Unprecedented Rearrangement of 2-(2-Aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-Dihydro-1H-imidazo[1,2-b]indazoles

Abstract

Easily accessible 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides rearranged to 2,3-dihydro-1H-imidazo [1,2-b]indazoles under mild conditions. The rearrangement appeared to be general, tolerated a wide range of functional groups, and provided access to an as yet unexplored class of heterocycles. Herein we report the characterization of this heterocycles.In continuation of our search for novel and efficient routes to pharmacologically relevant heterocyclic compounds we discovered a process for tandem carbon-carbon followed by nitrogen-nitrogen bond formation yielding indazole oxides (Scheme 1) of excellent purity. 1 Synthetic compounds comprising indazole core have recently become an increasingly frequent subject of biological studies. A review article by Cerecetto and colleagues 2 portrayed the diversity of biological activities exhibited by indazoles, recent advances in the chemistry of indazoles were reviewed by Schmidt and colleagues. 3 Since then, numerous new studies identified indazole-based compounds as potent agents with anti-inflammatory, anticancer, 4-6 antimicrobial, 7,8 antifungal, 9,10 and cytotoxic 11 activities.Indazoles were found to be potent inhibitors of nitric oxide synthetase, [12][13][14] During the isolation of 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides, prepared following our recently published procedure, 27 we observed a quantitative rearrangement of the targeted compounds. Indazole oxide derivative 1(1,1) (R 1 = H, and R 2 = Me, refer to Table 2 for notation) prepared using 2-nitrobenzenesulfonyl chloride and 2-bromo-1-p-tolylethanone, was purified on semi preparative HPLC using aqueous ammonium acetate buffer and acetonitrile. The purified compound was isolated after solvent evaporation at elevated temperature (50 °C) and freeze drying. The LCMS analysis of supposedly purified compound revealed that the target compound had transformed to a new product that exhibited an identical mass spectrum. However, the retention time had changed; the new compound was more hydrophobic. Its UV spectrum was nearly identical to compound 1(1,1). We isolated and fully characterized the unexpected product by 1D and 2D NMR spectroscopy and high resolution MS. In addition, we were able to crystallize the product from acetonitrile solution and its structure was determined by a single crystal X-ray diffraction study ( Solutions of 1(1,1) in 50% aqueous acetonitrile were subjected to seven reaction conditions and the conversion of 1(1,1) to 2(1,1) was monitored by LCMS analysis. A solution containing 10 mM ammonium acetate was heated to 50 °C for 16 h and a quantitative conversion to 2 (1,1) was observed (Table 1). A solution containing 0.1% TFA, typically used for HPLC purification, was completely stable under identical conditions. The data indicated that solutions at pH above 7 caused a quantitative conversion to 2(1,1). Crude preparations of 1, obtained after TFA/DCM cleavage from resin and evaporation of TFA and DCM, still contained residual...