Solid-supported sulfonic acid-containing catalysts efficiently promoted one-pot multi-component synthesis of β-acetamido carbonyl compounds

Article abstract of DOI:10.1007/s12039-011-0210-4

Silica-functionalized sulfonic acid (SFSA) and sulfuric acid-modified polyethylene glycol-6000 (PEG-OSO₃H) efficiently catalysed one-pot multi-component condensation of enolizable ketones or alkyl acetoacetates with arylaldehydes, acetonitrile

Full text of DOI:10.1007/s12039-011-0210-4

c
J. Chem. Sci. Vol. 124, No. 2, March 2012, pp. 501–508. ꢀ Indian Academy of Sciences.
Solid-supported sulfonic acid-containing catalysts efficiently promoted
one-pot multi-component synthesis of β-acetamido carbonyl compounds
MOHAMMAD ALI ZOLFIGOLa,∗, ARDESHIR KHAZAEIa,∗, ABDOLKARIM ZAREb,
MOHAMMAD MOKHLESIa, TAHEREH HEKMAT-ZADEHb, ALIREZA HASANINEJADc,
FATEMEH DERAKHSHAN-PANAHa, AHMAD REZA MOOSAVI-ZAREa,
HASSAN KEYPOURa, AHMAD ALI DEHGHANI-FIROUZABADId
and MARIA MERAJODDINb
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran
bDepartment of Chemistry, Payame Noor University, PO BOX 19395-3697 Tehran, Iran
cDepartment of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
dDepartment of Chemistry, Yazd University, Yazd 89195741, Iran
e-mail: mzolfigol@yahoo.com; Khazaei_1326@yahoo.com
MS received 3 July 2011; revised 26 September 2011; accepted 7 October 2011
Abstract. Silica-functionalized sulfonic acid (SFSA) and sulfuric acid-modified polyethylene glycol-6000
(PEG-OSO3H) efficiently catalysed one-pot multi-component condensation of enolizable ketones or alkyl ace-
toacetates with arylaldehydes, acetonitrile and acetyl chloride to afford the corresponding β-acetamido ketone
or ester derivatives in high to excellent yields and in relatively short reaction times. Moreover, in this work,
some novel β-acetamido carbonyl compounds (i.e., one complex structure) are synthesized.
Keywords. Solid-supported catalysts; silica-functionalized sulfonic acid (SFSA); sulfuric acid-modified
polyethylene glycol-6000 (PEG-OSO3H); enolizable ketone; β-acetamido ketone; β-acetamido ester.
1. Introduction
as a most common synthetic route towards β-acetamido
carbonyl compounds. Some catalysts have been em-
ployed to promote this transformation, e.g., CoCl2,7
sulfamic acid,8 SnCl2.H2O,9 1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)
Multi-component reactions (MCRs) are sometimes
viewed as subdiscipline of organic chemistry; actually
this topical field transcends any narrow classification
and pervades essentially all chemistry. In fact, in MCRs,
besides the multi-step reaction and sequential synthe-
sis of target molecule, the desired product can also be
obtained in one-pot reaction of three or more starting
compounds.1 Speed, diversity, efficiency, and environ-
mental amiability are some of the key features of this
class of reactions.1
β-acetamido ketone or ester derivatives are useful
building blocks for a number of biologically and phar-
maceutically valuable compounds. They can be used as
precursor for synthesis of various antibiotics,2 β-amino
acids,3 1,3-amino alcohols,4 δ-lactams,5 as well as bio-
logically attractive compounds such as nikkomycins or
neopolyoxins.4,6 Generally, the one-pot multi-component
condensation of enolizable ketones with aromatic alde-
hydes, acetonitrile and acetyl chloride have been used
{selectfluorTM},10
Zr(HSO4)4,11
Mg(HSO4)2,11
La(OTf)3,12 ZnO,13 ZrOCl2.8H2O,14 K5CoW12O40.
3H2O,15 CeCl3.7H2O,16 and sulfated zirconia.17 How-
ever, the reported protocols for the synthesis of β-
acetamido ketones/esters suffer from one or more of the
following drawbacks: (i) low yields, (ii) long reaction
times, (iii) the use of large amount of catalyst, (iv) the
use of toxic or expensive catalysts, (v) tedious work-
up procedure, (vi) harsh reaction conditions, and (vii)
performing of the reaction under certain special condi-
tions. Thus, search for finding efficient, safe and inex-
pensive catalysts for the preparation of β-acetamido
ketones/esters is still relevant.
In recent years, the use of solid-supported catalysts
has gained considerable attention both in industrial and
academia research due to their unique properties such
as enhanced reactivity as well as selectivity, efficiency,
straightforward work-up, and the eco-friendly reaction
∗For correspondence
501

502
Mohammad Ali Zolfigol et al.
tetraones,18o thiocyanohydrines,18p acylals,18q bis(indolyl)
methanes,18r and poly-substituted quinolines.18s
Considering the above points, we report here new
catalytic applications of SFSA and PEG-OSO3H in the
synthesis of β-acetamido ketones and esters via the
one-pot multi-component condensation of enolizable
ketones/alkyl acetoacetates with aromatic aldehydes,
acetonitrile and acetyl chloride at room temperature
(scheme 1).
SiO
I:
SO H
2
PEG
OSO H
II:
3
3
Figure 1. The structure of silica-functionalized sulfonic
acid (SFSA, I) and sulfuric acid-modified polyethylene
glycol-6000 (PEG-OSO3H, II).
conditions.18 In this type of catalysts, various solid-
supports have been used, including porous inorganic
oxides such as silica, and organic polymers such as
polyethylene glycol, because of their high surface areas
and well-defined structures.18 One useful example of
silica-supported catalysts is silica-functionalized sul-
fonic acid (SFSA) in which the reactive centers are
highly mobile similar to that of homogeneous cata-
lysts (figure 1),18e−k and has been used as an efficient
acidic catalyst for some organic transformations such as
acetalization of carbonyl compounds,18e thioacetaliza-
tion of carbonyl compounds,18f synthesis of benzimida-
zoles,18g preparation of 3,4-dihydropyryimidinones,18h
synthesis of 1,4-dihydropyridines,18i brominatation of
carbonyl compounds,18j and brominatation of phenols,
alkoxy arenes and anilines.18k Polyethylene glycols
(PEGs) are another type of solid-supports which are
inexpensive, readily functionalized, environmentally
benign and commercially available polymeric matrixes
with their molecular weight is >2000 Da.181,m More-
over, high reactivity, lack of diffusion phenomena, and
2. Experimental
2.1 General
All chemicals were purchased from Merck or Fluka
Chemical Companies. All known compounds were iden-
tified by comparison of their melting points and spectral
data with those reported in the literature. Progress of
the reactions was monitored by TLC using silica gel
SIL G/UV 254 plates. The 1H NMR (300 MHz) and 13C
NMR (75 MHz) were run on a Bruker Avance DPX-
250, FT-NMR spectrometer (δ in ppm). Microanalysis
was performed on a Perkin-Elmer 240-B microana-
lyzer. Melting points were recorded on a Büchi B-545
apparatus in open capillary tubes.
2.2 General procedure for the synthesis
of β-acetamido carbonyl compounds
analytical simplicity (advantageous features of homo- To a mixture of compounds consisting of enoliz-
geneous solution chemistry) besides the ready isola- able ketone or alkyl acetoacetate (1 mmol), arylalde-
tion and purification of products (advantageous features hyde (1 mmol), acetonitrile (3 mL) and acetyl chloride
of solid phase methods)18m introduce PEGs as an im- (0.3 mL) in a 10 mL round-bottomed flask, was added
portant group of polymeric supports for the preparation SFSA (0.05 g) or PEG-OSO3H (0.15 g, 0.025 mmol,
of polymer-supported catalysts. Sulfuric acid-modified 2.5 mol%), and the resulting mixture was stirred at
polyethylene glycol-6000 (PEG-OSO3H) is an interest- room temperature. After completion of the reaction, as
ing case of PEG-supported catalysts that functionalized monitored with TLC, crushed ice (10 mL) was added to
by sulfonic acid groups, and has been successfully used the reaction mixture and stirred thoroughly. On solid-
for synthesis of 3,4-dihydropyrimidones,18n triazolo[1, ification, the crude product was filtered, dried, and
2-a]indazole-triones and spiro triazolo[1,2-a]indazole- purified by short column chromatography on silica gel
O
O
O
O
R
O
O
NH OR"
I or II
+
R'
CH3
or
R
H
+ CH3CN
OR"
NH O
or
CH3COCl, r.t.
R
O
O
R'
R = Phenyl, Naphthyl, Aryl
R' = Phenyl, Aryl R" = Me, Et
SiO2
PEG
OSO3H
I:
SO3H II:
Scheme 1. The synthesis of β-acetamido ketones/esters from enolizable ketones/alkyl
acetoacetates, aldehydes, acetonitrile and acetyl chloride using SFSA and PEG-OSO3H.

Synthesis of β-acetamido carbonyl compounds
503
eluted with EtOAc/n-hexane (1/4). Note: Compounds
8, 9, 10, 17, 20, 21, 22, 23, 25, 26 and 2a are new.
Table 2. Study of the role of silica as well as polyethylene
glycol skeletons of the catalysts on the reaction.
Entry Catalyst
Catalyst
amount
Time Yielda
(h)
(%)
3. Results and discussion
1
2
3
4
5
6
7
8
SFSA
PEG-OSO3H
H2SO4
ClSO3H
SiO2
PEG-6000
H2SO4/SiO2
0.05 g
1.5
1.75
7
7
10
90
92
36
23
11
15
40
46
0.15 (2.5 mol%)
2.5 mol%
2.5 mol%
0.05 g
0.15 g (2.5 mol%) 10
2.5 mol%/0.05 g
Initially, the silica and polymer-supported SO3H-
containing catalysts (SFSA and PEG-OSO3H) were
prepared according to the reported procedures.18f,o, To
examine the applicability of the catalysts in the syn-
thesis of β-acetamido carbonyl compounds, the multi-
component condensation of 4-bromoacetophenone
(1 mmol) with benzaldehyde (1 mmol), acetonitrile
(3 mL) and acetyl chloride (0.3 mL) was selected as a
model reaction, and studied in the presence of differ-
ent amounts of SFSA as well as PEG-OSO3H at room
temperature. The results are summarized in table 1.
As it is shown in table 1, 0.15 g (2.5 mol%) of PEG-
OSO3H or 0.05 g of SFSA efficiently catalysed the reac-
tion, and produced the product in high yields and in
short reaction times (table 1, entries 3 and 8). Increas-
ing the amounts of the catalysts showed no substantial
improvement in the yields. Moreover, it was observed
that the reaction did not proceed at all in the absence of
SFSA or PEG- OSO3H (table 1, entry 1).
To recognize the role of silica as well as polyethy-
lene glycol skeletons of the catalysts in the reaction,
the condensation between 4-bromoacetophenone, ben-
zaldehyde, acetonitrile and acetyl chloride was checked
using SO3H residues of the catalysts without solid sup-
ports (H2SO4 and ClSO3H) as well as solid supports
(SiO2 and PEG-6000) separately, in which significant
decrease in the yields, and increase in the reaction
times were observed (table 2, entries 2–6). Furthermore,
7
7
H2SO4/PEG-6000 2.5 mol%/0.15 g
aIsolated yield.
the reaction was examined in the presence of H2SO4
together with SiO2, H2SO4 together with PEG wherein
the reaction times were longer, and the yields were
lower than SFSA or PEG-OSO3H (table 2, entries 7 and
8). These results confirmed that supporting the SO3H
group on silica or PEG-6000 significantly increased the
efficacy of the catalysts.
In another study, generality and efficiency of SFSA
and PEG-OSO3H in the synthesis of β-acetamido car-
bonyl compounds were explored under the optimized
reaction conditions by the reaction of different enoliz-
able carbonyl compounds with a broad range of struc-
turally and electronically diverse arylaldehydes, ace-
tonitrile and acetyl chloride. The results are given in
table 3. As it can be seen in table 3, all enolizable car-
bonyl compounds (acetophenone and its derivatives bear-
ing electron-releasing substituents, electron-withdrawing
substituents and halogens on their aromatic rings, and
alkyl acetoacetates) as well as arylaldehydes (benzalde-
hyde and its derivatives possessing electron-releasing
substituents, electron-withdrawing substituents and
halogens on their aromatic rings) afforded the desired
β-acetamido carbonyl compounds in high to excel-
lent yields and in short reaction times. Moreover,
the method worked well when 2-naphthaldehyde and
anthracene-9-carbaldehyde were used instead of ben-
zaldehydes (table 3, compounds 9, 10, 13, 17, 21–23,
25 and 26). In the reaction of p-aminoacetophenone
with 2-naphthaldehyde (or anthracene-9-carbaldehyde),
acetonitrile and acetyl chloride, the corresponding N-
acylated β-acetamido ketones were obtained (table 3,
compounds 22 and 23).
Table 1. Effect of different amounts of the catalysts on
the reaction of 4-bromoacetophenone (1 mmol) with ben-
zaldehyde (1 mmol), acetonitrile (3 mL) and acetyl chloride
(0.3 mL) at room temperature.
Entry Catalyst
Catalyst
Amount (g)
Time (h) Yielda (%)
1
2
3
4
5
6
7
8
9
None
SFSA
SFSA
SFSA
SFSA
PEG-OSO3H 0.05
PEG-OSO3H 0.1
-
12
3
No reaction
0.01
0.05
0.1
0.2
45
90
86
88
68
84
92
92
1.5
1.5
1.5
6
Interestingly,
the
condensation
of
p-
bromoacetophenone (3.2 equiv.) with a tris-aldehyde (1
equiv.), acetonitrile (6 mL) and acetyl chloride (0.9 mL)
in the presence of SFSA as well as PEG-OSO3H at
room temperature afforded complex compound 2a in
85 and 88% yields within 2.5 and 2.25 h, respectively
3
PEG-OSO3H 0.15 (2.5 mol%) 1.75
PEG-OSO3H 0.2 1.75
aIsolated yield.

504
Mohammad Ali Zolfigol et al.
Table 3. The synthesis of β-acetamido ketones and esters via the condensation of enolizable ketones or alkyl acetoacetates
with aldehydes, acetonitrile and acetyl chloride.
SFSA
Time (h)/Yielda (%)
PEG-OSO3H
Time (h)/Yielda (%)
Entry
1
Product
M.p. ˚C (lit.)
O
NH
O
O
1.75/91
1.5/88
2/93
101–103
(104–106)25
NH
O
2
3
1.5/89
109–111
(110–112)26
MeO
O
NH
O
2.5/83
2.5/86
3/88
151–152
148–149)30
O2N
O
NH
O
4
5
2.75/84
120–123
(119–121)30
NO2
O
NH
O
1.5/89
1.5/90
157–159
(156–158)30
Cl
O
NH
O
6
7
2.25/86
1.25/88
2.5/84
158–160
(155–157)33
Cl
O
NH
O
1.75/85
127–129
(130–132)33
OMe

Synthesis of β-acetamido carbonyl compounds
505
Table 3. (continued)
SFSA
Time (h)/Yielda (%)
PEG-OSO3H
Time (h)/Yielda (%)
Entry
Product
M.p. ˚C (lit.)
124–127b
O
O
NH
O
8
0.75/93
1.0/91
MeO
OMe
OMe
NH
O
9
1.75/89
3/80
1.75/90
3.5/84
108–110b
138–140b
OMe
O
O
HN
10
O
O
O
NH
NH
NH
O
O
O
11
12
1.25/85
1.5/90
1.75/81
2/90
118–119
(-)18
Me
Me
Me
Me
130–132
(-)18
Cl
13
14
2.25/83
2.5/84
3/85
111–112
(112–114)26
O
NH
O
O
2.5/89
75–77
(74–76)33
NO2
NH
O
15
3/80
2.75/86
185–188
(187–188)25
O2N
NO2

506
Mohammad Ali Zolfigol et al.
Table 3. (continued)
SFSA
Time (h)/Yielda (%)
PEG-OSO3H
Time (h)/Yielda (%)
Entry
Product
M.p. ˚C (lit.)
O
NH
O
16
2.5/81
3/86
114–116
(116–118)26
Cl
NO2
O
NH
O
17
2.5/82
1.5/90
2.75/84
1.75/92
165–166b
NO2
O
NH
O
18
19
100–101
(98–100)26
Br
O
NH
O
2.25/81
2/87
162–163
(-)18
O2N
Br
O
NH
NH
O
20
21
22
2/85
1.5/87
2/88
1.75/88
1.5/89
104–105b
138–140b
168–174b
OHC
Br
O
O
Br
O
O
NH
O
1.25/80
N
H
O
NH
O
O
23
3.25/79
3.75/81
166–167b
HN

Synthesis of β-acetamido carbonyl compounds
507
Table 3. (continued)
SFSA
Time (h)/Yielda (%)
PEG-OSO3H
Time (h)/Yielda (%)
Entry
Product
M.p. ˚C (lit.)
O
NH
O
24
2.25/88
2.25/86
140–142
O
O
(140–141)25
O
O
NH
25
26
2/89
2.25/89
2/90
138–139b
149–152b
O
O
O
O
O
NH
1.75/85
O
aIsolated yield. bThis compound is new.
O
HN
O
O
OHC
O
Br
O
O
HN
O
O
O
CHO
+
I or II
CH3COCl/rt
2.25-2.5h
CH3CN
+
Br
O
O
O
Br
CHO
N
H
O
(2a)
85-88%
Br
SiO2
I:
SO3H
PEG
II:
OSO3H
Scheme 2. The synthesis of complex compound 2a.
(scheme 2). For the first time, we have reported the Supporting information
synthesis of this class of β-acetamido ketones.
Spectral data for compound entries 7–23 and entries
25, 26 are given as supplementary material (www.ias.
ac.in/chemsci).
4. Conclusion
In conclusion, we have introduced the new applications
of SFSA and PEG-OSO3H in organic synthesis. In this
work, we have successfully used them for the prepa-
ration of β-acetamido ketone/ester derivatives from
enolizable ketones or alkyl acetoacetate, arylaldehydes,
acetonitrile and acetyl chloride. The promising points
for the application of the solid-supported catalysts in the
reaction are efficiency, generality, high yields, relatively
Acknowledgements
The authors gratefully acknowledge the partial support
received from the Research Affairs Office of Bu-Ali
Sina University (Grant number 32-1716 entitled devel-
opment of chemical methods, reagents and molecules),
short reaction times, mild conditions, cleaner reaction and Center of Excellence in Development of Chemical
profile and simplicity.
Method (CEDCM), Hamedan, I.R. Iran.

508
Mohammad Ali Zolfigol et al.
15. Nagarapu L, Kantevari S, Cheemalapati V N, Apuri S
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