Catalyst-free multicomponent synthesis of β-mercapto diketones in water

Article abstract of DOI:10.1002/cjoc.201180324

A simple, efficient and eco-friendly route has been developed for the synthesis of β-mercapto diketones via a multicomponent reaction of an aldehyde, acetylacetone and thiol in water. This methodology affords a number of β-mercapto diketone derivatives in

Full text of DOI:10.1002/cjoc.201180324

FULL PAPER
Catalyst-free Multicomponent Synthesis of β-Mercapto
Diketones in Water
Li, Li(李莉)
Liu, Bokai(刘博凯)
Wu, Qi*(吴起)
Lin, Xianfu*(林贤福)
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China
A simple, efficient and eco-friendly route has been developed for the synthesis of β-mercapto diketones via a
multicomponent reaction of an aldehyde, acetylacetone and thiol in water. This methodology affords a number of
β-mercapto diketone derivatives in moderate to good yields.
Keywords catalyst-free, multicomponent reaction, β-mercapto diketone, water chemistry, thiol
Introduction
workup procedure and the inherent environmental and
economical advantages of such processes.5 Fülöp5a re-
ported the application of a modified Ugi reaction in
aqueous medium to construct bi- and tricyclic β-lactam
libraries. Recently, a novel MCR in water was estab-
lished to prepare 2-amino-4-(5-hydroxy-3-methyl-1H-
pyrazol-4-yl)-4H-chromene-3-carbonitrile derivatives.5b
The preparation of sulfur-containing molecules has
become a particular interest in organic synthesis as a
result of their broad applications in organic and medici-
nal chemistry.6 For example, β-mercapto diketone de-
rivatives are an important class of compounds display-
ing remarkable pharmacological properties such as diu-
retic and HIV protease inhibitory activities.7-10 Recently,
several MCRs related to sulfur have been described.11
Kornienko and Magedov11a have reported one-step syn-
thesis of heterocyclic privileged medicinal scaffolds by
a MCR of malononitrile with aldehydes and thiols in
ethanol catalyzed by triethylamine. However, cata-
lyst-free aqueous MCRs related to sulfur have been re-
ported rarely. In 2009, a facile and direct synthetic entry
to rhodanine derivatives via the three-component cou-
pling of carbon disulfide, primary amines, and acety-
lenic esters under neutral conditions in water was re-
ported by Alizadeh.12 Thus, it has been our interest to
develop new methodologies for catalyst-free aqueous
MCRs related to sulfur.
The multicomponent reactions (MCRs) represent a
fascinating tool in organic synthesis.1 There are many
representative examples of these reactions, such as the
Biginelli, Hantzsch, Mannich, Passerini, Strecker and
Ugi reactions, which have the features of atom economy,
bond-forming efficiency, synthetic convergency and
environmental amiability. Judging from numerous re-
cent reports, great efforts have been made to develop
novel catalysts to achieve highly efficient synthesis, or
to develop new substrates to construct more complex
molecules on the basis of traditional classic MCRs.2 At
the same time, efforts have now intensified in the de-
velopment of new MCRs for the synthesis of novel
small molecules.3 Wu et al.3a have described a facile
and efficient route for the synthesis of functionalized
1,2-dihydroisoquinolines via the multicomponent
one-pot reaction of 2-alkynylbenzaldehydes, amines,
zinc dust, allylic bromides, or benzyl bromides cata-
lyzed by Mg(ClO4)2/Cu(OTf)2 in THF/DCE (1,2-di-
chloroethane). Scheidt3b prepared the spiropyrrolidiny-
loxindole compounds through a highly diastereoselec-
tive Cu(I)-catalyzed three-component assembly reaction
involving an imine, diazo-compound and substituted
olefin dipolarophile. However, these MCRs have pre-
dominantly carried out in organic solvents or need the
participation of the catalysts.
Herein, we report a catalyst-free, simple and effi-
cient three-component procedure for the synthesis of
β-mercapto diketones from the corresponding aldehydes
(1), acetylacetone (2) and thiols (3) in water under re-
flux conditions (Scheme 1). Most importantly, after the
reaction was completed, the solid crude products pre-
cipitated, which were easy to separate just followed by
filtration and drying. Besides, the liquid crude products
could be separated simply from water through extrac-
Designing organic reactions in aqueous media is a
very attractive area for organic chemists, since water is
a safe, non-toxic, abundant and eco-friendly solvent.
Moreover, in many cases organic reactions in water ex-
hibit unique reactivity and selectivity, which are differ-
ent from reactions in organic solvents.4 From the per-
spective of green chemistry, attention has recently
turned to the possibility of designing catalyst-free
MCRs using water as a sole solvent owing to an easier
*
E-mail: llc123@zju.edu.cn; Tel.: 0086-0571-87953001; Fax: 0086-0571-87952618
Received December 27, 2010; revised April 1, 2011; accepted May 17, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20704037, 20872130 and 20874086) and the Zhejiang Provincial
Natural Science Foundation (Nos. 2008-Y407086, 2009-Y4080198 and 2010-Z4090225).
1856
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1856— 1862

Catalyst-free Multicomponent Synthesis of β-Mercapto Diketones in Water
tion method. A series of β-mercapto diketones were ob-
reactions.
tained successfully.
For further research, the model reaction (as shown in
Table 2) between 1b, 2 and 3a was performed using
different molar ratio. After optimization of the reaction
conditions (molar ratio 1b/2/3a＝1/2/1), 4b was isolated
with 94% yield (Table 2, Entry 6).
Scheme
1
Catalyst-free three-component synthesis of
β-mercapto diketones
O
O
S
Table 2 Optimization of molar ratio between 1b, 2 and 3aa
O
O
H2O
R1 CHO
+
R2 SH
+
R2
Entry
1b/2/3ab
1/1/1.1
2/1/1.1
2/1/2
Yield c/%
reflux
R1
1
3
2
1
2
3
4
5
6
72
87
73
63
73
94
4
Results and discussion
1/1/2
Initially, to better understand the role of solvents, a
model reaction (as shown in Table 1) between
4-nitrobenzaldehyde (1b), acetylacetone (2) and benzyl
mercaptan (3a) was performed using different solvents
with different properties. There was no product avail-
able in hexane, THF and acetonitrile (Table 1, Entries
1—3). In toluene, only a trace amount of 3-(benzylthio-
(4-nitrophenyl)methyl)pentane-2,4-dione (4b) was ob-
served (Table 1, Entry 4), while nearly equal yields of
the desired product were furnished with 22% and 23%
in DMF and methanol, respectively (Table 1, Entries 5
and 6). When the reaction was carried out in DMSO, the
yield was increased to 33% (Table 1, Entry 7). To our
delight, as an efficient solvent, water showed a superior
advantage in promoting the reaction, and excellent yield
of 94% was achieved (Table 1, Entry 8). So water was
employed as the reaction media for the following
1.2/1.2/1
1/2/1
a
The reaction was performed in water (5 mL) at reflux tempera-
ture for 12 h. b Molar ratio. c Isolated yield.
To explore the generality and scope of this method, a
wide variety of substituted aldehydes and acetylacetone
were reacted with substituted thiols under the aqueous
media reaction procedure. On one hand, as can be seen
from Table 3, the electronic effect of substituents on
aromatic aldehydes has a significant impact on the reac-
tion. The aromatic aldehydes with electron-withdrawing
substituents enhanced the rate of reaction and gave the
corresponding products in higher yields (Table 3, En-
tries 2—7). By contrast, a significant decrease in the
yields of aromatic aldehydes with electron-donating
substituents was observed, even after longer reaction
time (Table 3, Entries 8, 9, 18 and 19). Besides, the het-
ero aromatic aldehydes such as nicotinaldehyde, and the
aliphatic aldehydes with electron-withdrawing substitu-
ents such as trifluoroacetaldehyde also displayed high
reactivity under the identical condition (Table 3, Entries
10 and 17). On the other hand, the substituents located
at para, ortho or meta positions of aromatic aldehydes
have also shown the dramatic effects on the formation
of products. Compared with 3-nitrobenzaldehyde and
4-nitrobenzaldehyde, 2-nitrobenzaldehyde gave no de-
sired product but just a Knoevenagel condensation
product possibly due to the steric hindrance (Table 3,
Entries 2, 3 versus Entry 16). However, when butane-1-
thiol was used with 2-nitrobenzaldehyde and acetylace-
tone under the same conditions, the expected product
was obtained (Table 3, Entry 15). Meanwhile, various
aromatic and aliphatic thiols were also examined on this
reaction. In comparison with 3a, thiophenol showed
lower reactivity as nucleophilic reagent, possibly due to
the lower nucleophilicity (electron-withdrawing induc-
tive effect of benzene ring and p-π conjugative effect),
and the steric hindrance (Table 3, Entry 2 versus Entry
11). At the same time, the aliphatic thiols reacted well,
giving good yields (Table 3, Entries 12—15). To reac-
tant thiols, both the nucleophilicity of the sulfur atom in
thiols and the steric effect played a key role in the reac-
tion.
Table 1 The solvent effect on the model reaction under cata-
lyst-free conditionsa
CHO
O
O
Solvent
SH
+
+
NO2
3a
2
1b
O
O
S
O2N
4b
Entry
Solvent Temperature/℃ Time/h
Yieldb/%
1
2
3
4
5
6
7
8
Hexane
THF
Reflux
Reflux
Reflux
24
24
24
24
24
24
24
12
NR
NR
NR
Trace
22
CH3CN
Toluene 100
DMF
100
MeOH
DMSO
Water
Reflux
100
23
33
Reflux
94
a
The reaction was performed by using 1b (1 mmol), 2 (2 mmol)
and 3a (1 mmol) in 5 mL mentioned solvent. b Isolated yield.
Chin. J. Chem. 2011, 29, 1856— 1862
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1857

Li et al.
FULL PAPER
Table 3 The three-component reaction of substituted aldehydes
Scheme 2 Control experiments for understanding the mecha-
nism of the three-component reaction of 4-nitrobenzaldehyde
(1b), acetylacetone (2) and benzyl mercaptan (3a)
with acetylacetone and substituted thiols in aqueous mediaa
Entry
R1
R2
Time/h Product Yieldb/%
1
2
3
4
5
6
7
8
9
C6H5
C6H5CH2
18
12
12
12
12
12
12
18
18
12
12
12
12
12
12
12
12
18
18
4a
4b
4c
4d
4e
4f
51
94
CHO
p-NO2-C6H4 C6H5CH2
m-NO2-C6H4 C6H5CH2
H2O
SH
+
no reaction
85
reflux
p-Cl-C6H4
m-Cl-C6H4
p-F-C6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
69
NO2
63
3a
1b
73
O
O
H2O
reflux
p-CF3-C6H4
p-Me-C6H4
4g
4h
4i
93
SH
no reaction
+
45
2
p-MeO-C6H4 C6H5CH2
C6H5CH2
35
3a
10 3-Pyridyl
4j
98
11 p-NO2-C6H4 C6H5
4k
4l
70
12 p-NO2-C6H4 n-C4H9
13 p-NO2-C6H4 n-C12H25
14 p-NO2-C6H4 Cyclohexyl
15 o-NO2-C6H4 n-C4H9
16 o-NO2-C6H4 C6H5CH2
80
CHO
O
O
O
4m
4n
4o
—
4p
4q
4r
86
H2O
reflux
+
80
O
O2N
2
75
ND c, 40d
NO2
5b
1b
17 CF3
C6H5CH2
90
O
O
SH
18 p-Me-C6H4
n-C4H9
15
19 o-MeO-C6H4 C6H5CH2
30
3a
H2O, reflux
S
a
The reaction was performed by using aldehyde (1) (1 mmol),
acetylacetone (2) (2 mmol) and thiol (3) (1 mmol) in water (5 mL)
at reflux temperature. Isolated yield. No desired product was
O2N
b
c
4b
d
detected. The major product obtained was the Knoevenagel
condensation product 3-(2-nitrobenzylidene)pentane-2,4-dione
(5o).
helps in the enolization of 2 by making hydrogen bonds
with the OH of 2' which increases the nucleophilic char-
acter of the methylene carbon of 2. Meanwhile, it also
increases the electrophilic character of the carbonyl
carbon of 1 by forming hydrogen bonds with the car-
bonyl oxygen of aldehyde (1).16 Moreover, water plays
a dual role in simultaneously activating the intermediate
(5) and the thiol.17 Hydrogen bond formation between
water and the carbonyl oxygen atom of the intermediate
(5) increases the electrophilic character at the β-carbon
of 5. On the other hand, hydrogen bond formation be-
tween water and thiol increases the nucleophilicity of
the sulfur atom of the thiol via the transition state (6a).
Afterwards, intramolecular nucleophilic attack occurs
via the transition state (6b), followed by intramolecular
proton transfer leading to the conjugate adduct (4).
In order to discuss the mechanism of this MCR,
three control experiments were undertaken. First, benzyl
mercaptan (3a) was heated with 4-nitrobenzaldehyde
(1b) in water under reflux conditions. Second, benzyl
mercaptan (3a) was heated with acetylacetone (2) under
the same conditions (Scheme 2). In these cases, no reac-
tion occurred and the reactants remained unaltered.
These results are consistent with the literature. Indeed,
successful reactions between mercaptan derivatives and
aldehydes normally require assistance of acid cata-
lysts.13 Besides, the reactions between mercaptan de-
rivatives and 1,3-dicarbonyl compounds often need the
participation of acid or base catalysts.14,15 Interestingly,
when 4-nitrobenzaldehyde (1b) and acetylacetone (2)
were mixed together under the same conditions, the
corresponding Knoevenagel condensation product (5b)
was obtained. Then, the Knoevenagel condensation
product (5b) reacted with benzyl mercaptan (3a) under
the same conditions, as a result, the final Michael addi-
tion product (4b) was obtained.
Conclusion
In conclusion, we have developed an efficient
method for the synthesis of β-mercapto diketones in
15%—98% yields, through the three-component one-
pot reaction in aqueous media. It was suggested that the
three-component reaction was influenced by the elec-
tronic and steric factors associated with substituents on
aldehydes and the thiols. A remarkable feature of this
three-component reaction is that C—C and C—S bond
formation occurs in the absence of any catalyst. Besides,
On the basis of these control experiments, a plausi-
ble mechanism for the reaction was depicted in Scheme
3. Initially, a Knoevenagel condensation occurs between
aldehyde (1) and acetylacetone (2), leading to the for-
mation of intermediate (5). During this process, water
1858
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1856— 1862

Catalyst-free Multicomponent Synthesis of β-Mercapto Diketones in Water
Scheme 3 Plausible mechanism of the three-component reaction of aldehydes, acetylacetone and thiols in water
H
O
H
R1
O
H
O
R1
O
O
H
H
R2
O
OH
R1
R2 SH
H
R1
O
O
O
S
-H2O
O
1
3
H
O
H
O
H
O
H
O
H
O
2
2'
5
6a
R1
R2
O
O
O
S
+
S
O
R1
R2
H
O
- H2O
S
H
R2
R1
-
O
O
H
H
7
6b
4
this method offers several advantages such as simple
and readily available reactants, metal-free and nonhaz-
ardous experimental conditions and facile experimental
procedures, which makes it a useful and attractive proc-
ess for the synthesis of these important compounds.
3-(Benzylthio(4-nitrophenyl)methyl)pentane-2,4-
dione (4b) Yellowish solid, 94% yield. m.p.
1
123—124 ℃; H NMR (CDCl3, 400 MHz) δ: 8.15 (d,
J＝8.8 Hz, 2H), 7.41 (d, J＝8.8 Hz, 2H), 7.31—7.26 (m,
3H), 7.19—7.17 (m, 2H), 4.37 (d, J＝12 Hz, 1H), 4.20
(d, J＝12 Hz, 1H), 3.60 (d, J＝13.6 Hz, 1H), 3.39 (d,
J＝13.6 Hz, 1H), 2.16 (s, 3H), 1.89 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 200.2, 200.1, 147.2, 147.1, 136.5,
129.3, 128.9, 128.6, 127.5, 123.8, 74.2, 46.6, 35.7, 30.2,
28.2; IR (KBr) ν: 3030, 2924, 2850, 1720, 1693, 1514,
1350, 857, 729, 712, 696 cm－ 1; HRMS calcd for
C19H19NO4S 357.1035, found 357.1038.
3-(Benzylthio(3-nitrophenyl)methyl)pentane-2,4-
dione (4c) Yellowish solid, 85% yield. m.p. 105—106
℃; 1H NMR (CDCl3, 400 MHz) δ: 8.11—8.08 (m, 2H),
7.56 (d, J＝7.6 Hz, 1H), 7.49—7.45 (m, 1H), 7.32—
7.23 (m, 3H), 7.17 (d, J＝7.6 Hz, 2H), 4.37 (d, J＝12
Hz, 1H), 4.23 (d, J＝12 Hz, 1H), 3.60 (d, J＝14 Hz,
1H), 3.38 (d, J＝14 Hz, 1H), 2.16 (s, 3H), 1.90 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ: 200.2, 200.1, 148.3,
141.9, 136.5, 134.5, 129.5, 128.9, 128.6, 127.5, 123.2,
122.7, 74.2, 46.6, 35.8, 30.2, 28.3; IR (KBr) ν: 3103,
3063, 3030, 2925, 2853, 1718, 1696, 1530, 1351, 823,
810, 765, 733, 704, 688 cm － 1; HRMS calcd for
C19H19NO4S 357.1035, found 357.1042.
Experimental
The structures of products were confirmed by IR, 1H
1
NMR, 13C NMR and HRMS. H (400 MHz) and 13C
(100 MHz) NMR spectra were recorded on a Bruker
Avance 400 spectrometer in CDCl3 using TMS
(tetramethylsilane) as internal reference. IR spectra
were obtained with a Nicolet Nexus 470 FT-IR spec-
trophotometer. High resolution mass spectra (HRMS)
were run on Waters GCT Premier mass spectrometer.
Benzaldehyde and acetylacetone were distilled prior to
use. All the other chemicals were obtained from com-
mercial suppliers.
General procedure for the synthesis of β-mercapto
diketones
A mixture of 1 (1 mmol), 2 (2 mmol) and 3 (1 mmol)
in water (5 mL) was heated under reflux conditions with
magnetic stirring. The reaction was monitored by TLC
analysis. After the reaction was completed, cooled down
to room temperature, the solid crude products precipi-
tated, which were easy to separate just followed by fil-
tration and drying. Besides, the liquid crude products
could be separated simply from water through extrac-
tion method, and then purified by column chromatog-
raphy to give the pure products.
3-(Benzylthio(4-chlorophenyl)methyl)pentane-2,4-
dione (4d) White solid, 69% yield. m.p. 105—106 ℃;
1H NMR (CDCl3, 400 MHz) δ: 7.31—7.17 (m, 9H),
4.26 (d, J＝12 Hz, 1H), 4.13 (d, J＝12 Hz, 1H), 3.54 (d,
J＝13.2 Hz, 1H), 3.36 (d, J＝13.2 Hz, 1H), 2.13 (s, 3H),
1.85 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 200.8,
200.7, 137.5, 136.8, 133.5, 129.7, 128.9, 128.8, 128.5,
127.3, 74.5, 46.7, 35.3, 30.2, 27.9; IR (KBr) ν: 2943,
2916, 1718, 1693, 1597, 1492, 1448, 1090, 1014, 970,
3-(Benzylthio(phenyl)methyl)pentane-2,4-dione
1
(4a) White solid, 51% yield. m.p. 72—73 ℃; H
－
1
833, 746, 719, 704 cm ; HRMS calcd for C19H19ClO2S
NMR (CDCl3, 400 MHz) δ: 7.34—7.18 (m, 10H), 4.30
(d, J＝12.4 Hz, 1H), 4.19 (d, J＝12.4 Hz, 1H), 3.53 (d,
J＝13.6 Hz, 1H), 3.37 (d, J＝13.6 Hz, 1H), 2.14 (s, 3H),
1.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 201.0,
138.6, 137.0, 128.7, 128.4, 128.2, 128.1, 127.6, 127.0,
74.3, 47.4, 35.0, 30.0, 27.9; IR (KBr) ν: 3063, 3027,
2933, 1719, 1693, 1598, 1491, 1448, 1420, 1093, 1070,
1026, 723, 699 cm－ 1; HRMS calcd for C19H20O2S
312.1184, found 312.1190.
346.0794, found 346.0800.
3-(Benzylthio(3-chlorophenyl)methyl)pentane-
2,4-dione (4e) White solid, 63% yield. m.p. 63—64
℃; 1H NMR (CDCl3, 400 MHz) δ: 7.34—7.13 (m, 9H),
4.25 (d, J＝12 Hz, 1H), 4.16 (d, J＝12 Hz, 1H), 3.56 (d,
J＝13.2 Hz, 1H), 3.39 (d, J＝13.2 Hz, 1H), 2.13 (s, 3H),
1.87 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 200.7,
200.6, 141.3, 136.8, 134.5, 129.9, 129.0, 128.6, 128.5,
Chin. J. Chem. 2011, 29, 1856— 1862
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1859

Li et al.
FULL PAPER
128.0, 127.4, 126.7, 74.4, 46.9, 35.5, 30.3, 28.1; IR
3-(Benzylthio(pyridin-3-yl)methyl)pentane-2,4-
dione (4j) Colorless oil, 98% yield. 1H NMR (CDCl3,
400 MHz) δ: 8.51—8.48 (m, 2H), 7.65—7.62 (m, 1H),
7.34—7.18 (m, 6H), 4.29 (d, J＝12 Hz, 1H), 4.18 (d,
J＝12 Hz, 1H), 3.58 (d, J＝13.6 Hz, 1H), 3.37 (d, J＝
13.6 Hz, 1H), 2.14 (s, 3H), 1.88 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 200.4, 200.3, 149.8, 149.0, 136.6,
135.8, 135.1, 128.9, 128.6, 127.4, 123.6, 74.2, 44.6,
35.4, 30.1, 28.0; IR (KBr) ν. 3029, 2919, 1734, 1700,
1494, 1479, 1454, 1423, 1357, 1329, 1246, 1178, 1148,
(KBr) ν: 3056, 3029, 2922, 1697, 1357, 1182, 1153, 877,
－
1
757, 703, 694, 685 cm ; HRMS calcd for C19H19ClO2S
348.0765, found 348.0791.
3-(Benzylthio(4-fluorophenyl)methyl)pentane-2,4-
dione (4f) Yellowish solid, 73% yield. m.p. 87 ℃; 1H
NMR (CDCl3, 400 MHz) δ: 7.33—7.24 (m, 5H), 7.18 (d,
J＝6.8 Hz, 2H), 7.03—6.99 (m, 2H), 4.27 (d, J＝12.4
Hz, 1H), 4.13 (d, J＝12.4 Hz, 1H), 3.54 (d, J＝13.2 Hz,
1H), 3.35 (d, J＝13.2 Hz, 1H), 2.13 (s, 3H), 1.84 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ: 201.1, 201.0, 163.3,
160.8, 137.0, 134.8, 134.7, 130.1, 130.0, 129.0, 128.5,
127.3, 115.7, 115.5, 74.8, 46.8, 35.3, 30.4, 28.0; IR
(KBr) ν: 2949, 2920, 1717, 1693, 1600, 1512, 1358,
－
1
1072, 1026, 705 cm ; HRMS calcd for C18H19NO2S
313.1137, found 313.1130.
3-((4-Nitrophenyl)(phenylthio)methyl)pentane-
2,4-dione (4k) Yellowish solid, 70% yield. m.p.
80—81 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.06 (d, J＝
8.8 Hz, 2H), 7.29—7.14 (m, 7H), 4.85 (d, J＝12 Hz,
1H), 4.39 (d, J＝12 Hz, 1H), 2.45 (s, 3H), 1.95 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ: 200.3, 200.1, 147.0,
146.8, 134.4, 130.9, 129.2, 129.1, 128.8, 123.7, 73.3,
51.9, 29.8, 29.4; IR (KBr) ν: 3081, 2961, 1694, 1515,
－
1
1227, 839 cm ; HRMS calcd for C19H19O2FS 330.1090,
found 330.1098.
3-(Benzylthio(4-(trifluoromethyl)phenyl)methyl)-
pentane-2,4-dione (4g) Yellowish solid, 93% yield
1
(keto/enol, 85%/15%). m.p. 112 ℃; H NMR (CDCl3,
400 MHz) δ: 17.20 (s, 0.18H, enol), 7.62—7.61 (m,
0.54H, enol), 7.57 (d, J＝8 Hz, 2H, keto), 7.39 (d, J＝8
Hz, 2H, keto), 7.33—7.22 (m, 1.08H＋3H, enol＋keto),
7.18 (d, J＝6.8 Hz, 2H, keto), 4.81 (s, 0.18H, enol),
4.33 (d, J＝12 Hz, 1H, keto), 4.19 (d, J＝12 Hz, 1H,
keto), 3.82 (d, J＝13.6 Hz, 0.18H, enol), 3.71 (d, J＝
13.6 Hz, 0.18H, enol), 3.57 (d, J＝13.6 Hz, 1H, keto),
3.36 (d, J＝13.6 Hz, 1H, keto), 2.14 (s, 3H, keto), 1.86
(s, 3H, keto), 1.78 (s, 1.08H, enol); 13C NMR (CDCl3,
100 MHz) δ: 200.6, 200.5, 143.4, 136.7, 128.9, 128.8,
128.6, 127.4, 125.7, 125.6, 125.6, 125.5, 74.4, 46.8,
35.5, 30.3, 28.0; IR (KBr) ν: 2958, 2918, 2851, 1719,
1693, 1618, 1600, 1358, 1334, 1159, 1116, 1071, 843
－
1
1351, 1186, 1148, 747, 693 cm ; HRMS calcd for
C18H17NO4S 343.0878, found 343.0886 .
3-(Butylthio(4-nitrophenyl)methyl)pentane-2,4-
dione (4l) Yellowish solid, 80% yield. m.p. 81—82
1
℃; H NMR (CDCl3, 400 MHz) δ: 8.18 (d, J＝8 Hz,
2H), 7.50 (d, J＝8 Hz, 2H), 4.55 (d, J＝12 Hz, 1H),
4.25 (d, J＝12 Hz, 1H), 2.38 (s, 3H), 2.34—2.22 (m,
2H), 1.94 (s, 3H), 1.49—1.23 (m, 4H), 0.83 (t, J＝7.2
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 200.2, 147.5,
147.1, 129.0, 123.9, 74.0, 47.4, 31.0, 30.7, 30.1, 29.2,
21.7, 13.5; IR (KBr) ν: 3077, 2959, 2931, 2872, 1735,
－
1
1702, 1521, 1347, 854, 732 cm ; HRMS calcd for
C16H21NO4S 323.1191, found 323.1195.
－
1
cm ; HRMS calcd for C20H19O2F3S 380.1058, found
3-(Dodecylthio(4-nitrophenyl)methyl)pentane-2,4-
dione (4m) Yellowish solid, 86% yield. m.p. 61—62
380.1060.
3-(Benzylthio(p-tolyl)methyl)pentane-2,4-dione
1
℃; H NMR (CDCl3, 400 MHz) δ: 8.18 (d, J＝8 Hz,
1
(4h) White solid, 45% yield. m.p. 74—75 ℃; H
2H), 7.50 (d, J＝8 Hz, 2H), 4.55 (d, J＝12 Hz, 1H),
4.24 (d, J＝12 Hz, 1H), 2.38 (s, 3H), 2.34—2.21 (m,
2H), 1.94 (s, 3H), 1.50—1.38 (m, 2H), 1.25—1.20 (m,
20H), 0.88 (t, J＝6.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ: 200.2, 147.6, 147.1, 129.0, 123.9, 74.0, 47.4,
31.8, 31.3, 30.1, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 28.7,
28.6, 22.6, 14.1; IR (KBr) ν: 2917, 2850, 1724, 1694,
NMR (CDCl3, 400 MHz) δ: 7.30—7.11 (m, 9H), 4.27 (d,
J＝12 Hz, 1H), 4.18 (d, J＝12 Hz, 1H), 3.52 (d, J＝
13.6 Hz, 1H), 3.37 (d, J＝13.6 Hz, 1H), 2.33 (s, 3H),
2.13 (s, 3H), 1.82 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 201.5, 201.4, 137.6, 137.3, 135.7, 129.4, 129.0, 128.5,
128.3, 127.2, 74.6, 47.4, 35.2, 30.2, 28.2, 21.1; IR (KBr)
ν: 3061, 3028, 2922, 2862, 1734, 1699, 823 cm－
;
1
－
1
1519, 1354, 858, 730 cm ; HRMS calcd for C24H37-
HRMS calcd for C20H22O2S 326.1341, found 326.1333.
NO4S 435.2443, found 435.2451.
3-(Benzylthio(4-methoxyphenyl)methyl)pentane-
2,4-dione (4i) White solid, 35% yield. m.p. 82—83
℃; 1H NMR (CDCl3, 400 MHz) δ: 7.32—7.18 (m, 7H),
6.85 (d, J＝8.4 Hz, 2H), 4.26 (d, J＝12 Hz, 1H), 4.15 (d,
J＝12 Hz, 1H), 3.81 (s, 3H), 3.52 (d, J＝13.6 Hz, 1H),
3-(Cyclohexylthio(4-nitrophenyl)methyl)pentane-
2,4-dione (4n) Yellowish solid, 80% yield. m.p. 117
1
℃; H NMR (CDCl3, 400 MHz) δ: 8.17 (d, J＝8 Hz,
2H), 7.52 (d, J＝8 Hz, 2H), 4.62 (d, J＝12 Hz, 1H),
4.20 (d, J＝12 Hz, 1H), 2.36 (s, 3H), 2.34—2.31 (m,
1H), 2.08—1.96 (m, 1H), 1.92 (s, 3H), 1.72—1.52 (m,
4H), 1.35—1.18 (m, 5H); 13C NMR (CDCl3, 100 MHz)
δ: 200.3, 200.2, 148.3, 147.0, 129.0, 123.8, 74.2, 46.0,
43.5, 33.1, 32.9, 30.3, 29.2, 25.7, 25.5, 25.4; IR (KBr) ν:
3.37 (d, J＝13.6 Hz, 1H), 2.13 (s, 3H), 1.83 (s, 3H); 13
C
NMR (CDCl3, 100 MHz) δ: 201.4, 201.3, 159.0, 137.3,
130.6, 129.6, 129.0, 128.5, 127.2, 114.0, 74.8, 55.2,
47.2, 35.2, 30.3, 28.1; IR (KBr) ν: 3028, 2956, 2932,
2834, 1718, 1693, 1611, 1585, 1516, 1495, 1455, 1438,
1418, 1266, 1234, 1179, 1150, 1119, 1029, 837, 825
cm－ 1; HRMS calcd for C20H22O3S 342.1290, found
342.1291.
－
1
2931, 2852, 1722, 1698, 1518, 1351, 857 cm ; HRMS
calcd for C18H23NO4S 349.1348, found 349.1356.
3-(Butylthio(2-nitrophenyl)methyl)pentane-2,4-
1
dione (4o) Yellow oil, 75% yield. H NMR (CDCl3,
1860
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1856— 1862

Catalyst-free Multicomponent Synthesis of β-Mercapto Diketones in Water
400 MHz) δ: 7.79 (d, J＝8 Hz, 1H), 7.65 (d, J＝8 Hz,
1H), 7.57 (t, J＝8 Hz, 1H), 7.38 (t, J＝8 Hz, 1H), 5.34
(d, J ＝11.2 Hz, 1H), 4.25 (d, J ＝11.2 Hz, 1H),
2.59—2.50 (m, 1H), 2.46—2.39 (m, 1H), 2.35 (s, 3H),
1.95 (s, 3H), 1.55—1.39 (m, 2H), 1.34—1.23 (m, 2H),
0.83 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ:
200.6, 200.5, 150.0, 135.5, 132.9, 130.0, 128.3, 124.4,
75.0, 41.3, 31.4, 31.1, 29.5, 28.9, 21.8, 13.5; IR (KBr) ν:
2959, 2931, 2873, 1732, 1703, 1605, 1578, 1529, 1357,
3-(2-Nitrobenzylidene)pentane-2,4-dione (5o) 1H
NMR (CDCl3, 400 MHz) δ: 8.23 (d, J＝8 Hz, 1H), 7.92
(s, 1H), 7.68—7.65 (m, 1H), 7.61—7.58 (m, 1H), 7.40
(d, J＝8 Hz, 1 H), 2.49 (s, 3H), 2.12 (s, 3H); IR (KBr) ν:
3104, 1692, 1672, 1521, 1374, 1349, 1337, 1249, 1184
－
1
cm .
References
－
1
1
(a) Bannwarth, W.; Felder, E. Combinatorial Chemistry,
Wiley-VCH, Weinheim, 2000.
1256, 1236, 1188, 1142, 857, 785, 731 cm ; HRMS
calcd for C16H21NO4S 323.1191, found 323.1186.
3-(1-(Benzylthio)-2,2,2-trifluoroethyl)pentane-2,4-
dione (4p) Colorless oil, 90% yield (keto/enol, 40%/
(b) Zhu, J.; Bienaymé, H. Multicomponent Reactions,
Wiley-VCH, Weinheim, 2005.
(c) Döling, A. Chem. Rev. 2006, 106, 17.
(d) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(e) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
(f) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007,
36, 1095.
1
60%). H NMR (CDCl3, 400 MHz) δ: 17.59 (s, 0.6H,
enol), 7.40—7.26 (m, 5H, enol＋keto), 4.03 (d, J＝10.4
Hz, 0.4H, keto), 3.93 (d, J ＝14 Hz, 0.8H, keto),
3.90—3.83 (m, 2.2H, enol＋keto), 2.29 (s, 1.8H, enol),
2.16 (s, 1.2H, keto), 2.05 (s, 1.2H, keto), 1.50 (s, 1.8H,
enol); 13C NMR (CDCl3, 100 MHz) δ: 199.3 (keto),
2
(a) Yadav, J. S.; Reddy, B. V. S.; Sridhar, P.; Reddy, J. S. S.;
Nagaiah, K.; Lingaiah, N.; Saiprasad, P. S. Eur. J. Org.
Chem. 2004, (3), 552.
198.9 (keto), 195.0 (enol), 192.5 (enol), 136.2 (enol),
135.6 (keto), 129.5 (enol), 129.3 (keto), 129.0 (enol),
128.8 (keto), 128.0 (enol), 127.9 (keto), 127.6 (keto),
125.6 (enol), 105.4 (enol), 67.2 (keto), 45.1 (keto), 42.1
(b) Sperger, C. A.; Mayer, P.; Wanner, K. T. Tetrahedron
2009, 65, 10463.
3
As selected works see:
(enol), 37.7 (enol＋keto), 29.6 (keto), 29.0 (enol), 24.6
(a) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611.
(b) Galliford, C. V.; Martenson, J. S.; Stern, C.; Scheidt, K.
A. Chem. Commun. 2007, (6), 631.
(c) Gall, E. L.; Haurena, C.; Sengmany, S.; Martens, T.;
Troupel, M. J. Org. Chem. 2009, 74, 7970.
(d) Airiau, E.; Girard, N.; Mann, A.; Salvadori, J.; Taddei,
M. Org. Lett. 2009, 11, 5314.
(e) Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Riva, R. J.
Org. Chem. 2008, 73, 1608.
(f) Gulevich, A. V.; Shpilevaya, I. V.; Nenajdenko, V. G. Eur.
J. Org. Chem. 2009, (22), 3801.
(g) Fringuelli, F.; Girotti, R.; Piermatti, O.; Pizzo, F.; Vac-
caro, L. Org. Lett. 2006, 8, 5741.
(h) Shang, Y. J.; He, X. W.; Hu, J. S.; Wu, J. W.; Zhang, M.;
Yu, S. Y.; Zhang, Q. Q. Adv. Synth. Catal. 2009, 351, 2709.
(i) Siamaki, A. R.; Black, D. A.; Arndtsen, B. A. J. Org.
Chem. 2008, 73, 1135.
(j) Yan, C. G.; Wang, Q. F.; Song, X. K.; Sun, J. J. Org.
Chem. 2009, 74, 710.
(k) Pandey, J.; Anand, N.; Tripathi, R. P. Tetrahedron 2009,
65, 9350.
(keto), 23.7 (enol); IR (KBr) ν: 3062, 3032, 2966, 2931,
1736, 1709, 1559, 1494, 1454, 1426, 1360, 1328, 1257,
1152, 1103 cm － 1; HRMS calcd for C14H15O2F3S
304.0745, found 304.0743.
3-((Butylthio)(p-tolyl)methyl)pentane-2,4-dione
1
(4q) White solid, 15% yield. m.p. 57 ℃; H NMR
(CDCl3, 400 MHz) δ: 7.18 (d, J＝7.5 Hz, 2H), 7.11 (d,
J＝7.5 Hz, 2H), 4.43 (d, J＝12.5 Hz, 1H), 4.23 (d, J＝
12.5 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.31—2.21 (m,
2H), 1.88 (s, 3H), 1.50—1.39 (m, 2H), 1.34—1.26 (m,
2H), 0.83 (t, J＝7.5 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ: 201.8, 201.7, 137.7, 136.4, 129.6, 128.2, 74.9,
48.2, 31.2, 30.9, 30.1, 29.5, 22.1, 21.3, 13.7; IR (KBr) ν:
3030, 2953, 2923, 2867, 1735, 1701, 1510, 1414, 1358,
－
1
1274, 1138, 953, 822 cm ; HRMS calcd for C17H24O2S
292.1497, found 292.1502.
3-((Benzylthio)(2-methoxyphenyl)methyl)pentane-
2,4-dione (4r) Yellow oil, 30% yield. 1H NMR
(CDCl3, 400 MHz) δ: 7.29—7.17 (m, 7H), 6.93—6.86
(m, 2H), 4.85 (t, J＝11.5 Hz, 1H), 4.48 (d, J＝11.5 Hz,
1H), 3.84 (s, 3H), 3.60 (d, J＝13.5 Hz, 1H), 3.55 (d, J＝
13.5 Hz, 1H), 2.20 (s, 3H), 1.86 (s, 3H); 13C NMR
4
(a) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous
Media, Wiley, New York, 1997.
(CDCl3, 100 MHz) δ: 202.2, 201.6, 156.8, 137.8, 129.7,
129.1, 128.9, 128.4, 127.4, 127.1, 120.9, 111.3, 73.3,
55.6, 42.2, 36.2, 30.0, 28.8; IR (KBr) ν: 3061, 3030,
(b) Grieco, P. A. Organic Synthesis in Water, Blackie,
London, 1998.
5
(a) Kanizsai, I.; Gyónfalvi, S.; Szakonyi, Z.; Sillanpää, R.;
Fülöp, F. Green Chem. 2007, 9, 357.
3009, 2938, 2837, 1725, 1700, 1599, 1585, 1493, 1464,
1454, 1438, 1420, 1355, 1288, 1246, 1180, 1150, 1118,
－
1
(b) Kumaravel, K.; Vasuki, G. Green Chem. 2009, 11, 1945.
(c) Adib, M.; Mahdavi, M.; Noghani, M. A.; Mirzaei, P.
Tetrahedron Lett. 2007, 48, 7263.
1071, 1050, 1026, 755, 701 cm ; HRMS calcd for
C20H22O3S 342.1298, found 342.1290.
3-(4-Nitrobenzylidene)pentane-2,4-dione (5b) 1H
6
(a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic
Synthesis, Academic Press, New York, 1994.
(b) Nudelman, A. The Chemistry of Optically Active Sulfur
Compounds, Gordon and Breach, New York, 1984.
NMR (CDCl3, 400 MHz) δ: 8.25 (d, J＝8.8 Hz, 2H),
7.56 (d, J＝8.8 Hz, 2H), 7.50 (s, 1H), 2.46 (s, 3H), 2.29
(s, 3H); IR (KBr) ν: 3074, 3050, 2921, 1709, 1654, 1514,
－
1
1345, 1238, 1173 cm .
Chin. J. Chem. 2011, 29, 1856— 1862
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1861

Li et al.
FULL PAPER
(c) Chatgilialoglu, C.; Asmus, K. D. Sulfur-Centered Reac-
tive Intermediates in Chemistry and Biology, Springer, New
York, 1991.
(c) Singh, O. M.; Devi, N. S. J. Org. Chem. 2009, 74, 3141.
(d) Guo, K.; Thompson, M. J.; Chen, B. N. J. Org. Chem.
2009, 74, 6999.
7
8
9
Bicking, J. B.; Holtz, W. J.; Watson, L. S.; Cragoe, Jr. E. J. J.
Med. Chem. 1976, 19, 530.
Ding, Y.; Vara Prasad, C. V. N. S.; Smith, K. L.; Chang, E.;
Hong, J.; Yao, N. Lett. Org. Chem. 2009, 6, 130.
Inomata, K.; Barragué, M.; Paquette, L. A. J. Org. Chem.
2005, 70, 533.
12 Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hosseinpour, R.
Tetrahedron Lett. 2009, 50, 1533.
13 Wuts, P. G. M.; Greene, T. W. Greene's Protective Groups in
Organic Synthesis, 4th ed., Wiley-interscience, USA, 2006.
14 Arcadi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli, F. Green
Chem. 2003, 5, 64.
10 Yamauchi, M.; Katayama, S.; Watanabe, T. Synthesis 1982,
11, 935.
15 Tan, J.; Liang, F.; Wang, Y.; Cheng, X.; Liu, Q.; Yuan, H.
Org. Lett. 2008, 10, 2485.
11 As selected works see:
16 (a) Yadav, L. D. S.; Singh, S.; Rai, V. K. Green Chem. 2009,
11, 878.
(a) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; An-
tipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem.
2007, 72, 3443.
(b) Yu, J. J.; Wang, L. M.; Liu, J. Q.; Guo, F. L.; Liu, Y.;
Jiao, N. Green Chem. 2010, 12, 216.
(b) Gulevich, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J.
Org. Chem. 2007, 72, 7878.
17 Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006,
8, 2433.
(E1012272 Cheng, B.; Fan, Y.)
1862
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1856— 1862