Synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes by the electrophilic amination of perimidines using sodium azide in PPA

Abstract

It is difficult to overstate the importance of indole derivatives among biologically active compounds. Benzo [c,d]indoles occupy a special position and include efficient thymidylate synthase inhibitors [1].The standard methods for the synthesis of such compounds involve annelation of a benzene [2] or pyrrole ring [3] starting from 1-naphthylamines containing a carbonyl [3] or cyano group [1,3] in the neighboring peri position. When there is an electron-donor group at position 5, the carbonyl group may be introduced in reaction [3, 4].Prior to our work benzo[c,d]indole derivatives of perimidine had not been reported. This was primarily a consequence of the lack of availability of perimidines containing an amino group in the peri position due to the low yield of the corresponding nitro derivatives [5]. We have recently proposed a method for the preparation of such compounds based on the Schmidt reaction and thermal cyclization of the intermediate amide [6]. However, this method does not yield 1H-1,5,7-triazacyclopenta[c,d]phenalenes 3 lacking substituents in the pyrrole ring.In the present work, we propose a method of synthesis for such compounds involving electrophilic amination [7,8] by means of the sodium azide/PPA reagent system recently discovered in our laboratory and subsequent reaction with 1,3,5-triazines. The PPA sample used containing 87% P 2 O 5 was obtained according to Uhlig [9].As noted in our previous work [7,8], the reaction of perimidines 1a-c with a threefold excess of sodium azide in PPA at 80-90°C leads to the corresponding 6(7)-aminoperimidines 3a-c in high yield. The mechanism proposed in our previous work [7,8] involves formation of intermediates 2, which subsequently undergo hydrolysis.

Novel one-pot synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes

“…AG 331 [1]. We have previously developed a series of methods for the synthesis of these compounds [2][3][4]. The drawback of these methods is the use of polyphosphoric acid (PPA) as solvent and hence the difficulty of working on a large scale.…”