L-(+)-Tartaric acid and choline chloride based deep eutectic solvent: An efficient and reusable medium for synthesis of N-substituted pyrroles via Clauson-Kaas reaction

Article abstract of DOI:10.1016/j.molliq.2014.07.015

l-(+)-Tartaric acid-choline chloride based deep eutectic solvent has been found to be an effective promoted medium for Clauson-Kaas reaction of aromatic amines and 2,5-dimethoxytetrahydrofuran. Structurally diverse N-substituted pyrroles were obtained in high to excellent yields under mild conditions. The deep eutectic solvent is inexpensive, non-toxic, reusable and biodegradable.

Full text of DOI:10.1016/j.molliq.2014.07.015

Journal of Molecular Liquids 198 (2014) 259–262
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
L-(+)-Tartaric acid and choline chloride based deep eutectic solvent: An
efficient and reusable medium for synthesis of N-substituted pyrroles via
Clauson-Kaas reaction
Ping Wang a,b, Fei-Ping Ma b, Zhan-Hui Zhang b,
⁎
a
Department of Chemical and Environmental Engineering, Hebei Chemical and Pharmaceutical Vocational Technology College, Shijiazhuang 050026, PR China
College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2014
Received in revised form 29 June 2014
Accepted 14 July 2014
Available online 27 July 2014
L-(+)-Tartaric acid–choline chloride based deep eutectic solvent has been found to be an effective promoted me-
dium for Clauson-Kaas reaction of aromatic amines and 2,5-dimethoxytetrahydrofuran. Structurally diverse N-
substituted pyrroles were obtained in high to excellent yields under mild conditions. The deep eutectic solvent
is inexpensive, non-toxic, reusable and biodegradable.
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Deep eutectic solvent
Low melting mixture
L-(+)-Tartaric acid–choline chloride
Clauson-Kaas reaction
Pyrroles
1. Introduction
low vapour pressure and flammability. They often show low volatility,
water-compatibility, non-toxicity, bio-compatibility, bio-degradability,
Pyrroles constitute an interesting class of nitrogen-containing
heterocycles that widely occur in bioactive natural products, pharmaceu-
ticals, functional materials, ligands and synthetic building blocks [1].
Consequently, many approaches have been developed for the synthesis
of substituted pyrroles including Paal–Knorr reaction [2], conjugate addi-
tion reactions [3], coupling reaction [4], cycloaddition reaction [5],
Hantzsch procedure [6], annulation reactions [7], transition metal-
mediated cyclization [8] as well as multi-component reactions [9–11].
Clauson-Kaas reaction is one of the most widely-used protocols for the
synthesis of N-substituted pyrroles [12]. Despite some improved
methods have been developed for this reaction [13–15], some of these
procedures are associated with one or more disadvantages such as the
use of volatile and hazardous organic solvents, the requirement of expen-
sive catalyst and additional microwave oven. Thus, the development of a
simple, efficient, economical and green procedure for the preparation of
N-substituted pyrroles would be attractive.
and recyclability. DESs are mainly prepared by mixing quaternary ammo-
nium salt such as choline chloride (ChCl) with hydrogen-bond donors
such as urea, citric acid, and glycerol without any further purification
steps. Moreover, most of materials are ready availability from bulk renew-
able resources. Some organic reactions such as Ugi reaction [18], esterifi-
cation reaction [19], ring opening of epoxides [20], synthesis of aurones
[21], quinolines [22], quinazolines [23], 1,8-dioxo-dodecahydroxanthene
[24], benzopyran derivatives [25], β-functionalized ketonic derivatives
[26], spirooxindoles [27], tetrasubstituted imidazoles [28] as well as re-
ductive amination of aldehydes and ketones [29] have been reported to
proceed using DESs as solvent or catalyst. As part of our ongoing studies
devoted towards the development of novel and environmentally benign
synthetic methodologies [30–40], herein we report L-(+)-tartaric acid–
ChCl as reaction medium and catalyst for the synthesis of N-substituted
pyrroles via Clauson-Kaas reaction (Scheme 1).
Recently, deep eutectic solvents (DESs) have been emerged as new
alternative renewable reaction media or catalyst for the development
of environmentally benign organic transformations [16,17]. The proper-
ties of DESs are similar to that of conventional ionic liquids in terms of
2. Experimental section
2.1. General
All reagents were obtained from local commercial suppliers and
used without further purification. Melting points were determined on
an X-4 apparatus and are uncorrected. NMR spectra were recorded on
a Bruker DRX-500 spectrometer at 500 MHz (1H) and 125 MHz (13C)
⁎
Corresponding author. Fax: +86 31180787431.
E-mail addresses: zhanhui@mail.hebtu.edu.cn, zhanhui@mail.nankai.edu.cn
(Z.-H. Zhang).
http://dx.doi.org/10.1016/j.molliq.2014.07.015
0167-7322/© 2014 Elsevier B.V. All rights reserved.

260
P. Wang et al. / Journal of Molecular Liquids 198 (2014) 259–262
ppm; 13C NMR (CDCl3, 125 MHz) δ: 24.7, 28.1, 108.4, 123.1, 123.4, 128.9,
137.1, 147.1 ppm; ESI-MS: m/z = 228 (M + 1)+.
1-(4-(tert-Butyl)phenyl)-1H-pyrrole (3j). 1H NMR (CDCl3, 500 MHz)
δ: 1.35 (s, 9H), 6.34 (t, J = 2.0 Hz, 2H), 7.07 (t, J = 2.0 Hz, 2H), 7.33
(d, J = 7.0 Hz, 2H), 7.44 (d, J = 7.0 Hz, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ: 31.4, 34.5, 110.1, 119.4, 120.3, 126.4, 138.4, 148.7 ppm;
ESI-MS: m/z = 200 (M + 1)+.
Scheme 1. Synthesis of N-substituted pyrroles via Clauson-Kaas reactions in DES.
1-(2-Fluorophenyl)-1H-pyrrole (3k). 1H NMR (CDCl3, 500 MHz) δ:
6.38 (t, J = 2.0 Hz, 2H), 7.06 (t, J = 2.0 Hz, 2H), 7.19–7.26 (mk, 3H), 7.41
(t, J = 8.0 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 110.1, 117.1 (d,
using CDCl3 as the solvent with TMS as internal standard. Mass spectra
were operated at a ThermoFinnigan LCQ Advantage instrument with an
ESI source (4.5 keV).
4
4
2JFC = 20.3 Hz), 121.4 (d, JFC = 3.5 Hz), 124.8 (d, JFC = 3.8 Hz),
125.0, 127.2 (d, 3JFC = 7.9 Hz), 129.1 (d, 3JFC = 10.4 Hz), 155.1 (d, 1JFC
=
247.8 Hz) ppm; ESI-MS: m/z = 162 (M + 1)+.
2.2. Typical procedure for the preparation of N-substituted pyrroles
1-(4-Fluorophenyl)-1H-pyrrole (3l). 1H NMR (CDCl3, 500 MHz) δ:
6.35 (t, J = 2.0 Hz, 2H), 7.02 (t, J = 2.0 Hz, 2H), 7.12 (t, J = 8.5 Hz,
2H), 7.35 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 110.5, 116.3 (d, 2JFC = 22.6 Hz), 119.6, 122.3 (d,
3JFC = 8.1 Hz), 137.2, 160.7 (d, 1JFC = 243.2 Hz) ppm; ESI-MS: m/z =
162 (M + 1)+.
Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)
and L-(+)-tartaric acid–choline chloride based DES (1.5 g) were
added to a 50 mL round bottom flask and the reaction mixture
was stirred at 90 °C. The progress of the reaction was monitored
by TLC. After completion of the reaction, the mixture was cooled
to room temperature and the product was extracted with ethyl acetate.
After the evaporation of the solvent, the residue was purified by column
chromatography on silica gel to afford the pure product. The DES was
dried under vacuum and reused for the next cycle.
1-(3-Chlorophenyl)-1H-pyrrole (3m). 1H NMR (CDCl3, 500 MHz) δ:
6.30 (t, J = 2.0 Hz, 2H), 6.99 (t, J = 2.0 Hz, 2H), 7.12–7.20 (m, 2H),
7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 141.5, 135.0, 130.4, 125.3, 120.4, 119.0, 118.1,
110.8 ppm; ESI-MS: m/z = 179 (M + 1)+.
1-(4-Chlorophenyl)-1H-pyrrole (3n). 1H NMR (CDCl3, 500 MHz) δ:
6.36 (t, J = 2.0 Hz, 2H), 7.05 (t, J = 2.0 Hz, 2H), 7.33 (d, J = 8.5 Hz,
2H), 7.39 (d, J = 8.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ:
110.9, 119.3, 121.6, 129.7, 131.1, 139.4 ppm; ESI-MS: m/z = 179
2.3. Spectra data of the products
1-Phenyl-1H-pyrrole (3a). 1H NMR (CDCl3, 500 MHz) δ: 6.36 (t, J =
2.0 Hz, 2H), 7.10 (t, J = 2.0 Hz, 2H), 7.24–7.26 (m, 1H), 7.40–7.45 (m,
4H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 110.5, 119.4, 120.6, 125.7,
129.6, 140.9 ppm; ESI-MS: m/z = 144 (M + 1)+.
(M + 1)+
.
1-(2-Bromophenyl)-1H-pyrrole (3o). 1H NMR (CDCl3, 500 MHz) δ:
6.34 (t, J = 2.0 Hz, 2H), 6.99 (t, J = 2.0 Hz, 2H), 7.24 (td, J = 8.5, 1.5 Hz,
1H), 7.33 (dd, J = 8.5, 1.5 Hz, 1H), 7.39 (td, J = 8.5, 1.5 Hz, 1H), 7.69 (dd,
J = 8.5, 1.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 109.2, 119.8,
3-(1H-Pyrrol-1-yl)phenol (3b). 1H NMR (CDCl3, 500 MHz) δ: 4.88
(brs, 1H), 6.34 (t, J = 2.0 Hz, 2H), 6.70 (dd, J = 8.0 Hz, 2.0 Hz, 1H),
6.89 (t, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.07 (t, J =
2.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz)
δ: 107.9, 110.7, 127.8, 113.1, 119.5, 130.8, 142.2, 156.6 ppm; ESI-MS:
m/z = 160 (M + 1)+.
122.2, 128.1, 128.3, 133.7, 140.4 ppm; ESI-MS: m/z = 223 (M + 1)+
.
1-(3-Bromophenyl)-1H-pyrrole (3p). 1H NMR (CDCl3, 500 MHz) δ:
6.35 (s, 2H), 7.06 (s, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz,
1H), 7.36 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H) ppm; 13C NMR (CDCl3,
125 MHz) δ: 111.1, 118.9, 119.3, 123.2, 123.5, 128.6, 130.9,
141.9 ppm; ESI-MS: m/z = 223 (M + 1)+.
1-(2-Methoxyphenyl)-1H-pyrrole (3c). 1H NMR (CDCl3, 500 MHz) δ:
3.85 (s, 3H), 6.34 (s, 2H), 7.01–7.05 (m, 4H), 7.28–7.32 (m, 2H) ppm;
13C NMR (CDCl3, 125 MHz) δ: 55.7, 108.7, 112.2, 120.8, 121.9, 125.6,
127.4, 130.2, 152.6 ppm; ESI-MS: m/z = 174 (M + 1)+.
1-(4-Bromophenyl)-1H-pyrrole (3q). 1H NMR (CDCl3, 500 MHz) δ:
6.40 (s, 2H), 7.14 (s, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz,
2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 111.6, 119.1, 119.9, 126.9,
143.2 ppm; ESI-MS: m/z = 223 (M + 1)+.
1-(4-Methoxyphenyl)-1H-pyrrole (3d). 1H NMR (CDCl3, 500 MHz)
δ: 3.84 (s, 3H), 6.32 (t, J = 2.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 7.00
(t, J = 2.0 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ: 55.6, 109.8, 114.6, 119.7, 122.2, 134.5, 157.7 ppm;
1-(4-Iodophenyl)-1H-pyrrole (3r). IR (KBr): 3130, 1587, 1496,
1409, 1330, 1247, 1126, 1078, 1001, 920, 815, 729 cm−1 1H NMR
;
ESI-MS: m/z = 174 (M + 1)+
.
(CDCl3, 500 MHz) δ: 6.36 (t, J = 2.0 Hz, 2H), 7.05 (t, J = 2.0 Hz, 2H),
7.15 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 89.4, 111.0, 119.1, 122.2, 138.6, 140.4 ppm; ESI-
MS: m/z = 270 (M + 1)+.
1-(2-Tolyl)-1H-pyrrole (3e). 1H NMR (CDCl3, 500 MHz) δ: 2.25 (s,
3H), 6.35 (t, J = 2.0 Hz, 2H), 6.83 (t, J = 2.0 Hz, 2H), 7.27–7.32 (m,
4H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 17.7, 108.6, 121.9, 126.4, 126.5,
127.4, 130.9, 133.6, 140.5 ppm; ESI-MS: m/z = 158 (M + 1)+.
1-(4-Tolyl)-1H-pyrrole (3f). 1H NMR (CDCl3, 500 MHz) δ: 2.38 (s, 3H),
6.34 (t, J = 2.0 Hz, 2H), 7.06 (t, J = 2.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H),
7.29 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 20.9, 110.2,
119.5, 120.6, 130.1, 135.4, 138.6 ppm; ESI-MS: m/z = 158 (M + 1)+.
1-(2,5-Dimethylphenyl)-1H-pyrrole (3g). 1H NMR (CDCl3, 500 MHz)
δ: 2.34 (s, 3H), 2.51 (s, 3H), 6.49 (t, J = 2.0 Hz, 2H), 6.62 (t, J = 2.0 Hz,
2H), 7.25 (s, 2H), 7.33 (s, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ:
17.6, 20.9, 108.8, 122.1, 127.4, 128.3, 130.6, 131.0, 136.4, 140.6 ppm;
ESI-MS: m/z = 172 (M + 1)+.
1-(3-Nitrophenyl)-1H-pyrrole (3s). 1H NMR (CDCl3, 500 MHz) δ:
6.38 (t, J = 2.0 Hz, 2H), 6.82 (t, J = 2.0 Hz, 2H), 7.46-7.49 (m, 2H),
7.65 (t, J = 8.5 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 145.0, 133.9, 133.0, 127.6, 127.5, 124.7, 121.1,
110.8 ppm; ESI-MS: m/z = 189 (M + 1)+.
1-(4-Nitrophenyl)-1H-pyrrole (3t). 1H NMR (CDCl3, 500 MHz) δ: 6.43
(t, J = 2.0 Hz, 2H), 7.18 (t, J = 2.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 8.31
(d, J = 9.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 112.6, 119.1,
119.4, 125.6, 144.7, 145.2 ppm; ESI-MS: m/z = 189 (M + 1)+.
1-(4-(1H-pyrrol-1-yl)phenyl)ethanone (3u). 1H NMR (CDCl3, 500
MHz) δ: 2.62 (s, 3H), 6.39 (t, J = 2.0 Hz, 2H), 7.17 (t, J = 2.0 Hz, 2H),
7.47 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 26.6, 111.7, 119.0, 119.3, 130.2, 133.9, 144.0,
196.8 ppm; ESI-MS: m/z = 186 (M + 1)+.
1-(2,6-Dimethylphenyl)-1H-pyrrole (3h). 1H NMR (CDCl3, 500 MHz)
δ: 2.05 (s, 6H), 6.33 (s, 2H), 6.62 (s, 2H), 7.13 (d, J = 7.5 Hz, 2H), 7.21
(t, J = 7.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 17.4, 108.6,
121.4, 128.0, 136.3, 140.0 ppm; ESI-MS: m/z = 172 (M + 1)+.
1-(2,6-Diisopropylphenyl)-1H-pyrrole (3i). 1H NMR (CDCl3, 500 MHz)
δ: 1.14 (d, J = 7.0 Hz, 12H), 2.39-2.48 (m, 1H), 6.32 (t, J = 2.0 Hz, 2H),
6.64 (t, J = 2.0 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H)
1-(3-(Trifluoromethyl)phenyl)-1H-pyrrole (3v). 1H NMR (CDCl3,
500 MHz) δ: 6.39 (t, J = 2.5 Hz, 2H), 7.11 (t, J = 2.0 Hz, 2H), 7.50
(d, J = 7.5 Hz, 1H), 7.53-7.58 (m, 2H), 7.63 (s, 1H) ppm; 13C NMR

P. Wang et al. / Journal of Molecular Liquids 198 (2014) 259–262
261
(CDCl3, 125 MHz) δ: 111.4, 117.1 (q, 3JFC = 4.0 Hz), 119.2, 122.1 (q, 3JFC
=
detected when the reaction was performed in low-melting mixtures,
such as D-(−)-fructose-N,N-dimethylurea (DMU), lactose–DMU–
NH4Cl, glucose–urea–CaCl2, glucose–urea–NaCl, sucrose–choline
chloride and glucose–guanidinium HCl at their minimal melting tem-
perature. When the reaction was conducted in mannose–DMU–NH4Cl,
the yield of desired product could be improved to 25% (Table 1, entry
8). Consider this reaction works well under acidic conditions, some
acidic medium was investigated in order to obtain more satisfactory re-
sults. To our great delight, a significant improvement was observed
when deep eutectic solvents such as L-(+)-tartaric acid–DMU and citric
acid–DMU were used as the reaction medium (entries 9 and 10).
Screening revealed that the use of L-(+)-tartaric acid–ChCl melt
produced the best result (entry 11). In contrast, the reaction did not pro-
ceed in organic solvents such as MeOH, EtOH and MeCN in the presence
of a catalytic amount of L-(+)-tartaric acid–ChCl (10 mol%) (entries 12–
14).
In order to demonstrate the practical applicability of this process, the
model reaction was carried out in a scale of 50 mmol. The reaction was
completed in 1 h with 94% yield (entry 15). On the same scale, the
recyclability of deep eutectic solvent was investigated. After completion
of the reaction, the mixture was cooled to room temperature and the
product was extracted with ethyl acetate. The DES was dried under
vacuum and subjected to the next cycles without further purification.
The results of five runs showed almost consistent yields (entry 16).
Having obtained satisfactory results, the substrate scope and gener-
ality of this novel process were evaluated under the above optimized
conditions and the typical results are presented in Table 2. Anilines con-
taining different substituents such as OH, OMe, Me, F, Cl, Br, NO2, Ac and
CF3 were smoothly reacted with tetrahydro-2,5-dimethoxyfuran to pro-
vide expected N-substituted pyrroles in good to excellent yields. The
electronic properties of the substituents on the phenyl ring of anilines
had a little effect on the reaction. In general, anilines bearing an
electron-donating group produced a slightly higher yield of products
than those analogues bearing electron-withdrawing group. The steric
effect of substituents had an obvious impact on the yield of the reaction.
For example, Clauson-Kaas reaction of tetrahydro-2,5-dimethoxyfuran
with para-, meta- and ortho-bromoaniline provided 86% of 3p and
89% of 3q, while the yield of 3o was decreased to 79% (Table 2,
entries 15–17). The same phenomenon was observed in the reaction of
tetrahydro-2,5-dimethoxyfuran with para- and ortho-methoxyaniline
(entries 3 and 4). Moreover, naphthylamine was proved applicable for
this reaction, generating the desired product in 94% yield (Table 2,
3.6 Hz), 123.4, 123.9 (q, 1JFC = 270.8 Hz), 130.3, 132.2 (q, 2JFC = 32.5 Hz),
141.2 ppm; ESI-MS: m/z = 212 (M + 1)+.
1-(4-(Trifluoromethyl)phenyl)-1H-pyrrole (3w). 1H NMR (CDCl3, 500
MHz) δ: 6.40 (t, J = 2.0 Hz, 2H), 7.14 (t, J = 2.0 Hz, 2H), 7.50 (d, J =
8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz)
1
3
δ: 111.5, 119.1, 119.9, 124.1 (q, JFC = 270.0 Hz), 126.9 (q, JFC
=
2
3.6 Hz), 127.4 (q, JFC = 32.8 Hz), 143.2 ppm; ESI-MS: m/z = 212
(M + 1)+
.
Ethyl 4-(1H-pyrrol-1-yl)benzoate (3x). 1H NMR (CDCl3, 500 MHz) δ:
1.41 (t, J = 7.0 Hz, 3H), 4.39 (q, J = 7.0 Hz, 2H), 6.39 (t, J = 2.5 Hz, 2H),
7.16 (t, J = 2.5 Hz, 2H), 7.45(d, J = 8.5 Hz, 2H), 8.11(d, J = 8.5 Hz, 2H)
ppm; 13C NMR (CDCl3, 125 MHz) δ: 14.4, 61.1, 111.5, 119.1, 119.3, 127.3,
131.3, 143.9, 166.0 ppm; ESI-MS: m/z = 216 (M + 1)+.
1-(Naphthalen-1-yl)-1H-pyrrole (3y). 1H NMR (CDCl3, 500 MHz) δ:
6.45 (t, J = 2.0 Hz, 2H), 7.04 (t, J = 2.0 Hz, 2H), 7.49–7.57 (m, 4H),
7.80 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.95 (d, J =
8.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 109.3, 123.3,
123.4, 125.4, 126.7, 127.1, 128.0, 128.3, 130.0, 134.4, 138.4 ppm;
ESI-MS: m/z = 194 (M + 1)+
.
2-(1H-Pyrrol-1-yl)pyridine (3z). 1H NMR (CDCl3, 500 MHz) δ: 6.45 (t,
J = 2.0 Hz, 2H), 7.12 (dd, J = 8.0, 5.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H),
7.61 (t, J = 2.0 Hz, 2H), 7.74 (td, J = 8.0, 1.5 Hz, 1H), 8.48 (dd, J = 5.0,
1.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 111.3, 111.5, 118.1,
120.2, 138.5, 148.7, 151.3 ppm; ESI-MS: m/z = 145 (M + 1)+.
2-(1H-pyrrol-1-yl)pyrimidine (3aa). 1H NMR (CDCl3, 500 MHz) δ:
6.34 (t, J = 2.5 Hz, 2H), 7.05 (t, J = 4.5 Hz, 1H), 7.78 (t, J = 2.5 Hz,
2H), 8.62 (d, J = 4.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ:
112.0, 117.1, 119.1, 158.4 ppm; ESI-MS: m/z = 146 (M + 1)+; Anal.
Calcd for C8H7N3: C, C, 66.19; H, 4.86; N, 28.95. Found: C, 66.01; H,
5.02; N, 29.13.
4-(1H-pyrrol-1-yl)aniline (3ab). 1H NMR (CDCl3, 500 MHz) δ: 3.68
(br s, 2H), 6.30 (t, J = 2.0 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.97
(t, J = 2.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 109.5, 115.7, 119.7, 122.4, 133.0, 144.5 ppm;
ESI-MS: m/z = 159 (M + 1)+
.
3. Results and discussion
The examination of the reaction conditions commenced with the re-
action of aniline and 2,5-dimethoxytetrahydrofuran as model reaction.
As shown in Table 1, only a trace amount of the target product was
Table 1
Optimization of the reaction conditionsa.
Entry
Solvent
No
Temperature (°C)
Time (min)
Yield (%)b
1
2
100
71
240
120
21
trace
D-(−)-Fructose–DMU (70:30)
Lactose–DMU–NH4Cl (50:40:10)
Glucose–urea–CaCl2 (50:40:10)
Glucose–urea–NaCl (60:30:20)
Sucrose–ChCl (50:50)
3
4
5
6
7
8
9
88
75
78
80
70
73
70
160
180
180
180
180
110
60
trace
trace
trace
trace
trace
25
Glucose–guanidinium HCl (40:60)
Mannose–DMU–NH4Cl (50:40:10)
77
L-(+)-Tartaric acid–DMU (30:70)
Citric acid–DMU (40:60)
10
11
65
90
60
50
86
95
L-(+)-Tartaric acid–ChCl (50:50)
12c
13c
14c
15d
MeOH
EtOH
MeCN
reflux
reflux
reflux
90
60
60
60
60
trace
trace
trace
94
L-(+)-Tartaric acid–ChCl (50:50)
L-(+)-Tartaric acid–ChCl (50:50)
16e
90
50
95, 93, 92, 91, 90
a
Reaction conditions: aniline (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol), solvent (1.5 g).
Isolated yields.
The reaction was carried out in the presence of L-(+)-tartaric acid–ChCl (10 mol%), organic solvent (3 mL).
The reaction was carried out in 50 mmol scale.
b
c
d
e
L-(+)-Tartaric acid–ChCl was reused for 5 times.

262
P. Wang et al. / Journal of Molecular Liquids 198 (2014) 259–262
Table 2
Synthesis of N-substituted pyrroles in L-(+)-tartaric acid–ChCl.
Entry
Amine
Product
Time (min)
Yield (%)a
Mp (°C)
1
2
3
4
5
6
7
8
PhNH2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
50
50
40
30
40
30
60
80
100
90
90
80
80
80
100
80
80
95
92
89
95
90
95
89
86
76
92
83
86
85
83
79
86
89
82
78
89
88
83
90
90
94
75
85
93
60–61
62–63
Oil
111–112
Oil
82–83
52–53
46–47
76–77
71–72
Oil
51–52
50–51
87–88
Oil
81–82
93–94
130–131
Oil
187–188
120–121
48–49
112–113
76–77
Oil
3-OHC6H5NH2
2-OCH3C6H5NH2
4-OCH3C6H5NH2
2-CH3C6H4NH2
4-CH3C6H4NH2
2,5-Me2C6H3NH2
2,6-Me2C6H3NH2
2,6-iPr2C6H3NH2
4-tBuC6H4NH2
2-FC6H4NH2
4-FC6H4NH2
3-ClC6H4NH2
4-ClC6H4NH2
2-BrC6H4NH2
3-BrC6H4NH2
4-BrC6H4NH2
4-IC6H4NH2
2-NO2C6H4NH2
4-NO2C6H4NH2
4-AcC6H4NH2
3-CF3C6H4NH2
4-CF3C6H4NH2
4-COOEtC6H4NH2
Naphthalen-1-amine
Pyridin-2-amine
Pyrimidin-2-amine
Benzene-1,4-diamine
Scheme 3. Plausible reaction mechanism.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Acknowledgments
Financial support from the National Natural Science Foundation of
China (Nos. 21272053 and 21072042) is greatly appreciated.
References
90
3s
3t
110
100
80
90
90
80
60
120
80
100
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acetonylacetone proceeded well, and the desired product 5 could also
be obtained in 95% yield.
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form intermediate 6. Next, the reaction of intermediate 4 with amines 1
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pulsion of MeOH, dehydration, and intramolecule aromatization steps. In
this process, the acidity of the DES may play an important role for the
deprotection of methoxy groups. The hydrogen bonding interactions
between DES and aromatic amino group might assist in improving the
nucleophilicity of aromatic amine 1 leading to its faster attack on interme-
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In summary, we have developed a simple, greener and efficient pro-
cedure for the synthesis of N-substituted pyrroles by Clauson-Kaas reac-
tion of amines and 2,5-dimethoxytetrahydrofuran using a deep eutectic
mixture as a novel and green medium. The present protocol offers some
advantages such as operational simplicity, metal-free, wide range of
substrates, high yields and environmentally benign reaction conditions.
Scheme 2. Synthesis of substituted pyrroles via Paal–Knorr reactions in DES.