A Facile One-pot Synthesis of 1-Arylpyrazolo[3,4-d]Pyrimidin- 4-ones

One pot synthesis of 1-arylpyrazolo[3,4-d]pyrimidin-4-ones by the reaction of 5-amino-N-substituted-1H-pyrazole-4-carbonitrile with different lower aliphatic acids in the presence of POCl3 has been developed. The structures of all the title compounds have been confirmed by IR, 1H-NMR, 13C-NMR, and elemental analyses. Moreover, the structures of one of these compounds, 2c, was confirmed by single-crystal X-ray diffraction.


Introduction
Pyrazolopyrimidinone derivatives have attracted the attention of numerous researchers over many years due to their important biological activities [1][2][3][4]. Structural analogs of pyrazolo [3,4-d]pyrimidines have displayed good activities as inhibitors of cyclin-dependent kinase 2 [5] and PI3 kinase-A [6], anticancer and radioprotective activity [7], antimicrobial [8] and other biology activity [9]. The importance of pyrazolo [3, 4-d]pyrimidines had resulted in the development of several synthetic methods for their construction [10,11]. The traditional transformation utilizes two steps to assemble aminopyrazolo [3, 4-d] pyrimidin-4-ones, as illustrated in Schemes 1 and 2. However, the transformation of compounds 2 requires two steps and sufferes from several disadvantages such as OPEN ACCESS vigorous conditions, long reaction times and low yields [12,13]. The development of one-step and efficient syntheses of aminopyrazolo [3,4-d]pyrimidin-4-ones under mild conditions remained a work in progress. Scheme 1. Synthesis of pyrazolo [3, 4- Here, we report a simple and efficient method for the synthesis of usefully functionalized pyrazolo [3,4-d] pyrimidins-4-ones 2 by heteroannulation under mild conditions using POCl 3 .

Result and Discussion
The 5-amino-N-substituted-1H-pyrazole-4-carbonitrile starting materials 1, synthesized by a one-pot synthesis literature procedure [14], was then reacted with lower aliphatic acids in the presence of POCl 3 to give the target N-substituted pyrazolo [3,4-d]pyrimidin-4-ones 2 (Scheme 3). A number of works about POCl 3 -catalyzed reactions, especially intramolecular condensations [15] have been reported. In our reaction system POCl 3 acted not only as a chlorinating reagent, but also an oxidant. Thus, we concluded that the 5-amino-N-substituted-1H-pyrazole-4-carbonitrile were first oxidized to give the corresponding N-substituted-5-amino-pyrazole-4-carboxamide, which immediately reacted with the acyl chloride which might be generated in situ from the reaction of the carboxylic acid with POCl 3 . Followed by cyclization and condensation of the intermediate, the target products were formed. The reaction went smoothly by controlling the amount of POCl 3 , and the products were obtained in good yields. The results were presented in Table 1. The structures of compounds 2a-j were deduced from their elemental analyses and their IR, 1 H-NMR, 13 C-NMR and mass spectra and all elemental and spectral data of compounds 2a-j were in accord with the suggested structures. The 1 H-NMR spectrum of 2c, as an example, consisted of a singlet at δ 11.06 from the NH function, a singlet at δ 8.27 is from the H-3 proton, a singlet at δ 8.11 due to the phenyl ring (two protons), a multiplet at δ 2.74 (two protons) from the CH 2 and a triplet at δ 1.23 due to the methyl group (three protons). Moreover the structure of 2c was confirmed via X-ray crystallographic analysis ( Figure 1).

Figure 1.
Single crystal X-ray crystal structure of 2c.

General
All the melting points were uncorrected. 1 H-, 13 C-, and 19 F-NMR spectra were recorded on a FT-Bruker AT-300 instrument using CDCl 3 or CD 3 COCD 3 as a solvent with tetramethylsilane (TMS) as the internal standard. J-values are given in Hz. Compounds were properly characterized by elemental analyses using a Carlo-Erba EA-1112 instrument. IR spectra were measured on a Bruker VECTOR55 instrument. Silica gel 60 GF254 was used for analytical and preparative TLC.

General procedure for the preparation of the pyrazolo[3,4-d]pyrimidines 2a-2j: preparation of 2c
5-Amino-1-[2,6-dichloro-4-(trifloromethyl)phenyl]-1H-pyrazole-4-carbonitrile (0.321 g, 1 mmol) was dissolved in propanoic acid (3 mL). Then POCl 3 (0.2 mL) was added quickly. The mixture was refluxed for 2 h (the reaction system was carefully observed by TLC). After the mixture was cooled, added ice water (50 mL). A mass of white precipitate was produced. K 2 CO 3 was added to neutralize the acid till no bubble occurs. The reaction mixture was filtered, and washed with a small amount of ethanol, dried. A 90% yield of the compound was obtained. Crystals of 2c suitable for X-ray diffraction were obtained by slow evaporation of ethanol-acetone mixture solution. The other compounds were also synthesized according to this method.

X-ray crystallography
Compound 2c was subjected to single crystal X-ray crystallography and intensity data were collected at 298(2)K on an Siemens P4 diffractometer and use graphite Monochromated MoK a adiation (λ = 0.71073Å). The structure was solved by a direct method using the SHELXL-97 program [16] and refined with the SHELXL-97 program. All H atoms bonded to the C atoms were placed geometrically at the distances of 0.93-0.96Å and included in the refinementin riding motion approximation with U iso (H) = 1.2 or 1.5U eq of the carrier atom. The thermal ellipsoids were plotted with the SHELXL-97 program at 50% probability. The molecular structure is shown in Figure 1. Selected crystal data and structure refinement details are presented in Table 2. Selected bond distances and angles are listed in Table 3.
CCDC 774536 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK; E-mail: deposit@ccdc.cam.ac.uk.

Conclusions
In summary, we have successfully developed a simple and efficient method for the synthesis of variously functionalized pyrazolo [3,4-d]pyrimidin-4-ones by heteroannulation under mild conditions using POCl 3 . This works has been patented [17]. Further heteroannulation studies are underway in our laboratory.