Bismuth subnitrate catalyzed efficient synthesis of 3,4-dihydropyrimidin- 2(1H)-ones: An improved protocol for the Biginelli reaction

Article abstract of DOI:10.1081/SCC-200032533

An efficient synthesis of 3,4-dihydropyrimidinones (DHPMs) using bismuth subnitrate as the catalyst for the first time from an aldehyde, β-ketoester, and urea in acetonitrile is described. This new method consistently has the advantage of excellent yields

Full text of DOI:10.1081/SCC-200032533

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Bismuth Subnitrate Catalyzed
Efficient Synthesis of
3,4‐Dihydropyrimidin‐2(1H)‐Ones:
An Improved Protocol for the
Biginelli Reaction
Y. Thirupathi Reddy a , (Ms.) B. Rajitha a , P.
Narsimha Reddy a , B. Sunil Kumar a & V. P. Rao G a
a Department of Chemistry, National Institute of
Technology, Warangal, India
Published online: 19 Apr 2010.
To cite this article: Y. Thirupathi Reddy , (Ms.) B. Rajitha , P. Narsimha Reddy ,
B. Sunil Kumar & V. P. Rao G (2004): Bismuth Subnitrate Catalyzed Efficient
Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐Ones: An Improved Protocol for the
Biginelli Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:20, 3821-3825
To link to this article: http://dx.doi.org/10.1081/SCC-200032533
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3821–3825, 2004
Bismuth Subnitrate Catalyzed Efficient
Synthesis of 3,4-Dihydropyrimidin-
2(1H)-Ones: An Improved Protocol
for the Biginelli Reaction
*
Y. Thirupathi Reddy, (Ms.) B. Rajitha, P. Narsimha Reddy,
B. Sunil Kumar, and V. P. Rao, G
Department of Chemistry, National Institute of Technology,
Warangal, India
ABSTRACT
An efficient synthesis of 3,4-dihydropyrimidinones (DHPMs) using
bismuth subnitrate as the catalyst for the first time from an aldehyde,
b-ketoester, and urea in acetonitrile is described. This new method
consistently has the advantage of excellent yields (88–96%) and short
reaction times (1.5–4 h) than do classical Biginelli reaction conditions.
Key Words: Biginelli reaction; Bismuth subnitrate; Dihydropyri-
midinones; One-pot condensation.
*
Correspondence: B. Rajitha, Department of Chemistry, National Institute of Technol-
ogy, Warangal, India; Fax: 0091-9712-2459547; E-mail: rajitabhargavi@yahoo.com.
3821
DOI: 10.1081/SCC-200032533
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3822
Reddy et al.
INTRODUCTION
Dihydropyrimidinones form an important class of compounds that are
becoming increasingly considered due to their therapeutic and pharmacologi-
cal properties as calcium channel blockers, antihypertensive agents and a-1a-
antagonists, and neuropeptide Y (NPY) antagonists.[1]
The simple and direct procedure first recorded by Biginelli involving
three-component condensation of a b-ketoester with an aldehyde and urea
(or) thiourea in ethanol solution often suffers from low yields (25–60%).[2]
Several improved procedures for the synthesis of dihydropyrimidinones
have recently been reported. Hu[3] and Kappe[4] reported reagents involving
.
the use of BF3 OEt2/CuCl and PPE (polyphosphate ester) mediated variation
of the Biginelli reaction giving high yields of dihydropyrimidinones, but the
reaction requires 15–18 h of reaction time. More recently, Lewis acids
.
like BiCl3, Bi(OTf)3, InCl3, LiClO4, ZrCl4, La(OTf)3, NiCl2 6H2O,
FeCl3 6H2O, and ionic liquids[5] have been employed for this transformation.
.
Recently, acidic montmorillonite KSF and microwave irradiation were also
reported to be effective for Biginelli reaction.[6] In this note, we describe a
general and practical route for the Biginelli cyclocondensation reaction
using bismuth subnitrate as the catalyst in solution conditions.
RESULTS AND DISCUSSION
As shown in Sch. 1, the one-pot reaction of benzaldehyde 1 (1 mmol) with
urea 2 (1.5 mmol) and ethylacetoacetate 3 (1 mmol) in the presence of
BiONO3 (0.2 mmol) in acetonitrile as solvent at 70–808C gave 4-phenyl-5-
ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one 4a in 96% yield
within 1.5 h. Many pharmacologically relevant substitution patterns on the
aromatic ring could be introduced with high efficiency. We noted that all aro-
matic aldehydes carrying either electron-donating or electron-withdrawing
substituents reacted well, giving moderate to excellent yields (Table 1).
Scheme 1.

Bismuth Subnitrate Catalyzed Efficient Synthesis
3823
Table 1. BiONO3-catalyzed efficient synthesis of dihydropyrimidin-2(1H)-ones.
Product
R
R1
X
Time (h)
Yield (%)a
4a[5h]
4b[5h]
4c[5h]
4d[5h]
4e
4f[5h]
4g[5h]
4h[5k]
4i[5h]
4j[5h]
4k[5h]
4l[5h]
4m
C6H5
OEt
OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
1.5
3.0
3.5
3.0
2.5
3.0
3.0
4.0
2.5
3.5
3.5
3.0
3.0
3.0
3.5
4.0
3.5
96
90
92
90
88
90
92
90
92
88
89
92
90
89
91
90
92
3-(NO2)-C6H4
4-(NO2)-C6H4
4-(OCH3)-C6H4
3-(Cl)-C6H4
4-(Cl)-C6H4
4-(OH)-C6H4
2-Furyl
OEt
OEt
OEt
OEt
OEt
OEt
C6H5
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
3-(NO2)-C6H4
4-(NO2)-C6H4
4-(OCH3)-C6H4
3-(Cl)-C6H4
4-(Cl)-C6H4
4-(OH)-C6H4
4-(OH)-C6H4
4-(OCH3)-C6H4
4n[5h]
4o[5h]
4p[5i]
4q[5i]
OEt
S
aYields refer to pure solid products; all products were characterized by comparison of
their physical and spectral data with those of authentic samples.
In conclusion, we developed a simple modification of the Biginelli
dihydropyrimidinone synthesis by using the inexpensive and commercially
available BiONO3 as an efficient Lewis acid catalyst. The method offers
several advantages, including high yields, short reaction times and a simple
experimental workup procedure and product isolation; hence, it is a useful
addition to the existing methods.
EXPERIMENTAL
General Procedure
A solution of an appropriate b-keto ester (1 mmol), corresponding alde-
hyde (1 mmol), urea or thiourea (1.5 mmol), and BiONO3 (0.2 mmol) in anhy-
drous acetonitrile (10 mL) was stirred at 40–508C for a certain period of time
as required to complete the reaction (TLC). The solvent was removed under
reduced pressure to yield a solid, which was washed thoroughly with water,
filtered, and recrystallized from ethanol to afford pure product.

3824
Reddy et al.
1.12
4e: Mp 217–2198C; [1]H-NMR (200 MHz, DMSO-d6):
d
(t, J ¼ 7 Hz, 3H, CH3), 2.36 (s, 3H, CH3), 3.88 (q, J ¼ 5.22 Hz, 2H,
OCH2), 5.42 (s, 1H, CH), 7.55–7.78 (m, 2H, Ar), 7.88 (bs, 1H, NH),
8.06–8.18 (m, 2H, Ar), 9.38 (bs, 1H, NH). IR (KBr): 1585, 1640,
1688, 2965, 3102, 3218, 3352 cm21
. Anal. calculated for
C14H15ClN2O3: C, 57.05; H, 5.13; Cl, 12.03; N, 9.50. Found: C,
57.10; H, 5.10; Cl, 12.08; N, 9.47.
1
4m: Mp 208–2108C; H-NMR (200 MHz, DMSO-d6): d 2.32 (s, 3H,
CH3), 2.55 (s, 3H, CH3), 5.38 (s, 1H, CH), 7.60–7.75 (m, 2H, Ar),
7.91 (bs, 1H, NH), 8.01–8.12 (m, 2H, Ar), 9.41 (bs, 1H, NH). IR
(KBr): 1578, 1646, 1692, 2962, 3102, 3222, 3348 cm21. Anal. calcu-
lated for C13H13ClN2O3: C, 55.62; H, 4.67; Cl, 12.63; N, 9.98.
Found: C, 55.63; H, 4.70; Cl, 12.68; N, 9.97.
ACKNOWLEDGMENT
The authors are thankful to AICTE, New Delhi, for financial assistance
and to the director, IICT, Hyderabad for 1H-NMR and mass spectral analysis.
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Received in the UK June 20, 2004