SBA-15-Pr-SO3H: An efficient, environment friendly and recyclable heterogeneous nanoreactor catalyst for the one-pot multicomponent synthesis of β-acetamido ketones

Article abstract of DOI:10.1007/s12039-014-0762-1

SBA-15-Pr-SO₃H catalyzes the multi-component condensation of aromatic aldehydes, ketones and acetonitrile in the presence of acetyl chloride at 80°C to afford β-acetamido ketones in excellent yields. The catalyst can be recovered and recycled f

Full text of DOI:10.1007/s12039-014-0762-1

c
J. Chem. Sci. Vol. 127, No. 1, January 2015, pp. 167–172. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-014-0762-1
SBA-15-Pr–SO3H: An efficient, environment friendly and recyclable
heterogeneous nanoreactor catalyst for the one-pot multicomponent
synthesis of β-acetamido ketones
KIUMARS BAHRAMIa,b,∗, MOHAMMAD M KHODAEIa,∗ and PEYMAN FATTAHPOURa
aDepartment of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, 67149-67346, Iran
bNanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah,
67149-67346, Iran
e-mail: Kbahrami2@hotmail.com; mmkhoda@razi.ac.ir
MS received 01 April 2013; revised 18 June 2014; accepted 23 June 2014
Abstract. SBA-15-Pr–SO3H catalyzes the multi-component condensation of aromatic aldehydes, ketones
and acetonitrile in the presence of acetyl chloride at 80◦C to afford β-acetamido ketones in excellent yields.
The catalyst can be recovered and recycled for subsequent reactions without any appreciable loss of efficiency.
Keywords. Multicomponent reactions; β−acetamido ketones; nanoporous silica; nanoreactor
CeCl3.7H2O,10b various metal chlorides,11a TMSCl,11b
Borax/POCl3,12a solid acid Hβ-zeolite,12b and iodine.
However, in spite of their potential utility, some of
these reported methods suffer from some drawbacks
such as low yield, prolonged reaction time, use of haz-
ardous and noxious reagents, use of excess amounts
of reagents, and incompatibility of sensitive groups
to the reaction conditions. In recent years, the devel-
opment of more economical and environment-friendly
conversion processes is gaining interest in the chemical
community.
1. Introduction
The demand for structure diversification to synthesize
compound libraries for screening in drug discovery
is the driving force behind the development of new
methodologies and structural motifs.
Multi-component reactions are a promising and vital
field of chemistry because the synthesis of complex
molecules can be accomplished in a very fast, effi-
cient and time saving manner without the isolation of
any intermediates and hence it has attracted organic
chemists to develop new multi-component reactions1
(figure 1).
β−Acetamido ketones are versatile intermediates in
organic synthesis due to their polyfunctional nature
and also their presence in a number of biologically
or pharmacologically important compounds.2,3 These
compounds are also useful in the synthesis of other
important organic molecules like 1,3-amino alcohols4,5
units common in natural nucleoside peptide antibiotics,
e.g., nikkomycines or neopolyoxins6,7 (figure 2).
Owing to the versatile biological activity of
β−acetamido ketones, development of an alternative
synthetic methodology is of paramount importance.
Earlier reports on the synthesis of β-acetamido ketones
through multi-component reactions is mainly by using
catalysts such as CoCl2,8a FeCl3.6H2O,8b montmoril-
lonite K10 clay,9a selectfluor,9b silica sulphuric acid,10a
Mesoporous materials have attracted considerable
attention since they possess potential applications as
catalysts, catalysts supports, adsorbents as well as
nanoreactors for making new materials.13–18
The SBA-15 is nanoporous silica with a hexagonal
structure, large pore size, high surface area, high ther-
mal stability and is also diffusion-free due to the thicker
pore walls and larger pore size (figure 3). Integration of
acidic functional groups (e.g., SO3H) into SBA-15 has
been explored to produce promising solid acids. Surface
functionalization with sulfonic acid groups was carried
out according to the known literature procedure19 with
modification in the oxidation step20 (scheme 1). Typi-
cally, the acid content of SBA-15-Pr-SO3H was mea-
sured by ion-exchange pH analysis. The acid amount of
SBA-15-Pr-SO3H was determined to be 1 mmolg−1.
As a part of our continued activities in this area,21
we have investigated a mild and suitable method
for the preparation of β-acetamido ketones by multi-
component reactions of an aromatic aldehyde, acetyl
∗For correspondence
167

168
Kiumars Bahrami et al.
Stepwise reactions:
Multicomponent reactions:
Figure 1. Stepwise reaction versus multi-component
reaction.
chloride, ketone and acetonitrile in the presence of
sulfonic acid functionalized mesoporous SBA-15
as a heterogeneous recyclable nanoreactor catalyst
(scheme 2).
Figure 3. SEM images of SBA-15.
2. Experimental
of the reaction as indicated by TLC, the reaction mix-
ture was filtered, and the heterogeneous catalyst was
separated. The organic portion was poured into cold
water (10 mL). The solid was suction filtered, washed
with cold water (20 mL × 2), filtered and recrystallized
from ethyl acetate/n-hexane to afford pure β-acetamido
ketone in good to excellent yields. The wet catalyst
was recycled and no significant change in activity was
observed after three cycles.
Products were known and characterized by compari-
son of their spectral data (NMR) and melting points
with those reported in the literature. Monitoring of the
reaction was accomplished by TLC on SIL G/UV 254
sheets. All yields refer to isolated products.
2.1 General procedure for synthesis of β-acetamido
ketones
A mixture of aromatic aldehyde (1 mmol), acetophe-
none (1 mmol), acetyl chloride (2 mmol) and SBA-
15-Pr–SO3H (0.6 g, 0.6 mmol, –SO3H groups) in ace-
tonitrile (5 mL) was stirred at 80◦C. After completion
2.2 Spectral data of some of the products
2.2a N-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-
acetamide (5g): 1H NMR (CDCl3, 200 MHz): δ 1.94
2
3
(s, 3H), 3.39 (dd, J17.0 Hz and J6.1 Hz, 1H), 3.65
2
3
HO
(dd, J17.0 Hz and J5.7 Hz, 1H), 5.46 (m, 1H),
7.18–7.52 (m, 8H), 7.83–7.87 (m, 2H).
O
NH
N
13C NMR (CDCl3, 50 MHz): δ 22.9, 43.8, 49.0,
127.9, 128.1, 128.4, 128.5, 132.6, 133.3, 136.3, 140.3,
169.7, 197.4.
N
O
O
HO
O
OH
H2N
HN
O
OH
HO
2.2b N-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)-
acetamide (5h): 1H NMR (CDCl3, 200 MHz): δ 2.10
Nikkomycine Z inhibits the formation of the fungal cell wall
2
3
(s, 3H), 3.52 (dd, J 16.7 Hz and J 5 Hz, 1H), 3.82
2
3
(dd, J 16.7 Hz and J 5.8 Hz, 1H), 5.89 (m, 1H),
7.13–7.62(m, 9H), 7.96 (d, J7.4Hz, 2H).
13C NMR (CDCl3, 50 MHz): δ 23.3, 41.4, 48.1,
127.0, 128.1, 128.4, 128.7, 129.9, 132.5, 133.6, 136.4,
138.1, 198.8.
HO
HO
H
N
O
O
N
N
O
HO
O
OH
H2N
HN
OH
O
HO
2.2c N-(3-(4-Chlorophenyl)-1-(4-chlorophenyl)-3-
oxopropyl)acetamide (5i): 1H NMR (CDCl3, 200
Neopolyoxin B as chitin synthetase inhibitor
2
3
Figure 2. Structures of nikkomycine Z and neopolyoxin B
MHz): δ 2.01 (s, 3H), 3.36 (dd, J17.0 Hz and J6.1
2
3
as drug candidates.
Hz, 1H), 3.7 (dd, J17.0 Hz and J5.0 Hz, 1H), 5.50

Efficient and recyclable heterogeneous nanoreactor catalyst
169
3. Results and Discussion
In order to carry out such a multi-component reaction
in a more efficient way, some experimentation varying
the molar ratio of the reactants, reaction temperature,
reaction time and possible solvents were conducted.
The optimized condition utiliziing a 1:1:2 ratio of alde-
hyde, ketone and acetyl chloride in a one-pot reac-
tion employing refluxing acetonitrile (reagent as well
as solvent), 0.6 equivalent of propylsulfonic acid func-
tionalized mesoporous silica (SBA-15-Pr–SO3H) with
respect to the aldehyde suffices for complete conversion
of the starting materials.
The reaction remains incomplete if lower amounts
of catalyst are used. The effect of temperature was
studied by carrying out the model reaction in the pre-
sence of SBA-15-Pr–SO3H (0.6 g, 0.6 mmol, –SO3H
groups) in acetonitrile at different temperatures (room
temperature, 60 and 80◦C). It was observed that
the time reaction was decreased and the yield was
increased as the reaction temperature was raised. From
these results, 80◦C is selected as the best tempera-
ture for all subsequent studies. It is noteworthy that,
increasing the amount of SBA-15-Pr–SO3H and time
did not increase the yield of product in the model
reaction.
Scheme 1. Schematic representation for the preparation of
SBA-15-Pr–SO3H as a nanoreactor catalyst.
(m, 1H), 6.69 (d, J 7.9 Hz, 1H), 7.41(d, J8.6 Hz, 4H),
7.83 (d, J8.6 Hz, 4H).
13C NMR (CDCl3, 50 MHz): δ 23.4, 43.0, 49.3,
127.9, 128.8, 129.1, 129.5, 133.3, 134.7, 139.3, 140.2,
169.6, 197.0.
The used catalyst could be washed with dichloro-
methane and subjected to a second run of the reac-
tion process with benzaldehyde and acetophenone. The
results of the first experiment and subsequent experi-
ments were almost consistent in yields (93, 94 and 91%
after three runs). Thus, the catalyst can be recycled sev-
eral times with negligible loss of catalytic activity and
there is no need for regeneration of the catalyst.
2.2d N-(1-(3-Nitrophenyl)-3-oxo-3-phenylpropyl)-
acetamide (5j): 1H NMR (CDCl3, 200 MHz): δ1.98
2
3
(s, 3H), 3.42 (dd, J17.6 Hz and J5.2 Hz, 2H), 3.71
2
3
(dd, J17.6 Hz and J8.5 Hz, 2H), 5.54–563(m, 1H),
6.99–8.14 (m, 10H).
13C NMR (CDCl3, 50 MHz): δ 23.0, 42.4, 48.7,
120.9, 122.0, 128.0, 128.4, 129.1, 132.6, 133.5, 135.8,
143.1, 148.0, 169.4, 197.5.
To show the generality of this method, a wide
range of aldehydes and acetophenones were subjected
to optimized reaction conditions and the results are
summarized in table 1. It is evident from table 1
that this method is effective for the preparation of
β-acetamido ketones from both aldehydes as well as
acetophenone derivatives. Aromatic aldehydes or ace-
tophenones with activating and deactivating groups
underwent smooth transformation to the correspond-
ing β-acetamido ketones, without the formation of any
side products, in high to excellent yields and reason-
able reaction times, emphasizing the generality of our
methodology. The results also showed that the reaction
times for the substrates containing electron withdra-
wing groups are slightly longer. Several functionalities
such as bromo, chloro, hydroxyl, methoxy and nitro
were compatible with this procedure. The experiment
for this reaction is remarkably simple and requires
no inert atmosphere. Anyway, this protocol has its
2.2e N-(1-(4-Chlorophenyl)-3-(4-nitrophenyl)-3-
oxopropyl)acetamide (5k): 1H NMR (CDCl3, 200
2
3
MHz): δ 1.70 (s, 3H), 3.40 (dd, J17.0 Hz and J6.0
Hz, 1H), 3.54 (dd, 2J 17.0 Hz and 3J 4.5Hz, 1H), 5.43
(m, 1H), 6.51 (s, 1H), 7.21(s, 4H), 8.00 (d, J8.5 Hz,
2H), 8.22 (d, J8.5 Hz, 2H).
13C NMR (CDCl3, 50 MHz): δ22.9, 43.5, 49.0, 123.6,
127.6, 128.5, 128.8, 133.1, 138.5, 140.3, 150.1, 169.3,
196.1.
R
CHO
1
R
O
O
NHCOCH3
O
SBA-15-PrSO3H
80 °C
H3C
C
3
Cl
Ar
C
2
CH3
CH3
C
N
Ar
5
4
Scheme 2. Synthesis of β-acetamido carbonyl compounds.

170
Kiumars Bahrami et al.
Table 1. One-pot condensation of aryl aldehydes, ketones, acetyl chloride and acetonitrile to give the corresponding β-
acetamido ketones catalyzed by SBA-15-Pr-SO3H.
Entry Ar
R
Product
Yield %b/t(min) M.p. (◦C)Ref
1
C6H5
C6H5
93 (60)
99–102 (102–104)22
2
3
4
C6H5
4-CH3OC6H4
75 (45–50)
80 (50–60)
85 (60)
128–129 (130)23
17–119 (120)24
127 (126–128)25a
4-CH3OC6H4 4-ClC6H4
2-HOC6H4
4-NO2C6H4
4-NO2C6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
5
6
90 (75)
181 (182–183)25b
176 (176–179)25c
83 (130)
7
8
9
4-ClC6H4
2-ClC6H4
4-ClC6H4
C6H5
94 (50)
95 (85)
94 (70)
146–148 (146–148)10
147–149 (149–151)26
141–143 (141–143)10
C6H5
4-ClC6H4
10
3-NO2C6H4
C6H5
90 (85)
113 (114–116)25b

Efficient and recyclable heterogeneous nanoreactor catalyst
171
Table 1. (Continued)
11
12
4-ClC6H4
4-NO2C6H4
85 (110)
70 (60)
118–120 (116–118)26
4-CH3C6H4
4-NO2C6H4
87–90 (83–85)9
13
4-CH3C6H4
CH3CH2
4-Ph C6H4
90 (100)
30 (60)
137 (138–140)27
97 (98–100)25
14
C6H5
a
All products were characterised by comparison of their spectral and physical data with those of the authentic samples.
b Yields refer to pure isolated products.
Table 2. Comparison of some of the results obtained with
some of those reported in the literature.
Entry Substrate Conditions Ref.
Yield %/(Time)
1
2
3
5a
5e
5h
this work
93 (1 h)
90 (6 h)
ZnO/80◦C28
silica sulfuric acid/80◦C10 91 (65 min)
H7SiW9V3O40/80◦C29
HClO4-SiO2/80◦C30
this work
70 (4 h)
89 (2.5 h)
94 (50 min)
93 (5.5 h)
ZnO/80 ◦C28
silica sulfuric acid/80◦C10 89 (70 min)
H7SiW9V3O40/80◦C29
HClO4-SiO2/80◦C30
this work
76 (3 h)
94 (2.5 h)
90 (85 min)
88 (5.5 h)
ZnO/80◦C28
silica sulfuric acid/80◦C10 82 (110 min)
H7SiW9V3O40/80◦C29
HClO4-SiO2/80◦C30
88 (5 h)
82 (3 h)
Scheme 3. A plausible mechanism for the preparation of
β-acetamido carbonyl compounds.
Next, the enol form of acetophenone derivative attacks
limitations, for example, it produces low yields for II to give III. Hydrolysis of III with elimination of
aliphatic aldehydes (table 1, entry 15).
acetate gave the desired β-acetamido ketone.
The suggested mechanism for this reaction is pre-
A comparison of the efficiency of this method to
sented in scheme 3. It is suggested that the first proto- previously selected methods is gathered in table 2. As
nation of the aldehyde produces intermediate I which can be seen, the present protocol is indeed superior to
then reacts with acetonitrile to produce intermediate II. several other protocols.

172
Kiumars Bahrami et al.
8. (a) Mukhopadhyay M, Bhatiaand B and Iqbal J 1997
4. Conclusion
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9. (a) Bahulayan D, Das S K and Iqbal J 2003 J.
Org. Chem. 68 5735; (b) Shinu V S, Sheeja B,
Purushothaman E and Bahulayan D 2009 Tetrahedron
Lett. 50 4838
10. (a) Khodaei M M, Khosropour A R and Fattahpour
P 2005 Tetrahedron Lett. 46 2105; (b) Khan A T,
Choudhury L H, Parvin T and Ali M A 2006 Tetrahe-
dron Lett. 47 8137
11. (a) Pandey G, Singh R P, Garg A and Singh V K 2005
Tetrahedron Lett. 46 2137; (b) Mao H, Wan J and Pan Y
2009 Tetrahedron 65 1026
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mun. 41 1786; (b) Bhat R P, Vivek P R, Varghese M A,
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4801; (c) Das B, Reddy K R, Ramu R, Thirupathi P and
Ravikanth B 2006 Synlett 1756
We have described an efficient method for the one-pot
synthesis of β-acetamido ketones using an environment
friendly, heterogeneous nanoreactor catalyst. Simpli-
city, excellent yield of products, reusability of the cat-
alyst, and clean reaction conditions are established.
This methodology also overcomes the formation of
unwanted by-product. Thus, we believe that the present
methodology opens up new possibilities for medicinal
chemistry and material sciences, and can prove to be an
important addition to the existing methodologies. Fur-
ther investigations into the scope and synthetic appli-
cations of this nanoreactor catalyst are currently under
investigation in our laboratory.
Supplementary Information
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and Vafaeezadeh M 2012 Chem. Commun. 48 3327
14. Li C 2004 Catal. Rev. 46 419
Complete experimental procedures and relevant spectra
(1H NMR and 13C NMR spectra) for some compounds
(figure S1–S8) are given in Supplementary Informa-
tion, which is available free of charge in www.ias.ac.in/
chemsci.
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Mater. 77 1
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9040
Acknowledgments
We are thankful to the Razi University Research Coun-
cil for partial support of this work.
19. Yang L M, Wang Y J, Luo G S and Dai Y Y 2005
Microporous Mesoporous Mater. 84 275
20. Bahrami K, Khodaei M M and Abbasi J 2012 Synthesis
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