KF/Al 2 O 3 as a highly efficient reagent for the synthesis of N -aryl derivatives of pyrimidine and purine nucleobases

KF/Al 2 O 3 acts as a highly efficient reagent for the synthesis of N-aryl derivatives of pyrimidine and purine nucleobases as biologically interesting compounds via N-arylation reaction under microwave as well as conventional heating conditions. Using this method, the title compounds are produced in good to excellent yields and relatively short reaction times


Introduction
Recently, solid-supported reagents have proved to be useful to chemists in the laboratory and industry due to the good activation of adsorbed compounds, reaction rate enhancement, selectivity and easier workup. 1,2Alumina-supported KF is one of the most interesting of these reagents because it has surface properties that suggest that very rich organic reactions may occur there. 2 KF/Al 2 O 3 is an inexpensive and commercially available reagent which has been used in several organic transformations, such as acetylation of amines, alcohols and phenol, 2a preparation of amides from nitriles, 2b cycloaddition of azomethine ylides, 2c and hydrothilation of alkynes, 2d etc. 2e-2k The coupling of microwave irradiation with the use of mineral-supported reagents provides chemical processes with special attributes, such as enhanced reaction rates, higher yields, better selectivity and improved ease of manipulation. 3Consequently, the combination of solid-supported reagents with the use microwave irradiation represents a suitable way toward the so-called ideal synthesis.
N-Aryl nucleobases have been frequently used as antitumor, 4a,b antimicrobial, 4c,d and plant growth stimulating agents.4e Furthermore, they have been applied as agonist or antagonist for various receptors, 5a-c and enzymes.5d-i Therefore, there is a great deal of interest in the synthesis of this class of compounds.The methods have been established for the preparation of N-aryl derivatives of nucleobase are multi-step reactions 6 and N-arylation of nucleobases via crosscoupling reactions, 7 as well as nucleophilic aromatic substitution (SN Ar ). 8 It is worth noting that the reported methods have one or more of the following drawbacks: (i) long reaction time, (ii) unsatisfactory yield, (iii) low selectivity, (iv) the use of expensive reagent, (v) application of the method for the synthesis of only N-aryl pyrimidines or only N-aryl purines, and (vi) tedious experimental procedure.Moreover, N-arylation of nucleobases via SN Ar reaction has been scarcely studied so far.Thus, it seems highly desirable to find an efficient, general, rapid, simple and inexpensive protocol for the synthesis of this class of nucleosides.
Having the above facts in mind, and also in extension of our previous researches on nucleosides chemistry, 8a,9 we report here a highly efficient method for the preparation of N-aryl derivatives of pyrimidine and purine nucleobases via SN Ar in the presence of KF/Al 2 O 3 under microwave and thermal conditions (Scheme 1).Interestingly, this method has none of the abovementioned disadvantages at all.

Results and Discussion
As previously mentioned KF/Al 2 O 3 has been applied as a highly efficient reagent for different organic transformations. 2 This subject encouraged us to use it for the synthesis of N-aryl nucleobases as one of the most interesting derivatives of nucleosides via N-arylation of nucleobases with activated aryl halides.Therefore, firstly we examined N-arylation reaction of uracil (1 mmol) with 1-fluoro-2-nitrobenzene (1.1 mmol) in DMF (1 mL) in the presence KF/Al 2 O 3 (1 mmol) under microwave irradiation (300 W, max.130 ºC) (Scheme 1).In these conditions, the desired product 1a was produced in 91% within 18 min.The reaction was also tested at different microwave powers (100-600 W, max.130 ºC); however, the reasonable results were observed at 300 W.Moreover, the reaction of uracil with 1-fluoro-2-nitrobenzene was efficiently achieved using conventional heating (130 ºC) (Scheme 1).This optimized reaction conditions was also extended to N-arylation of adenine as a purine nucleobase in which the product 2a was obtained in high yield under both microwave and thermal conditions (Scheme 1).
To recognize the efficiency of KF/Al 2 O 3 , the reaction of uracil with 1-fluoro-2-nitrobenzene was examined in the presence of KF as well as Al 2 O 3 separately in both microwave and thermal conditions.The results are summarized in Table 1.As Table 1 indicates, the reaction yields decreased when KF and Al 2 O 3 were separately applied in the reaction.Thus, it is necessary to support KF on Al 2 O 3 .To select the appropriate solvent for the N-arylation reaction, the model reaction was tested in different solvents under both microwave and thermal conditions (Table 2).As it can be seen from Table 2, the best results were obtained when DMF was used.The reaction was also checked under solvent-free conditions; however, these conditions were not efficient (Table 2).
To assess the efficiency and scope of our method, different pyrimidine and purine nucleobases were N-arylated with structurally diverse aryl halides.The results are displayed in Tables 3 and 4. As Tables 3 and 4 indicate, all reactions proceeded efficiently and the desired Naryl nucleobases were produced in good to excellent yields in both microwave and thermal conditions.Moreover, the reaction yields in both conditions were relatively similar.In our method pyrimidine and purine nucleobases were regioselectively arylated at N1 and N9 positions respectively.The sites of N-arylation in both pyrimidine and purine nucleobases were indicated and confirmed by 1 H and 13 C NMR spectra analysis.
The efficiency and capacity of the presented method was compared with the reported methods for N-arylation of nucleobases via SN Ar (Table 5).For this purpose, we have tabulated the results of the reported methods for the preparation of compounds 1a, 1c, 1h, 1k, 2a, 2c and 2d.As Table 5 demonstrates, our method has significantly improved N-arylation of nucleobases via SN Ar .

Conclusions
In summary, we have developed a highly efficient method for N-arylation of nucleobases via SN Ar .This new strategy for the synthesis of N-aryl nucleobases has several advantages, such as generality, high yield, high selectivity, short reaction time, low cost, and simple experimental as well as straightforward isolation.

Experimental Section
General Procedures.All chemicals were purchased from Merck or Fluka Chemical Companies.All compounds were identified by comparison of their melting points and spectral data with those in the authentic samples.All reactions were carried out using laboratory microwave oven (MicroSYNTH, MILESTONE Company, Italy).IR spectra were run on a Shimadzu FTIR-8300 spectrophotometer.The 1 H NMR (250 MHz) and 13 C NMR (62.

General procedure for the synthesis of N-aryl nucleobases
To a well-ground mixture of nucleobase (1 mmol), aryl halide (1.1 mmol) 10 and KF/Al 2 O 3 (0.16 g) in a microwave vessel was added DMF (1 mL) and mixed carefully with a small rod.The resulting mixture was irradiated and stirred in a microwave oven for the powers and the times reported in Tables 3 and 4. The microwave was programmed to give a maximum internal temperature of 130 °C.Afterward, the reaction mixture was cooled to room temperature and was poured in ice-water (10 mL), the solids was filtered and the filtrate was extracted with ethyl acetate (2×50 mL).The solvent was evaporated and the the residue was combined with the solids.This mixture was purified by column chromatography on silica gel eluting with EtOAc-nhexane.

Table 3 .
Synthesis of N-aryl derivatives of pyrimidine nucleobases

Table 3 .
Continued a Isolated yield.

Table 4 .
Synthesis of N-aryl derivatives of purine nucleobases a Isolated yield.
5 MHz) were run on a Bruker Avance DPX-250, FT-NMR spectrometer (δ in ppm).Mass spectra were recorded on a Shimadzu GC MS-QP 1000 EX apparatus.Microanalyses were performed on a Perkin-Elmer 240-B microanalyzer.Melting points were recorded on a Büchi B-545 apparatus in open capillary tubes.