Deep eutectic solvent based on choline chloride and malonic acid as an efficient and reusable catalytic system for one-pot synthesis of functionalized pyrroles

Article abstract of DOI:10.1039/c4ra13577f

A deep eutectic solvent (DES) based on choline chloride and malonic acid was prepared easily with high purity at a low cost. It has been applied as a dual catalyst and reaction medium for the synthesis of functionalized pyrroles by a one-pot, four-component reaction of amines, aldehydes, 1,3-dicarbonyl compounds and nitromethane. This green solvent could be recycled and reused three times without loss of its efficiency.

Full text of DOI:10.1039/c4ra13577f

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• Graphical Abstract:
Deep eutectic solvent based on choline chloride and malonic acid as an efficient and reusable catalytic system
for one-pot synthesis of functionalized pyrroles
Hai-Chuan Hu, Yu-Heng Liu, Bao-Le Li, Zhen-Shui Cui and Zhan-Hui Zhang*
Deep eutectic solvent (DES) based on choline chloride and malonic acid was prepared and applied as dual catalyst and
reaction medium for synthesis of functionalized pyrroles by one-pot, four-component reaction of amines, aldehydes,
1,3-dicarbonyl compounds and nitromethane.

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Deep eutectic solvent based on choline chloride and malonic acid as an
efficient and reusable catalytic system for one-pot synthesis of
functionalized pyrroles
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HaiꢀChuan Hua, YuꢀHeng Liub, BaoꢀLe Lia, ZhenꢀShui Cuia and ZhanꢀHui Zhang*,a
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Deep eutectic solvent (DES) based on choline chloride and malonic acid was prepared easily with
high purity at low cost. It has been applied as dual catalyst and reaction medium for synthesis of
functionalized pyrroles by oneꢀpot, fourꢀcomponent reaction of amines, aldehydes, 1,3ꢀdicarbonyl
compounds and nitromethane. This green solvent could be recycled and reused three times without
loss of its efficiency.
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Introduction
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Developing new environmentally benign solvents is one of the key subjects in chemistry industry.
During the past years, ionic liquids (ILs) as a class of green solvents have been applied in many
fields such as separation technology,1 biocatalysis2 and organic synthesis3 because of their
distinctive properties such as low vapor pressure, nonꢀvolatility, good stability and recyclability.
However, recent examples have also demonstrated the disadvantage of using ILs as solvents, such
as high cost, difficult preparation and some toxic properties.4 Therefore, developing a simple
synthetic and greener alternative solvent has very important practical significance. In recent years,
lowꢀcost eutectic mixtures include deep eutectic solvents (DESs) based on choline chloride (ChCl)
first introduced by Abbott and coꢀworkers,5 lowꢀmelting mixture (LMM) of sugar,
_________________________________
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aCollege of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, P. R. China. E-mail:
zhanhui@mail.nankai.edu.cn; zhanhui@mail.hebtu.edu.cn
bThe College of Preclinical Medicine, Hebei Medical University, Shijiazhuang 050017, China
1

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urea and inorganic salts first described by König and coꢀworkers,6 natural deep eutectic solvents
(NADES) first described by Choi and coꢀworkers,7 lowꢀtransition temperature mixtures (LTTMs)
descried by Kroon and coꢀworkers,8 and deep eutectic ionic liquids (DEILs) reported by Hillman’
group9 with similar physical properties and phase bahavior to ILs, are gaining increasing attention in
chemistry fields. Compared with ILs, the synthetic process of these eutectic mixtures is relatively
simple, which only by mixing two or more compounds under heating until a homogenous liquid is
formed without any purification with 100% atom untilzation rate.10 In addition, the synthetic
materials of these eutectic mixtures are abundant, lowꢀtoxic, relatively cheap, and biodegradable,
which makes them particularly desirable for largeꢀscale applications successfully in industrial
production.11 To date, they have been applied to many chemical processing such as extraction,12
polymerizations,13 biomass processing,14 materials synthesis15 and organic reactions.16
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The pyrrole nucleus is one of the most relevant simple heterocycles found in a large number of
natural products, agrochemicals, and pharmaceuticals.17 Many pyrroleꢀcontaining compounds
possess potent biological activity.18ꢀ19 Furthermore, pyrrole derivatives are particularly important in
materials science.20 Consequently, the preparation of pyrroles has received considerable attention
and a number of synthetic routes have been reported, such as Hantzsch,21 Paal–Knorr,22 and
ClausonꢀKaas reactions.23 Multicomponent reactions (MCRs) have been extensively used in organic
synthesis. Up to date, MCRs have emerged as vital tools for the preparation of substituted and
functionalized pyrrole derivatives from simple materials.24 In 2010, Jana and coꢀworkers reported
oneꢀpot, fourꢀcomponent coupling reactions of 1,3ꢀdicarbonyl compounds, amines, aromatic
aldehydes, and nitroalkanes for the synthesis of highly functionalized pyrroles catalyzed by FeCl3.
However, this method suffers from the shortcoming of long reaction time, low yield of products and
tedious workꢀup procedure.25 In the past several years, great efforts have been made in this area in
order to develop a simple and efficient method to improve this conversion. Khan,26 Saeidian,27
Jeong,28 and Zhang29 have reported some metalꢀcatalyzed methods for this conversion. Despite the
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advances achieved, all of these methods used transition metals, and these bring great difficulties
form the separation and purification of the target products, especially in the synthesis of
pharmaceutical molecules. To solve these problems, a series of metalꢀfree catalyzed methods for
this transformation have been reported, for example, the use of I2,30 Amberlystꢀ15,31
bromodimethylsulfonium bromide (BDMS),32 and ionic liquid.33 However, the major limitation of
these methods lies in the variable amines that must be aliphatic amines or benzylamines.
Montmorillonite clay,34 gluconic acid aqueous solution (GAAS)35 and 1ꢀbutylꢀ3ꢀmethylimidazolium
hydrogen sulfate ([bmim]HSO4)36 have also been used for this fourꢀcomponent reaction. However,
these methods required long reaction times. Thus, the development of a simple, more efficient
method for the synthesis of pyrroles remains an attractive goal.
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As a part of our ongoing research program aimed at developing multicomponent reactions37
and environmental benign synthetic methodologies,38 herein we wish to report a simple, practical
and metalꢀfree method for the construction of Nꢀprotected functionalized pyrroles by oneꢀpot,
fourꢀcomponent reaction of amines, aldehydes, 1,3ꢀdicarbonyl compounds and nitromethane in
choline chlorideꢀmalonic acid (Scheme 1).
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Scheme 1 Synthesis of fuctionalized pyrroles using ChClꢀmalonic acid
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Results and discussion
The preparation of choline chlorideꢀmalonic acid based DES was performed by stirring ChCl
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(1 mol) and malonic acid (1 mol) at 80 ºC until a homogenous liquid was formed. This method gave
DES with 100% atom economy since it completely forms a eutectic mixture with no byꢀproduct
formation. Thermal stability of ChClꢀmalonic acid was investigated by TG analysis in the N2
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atmosphere, which showed that there were two steps of weight loss (Figure 1). The weight loss at
o
temperatures below 110 C was due to the removal of water. The weight loss of the ChClꢀmalonic
o
acid system was nearly 43.6% in the temperature range 110ꢀ160 C, which was attributed to the
complete decomposition of malonic acid. In addition, there is less weight loss when ChClꢀmalonic
acid was heated for 5 h at100 oC, which indicaties that this DES is stable under 100 oC. It was hence
tempting and logical to study its potential as a green solvent in organic synthesis.
100
90
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60
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100
150
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300
Tempertature (oC)
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Fig. 1 TG analysis of ChClꢀmalonic acid
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To optimize the reaction conditions, the model reaction of aniline, 4ꢀchlorobenzaldehyde,
acetylacetone and nitromethane was investigated and the results are recorded in Table 1. To initiate
our study, the model reaction was performed in the absence of catalyst under solventꢀfree condition
and only a trace amount of the desired product was detected after prolonged reaction time (Table 1,
entry 1). The commerical available ionic liquids such as bmimBF4 and bmimPF6 were explored, no
improvement was observed. Recently, Handy and Lavender reported that ChCl/urea DES could
been used as effective solvent/catalyst for synthesis of pyrrole via the PaalꢀKnorr reaction,39
however, this fourꢀcomponent reaction could not proceed at all in this DES (entry 4). Furthermore,
the use of some ChCl based on DESs such as ChCl + oxalic acid/tartaric acid/citric acid provided
4

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the desired product in very low yields. When the reaction was performed in ChCl: FeCl3 or
ChCl:ZnBr2, the yields of product were significantly improved. This finding encouraged us to test
other DESs. Previously, Abbott and coꢀworkers reported that DESs can be formed between ChCl
and dicarboxylic acids such as malonic or succinic acid, and their physical properties of these DESs
such as viscosity, conductivity and surface tension were also investigated.5b Subsequently, the
model reaction was undertaken in ChCl + itaconic acid/ fumaric acid/ malic acid/ succinic acid/
malonic acidd. To our delight, ChClꢀmalonic acid was found to be a more efficient medium and
provided desired product in remarkably high yield (88% yield, entry 14). The difference in the
catalytic efficiency of these DESs may be due to their varying acidity. A lower reaction temperature
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of 60 C decreased the yield to 52% (Table 1, entry 17), but a higher reaction temperature (90 C)
did not make a significant effect in the yield of product (Table 1, entry 18). The reaction in the
presence of individual component such as ChCl and malonic acid instead of DES was also
investigated. It was found that 12% yield of product was obtained when only malonic acid was used
wheres no reaction was observed in the case of ChCl in the absence of malonic acid, which
indicated that neither ChCl nor malonic acid promotes the reaction alone. The coꢀexistence of ChCl
and malonic acid has shown the synergetic effect on the reaction, which is perhaps the main reason
for the high catalytic activity of the DES. This result is consistent with ChCl/oxalic acid system.16j
Malonic acid only forms deep eutectic solvent with choline chloride, and it does not participate in
the reaction. Finally, we examined the reaction with various amount of ChClꢀmalonic acid. The
reaction proceeded smoothly to give the desired product 5m in 88% yield when 0.5 g and 1.0 g
ChClꢀmalonic acid was used. A slightly lower yield was achieved using 1.5 g ChClꢀmalonic acid.
Thus, the most suitable reaction conditions for the model reaction were established (Table 1, entry
14).
To demonstrate the industrial applicability of this protocol, the model reaction was carried out
on a large scale (50 mmol). The reaction was completed in 1 h and afforded the corresponding
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product in 89% yield (Table 1, entry 21).
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Table 1 Reaction of 4ꢀchlorobenzaldehyde, aniline, acetylacetone and nitromethane in various
DESsa
Entry Catalyst
Temperature (oC)
Yield (%)
trace
trace
trace
trace
12
1b
no
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
90
80
80
80
2
bmimBF4
3
bmimPF6
4
ChCl: urea (1:2)
5
ChCl: Lꢀ(+)ꢀtartaric acid (2:1)
ChCl: citric acid (2:1)
ChCl: oxalic acid (1:1)
ChCl: FeCl3 (1:2)
6
18
7
20
8
49
9
ChCl: ZnBr2 (1:2)
70
10
11
12
13
14
15
16
17
18
19
20
ChCl: itaconic acid (1:1)
ChCl: fumaric acid (1:1)
ChCl: malic acid (1:1)
ChCl: succinic acid (1:1)
ChCl: malonic acid (1:1)
ChCl: malonic acid (1:1) 1.0 g
ChCl: malonic acid (1:1) 1.5 g
ChCl: malonic acid (1:1)
ChCl: malonic acid (1:1)
ChCl
78
80
71
65
88
88
86
52
88
0
malonic acid
12
21c
ChCl: malonic acid (1:1)
89
a
Reaction condition: 4ꢀchlorobenzaldehyde (1 mmol), aniline (1 mmol), acetylacetone (1 mmol),
b
nitromethane (3 mmol), ChCl: second component ratio in (mol:mol), solvent (0.5 g), 60 min. The
reaction time up to 12 h. c The reaction was carried out in 50 mmol scale.
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With these findings in hand, we examined this method to a wider range of amines, aldehydes,
and 1,3ꢀdicarbonyl compounds and the results was depicted in Table 2. Firstly, diverse amines were
investigated. The results demonstrated that a wide range of anilines, regardless of electronꢀdonating
or electronꢀwithdrawing groups on the benzene ring, could undergo the reaction smoothly to afford
the expected products in moderate to good yields. Anilines bearing a weakly electronꢀwithdrawing
were a little bit less efficient in the reaction. A decrease in reactivity was observed when
orthoꢀsubstitution substrate was used (Table 2, entry 5), thus revealing a strong steric effect.
Noticeably, the notoriously difficult 4ꢀnitroaniline was also successfully converted into the
corresponding product 5i (Table 2, entry 9). It is worth mentioning that the reaction time was
shortened obviously compared with previous reported method.35 In addition, this reaction was
amenable to polycyclic aromatic substrate such as naphthylamine, and the corresponding product 5g
was obtained in high yield (Table 2, entry 10). Amine containing heteroaromatic group such as
furanꢀ2ꢀylmethanamine was also subjected to the standard reaction conditions, very valuable
product 5k was obtained in good yield (Table 2, entry 11). Moreover, propꢀ2ꢀenꢀ1ꢀamine could be
employed as a facile substrate and provided the corresponding products in good yields (Table 2,
entries 18 and 19). Also, it was found that different kinds of aliphatic amines reacted successfully to
afford the desired products under the same reaction conditions in apparently shorter reaction time
(Table 2, entries 12 and 13).
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Next, the substrate scope of aldehydes with a variety of substituents was also investigated in
this 4CRs. The aromatic ring of benzaldehyde bearing electronꢀwithdrawing or electronꢀdonating
groups afforded the desired products in high yields, showing no significant influence on the reaction
time and the yield of the products. Notably, heteroaromatic aldehydes such as 2ꢀfuraldehyde and
2ꢀthiophenealdehyde were tolerated and furnished the corresponding products 5r and 5s in excellent
yields. 1ꢀNaphthaldehyde also afforded the product 5t in 80 % yield. Unfortunately, alkyl aldehyde
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such as cyclohexanecarboxaldehyde or benzylic aldehyde provided inseparable complex mixtures
under similar reaction conditions.
Encouraged by the good results with acetylacetone, we further expand the reaction scope. A
variety of 1,3ꢀdicarbonyl compounds such as methyl acetoacetate, ethyl acetoacetate,
2ꢀmethoxyethyl acetoacetate, allyl acetoacetate, tertꢀbutyl 3ꢀoxobutanoate, isobutyl 3ꢀoxobutanoate
and methyl 3ꢀoxopentanoate were applied to this 4CRs, the desired products were isolated in high
yields (Table 2, entries 21ꢀ27).
Table 2 Synthesis of multisubstituted pyrroles 5
Entry
Aldehyde
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
Amine
R3
R4
Product
5a
Time/h
1.0
Yield/%a
90
Ref.
25
1
2
3
4
5
6
7
8
9
PhNH2
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
4ꢀCH3C6H4NH2
4ꢀC(CH3)3C6H4NH2
4ꢀFC6H4NH2
2ꢀClC6H4NH2
3ꢀClC6H4NH2
4ꢀClC6H4NH2
4ꢀBrC6H4NH2
4ꢀNO2C6H4NH2
1.0
90
35
5b
1.0
91
35
5c
1.0
87
34
5d
1.8
56
5e
1.2
80
24c
26
5f
1.0
89
5g
1.0
86
35
5h
1.5
52
35
5i
10
PhCHO
Me Me
1.5
60
24c
5j
11
PhCHO
Me Me
0.5
80
5k
12
13
PhCHO
PhCHO
PhCH2NH2
Me Me
Me Me
0.5
0.5
82
85
24c
35
5l
NH2
5m
14
15
16
17
4ꢀCH3C6H4CHO
4ꢀClC6H4CHO
4ꢀNO2C6H4CHO
4ꢀCF3C6H4CHO
PhNH2
PhNH2
PhNH2
PhNH2
Me Me
Me Me
Me Me
Me Me
1.0
1.0
1.5
1.5
90
88
78
75
35
35
35
35
5n
5o
5p
5q
18
19
H2C=CHCH2NH2
H2C=CHCH2NH2
Me Me
Me Me
1.5
1.5
70
72
5r
5s
20
21
PhNH2
PhNH2
Me Me
1.5
1.5
81
80
29
35
5t
PhCHO
Me OMe
5u
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27
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
Me OEt
1.5
1.5
1.5
2.0
2.0
2.0
85
80
76
83
80
78
35
35
35
5v
Me OCH2CH2OMe
Me OCH2CH=CH2
Me OC(CH3)3
5w
5x
5y
Me OCH2CH(CH3)2
5z
Et
OMe
29
5aa
a Isolated yield.
1
2
3
4
The structures of the products were determined by their FTIR, 1H NMR, 13C NMR spectra and
elemental analysis. Furthermore, the structure of compound 5c was unambiguously confirmed by
single crystal Xꢀray analysis (Fig. 2).
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Fig. 2 Singleꢀcrystal Xꢀray structural of compound 5c (CCDC 1008451)
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Based on the literatures,34 the product formation for this fourꢀcomponent reaction can be
mechanistically rationalized via a domino reaction pathway (Scheme 2). We propose that choline
chlorideꢀmalonic acid DES catalyzes the reaction via hydrogenꢀbonding activation of carbonyl
group of acetylacetone and increases its electrophilicity, thereby facilitating the attack of aniline to
generate the enaminone A. Similarly, it also forms hydrogen bond with the oxygen of carbonyl
group of 4ꢀchlorobenzaldehyde to facilitate the Knoevenagel condensation with nitromethane to
produce intermediate B. The presence of intermolecular hydrogen bonding plays an important role
and provides additional attractive forces between molecules. The DES also might assist in
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improving the reactivity of enaminone A, which participates in the Michael addition with B to give
intermediate C. This can be verified by the fact that intermediate A and B could be isolated in the
present reaction process. In addition, product 5o can be obtained by twoꢀcomponent reaction of A
and B in this DES. Subsequently, an intramolecular cyclization of intermediate C involving the
attack by the imine nitrogen to the nearby –C=N(O)OH moiety affords intermediate D. Finally the
intermediate D undergoes aromatization by the elimination of nitroxyl (HNO) and water molecule
to lead the final product 5o.
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Scheme 2 Plausible mechanism for the synthesis of pyrrole 5o
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Deep eutectic solvents as a novel reaction media have been used to the development of a green
protocol for the simple and efficient preparation of various heterocyclic compounds owing to its
atom economy and ease of recovery and reuse. Thus, the reusability of the DESs was investigated
by using aniline, 4ꢀchlorobenzaldehyde, acetylacetone and nitromethane as starting materials under
optimized conditions (Table 3). Upon completion of the reaction, water was added to the reaction
mixture. The DES was dissolved in water and the crude product was obtained by extraction with
o
EtOAc. The DES was recovered by evaporating water at 80 C under vacuum and recycled for the
next batch. The result of the reusability of the DES was illustrated in Table 3. The DES can be
recycled for up to five times without significant loss in yield, which shows that this DES possessed
excellent activity and reusability.
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Table 3 Recycling of the solvent
Entry
Reaction runs
Yield (%)a
1
1 st
88
88
87
85
84
2
2 nd
3 rd
4 th
5 th
3
4
5
a Isolated yield.
2
3
4
5
Finally, in order to show the merit of the present method, we have compared our result with the
most recently reported catalytic systems in the literatures. As can be seen in Table 4, it is clear that
the present protocol is superior in terms of reaction time and product yield.
6
Table 4 Comparison of our result with previously reported systems
Entry Catalyst
Reaction conditions Product Time Yield (%)
1
2
3
FeCl3 (10 mol%)
NiCl2ꢁ6H2O (10 mol%)
Reflux
Reflux
14 h 5425
10 h 5226
5a
5a
5y
Silica supported tungsticacid (10 mol%) Reflux
4 h
7928
Magnetic nanoparticle CoFe2O4 supported
4
90 ºC
4 h
9029
5a
Mo (1.0 mol%)
5
I2 (10 mol%)
90ºC
6 h
4 h
9 h
6 h
7 h
3 h
1 h
8530
7231
7032
7034
8735
9036
5l
6
Amberlystꢀ15 (10 wt%)
BDMS (10 mol%)
Ultrasound
5u
7
Room temperature 5u
8
Montmorillonite clay Kꢀ10 (10 mol%)
GAAS (5 ml)
60 ºC
5a
9
100 ºC
5a
10
11
[bmim]HSO4 (20 mol%)
ChCl/malonic acid (0.1g)
90 ºC
5a
80 ºC
90 (this work)
5a
7
8
Conclusions
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In conclusion, we have developed a simple, green, and highly efficient procedure for synthesis
of diversely substituted pyrroles by oneꢀpot, fourꢀcomponent coupling reaction of amines, aldehydes,
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1,3ꢀdicarbonyl compounds and nitromethane. The reaction proceeded in deep eutectic solvent and
provided the corresponding products in good to excellent yields. The good catalytic potency and
excellent recyclability of choline chlorideꢀmalonic acid make this protocol more useful for
preparation of multisubstituted pyrroles in large scale over reported methodologies.
Experimental section
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General information
All solvents and chemicals were obtained commercially and were used without further
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purification. Melting points were measured on an Xꢀ4 digital melting point apparatus and were
corrected with benzoic acid. IR spectra were obtained as KBr pellets or as liquid films on KBr
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pellets with a BrukerꢀTENSOR 27 spectrometer. H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were recorded on Bruker DRXꢀ500 spectrometer using CDCl3 as the solvent and TMS as an
internal standard. Elemental analyses were determined on a Vario EL III CHNOS elemental
analyzer.
Preparation of deep eutectic solvents
A mixture of choline chloride and the second component was heated until a clear liquid
appeared, then allowed to cool at room temperature and used without further purification.
General procedure for synthesis of functionalized pyrroles 5
A mixture of aldehyde (1 mmol), amine (1 mmol), 1,3ꢀdicarbonyl compound (1 mmol),
o
CH3NO2 (3 mmol) in ChClꢀmalonic acid (0.5 g) was stirred at 80 C (monitored by TLC). Upon
completion of the reaction, the reaction mixture was cooled to room temperature and water (5 mL)
was added. The ChClꢀmalonic acid was dissolved in water and the products were extracted with
EtOAc (3 × 5mL). Pure products were obtained by evaporation of the solvent, followed by
recrystallization from ethanol or by column chromatography on silica gel using ethyl acetate/hexane
as the eluent.
1
1-(2-Methyl-1,4-diphenyl-1H-pyrrol-3-yl)ethanone (5a). White solid, mp 106ꢀ107 °C; H
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NMR (CDCl3, 500 MHz) δ 2.08 (s, 3H), 2.41 (s, 3H), 6.68 (s, 1H), 7.31ꢀ7.35 (m, 3H), 7.38ꢀ7.39 (m,
4H), 7.43 (t, J = 7.5 Hz, 1H), 7.49ꢀ7.51 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.9, 31.2,
120.6, 122.6, 126.3, 126.3, 126.9, 128.1, 128.3, 129.4, 129.4, 135.3, 136.0, 138.8, 197.7 ppm.
1-(2-Methyl-4-phenyl-1-(p-tolyl)-1H-pyrrol-3-yl)ethanone (5b). White solid, mp 109ꢀ111
°C; 1H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 6.64 (s, 1H), 7.21 (d, J =
8.5 Hz, 2H), 7.26ꢀ7.32 (m, 3H), 7.37ꢀ7.38 (m, 4H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.9, 21.1,
31.1, 120.7, 122.4, 126.1, 126.2, 126.8, 128.3, 129.4, 129.9, 135.4, 136.1, 136.2, 138.1, 197.6 ppm.
1-(1-(4-(tert-butyl)phenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5c). White solid,
3
4
5
6
7
8
1
9
mp 148ꢀ149 °C; H NMR (CDCl3, 500 MHz) δ 1.37 (s, 9H), 2.08 (s, 3H), 2.41 (s, 3H), 6.66 (s,
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11
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14
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18
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1H), 7.25 (d, J = 8.5 Hz, 2H), 7.29ꢀ7.34 (m, 1H), 7.38ꢀ7.39 (m, 4H), 7.49 (d, J = 8.5 Hz, 2H) ppm;
13C NMR (CDCl3, 125 MHz) δ 13.0, 31.1, 31.4, 34.8, 120.7, 122.4, 125.8, 126.2, 126.3, 126.8,
128.3, 129.4, 135.5, 136.1, 136.2, 151.3, 197.7 ppm.
1-(1-(4-Fluorophenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5d). White solid, mp
126ꢀ127 °C; 1H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3H), 2.38 (s, 3H), 6.63 (s, 1H), 7.16 (t, J = 8.0
Hz, 2H), 7.29ꢀ7.31 (m, 3H), 7.36ꢀ7.37 (m, 4H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.8, 31.1,
116.4 (d, 2JCF = 22.8 Hz), 120.7, 122.6, 126.4, 126.9, 128.1 (d, 3JCF = 8.4 Hz), 128.3, 129.3, 134.8(d,
4JCF = 2.9 Hz), 135.4, 135.9, 162.1 (d, 1JCF = 247.1 Hz), 197.5 ppm.
1-(1-(2-Chlorophenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5e). Pale yellow solid,
1
mp 98ꢀ99 °C; H NMR (CDCl3, 500 MHz) δ 2.09 (s, 3H), 2.28 (s, 3H), 6.56 (s, 1H), 7.34ꢀ7.29 (m,
1H), 7.44ꢀ7.35 (m, 7H), 7.57ꢀ7.55 (m, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.3, 31.1, 76.8,
77.0, 77.3, 120.3, 121.9, 126.3, 126.8, 127.6, 128.2, 129.5, 129.6, 130.2, 130.5,
132.6,136.0,136.4,136.5,197.5 ppm; Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.21; N, 4.52;
Found: C, 73.42; H, 5.01; N, 4.70; ESIꢀMS: m/z = 310 (M+1)+.
1-(1-(3-Chlorophenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5f). Yellow sticky
1
liquid; H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3H), 2.41 (s, 3H), 6.65 (s, 1H), 7.23ꢀ7.27 (m, 1H),
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7.30ꢀ7.44 (m, 8H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.9, 31.1, 98.5, 120.4, 122.6, 123.0, 124.5,
125.4, 126.5, 126.7, 127.0, 128.4, 129.3, 130.4, 135.0, 135.1, 135.7, 139.9, 197.6 ppm.
3
1-(1-(4-Chlorophenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5g). Yellow solid, mp
127ꢀ 128 °C; 1H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3H), 2.40 (s, 3H), 6.64 (s, 1H), 7.28 (d, J = 8.5
Hz, 2H), 7.31ꢀ7.40 (m, 5H), 7.47 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.8,
31.1, 120.4, 122.9, 126.6, 126.9, 127.5, 128.3, 129.3, 129.6, 134.1, 135.1, 135.8, 137.3, 197.6 ppm.
1-(1-(4-Bromophenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5h). White solid, mp
141ꢀ143 °C; 1H NMR (CDCl3, 500 MHz) δ 2.06 (s, 3H), 2.40 (s, 3H), 6.63 (s, 1H), 7.21 (d, J = 8.0
Hz, 2H), 7.31ꢀ7.39 (m, 5H), 7.61 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125MHz) δ 12.9, 31.1,
120.4, 122.0, 122.9, 126.7, 127.0, 127.8, 128.4, 129.3, 132.6, 135.1, 135.8, 137.8, 197.6 ppm.
1-(2-Methyl-1-(4-nitrophenyl)-4-phenyl-1H-pyrrol-3-yl)ethanone (5i). Yellow solid, mp
4
5
6
7
8
9
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23
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25
1
171ꢀ 172 °C; H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3H), 2.46 (s, 3H), 6.72 (s, 1H), 7.33ꢀ7.42 (m,
5H), 7.54 (d, J = 8.0 Hz, 2H), 8.39 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 13.1,
31.2, 119.9, 124.1, 125.0, 126.5, 127.3, 127.5, 128.5, 129.2, 134.7, 135.3, 144.1, 146.8, 197.7 ppm.
1-(2-Methyl-1-(naphthalen-1-yl)-4-phenyl-1H-pyrrol-3-yl)ethanone (5j). White solid, mp
143ꢀ144 °C; 1H NMR (CDCl3, 500 MHz) δ 2.15 (s, 3H), 2.22 (s, 3H), 6.71 (s, 1H), 7.32 (t, J = 7.5
Hz, 1H), 7.38ꢀ7.49 (m, 6H), 7.51ꢀ7.59 (m, 3H), 7.97 (t, J = 9.0 Hz, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ 12.4, 31.2, 121.8, 121.9, 122.9, 125.3, 125.4, 126.1, 126.8, 126.9, 127.6, 128.3, 128.3,
129.4, 129.5, 130.6, 134.1, 135.3, 136.1, 137.1, 197.8 ppm.
1-(1-(Furan-2-ylmethyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5k). White solid, mp
77ꢀ78 °C; IR (KBr): 2926, 1637, 1604, 1500, 1168, 943 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 2.00 (s,
3H), 2.54 (s, 3H), 4.98 (s, 2H), 6.25 (d, J = 8.0 Hz, 1H), 6.34 (dd, J = 2.5, 2.0 Hz, 1H), 6.53 (s, 1H),
7.28ꢀ7.30 (m, 3H), 7.34 (t, J = 7.5 Hz, 2H), 7.38 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 11.2,
30.9, 43.1, 108.4, 110.4, 119.3, 121.8, 125.7, 126.5, 128.0, 129.1, 134.6, 136.0, 142.8, 149.2, 197.4
ppm; Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01; Found: C, 77.32; H, 6.02; N, 4.98;
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ESIꢀMS: m/z = 280 (M+1)+.
1-(1-Benzyl-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5l). White solid, mp 87ꢀ88 °C; 1H
NMR (CDCl3, 500 MHz) δ 2.04 (s, 3H), 2.44 (s, 3H), 5.06 (s, 2H), 6.54 (s, 1H), 7.09 (d, J = 7.5 Hz,
2H), 7.26ꢀ7.37 (m, 8H) ppm; 13C NMR (CDCl3, 125 MHz) δ 11.6, 31.1, 50.3, 120.2, 122.1, 125.9,
126.7, 127.9, 128.3, 129.0, 129.4, 135.2, 136.4, 136.7, 197.5 ppm.
6
1-(1-Cyclopropyl-2-methyl-4-phenyl-1H-pyrrol-3-yl)ethanone (5m). White solid，mp 80ꢀ81
7
8
°C; 1H NMR (CDCl3, 500 MHz) δ 0.94ꢀ0.97 (m, 2H), 1.00ꢀ1.06 (m, 2H), 2.00 (s, 3H), 2.58 (s, 3H),
3.13ꢀ3.17 (m, 1H), 6.50 (s, 1H), 7.26ꢀ7.36 (m, 5H) ppm; 13C NMR (CDCl3, 125 MHz) δ 6.9, 12.2,
28.2, 31.1, 119.6, 122.0, 125.1, 126.7, 128.3, 129.4, 136.5, 137.4, 197.5 ppm.
9
10
11
12
13
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1-(2-Methyl-1-phenyl-4-(p-tolyl)-1H-pyrrol-3-yl)ethanone (5n). White solid, mp 92ꢀ93 °C;
1H NMR (CDCl3, 500 MHz) δ 2.09 (s, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 6.65 (s, 1H), 7.19 (d, J = 8.0
Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.32 (d, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H) ppm;
13C NMR (CDCl3, 125 MHz) δ 13.0, 21.2, 31.2, 120.5, 122.6, 126.2, 126.3, 128.1, 129.0, 129.2,
129.4, 133.0, 135.2, 136.5, 138.8, 197.8 ppm.
1-(4-(4-Chlorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3-yl)ethanone (5o). White solid, mp
1
105ꢀ106 °C; H NMR (CDCl3, 500 MHz) δ 2.10 (s, 3H), 2.40 (s, 3H), 6.66 (s, 1H), 7.30ꢀ7.37 (m,
6H), 7.43 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 13.0,
31.2, 120.8, 122.5, 125.0, 126.3, 128.3, 128.5, 129.4, 130.5, 132.8, 134.5, 135.5, 138.6, 197.2 ppm.
1-(2-Methyl-4-(4-nitrophenyl)-1-phenyl-1H-pyrrol-3-yl)ethanone (5p). Brown sticky liquid;
1H NMR (CDCl3, 500 MHz) δ 2.18 (s, 3H), 2.40 (s, 3H), 6.78 (s, 1H), 7.34 (d, J = 7.0 Hz, 2H), 7.48
(d, J = 7.5 Hz, 1H), 7.51ꢀ7.54 (m, 4H), 8.25 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz)
δ 12.9, 31.3, 121.7, 122.5, 123.7, 124.1, 126.3, 128.6, 129.5, 129.6, 136.1, 138.3, 143.0, 146.5,
196.7 ppm.
1-(2-Methyl-1-phenyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-3-yl)ethanone (5q). Yellow
sticky liquid; 1H NMR (CDCl3, 500 MHz) δ 2.12 (s, 3H), 2.41 (s, 3H), 6.72 (s, 1H), 7.33 (d, J = 7.5
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Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.51 (m, 4H), 7.64 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3,
1
3
125 MHz) δ 12.9, 31.2, 121.2, 122.5, 124.4 (q, JFC = 270.5 Hz), 125.2 (q, JFC =3.6 Hz), 126.3,
3
128.4, 129.0, 129.4 (q, 2JFC =12.5 Hz), 135.7, 138.5, 139.8, 197.0 ppm.
4
1-(1-Allyl-4-(furan-2-yl)-2-methyl-1H-pyrrol-3-yl)ethanone (5r). Yellow sticky liquid; IR
(KBr): 2924, 1654, 1560, 1419, 1190, 1010, 937 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 2.15 (s, 3H),
2.46 (s, 3H), 4.45 (dt, J = 5.0, 1.5 Hz, 2H), 5.02 (d, J = 17.0 Hz, 1H), 5.23 (d, J = 10.0 Hz, 1H),
5.87ꢀ5.94 (m, 1H), 6.35 (d, J = 3.0 Hz, 1H), 6.46 (dd, J = 3.0, 2.0 Hz, 1H), 6.67 (s, 1H), 7.44 (s, 1H)
ppm; 13C NMR (CDCl3, 125 MHz) δ 11.4, 29.8, 41.0, 107.7, 111.0, 114.6, 117.7, 120.9, 132.5,
135.5, 141.6, 149.1, 196.5 ppm; Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11; Found: C,
73.30; H, 6.51; N, 5.99; ESIꢀMS: m/z = 230 (M+1)+.
5
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1-(1-Allyl-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-3-yl)ethanone (5s). Yellow sticky liquid;
1
IR (KBr): 2920, 1654, 1560, 1541, 1411, 1265, 991 cmꢀ1; H NMR (CDCl3, 500 MHz) δ 2.12 (s,
3H), 2.45 (s, 3H), 4.44 (dt, J = 5.5, 1.5 Hz, 2H), 5.03 (dd, J = 17.0, 1.0 Hz, 1H), 5.23 (dd, J = 10.5,
1.0 Hz, 1H), 5.87ꢀ5.95 (m, 1H), 6.58 (s, 1H), 6.93 (dd, J = 3.5, 1.0 Hz, 1H), 7.03 (dd, J = 5.0, 3.5
Hz, 1H), 7.25 (dd, J = 5.0, 1.0 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 11.4, 30.5, 49.0, 117.0,
117.8, 121.0, 122.3, 124.8, 126.9, 127.1, 132.6, 135.3, 137.2, 196.9 ppm; Anal. Calcd for
C14H15NOS: C, 68.54; H, 6.16; N, 5.71; Found: C, 68.44; H, 6.01; N, 5.68; ESIꢀMS: m/z = 246
(M+1)+.
1-(2-Methyl-4-(naphthalen-1-yl)-1-phenyl-1H-pyrrol-3-yl)ethanone (5t). White solid, mp
1
114ꢀ115 °C; H NMR (CDCl3, 500 MHz) δ 1.70 (s, 3H), 2.53(s, 3H), 6.73 (s, 1H), 7.38ꢀ7.52 (m,
9H), 7.84ꢀ7.89 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.9, 31.1,
118.8, 119.6, 120.8, 122.5, 124.2, 126.3, 126.7, 127.7, 128.4, 129.4, 130.1, 133.6, 135.6, 136.1,
156.3, 157.5, 197.6 ppm.
1
Methyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5u). Yellow sticky liquid; H
NMR (CDCl3, 500 MHz) δ 2.45 (s, 3H), 3.70 (s, 3H), 6.71 (s, 1H), 7.26ꢀ7.28 (m, 1 H), 7.32ꢀ7.36 (m,
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4H), 7.41ꢀ7.44 (m, 3H), 7.47ꢀ7.50 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.8, 50.7, 111.5,
121.0, 126.4, 126.7, 127.8, 128.2, 129.2, 129.4, 135.6 136.8, 139.0,166.3 ppm.
3
Ethyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5v). Yellow sticky liquid; 1H NMR
(CDCl3, 500 MHz) δ 1.14 (t, J = 7.0 Hz, 3H), 2.46 (s, 3H), 4.18 (q, J = 7.0 Hz, 2H), 6.71 (s, 1H),
7.25ꢀ7.28 (m, 1H), 7.32ꢀ7.35 (m, 4H), 7.42ꢀ7.43 (m, 3H), 7.47ꢀ7.50 (m, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ 12.8, 14.2, 59.5, 111.8, 120.9, 126.4, 126.7, 127.6, 128.1, 129.4, 129.4, 135.7, 136.6,
139.0, 165.9 ppm.
4
5
6
7
8
2-Methoxyethyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5w). Yellow sticky
liquid; 1H NMR (CDCl3, 500 MHz) δ 2.46 (s, 3H), 3.25 (s, 3H), 3.47 (t, J = 5.0 Hz, 2H), 4.28 (t, J =
5.0 Hz, 2H), 6.71 (s, 1H), 7.26ꢀ7.28 (m, 1 H), 7.32ꢀ7.35 (m, 4H), 7.41ꢀ7.44 (m, 3H), 7.47ꢀ7.50 (m,
9
10
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13
2H) ppm; C NMR (CDCl3, 125 MHz) δ 12.8, 58.7, 62.6, 70.4, 111.5, 121.0, 126.4, 126.9, 127.7,
128.2, 129.4, 135.7, 137.0, 139.0, 165.7 ppm.
1
Allyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5x). Yellow sticky liquid; H NMR
(CDCl3, 500 MHz) δ 2.46 (s, 3H), 4.64 (d, J = 4.5 Hz, 2H), 5.09 (m, 2H), 5.79ꢀ5.86 (m, 1H), 6.71 (s,
1H), 7.26ꢀ7.28 (m, 1 H), 7.32ꢀ7.35 (m, 4H), 7.42ꢀ7.43 (m, 3H), 7.48ꢀ7.51 (m, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 12.9, 64.4, 111.5, 117.4, 121.1, 126.4, 126.4, 126.9, 127.8, 128.2, 129.4, 129.4,
132.6, 135.6, 136.9, 139.0, 165.5 ppm.
tert-Butyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5y). Yellow sticky liquid; IR
(KBr): 2976, 1691, 1502, 1290, 1138, 1030, 962 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 1.35 (s, 9H),
2.44 (s, 3H), 6.69 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.31ꢀ7.35 (m, 4H), 7.39ꢀ7.43 (m, 3H), 7.48 (t, J
= 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 12.5, 28.1, 79.7, 120.5, 126.2, 126.3, 126.5,
126.7, 127.6, 128.0, 129.0, 129.3, 136.0, 136.0, 165.5 ppm; Anal. Calcd for C22H23NO2: C, 79.25;
H, 6.95; N, 4.20; Found: C, 79.23; H, 6.88; N, 4.18; ESIꢀMS: m/z = 334 (M+1)+.
iso-Butyl 2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5z). Yellow sticky liquid; IR
(KBr): 2958, 1697, 1523, 1408, 1224, 1138, 985 cmꢀ1; H NMR (CDCl3, 500 MHz) δ 0.78 (d, J =
1
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7.0 Hz, 6H), 1.76ꢀ1.84 (m, 1H), 2.50 (s, 3H), 3.95 (d, J = 6.5 Hz, 2H), 6.72 (s, 1H), 7.28 (t, J = 7.5
Hz, 1H), 7.34ꢀ7.37 (m, 4H), 7.42ꢀ7.46 (m, 3H), 7.50 (t, J = 7.0 Hz, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ 12.8, 19.2, 27.7, 70.0, 111.8, 120.9, 126.3, 126.8, 127.8, 128.1, 129.3, 129.4, 135.8,
136.6, 139.0, 166.0 ppm; Anal. Calcd for C22H23NO2: C, 79.25; H, 6.95; N, 4.20; Found: C, 79.23;
H, 6.86; N, 4.08; ESIꢀMS: m/z = 335 (M+1)+.
3
4
5
6
Methyl 2-ethyl-1,4-diphenyl-1H-pyrrole-3-carboxylate (5aa). White solid, mp 100ꢀ101 °C;
1H NMR (CDCl3, 500 MHz) δ 1.10 (t, J = 7.5 Hz, 3H), 2.86 (q, J = 7.5 Hz, 2H), 3.69 (s, 3H), 6.65
(s, 1H), 7.22ꢀ7.26(m, 1H), 7.32ꢀ7.35(m, 4H), 7.41ꢀ7.48 (m, 5H) ppm; 13C NMR (CDCl3, 125 MHz)
δ14.6, 19.2, 50.5, 110.6, 121.3, 126.3, 126.6, 126.8, 127.6, 128.4, 129.1, 129.3, 135.7, 139.2, 143.0,
166.0 ppm.
7
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9
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ACKNOWLEDGMENTS
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We are grateful for the financial support for this research from the National Natural Science
Foundation of China (No. 21272053) and the Nature Science Foundation of Hebei Province (No.
B2015205182).
References
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(a) S. K. Tang, G. A. Baker and H. Zhao, Chem. Soc. Rev., 2012, 41, 4030ꢀ4066; (b) A. C.
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