Synthesis and characterization of new 1H-pyrazolo[3,4-b]pyridine phosphoramidate derivatives

2014 ARKIVOC  
Twelve new 1H-pyrazolo[3,4-b]pyridine phosphoramidate derivatives were synthesized under mild conditions by nucleophilic aromatic substitution reaction of aminoalkylphosphoramidates over 4-Cl substituted pyrazolo [3,4-b]pyridine in good yields. The new compounds were characterized by IR, 1 H, 13 C and 31 P NMR spectroscopy and HRMS. The crystal structure of one compound was solved by X-ray diffraction and showed a network of intermolecular interactions involving phosphoramidate groups. The
more » ... te groups. The syntheses of the new 1H-pyrazolo[3,4-b]pyridine phosphoramidates 8a-l were performed by nucleophilic aromatic substitution of the chlorine atom in 4-substituted pyrazolo[3,4-b]pyridines (4a-c) by aminoalkylphosphoramidates 7a-d (Scheme 1). The starting 4-chloro-1H-pyrazolo-[3,4-b]pyridine derivatives 4a-c were available in our laboratory and could be easily prepared from condensation of appropriate hydrazine (1a,b) and β-aminocrotononitrile or benzoylacetonitrile, followed by condensation of the intermediate 5-aminopyrazoles (2a-c) with diethyl ethoxymethylenemalonate and then by 'chlorocyclization' with POCl 3 . Finally 4a-c were purified by recrystallization from ethanol. [21] [22] [23] [24] Scheme 1. Reagents and conditions: (i) β-aminocrotononitrile or benzoylacetonitrile (ii) diethyl ethoxymethylenemalonate, ethanol, reflux, 2 h (iii) POCl 3 , 110 ºC, 5 h, (iv) CCl 4 , ethanol, T < 55 ºC, 10 min; (v) 7a-d, THF, reflux, 9-12 h. The aminoalkylphosphoramidates 7a-d were synthesized from diisopropylphosphonate 5 and aliphatic diamines 6a-d. 25, 26 In order to guarantee monophosphorylation of the diamines, at least 2.5-fold excess of diamine in ethanol were used. Keeping alkaline pH and temperature below 55 °C is required to avoid bis-phosphorylation. Nucleophilic aromatic substitution of the chlorine atom in 4-substituted pyrazolo[3,4-b]pyridines by amines has been used as a versatile route to new pyrazolopyridine derivatives. 5, 9, [27] [28] [29] [30] Thus, reaction of 4a-c with an excess (2 equiv.) of aminoalkylphosphoramidates 7a-d in refluxing THF for 9 to 12 h afforded the 1H-pyrazolo[3,4-b]pyridine phosphoramidates derivatives 8a-l in 52-98% yield ( Table 1) . The presence of an electronwithdrawing group (-CO 2 Et) in 5-position of the substrate 4 and the excess of the nucleophilic agent 7 facilitate the reaction. The products were fully characterized by infrared, 1 H, 13 C, and 31 P NMR spectroscopies and by high resolution mass spectrometry (HRMS).
doi:10.3998/ark.5550190.p008.413 fatcat:jwm2q3pbyjashogealb5iut5am