Short synthesis of new 13,16-diazaestrone and 13,16-diazaequilenin analogs

Abstract

Diferentes 3-[2-(3,4-diidro-1-naftil)etil]imidazolidina-2,4-dionas e 3-[2-(1-naftil)etil]-imidazolidina-2,4-dionas, quando aquecidas em ácido polifosfórico a 150 °C, sofrem ciclização quimioseletiva intramolecular resultado nos respectivos esteróides 13,16-diazaestrona e 13,16-diazaequilenina.Different 3-[2-(3,4-dihydro-1-naphthyl)ethyl]imidazolidine-2,4-diones and 3-[2-(1-naphthyl)ethyl]imidazolidine-2,4-diones, when heated in polyphosphoric acid at 150 °C, underwent chemoselective intramolecular cyclization to afford the 13,16-diazaestrone steroids and 13,16-diazaequilenin steroids respectively.Keywords: polyphosphoric acid, chemoselective cyclization, 13,16-diazaestrone steroids, 13,16-diazaequilenin steroids IntroductionAzasteroids are known to exhibit various biological properties which include analgesic, 1 antiandrogenic, 2 antiphlogistic, 3 antimicrobial, 4 antileukemic, 5 antifungal, 6 bactericide, 7 antiestrogenic, 8 antifertility, 9 and cardiotonic and hypotensive activities. 10 Moreover, some azasteroids act as neuromuscular blockers 11 and inhibitors of 5-α reductase and androgen receptor binding. 12 Recently we have reported 13,14 the syntheses of 13,16-diazaestrone and 13,16-diazaequilenin analogs from the intramolecular cyclization of the corresponding 5-hydroxyimidazolidin-2-ones. We now wish to report a new synthesis of the title compounds from intramolecular cyclization of the corresponding imidazolidine-2,4-diones. Results and DiscussionTowards this end, the intramolecular cyclization of 3-[2-(3,4-dihydro-1-naphthyl)ethyl]imidazolidine-2,4-dione 13 1a was undertaken. All our attempts to cyclize 1a employing POCl 3 and P 2 O 5 in different solvents such as benzene, dichloroethane, toluene and xylene were unsatisfactory and gave the starting material back. Heating 1a with POCl 3 in refluxing tetralin gave a brown solid, which was insoluble in all organic solvents and hence could not be characterized. Attempts to cyclize 1a in polyphosphoric acid (PPA) at 100 °C gave starting material back. When the temperature increased to 120 °C the TLC (CHCl 3 -MeOH, 96:4) showed the formation of a new spot but the bulk of starting material remained intact even after 12h. The reaction was then carried out at 150 °C, which led to consumption of the starting material in 6h to give a yellow solid in 44% yield after aqueous work-up (Scheme 1). IR spectrum of the yellow solid showed the N-H band at 3250 cm -1 and the 1 H NMR spectrum displayed a 1H broad singlet due to N-H at δ 8.91 and 1 H singlet due to vinylic proton at δ 6.70 thus confirming the chemoselective formation of 13,16-diazaestrone 2a and not the corresponding 13,15-diazasteroids. This may be explained on the basis of more electrophilic nature of carbonyl carbon of amide than urea. 15,16 Proposed mechanism for intramolecular cyclization of 1a to give 2a is shown in Scheme 2. Following the above standardized protocol, intramolecular cyclization of other imidazolidine-2,4-diones 13,14 1b-h were carried out to afford the corresponding 13,16-diazasteroids...