Three-component synthesis of new o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines promoted by FeCl₃

Introduction

A large number of natural products and biologically active organic compounds contain the hydroxyl group [1]. Hydroxyl-substituted pyrazolo[3,4-b]pyridine derivatives have received much attention in drug discovery because of their wide biological activities [2]. In recent years, a variety of strategies have been reported for the synthesis of pyrazolo[3,4-b]pyridine derivatives [3–5] in the presence of various catalysts, such as iodine [6], L-proline [7], InCl₃ [8], acetic acid [9, 10] or under microwave/ultrasound irradiation [11, 12], among other approaches [13]. Iron(III) chloride has been widely used as the catalyst in organic synthesis [14]. Herein, we would like to report an efficient one-pot three-component reaction for the synthesis of novel o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines from 5-aminopyrazoles, β-keto esters and salicylic aldehydes using FeCl₃ as the catalyst.

Results and discussion

In order to optimize conditions for the synthesis of o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridine 4a, various reaction conditions have been investigated (Table 1). No expected product 4a was observed when commonly used catalysts iodine, acetic acid and L-proline were examined (Table 1, entries 1–3). After screening other catalysts such as InCl₃, ZrCl₄ and FeCl₃, it was found that the best yield of 89% of 4a was obtained by conducting the reaction in ethanol in the presence of 0.2 equiv of FeCl₃ (Table 1, entries 4–6). According to the literature reports, a fused coumarin 5a could be formed through transesterification reaction between the hydroxyl and ester group at high temperature [13, 15, 16]. In our hands, transesterification product 5a was not observed probably because of mild reaction conditions. The presence of a small amount of catalyst or lowering the reaction temperature leads to a relatively poor yield (Table 1, entries 7–11). The use of other solvents such as MeOH, MeCN, DMF and toluene also result in a low yield of 4a (Table 1, entries 12–15).

With these results in hand, the synthesis of additional products was investigated under the conditions optimized for the model compound 4a (Scheme 1). The reactions of substituted substrates 2a and 3a bearing electron-donating and electron-withdrawing groups afford the corresponding products 4b–g in good to excellent yields (65–90%). In case when R² is an alkyl group, products 4h–j are obtained in 70–78% yields. The use of ethyl 4,4,4-trifluoroacetoacetate (2, R = CF₃) also gives good results, delivering 4k–n in 70–78% yields. When 1,3-diphenyl-1H-pyrazol-5-amine (3b) was employed, 4o and 4p were isolated in 64% and 57% yields, respectively.

Scheme 1

Conclusions

An efficient FeCl₃-catalyzed three-component reaction for the synthesis of o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines from substituted salicylic aldehydes, β-keto esters and 5-aminopyrazoles in refluxing ethanol was developed. This reaction has the advantages of wide substrate scope, mild reaction conditions and good yields.

Experimental

All reagents were commercially available and used without further purification. Solvents were dried and freshly distilled before use. ¹H and ¹³C NMR spectra were recorded in CDCl₃ using Bruker AV 300 MHz spectrometers at 300 MHz and 75 MHz, respectively. IR spectra were obtained in KBr pellets using a Nicolet 5700 FT-IR spectrometer. High resolution mass spectra were recorded on a Bruker UltrafleXtreme MALDI TOF/TOF spectrometer. The CHN microanalyses were carried out with a Perkin-Elmer 2400 elemental analyzer. Flash column chromatography was performed on silica gel (200–300 mesh). Melting points were determined using X-4 apparatus and are not corrected.