Abstract
A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr3. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines. The experiments demonstrated that the reaction intermediates were the chemical equivalents of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl)formamidines. The rate of the reaction could be described as being proportional to the reactivity of amine reactants during intermolecular heterocyclization, especially when hexamethyldisilazane was used.
Highlights
One-flask reactions possess significant advantages and have emerged as a powerful tool in synthetic organic chemistry and reaction design approaches [1,2,3]
3a–n via the sequential Vilsmeier reaction and intermolecular heterocyclization and explain the the study illustrated in Scheme 2 was performed. 5-Amino-1,3-diphenylpyrazole (1a) was prepared mechanism the study illustrated in Scheme 2 was performed. 5-Amino-1,3-diphenylpyrazole (1a) was by our previously developed method [38,39] and used as the model starting material to improve the prepared by our previously developed method [38,39] and used as the model starting material to intermolecular heterocyclization reaction conditions
Following the reliable published the Vilsmeier reaction 5-aminopyrazole 1a was treated with 3.0 equivalent of PBr3 in N,Nprocedure for the Vilsmeier reaction 5-aminopyrazole 1a was treated with 3.0 equivalent of PBr3 in dimethylformamide (DMF) solution at 60 °C for 1.0–2.0 h
Summary
One-flask reactions possess significant advantages and have emerged as a powerful tool in synthetic organic chemistry and reaction design approaches [1,2,3]. The main advantages of using one-flask reactions in organic syntheses are their green chemistry nature and high atom economy due to the lack of workup or the isolation of intermediates involved [4,5,6,7,8,9,10,11,12]. We previously reported an efficient one-pot three-component synthesis of pyrazolo[3,4-d]pyrimidines that involved treatment of 5-aminopyrazoles with formamide using PBr3 as the coupling agent (Scheme 1) [13,14,15]. Synthesis of of pyrazolo[3,4-d]pyrimidines byby thethe different synthetic strategy viavia thethe Vilsmeier. Vilsmeier reaction and intramolecular or intermolecular heterocyclization. Pyrazolopyrimidine derivatives are important structural moieties, found in pharmacologically active.
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