Recyclable fluorous organocatalysts promoted three-component reactions of pyruvate, aldehyde and amine at room temperature

Article abstract of DOI:10.1016/j.tetlet.2013.10.058

A new fluorous imine carbothioate has been prepared as an organocatalyst for the synthesis of pyrrol-2-ones via the cyclo-condensation reaction of aldehydes, amines, and pyruvate at room temperature. The fluorous catalyst can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for next run reaction without further purification.

Full text of DOI:10.1016/j.tetlet.2013.10.058

Tetrahedron Letters 54 (2013) 7100–7102
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Recyclable fluorous organocatalysts promoted three-component
reactions of pyruvate, aldehyde and amine at room temperature
⇑
Jin-long Qian, Wen-bin Yi , Chun Cai
Chemical Engineering College, Nanjing University of Science and Technology, 200 Xiaolingwei, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2013
Revised 4 October 2013
Accepted 14 October 2013
Available online 20 October 2013
A new fluorous imine carbothioate has been prepared as an organocatalyst for the synthesis of pyrrol-2-
ones via the cyclo-condensation reaction of aldehydes, amines, and pyruvate at room temperature. The
fluorous catalyst can be easily recovered from the reaction mixture by simple fluorous solid-phase
extraction (F-SPE) and used for next run reaction without further purification.
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Keywords:
Fluorous organocatalyst
Pyrrol-2-ones
Multi-component reaction
Introduction
a
-oxo esters,3a or three-component reaction of amines, aldehyde,
and pyruvate. H2SO4,3a thiourea,3c phosphoric acid analogs,3c
SiO2–FeCl3,3b and triethylammonium hydrogen sulfate3d have been
used as the catalysts for the three-component transformations. As
part of our continuous efforts toward the development of metal-
free and recyclable fluorous organocatalyst for green chemistry
applications,9,10 we recently reported a series of fluorous thiourea
derivates for organic synthesis application.11
1,5-Dihydro-2H-pyrrol-2-ones, particularly their 3-amino-
substituted derivatives are found in many natural products.1–4 As
shown in Figure 1, those are selected biologically interesting pyr-
rol-2-one molecules including lipopeptides microcolin A and B,5
dithiolopyrrolones,6 and peptide deformylase inhibitors.7 Typi-
cally, the synthesis of pyrrol-2-ones can be accomplished by con-
densation of amines, pyrrolidine-2,3-diones,8 and b,
c
-unsaturated
OH
O
N
O
NH
O
N
CH3
N
CH3
O
O
N
N
MeO2C
OAc
O
O
peptide deformylase inhibitors
lipopeptides microcolin A
H
O
H
O
O
N
R
O
N
CH3
N
S
O
S
O
O
N
OAc
O
N
H3C
H3C
dithiolopyrrolones
lipopeptides microcolin B
Figure 1. Some selected biologically interesting pyrrol-2-ones.
⇑
Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: yiwenbin@mail.njust.edu.cn (W.-b. Yi).
0040-4039/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.058

J. Qian et al. / Tetrahedron Letters 54 (2013) 7100–7102
7101
X
tries 4, 12–14). As revealed in Table 1, the reaction of methyl pyru-
vate, benzaldehyde, and aniline was very sluggish in the absence of
any catalysts, affording only 10% yield after 24 h. The use of
5 mol % C1 in MeCN gave 90% yield, indicating superior catalytic
activity (entries 2–5). For the reaction with C1, no significant
improvement was observed by increasing reaction time or amount
of catalyst (entires 4 and 5).
X
HO
(CF2)5CF3
(CF2)5CF3
N
O
O
N
N
N
N
N
THF, RT. 12 h
X
X
NH4Cl
NEt3
F3C(F2C)5
(CF2)5CF3
N
H
O
C1
C2
X=S,
X=O
Further investigations indicated that the catalysis of C1 was
highly efficient. Moderate to excellent yields were obtained in
the solvents such as MeCN, MeOH, and C2H5OH. We also compared
C1 and C20s non-fluorous counterparts (C10 and C20) in the model
reaction with their fluorous structures (entries 12–14), and found
the non-fluorous version afforded a lower yield (44% vs 90%; 32%
vs 48%). The fluorous ponytail helped to recycle the catalysts and
probably contributed to generate the H+ in the reaction with its
electron-withdrawing property. A pKa value detection experiment
was used to prove this assumption.3c It was found that a correla-
tion between the catalytic activity of the catalyst and its corre-
sponding pKa is evident, with lower pKa values, that is, higher
acidity, leading to better yields.
Under the optimized conditions, reactions were performed with
C1 to explore the substrate scope with regard to the pyruvates,
aldehydes, and amines (Table 2). As expected, the organocatalyst
C1 worked well for this reaction except for those aromatic amines
containing electron-withdrawing groups or aliphatic amines (en-
tries 9–11, 13, 14). In all cases, aromatic aldehydes gave higher
yields than aliphatic aldehydes. The substituent group of pyruvate
showed low effect for this reaction (entries 11-15). Aliphatic alde-
hydes reacted with aromatic amines smoothly in medium yields
(entries 7, 15).
Scheme 1. Preparation of fluorous organocatalysts C1 and C2.
Herein, we report a novel fluorous imine-1,10-bis(carbothioate)
C1 and fluorous imine-1,10-dicarboxylate C2 (Scheme 1) for the
synthesis of 1,5-dihydro-2H-pyrrol-2-ones. The synthesis was ob-
tained by one-pot multi-component synthesis, which is an atom
economic way to prepare molecules with substitution and skeleton
diversities;12 it eliminates waste generated from intermediate
purifications; and is a favorable approach for green organic synthe-
sis.13 The fluorous imine-1,10-bis(carbothioate) C1 demonstrated
superior catalytic activity and efficiency under room temperature,
and could be easily recovered by fluorous solid-phase extraction
(F-SPE).
Results and discussions
The organocatalysts fluorous imine-1,10-bis(carbothioate) C1
and fluorous imine-1,10-dicarboxylate C2 were synthesized using
di(1H-imidazol-1-yl)methanethione or di(1H-imidazol-1-yl)meth-
anone I and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol II as
the starting materials (Scheme 1). The compounds C1 and C2 could
be easily isolated and purified by fluorous-solid phase extraction
(F-SPE) with a cartridge charged with fluorous silica gels.14 The cat-
alysts are stable in air and soluble in various solvents such as THF,
CH3OH, CH3Cl, and CH3CN.
Initially, we selected the reaction of benzaldehyde, aniline, and
methyl pyruvate as the model reaction to optimize the reaction
conditions (Table 1). Different solvents were screened, and acetoni-
trile is the best choice in the reaction (entries 4, 6–11). We also
tested different catalysts and catalyst C1 was the best choice (en-
To estimate the efficiency and generality of this methodology,
the result obtained by this method was compared with fluorous
thiourea and hydrazine, and also with some previously reported
cases. It was found that the present method is convincingly supe-
rior in terms of reaction time and product yield (Table 3).
The reusability of the catalyst C1 was tested in the synthesis of
1,5-diphenyl-3-(phenylamino)-1H-pyrrol-2(5H)-one, as shown in
Figure 2. The catalyst was recovered after each run, separated by
Table 2
Synthesis of 1,5-Dihydro-2H-pyrrol-2-one derivatives using C1 as catalysta
Table 1
Optimized reaction conditions in the synthesis of 1,5-diphenyl-3-(phenylamino)-1H-
R3
N
pyrrol-2(5H)-oneb
O
R2
Ph
N
C1
O
OR1
R2 CHO
R3 NH2
Ph
O
Na2SO4
MeCN, RT
CHO
NH2
Cat.
O
O
OMe
+
+
NH
R3
RT, 12 h
O
NH
4a-i
Ph
4a
3
2
1
Entry
R1
R2CHO
R3NH2
C6H5
4-CH3C6H4
4-CH3C6H4
C6H5
Yieldb (%)
Product
c
Entry
Cat. (mol %)
Sol
Yielda (%)
pKa
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
C6H5
C6H5
90
93
87
85
92
93
53
82
—
—
—
54
—
—
4a
4b
4d
4e
4i
4c
4f
4h
—
—
—
4f
—
—
1
2
3
4
5
6
7
8
None
C1(1)
C1(2)
C1(5)
C1(10)
C1(5)
C1(5)
C1(5)
C1(5)
C1(5)
C1(5)
C10(5)
C2(5)
C20(5)
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeOH
10
46
67
90
92
65
85
57
61
82
8
—
—
—
7.12
—
—
—
—
—
—
—
8.15
7.84
8.58
4-ClC6H4
4-ClC6H4
4-OCH3C6H4
C6H5
CH3(CH2)2CH2
4-NO2C6H4
C6H5
4-NO2C6H4
CH3(CH2)2CH2
CH3(CH2)2CH2
C6H5
C6H5
4-CH3OC6H4
4-CH3OC6H4
C6H5
4-NO2C6H4
4-NO2C6H4
CH3(CH2)2CH2
4-CH3OC6H4
Cyclohexyl
CH3(CH2)2CH2
C6H5
Toluene
CHCl3
C2H5OH
H2O
9
Me
Me
9
10
11
12
13
14
15
10
11
12
13
14
C2H5
C2H5
C2H5
C2H5
C2H5
MeCN
MeCN
MeCN
44
48
32
C6H5
CH3(CH2)2CH2
41
4g
a
a
Isolated yields based on 2.
The reactions were carried out on a 1 mmol scale in 3 mL of solvents with a
Reaction conditions: The reactions were carried out on a 1 mmol scale in 3 mL
b
of MeCN with a molar ratio of pyruvate/amine/aldehyde/Na2SO4 of 2:2:1:3. All new
compounds were characterized by 1H and 13C NMR spectroscopy.
molar ratio of pyruvate/aniline/benzaldehyde/Na2SO4 of 2:2:1:3.
c
b
Determined in this work with an uncertainty of 0.1.
Isolated yield based on aldehyde.

7102
J. Qian et al. / Tetrahedron Letters 54 (2013) 7100–7102
Table 3
yields. Moreover, the fluorous catalyst could be easily recovered
Comparison among various catalysts
by F-SPE and reused three times without significant loss of activity.
The present methodology offers several advantages, such as excel-
lent yields, mild conditions, and simple procedure, making it more
efficient.
Entry Catalyst
Condition
Yielda
(%)
Refs.
1
2
3
Thiourea
Toluene; rt;
18 h
Toluene; rt;
18 h
CH2Cl2; rt;
48 h
84
84
73
3c
3c
3a
Phosphoric acid
H2SO4
Acknowledgments
We thank the Fundamental Research Funds for the Central Uni-
versities (30920130111002), Jiangsu Provincial Natural Science
Foundation of China for Key Projects (BK2010070) and the National
Natural Science Foundation of China (20902047).
S
H
MeCN; rt;
24 h
O
N
C2H4Rf6
4
80
10
15
Rf6C2H4
S
N
H
O
S
Rf8
Toluene; rt;
24 h
Supplementary data
5
6
88
93
Ph
N
N
H
H
C1
MeCN; rt;
12 h
This
work
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013
.10.058.
a
The yield based on the reaction of benzaldehyde, toluidine, and pyruvate.
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in the subsequent run without being added with fresh catalyst. The
catalyst was tested for 5 runs. It was seen that the catalyst dis-
played strong reusability (Fig. 2).
Conclusion
In summary, we have prepared a series of fluorous organocata-
lysts and successfully applied it for the preparation of pyrrol-2-
ones via the cyclo-condensation reaction of aldehydes, amines,
and pyruvate. The catalyst showed high catalytic activity and the
corresponding products were obtained in moderate to excellent
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