3 Results and Discussion
3.4 Immobilization of Ruthenium Catalysts
3.4.2 meta -Selective Bromination of Purine Bases
Recent progress in transition metal-catalyzed C–H functionalizations enabled selective remote transformations of otherwise unreactive C–H bonds.[44a-c, 44e-g] Especially halogenations provide interesting transformations, because aryl halides can be easily further functionalized. So far, this approach is limited to pyridines, pyrazoles and pyrimidines.[60]
Unnatural nucleosides are of major interest and can be applied, amongst others, as antivirals and anticancer agents.[91] Therefore, the functionalization of purine bases is highly desirable to achieve differently functionalized structures, which could possibly show biological activity. D. J. Burns and Ackermann[141] developed a homogeneous system for the meta-selective C–H bromination of purine bases 85 (Scheme 118).
Scheme 118. Optimized conditions for the homogeneous meta-bromination of purine bases 85.
Intrigued by these findings several heterogeneous catalysts were probed in this reaction. The commercially available ruthenium on alox catalyst showed no reactivity at all and also literature known ruthenium on magnetite only gave low conversion (Table 16, entries 1-2). As the bromination worked with ruthenium(II) and ruthenium(III) catalysts in a homogeneous fashion, ruthenium(IV) oxide was also subjected to the reaction conditions, but did not show any activity (entry 3). However, sol-gel derived catalyst 144 led to the product in good yields (entry 5) and the catalyst loading could even be reduced, albeit with a slight decrease in the obtained yield (entries 10-11). Notably, a reduction of the catalyst was not viable in the homogeneous reaction.
Table 16. Optimization of the meta-bromination of phenylpurine 85a.[a]
entry [Ru] equiv NBS solvent T / °C Yield / %
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1 Ru/Al2O3 DMA 80 ---
2 Ru(OH)3∙Fe3O4 2 DMA 80 5 (NMR)
3 RuO2 DMA 80 ---
4 144 2 DMA 80 61 (16 h)
5 144 2 DMA 80 73
6 144 2 DMA 120 ---
7 144 2+2 DMA 80 54
8 140 2 DMA 80 30
9 144 2 DMA/H2O 80 ---
10[b] 144 (5 mol %) 2 DMA 80 68
11[b] 144 (2.5 mol %) 2 DMA 80 50
[a] Reaction conditions: 85a (0.25 mmol), NBS (0.50 mmol), catalyst (10 mol %), DMA (0.50 mL), 80 °C, 20 h under air. Yield of isolated product. [b] Reaction performed by K.
Korvorapun.[141]
The scope of the homogeneous meta-bromination of phenyl purines 85 is shown in Scheme 119, noteworthy is the direct drop in yield when reducing the catalyst loading to 5 mol %, while the heterogeneous catalyst still provided comparable yields (Table 16, entry 10).
Scheme 119. Scope of the homogeneous meta-bromination of phenyl purines 85. Reactions performed by D. J. Burns and C. Zhu.[a]
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The scope of the reaction proved comparable to the homogeneous one, while the substitution pattern on the aromatic motif was somewhat limited, the substituent on the nitrogen atom could be easily diversified (Scheme 120).
Scheme 120. Scope of the meta-bromination.[a]
It should be noted that arenes with electron-donating substituents showed reactivity in the absence of a catalyst (Scheme 121), albeit in a reduced efficiency.
Scheme 121. Bromination of purine 85i in absence of a catalyst, reactions performed by C. Zhu.[141]
The reaction with unsubstituted 2-phenylpyridine (32b) gave mainly the meta-bromination but in a difficult to separate mixtures of mono- and di-brominated products. Furthermore, substrates in Scheme 122 were not suitable for the reaction. Delivering either no or very low conversion or
99 unselective bromination. N-benzyl-1-phenylethan-1-imine 47d was selectively brominated on the methyl group, which is activated by the neighboring imine.
Scheme 122. Unsuitable substrates for the meta-bromination.
The huge advantage of heterogeneous catalysts is the usually straightforward recyclability and the chance for reusability of the system. The catalyst could be reused three times with comparable isolated yields (Figure 28). For this purpose the reaction mixture was extracted three times with a hexane/CH2Cl2 mixture and centrifuged to separate the solid from the liquid phase, followed by drying the catalyst under vacuum. No reactivation steps were necessary for reusing the catalyst.
100
Figure 28. Recycling Studies of the meta-bromination of purine base 85a.
It is noteworthy that the conditions for the recycling are very important. If, on the one hand, the extraction solution of hexane and CH2Cl2 is altered from a 7:1 to a 5:1 ratio (hexane : CH2Cl2), the reusability of the catalysts is severely diminished, most probably due to a major leaching. Reducing the amount of CH2Cl2 on the other hand led to reduced efficiency regarding the extraction of the product (Table 17).
Table 17. Influence of solvent mixture for extraction.
run 1st 2nd 3rd Extraction solvent
yield (86a) 70% 61% 48% 5:1 hexane/ CH2Cl2
63% 65% 55% 7:1 hexane/ CH2Cl2
101 To rule out that the reusability is simply achieved through catalyst precipitation, the same procedure was performed for the homogeneous catalyst ruthenium(III) chloride. The GC-conversion directly dropped by a factor of 1.6 (Scheme 123).
Scheme 123. Tested recycling of RuCl3.
Even though the heterogeneous catalyst 144 could be reused three times ICP-MS studies showed significant leaching of ruthenium into the crude product (Table 18). Furthermore XPS studies showed a slight difference in the oxidation state of ruthenium and a significant change in the nature of the silica.
Figure 29. XPS study of the catalyst 144 before, after the first and second run.
Table 18. Leaching of ruthenium into crude product, determined prior to workup procedures.
102
run 1st 2nd
[Ru] 756 ppm 739 ppm
The usability of the catalyst is limited by the leaching of the catalyst. Therefore, first tests regarding a system with PEG as reusable catalyst-solvent were conducted. The higher yield in the second run is most probably due to a poor extraction after the first run.
Table 19. Using a DMA/PEG mixture to enable recyclability of the system.
Run 1st 2nd
Yield / % 40 62
3.4.3 Mechanistic Studies
The strong leaching indicates that the reaction might proceed via a catch and release mechanism or fully in a homogeneous fashion.[75] To probe the heterogeneity of the reaction, mercury and hot-filtration tests were performed (Figure 30).
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The hot filtration test showed significantly reduced activity after filtration. The reason for this may either lie in the very inhomogeneous size of the particles and few very small particles passed the filter or the reactivity is solely reduced by the additional solvent required for the filtration. Both explanations are reasonable as the irregularity of the particle size was shown in SEM studies and the molarity of the reaction was shown to influence the reactivity.[141] The addition of mercury directly stopped the reaction, speaking for a heterogeneous nature of the reaction. The mercury test could be hampered by a reaction of mercury with NBS, therefore future studies should include a three-phase test to confirm the heterogeneous nature of the reaction.
Time of manipulation
105