English

• 1.   Introduction

  Purine bases and nucleosides show a wide range of biological and pharmaceutical activity such as antiviral or anticancer activity [1-9]. Especially, purine derivatives with alkyl group at C8 have played much more important role in heterocyclic compounds because of their unique bioactivities. For example, 8-metyladenosine is highly selective inhibitor of vaccinia virus, and 8-ethyladenosine shows special biochemistry activity against respiratory syncytial virus [10]. 8-Vinyladenosine has a high bioactivity against herpes simplex virus (type 1) [11], and 8-cyclopentyl-2, 6-diphenylpurine has been shown to be very promising with an affinity of 0.29 nmol/L at the human adenosine A1 receptor [12].

  The classical methods for the synthesis of 8-alkylpurines are transition-metal catalyzed cross-coupling reactions of 8-halogenopurines with various alkylating reagents including tetraorganotin [13-15], tetraorganozinc [16], alkylaluminium [17, 18], alkylboronic acids [19], grignard reagents [20-22], etc. (Scheme 1). Though the coupling reactions have received significant attention due to their generality over the last several years, they do involve the following disadvantage aspects: the reactions often demand expensive metal catalysts, complex ligands, organometallic reagents which usually need to be prepared by multi-step processes, the pre-activation of C-H bond to C-X (X=Cl, Br, I, OTf, etc.) bond, the anhydrous and anaerobic conditions. Therefore, it is still of great importance to develop alternative methods for the preparation of 8-alkylpurines.

  Scheme 1

  

  图 Scheme 1  Different routes for the synthesis of 8-alkylpurines.

  Scheme 1.  Different routes for the synthesis of 8-alkylpurines.

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  Double C-H activation was successfully developed by using transition-metal as catalyst for the efficient construction of carbon-carbon bond formation as a highly atom-economical and direct approach [23-34]. However, only one example of such direct double C-H activation process was used for the alkylation of C-6 of purines up to now. In 2002, Ellman et al. successfully synthesized C-6 alkylated purine via rhodium-catalyzed C-H bond activation using alkene as alkylating reagent at 150 ℃ in THF [35]. However, alkyl esters are seldom used as alkylating reagents though they are cheaper and more readily available than their corresponding alkyl halides [36]. On our continued interest on the modification of purines [37-41], herein, we report our discovery for the synthesis of C8 alkylated purine by direct C-H bond activation of purines in the presence of cheap and readily available Co catalyst from 8-H purines and tetrahydrofuran.

  2.   Experimental

  All reagents and solvents were purchased from commercial sources and purified commonly before used. For column chromatography silica gel (200-300 mesh) was used as the stationary phase. All reactions were monitored by thin layer chromatography (TLC). NMR spectra were recorded with a 400 MHz spectrometer for ¹H NMR and ¹³C NMR. Chemical shifts δ are given in ppm relative to tetramethylsilane as internal standard, residual CDCl₃/DMSO-d₆ for ¹H NMR or CDCl₃ in ¹³C NMR spectroscopy. High-resolution mass spectra were taken with a 3000 mass spectrometer, using Waters Q-TOF MS/MS system. Melting points were recorded with a micro melting point apparatus and uncorrected.

  Synthesis of 9-benzyl-6-methoxy-8-(tetrahydrofuran-2-yl)-9H-purin by direct alkylation of 8-H purine with tetrahydrofuran catalyzed by CoCl₂.6H₂O: A mixture of 9-benzyl-6-methoxy-9Hpurine (0.125 mmol), CoCl₂.6H₂O (20 mol%), MgSO₄ (0.625 mmol), and THF (2 mL) in a 25 mL of reaction tube was stirred at 70 ℃ for 48 h under O₂ atmosphere and monitored by TLC. After cooling, the reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to give the desired product 3a. The characterization data of the products are summarized in the Supporting information.

  3.   Results and discussion

  We initially carried out our experiments by employing 9-benzyl-6-methoxyl-9H-purine and tetrahydrofuran as model substrates (Table 1). First, the reaction was conducted by using air as oxidant in the presence of 20 mol% catalytic amount of CoCl₂.6H₂O, and the corresponding 8-alkylated product was given in poor yield (35%, entry 1). Since the reaction is a kind of dehydrogenation reaction between the substrates, we tried to use oxygen as the oxidant instead of air, and got a higher yield (50%, entry 2). Then different cobalt catalysts were tested and CoCl₂.6H₂O was proved to be the best choice (entries 2-4). Adding some oxidants such as oxone and AgOAc did not enhance the yield (entries 5-6), and no target product was obtained when CuI was added (entry 7). However, a higher yield was obtained when anhydrous magnesium sulfate or molecular sieves was used as an additive (entries 8-9), and 5 equiv. of anhydrous magnesium sulfate led to a best yield (85%, entry 10). In order to verify whether MgSO₄ acted as a desiccant, we used anhydrous cobalt dichloride as catalyst in redistilled THF, the yield of the target product was only 50% (entry 11), proving that the role of magnesium sulfate or molecular sieves was more than a desiccant. When the reaction time was reduced to 24 h, no product was obtained (entry 12). And when the reaction time was prolonged from 48 h to 72 h, the yield of the product was almost the same (entry 10 vs. 13). The reaction solvent was subsequently screened. When 1 equivalent of THF as the reaction raw material was added to dichloromethane, ethanol, benzene, acetonitrile, no product was obtained, which indicated that excess THF was essential for the reaction (entries 14-17). And the enhance of reaction temperature to 120 ℃ led to an obvious lower yield due to the increase of byproducts. So the optimized reaction conditions involved 20 mol% of CoCl₂.6H₂O as catalyst, O₂ as oxidant, 5 equiv. of MgSO₄ as additive in THF (2 mL) at 70 ℃ for 48 h.

  表 1

  

  表 1  Optimization of reaction conditions.^a

  Table 1.  Optimization of reaction conditions.^a

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  Under the optimal reaction conditions, this new cycloalkylation protocol was extended to a variety of purines, and the results are shown in Table 2. A series of 9-substituted-6-methoxy-9H-purines were subjected to the reaction and the corresponding products (3a-3f) were obtained in high yields. It was obvious that the longer the side chain at N9, the lower the yield of the product (entries 2-4). 9-Benzyl-2, 6-dimethoxy-9H-purine 1g afforded the desired products 3g in excellent yields (90%), while 1h could not give the corresponding product 3h. It seemed that electronic effect of the group on C2 had great influence on the reaction, electron-donating group on C2 was favorable to the reaction (entries 7 vs. 1), while electronwithdrawing group on C2 led to no reaction (entry 8). On the contrary, electron-withdrawing group on C6 was favorable to the reaction (entries 9 vs. 2).

  表 2

  

  表 2  The substrate scope.^a

  Table 2.  The substrate scope.^a

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  As shown in Table 2, several oxygenheterocycles were further explored. 2-Methyltetrahydrofuran 2b could afford the target compound 3j in good yield (entry 10), while 1, 4-dioxane 2c only gave the corresponding product 3k in poor yield (entry 11). Unfortunately, when morpholine or tetrahydro-2H-pyran was used as the substrate, no desired product was obtained.

  In addition, we also explored the reaction of tetrahydrofuran and benzimidazole, benzothiazole, benzoxazole or imidazole (Scheme 2). The substituted benzimidazoles could give the corresponding products in good yields (70% and 75%, Scheme 2). Unfortunately, the desired products could not be obtained from benzothiazole, benzoxazole or imidazole.

  Scheme 2

  

  图 Scheme 2  The reaction of tetrahydrofuran and benzimidazole.

  Scheme 2.  The reaction of tetrahydrofuran and benzimidazole.

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  4.   Conclusion

  In summary, we have developed a direct alkylation of 8-H purines with tetrahydrofuran by the sp²-sp³ C-C bond formation in the presence of inexpensive cobalt catalyst in a single step. A series of novel C8-oxygen heterocyclic alkyl purine compounds were synthesized in good yields under mild reaction conditions using the readily available alkylating reagents. Though the scope of this direct alkylation does not tolerate some substrates, this methodology still provides a complementary route to the classical coupling reactions for the synthesis of C8-alkyl-substituted purine analogues.

  Acknowledgments

  We are grateful for financial support from the National Natural Science Foundation of China (No. 21202039), the Program for Science & Technology Innovation Talents in Universities of Henan Province (No. 13HASTIT013), and the Foundation for University Young Key Teacher by Henan Province of China (No. 2011GGJS-132).

  Appendix A. Supplementary data

  Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.06.009.

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• 

  Scheme 1  Different routes for the synthesis of 8-alkylpurines.

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  Scheme 2  The reaction of tetrahydrofuran and benzimidazole.

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  Table 1.  Optimization of reaction conditions.^a

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  Table 2.  The substrate scope.^a

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•