Ru-Catalyzed highly site-selective C–H bond arylation of 9-(pyrimidin-2-yl)-9H-carbazole

Abstract

We describe here an efficient ruthenium-catalyzed C–H bond ortho-arylation of 9-(pyrimidin-2-yl)-9H-carbazole by using boronic acids. This methodology exhibits excellent and high site-selectivity, functional group tolerance and was found to give the desired product in moderate to good yields.

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Introduction

In recent years, transition-metal-catalyzed C–H bond activation has emerged as an atom economical process with step economy to produce structurally diverse organic molecules. Thus, C–H activation/functionalization emerged as a viable strategy for the synthesis of natural products and other compounds of pharmaceutical and research interest.^1–3

Carbazoles are heteroaromatic compounds which have attracted considerable attention because carbazole alkaloids are a growing class of natural products that exhibit a variety of biological activities.⁴ Carbazoles are widely used as building blocks for potential organic semiconductors,⁵ organic light-emitting diodes,⁶ and electroluminescent materials.⁷ Hyellazole, carazomycin and carazostatin are a few carbazole alkaloids that show both antioxidant activity and antibiotic activity (Fig. 1).

Fig. 1 Representative examples of biologically important carbazole derivatives.

In view of the significance of these carbazoles, several methods have been developed. But, the development of efficient methods to modify simple carbazoles is still a major issue, in which selective and direct ortho arylation is especially exciting. To the best of our knowledge, very few methods⁸ are reported for the ortho-phenylation of carbazoles.

Recently, the use of Ru(II) complexes as inexpensive, readily available, and environmentally friendly catalysts for C–H activation reactions has attracted considerable attention.⁹ In continuation of our efforts to design and develop novel methodologies in metal-catalyzed C–H activation¹⁰ and cross-coupling reactions,¹¹ Herein, we report an efficient Ru-catalyzed regio-selective C–H bond ortho arylation of 9-(pyrimidin-2-yl)-9H-carbazole with boronic acid using Ag₂O as oxidant, AgSbF₆ as additive in THF (2 ml) at 120 °C for 12 h (Scheme 1).

Scheme 1 Ru-Catalyzed ortho-arylation of 9-(pyrimidin-2-yl)-9H-carbazole.

Results and discussion

Our investigation began by examining several parameters such as the catalyst, additive, oxidants and solvent on Ru-catalyzed regio-selective C–H bond ortho-arylation of 9-(pyrimidin-2-yl)-9H-carbazole (0.25 mmol) with p-tolylboronic acid (0.5 mmol). The results are summarized in Table 1. At first we tried reactions without adding any additive/oxidant, in these cases we did not obtain the desired product (Table 1, entries 1–3). Notably, no product was observed when using various combination of additives and oxidants such as AgSbF₆/AgoTf, KPF₆/AgBr and KPF₆/Ag₂O (Table 1, entries 10–12) and AgSbF_6/Ag₂CO₃ provided the desired product in low yield (Table 1, entry 9). Better yield was observed when we used the combination of AgSbF₆/Ag₂O (Table 1, entry 4). The control experiment showed no detection of the product in the absence Ru catalyst (Table 1, entry 5). We then investigated the effect of a solvent on the reaction. When using DMF as solvent provided unsatisfactory results (Table 1, entry 6). DCE and dioxane solvents provided trace amount of products (Table 1, entries 7–8). Reaction proceeded most satisfactorily in THF as the solvent (Table 1, entry 4). After several trials, we concluded that the best results were obtained with [RuCl₂(p-cymene)]₂ (5.0 mol%)/Ag₂O (1.0 mmol)/AgSbF₆ (20 mol%) in THF (2 ml) at 120 °C for 12 h.

Table 1 Impact of reaction parameters on the Ru-catalyzed reaction of 9-(pyrimidin-2-yl)-9H-carbazole with p-tolylboronic acid^a

Entry	Catalyst	Additive/oxidant	Solvent	Yield (%)
a Conditions: 9-(pyrimidin-2-yl)-9H-carbazole (0.25 mmol), p-tolylboronic acid (0.5 mmol) Ru = [RuCl2(p-cymene)]2 (5.0 mol%), additive (20 mol%), oxidant (1.0 mmol), THF (2 ml), 120 °C, 12 h.
1	Ru	—	THF	0
2	Ru	AgSbF6/—	THF	0
3	Ru	—/Ag2O	THF	0
4	Ru	AgSbF6/Ag2O	THF	71
5	—	AgSbF6/Ag2O	THF	0
6	Ru	AgSbF6/Ag2O	DMF	45
7	Ru	AgSbF6/Ag2O	DCE	Trace
8	Ru	AgSbF6/Ag2O	Dioxane	10
9	Ru	AgSbF6/Ag2CO3	THF	48
10	Ru	AgSbF6/Ag2OTf	THF	0
11	Ru	KPF6/AgBr	THF	0
12	Ru	KPF6/Ag2O	THF	0

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We next explored the scope of the ruthenium-catalyzed C–H bond arylation of 9-(pyrimidin-2-yl)-9H-carbazole 1 with aryl boronic acid 2 using the optimized conditions (Table 2). A variety of aryl boronic acid with different functional groups were tested. Various kinds of functional groups, such as –Me, –OMe, CF₃, –F, –Cl, –I and even –CHO were well tolerated.

Table 2 Scope of various aryl-substituted boronic acids^a

a Conditions: 9-(pyrimidin-2-yl)-9H-carbazole (0.25 mmol), p-tolylboronic acid (0.5 mmol) Ru = [RuCl₂(p-cymene)]₂ (5.0 mol%), additive (20 mol%), oxidant (1.0 mmol), THF (2 ml), 120 °C, 12 h.

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Varying both electron-rich as well as electron-deficient on 2 did not significantly influence the reaction; as a result, the desired products 3b and 3c were obtained in 71 and 61% yields, respectively.

All products were characterized by ¹H and ¹³C NMR and mass spectra. However, a small amount di ortho-arylation side product detected in few cases. The structure of the product (3b) was confirmed by X-ray crystallographic analysis (Fig. 2).¹²

Fig. 2 ORTEP diagram of compound 3b (30% probability).

Conclusions

In conclusion, we have developed a general, mild and efficient procedure of Ru-catalyzed highly regioselective ortho-arylation of 9-(pyrimidin-2-yl)-9H-carbazoles with substituted aromatic and heteroaromatic boronic acids in the presence of AgSbF₆ and Ag₂O. This protocol exhibits a broad substrate scope and this reaction tolerates a wide range of functional groups. Moreover, the products could also be further transformed to diverse important derivatives.

Experimental section

General experimental procedure for the synthesis of 1-phenyl-9-(pyrimidin-2-yl)-9H-carbazole

To a mixture of 9-(pyrimidin-2-yl)-9H-carbazole (0.25 mmol), phenylboronic acid (0.5 mmol), [RuCl₂(p-cymene)]₂ (5.0 mol%), Ag₂O (1.0 mmol) and AgSbF₆ (20 mol%), THF (2 ml) was added and thereafter, the reaction mixture was stirred at 120 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with anhydrous Na₂SO₄. The solvent was evaporated under vacuum to give the crude product which was purified by column chromatography on silica gel. The purity of the product was confirmed by ¹H NMR, ¹³C NMR and mass spectra. 3a (69% yield) ¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, J = 4.8 Hz, 2H), 8.12 (dd, J = 8.5, 3.4 Hz, 3H), 7.51–7.22 (m, 6H), 7.14–7.02 (m, 3H), 6.82 (t, J = 4.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 157.1, 140.7, 128.5, 127.9, 127.4, 126.6, 125.9, 122.2, 121.8, 119.9, 119.1, 116.8, 112.0; ESI-MS: m/z 322 [M + 1].

Acknowledgements

The authors thank the Council of Scientific and Industrial Research (CSIR), New Delhi for financial assistance.

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12. X-ray data for the compound (3b) were collected at room temperature using a Bruker Smart Apex CCD diffractometer with graphite monochromated MoKα radiation (λ = 0.71073 Å) with ω-scan method. Preliminary lattice parameters and orientation matrices were obtained from four sets of frames. Unit cell dimensions were determined using 9274 reflections for 3b data. Integration and scaling of intensity data were accomplished using SAINT program. The structures were solved by Direct Methods using SHELXS97 and refinement was carried out by full-matrix least-squares technique using SHELXL97. Anisotropic displacement parameters were included for all non-hydrogen atoms. All H atoms were positioned geometrically and treated as riding on their parent C atoms, with C–H distances of 0.93–0.97 Å, and with U_iso (H) = 1.2U_eq. (C) or 1.5U_eq. for methyl atoms. Crystal data for the compound 3b: C₂₃H₁₇N₃, M = 335.40, colourless block, 0.49 × 0.33 × 0.28 mm³, monoclinic, space group P2₁/n (no. 14), a = 9.5942(6), b = 11.3101(7), c = 16.4330(10) Å, β = 96.6930(10)°, V = 1771.01(19) ų, Z = 4, D_c = 1.258 g cm⁻³, F₀₀₀ = 704, CCD area detector, MoKα radiation, λ = 0.71073 Å, T = 293(2) K, 2θ_max = 50.0°, 16640 reflections collected, 3128 unique (R_int = 0.0178), Final GooF = 1.035, R₁ = 0.0377, wR₂ = 0.1041, R indices based on 2784 reflections with I > 2σ(I) (refinement on F²), 236 parameters, μ = 0.075 mm⁻¹. CCDC 1059104 contains the supplementary crystallographic data for this paper.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1059104. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra09825h

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