5).…”

“…Furthermore, the reversible cyclization of 1 into 2 is sensitive to the nature of the substituent R. Thus, whereas the cyclization of trisoximes 1 with R = H or alkyl to 1,4,6,10-tetraazaadamantanes 2 proceeds smoothly, formation of the corresponding adamantanes from tris-oximes 1 with R = Ph or CO 2 Et was not observed. 2 Clearly, for a more detailed study of the effects of the substituent on the equilibrium between 1 and 2 it would be beneficial to explore the cyclization of 'mixed' tris-oximes 1 containing substituents that favor or disfavor the transformation into tetraazaadamantanes 2. Furthermore, the successful realization of the cyclization of unsymmetrically substituted tris-oximes 1 will provide access to a large library of 1,4,6,10-tetraazaadamantanes so that their properties and, in particular, their biological activity, can be explored.…”

“…In the 1 H and 13 C NMR spectra of tetraazaadamantanes 2 and 4, a broadening of signals, which is characteristic for this class of compounds, was observed. 2,4 The structure of salt 4e was established by X-ray diffraction analysis of its hydrate obtained by crystallization of 4e from a solution in aqueous methanol ( Figure 1). 9 Thus, tris-oximes 1, containing two or three different oximinoalkyl fragments, were involved in the cyclotrimerization reaction leading to 1,4,6,10-tetraazaadamantanes 2.…”

A General Procedure for the Synthesis of Unsymmetrically Substituted Tris(β-oximinoalkyl)amines

“…Thus, recently we reported an unusual intramolecular cyclotrimerization of oxime groups in TRISOXH 3 resulting in 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes 2 (Scheme 1). 2 Products 2 represent a new class of azaadamantanes with a cage isomeric to urotropin (1,3,5,7-tetraazaadamantane). These new molecules can be of interest for medicinal chemistry and also may find applications in macromolecular chemistry.…”

“…3 Scheme 1 Cyclization of tris-oximes 1 to tetraazaadamantanes 2 However, the scope of tetraazaadamantanes 2, which can be synthesized according to Scheme 1, is limited to only 'symmetrical' products possessing three identical substituents R. The cyclotrimerization reaction is reversible and not all 'symmetrical' tris-oximes 1 are able to cyclize to the corresponding tetraazaadamantanes 2 (see Scheme 1). 2 Furthermore, so called 'unsymmetrical' trisoximes 1, i.e. those possessing different b-oximinoalkyl fragments, are virtually unknown, 4 and no reasonable approach to their synthesis exists to date.…”