Urea decomposition: Efficient synthesis of pyrroles using the deep eutectic solvent choline chloride/urea

Article abstract of DOI:10.1016/j.tetlet.2018.03.043

A simple and efficient method is reported for the synthesis of pyrroles via condensation of a series of tricarbonyl compounds with ammonia, which was generated in situ from decomposition of the deep eutectic solvent choline chloride/urea.

Full text of DOI:10.1016/j.tetlet.2018.03.043

Accepted Manuscript
Urea Decomposition: Efficient Synthesis of Pyrroles Using the Deep Eutectic
Solvent Choline Chloride/Urea
Lanfang Hu, Juan Luo, Dan Lu, Qiang Tang
PII:
S0040-4039(18)30357-5
https://doi.org/10.1016/j.tetlet.2018.03.043
TETL 49812
DOI:
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 January 2018
10 March 2018
15 March 2018
Please cite this article as: Hu, L., Luo, J., Lu, D., Tang, Q., Urea Decomposition: Efficient Synthesis of Pyrroles
Using the Deep Eutectic Solvent Choline Chloride/Urea, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.043
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Urea Decomposition: Efficient Synthesis of Pyrroles Using the Deep Eutectic Solvent
Choline Chloride/Urea
a
Lanfang Hu, Juan Luo, Dan Lu, Qiang Tang *
a
a
a
a
College of Pharmacy, Faculty of Laboratory Medicine, Chongqing Research Center for Pharmaceutical Engineering, Chongqing Key Laboratory of
Biochemistry and Molecular Pharmacology, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, P. R. China
Corresponding author: e-mail address: tangqiang@cqmu.edu.cn (Q. Tang).
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient method is reported for the synthesis of pyrroles via condensation of a
series of tricarbonyl compounds with ammonia, which was generated in situ from
decomposition of the deep eutectic solvent choline chloride/urea.
Received in revised form
Accepted
2
017 Published by Elsevier Ltd.
Available online
Keywords:
Deep eutectic solvents
Decomposition
Urea
Choline Chloride
Pyrrole
In recent years, deep eutectic solvents (DES), a low-cost and
environmentally benign solvent system, have attracted significant
also reported that the partial decomposition of urea in DES took
o 17
place at 80 C in the presence of transition metal salts.
1
attention. DES are mixtures of two components; one of them a
hydrogen bond donor (HBD) and the other a hydrogen bond
Recently, we reported several methods for the synthesis of
para-carbonyl compounds. In an attempt at developing efficient
18
2
accepter (HBA). The HBA is usually a phosphonium or
19
condensation conditions, we conducted the Paal–Knorr furan
3
quaternary ammonium salt, while the HBD are typically acids,
1b
4
1a
alcohols, amines, amides,
1c
synthesis using tri-carbonyl compounds in the eutectic mixture of
choline chloride/urea. Surprisingly, and without the addition of
ammonia, this reaction afforded the corresponding pyrrole.
Therefore, it was reasonable to infer that ammonia as a reactant
could be generated in situ from the decomposition of urea in DES.
or carbohydrates.
hydrogen bond interactions between them, DES possess a
Due to
5
freezing point much lower than that of either component.
DES offer some notable advantages when compared with
traditional solvents, including low volatility, wide thermal and
electrical windows, water tolerance, biodegradability,
renewability, low toxicity, wide liquid temperature range, and
high solvation ability for a large number of organic or inorganic
compounds. Furthermore, their properties such as freezing point,
conductivity and viscosity can be fine-tuned by appropriate
selection of the mixture components. Due to these advantages,
the applications of DES have increased progressively in the fields
Thus, we began by examining the stability of different ureas in
DES (Table 1). When triketone 1a was stirred at 40 °C for 24
hours using the eutectic mixture of choline chloride/urea as
solvent, trace amounts of pyrrole 3a was detected by TLC (Entry
1
). However the condensation reaction proceeded efficiently
when the temperature was increased to 100 °C. Triketone 1a was
completely transformed into pyrrole 3a in 12 hours without any
furan product detected (Entry 2). No reaction occurred using the
eutectic mixture of choline chloride/glycerol and one equivalent
of urea to react with triketone 1a at reaction temperatures lower
6
1a, 7
8
of electrochemistry, synthesis,
biotransformation, separation
9 10
processes, and material preparation. The DES based on choline
chloride and urea was developed firstly by Abbott and co-
o
11
than 80 C. When the temperature was increased, both pyrrole
workers. Both choline chloride and urea are biodegradable,
1
2
and furan products were obtained (Entry 3). Furthermore, no
pyrrole or furan product was detected when the DES was
replaced with other solvents, even when the reaction was stirred
at reflux for extended periods (Entry 4). However, trace amounts
of the pyrrole product was detected when the reaction was carried
nontoxic, and readily available components. Previously, the
choline chloride based DES was reported as an efficient
dehydrating medium for the preparation of pyrroles from amines
13
and 1,4-diketones.
o
Despite the applications of DES, their stability has been
out at 120 C using DMSO as solvent (Entry 5). Other ureas were
1
seldom studied. The thermal decomposition temperature for an
4
also examined (Entries 6-7) using the eutectic mixture of choline
chloride/glycerol as solvent. Ureas 2b and 2c both produced the
corresponding pyrrole and furan when the reaction mixtures were
o
16
urea containing DES system is over 200 C. However, it was

2
Tetrahedron
3
o
stirred at 120 C. It should be noted that 1,3-
8
75
diphenylurea was also produced in the reaction using 1-
phenylurea 2c, which might have resulted from the decompositio
n of 2c (Entry 7).
4
5
8
8
67
86
Table 1. Model reaction optimization.
6
7
8
8
78
74
o
Entry
Urea
Solvent
C
3a
a
4a
[%]
a
[
%]
b
c
f
--
1
2
3
--
CC/U
40
trace
75
b
c
f
--
--
CC/U
100
120
d
CC/G
58
27
8
9
8
4
4
71
93
90
e
f
f
4
5
6
Solvents
DMSO
reflux
120
--
--
f
--
trace
trace
d
CC/G
120
62
10
d
g
64
7
CC/G
120
trace
1
1
4
8
82
44
a
b
c
d
Isolated yield; Without urea; Choline chloride:urea (1:2); Choline
e
chloride:glycerol (1:2); Solvents: CH
f
Cl, and toluene; Not
2
Cl
2
, ClCH
2
CH
2
g
detected; 1,3-diphenylurea was detected.
Next, we examined the scope of tri-carbonyl compounds in
the condensation reaction with ammonia generated in situ from
the eutectic mixture of choline chloride/urea (Table 2). The
condensation reactions of triketones 1a-h proceeded smoothly
and produced 2a-h in moderate to good yields at 100 C (Entries
1
12
13
o
8
8
80
77
-8). The reactions for triketones 1i-k, however, were faster
Entries 9-11). Pyrrole products could be detected when the
(
reaction mixture was stirred at room temperature. Elevating the
14
o
temperature to 60 C, triketones could be completely transformed
to pyrroles with high yields after four hours. Surprisingly,
decreased reactivity was observed for substrate 1l (Entries 12)
a
o
and a poor yield was obtained at 100 C. When the reaction
Reagents and conditions: tri-carbonyl (1.0 mmol), choline
o
b
chloride/urea (2 mL), 100 C; Isolated yield.
o
temperature was lower than 60 C, no reaction occurred, while
o
when it was raised to 120 C, there was significant by-product
In conclusion, we report that the decomposition of ureas in
DES is a temperature dependent reaction. Without the addition of
ammonia, pyrroles were formed efficiently by stirring tri-
carbonyl compounds in the eutectic mixture of choline
chloride/urea.
formation. Substrates with an ester group also gave the
corresponding pyrroles (Entries 13-14).
a
Table 2. Scope of tricarbonyl compounds for the pyrrole synthesis
Acknowledgments
We appreciate the financial support from the Fundamental and
Advanced Research Projects of Chongqing City (No.
cstc2014jcyjA10022), and Starting Foundation for Talents
Returning from Overseas of Ministry of Education.
Entry
Ketone
Pyrrole
Time
Yield 3
b
[%]
[h]
1
8
75
O
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O
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Tetrahedron
Graphical Abstract
A series of pyrroles were synthesized by heating tricarbonyl
compounds in the eutectic solvent of choline chloride/urea
without addition of ammonia.
Urea Decomposition: Efficient Synthesis of
Pyrroles Using the Deep Eutectic Solvent
Choline Chloride/Urea
Leave this area blank for abstract info.
Lanfang Hu, Juan Luo, Dan Lu, Qiang Tang

•
•
•
•
Urea decomposition in the eutectic
solvent choline chloride/urea
The thermal stability of urea based
DES
Pyrrole synthesis using DES as an
efficient dehydrating medium
Pyrrole synthesis without addition of
any amine