PMA/SiO2: An efficient and reusable heterogeneous catalyst for the synthesis of β-acetamidocarbonyl compounds by multicomponent reaction

Article abstract of DOI:10.1080/00397910902756189

Phosphomolybdic acid supported on silica (PMA/SiO2) has been used as an efficient heterogeneous catalyst for the preparation of β-acetamidoketones and esters in good yields. The reaction conditions are mild, and the catalyst can be recycled. Copyright Tay

Full text of DOI:10.1080/00397910902756189

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PMA/SiO2: An Efficient and
Reusable Heterogeneous
Catalyst for the Synthesis of β-
Acetamidocarbonyl Compounds
by Multicomponent Reaction
Biswanath Das a , Rathod Aravind Kumar a
,
Ponnaboina Thirupathi a & Yallamalla Srinivas a
a Organic Chemistry Division I, Indian Institute of
Chemical Technology , Hyderabad, Andhra Pradesh,
India
Published online: 12 Aug 2009.
To cite this article: Biswanath Das , Rathod Aravind Kumar , Ponnaboina
Thirupathi & Yallamalla Srinivas (2009) PMA/SiO2: An Efficient and Reusable
Heterogeneous Catalyst for the Synthesis of β-Acetamidocarbonyl Compounds by
Multicomponent Reaction, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:18, 3305-3314, DOI:
10.1080/00397910902756189
To link to this article: http://dx.doi.org/10.1080/00397910902756189
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Synthetic Communications1, 39: 3305–3314, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902756189
PMA/SiO2: An Efficient and Reusable
Heterogeneous Catalyst for the Synthesis of
b-Acetamidocarbonyl Compounds by
Multicomponent Reaction
Biswanath Das, Rathod Aravind Kumar, Ponnaboina Thirupathi,
and Yallamalla Srinivas
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, Andhra Pradesh, India
Abstract: Phosphomolybdic acid supported on silica (PMA=SiO2) has been used
as an efficient heterogeneous catalyst for the preparation of b-acetamidoketones
and esters in good yields. The reaction conditions are mild, and the catalyst can be
recycled.
Keywords: b-Acetamidocarbonyl compound, heterogeneous catalyst, multicom-
ponent reaction, PMA=SiO2
INTRODUCTION
Multicomponent reactions (MCRs) are powerful tool in modern
organic synthesis because they have several advantages over conventional
multistep synthesis. These processes consist of two or more synthetic
steps, which are performed without isolation of any intermediate. Thus
MCRs reduce time and save both energy and raw materials. In drug
discovery as well as in green chemistry, these processes are the preferred
techniques because of their high-throughput synthesis of compounds in a
Received November 11, 2008.
Part 145 in the series ‘‘Studies on novel synthetic methodologies.’’
Address correspondence to Biswanath Das, Organic Chemistry Division I,
Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007,
Andhra Pradesh, India. E-mail: biswanathdas@yahoo.com
3305

3306
B. Das et al.
cost- and time-effective manner. Hence, the development of MCRs is of
current interest in the synthesis of various useful organic products.[1]
b-Acetamido- or amino-ketones are important for their biological
and pharmaceutical properties[2] and in the preparation of antibiotic
drugs such as nikkomycine and neopolyxine.[3] The best-known synthesis
of this class of compounds is the Dakin-West reaction,[4] which involves
the condensation of an a-amino acid with acetic anhydride in the
presence of a base via an azolactone intermediate.[5] The syntheses of
b-acetamidoketones by the multicomponent coupling method in the
presence of a Lewis acid such as CoCl2[6] or montmorillonite K-10clay,[7]
silica sulfuric acid,[8] ZrOCl2 ꢀ 8H2O,[9] Sc(OTf)3,[10] BiCl3 generated from
BiOCl,[11] ZnO,[12] and I2[13] have been reported. Because b-acetamidoke-
tones or esters have become increasingly useful and important in the field
of pharmaceuticals, the development of clean, high-yielding, and environ-
mentally friendly approaches is still desirable and much in demand.
RESULTS AND DISCUSSION
In recent years, heterogeneous catalysts have gained considerable
importance because of environmental and economic considerations. In con-
tinuation of our work[14] on heterogeneous catalysts for the development of
useful synthetic methodologies, we have observed that phosphomolybdic
acid supported on silica (PMA=SiO2)[15] is very suitable to catalyze one-pot
coupling of aldehydes, enolizable ketones, or ketoesters and acetylchloride
in the presence of acetonitrile to form b-acetamidoketones or esters at room
temperature (Scheme 1). PMA=SiO2 has great potential as an environmen-
tally friendly alternative to the more wasteful traditional catalysts. This
catalyst possesses excellent activity, low toxicity, and good stability to
humidity. It can be recovered from the reaction mixture and reused.
Initially, we prepared N-(3-oxo-1,3-diphenyl propyl) acetamide in
excellent yield from the reaction of benzaldehyde, acetophenone, acetyl-
chloride, and acetonitrile (reactant as well as solvent) in the presence
Scheme 1. Synthesis of b-acetamidocarbonyl compounds using PMA=SiO2.

PMA/SiO2 as Catalyst
3307
Table 1. PMA=SiO2-catalyzed formation of b-acetamidoketones and esters
Time
(h)
Isolated
yield (%)
Mp[ref]
Entry
1
b-Acetamidoketone or estera
(ꢁC)
6.0
6.0
8.0
7.5
94
92
89
88
102–104[7]
2
3
4
170[9]
148–149[7]
151–153[9]
5
6.0
91
108–111
6
7
8
6.5
6.0
6.0
92
90
92
130[9]
160–162
152–154
(Continued )

3308
B. Das et al.
Table 1. Continued
Time
(h)
Isolated
yield (%)
Mp[ref]
(ꢁC)
Entry
9
b-Acetamidoketone or estera
6.0
6.0
6.0
6.0
85
82
91
89
104–105[9]
10
11
12
112[9]
174[9]
159[9]
13
6.0
90
174–176
14
15
16
7.0
8.0
6.0
89
82
88
162[9]
143[9]
129–131[6c]
(Continued )

PMA/SiO2 as Catalyst
3309
Table 1. Continued
Time
(h)
Isolated
yield (%)
Mp[ref]
Entry
17
b-Acetamidoketone or estera
(ꢁC)
6.0
8.0
7.0
88
78
90
142–144[6c]
18
19
149–151[6c]
105–107
20
7.0
89
130–134
aThe structures of the products were determined from their spectroscopic
(1H NMR and MS) and analytical data.
of PMA=SiO2 at room temperature (Table 1, entry 1). In the absence of
catalyst, the product was obtained in very poor yield even after 24 h,
whereas in the absence of PMA and only with SiO2 the transformation
took a long time and the yield was only 12% after 24 h.
A variety of other aromatic aldehydes with electron-donating groups
as well as electron-withdrawing substituents underwent the reaction
smoothly, giving the desired products in good yields (the result is sum-
marized in Table 1). An aromatic aldehyde containing a nitro substituent
took longer (entry 3). Several enolizable ketones served as good sub-
strates for the present one-pot synthesis of b-acetamidoketones. Thus,
the reaction of benzaldehyde with a variety of acetophenones (p-
methoxy, p-nitro, p-hydroxy, p-isopropyl acetophenones), acetylchloride,
and acetonitrile proceeded efficiently in the presence of PMA=SiO2,
resulting in the formation of the desired products in impressive yields.
The reaction between p-hydroxy acetophenone and 2-naphathaldehyde
yielded the corresponding b-acetamidoketone (entry 7) as acetylated pro-
duct. A mixture of acetophenone or p-isopropyl acetophenone, hexanal,

3310
B. Das et al.
acetylchloride, and acetonitrile failed to generate the corresponding pro-
duct in the presence of a catalytic amount of PMA=SiO2 even after 36 h.
To demonstrate the versatility of the catalyst PMA=SiO2, we have
examined the reaction of benzaldehyde derivatives with ethyl methyl
ketone, propiophenone, ethyl acetoacetate, methyl acetoacetate, and
ethyl benzoylacetate (Table 1, entries 9–20). With these substrates, the
b-acetamidoketones or esters were obtained in good yields, but the syn-
and the anti-products were produced in almost equal amounts. The struc-
tures of the products were settled from their spectral (1H NMR and mass
spectral, MS) data. The coupling constants between H-2 and H-3 is
6–9 Hz for an anti-isomer and 2–5 Hz for a syn-isomer.[5c,12]
CONCLUSION
In conclusion, we have revealed a simple, efficient, and green protocol for
the preparation of b-acetamidoketones and esters using PMA=SiO2 as a
heterogeneous catalyst. The salient features of this protocol include
operational simplicity, low toxicity, excellent activity, good stability to
humidity, and reusability of the catalyst.
EXPERIMENTAL
General
PMA=SiO2 (113 mg, 0.005 mol based on PMA) was added to a solution of
an aldehyde (1 mmol), an enolizable ketone or ester (1 mmol), and
acetylchloride (1.5 mmol) in acetonitrile (4 mL). The mixture was stirred at
room temperature, and the reaction was monitored by thin-layer chromato-
graph (TLC). After completion of the reaction, the mixture was filtered to
recover the catalyst and the filtrate was poured onto ice-cold water
(25 mL). The precipitated solid was filtered, washed with ice-cold water, and
recrystalized from ethylacetate=n-hexane to give the pure product.
The recovered catalyst was recycled three times without affecting the
yields of the products.
Spectroscopic (1H NMR and MS) and Analytical Data of the
New Compounds
Compound 3e
1H NMR (CDCl3, 200 MHz): d 7.81 (2H, d, J ¼ 8.0 Hz), 7.32–7.10 (6H, m),
6.78 (2H, d, J ¼ 8.0 Hz), 5.46 (1H, m), 4.57 (1H, m), 3.56 (1H, dd, J ¼ 17.0,

PMA/SiO2 as Catalyst
3311
4.4 Hz), 3.22 (1H, dd, J ¼ 17.0, 5.2 Hz), 1.88 (3H, s), 1.31 (6H, d,
J ¼ 8.0 Hz); FABMS: m=z 310 [M þ H]þ. Anal. calc. for C20H23NO2: C,
77.66; H, 7.44; N, 4.53%. Found: C, 77.02; H, 7.29; N, 4.39%.
Compound 3g
1H NMR (CDCl3, 200MHz): d 7.95 (2H, d, J¼ 8.0 Hz), 7.89–7.71 (4H, m),
7.55–7.38 (3H, m), 7.16 (2H, d, J¼ 8.0 Hz), 6.84 (1H, d, J¼ 8.0 Hz), 5.69 (1H,
m), 3.81 (1H, dd, J¼ 17.0, 4.5 Hz), 3.46 (1H, dd, J ¼ 17.0, 5.5 Hz), 2.30 (3H,
s), 2.01 (3H, s); FABMS: m=z 364 [M þ H]þ. Anal. calc. for C22H21NO4: C,
72.72; H, 5.78; N, 3.85%. Found: C, 71.58; H, 5.69; N, 3.80%.
Compound 3h
1H NMR (CDCl3, 200 MHz): d 7.92 (2H, d, J ¼ 8.0 Hz), 7.86–7.72 (4H, m),
7.53 (1H, t, J ¼ 8.0 Hz), 7.48–7.39 (5H, m), 6.83 (1H, d, J ¼ 8.0 Hz), 5.67
(1H, m), 3.81 (1H, dd, J ¼ 17.0, 4.5 Hz), 3.48 (1H, dd, J ¼ 17.0, 5.0 Hz),
2.03 (3H, s); FABMS: m=z 318 [M þ H]þ. Anal. calc. for C21H19NO2: C,
79.49; H, 5.99; N, 4.41%. Found: C, 78.98; H, 5.78; N, 4.38%.
Compound 3m (syn)
1H NMR (CDCl3, 200 MHz): d 7.82 (2H, d, J ¼ 8.0 Hz), 7.43–7.31 (4H,
m), 6.80–6.72 (3H, m), 5.22 (1H, dd, J ¼ 8.0, 4.0 Hz), 4.05 (1H, m), 3.63
(3H, s), 2.21 (3H, s), 2.02 (3H, s), 1.21 (3H, t, J ¼ 7.0 Hz); FABMS: m=z
370 [M þ H]þ. Anal. calc. for C21H23NO5: C, 68.29; H, 6.23; N, 3.79%.
Found: C, 68.07; H, 6.17; N, 3.69%.
Compound 3m (anti)
1H NMR (CDCl3, 200 MHz): d 7.71 (2H, d, J ¼ 8.0 Hz), 7.53–7.46 (4H,
m), 6.84–6.79 (2H, m), 6.62 (1H, d, J ¼ 8.0 Hz), 5.40 (1H, t, J ¼ 8.0 Hz),
4.01 (1H, s), 3.68 (3H, s), 2.22 (3H, s), 2.02 (3H, s), 1.28 (3H, t, J ¼ 7.0 Hz);
); FABMS: m=z 370 [M þ H]þ. Anal. calc. for C21H23NO5: C, 68.29; H,
6.23; N, 3.79%. Found: C, 67.99; H, 6.11; N, 3.68%.
Compound 3s (syn)
1H NMR (CDCl3, 200 MHz): d 7.98 (1H, d, J ¼ 8.0 Hz), 7.87–7.71 (5H, m),
7.61–7.40 (7H, m), 6.02 (1H, dd, J ¼ 7.0, 4.0 Hz), 5.05 (1H, d, J ¼ 4.0 Hz),

3312
B. Das et al.
4.17 (2H, q, J ¼ 7.0 Hz), 2.05 (3 H, s), 1.20 (3 H, t, J ¼ 7.0 Hz); FABMS:
m=z 378 [M þ H]þ. Anal. calc. for C23H23NO4: C, 73.20; H, 6.10; N,
3.71%. Found: C, 72.93; H, 5.97; N, 3.64%.
Compound 3s (anti)
1H NMR (CDCl3, 200 MHz): d 7.83 (1H, d, J ¼ 8.0 Hz), 7.72–7.61 (5H,
m), 7.49–7.32 (7H, m), 5.91 (1H, dd, J ¼ 9.0, 6.0 Hz), 4.99 (1H, d,
J ¼ 6.0 Hz), 4.10 (2H, q, J ¼ 7.0 Hz), 2.01 (3 H, s), 1.11 (3H, t, J ¼ 7.0 Hz);
); FABMS: m=z 378 [M þ H]þ. Anal. calc. for C23H23NO4: C, 73.20; H,
6.10; N, 3.71%. Found: C, 72.88; H, 5.90; N, 3.60%.
Compound 3t (syn)
1H NMR (CDCl3, 200 MHz): d 7.82 (2H, d, J ¼ 8.0 Hz), 7.53–7.40 (4H, m),
6.93–6.85 (3H, m), 5.88 (1H, dd, J ¼ 8.0, 4.0 Hz), 4.94 (1H, d, J ¼ 4.0 Hz),
4.18 (2H, q, J ¼ 7.0 Hz), 3.75 (3H, s), 2.22 (3H, s), 2.03 (3H, s), 1.12 (3H, t,
J ¼ 7.0 Hz); FABMS: m=z 428 [M þ H]þ. Anal. calc. for C23H25NO7: C,
64.63; H, 5.85; N, 3.27%. Found: C, 64.03; H, 5.78; N, 3.21%.
Compound 3t (anti)
1H NMR (CDCl3, 200 MHz): d 7.95 (2H, d, J ¼ 8.0 Hz), 7.66–7.51 (4H, m),
7.01–6.90 (3H, m), 5.72 (1H, dd, J ¼ 9.0, 6.0 Hz), 4.90 (1H, d, J ¼ 6.0 Hz),
4.09 (2H, q, J ¼ 7.0 Hz), 3.80 (3H, s), 2.30 (3H, s), 1.98 (3H, s), 1.21 (3 H, t,
J ¼ 7.0 Hz); FABMS: m=z 428 [M þ H]þ. Anal. calc. for C23H25NO7: C,
64.63; H, 5.85; N, 3.27%. Found: C, 64.13; H, 5.65; N, 3.14%.
ACKNOWLEDGMENTS
The authors thank the Council of Scientific and Industrial Research and
the University Grants Commission, New Delhi, for financial assistance.
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