Sulfonic acid functionalized nano Γ-Al 2O 3: A new, efficient, and reusable catalyst for synthesis of thioamides

Article abstract of DOI:10.1080/10426507.2013.769983

Sulfonic acid functionalized nano γ-Al₂O₃ is easily prepared by the reaction of nano γ-Al₂O₃ with 1,3-propane sulfone. This reagent can be used as an eficient catalyst for the synthesis of thioamides. This new method consistently has the advantages of excellent yields and short reaction times. Further, the catalyst can be recovered for several times.

Full text of DOI:10.1080/10426507.2013.769983

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Sulfonic Acid Functionalized Nano Γ-
Al2O3: a New, Efficient, and Reusable
Catalyst for Synthesis of Thioamides
Zhikui Yin a , Bin Zheng b & Fang Ai c
a School of Pharmacy , Xinxiang Medical University , Xinxiang ,
Henan , 453003 , P. R. China
b Department of Parasitology , Xinxiang Medical University ,
Xinxiang , Henan , 453003 , P. R. China
c The First Afiliated Hospital , Xinxiang Medical University ,
Xinxiang , Henan , 453100 , P. R. China
Accepted author version posted online: 31 May 2013.Published
online: 06 Sep 2013.
To cite this article: Zhikui Yin , Bin Zheng & Fang Ai (2013) Sulfonic Acid Functionalized Nano Γ-Al2O3:
a New, Efficient, and Reusable Catalyst for Synthesis of Thioamides, Phosphorus, Sulfur, and Silicon
and the Related Elements, 188:10, 1412-1420, DOI: 10.1080/10426507.2013.769983
To link to this article: http://dx.doi.org/10.1080/10426507.2013.769983
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Phosphorus, Sulfur, and Silicon, 188:1412–1420, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.769983
SULFONIC ACID FUNCTIONALIZED NANO ꢀ-AL2O3:
A NEW, EFFICIENT, AND REUSABLE CATALYST FOR
SYNTHESIS OF THIOAMIDES
Zhikui Yin,1 Bin Zheng,2 and Fang Ai3
1School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R.
China
2Department of Parasitology, Xinxiang Medical University, Xinxiang, Henan
453003, P. R. China
3The First Afiliated Hospital, Xinxiang Medical University, Xinxiang, Henan
453100, P. R. China
GRAPHICAL ABSTRACT
Abstract Sulfonic acid functionalized nano γ -Al2O3 is easily prepared by the reaction of
nano γ -Al2O3 with 1,3-propane sulfone. This reagent can be used as an eficient catalyst for the
synthesis of thioamides. This new method consistently has the advantages of excellent yields
and short reaction times. Further, the catalyst can be recovered for several times.
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
files: Additional text.
Keywords Thioamides; sulfonic acid functionalized nano γ -Al2O3; synthesis
INTRODUCTION
Due to the high surface area:volume ratios, nanoparticles can effectively improve
the loading and the catalytic efficiency of immobilized catalysts. Therefore, the use of
nanostructured materials as supports for different versions of catalyst immobilization is
ever increasing.1
Thioamide derivatives are important biologically and pharmaceutically active com-
pounds. They have received considerable attention in the field of pharmaceutical industry
Received 10 October 2012; accepted 13 January 2013.
Address correspondence to Zhikui Yin, School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan
453003, P. R. China. E-mail: yinzhikui2004@163.com; yinzhikui@xxmu.edu
1412

SULFONIC ACID FUNCTIONALIZED NANO ꢀ-AL2O3
1413
Scheme 1
Scheme 2
owing to their wide range of pharmaceutical properties such as antifungal,2 anticonvul-
sant,3 antithyroid,4 and antioxidant5 activities. In addition, they also find wide applications
as intermediates in synthesis of five- and six-membered heterocycles,6 and active phar-
maceutical ingredients such as fentiazac, fenclosic acid, and febuxostate.7 Therefore, the
synthesis of thioamide derivatives has aroused great interest in the organic and medicinal
communities.
There are several methods available for the preparation of thioamide derivatives in-
cluding thionation of amides using PSCl3 or TsCl-mediated Beckmann rearrangement,8
basic-catalyzed Willgerodt–Kindler reaction,9 via Kindler reaction in the presence of sul-
fated tungstate,10 and thionation of amides using thionating reagents.11 Despite the impor-
tance of these reported protocols, they may suffer from drawbacks such as use of expensive
reagents, harsh reaction conditions, prolonged reaction times, cumbersome product isola-
tion procedures, and low yields. Hence, to explore a mild, efficient, and synthetic protocol
for the thioamide derivatives is highly desirable.
As a part of our endeavors toward the development of efficient and environmentally
benign synthetic methodologies using economic and eco-friendly heterogeneous catalysts,
we now report a highly efficient procedure for the preparation of thioamide derivatives via
a one-pot, three-component Willgerodt–Kindler reaction of aldehydes, amines, and sulfur
using sulfonic acid functionalized nano γ -Al2O3 as an efficient and reusable catalyst in
dimethylformamide (DMF; Scheme 1).
RESULTS AND DISCUSSION
Sulfonic acid functionalized nano γ -Al2O3 was easily prepared by the reaction of
nano γ -Al2O3 with 1,3-propane sulfone (Scheme 2), and it was characterized by FTIR, X-
ray powder diffraction (XRD), thermogravimetric (TG) analysis, and transmission electron
microscopy (TEM). The amount of sulfonic acid loaded on the surface of nano γ -Al2O3 is
determined by TG analysis and confirmed by ion-exchange pH analysis.
Figure 1 presents the FTIR spectra of nano γ -Al2O3 and sulfonic acid functionalized
nano γ -Al2O3. As shown in this figure, the presence of an extra sulfonic acid group

1414
Z. YIN ET AL.
Figure 1 FTIR spectra of nano γ -Al2O3 (up) and sulfonic acid functionalized nano γ -Al2O3 (down).
in the sulfonic acid functionalized nano γ -Al2O3 increases the number of vibrational
modes and brought completely different FTIR spectrum. The FTIR spectra of sulfonic acid
functionalized nano γ -Al2O3 exhibit two characteristic peaks at 589 cm−1 and 758 cm−1
due to the stretching vibrations of Al O bond in γ -Al2O3. Moreover, two important peaks
at 1043 cm−1 and 1187 cm−1 are assigned to S O stretching vibration. The broad peak
at 3444 cm−1 belongs to the stretching of OH groups in the SO3H. These results indicate
that the reaction of nano γ -Al2O3 with 1,3-propane sulfone was succeeded in incorporating
sulfated groups in nano γ -Al2O3.
XRD measurements of nano γ -Al2O3 and sulfonic acid functionalized nano γ -Al2O3
exhibit diffraction peaks at around 19.5, 32.6, 36.6, 39.5, 45.8, 60.6, and 67.2 corresponding
to the (111), (220), (311), (222), (400), (511), and (440) faces (Figure 2). The observed
diffraction peaks agree well with the cubic structure of γ -Al2O3 (JCPDS file no. 29-0063).
It is clear that the ordered structure of nano γ -Al2O3 is retained after the introduction of
the propylsulfonic acid group. The average crystallite sizes are calculated to be 14.9 nm
using the Scherrer equation,12 which are in good accordance with TEM results.
The stability of the nano γ -Al2O3 and sulfonic acid functionalized nano γ -Al2O3 is
determined by thermogravimetric analysis (TGA; Figure 3). A significant decrease in the
weight percentage of the nano γ -Al2O3 and sulfonic acid functionalized nano γ -Al2O3 at
about 150◦C is related to the desorption of water molecules from the catalysts’ surface. In the
TG curve of sulfonic acid functionalized nano γ -Al2O3, complete loss of all the covalently
attached organic structure is seen in the temperature range of 230–960◦C. The shoul-
dering observed from 328◦C onward may be due to the decomposition of alkyl–sulfonic
acid groups. The amount of nano sulfonic acid functionalized nano γ -Al2O3 is eval-
uated to be 0.78 mmol·g−1. This result is in agreement with that of ion-exchange pH
analysis.

SULFONIC ACID FUNCTIONALIZED NANO ꢀ-AL2O3
1415
Figure 2 XRD patterns of nano γ -Al2O3 (up) and sulfonic acid functionalized nano γ -Al2O3 (down).
The sizes of nano γ -Al2O3 and sulfonic acid functionalized nano γ -Al2O3 are further
analyzed by TEM, and the results (Figures 4a and 4b) show that the nano particles have
nano dimensions ranging from 10 to 20 nm. In TEM images, the shapes of γ -Al2O3
particles are relatively round, and those of treated n-propylsufonated γ -Al2O3 are rather
Figure 3 TG analysis of nano γ -Al2O3 (up) and sulfonic acid functionalized nano γ -Al2O3 (down).

1416
Z. YIN ET AL.
Figure 4 (a) TEM images of nano γ -Al2O3. (b) TEM images of sulfonic acid functionalized nano γ -Al2O3.
rectangular, which is attributed to the presence of sulfonic acid groups covalently attached
to the γ -Al2O3 surfaces.
To achieve suitable conditions for the synthesis of thioamides, we tested the three-
component reaction of benzaldehyde, aniline, and sulfur as a simple model system in DMF
at 100◦C using various catalysts (Table 1). As can be seen in Table 1, the best result was
obtained with 150 mg/mmol of nano n-propylsulfonated γ -Al2O3 as the catalyst in DMF
at 100◦C (entry 3). Using less catalyst resulted in lower yields, whereas higher amounts
of catalyst did not affect reaction times and yields. When this reaction was carried out
without nano n-propylsulfonated γ -Al2O3 or with other catalysts, such as FeCl3, AlCl3,
and nano γ -Al2O3, the yield of the expected product was trace. In the presence of p-TsOH,

SULFONIC ACID FUNCTIONALIZED NANO ꢀ-AL2O3
Table 1 Catalyst optimization for the synthesis of 4ca
1417
Entry
Catalyst
Mg/mmol
Time/h
Yield/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
—
—
50
10
6
4
4
4
6
6
6
7
12
62
83
93
93
68
59
62
59
72
18
25
15
Nano n-propylsulfonated γ -Al2O3
Nano n-propylsulfonated γ -Al2O3
Nano n-propylsulfonated γ -Al2O3
Nano n-propylsulfonated γ -Al2O3
p-TsOH
100
150
200
150
150
150
150
150
150
150
150
Fe(HSO4)3
Sulfamic acid
Nano n-propylsulfonated SiO2
Nano n-propylsulfonated ZnO
AlCl3
7
12
12
12
Nano γ -Al2O3
FeCl3
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), sulfur (1.2 mmol), DMF (10 mL); 100◦C.
bIsolated yield.
Fe(HSO4)3, sulfamic acid, or other nano n-propylsulfonated metal oxide, such as nano
n-propylsulfonated SiO2, nano n-propylsulfonated ZnO, the product was obtained in low
yield. In the course of optimization of the reaction conditions for the synthesis of 4c,
we found also that using a solvent, such as CH2Cl2, CH3CN, ethanol (EtOH), dimethyl
sulfoxide, or raising reaction temperature did not prove fruitful.
A range of thioamide derivatives was synthesized by the reaction of aldehydes
(1 mmol) with amines (1 mmol) and sulfur (1.2 mmol). The reaction proceeded at 100◦C
in DMF medium within 6 h in excellent yields after the addition of 150 mg/mmol sulfonic
acid functionalized nano γ -Al2O3 (Table 2). Several types of amines (primary, secondary,
Table 2 Preparation of thioamidesa
Entry
Ar
R1
R2
Product
Time/h
Yield/%b
mp/◦C (Lit.)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
c-Hex
C6H5
4-Cl-C6H4
4-Me-C6H4
2-Cl-C6H4
(CH2)5
H
H
H
H
C6H5
H
H
H
H
H
H
—
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4o
5
4
4
5
5
5
5
5
6
6
6
5
6
5
83c
94
113–115 (115–116)10
82–83(81–82)10
93(90,87,84)d
95–96(97–98)10
88
93
95
149–151(152–153)10
130–131(129–130)10
69–71(70–72)10
93
60–61(62–63)10
4-Cl-C6H4
80c
74c
68c
74c
91
116–117(114–116)10
152–154(154–156)10
144–145(146–148)10
113–114(112–114)10
150–152(152–153)10
151–153(149–150)10
90–92(92–93)10
4-NO2-C6H4
4-MeOC6H4
3-NO2-C6H4
4-MeO-C6H4
4-MeO-C6H4
2-thiophenyl
4-MeO-C6H4
C6H5
87
85
aReaction conditions: aldehyde (1 mmol), amine (1 mmol), sulfur (1.2 mmol), DMF (10 mL); sulfonic acid
functionalized nano γ -Al2O3 (150 mg); 100◦C.
bIsolated yield.
cAmmonia as ammonium acetate.
dYields after three times of catalyst recovery.

1418
Z. YIN ET AL.
Scheme 3
aliphatic, benzylic, cyclic) efficiently reacted with aldehydes and sulfur to produce the
corresponding of thioamide derivatives (Table 2). However, aliphatic amines generally
necessitate longer reaction times and decrease the reaction yields.
The reusability of the catalyst was tested in the synthesis of thiobenzanilide (4c). The
catalyst was recovered after each run, washed with EtOH, dried in an oven at 100◦C for
30 min prior to use, and tested for its activity in the subsequent run with no fresh catalyst
added. The catalyst was tested for seven runs. It was seen that the catalyst displayed very
good reusability (Table 2, entry 3).
Scheme 3 shows a plausible role for sulfonic acid functionalized nano γ -Al2O3 in the
Willgerodt–Kindler reaction. The suspension of elemental sulfur in the DMF solution of
aniline remained unreacted because of the poor nucleophilicity of aniline. The addition
of a small amount of sulfonic acid functionalized nano γ -Al2O3 into the reaction mixture
of sulfur with aniline caused a color change of the reaction system, from pale yellow to
deep blue. Therefore, the catalyst is considered to initiate the nucleophilic cleavage of the
elemental sulfur ring to give the polysulfide anions as depicted in Scheme 3.
To illustrate the efficiency of the proposed method, Table 3 compares some of our
results with some of those reported for relevant reagents in the literature, which demonstrates
its significant superiority. Compared with some of the reported methods in Table 3, the
present method has a short reaction time, good yield, and solvent-free conditions. In
addition, sulfonic acid functionalized nano γ -Al2O3 is a stable, cost effective, recyclable,
and noncorrosive catalyst with high efficiency.
EXPERIMENTAL
γ -Alumina powder with particle size at about 20 nm was purchased from Aladdin
(Shanghai, China) and was used without further purification. Other reagents and start-
ing materials were purchased from commercial resources and were used as received. All
products were characterized by comparison of their spectral and physical data with those
Table 3 Sulfonic acid functionalized nano γ -Al2O3-catalyzed synthesis of 4c in comparison with other literatures
Entry
Catalyst and conditions
Solvent
DMF
Time/h
Yield/%
91
Ref.
1
2
3
Na2S · 9H2O (15 mmol%);
115◦C.
Sulfated tungstate (10 wt%);
110◦C.
Sulfonic acid functionalized
nano γ -Al2O3
(150 mg/mmol); 100◦C.
12
8
9
10
DMF
90
DMF
6
93
This work

SULFONIC ACID FUNCTIONALIZED NANO ꢀ-AL2O3
1419
previously reported. Progress of the reactions was monitored by thin layer chromatogra-
phy (TLC). XRD patterns were recorded using a Cu Kα radiation source on a Bruker D8
Advance Bruker powder diffractometer. TEM studies were performed using a JEM 2100
transmission electron microscope on an accelerating voltage of 150 kV. TGA curves are
recorded using a DT-40 thermoanalyzer. IR spectra were determined on FTS-40 infrared
spectrometer. 1H NMR spectra were determined on Bruker AV-400 spectrometer at room
temperature using tetramethylsilane as an internal standard (CDCl3 solution), coupling
constants (J) were measured in Hz. Elemental analyses were performed by a Vario-III
elemental analyzer. Melting points were determined on a XT-4 binocular microscope and
were uncorrected. pH analyses were conducted on a JENCO6171 pH meter.
Synthesis of Sulfonic Acid Functionalized Nano γ -Al2O3
Nano γ -Al2O3 (6 g) was suspended in a toluene solution of 1,3- propane sulfone
(0.1 M, 600 mL) and the colloidal solution was refluxed for 48 h. The sulfonated nano
γ -Al2O3 were isolated and purified by repeated washing and centrifugation.
IR (KBr) ν: 3844, 1640, 1187, 1043, 758, 588 cm−1
.
Ion-Exchange pH Analysis
To an aqueous solution of NaCl (1 M, 25 mL) with a primary pH 5.93, the catalyst
(500 mg) was added and the resulting mixture was stirred for 2 h after which the pH of
solution decreased to pH 1.81. This is equal to a loading of 0.78 mmol SO3H·g−1
.
General Procedure for the Preparation of 4
To a mixture of aldehyde (1 mmol), amine (1 mmol), sulfur (1.2 mmol), and DMF
(10 mL), sulfonic acid functionalized nano γ -Al2O3 (150 mg) was added. The mixture
was stirred at 100◦C for the appropriate time (Table 3). After completion of the reaction
(TLC), the mixture was put into diethyl ether (20 mL) and filtered. The organic layer was
washed with saturated aq. NH4Cl solution, water, dried over Na2SO4, and concentrated
under reduced pressure to get the crude product, which was purified by chromatography
on silica gel with hexane-ethyl acetate (8:2) as eluent to get pure products. The catalyst
was washed with EtOH, dried, and reused for a consecutive run under the same reaction
conditions. The characterization data for the known compounds 4a–4n are presented in the
supplemental materials.
CONCLUSION
In conclusion, we have successfully developed a novel and more environmentally
friendly procedure for the preparation of thioamide derivatives of potential synthetic and
pharmacological interest. The use of sulfonic acid functionalized nano γ -Al2O3 as a non-
toxic and low loading of catalytic system with little reaction times and excellent product
yields are the main advantages of this methodology, which appears to have a broad scope
to represent a straightforward procedure for the synthesis of thioamide derivatives.

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Z. YIN ET AL.
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