Synthesis of 2-amino-4,5,7-triarylimidazo[1,5-b]pyridazines

Abstract

Diaminoimidazoles hold interest in light of their dual reactivity. Both imidazotriazepins [1,2] and imidazopyrimidines [31 are formed in their reactions with carbonyl compounds. In the present work, we studied the cyclocondensation of 4-aryl-l,2-diaminoimidazoles (I and II) with chalcone dibromides (IVa-lVh). This reaction was carried out upon heating diamines I and II with ketones IVa-IVh in methanol at reflux for 6-8 h using N-methylmorpholine as the catalyst.The reaction of aromatic o-diamines with a,/3-dibromochalcones proceeds through a series of steps involving formation of an t~-bromochalcone as the result of the elimination of HBr, addition of the diamine at the C=C bond to give a B-adduct, and separation of a B--enaminochalcone or the product of its cyclization, namely, 1,5-diazepin, from the reaction mixture [4, 5].Products Va-Vh and chalcones VIa-Vlh were isolated from the reaction mixture under the conditions described, indicating participation of tertiary amines in the reduction of the resultant ot-bromochalcones [6]. This behavior may account for the low yields of Va-Vh. Indirect evidence for initial dehydrobromination of ketones IVa-IVh is found in the formation of Vk in the reaction of diamine III with ot-bromochalcone VII. Products Vi and Vj were isolated in satisfactory yield in the reaction of diamines I and II with acetylenic ketones VIII and IX. The IR spectra of these products show bands at 3280 and 3452 cm -t assigned to primary amino group stretching vibrations and bands at 1637-1652 cm -t (superposition of stretching bands Vc= N and Vc=c). The electronic absorption spectra of imidazopyridazines Va-Vk show a strong band in the vicinity of 290 run and long-wavelength band at 490-500 nm.The PMR spectra of Va, Ve, and Vi (see Experimental section) show aromatic proton signals at 6.9-8.2 ppm and a broad singlet at 6.5 ppm assigned to NH 2 group protons, which disappears upon the addition of methanol. The signal for the pyridazine ring proton is sometimes overlapped by the aromatic proton multiplet but is readily determined by analyzing the integral signals.The mass spectrum of Ve shows quasimolecular ions [M + HI + with m/z 518.9, 520.9, and 522.9, wliich corresponds to the isotopic composition of the molecule assuming the presence of one bromine atom and one chlorine atom. The mass spectrum also shows fragmentation ions with m/z 504 [M-O] + and m/z 474 [M-NO] +.

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

“… Heterocyclization of 1-aminoimidazoles with 1,3-dicarbonyl or α,β-unsaturated carbonyl compounds (route B). Conditions: i) R 1 = NH 2 , NHAlk, R 2 = Ph, R 3,4 = Alk, Ar, solvent-free [ 24 ], AcOH [ 25 – 26 ], R 3 = Ph, R 4 = OEt, solvent-free [ 24 ]; ii) R 1 = NH 2 , R 2 = Ph, R 3 = H, Me, R 4 = Ar, ArCHO/MeOH/DMF [ 29 ] or R 4 = H, HC(OEt) 3 /iPrOH [ 30 ]; iii) R 1 = NH 2 , R 2 = Ar, R 3,4 = Alk, Ar, MeOH/ N -methylmorpholine or DMF or AcOH [ 27 – 28 ], R 3 = Ar, R 4 = COOH, DMF [ 31 ], R 3 = Ar, R 4 = NMe 2 , AcOH/DMF [ 32 ]. …”

“…In the synthesis of imidazo[1,5- b ]pyridazines along route B, 1-aminoimidazoles with no substituents at the C-5 atom of the original heterocycle and 1,3-dielectrophilic reagents are used, e.g., 1,3-diketones [ 24 – 26 ], β-ketoesters [ 24 ], α,β-unsaturated ketones [ 27 – 28 ], including those obtained in situ [ 29 – 30 ] or containing good leaving groups [ 31 – 32 ] ( Scheme 2 ).…”

Regioselective interaction of β-aroylacrylic acids with 1,2-diaminoimidazoles

“…The structures of compounds 3a-c were confirmed by 1 H NMR and IR-spectroscopic data. † Thus, the 1 H NMR spectra exhibited pronounced signals due to protons of both aromatic nuclei at 8.01-7.18 ppm; a singlet due to protons of the amino group with d 6.17-6.10 ppm, which disappeared after exchange for deuterium; a group of signals due to protons of the CH 2 -CH unit with a typical ABX structure (two doublets and a doublet of doublets: J AB 16.8 Hz, J AX 0 Hz and J BX 6.4 Hz); and (in 3a) a singlet due to protons of the methyl group.…”

“…The interaction of chalcones and α,β-dibromochalcones with 1,2-diaminoazoles containing hydrazine amino groups is a convenient method for the synthesis of azolopyridazine and azolopyrimidine systems. [1][2][3] Based on indirect data, it was postulated 1 that the reaction began at the step of Michael (or 1,4) addition of the azole to the enone (path A) or (if it is substituted) the endo nitrogen atom of diaminoazole (path B). 2,3 However, previously, we failed to obtain direct evidence for this interaction, namely, to isolate its intermediates, which rapidly underwent cyclization at an amino group (Scheme 1).…”

A novel method for the synthesis of imidazo[1,5-b]pyridazines

“…Reaction of diaminoimidazoles with 1-aryl-2,3-dibromo-3-(4-nitrophenyl)propanones ("dibromochalcones") gives a mixture of imidazopyridazines and the corresponding enones. 9 Imidazotriazepines are also formed by the reaction of diaminoimidazoles with acetylarenes 10 or β-ketoesters. 11 But in the latter case imidazo[1,5-b]-pyridazinones or imidazo[3,2-а]pyrimidinones may also be formed depending on the type of reactants.…”