Synthesis of polysubstituted pyrroles via a gold(I)-catalyzed tandem three-component reaction at room temperature

Article abstract of DOI:10.1016/j.cclet.2018.09.004

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

Full text of DOI:10.1016/j.cclet.2018.09.004

Accepted Manuscript
Title: Synthesis of polysubstituted pyrroles via a
gold(I)-catalyzed tandem three-component reaction at room
temperature
Authors: Li Li, Qi Chen, Xiaonan Xiong, Chuang Zhang,
Jingjing Qian, Jie Shi, Qiong An, Ming Zhang
PII:
DOI:
Reference:
S1001-8417(18)30353-X
https://doi.org/10.1016/j.cclet.2018.09.004
CCLET 4646
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
16-7-2018
16-8-2018
6-9-2018
Please cite this article as: Li L, Chen Q, Xiong X, Zhang C, Qian J, Shi J, An
Q, Zhang M, Synthesis of polysubstituted pyrroles via a gold(I)-catalyzed tandem
three-component reaction at room temperature, Chinese Chemical Letters (2018),
https://doi.org/10.1016/j.cclet.2018.09.004
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Communication
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
 Corresponding authors.
E-mail addresses: qan@njmu.edu.cn (Q. An), mingzhang@njmu.edu.cn (M. Zhang)
Graphical 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
ARTICLE INFO
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.
Article history:
Received 16 July 2018
Received in revised form 16 August 2018
Accepted 3 September 2018
Available online
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 step-economic 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 oC. 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.
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 also 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
Catalyst
(5 mol%)
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Additive
(5 mol%)
-
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
DMF
7
AgOTf
AgSbF6
AgBF4
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
79
71
73
18
65
32
48
71
15
12
76
PhMe
THF
MeCN
CH2Cl2
1,4-Dioxane
EtOH
10 Ph3PAuCl
11
12 c Ph3PAuCl
-
EtOH
a
Reaction conditions: 1a (0.4 mmol), 2a (0.42 mmol), 3a (0.42 mmol), catalyst (5 mol%), additive (5 mol%), solvent (2 mL), r.t., 12 h.
AgOTf = silver trifluoromethanesulfonate.
b Isolated yield
c Ph3PAuCl and AgOTf in EtOH (2 mL) for 5 min, after filtration, then added 1a (0.4 mmol), 2a (0.42 mmol), 3a (0.42 mmol), r.t., 12 h.
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 4g). 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-4g). 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).
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 electron-donating 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 electron-
withdrawing 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 (1823465) are provided free of charge by The Cambridge Crystallographic Data
Centre.
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.
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 electron-withdrawing 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 electron-withdrawing groups (5i) and the aromatic amine with electron-donating 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).

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 I [14], which undergoes the Michael addition with β-nitrostyrene 1 to generate the intermediate II. II undergoes an imine-
enamine tautomerization to give the resulting intermediate III, 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].
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 (No. KD2016GCCRCYJ01 and KD2016KYJJZD002).
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