Synthesis of Highly Functionalized Imidazo[1,5-a]pyrazines

Abstract

Four 'one-pot' syntheses of highly substituted imidazo[1,5-a]pyrazines 7-9, starting from diaminomaleonitrile derivatives 1 and 2, and imidazoles 3 and 5, are described.The imidazo[1,5-a]pyrazine system has attracted considerable interest during the last few decades mainly due to the intensive search for biologically active compounds. 1 Its derivatives have been usually prepared from suitably substituted pyrazines such as (aminomethyl)pyrazines, 2 cyano substituted dihydropyrazinecarboxamide, 3 and (ureidomethyl)pyrazines 4 by the closure of the imidazole ring. On the other hand, this bicyclic system is also accessible from some imidazole derivatives. Such examples are cyclization of imidazolecarboxamides, 5 ring opening of theophyllin-7-acetic acid with subsequent cyclization, 6 cyclization of chiral hydroxyethylaminocarbonyl substituted imidazole derivatives, 7 and a modification of the Ugi reaction with 4-methoxycarbonyl-1-(2-oxopropyl)-1H-imidazole-5-carboxylic acid. 8 Furthermore, some fused imidazo[1,5-a]pyrazines have also been investigated. For example, such compound is the 5,10-methylenetetrahydrofolate, a very important coenzyme. 9 In addition, several synthetic imidazo[1,5-a]quinoxalines have been proven as biologically important and medicinally useful compounds. 10 A few years ago, we began to investigate the use of diaminomaleonitrile, an excellent synthetic tool in heterocyclic synthesis, 11,12 in the preparation of heteroaryl-substituted amino acid derivatives and other compounds. In these investigations, the compound 1 was prepared from diaminomaleonitrile and 4-ethoxymethylidene-2-phenyl-1,3-oxazole-5(4H)-one and transformed further with alcohols into 2. 13,14 Moreover, the imidazole 3 was synthesized from 1 and transformed further into a series of 5. 15 We published a preliminary communication on the synthesis of the imidazo[1,5-a]pyrazines 7 and 8, existing as the tautomers A and B. 16 Herein, we wish to give a full description of various one-pot possibilities for the preparations of the imidazo[1,5-a]pyrazines 7-9 starting from the compounds 1-6 ( Figure 1).As reported previously, heating of various 3-[(2-amino-1,2-dicyanovinyl)amino]-2-(benzoylamino)propenoates 2a-g in triethyl orthoformate resulted in the formation of the corresponding 8-benzoylimino-3-cyano-7,8-dihydroimidazo[1,5-a]pyrazine-6-carboxylates 7a-g. 17 In order to extend the scope of this interesting transformation, the esters 2 were then treated with triethyl orthoacetate affording the 3-methyl substituted imidazopyrazines 8a-g. This methodology was then also used for the preparation of the chloromethyl substituted imidazopyrazine 9f, which was obtained in 66% yield when 2f was heated with trimethyl orthochloroacetate for 3.5 hours (Scheme 1). Figure 1Scheme 1 One-pot transformation of 2 into imidazopyrazines 7-9. Reagents and conditions: i) for products 7a-g: HC(OEt) 3 , D, 2-8 h, 48-78%); for products 8a-g: MeC(OEt) 3 , D, 3.5-5 h, 65-89%; for product 9f: R = pentyl, R¢ = CH 2 ClClCH 2 C(OMe) 3 , D, 3.5 h, 66%.

Challenge N- versus O-six-membered annulation: FeCl3-catalyzed synthesis of heterocyclic N,O-aminals

“…Given the established potencies of this class of N-ring-fused compounds, planned syntheses that simplify their preparation by using small building blocks and that lead, through appropriate transformations, to a product that becomes a substrate for another complexity-generating reaction, merit investigation [13][14][15].…”