Chinese Chemical Letters  2018, Vol. 29 Issue (12): 1893-1896   PDF    
Synthesis of polysubstituted pyrroles via a gold(Ⅰ)-catalyzed tandem three-component reaction at room temperature
Li Li, Qi Chen, Xiaonan Xiong, Chuang Zhang, Jingjing Qian, Jie Shi, Qiong An*, Ming Zhang*     
Kangda College of Nanjing Medical University, Lianyungang 222000, China
Abstract: A gold(Ⅰ)-catalyzed three-component reaction of β-nitrostyrenes with 1,3-dicarbonyl compounds and primary amines to form polysubstituted pyrroles has been developed at room temperature in ethanol. The key advantages of the three-component reaction are the mild reaction conditions and environmentally safer solvent.
Keywords: Gold(Ⅰ) complex     Multicomponent reaction     Nitrogen heterocycles     Room temperature     Pyrroles    

The polysubstituted pyrrole derivatives are important heterocycles that are embedded in a broad range of natural products, pharmaceutical agents and organic functional materials (Fig. 1) [1]. Accordingly, the construction of highly functionalized pyrroles has attracted significant attention of chemists [2]. Except for the classical methods such as Hantzsch [3], Paal-Knorr procedure [4], enormous efforts have been dedicated to the development of efficient methods for its preparation [5]. The development of general and efficient strategies for the synthesis of pyrroles from simple and readily available precursors in an atom- and stepeconomic manner is of great interest. Recently, three-component reactions have emerged as powerful tools toward the synthesis of polysubstituted pyrroles in a one-pot fashion [6]. One of the interesting strategies available for the synthesis of polysubstituted pyrroles involves the reaction between nitroalkenes, β-dicarbonyl compounds and amines using zirconocene dichloride, (diacetoxyiodo)benzene, CeCl3·7H2O or FeCl3 as the catalyst [7]. Beyond that, Kumar et al. [8] developed a method for the synthesis of polysubstituted pyrroles in PEG-400 at 85 ℃. Although this strategy has been well explored during the past few years, the reactions in many cases suffered from one or more drawbacks such as high temperature, harsh reaction conditions, environmentally non-benign solvents and toxicity. Contemplating on this, we decided to study the reaction for an efficient, high yielding and commercially available catalyst in an environmentally safer solvent under mild conditions.

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Fig. 1. Selected bioactive multisubstituted pyrroles.

The gold catalysis can certainly be considered "hot topics" in synthetic organic chemistry in recent years, since gold has its special catalytic character [9]. The homogeneous gold catalysis has emerged as a powerful tool for synthesizing a variety of important heterocycles under mild reaction conditions [10]. Herein we present our results on the gold(Ⅰ)-catalyzed tandem multicomponent reaction of simple β-nitrostyrenes with 1,3-dicarbonyl compounds and primary amines for the synthesis of polysubstituted pyrroles in an environment-friendly ethanol medium at room temperature.

As a preliminary study, β-nitrostyrene 1a, acetoacetanilide 2a and aniline 3a were submitted to reaction in the presence of Ph3PAuCl (5 mol%) in EtOH at room temperature, but the desired product 2-methyl-N, 1,4-triphenyl-1H-pyrrole-3-carboxamide 4a could be obtained only in a trace amount (Table 1, entry 1). The reaction was considerably promoted by using AgOTf (5 mol%) as an additive (Table 1, entry 2), while using AgOTf only resulted in lower reactivity (Table 1, entry 11). Changing the silver additives to AgSbF6 and AgBF4 did not give any satisfactory results (Table 1, entries 3 and 4). Obviously, the Ph3PAuCl/AgOTf system exhibited better activity than Ph3PAuCl or AgOTf alone, which might be because of the silver salt effect [11] and anion effect [12]. Besides, various other solvents such as DMF, PhMe, THF, MeCN, CH2Cl2, and 1,4-dioxane were also examined for this reaction, the result demonstrated that EtOH (Table 1, entry 2) was superior to other solvents (Table 1, entries 5–10). The catalyst (Ph3PAu)+OTf-, which was prepared from Celite filtration of the Ph3PAuCl/AgOTf mixtures also could promote this reaction (entry 12). After the optimization process, the optimal reaction conditions was obtained, that is, β-nitrostyrene 1a, acetoacetanilide 2a and aniline 3a were conducted in a tube at room temperature for 12 h with EtOH as solvent (Table 1, entry 2).

Table 1
Optimization of reaction conditions.a

With the optimized reaction conditions in hand (Table 1, entry 2), we proceeded to explore the reaction scope with an array of β-nitrostyrenes, β-ketoamides and primary aromatic amines as shown in Scheme 1. The β-nitrostyrenes with electron-withdrawing substituents gave the corresponding products in higher yields, where as the β-nitrostyrenes with electron-donating substituents obtained a slight decrease in the yields for longer reaction time (4b, 4d, 4e and 4f vs. 4c and 4 g). The steric effects of the substituents located at ortho and para positions on the benzene ring of the β-nitrostyrenes did not show clear differences in terms of yields (4b-g). In comparison with β-nitrostyrene (1a), (E)-(2-nitroprop-1-en-1-yl)benzene (1h) showed lower reactivity, possibly due to steric hindrance (4a vs. 4h).

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Scheme 1. Scope for the reaction of β-nitrostyrenes with β-ketoamides and primary aromatic amines under optimal conditions. Reaction conditions: β-nitrostyrene 1 (0.4 mmol), β-ketoamide 2 (0.42 mmol), primary aromatic amine 3 (0.42 mmol), EtOH (2.0 mL), r.t., 10–15 h. Yields are for the isolated products.

It was found that electron-withdrawing groups on the aromatic rings of β-ketoamides exhibited better activity and higher yields compared with their counterparts carrying electrondonating groups (4k, 4l, 4n and 4o vs. 4i, 4j and 4m). The steric effects of the substituents located at ortho and para positions on the benzene ring of the β-ketoamides did not show significant differences, and offered the desired product 4i-4o in moderate to good yields (4i-4o).

The aniline derivatives with electron-donating substituents were found to be less reactive than the counterparts with electronwithdrawing substituents (4p, 4r-t vs. 4q). Furthermore, in comparison with the aniline derivatives with substituents located at para positions, the aniline derivatives with substituents located at the ortho position gave a slightly decreased yield (4p vs. 4s; 4r vs. 4t). Finally, the structure of representative compound 4h and 4l were ascertained by X-ray single crystal analysis, as represented in Fig. 2. The crystal data of 4h (CCDC 1823466) and 4l (CCDC1823465) are provided free of charge by The Cambridge Crystallographic Data Centre.

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Fig. 2. ORTEP diagram of compounds 4h and 4l.

Furthermore, ethyl acetoacetate 2b, another 1,3-dicarbonyl compound, was examined to probe the generality of this method, and the results are given in Scheme 2. Ethyl acetoacetate 2b, β-nitrostyrenes 1, and primary amines 3 participated in this reaction readily. A wide variation in aromatic groups of β-nitrostyrenes were tolerated in this procedure, the ones with electronwithdrawing gave the corresponding pyrroles in higher yields within shorter reaction time than those with electron-donating groups (5b-f vs. 5a and 5e). Both the aromatic amine with electronwithdrawing groups (5i) and the aromatic amine with electrondonating groups (5g, 5h, 5j and 5k) gave the corresponding pyrroles in good yields. In addition, n-butylamine could also participate in the multicomponent reaction to produce the desired product 5l in good yield (5l).

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Scheme 2. Scope for the reaction of β-nitrostyrenes with ethyl acetoacetate and primary amines under optimal conditions. Reaction conditions: β-nitrostyrene 1 (0.4 mmol), ethyl acetoacetate 2b (0.42 mmol), primary amine 3 (0.42 mmol), EtOH (2.0 mL), 10–15 h. Yields are for the isolated products. For 5l, n-butylamine 3 (0.42 mmol), ethyl acetoacetate 2b (0.42 mmol), Ph3PAuCl (5 mol%), AgOTf (5 mol%) in 2.0 mL of EtOH for 1 h, then added β-nitrostyrene 1 (0.4 mmol) at room temperature for another 9 h.

A mechanistic proposal for this reaction is depicted in Scheme 3 based on results described above and other reported literatures [13]. In the presence of Ph3PAuCl and AgOTf [12], the 1,3-dicarbonyl compound 2 is attacked by primary amine 3 to form the key intermediate [14], which undergoes the Michael addition with β-nitrostyrene 1 to generate the intermediate . undergoes an imine-enamine tautomerization to give the resulting intermediate , which processes an intramolecular attack through the nitrogen atom on the enamine, followed by an elimination reaction to gain the substituted pyrrole 4 (5) [15].

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Scheme 3. Plausible reaction mechanism.

In summary, we have developed an efficient gold(Ⅰ)-catalyzed three-component reaction between nitroalkenes, 1,3-dicarbonyl compounds, and primary amines, leading to the concise and flexible synthesis of polysubstituted pyrroles. The reactions were carried out under mild reaction conditions in an ethanol medium at room temperature. The products are cleanly obtained in moderate to good yields, resulting in an appealing alternative for accessing polysubstituted pyrroles.

Acknowledgments

We thank the Natural Science Foundation for Colleges and Universities of Jiangsu Province (No. 17KJD150005), Science and Technology Project Funds of Lianyungang City (No. SH1627), Science and Technology Development Fund of Nanjing Medical University (Nos. 2016NJMU011 and 2016NJMUZD021), Science and Technology Funds of Kangda College of Nanjing Medical University (Nos. KD2016GCCRCYJ01 and KD2016KYJJZD002).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.cclet.2018.09.004.

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