Unexpected reaction of 3-benzoyl-4-hydroxy-1-methyl-4-phenylpiperidine with 1,2-diaminobenzene

Abstract

In a study of the condensation of 3-benzoylpiperidol (1) [1] and 1,2-diaminobenzene (2), we observed an unexpected direction for the reaction. In fact, by crystallization we isolated the product of N(1),N(2)-dialkylation of diaminobenzene 3 in 67% yield from the reaction mixture obtained after boiling these reagents for four hours in toluene, in the presence of catalytic amounts of p-toluenesulfonic acid. In subsequent chromatography of the residue obtained from the mother liquor, we isolated benzo[b]triazacycloundecatriene 4 and aminopropanone 5 (the latter was converted to the diacetate 6). Furthermore, we established by chromatography/mass spectrometry that the indicated residue also contained the 2,3-dihydro derivative of 1H-benzo-1,5-diazepine 7 and vinyl phenyl ketone 8. If we consider heterocycle 4 as a double Schiff base, then it becomes obvious that it was formed as a result of the following reaction cascade: first of all, retroaldol decyclization of the starting piperidol 1 leads to amino diketone A, and then tandem reaction of the latter with phenylene diamine 2 occurs: imination and cyclization. The most likely route to formation of Mannich bases 4 and 5 can be assumed to be deamination of amino ketone A to form vinyl phenyl ketone 8 according to a Michael retroreaction. In the case of subsequent reaction of the phenylenediamine molecule with one or two equivalents of this unsaturated ketone, Mannich bases 5 or 4 respectively are generated. Intramolecular cyclocondensation of amino ketone 5 leads to the derivative of 1,5diazepine 7. We should note that in the case of 10-minute microwave treatment of the solid mixture of the starting compounds 1 and 2 (without addition of the catalyst), the reaction becomes more selective with respect to amino ketone 5, isolated in 61% yield. According to the predictions of the Internet program PASS [2], compound 4 may exhibit psychotropic and nootropic activity (70-80%); compound 5 may have the properties of an interferon agonist (70%), and its diacetate 6 may have the properties of a fibrinogen receptor antagonist (76%); diketone 3 may exhibit antileishmanial activity (74%). The H NMR spectra were taken on a Bruker WP-400 (400 MHz) in CDCl3; the mass spectra (electron impact) were taken on a Finnigan MAT Incos 50 mass spectrometer (70 eV).