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Home > Ruthenium-catalyzed synthesis of indole derivatives from N-aryl-2-aminopyridines and alpha-carbonyl sulfoxonium ylides
Ruthenium-catalyzed synthesis of indole derivatives from N-aryl-2-aminopyridines and alpha-carbonyl sulfoxonium ylides
Xin-Feng Cui, Zi-Hui Ban, Wa-Fa Tian, Fang-Peng Hu, Xiao-Qiang Zhou, Hao-Jie Ma, Zhen-Zhen Zhana and Guo-Sheng Huang
The skeleton of indole is widely prevalent in biologically active compounds, natural products and materials.1 Owing to the great structural diversity of biologically active indoles, highly convenient methods for their synthesis have been constantly pursued for a long time and varieties of approaches have been achieved. Among them, the well-established Fischer indole synthesis2 and Larock indole synthesis3 have attracted signifi- cant attention because of their extensive application prospects. However, these reactions also face some nonignorable draw- backs. For example, the Fischer reaction can be limited in scope due to the stability of the hydrazine component and strong acidic reaction conditions. Moreover, poor selectivity was also observed when it was applied to synthesize 4- or 6-monosubstituted indoles; on the other hand, expensive multi-substituted 2-iodinated anilines are required as starting materials in the Larock indole synthesis. As a result, development of an efficient, atom-economical and environmentally benign synthetic strategy appears to be attractive and highly desirable.
In recent years, researchers have focused on the develop- ment of transition-metal-catalyzed C–H bond functionalization for the construction of C–C and C–heteroatom bonds.4 This strategy takes advantage of the ubiquitous C–H bond in unacti- vated arenes as the direct source. Various transition metal complexes involving Ru,5 Rh,6 Pd,7 Ir8 and Co9 have been effec- tively applied for the ortho C–H functionalization of the pyri- midyl moiety and other directing groups. Moreover, efficient synthesis of indole derivatives using transition metals has also been greatly employed. Among them, transition metal-cata- lyzed C–H activation/metal–carbenoid insertion provides an effective and atom-economical approach for C–X (X = C, N, O and S, etc.) bond construction. Significant work by Li10 and co- workers has realized efficient synthesis of indoles using the imidamides and diazo compounds as substrates by employing this strategy [Scheme 1, eqn (1)]. Very recently, Li11 and Mishra12 reported Ir(III)- and Rh(III)-catalyzed intermolecular indole synthesis which also employed diazo compounds as car- benes [Scheme 1, eqn (2)]. However, diazo substrates face the drawbacks of being potentially unstable explosives (Table 1).
Sulfur ylides have been known as potentially safe precursors of metal carbenes.13 They are safe to synthesize and provide crystalline, bench-stable compounds. They are widely used as important building blocks in annulation reactions with nucleophilic directing groups. For example, in 2018, Fan14 pre- sented a highly regioselective synthesis of diversely substituted benzo[a]carbazoles and indolo[2,1-a]-isoquinolines using 2-arylindoles with sulfoxonium ylides. In the same year, Zeng15 developed an alternative synthetic approach toward 1,2-benzothiazines through Ru(II)-catalyzed coupling-cycliza- tion of sulfoximines with alpha-carbonyl sulfoxonium ylides. Sulfoxonium ylides used as methylene synthons are also widely applied in other organic syntheses, including metal-free catalytic systems.13b Encouraged by these eminent studies, herein a simple Ru-catalyzed synthesis of indole was developed by introducing N-aryl-2-aminopyridines with alpha-carbonyl sulfoxonium ylides as substrates [Scheme 1, eqn (3)].
At the outset of this study, we first performed a reaction between N-aryl-2-pyridinamine (1a, 0.20 mmol) and sulfoxo- nium ylide (2a, 0.30 mmol) using [IrCp*Cl2]2 (5 mol%) as a catalyst in dichloroethane (2.5 mL) at 100 °C under an enclosed atmosphere for 12 h. The desired product 3aa was obtained in 18% yield (entry 1). Other catalysts such as [RhCp*Cl2]2 and Cp*Co(CO)I2 gave inferior results (entries 2 and 3). To our delight, the isolated yield of 3aa dramatically increased to 48% when [Ru( p-cymene)Cl2]2 was used as a cata- lyst (entry 4). Encouraged by this result, we investigated other additives and found that the yield could not be further improved compared to the Zn(OAc)2 additive (entries 4–9). Further optimization studies indicated that the addition of a cationic generator i.e. silver hexafluoroantimonate (AgSbF6), could further improve the yield, indicating that AgSbF6 was the most effective cationic generator. Subsequently, screening of solvents revealed that 1,2-dichloroethene was the optimal choice (entries 13–17). Temperature also significantly influ- enced this reaction, as 1a showed low reactivity at 90 °C or 110 °C (entry 18). Surprisingly, when the reaction was carried out under a N2 atmosphere, a dramatic increase in the reaction yield (78%) was observed (entry 19). Control experiments revealed that no reaction occurred when the catalyst [Ru( p- cymene)Cl2]2 was absent, which indicated that the metal cata- lyst was essential for this transformation (entry 20).
With an optimized catalytic system in hand, we examined the scope of N-phenylpyrimidin-2-amines (Scheme 2). N-(Substituted phenyl)-2-pyridin-amines bearing halide substi- tuents (4-F, 4-Cl, and 4-Br) and other electron-donating groups (4-Me, 4-iPr, 4-OMe) were well tolerated and gave the corres- ponding products (3ba–3ga, 69–83%) in moderate to good yields. N-Phenyl-pyridin-2-amine bearing an electron-with- drawing group (1j), halide groups (1h, 1i) or an alkyl group (1k) at the meta position all coupled smoothly with 2a to furnish the corresponding indoles in good yields (3ha–3ka). The substituent on the pyridine ring of N-(substituted phenyl)-2-pyridin-amines showed obvious electronic effects on the reaction activity, affording the products 3la–3pa in moderate to good yields (49–93%). When disubstituted substrates (1t, 1u) were used, the substituted indole derivatives 3qa and 3ra were obtained with 75% and 92% yields, respectively. The large N-(naphthalene-2-yl)pyridine-2-amine also readily participated in the coupling reaction to provide product 3sa in 43% yield.
In addition to anilines, the scope of the reaction with sul- foxonium ylides was also explored (Scheme 3). In general, the coupling reaction of substrate 1a and various benzoyl-substi- tuted sulfoxonium ylides afforded the annulated products in good yields. The corresponding products were obtained in good yields with electron-withdrawing groups (F, Cl, Br and CF3) or electron-donating groups (Me and MeO−) attached to the para-position and meta-position of the benzoyl ring of sul- foxonium ylides (3ab–3aj). When the disubstituted sulfoxo- nium ylide (2k) was explored, the reaction afforded the desired product (3ak) in good yield. Moreover, introduction of a methyl group to the ortho-position of benzoyl was also toler- ated (3al), despite the fact that it provided a lower yield. To our delight, this catalytic system could be further extended to α-2- thienoyl sulfoxonium ylide, which could also react with 1a to give 3am in 74% yield. The versatility of this robust catalytic system was further mirrored by successfully using alkyl substi- tuted sulfoxonium ylides, which provided the corresponding product (3an) in good yield.
To demonstrate the synthetic utility of this catalytic reaction, a 6 mmol scale synthesis of 3aa was carried out, and a good yield of 72% was still obtained (Scheme 4). We attempted to remove the pyridyl group in the product, but unfortunately failed by following various typical conditions.
Based on literature reports,8b,16,17 a plausible mechanism for the annulation of 1a with 2a was proposed as depicted in Scheme 5. Initially, the dimeric precursor [Ru(p-cymene)Cl2]2 is converted into [Ru(II)X2] as an active catalyst through the anion exchange. Next, nitrogen coordination of 1a is followed by cyclometalation to deliver a six-membered ruthenacycle intermediate
A. Coordination of sulfur ylide 2a and subsequent elimination of DMSO generate Ru(II) carbene B, which then undergoes migratory insertion of the Ru–aryl bond into the activated carbene to afford a seven-membered ruthenacycle intermediate C. Protonolysis of the Ru–C bond by HX gives the corresponding intermediate D, together with the regeneration of the Cp*Ru(II) catalyst. Intramolecular nucleophilic attack of the imine on the carbonyl group produces D, which undergoes dehydration, furnishing 3aa.
Conclusions
We reported a ruthenium-catalyzed direct C–H functionalization and cross-annulation between N-phenylpyrimidin-2-amines and α-aroyl sulfur ylides toward a series of functionalized indoles in good to moderate yields. This catalytic system features mild con- ditions and a wide range of substrates with excellent functional group tolerance, with DMSO and H2O being the only byproducts.
Conflicts of interest
There are no conflicts to declare.
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