Ionic liquid-accelerated Michael addition of pyrimidine and purine nucleobases to α , β -unsaturated esters: a rapid approach to carboacyclic nucleosides synthesis

Ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) efficiently accelerates Michael addition of pyrimidine and purine nucleobases to α , β -unsaturated esters in the presence of catalytic amount of Cs 2 CO 3 under microwave irradiation to give carboacyclic nucleosides in good to high yields and short reaction times.


Introduction
Currently, ionic liquids are the subject of considerable interest as benign reaction media in organic synthesis because of their unique properties, such as non-volatility, non-flammability, recyclability, high thermal stability and ability to dissolve a wide range of materials.During the past decade, a variety of ionic liquids have been demonstrated as efficient and practical alternatives to volatile organic solvents for many important organic reactions, including carboncarbon, carbon-oxygen, carbon-sulfur carbon-nitrogen and carbon-phosphorus bonds formation. 1arboacyclic nucleosides have attracted much interest due to their potential use as antiviral, 2 anticancer, 3 antibiotic, 4 and antipsychotic agents. 5][8][9][10][11][12][13] Several catalysts have been applied to achieve this transformation, including ZnOtetrabutylammonium bromide, 6 1,4-diazabicyclo[2,2,2]octane, 7 t-BuOK, 8 NaOEt, 9 PBu 3 , 10 enzyme, 11 and [bmim]OH. 12K 2 CO 3 in DMF has been also used for Michael addition of only purine nucleobases to α,β-unsaturated esters as well as acrylonitrile. 13It is worth noting that the methods that have been established for the Michael reaction of nucleobases are associated with some drawbacks, such as long reaction time, low yield, low selectivity, the use of expensive catalysts, the use of only unhindered electrophilic alkenes, and no compliance with the green chemistry protocols.Moreover, some methods can be used for Michael reaction of only pyrimidines or only purines.
Cesium carbonate is a commercially available, heterogeneous, reusable and environmentally benign basic reagent that has been used in various organic transformations, such as N3-alkylation of N1-substituted pyrimidine nucleobases, 14 N-arylation of nucleobases, 15 N-alkylation of diethyl acetamidomalonate, 16 O-alkylation of alcohols, 17 diarylation of ketones, 18 S-alkylation of thiols, 19 synthesis of calix [8]crowns by direct alkylation of p-tert-butylcalix [8]arene, 20 and synthesis of nucleoside antibiotic Ascamycin. 21he application of microwave technology in organic synthesis has been explored extensively within the last decade.Microwave irradiation has been demonstrated to be as an efficient technique for various organic reactions instead of using conventional heating. 21This technique often leads to a remarkable decrease in reaction times, increased yields, easier workup, matches with the green chemistry protocols, and may enhance the regio-and stereoselectivity of reactions. 22onsidering the above facts, and in continuation of our previous studies on nucleoside chemistry, 6,7,14,15,23 we report here an efficient green method for the synthesis of N-alkyl nucleobases (carboacyclic nucleosides) via microwave-assisted Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters using catalytic amount of Cs 2 CO 3 in [bmim]Br (Scheme 1).Scheme 1. Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters.

Results and Discussion
We have found previously Cs 2 CO 3 acts as an efficient basic reagent for N3-alkylation of N1substituted pyrimidines, 14 and N-arylation of nucleobases. 157][18][19][20][21] These subjects encouraged us to use this base as catalyst for N-alkylation of nucleobases via Michael addition reaction.Therefore, firstly we used different amounts of Cs 2 CO 3 to accomplish Michael addition of uracil (2 mmol) to n-butyl acrylate (2.1 mmol) in [bmim]Br (0.5 g) under microwave irradiation (200 W, max.110 ºC) to provide compound 1b (Scheme 1).The results are summarized in Table 1.As it can be seen from Table 1, the reaction proceeded efficiently in the presence of 15 mol% of Cs 2 CO 3 at 200 W of microwave power and the desired Michael adduct was obtained in 93% yield after 5 min.We also examined the Michael reaction in the presence of other basic catalysts (Table 1).The results showed that the catalysts K 2 CO 3 , basic Al 2 O 3 , CaO and MgO afforded lower yields and longer reaction times in comparison to Cs 2 CO 3 .Furthermore, we extended this reaction to adenine as a purine nucleobase that gave carboacyclic nucleoside 2b at 200 W of microwave power (max.140 ºC) in 81% yield within 8 min (Scheme 1).Considering the excellent results obtained from Cs 2 CO 3 , we applied this catalyst for all other reactions.To compare the efficiency of ionic liquid versus the conventional solvents, we examined the model reaction in some conventional solvents.Thus, a mixture of uracil (2 mmol), Cs 2 CO 3 (15 mol%) and n-butyl acrylate (2.1 mmol) was irradiated in a microwave oven (200 W, max.110 ºC) in several conventional solvents (5 mL) (Table 3).As it is shown in Table 3, higher yield and shorter reaction time were observed in [bmim]Br with respect to the conventional solvents.Therefore, ionic liquid is an essential factor to promote the Michael reaction.We also studied the effectiveness of microwave heating in comparison to conventional heating on the Michael reaction.For this purpose, compounds 1b as well as 2b were also prepared via Michael addition of uracil as well as adenine to n-butyl acrylate in the presence of Cs 2 CO 3 in [bmim]Br under thermal conditions.The results are displayed in Table 4. Clearly, the microwave procedure is more efficient.It must be mentioned that increasing the reaction temperature or the reaction times under the conventional heating did not improve the reaction yields.Temperature in microwave and thermal conditions.b Isolated yield.
To realize the generality and scope of this method, different pyrimidine and purine nucleobases were introduced to structurally diverse α,β-unsaturated esters (Table 5).As Table 5 indicates, all reactions proceeded efficiently and the desired Michael adducts were obtained in good to high yields and short reaction times.It has been observed that the bulkiness of alkoxy group (-OR) in the α,β-unsaturated esters affected slightly on the Michael reactions.The bulkier alkoxy groups afforded lower yields and longer reaction times (Table 5, entries 1-4 and 10-12).The structure of α,β-unsaturated esters had significant effect on the reaction.When nucleobases were reacted with sterically hindered α,β-unsaturated esters such as ethyl methacrylate and ethyl crotonate, the reaction yields decreased (Table 5, entries 5, 6, 13 and 14).Moreover, higher microwave power was applied in these cases.The presence of substituents (Me, Br and F) on 5position of the pyrimidine nucleobases had no significant effect on the reaction results (Table 5, entries 7-9).When adenine was used in the Michael reaction, exclusively N9-alkylated products were produced (Table 5, entries 10-14).However, Michael reactions of 6-chloropurine and hypoxanthine gave N7-isomers beside N9-ones in low yields (Table 5, entries 15 and 16).The interesting behavior of [bmim]Br/Cs 2 CO 3 system lies in the fact that it can be re-used after simple washing with Et 2 O, rendering thus process more economical.The yields of compound 1b (model compound) in the 2 nd and 3 rd uses of the [bmim]Br/Cs 2 CO 3 were almost as high as in the first use.
To compare the efficiency and capacity of the present method with the reported methods for the Michael reaction of nucleobases, we have tabulated the results of some these methods in the synthesis of carboacyclic nucleosides 1b, 1e, 1f, 2b, 2d and 2e in Table 6.As it is clear from Table 6, our method have significantly improved Michael addition of pyrimidine nucleobases to sterically hindered α,β-unsaturated esters as well as Michael reaction between purines with either unhindered or hindered α,β-unsaturated esters.

Conclusions
In summary, Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters can be effectively performed in ionic liquids under microwave irradiation.This new method for the synthesis of carboacyclic nucleosides has the advantage of high yield, high selectivity, short reaction time, generality, ease of product isolation, potential for recycling of ionic liquid as well as catalyst, and compliance with the green chemistry protocols.Table 6.Comparative synthesis of compounds 1b, 1e, 1f, 2b, 2d and 2e using the reported methods versus our method Cai et al. 11 Khalafi-Nezhad et al. 7  FT-NMR spectrometer.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.

General procedure for Michael addition of nucleobases to α,β-unsaturated esters in ionic liquids
To a well-ground mixture of nucleobase (2 mmol) and Cs 2 CO 3 (0.098 g, 0.3 mmol) in a microwave vessel was added [bmim]Br (0.5 g) and α,β-unsaturated ester (2.1 to 2.3 mmol) (Table 4), and mixed carefully with a small rod.The resulting mixture was irradiated in a microwave oven for the powers, the temperatures and the times reported in Table 4. Afterward, the reaction mixture was cooled to room temperature and was extracted with Et 2 O (3×50 mL).The organic extracts were then combined.After removal of the solvent, the crude product was purified by column chromatography on silica gel eluted with EtOAc/n-hexane.After isolation of the product and evaporating of the remaining Et 2 O in ionic liquid, the ionic liquid containing the catalyst (Cs 2 CO 3 /[bmim]Br) was used for next run under identical reaction conditions.

Table 5 .
Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters in the presence of Cs 2 CO 3 in [bmim]Br promoted by microwave irradiation Entry Product MW Power (W) T (º C) Time (min) Yield a (%) .b  In this reaction, the ester/nucleobase ratio (mol/mol) was 1.15/1.c In this reaction, the ester/nucleobase ratio (mol/mol) was 1.05/1.d This reaction was performed at 110 ºC because of lower boiling point of the corresponding α,β-unsaturated ester, ethyl acrylate.

Table 1 .
The influence of different molar ratios of Cs 2 CO 3 to substrate as well as other basic catalysts on the reaction of uracil with n-butyl acrylate in [bmim]Br under microwave irradiation

Table 2 .
The Michael addition of uracil to n-butyl acrylate using Cs 2 CO 3 in different ionic liquids promoted by microwave irradiation a Isolated yield.

Table 3 .
Comparative the Michael addition of uracil to n-butyl acrylate using Cs 2 CO 3 in conventional solvents versus [bmim]Br under microwave irradiation (200 W, max.110 ºC) a Isolated yield.

Table 4 .
Comparative synthesis of compounds 1b and 2b using conventional heating versus the microwave method (200 W)