NbCl5-catalyzed rapid and efficient synthesis of 3,4-dihydropyrimidinones under ambient conditions

Article abstract of DOI:10.1246/cl.2004.926

Three-component condensation of an aldehyde, 1,3-dicarbonyl compound and urea or thiourea proceeds smoothly at room temperature in the presence of 5 mol % of NbCl₅ under extremely mild conditions to afford the corresponding 3,4-dihydropyrimidin

Full text of DOI:10.1246/cl.2004.926

926
Chemistry Letters Vol.33, No.7 (2004)
NbCl5-catalyzed Rapid and Efficient Synthesis of 3,4-Dihydropyrimidinones
Under Ambient Conditions
J. S. Yadav,ꢀ B. V. S. Reddy, Jaishri J. Naidu, and K. Sadashiv
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received March 18, 2004; CL-040309)
Three-component condensation of an aldehyde, 1,3-dicar-
R
bonyl compound and urea or thiourea proceeds smoothly at room
temperature in the presence of 5 mol % of NbCl5 under extremely
mild conditions to afford the corresponding 3,4-dihydropyrimi-
dines in high to quantitative yields. This method is very useful
for the synthesis of a wide range of dipyrimidinones at room tem-
perature from aromatic, heterocyclic, and aliphatic aldehydes.
O
R
O
O
H
5 mol% NbCl5
EtOH, r.t.
R''
NH
NH2
X
R''
+
R'
N
H
X
H2N
R'
O
X = O, S
Scheme 1.
using 5 mol % of NbCl5 in ethanol (Scheme 1).
The reaction proceeded rapidily at room temperature under
extremely mild conditions and the product started to precipitate
out after 30 min and more than 90% conversion was observed
within 2 h. Encouraged by the results obtained with benzalde-
hyde, we turned our attention towards various substituted alde-
hydes and 1,3-dicarbonyl compounds. Interestingly, a wide range
of substrates including aromatic, aliphatic, heterocyclic, and ꢀ,ꢁ-
unsaturated aldehydes reacted rapidly with ethyl acetoacetate and
urea or thiourea to give the corresponding dihydropyrimidinones.
Most importantly, aromatic aldehydes carrying either electron-
donating or -withdrawing substituents reacted well under the re-
action conditions to give the corresponding dihydropyrimidi-
nones in high to quantitative yields with high purity. The crude
products obtained are of high purity (>95% by 1H NMR). Many
of the pharmacological relevant substitution patterns on the aro-
matic ring can be introduced with high efficiency using this pro-
cedure (Table). Compared to the classical Biginelli method, one
additional important feature of the present protocol is the ability
to tolerate the variations in all the three components. Another im-
portant feature of this procedure is the survival of a variety of
functional groups such as olefins, ethers, esters, nitro group,
and halides under the reaction conditions. This method is even ef-
fective with aliphatic and ꢀ,ꢁ-unsaturated aldehydes, which nor-
mally show extremely low conversions in the Biginelli reaction
(Entries p, q, and r, Table). Unlike reported methods, this proce-
dure does not require high temperature7,8 or anhydrous condi-
tions. Furthermore, this method is not only preserves the simplic-
ity of Biginelli reaction but also produces excellent yields of the
products. Thiourea has been used with similar success to produce
the corresponding thio-derivatives of dihydropyrimidinones
which are also of much interest with respect to their biological ac-
tivities (Entries i and j, Table).2a Besides the ꢁ-keto esters, 1,3-
diketone was employed to produce a dihydropyrimidinone (Entry
o, Table). Decreased reaction times and improved yields are real-
ized due to the increased reactivity of the substrates in the etha-
nolic solution of niobium(V) chloride. By using this method, the
yields of the one-pot Biginelli reaction can be improved from 20–
60%1b to 70–96% while the reaction time was shortened from
18 h to 2.5–5.0 h. In order to optimize the conditions, we carried
out the reactions using different quantities of reactants. The best
results were obtained with 0.05:1:1:1.5 ratio of NbCl5, aldehyde,
1,3-dicarbonyl compound and urea or thiourea. In the absence of
niobium(V) chloride, the reaction did not proceed at room tem-
Many functionalized dihydropyrimidinones have emerged as
the integral backbones of several calcium channel blockers, anti-
hypertensives, ꢀ1a-adrenergic antagonists, and neuropeptide Y
(NPY) antagonists.1 Particularly, aryl 3,4-dihydropyrimidinones
are found to exhibit a wide spectrum of biological activities such
as antiviral, antitumor, antibacterial, and antiinflammatory be-
havior.2 Furthermore, several alkaloids containing the dihydro-
pyrimidine core structure have been isolated from marine sour-
ces, which also exhibit interesting biological properties. Most
notably, among these are the batzelladine alkaloids which are
found to be potent HIV gp-120-CD4 inhibitors.3 Thus, the synthe-
sis of the pyrimidinone nucleus is of much current importance.
The simplest and most straightforward procedure for the prepara-
tion of pyrimidinones involves three-component one-pot conden-
sation of an aldehyde, (ꢁ-ketoester, and urea under strongly acid-
ic conditions.4 However, this so-called Biginelli reaction often
suffers from low yields of products particularly in the case of sub-
stituted aromatic and aliphatic aldehydes.5 This has led to the de-
velopment of multi-step synthetic strategies, which produce rela-
tively higher yields but lack the simplicity of the original one-pot-
Biginelli protocol.6 The Biginelli one-pot reaction has received
renewed interest of researchers for the discovery of milder and ef-
ficient procedures for a wide variations of substituents in all three
components and better yields. As a result, several improved pro-
cedures have recently been reported using Lewis acids as well as
protic acids as promoters.7,8 Besides their potential utility, most
of these methods require high temperature and extended reaction
times to achieve satisfactory results. Therefore, the development
of an efficient and versatile catalyst for Biginelli reaction is an ac-
tive ongoing research area and thus there is scope for further im-
provements toward milder reaction conditions, variations of sub-
stituents in all three components, and better yields. Recently
niobium(V) chloride has emerged as an efficient Lewis acid in
promoting various organic transformations such as the Diels–
Alder reaction, ring-opening of epoxides, Mukaiyama aldol reac-
tion and allylation of aldehydes, imines and N-acyliminium ions
under mild conditions.9,10
In this report, we describe a simple, convenient, and high
yielding protocol for the synthesis of dihydropyrimidinones by
a three-component one-pot condensation of an aldehyde, ꢁ-keto
ester and urea using NbCl5 as a catalyst. Initially, we have carried
out a model raction of benzaldehyde, ethyl acetoacetate and urea
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.7 (2004)
927
Table 1. NbCl5-catalyzed
dihydropyrimidinonesa
three-component
synthesis
of
3,4-
imidinones with a wide range of substitution patterns on all three
components. To the best of our knowledge, there are only few re-
ports on the one-pot Biginelli reaction at room temperature,11 as
most of the reported methodologies to date are carried out under
drastic conditions. The scope and generality of this process is il-
lustrated with respect to various aldehydes, 1,3-dicarbonyl com-
pounds, and urea or thiourea and the results are presented in the
Table.
In summary, we found that niobium(V) chloride is an ex-
tremely mild and highly efficient Lewis acid for the synthesis
of biologically significant aryl-substituted dihydropyrimidinones
by means of a three-component condensation of an aldehyde, 1,3-
dicarbonyl compound and urea or thiourea in a one-pot operation.
This method is applicable for a wide range of substrates including
aromatic, aliphatic, ꢀ,ꢁ-unsaturated and heterocyclic aldehydes
and provides a variety of biologically relevant dihydropyrimidi-
nones in high to quantitative yields over a short reaction time.
Aldehyde
CHO
R''
Yield/%b
Time/h
2.5
Entry
X
R'
1
2
O
Me
OEt
95
93
CHO
CHO
O
Me
OEt
3.0
Cl
3
4
O
O
Me
Me
OEt
OEt
4.0
2.0
91
89
MeO
O2N
CHO
CHO
5
O
Me
OEt
6.0
85
Me
N
Me
O
CHO
CHO
6
7
O
O
Me
Me
OEt
OEt
3.0
3.0
94
96
O
MeO
MeO
BVS, JJN thank CSIR, New Delhi, for the award of fellow-
ships.
CHO
8
9
O
S
Me
Me
OEt
OEt
5.0
3.5
90
91
CHO
CHO
References and Notes
Cl
1
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10
11
S
Me
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4.0
3.0
93
70
MeO
CHO
2
3
O
N
H
12
13
O
O
Me
Me
OEt
2.5
3.0
91
93
CHO
CHO
S
OMe
4
5
P. Biginelli, Gazz. Chim. Ital., 23, 360 (1893).
CHO
CHO
CHO
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14
15
O
O
Ph
OEt
Me
5.0
4.0
85
80
Me
6
7
16
O
Me
OEt
4.0
87
CHO
17
18
O
O
Me
Me
OEt
OEt
3.0
3.5
90
82
CHO
CHO
19
20
O
O
Me
Me
OEt
OEt
3.0
5.0
85
91
N
H
8
9
CHO
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perature even after a long reaction time (8–12 h). The efficacy of
other Lewis acids such as InCl3, CeCl3, GdCl3, TaCl5, and YCl3
was studied for this reaction. Among these catalysts, NbCl5 was
found to be superior in terms of conversion and reaction time.
This three-component reaction did not proceed at room tempera-
ture using the above mentioned catalysts. However, the reaction
proceeded with these reagents under reflux conditions. It seems
that methanol or ethanol is a much better solvent in terms of con-
version than all the other tested solvents which included acetoni-
trile, dichloromethane and tetrahydrofuran. Furthermore, the use
of just 5 mol % of niobium(V) chloride in methanol is sufficient to
promote the reaction and no additives such as HCl or
CH3COOH7e are required for this conversion. Thus, this proce-
dure provides an easy access to the preparation of substituted pyr-
12 Experimental procedure:
A mixture of ꢁ-keto ester (1.0 mmol), aldehyde
(1.0 mmol), urea or thiourea (1.5 mmol), and NbCl5 (5 mol %) in methanol
(10 mL) was stirred at room temperature for a certain period of time as required
to complete the reaction. The progress of the reaction was monitored by TLC. On
completion, the solvent was removed under reduced pressure and the resulting
product was washed with water, filtered and recrystallized from hot methanol
to afford pure dihydropyrimidinone. The spectral data of all the products were
identical with those of authentic samples.6–8 Spectroscopic data for selected
products: 3n: Solid, m.p. 157–158 ꢁC. IR (KBr): v 3215, 3085, 2978, 1697,
1650 cmꢂ1 1H NMR (200 MHz, DMSO-d6): ꢂ 0.90 (t, 3H, J = 6.8 Hz), 3.85
.
(q, 2H, J = 6.8 Hz), 5.45 (d, 1H, J = 1.9 Hz), 6.55 (brs, NH, 1H), 7.30–7.40
(m, 10 H), 7.80 (brs, NH, 1H). EIMS: m=z: 322 (Mþ), 294, 278, 249, 185,
157, 138, 91, 77, 69. 3o: Solid, m.p. 240–242 ꢁC. IR (KBr): v 3286, 3251,
.
2920, 1703, 1675, 1598, 1414, 1327, 1235, 1105, 997, 965, 768 cmꢂ1 1H
NMR (200 MHz, DMSO-d6): ꢂ 2.10 (s, 3H), 2.25 (s, 3H), 5.30 (d, 1H, J =
2.0 Hz), 7.20–7.30 (m, 5H), 7.60 (brs, NH, 1H), 9.05 (brs, NH, 1H). EIMS:
m=z: 230 (Mþ), 188, 154, 144, 115, 77, 43.
Published on the web (Advance View) June 26, 2004; DOI 10.1246/cl.2004.926