Highly convenient one-pot conversion of aryl acyals or aryl aldehyde bisulfites into dihydropyrimidones using Bi(NO3)3· 5H2O

Article abstract of DOI:10.1002/hc.20352

A new, facile, and efficient one-pot deprotection-cyclocondensation method is presented for the Biginelli reaction from aryl acylals or aryl aldehyde bisulfites in the presence of catalytic amounts of Bi(NO₃) ₃·5H₂O under

Full text of DOI:10.1002/hc.20352

Heteroatom Chemistry
Volume 18, Number 6, 2007
Highly Convenient One-Pot Conversion of Aryl
Acylals or Aryl Aldehyde Bisulfites into
Dihydropyrimidones Using Bi(NO ) ·5H O
3 3 2
Ahmad R. Khosropour,1 Mohammad M. Khodaei,2
and Mojtaba Beygzadeh2
1Catalyst Division, Department of Chemistry, Faculty of Science, Isfahan University,
Isfahan 81746-73441, Iran
2Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 1 April 2006; revised 26 October 2006
steps, which are carried out without isolation of
ABSTRACT: A new, facile, and efficient one-pot
any intermediates thus reducing time, saving energy,
deprotection–cyclocondensation method is presented
and raw materials. As part of our program aimed at
for the Biginelli reaction from aryl acylals or aryl alde-
developing new selective and environment friendly
hyde bisulfites in the presence of catalytic amounts
methodologies for the preparation of fine chemicals,
of Bi(NO3)3·5H2O under solvent-free conditions. In
another catalytic 3,4-dihydropyrimidin-2(1H)-ones
addition, high levels of chemoselectivity for this syn-
(DHPMs) synthesis is reported.
ꢀ
C
thesis have been achieved.
2007 Wiley Periodicals,
Inc. Heteroatom Chem 18:684–687, 2007; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20352
RESULT AND DISCUSSION
The synthesis of DHPMs remains a great interest
due to wide applications of such heterocycles in
the pharmacological and biological sciences. Antihy-
pertensive agents [1], calcium channel blockers [2],
α-adrenergic [3], and neuropeptide Y antagonists
[4] antitumor, antibacterial, and anti-inflammatory
[5] behaviors are the properties of some DHPM
derivatives. Recently, batzelladine alkaloids contain-
ing a dihydropyrimidinone-5-carboxylate core [6]
have been found to be potent HIV-gp-120-CD4 in-
hibitors [7]. In addition, because these compounds
are important as synthons in organic synthesis, the
development of facile and environment friendly syn-
thetic methods for dihydropyrimidones is an active
area of investigation in organic synthesis. The most
well-known route to DHPMs is the Biginelli method
that involves the direct condensation of aldehydes
with β-dicarbonyls and urea under Lewis acid con-
ditions [8–14].
INTRODUCTION
The increasing attention during the last decades for
environmental protection has influenced both mod-
ern academic and industrial groups to develop chem-
ical processes with maximum yield and minimum
cost while using nontoxic reagents, catalysts and sol-
vents, or even better without solvents. One of the
tools to combine economic aspects with the environ-
mental ones is the multicomponent reaction strat-
egy; this process consists of two or more synthetic
Correspondence to: Ahmad R. Khosropour; e-mail:
arkhosropour@razi.ac.ir.
Contract grant sponsor: Center of Excellence of Chemistry
of University of Isfahan (CECUI) and Razi University Research
Council.
c
ꢀ
2007 Wiley Periodicals, Inc.
684

One-Pot Conversion of Aryl Acylals or Aryl Aldehyde Bisulfites into Dihydropyrimidones Using Bi(NO3)3·5H2O 685
SCHEME 1
SCHEME 2
Acylals (geminal diacetates), because of their re-
We found that treatment of both electron-rich
and electron-deficient aryl aldehyde bisulfite adducts
with β-dicarbonyl compounds and urea in the pres-
ence of catalytic amounts of Bi(NO3)3·5H2O pro-
vided the corresponding DHPMs in good to excel-
lent yields (74–99%). The reaction time was usually
short (10–45 min), and isolation of the product was
straightforward (Table 2, entries 1–21). However,
aliphatic bisulfites did not form the product under
similar experimental conditions and remained un-
changed (Table 2, entry 22). The experimental results
show that electron-deficient aryl aldehyde bisulfites
markable stability toward a variety of reaction condi-
tions, have become important in organic synthesis as
an alternative to acetals for the protection of aldehy-
des [15]. The majority of studies have aimed at their
deprotection [16]; however, there are no reports
on the deprotection–cyclocondensation reaction of
acylals.
In many recent papers, the use of bismuth com-
pounds in organic transformations is described as
ecological friendly compounds [17]. In addition, bis-
muth derivatives have been widely used in medicine
[18]. Most of bismuth salts have attracted atten-
tion because of their low toxicity, ease of handling,
low cost, and relative insensitivity to air and small
amounts of moisture [19]. In the course of our re-
search on catalysis by Bi(III) salts [20], we report
herein, for the first time, an efficient and environ-
mentally benign method for the one-pot synthesis
of 3,4-dihydropyrimidin-2-ones from aryl acylals,
β-dicarbonyl compounds, and urea under solvent-
free conditions (Scheme 1).
The experimental procedure for the synthesis
of these compounds is straightforward and involves
stirring of acylals with β-dicarbonyl compounds and
urea in the presence of Bi(NO3)3·5H2O at 100◦C. Var-
ious substituted aromatic acylals reacted well to give
the corresponding dihydropyrimidinones in 64–97%
yields (Table 1). Interestingly, aromatic acylals with
electron-donating groups gave comparatively better
yields and reaction times than those with electron-
withdrawing groups. Aliphatic acylals, such as 1,1-
diacetoxypropane, did not give any products with
the above-mentioned catalyst even after 3 h (Table 1,
entry 20). Acid-sensitive substrates, such as cin-
namyl acylals, reacted in high yields without the for-
mation of any side products (Table 1, entry 7). This
methodology is also compatible in the presence of
other functional groups such as methoxy and nitro
groups and alkene double bonds.
TABLE 1 Formation of Dihydropyrimidinonesa from Acylals
Catalyzed by Bi(NO3)3·5H2O under Solvent-Free Conditions
Entry R1
R2
Time (min) Yield (%)b
1
2
3
4
5
6
7
9
10
11
12
13
14
15
16
17
18
19
20
C6H5
4-CH3C6H4
4-CH3OC6H4
2,4-(CH3O)2C6H3 OEt
OEt
OEt
OEt
10
10
10
15
20
97
93
94
88
92
95
91
83
85
66
64
68
96
70
85
87
69
64
0
4-(CH3)2NC6H4
α-Naphthyl
C6H5CH CH
4-ClC6H4
2,4-Cl2C6H3
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CH3C6H4
4-ClC6H4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Me
20
30
120
150
180
120
100
15
120
20
15
C6H5
4-CH3OC6H4
4-NO2C6H4
2-NO2C6H4
CH3CH2CH2
Me
Me
Me
OEt
120
180
180
aAll products were characterized by comparison of their physical and
spectral data with those of authentic samples.
Bisulfite addition products are widely used for
protection and purification of aldehydes, and the
regeneration of the aldehyde can be performed
by treatment of the addition product with min-
eral acid or base [21,22]. To extend the scope of
Bi(NO3)3·5H2O as a catalyst, the reaction with alde-
hyde bisulfites, as another protected form of aldehy-
des, was also investigated (Scheme 2).
Analytical
data
for
5-(ethoxycarbonyl)-6-methyl-4-styryl-3,4-
dihydropyridin-2(1H)-one (entry 7): mp 233–234◦C; νmax (KBr): 3240,
1700, 1648 cm−1; δH (200 MHz, CDCl3) 9.10 (s, 1H, NH), 7.50 (d, J
= 1.9 Hz, 1H, NH), 7.18–7.43 (m, 5H, Ar), 6.34 (d, J = 15.9 Hz, 1H,
H
C
CH), 6.18 (dd, J = 15.8, 6.0 Hz, 1H, CH
C H), 4.73 (d, J
= 5.80 Hz, 1H, CH), 4.06 (m, 2H, OCH2), 2.18 (s, 3H, CH3), 1.17
(t, J = 7.0 Hz, 3H, CH3); δc (50 MHz, CDCl3) 165.3, 152.4, 148.5,
136.0, 130.0, 128.5, 128.0, 127.3, 126.2, 97.7, 59.2, 51.7, 17.7,
14.2; HRMS calcd. for C16H18N2O3 286.1346; found 286.1317.
bIsolated yields.
Heteroatom Chemistry DOI 10.1002/hc

686 Khosropour, Khodaei, and Beygzadeh
TABLE 2 Formation of Dihydropyrimidinonesa from Alde-
hyde Bisulfites Catalyzed by Bi(NO3)3·5H2O under Solvent-
Free Conditions
are more reactive than the corresponding acylals and
work better in terms of reaction times and yields.
To explore further the synthetic utility of
this procedure, the competitive deprotection–
cyclocondensation of aryl acylals and aldehyde
bisulfites in the presence of sensitive functional
groups was also investigated (Table 3).
The net result was that the sensitive groups such
as acetals, oximes, and aliphatic aldehydes were
mostly intact and were stable under the described
reaction conditions (Table 3, entries 1–3). In sum-
mary, we have demonstrated a new, efficient, and
environment friendly method for the one-pot prepa-
ration of DHPMs from aryl acylals and aryl bisulfites
with Bi(NO3)3·5H2O as a low toxic, inexpensive, oxy-
gen and moisture tolerant catalyst under solvent-free
conditions. In addition, the high levels of chemose-
lectivity described in this report are another merit of
this method.
Entry R1
R2
Time (min) Yield (%)b
1
2
3
4
5
6
7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
4-CH3C6H4
4-CH3OC6H4
2,4-(CH3O)2C6H3 OEt
4-(CH3)2NC6H4
2-HOC6H4
α-Naphthyl
C6H5CH CH
4-FC6H4
OEt
OEt
OEt
10
20
10
10
15
25
25
35
20
25
45
25
20
10
15
15
20
20
20
35
180
99
86
96
93
97
86
84
83
92
89
82
83
90
94
86
91
84
82
84
74
3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Me
4-ClC6H4
2,4-Cl2C6H3
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CH3C6H4
4-NO2C6H4
C6H5
4-CH3OC6H4
4- NO2C6H4
2- NO2C6H4
CH3CH2CH2
Me
Me
Me
OEt
GENERAL EXPERIMENTAL PROCEDURE
To a solution of aryl acylal or aryl bisulfite (1 mmol)
and urea (1.5 mmol) in β-ketoester or β-diketone (2
mmol), Bi(NO3)3·5H2O (0.25 mmol) was added. The
aAll products were characterized by comparison of their physical and
spectral data with those of authentic samples.
bIsolated yields.
TABLE 3 Competitive Deprotection–Cyclocondensation of Aryl Acylals and Aryl Aldehyde Bisulfites in the Presence of
Bi(NO3)3 ·5H2Oa under Solvent-Free Conditions
Yield (%)b /Time (min)
Entry
1
R1
Product
Y = CH(OAc)2
Y = CH(OH)SO3Na
91 (10 min)
90 (10 min)
100
100
2
3
95 (10 min)
92 (10 min)
100
100
90 (10 min)
87 (10 min)
100
97
a0.25 mmol.
bIsolated yields.
Heteroatom Chemistry DOI 10.1002/hc

One-Pot Conversion of Aryl Acylals or Aryl Aldehyde Bisulfites into Dihydropyrimidones Using Bi(NO3)3·5H2O 687
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