1 Introduction

Pyrazolo[3,4-d]pyrimidines are of pharmaceutical interest in a variety of therapeutic areas [1]. They have attracted much attention in drug discovery programs because of their structural resemblance to purine nucleobases. In recent years, researchers have reported the use of purine derivatives of allopurinol (Scheme 1, compound 1) as kinase inhibitors [2], antiviral agents [3], adenosine antagonists [3c,4], glutamate modulators [5], and antitubercular agents [6].

Recently, the direct CH arylation of aromatic and heteroaromatic compounds has proved to be an attractive alternative method to traditional cross-coupling reactions [7]. Contrary to palladium-catalyzed couplings, including Suzuki et al. [8], Stille [9], or Negishi et al. [10] couplings, which require the preparation of organometallic reagents (boronic acids, tin, or zinc derivatives), preliminary functionalization is not carried out in direct CH arylation. In our research program on the stimulation of CH activation [11], we suggest a new approach for the direct and selective C-3 arylation of substituted 1H-pyrazolo[3,4-d]pyrimidines using Pd(OAc)₂ as a catalyst, with various ligands and bases. The results obtained with this approach in the present investigation are reported and discussed herein.

2 Results and discussion

The general synthetic pathway for the preparation of a series of 1H-pyrazolo[3,4-d]pyrimidines is shown in Scheme 1.

In the pyrazolopyrimidine ring system, the chloro substituent (as a leaving group) was introduced at C-4, which was the most reactive site for nucleophilic attack. The high-temperature reaction of the commercially available allopurinol 1 with excess phosphorus oxychloride in the presence of NN-dimethylaniline gave an intermediate product 2 [12], which was then allowed to react with methyl iodide so as to afford the corresponding 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine [13] 3. The use of 1 equiv of methyl iodide allowed us to selectively obtain N1 methylated isomer. Compound 3 also demonstrated the Suzuki cross-coupling reaction [14]. The 4-chloro substituent of 3 was directly displaced with phenyl to generate compound 4, affording an additional opportunity for the selective functionalization of this molecule.

We started our optimization by investigating the direct arylation of 4-phenyl-1-methyl pyrazolopyrimidine 4 with 4-bromotoluene 5a. The reaction conditions were the same as those already used in our previous study [11f]. Compound 4 (1 equiv) was allowed to react with 5a (2 equiv) in the presence of palladium(II) acetate (10 mol %), triphenylphosphine (20 mol %), and K₂CO₃ (2 equiv) in toluene at 110 °C for 48 h, but no C-3 arylation was observed (Table 1, entry 1). On replacing the ligand by tricyclohexylphosphine (20%), direct CH arylation then took place at the 3-position of 4 to give product 7 in 28% yield (Table 1, entry 3). Using another base such as cesium carbonate and increasing the amount of Pd(OAc)₂ and tricyclohexylphosphine to 20% and 40% mol, respectively, no noticeable improvement in the reaction was detected (Table 1, entries 4 and 5). Using 1,10-phenanthroline instead of tricyclohexylphosphine in the presence of Pd(OAc)₂, 4-iodotoluene (2 equiv), and Cs₂CO₃ (3 equiv) in DMA at 165 °C produced 7 in 65% yield (Table 1, entry 7). With K₃PO₄ as additive conversion improved to 80% (Table 1, entry 8), whereas using 4-bromotoluene instead of 4-iodotoluene led to a decrease in conversion to 72% (Table 1, entry 9). When decreasing the amount of Pd(OAc)₂ and 1,10-phenanthroline to 10 and 20 mol %, respectively, the yield of the desired product 7 diminished (60%, Table 1, entry 10).

We tested the latter conditions without using 1,10-phenanthroline, but no C3 arylation was detected (Table 1, entry 11). This result displays the crucial role of the ligand in CH activation.

Finally the best results were obtained in the presence of palladium (II) acetate (20 mol %), 1,10-phenanthroline (40 mol %), 4-iodotoluene (2 equiv), Cs₂CO₃ (3 equiv), and K₃PO₄ (2.5 equiv) in DMA at 165 °C for 48 h (entry 8).

Comparable yields were attained using diverse aryl iodides bearing ortho, meta, and para substituents (Table 2, entries 1–7). This result highlights the great adaptability of our strategy. Indeed, we were pleased to observe that aryl-bearing electron-rich (MeO, Me) or electron-poor (CF3, CN, and so forth) substituents in the C-3 position were well tolerated. The molecular structure of compound 7 was confirmed by X-ray crystallographic analysis and proved that CH arylation occurred regioselectively at position 3 (Fig. 1).

Afterward, we prepared the compound 4-methoxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidine [15] 14 by reacting 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 3 with sodium methoxide and methyl alcohol in THF, then we tested the optimal conditions found (Table 1, entry 8) on these compounds functionalized at position 4 (3 and 14). No C-3 arylation was detected, and only degradation was observed (Scheme 2).

On the basis of the newly reported studies on the C-3 arylation reaction [11b,11c], a probable mechanism for the C-3 arylation on pyrazolopyrimidine is put forward (Scheme 3). Pd(OAc)₂ and ligand form a Pd(II) intermediate (complex 1, Scheme 3) followed by a Pd(II)–pyrazolopyrimidine complex (complex 2, Scheme 3). Then an oxidative addition of aryl halide (X = I or Br) results in a Pd(IV) complex (complex 3, Scheme 3). After reductive elimination, the required compound 7 is achieved, and complex 4 is formed. In the end, complex 4 is transformed into complex 1.

3 Conclusion

It has been shown for the first time that Pd-catalyzed regioselective direct C-3 arylation of substituted 1H-pyrazolo[3,4-d]pyrimidine is possible by using 1,10-phenanthroline as a ligand. Satisfactory to excellent yields were achieved for a wide range of aryl coupling partners with both electron-rich and electron-poor substituents, providing access to a library of various 1H-pyrazolo[3,4-d]pyrimidine compounds.

4 Experimental section