VB1-Al2O3-catalyzed one-pot condensation of aromatic ketone, aromatic aldehyde, and amide

Article abstract of DOI:10.1016/j.tetlet.2010.07.008

A novel and green approach for the efficient synthesis of β-amido ketones using VB₁-Al₂O₃ as a heterogeneous catalyst for the first time from an aldehyde, enolizable ketones, and an amide in EtOH is described. The present methodology has several advantages from the economical and environmental points of view, such as simple procedure, low catalyst loading, high atom economy, and good yields.

Full text of DOI:10.1016/j.tetlet.2010.07.008

Tetrahedron Letters 51 (2010) 4746–4749
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
VB1–Al2O3-catalyzed one-pot condensation of aromatic ketone, aromatic
aldehyde, and amide
a,b,
Min Lei a, Lei Ma a, , Lihong Hu
*
*
a School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200 237, PR China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201 203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and green approach for the efficient synthesis of b-amido ketones using VB1–Al2O3 as a hetero-
geneous catalyst for the first time from an aldehyde, enolizable ketones, and an amide in EtOH is
described. The present methodology has several advantages from the economical and environmental
points of view, such as simple procedure, low catalyst loading, high atom economy, and good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 May 2010
Revised 28 June 2010
Accepted 2 July 2010
Available online 7 July 2010
Carrying out an organic reaction using solid-supported catalysts
has become highly desirable in recent years to meet the environ-
mental considerations.1 The common features of solid-supported
catalysts are low toxicity, moisture resistance, air tolerance, and
low price. The literature conveys that they can effectively promote
several carbon–carbon and carbon–heteroatom bond formation
reactions in good yields.2
Initially, we investigated the condensation reaction of benzalde-
hyde 1a (5 mmol), acetophenone 2a (5 mmol), and benzamide 3a
(5 mmol) in alcohol (3 mL) as the solvent in the presence of differ-
ent catalysts and the results are summarized in Table 1.
In this three-component reaction, we found catalysts had signif-
icant effects on the reaction time and yields (Table 1). The results
indicated that this three-component reaction could not take place
in the presence of 10 mol % classical Lewis acid as catalysts, such as
ZnCl2, CuCl2, MgCl2, FeCl3, Yb(OTf)3, and Cu(ClO4)2 (Table 1, entries
1–6). Then, we carried out the reaction using VB1 as an organocat-
alyst, but the desired product was not afforded (Table 1, entry 7).
Moreover, we also found that this reaction could be carried out
in the presence of Al2O3 as the catalyst, but the yield was very
low (30%). To detect whether the use of VB1–Al2O3 was efficient,
we carried out the reaction in EtOH in the presence of 10 mol %
VB1–Al2O3 for 15 h to afford the desired product 4a in 84% yield.
Encouraged by the result, we subsequently changed the amount
of VB1–Al2O3 from 1 to 10 mol %, finding that 5 mol % had a
b-Amido ketones are important intermediates in organic synthe-
sis due to their multifunctional nature and presence in several bioac-
tive compounds.3 They can be converted into amino alcohols,4
b-amino acids,5 and
c
-lactams,6 which may be applied for the
synthesis of various important antibiotics.4–7 The preparation of
b-amido ketonescan becarriedout bythe condensationofaldehydes,
enolizable ketones, acetyl chloride, and acetonitrile (Scheme 1) in the
8
ꢀ
presence of Lewis or Brønsted acid catalysts, such as Iodine, mont-
morillonite K10 clay,9 CoCl2,5,10 ZrOCl2Á8H2O,11 CeCl3Á7H2O,12
Sc(OTf)3,13 heteropoly acid,14 Nafion-H,15 FeCl3Á6H2O,16 SiCl4–
ZnCl2,17 Zr(HSO4)4, and Mg(HSO4)2.18 However, this method so far
suffers from a low atom economy because the use of stoichiometric
amounts of acetyl chloride as an additional reagent is necessary
to obtain satisfactory results. Therefore, it is necessary to develop
an efficient and versatile method for the synthesis of these
compounds.19
O
CH3COCl
Cat
O
O
HN
R1 CHO
+
+
CH3CN
In continuation of our work on the application of heterogeneous
catalysts for the development of useful synthetic methodologies,
we now show that b-amido ketones can be produced using VB1–
Al2O3 as an efficient heterogeneous catalyst via a direct condensa-
tion of aldehydes, enolizable ketones, and amides (Scheme 2). To
the best of our knowledge, there has been no report on the use
of VB1–Al2O3 as a catalyst in synthetic organic chemistry.20
R2
R2
R1
Scheme 1. The classical method for the synthesis of b-amido ketones.
O
O
O
Cat
O
HN
R3
R1 CHO
+
+
EtOH
R3
NH2
R2
R2
R1
* Corresponding authors. Tel.: +86 21 6425 3691; fax: +86 21 5027 2221 (L.M.).
E-mail addresses: malei@ecust.edu.cn (L. Ma), simmhulh@mail.shcnc.ac.cn (L.
1
2
3
4
Hu).
Scheme 2. One-pot synthesis of b-amido ketones 4.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.008

M. Lei et al. / Tetrahedron Letters 51 (2010) 4746–4749
4747
Table 1
Table 3
Optimization of catalystsa
Synthesis of b-amido ketones catalyzed by VB1–Al2O3
a
Entry
Catalyst
Catalyst (mol %)
Time (h)
Yield of 4ab (%)
Entry Product 4
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
ZnCl2
CuCl2
FeCl3
MgCl2
Yb(OTf)3
Cu(ClO4)2
VB1
10
10
10
10
10
10
10
0.8 g
10
1
24
24
24
24
24
24
24
24
15
24
18
15
15
0
0
0
0
0
1
15
82
0
0
O
O
O
HN
HN
HN
O
O
O
Al2O3
30
84
50
75
82
82
VB1–Al2O3
VB1–Al2O3
VB1–Al2O3
VB1–Al2O3
VB1–Al2O3
4a
3
5
8
a
The reaction carried out in EtOH at reflux temperature.
Isolated yields.
b
2
15
15
24
24
15
84
significant improvement in the yield (82%). The results indicated
that 5 mol % of VB1–Al2O3 was sufficient and excessive amount of
the catalyst did not increase the yields significantly.
4b
In order to find the optimum solvent, the reaction using 5 mol %
VB1–Al2O3 as the catalyst was performed in various solvents, such
as EtOH, THF, acetonitrile, DMF, DMSO, 1,4-dioxane, CCl4, and H2O.
Acetonitrile, DMF, and DMSO afforded low yields (22–30%),
whereas, when CCl4, and H2O were used as solvents, no desired
products were detected (Table 2, entries 7 and 8). The reaction
using EtOH as the solvent gave the best result (Table 2, entry 1),
hence, it was chosen as the solvent for all further reactions.
Furthermore, the recyclable character of VB1–Al2O3 was also
investigated. Of particular note was the fact that the catalyst was
easy to recover by simple filtration from the reaction medium
and could be reused without any loss of activity (Table 2, entry
1). We obtained the desired product in 82%, 82%, 80%, 77% yields
after 1–4 runs, respectively.
3
4
5
6
83
O
4c
0
O
HN
O
NO2
In order to evaluate the generality of the process, several exam-
ples illustratES the present method for the synthesis of b-amido
ketones 4 was studied (Table 3).21
4d
As shown in Table 3, the electronic effect of substituents pres-
ent on the benzene ring of the aldehyde moiety had a significant
effect on the overall yields of the products of b-amido ketones 4.
The substituted aromatic aldehydes, bearing the electro-donating
group afforded the corresponding products in good yields. How-
ever, under the same reaction conditions, no desired products were
obtained when using the aromatic aldehydes carrying strong elec-
tron-withdrawing groups as starting materials (Table 3, entries 4, 5
and 17). Furthermore, we also found that the aromatic ketones car-
rying either the electron-donating or electron-withdrawing sub-
stituents could react efficiently giving the products in good yields
(Table 3).
0
O
HN
Cl
O
Cl
4e
82
O
HN
O
Table 2
Optimization of solvents
4f
Entry
Solvent
Temp (°C)
Time (h)
Yield of 4aa (%)
1b
2
3
4
5
6
7
8
EtOH
THF
Reflux
Reflux
Reflux
100
100
100
15
24
24
24
24
15
24
24
82, 82, 80, 77
52
28
22
30
70
0
Acetonitrile
DMF
DMSO
1,4-Dioxane
CCl4
O
HN
O
7
15
81
Reflux
100
O
H2O
0
4g
a
Isolated yields.
Catalyst was reused for four times.
b
(continued on next page)

4748
M. Lei et al. / Tetrahedron Letters 51 (2010) 4746–4749
Table 3 (continued)
Table 3 (continued)
Entry
Product 4
Time (h)
Yieldb (%)
Entry
16
Product 4
Time (h)
24
Yieldb (%)
O
HN
O
52
O
HN
O
8
15
83
4p
O2N
O
HN
O
4h
NO2
17
18
19
24
24
24
0
0
0
Cl
4q
9
15
84
O
O
O
HN
O
O
O
O
O
N
N
O
O
4i
4r
10
15
85
HN
4s
a
The reaction carried out in EtOH at reflux temperature.
Isolated yields.
b
4j
To demonstrate the scope and limitations of the procedure, the
condensation of aromatic aldehyde 1, aromatic ketone 2, and dif-
ferent amides 3 including aromatic amide, phenylacetamide, acet-
amide, acrylamide, and N-substituted amides, such as N-methyl
benzamide and caprolactam were carried out in the presence of
VB1–Al2O3 in EtOH at reflux temperature for 15–24 h. The results
of Table 3 indicated that both aromatic amides (Table 3, entries
1–9) and phenylacetamide (Table 2, entries 10 and 11) worked
well, giving high yields of products with little difference. Acetam-
ide and acrylamide afforded relevant lower yields (45–52%). The
expected products were obtained in moderate yields under similar
conditions. However, the condensation was unsuccessful with N-
substituted amides. As shown in Table 3 entries 18 and 19, the
reaction could not take place when using N-substituted amides
as the starting materials.
We propose a mechanism of the condensation as shown in
Scheme 3. Initially, the condensation between aldehyde 1 and
amide 3 gave 5. Ketone 2 isomerized to 6, then the Mannich
reaction between 5 and 6 furnished the product 4. We have
mentioned previously that the three-component condensation
reaction could not proceed smoothly when using the aromatic
aldehydes carrying strong electron-withdrawing groups as the
starting materials. The probable reason was that it was difficult
for these aldehydes to form the intermediate 5, which meant
that the reaction could not proceed smoothly to afford the corre-
sponding products.
HN
11
15
86
O
4k
O
HN
O
12
13
24
24
52
45
4l
O
HN
O
4m
O
O
HN
HN
O
O
14
15
24
24
48
48
4n
4o
In conclusion, we have described a simple and efficient method
for one-pot, three-component synthesis of b-amido ketones from
aromatic aldehyde, aromatic ketone, and amide in the presence
of VB1–Al2O3 as a heterogeneous catalyst. This procedure not only
affords the products in good yields but also avoids the problems
associated with the catalyst cost, handling safety and pollution.
Hence, it is a useful addition to the existing methods.
O

M. Lei et al. / Tetrahedron Letters 51 (2010) 4746–4749
4749
O
O
O
VB1-Al2O3
-H2O
R1 CHO
+
R3
N
O
HN
R3
R3
NH2
R1
R2
R1
1
3
5
4
O
VB1-Al2O3
R2
R2
OH
2
6
Scheme 3. Plausible mechanism for the formation of b-amido ketones.
5. Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett. 1997, 38, 1083.
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Acknowledgments
This work was supported by the Chinese National Science and
Technology Major Project ‘Key New Drug Creation and Manufactur-
ing Program’ (Grants 2009ZX09301-001, 2009ZX09102), the
Chinese National High-Tech R&D Program (Grant 2007AA02Z147),
the National Natural Science Foundation of China (Grants
90713046, 30772638 and 30925040) and CAS Foundation (Grant
KSCX2-YW-R-179).
8. Das, B.; Reddy, K. R.; Ramu, R.; Thirupathi, P.; Ravikanth, B. Synlett 2006, 11,
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9. Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735.
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Tetrahedron 2006, 62, 4059.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.008.
16. Khan, A. T.; Choudhury, L. H.; Parvin, T.; Ali, M. A. Tetrahedron Lett. 2006, 47,
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References and notes
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20. Preparation of VB1–Al2O3: The catalyst was prepared by mixing aluminum oxide
(9 g, 90 active acidic, 0.063–0.200 mm) with a solution of VB1 (1 g) in distilled
water (15 ml). The suspension was stirred for 1 h at room
temperature,followed by removal of water in a rotary evaporator, and the
solid powder was dried at 100 °C for 3 h in an oven and then cooled in a
desiccator.
21. General procedures for the synthesis of b-amido ketones: A mixture of aldehyde 1
(5 mmol), ketone 2 (5 mmol), amide 3 (5 mmol) and VB1–Al2O3 (0.8 g, 5 mol %)
in EtOH (3 mL) was heated to reflux under stirring for 15–24 h. After cooling,
EtOAc (30 mL) was added and the catalyst was recovered by simple filtration.
The catalyst was rinsed with EtOAc and dried at 100 °C for 3 h, which could be
reused without loss of activity. The organic layer was washed with brine, dried
over MgSO4 and concentrated. The crude product residue was purified by
chromatography on silica to give pure product 4.