A green and efficient method for the synthesis of pyrroles using a deep eutectic solvent ([CholineCl][ZnCl2]3) under solvent-free sonication

Article abstract of DOI:10.1039/c7nj02396k

An efficient deep eutectic solvent-based synthesis of pyrroles under ultrasound irradiation has been developed to provide a significant improvement of the yield up to 99% in a short reaction time. The synthesis of pyrroles is highly atom-economical, producing water as the sole byproduct. In addition, [CholineCl][ZnCl₂]₃ is easily synthesized from commercially available choline chloride and zinc chloride via a cost-effective and environmentally benign pathway. The obtained [CholineCl][ZnCl₂]₃ has been characterized by FT-IR, ¹H-NMR, ¹³C-NMR, HRMS (ESI), Raman, and TGA. Five new pyrroles are synthesized by the current method. Moreover, [CholineCl][ZnCl₂]₃ could be reused up to four times without significant loss of catalytic activity.

Full text of DOI:10.1039/c7nj02396k

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

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A green and efficient method for the synthesis of pyrroles using a
deep eutectic solvent ([CholineCl][ZnCl2]3) under solvent-free
sonication.
33Received 00th January
20xx,
Hai Truong Nguyen, Duy-Khiem Nguyen Chau and Phuong Hoang Tran*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient deep eutectic solvent-based synthesis of pyrroles under ultrasound irradiation has been developed to provide a
significant improvement of the yield up to 99% in a short reaction time. The synthesis of pyrroles is highly atom-economical,
producing water as the sole byproduct. In addition, [CholineCl][ZnCl2]3 is easily synthesized from commercially available choline
chloride and zinc chloride via a cost-effective and environmentally benign pathway. The obtained [CholineCl][ZnCl2]3 has been
characterized by FT-IR, 1H-NMR, 13C-NMR, HRMS (ESI), Raman and TGA. Five new pyrroles are synthesized by the current
method. Moreover, [CholineCl][ZnCl2]3 could be reused up to four times without significant loss of catalytic activity.
49-55
multicomponent reactions.41,
Recently, Rogers and
Introduction
coworkers reported the structure determination of
[CholineCl]2[ZnCl2]3, crystallized from a combination of choline
chloride and ZnCl2 at 2 : 3 molar ratio.56 Due to interesting
properties such as the ease of handling, excellent catalytic
activity, nontoxicity, and simplicity in processing, DESs have
emerged as a promising green reaction media for organic
transformations.44-46
Pyrroles are important heterocyclic compounds, which are found
in core structures of many biologically active products such as
alkaloids, vitamins, anticancer agents and antibiotics.1-6
Therefore, their syntheses and further functionalization have
attracted much interest. The well-known synthetic procedures of
pyrroles are the Hantzsch,7 Paal-Knorr,
syntheses.12-14 Among these, the Paal-Knorr reaction is favored
as an efficient, straightforward and green pathway to obtain
pyrroles from primary amines/ammonia and 1,4-dicarbonyl
compounds under slightly acidic condition.8, 11, 15, 16
4, 8-11
Barton-Zard
In recent years, various pathways for pyrrole synthesis in DESs
have been achieved in good to excellent yields. Prakash et al.
reported pyrrole synthesis from the reaction of methyl 2-
isocyanoacetate with various α,β-unsaturated aromatic and
To date, many acidic catalysts have been widely employed in the
Paal-Knorr reaction such as Brӧnsted acids,11, 16-18 Lewis acids,10,
aliphatic ketones catalyzed by CuI/choline hydroxide deep
15, 19-22
zeolite,23 ionic liquids,24 Bi(OTf)3/[bmin]BF4,25 layered
eutectic solvent.57 Bhate et al. developed the multicomponent
reaction between amines, 1,3-dicarbonyl compounds, and sugars
in DES to provide pyrroles in good yields.58 Zhang et al. used L-(+)-
tartaric acid–choline chloride based deep eutectic solvent
promoted the Clauson-Kaas pyrrole synthesis in good to
excellent yields.59 Recently, Zhang et al. have developed a simple
and efficient pathway for synthesis of substituted pyrroles by
four-component coupling reaction of amines, aldehydes, 1,3-
dicarbonyl compounds and nitromethane in choline chloride–
malonic acid deep eutectic solvent.50
zirconium phosphate and phosphonate,26 and metal-organic
frameworks.8 Despite the potential utility of the catalysts, some
of these methods for the synthesis of pyrrole derivatives still
suffer from certain drawbacks, such as hazardous organic
21, 27, 28
30
solvents,8,
prolonged reaction time,29,
high cost,31-32
large amounts of solid catalysts,33 toxic metal-containing
wastes,34, 35 high temperature,22 and catalytic irrecoverability.36
Thus, the search for a better catalyst as well as a modified
method allowing the synthesis of pyrroles in a greener and more
efficient manner is incomplete.
To our best knowledge, there has been only one literature
reporting the Paal-Knorr synthesis of pyrroles using choline
In recent years, deep eutectic solvents (DESs) have attracted
considerable attention especially in the fields of material
chemistry, gas adsorption, catalysis, biotransformations, and
biodiesel refinement and production.37-46 Since the first one was
prepared by Abbott's group in 2001, a variety of DESs have been
developed as solvents/catalysts for organic transformations such
as carbon-carbon,47, 48 carbon-heteroatom bond formation, and
chloride–urea
deep
eutectic
solvent
as
effective
solvents/catalysts.30 However, the existing method involved a
bulk loading of DES (460 mol%), long reaction time (up to 12 h),
and limited substrate scope study.30 Therefore, a mild and
efficient synthesis of pyrroles using novel DESs is highly desired.
Our group recently developed DESs as dual solvents/catalysts for
the Friedel-Crafts acylation60 and esterification.54 Herein, we
report a mild, fast, and efficient method for Paal-Knorr synthesis
of pyrroles using [CholineCl][ZnCl2]3 deep eutectic solvent under
solvent-free sonication.
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polynuclear entities.67, 68 With AlCl3 or FeCl3, Raman scattering
showed the presence of [AlCl4]-/[FeCl4]-, then the formation of
[Al2Cl7]-/[Fe2Cl7]- when AlCl3 or FeCl3 were in excess.68 As
displayed in Fig. 2, the Raman vibration bands found at below
Results and discussion
To prepare the [CholineCl][ZnCl2]3, ZnCl2 and choline chloride
were heated to 100 oC until a clear colorless liquid was achieved.
1
The structure of [CholineCl][ZnCl2]3 was characterized by H and
13C NMR spectra, FTIR, HRMS (ESI), and TGA. H and 13C NMR
69
130 cm-1 were attributed to Zn–Cl stretching modes.67, The
1
Raman vibration frequencies for ZnCl3- can be found at ∼280 cm-1
data were in good agreement with the previous literature
(Supporting Information, Section S1).61 Besides, no relevant
impurities were detected by NMR spectra. FT-IR and HRMS (ESI+
and ESI-) of the DES structure provide information about
interactions and complexation between constituents.62-64 For
pure choline chloride, vibrational bands at 3409 cm-1 refer to the
presence of a hydroxyl, while the bands at 3025–2965 cm-1 and
1479–1418 cm-1 indicate the presence of an alkyl group. The
characteristic C-N vibration can be found at 1134 and 1052 cm-
and ∼340 cm-1 (Fig. 2).64
Thermal gravimetric analysis (TGA) of the [CholineCl][ZnCl2]3 was
performed to investigate the thermal stability of the catalyst. Fig.
3 shows the TGA profile of the experimented DES system. The
analysis indicates that the DES system is stable up to 350–370 °C
before undergoing a single-step degradation, which makes the
experimented [CholineCl][ZnCl2]3 suitable for the reaction
conditions (Fig. 3).
.
1 65 The vibration bands at 1084 and 955 cm-1 are assigned to C-O
and C-C-O asymmetric stretching associated with –CH2CH2-OH
group of choline cation (Fig. 1).65 The formation of DES was
confirmed by the FT-IR spectrum of [CholineCl][ZnCl2]3; it can be
noted that the characteristic spectrum of [CholineCl][ZnCl2]3 is an
overlap of choline chloride. The result shows that the structure
of choline cation was not destroyed in [CholineCl][ZnCl2]3. The
HRMS spectrum indicates the presence of complex zinc chloride
ions [ZnCl3]- (m/z = 170.8356), [Zn2Cl5]- (m/z = 306.69680,
[Zn3Cl7]- (m/z = 444.5604) in negative mode (ESI-).66 The complex
zinc anions are necessary for the formation of deep eutectic
solvent.61 In positive mode (ESI+), the most intensive peak was
observed in m/z = 105.0504, corresponding to the [Choline + H]+
ion (SupportingInformation, Section S1)
Fig. 2 The Raman spectra of [CholineCl][ZnCl2]3
Fig. 1 FT-IR spectra of choline chloride (a), [CholineCl][ZnCl2]3
catalyst (b), and recycled [CholineCl][ZnCl2]3 after four cycles.
Raman spectroscopy has proved to be excellent tool in the direct
identification of the halometallate species.62, 64, 66-70 As previously
reported, the anions in the imidazolium halometallate molten
salts with AlCl3, FeCl3, ZnCl2, and SnCl2 were characterized as
Fig. 3 TGA curve of the [CholineCl][ZnCl2]3.
2 | J. Name., 2012, 00, 1-3
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c 60 mol% ZnCl2 was used.
In exploratory experiments, the catalytic activity was evaluated
using representative condensation of aniline with
a
acetonylacetone (1.2 equiv.) in the presence of homogeneous
catalysts (20 mol%). The results are listed in Table 1. Aniline was
converted to 2,5-dimethyl-1-phenyl-1H-pyrrole in good to
excellent yields after 10 minutes under solvent-free sonication
(40 kHz). The best result was obtained with [CholineCl][ZnCl2]3
(Table 1, entry 8). The control experiments using only choline
chloride (Table 1, entry 1) or ZnCl2 (Table 1, entry 2) were
conducted under the same condition to testify the outstanding
performance of DESs. Interestingly, ZnCl2 was able to afford the
desired product in a good yield (87%), but it can not be
recovered and reused after aqueous workup. Other DESs
Then, optimizations were also investigated in the current
method. The influence of [CholineCl][ZnCl2]3 loading on the
reaction efficiency was considerable when only 25% yield of the
desired pyrrole was formed in the absence of [CholineCl][ZnCl2]3
(Table 2, entry 1). As expected, raising the [CholineCl][ZnCl2]3
loading from 5 to 20 mol% led to a significant increase in the
yield from 81 to 96% (Table 2, entries 2-5). However, if the
amount of [CholineCl][ZnCl2]3 was increased to 35 mol% (Table 2,
entry 6), response performance was no change compared to
using 20 mol% of the catalyst. The reaction reached the highest
performance, the best result (96%) was obtained with 20 mol%
[CholineCl][ZnCl2]3 at room temperature under solvent-free
ultrasonic activation. As previously reported, only a low yield
(78%) was obtained in the presence of up to 1 mL (460 mol%) of
deep eutectic solvent (choline chloride and urea), higher
temperature (80 oC), and long reaction periods (24 h).30
including
[CholineCl][urea]2,
[CholineCl][Glycerol]2,
[CholineCl][Oxalic acid], [CholineCl][ZnCl2], [CholineCl][ZnCl2]2
were also examined for their reactivity (Table 1, entries 3-7).
Moreover, the conversion of aniline and acetonylacetone to 2,5-
dimethyl-1-phenyl-1H-pyrrole was also investigated in the
presence of ionic liquids, such as [AMIm][OTf (1-allyl-3-
methylimidazolium trifluoromethanesulfonate), [EMIm]Cl (1-
ethyl-3-methylimidazolium chloride), [BMIm]PF6 (1-butyl-3-
methylimidazolium hexafluorophosphate), and [BMIm]BF4 (1-
butyl-3-methylimidazolium tetrafluoroborate) (Table 1, entries
9-12). Although ionic liquids demonstrated comparable catalytic
activity with DESs, many reports pointed out the toxicity, the
poor biodegradability, as well as the high price of most ionic
liquids.71, 72 On the other hand, [CholineCl][ZnCl2]3 has proved to
be an efficient and green catalyst for the Paal-Knorr synthesis of
pyrroles under milder conditions in comparison with previously
reported catalysts. 10, 11, 21, 73
Table 2. Effect of [CholineCl][ZnCl2]3 loading on the synthesis
of 2,5-dimethyl-1-phenyl-1H-pyrrole.a
Entry
[CholineCl][ZnCl2]3 (mol%)
Yield (%)b
1
2
3
4
5
6
0
25
81
85
87
96
96
5
10
15
20
35
a
Reaction conditions: Aniline (1 mmol), acetonylacetone (1.2 mmol),
[CholineCl][ZnCl2]3 (mol%), under solvent-free sonication.
b Isolated yield.
Table 1 The Paal-Knorr pyrrole synthesis in the presence of
various homogeneous catalysts at room temperature under
solvent-free sonication. a
Effect of the molar ratio of the reactants on the reaction yield
was subsequently investigated for the same cyclocondensation
between aniline and acetonylacetone (Table 3). It was found that
an equimolar mixture of aniline and acetonylacetone assured the
formation of 2,5-dimethyl-1-phenyl-1H-pyrrole in an excellent
yield of 88%. The best yield of 96% can be easily achieved when
a little excess amount of acetonylacetone (1.2 equiv.) was
introduced to the reaction mixture.
O
Catalyst 20 mol%
NH2
H2O
N
+
+
US, 10 mins, solvent-free
O
Entry Catalyst
Yieldb (%)
1
Choline chloride
ZnCl2
65
87c
72
83
86
84
87
96
89
70
86
82
2
3
[CholineCl][urea]2
[CholineCl][Glycerol]2
[CholineCl][Oxalic acid]
[CholineCl][ZnCl2]
[CholineCl][ZnCl2]2
[CholineCl][ZnCl2]3
[AMIm][OTf]
4
Table 3 Effect of reagent molar ratio on the Paal-Knorr synthesis
5
of 2,5-dimethyl-1-phenyl-1H-pyrrole
.
Yielda (%)
6
Entry
Aniline : Acetonylacetone
7
1
1 : 1
88
90
96
96
8
2
1 : 1.1
1 : 1.2
1 : 1.5
9
3
10
11
12
a
[EMIm]Cl
4
a Isolated yield
[BMIm]PF6
[BMIm]BF4
Reaction conditions: Aniline (1 mmol), acetonylacetone (1.2 mmol),
[CholineCl][ZnCl2]3 (mol%), under solvent-free sonication.
b Isolated yield.
Further optimization study demonstrated that reaction time also
had certain effects on the reaction yield. As stated in Table 4, the
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[CholineCl][ZnCl2]3-mediated Paal-Knorr reaction provided the
best yield in the presence of 20 mol% of [CholineCl][ZnCl2]3 for
10 minutes (Table 4, entry 6). This method overcame the main
drawback in Lavender’s work where [CholineCl][Urea]-catalysed
Pall-Knorr reaction required longer reaction time up to 24 h. 30
proceeded smoothly to produce corresponding pyrroles in good
to excellent yields. A variety of anilines bearing electron-
donating substituents behave well to give the desired products
in excellent yields with short reaction time (Table 5, entries 1-6).
Interestingly, haloanilines, commonly solid amines at room
temperature, were reactive under current method (Table 5,
entries 7-10). Notably, the C-I bond remained intact during the
reaction, and the corresponding product was obtained in a yield
of 97% (entry 10). 2-Phenylaniline and methyl 4-aminobenzoate
were also reactive and afforded expected product in 97% and
96% yields, respectively (entry 12 and 13). Aromatic amines
bearing strong electron-withdrawing substituents show poor
activity. For 4-aminobenzonitrile (Table 5, entry 14), the desired
product was obtained in moderate yield although the reaction
time was prolonged up to 20 min. Remarkably, after 30 minutes
of being exposed to ultrasound, 4-nitroaniline can be
quantitatively converted into the corresponding product 2,5-
dimethyl-1-(4-nitrophenyl)-1H-pyrrole with the yield of 94%
(Table 5, entry 15) which is much higher than those previously
reported in different methods using BiCl3/SiO2 (50%),15 PS/GaCl3
(83%),22 Sc(OTf)3 (90%),31 and [CholineCl][Urea] (56%).30
Moreover, this method allowed the synthesis of pyrroles at room
Table 4 Effect of time reaction on Paal-Knorr synthesis of 2,5-
dimethyl-1-phenyl-1H-pyrrole.a
Entry
Time reaction (minute)
Yieldb (%)
72
1
2
3
4
5
6
7
8
a
1
2
80
3
82
5
86
7
89
10
15
30
96
96
97
Reaction conditions: Aniline (1 mmol), acetonylacetone (1.2 mmol),
[CholineCl][ZnCl2]3 (mol%), under solvent-free sonication.
b Isolated yield.
temperature within
a very short time under solvent-free
To extend the scope of the Paal-Knorr reaction, various
substrates were also explored and the results are presented in
Table 5. Under the similar reaction conditions, the reaction
sonication. However, 2,4-dinitroaniline was totally unreactive
under all investigated conditions (Table 5, entry 16).
Table 5. Synthesis of pyrroles with a wide range of amine under solvent-free sonication.a
O
[CholineCl][ZnCl2]3 20 mol%
R NH2
+
R N
H2O
+
solvent-free sonication, 10 min
O
1 eq.
1.2 eq.
Entry
1
Amine
Time (min)
10
Products
Yieldb (%)
96 (95)c
NH2
2
3
10
10
87
97
4
10
97
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5
6
7
10
98
N
10
79d
O2N
NH2
10
88
8
10
10
86
88
9
10
15
30
63
77
80
10
11
10
10
97
97
12
O
13
14
10
30
96
75
O
H2N
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15
30
94
10
15
20
16
17
trace
15
30
50
65
10
30
52
70
18
19
20
21
10
51 (83)e
10
15
30
No
reaction
10
15
30
No
reaction
10
15
30
No
reaction
22
a The reaction conditions: amines (1 mmol), acetonylacetone (1.2 mmol), [CholineCl][ZnCl2]3 (20 mol%), solvent-free under ultrasonic
activation (40 kHz).
b Isolated yield.
c Yield in parenthesis was performed on 20 mmol scale.
d Product yield of another isomer was reported in 15% by GCMS.
e Yield in parenthesis was reported by the reaction with 2.4 equiv. of acetonylacetone.
With phenylhydrazine and 2,4-dinitrophenylhydrazine as
reagents (Table 5, entries 17-18), the desired products were
obtained in moderate yields. The cyclocondensation of 1,2-
ethanediamine led to the corresponding bispyrrole; attempt to
increase the yield by increasing the molar of acetonyacetone to
greater than two equiv. was successful (Table 5, entry 19). This
is the first time when the phenylhydrazine derivatives, as well
as 1,2-ethanediamine, were used as the reagents for the Paal-
Knorr pyrroles synthesis. Despite the much synthetic effort, the
failure of obtaining pyrrolic products derived from urea, amino
acids (L-phenylalanine) and aminobenzoic acid (4-amino-3-
hydroxybenzoic acid) was recorded by the present method
(Table 5, entries 20-22). The strongly electron-withdrawing
effect caused by adjacent carbonyl group in urea as well as the
domination of carboxylic acid-amine reaction in L-
phenylalanine and 4-amino-3-hydroxybenzoic acid are
considered as crucial factors drastically diminishing the
reactivity of amino groups towards Paal-Knorr reaction.
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The recycling ability of [CholineCl][ZnCl2]3 was investigated
under optimized condition by using aniline and 2,5-hexadione
as reagents. After extraction, [CholineCl][ZnCl2]3 is kept under
vacuum at 80 oC for one hour. Then the recovered
[CholineCl][ZnCl2]3 is used in the further Paal-Knorr synthesis of
pyrrole (Scheme 1). Remarkably, the catalyst was still active
after four consecutive cycles to afford 2,5-dimethyl-1-phenyl-
1H-pyrrole in quantitative yields up to 96%. Data from FT-IR
spectra of fresh and recovered [CholineCl][ZnCl2]3 confirmed
that no structural degeneration occurred (Fig. 1).
chloroform (purity ≥ 99%) were obtained from Xilong Chemical
Co., Ltd (China). Chloroform-d, 99.8 Atom %D, stab. with Ag
was obtained from Armar (Switzerland). All starting materials,
reagents, and solvents were used without further purification.
Sonication was performed in an Elma S30H with a frequency of
40 kHz. GC–MS spectra were recorded on an Agilent GC System
7890 equipped with a mass selective detector Agilent 5973N
and a capillary DB–5MS column (30 m x 250 µm x 0.25 µm). FT-
IR spectra were analyzed from KBr pellets by a Bruker Vertex
70. 1H and 13C NMR spectra were recorded on a Bruker
Advance 500. HRMS (ESI) data were performed on Bruker
micrOTOF-QII MS at 80 eV.
96
96
96
95
95
Preparation of [CholineCl][ZnCl2]3.
A mixture of choline chloride (5 mmol, 0.695 g) and zinc
o
chloride (15 mmol, 2.04 g) was heated to 100 C until a clear
60, 61
colourless liquid was obtained.54,
The structure of
[CholineCl][ZnCl2]3 was confirmed by 1H-NMR, 13C-NMR, IR,
Raman and HRMS (ESI).
General procedure for Paal-Knorr synthesis.
Aniline (1.0 mmol, 0.094 g), acetonylacetone (1.2 mmol, 0.1368
g) and [CholineCl][ZnCl2]3 (0.2 mmol, 0.1095 g) were added into
a 10 mL pressurized glass tube with Teflon-coated septum. The
reaction mixture was irradiated by ultrasound for an
appropriate time. After completion of the reaction, the mixture
was monitored by TLC and GC. The reaction mixture was
separated from DES by the multiple dilution with diethyl ether
(10 x 5 mL). All ethereal fractions were then combined and
washed with H2O (2 x 15 mL). The organic layer was dried over
MgSO4 and the solvent was removed by a rotary evaporator.
The crude product was purified by silica gel chromatography
using ethyl acetate–hexane (1:9). The purified product was
then characterized by 1H and 13C NMR, GC-MS or HRMS (ESI).
1-(2’-Hydroxy-5’-methylphenyl)-2,5-dimethyl-1H-pyrrole.
Black oily liquid; 1H NMR (500 MHz, CDCl3) δ 7.14 – 7.12 (dd, J =
2 Hz, 2 Hz, 1H), 6.96 – 6.95 (d, J = 8.5 Hz, 1H), 6.92 – 6.91 (d, J =
1.5 Hz, 1H), 5.94 (s, 2H), 5.08 (s, 1H), 2.31 (s, 3H), 1.98 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 150.4, 130.5, 130.1, 129.4, 129.0,
116.5, 115.9, 106.7, 20.4, 12.3; HRMS (ESI) m/z calcd for [M +
H]+ C13H16NO+ 202.1226, found 202.1201.
Run 0
Run 1
Run 2
Run 3
Run 4
Scheme 1. Recycling of [CholineCl][ZnCl2]3.
.
Experimental
Chemicals, supplies and instruments.
(2-Hydroxyethyl)trimethylammonium (Choline chloride, purity
≥ 99.0%), zinc chloride (purity ≥ 98%), aniline (ACS reagent, ≥
99.5%), o-toluidine (assay ≥ 99%), 3,5-dichoroaniline (assay ≥
98%), 2,5-dichoroaniline (assay ≥ 99%), 3,4-dichoroaniline
(assay
≥
99%), 2,5-dibromoaniline (assay
≥
98%),
triethylenetetramine (assay ≥ 97.0% (T)), tetraethylenepent-
amine (technical grade), phenylhydrazine (assay 97%), 2,4-
dinitrophenylhydrazine (reagent grade, 97%), 4-nitroaniline
(assay ≥ 99%), 4-nitro-o-phenylenediamine (assay 98%), 2-
amino-4-nitrophenol (assay ≥ 99.0% (NT)), 2-amino-p-cresol
(assay 97%), 4-aminobenzonitrile (assay 98%), 4-iodoaniline
(assay 98%), 2-aminobiphenyl (assay 97%), methyl 4-
aminobenzoate (assay 98%), and 4-aminophenol (assay 99%),
2,4-dinitroaniline (assay 98%), urea (reagent grade, 98%), 4-
amino-3-hydroxybenzoic acid (assay 97%), L-phenylalanine
(reagent grade, 98%) were purchased from Sigma-Aldrich.
Acetonylacetone (analysis EMSURE®), anhydrous glycerol
(excipient EMPROVE®), anhydrous oxalic acid (for synthesis),
and TLC (silica gel 60 F254) were obtained from Merck. Silica
gel 230–400 mesh (for column chromatography) was obtained
from Merck. Ethyl acetate (purity ≥ 99.5%), n-hexane, and
1-(2’-Hydroxy-5’-nitrophenyl)-2,5-dimethyl-1H-pyrrole.
°
1
Orange solid; mp 167-170 C ; H NMR (500 MHz, CDCl3) δ 8.28
– 8.24 (dd, J = 2.5 Hz, 2.5 Hz, 1H), 8.09 – 8.08 (d, J = 3 Hz, 1H),
7.18 – 7.16 (d, J = 9.5 Hz, 1H), 5.99 (s, 2H), 1.99 (s, 6H) ; 13C-
NMR (125 MHz, CDCl3) δ 158.7, 141.3, 129.1, 126.1, 125.7,
116.8, 107.9, 12.3 ; HRMS (ESI) m/z calcd for [M + H]+
C12H13N2O3+ 233.0920, found 233.0939.
1-(2’-Amino-4’-nitrophenyl)-2,5-dimethyl-1H-pyrrole.
Yellow solid; mp 128-130 °C; 1H NMR (500 MHz, CDCl3) δ 7.65 –
7.63 (m, 2H), 7.21 – 7.19 (d, J = 9 Hz, 1H), 5.97 (s, 2H), 3.82 (s,
2H), 1.97 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 145.1, 130.3,
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130.2, 124.0, 118.0, 112.8, 109.8, 107.1, 12.2; HRMS (ESI) m/z
calcd for [M + H]+ C12H14N3O2+ 230.1049, found 230.1011.
N1,N2-bis(2-(2,5-Dimethyl-1H-pyrrol-1-yl)ethyl)ethane-1,2-
diamine
5.
6.
7.
8.
X. B. Ding, M. A. Brimble and D. P. Furkert, Org.
Biomol. Chem., 2016, 14, 5390-5401.
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364, 178-185.
1
Yellow oil; H NMR (500 MHz, CDCl3) δ 5.77 – 5.76 (d, J = 5 Hz,
4H), 3.88 – 3.85 (t, J = 7 Hz, 4H), 2.83 – 2.81 (t, J = 7 Hz, 4H),
2.71 (s, 4H), 2.23 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 127.6,
105.4, 49.7, 49.0, 43.7, 12.6; HRMS (ESI) m/z calcd for [M + H]+
C18H31N4+ 303.2543, found 303.2575.
9.
C. Paal, Eur. J. Inorg. Chem., 1885, 18, 367–
371.
Recycling of [CholineCl][ZnCl2]3.
To recover the [CholineCl][ZnCl2]3 after the completion of the
reaction, diethyl ether was added to the reaction mixture as
many times as necessary to extract both starting materials and
products completely. After the removal of solvent under
vacuum at 80 oC for 60 min, the [CholineCl][ZnCl2]3 was
recycled and reused for four consecutive runs. It is worth
noting that the yield of the product decreased slightly after
each run.
10.
11.
A. A. Jafari and H. Mahmoudi, Environ. Chem.
Lett., 2013, 11, 157-162.
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J. Org. Chem., 2016, 2016, 31-35.
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12.
13.
Conclusions
We have developed a green and efficient [CholineCl][ZnCl2]3 as
a reaction medium for Paal-Knorr pyrroles synthesis. This
protocol provides a fast and effective pathway for the synthesis
of pyrrole under the mild condition where ultrasound-assisted
Paal-Knorr reaction catalyzed by DESs was reported for the first
time. As expected, the [CholineCl][ZnCl2]3 possesses several
advantages such as easy preparation from cheap and available
materials, low toxicity, easy handling, and easy recycling.
14.
15.
Acknowledgement
.
This research is funded by Viet Nam National Foundation for
Science and Technology Development (NAFOSTED) under grant
number 104.01-2016.59. We thank Hoang-Tan Le Doan (VNU-
HCM) and Ngoc-Mai Hoang Do (IPH-HCM) for their valuable
discussions.
16.
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A green and efficient method for the Paal-Knorr pyrrole synthesis has been developed under mild
conditions.
O
[CholineCl][ZnCl]3 20 mol%
H2O
+
N
R
R NH2
+
solvent-free sonication
10 - 30 min
O
22 examples, 50-98% yields