Chinese Chemical Letters  2014, Vol.25 Issue (01):90-92   PDF    
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Li-Jun Gu, Ji-Yan Liu, Li-Zhu Zhang, Yong Xiong, Rui Wang.Synthesis of 3-acylindoles via decarboxylative cross-coupling reaction of free (N-H) indoles with α-oxocarboxylic acids[J]. Chin. Chem. Lett., 2014,25(01): 90-92   
Synthesis of 3-acylindoles via decarboxylative cross-coupling reaction of free (N-H) indoles with α-oxocarboxylic acids
Li-Jun Gu , Ji-Yan Liu, Li-Zhu Zhang, Yong Xiong, Rui Wang    
* Corresponding authors at:Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities, Kunming 650500, China
Received:2013-7-1, Revised:2013-9-24, online:2013-11-12.
E-mail addresses:gulijun2005@126.com
Abstract: A convenient and general method for acylation of free (N-H) indoles via palladium-catalyzed decarboxylative cross-coupling reaction was developed. This process provided a useful method for the preparation of diverse 3-acylindoles in high yields utilizing a reaction with readily accessible reactants under mild conditions.
Key words: 3-Acylindoles     Decarboxylative acylation     α-Oxocarboxylic acids    
1. Introduction

The indole ring systemrepresents one class of the most abundant and ubiquitous heterocycles in nature. Owing to their structural diversity and remarkable biological functions, the synthesis and transformation of indoles has been and continues to be a topic of research interest for synthetic organic chemists [1, 2, 3]. 3-Acylindoles are versatile intermediates in the syntheses of awide range of indole derivatives since their carbonyl groups can readily undergo a variety of transformations such as C-C and C-N coupling reactions and reductions [4, 5, 6]. Thus, the synthesis of 3-acylindoles has gained considerable attention. Traditionally, the common method for the preparation of 3-acylindoles is the Friedel-Crafts reaction (Scheme 1a) [7, 8, 9]. The other significant approaches include the Vilsmeier- Haack type reaction [10], and Grignard reactions [11]. Other methods involve nitrilium salts with dialkyl carbenium ions and pyridinium salts. Under the acidic conditions of Friedel-Crafts reactions, indole polymerization readily occurs. Vilsmeier-Haack acylindoles useunacceptable amounts of environmentallyunfriendly POCl3. The reactions of indole salts with acyl chlorides cannot tolerate the functional group sensitivities to strong nucleophiles because Grignard reagents are used in these reactions. The existing methods often involve uncommonly used acylated reagents or unbenign reaction conditions. As a consequence, the demand for alternative efficient methods has encouraged the development of newmethods for the synthesis of 3-acylindoles. In 2011, Su and coworkers reported a convenient and general method for formylation and acylation of free (N-H) indoles via Ru- or Fe- catalyzed oxidative coupling using anilines as the carbonyl source (Scheme 1b) [1]. Recently, Song and Wang independently reported the synthesis of 3-acylindoles through palladium-catalyzed addition of indoles to nitriles (Scheme 1c) [12, 13].

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Scheme 1.Existing routes and our strategy to 3-acylindoles.
Palladium-catalyzed decarboxylative cross-coupling reactions using simple carboxylic acids as coupling partners have emerged as a new type of C-C bond formation reaction [14, 15, 16]. In these reactions, using readily available and stable carboxylic acids instead of organometallic reagents enabled the decarboxylative cross-coupling reactions to proceed with good selectivities and tolerance of functional groups. In 2008, Goossen first reported the synthesis of unsymmetrical diaryl ketone using α-oxocarboxylic acid salts as acyl anion equivalents through palladium-catalyzed decarboxylative cross-coupling [17]. Later, Ge described elegant studies on Pd-catalyzed decarboxylative ortho-acylation of acetanilides and phenylpyridines with α-oxocarboxylic acids via C-H bond activation [18]. Thereupon, we envision that an efficient and general Pd-catalyzed decarboxylative cross-coupling reaction to synthesize 3-acylindoles would be more intriguing than the existing protocols. As part of our ongoing research program on transition-metal-catalyzed reactions [19, 20, 21], we herein describe a new strategy to construct 3-acylindoles that relies on palladium-catalyzed decarboxylative acylation of free (N-H) indoles (Scheme 1d) [22, 23].

2. Experimental

Reagents were obtained commercially and used as received. Solvents were purified and dried by standard methods. The melting points were determined on an XT-4 micro melting point apparatus and uncorrected. IR spectra were recorded on an EQUINOX-55 spectrometer on a KBr matrix. NMR spectra were recorded on an INOVA-400 NMR instrument at room temperature using TMS as internal standard. Coupling constants (J) were measured in Hz. Chemical shift values (δ) are given in ppm. High Resolution mass spectrometer (HRMS) spectra were recorded on a Bruker micrOTOF-Q Ⅱ analyzer. A 200-300 mesh silica gel was used for column chromatography.

Representative procedure for the synthesis of 3-acylindoles (3): A 10 mL oven-dried Schlenk tube was charged with phenylglyoxylic acid 1a (49.5 mg, 0.33 mmol), indole 2a (35.1 mg, 0.3 mmol), I2 (164.5 mg, 0.65 mmol), Pd(OAc)2 (10 mol%, 6.7 mg, 0.03 mmol), Cs2CO3 (292 mg, 0.9 mmol). The tube was evacuated and filled with O2 (this procedure was repeated three times). Then NMP (1.5 mL) were added with a syringe under a counter flow of O2. The tube was sealed with a screw cap. The reaction was stirred at 45 ℃ for 12 h, and was then allowed to cool to ambient temperature. The mixture was added 20 mL EtOAc, and filtered, washed with water. The organic layers were dried over Na2SO4 and filtered. Solvents were evaporated under reduced pressure. The residue was purified by flash column chromatography with hexane/ethyl acetate to give the corresponding product 3.

(5,6-Dimethyl-1H-indol-3-yl)(phenyl)methanone (3af): Gray solid; Mp 192-194 ℃; IR (KBr, cm-1): vmax 3109, 2921, 1724, 1521, 1104; 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.92 (s, 1H), 7.82-7.79 (m, 2H), 7.49-7.43 (m, 3H), 7.23 (s, 1H), 2.33 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 189.5, 137.8, 137.3, 136.2, 133.0, 132.3, 129.4, 128.6, 127.5, 120.8, 117.4, 113.4, 110.7, 20.5 20.3; HRMS (ESI) calcd. for C17H16NO (M+H)+ (m/z): 250.1227, found: 250.1231.

3. Results and discussion

Our initial study started from the coupling of indole 2a with phenylglyoxylic acid 1a using O2 as the oxidant, Pd(TFA)2 as the catalyst in the presence of I2, K2CO3 and N,N-dimethylformamide (DMF) at 45 ℃ for 12 h. To our delight, the desired product 3aa was obtained in 43% yield (entry 1, Table 1). It was found that Pd(OAc)2 was superior to other Pd sources (entries 1-4, Table 1). Further studies indicated that the presence of iodine could promote the efficiency of this transformation (entry 5, Table 1). It was found that Cs2CO3 was superior to other bases (entries 4 and 6-8, Table 1). The influence of solvent on the reaction efficiency was also significant; when N-methylpyrrolidone (NMP) was chosen as the solvent, the yield was enhanced to 82% (entries 8-13, Table 1).

Table 1
Palladium-catalyzed decarboxylative acylation of free (N–H) indoles.a
With the optimized conditions in hand, a series of α-oxocarboxylic acids 1 were investigated, as shown in Table 2. Both electron-donating and electron-withdrawing α-oxocarboxylic acids could be successfully converted to the corresponding 3-acylindoles in good yields. In addition, a high level of tolerance by functional groups was observed, and the efficiency of the reaction was not affected in the presence of halide, ether, and nitro group. Furthermore, substituents at different positions on the arene group (para, meta, and ortho positions) did not affect the reaction efficiency. It is noteworthy that halo-substituted aoxocarboxylic acids were tolerated well, thus leading to halosubstituted products, which could be used for further transformations (entries 2 and 3, Table 2). Subsequently 2-thienylglyoxylic acid was used in this reaction, affording the corresponding products in good yields (entry 7, Table 2). Gratifyingly, aliphatic α-oxocarboxylic acids were also compatible in this reaction, giving the desired product in 71% yield (entries 8 and 9, Table 2).

Table 2
Palladium-catalyzed decarboxylative acylation of α-oxocarboxylic acids 1 with 2a.a
To expand the scope of this direct acylation reaction further, we next investigated the decarboxylative coupling of phenylglyoxylic acid 1a with substituted free (N-H) indoles 2. The variation of indole substituents gave the desired product in good to excellent yield. Generally, indoles bearing an electron-donating group (methyl or methoxyl group) on the benzene ring (entries 2, 3 and 6, Table 3) regardless of the position showed better reactivity compared with those bearing fluoro or nitro group (entries 4 and 5, Table 3). The results suggest that the electron-donating substituent might facilitate the iodination step occurring on the C3-position of indole.

Table 3
Palladium-catalyzed decarboxylative acylation of α-oxocarboxylic acids 1a with 2.a
To gain some understanding of the reaction, 1.0 equiv. of TEMPO, a radical-trapping reagent, was added into the reaction under the standard conditions. The same yield of 3aa was obtained, suggesting that no free radical intermediate was involved in the reaction. On the basis of the observations and previous studies [24, 25, 26], a plausible mechanism was proposed as shown in Scheme 2. Initially 1H-indole 1a is oxidized to 3-iodo-1H-indole A, and then addition of 3-iodo-1H-indole A to the palladium(II) catalyst affords intermediate B rather than coordinating to the HN-position of 2aa and the palladium(Ⅱ) is oxidized to palladium(Ⅳ). Anion exchange with phenylglyoxylic acid 1aa gave a Pd complex C. Decarboxylation of complex C to form the complex D which undergoes reductive elimination to furnish (1H-indol-3-yl)phenylmethanone 3aa and simultaneously regenerates the palladium(Ⅱ) catalyst to complete this catalytic cycle.

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Scheme 2.Proposed reaction mechanism.
4. Conclusion

In summary, we have developed a convenient and general method for acylation of free (N-H) indoles via a palladiumcatalyzed decarboxylative cross-coupling reaction. This process provided a useful method for the preparation of diverse 3- acylindoles in high yields from readily accessible reactants under mild reaction conditions. This protocol offers several advantages including use of readily accessible carboxylic acids, a simple procedure, generality, which enhances its potential in future applications.

Acknowledgments

We are grateful for the financial support from the State Ethnic Affairs Commission (No. 12YNZ005).

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