A one-pot synthesis of 3,4-dihydropyrimidin-2-(IH)-onesfrom primary alcohols promoted by Bi(NO3)3.5H2O in two different media: Organic solvent and ionic liquid

Article abstract of DOI:10.3987/COM-04-10257

A new, simple and efficient procedure for the one-pot conversion of alcohols instead of aldehydes to the corresponding 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) with Bi(NO₃)₃.5H₂O as a commercially available, inexpensive, st

Full text of DOI:10.3987/COM-04-10257

HETEROCYCLES, Vol. 65, No. 4, 2005
767
HETEROCYCLES, Vol. 65, No. 4, 2005, pp. 767 - 773
Received, 22nd October, 2004, Accepted, 7th February, 2005, Published online, 8th February, 2005
A ONE-POT SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONES
3 3 2
FROM PRIMARY ALCOHOLS PROMOTED BY Bi(NO ) .5H O IN TWO
DIFFERENT MEDIA: ORGANIC SOLVENT AND IONIC LIQUID
Ahmad R. Khosropour,* Mohammd M. Khodaei,* Mojtaba Beygzadeh, and
Mahbubeh Jokar
Department of Chemistry, Faculty of Science, Razi University, Kermanshah
6
7149, Iran Tel.: +98-831-427-4559; fax: +98-831-427-4559; e-mail:
arkhosropour@razi.ac.ir or mmkhoda@razi.ac.ir
Abstract – A new, simple and efficient procedure for the one-pot conversion of
alcohols instead of aldehydes to the corresponding 3,4-dihydropyrimidin-2(1H)-
ones (DHPMs) with Bi(NO ) .5H O as a commercially available, inexpensive,
3
3
2
stable and non-toxic reagent in two media, acetonitrile (as an organic solvent) and
tetrabutylammonium bromide (as an ionic liquid) is described. This one-pot
oxidation-cyclocondensation reaction is performed without isolation of any
intermediate (aldehyde) and thus reducing time, saving energy and raw materials.
On the other hand treatment of primary alcohols with this new one-pot method
produce the dehydropyrimidinones in higher yields than those are obtained in the
traditional method.
INTRODUCTION
One of the strategies for combination of economic aspects with the environmental ones is the
multicomponent reaction. This process consists of two or more synthetic steps, which are performed
without isolation of any intermediates thus reducing time, saving energy and raw materials. In the past
decade there have been tremendous developments in three and four component reactions and great efforts
1
have been and still are being made to find and develop new multicomponent reactions. One of the most
attractive three component condensation is Biginelli reaction that has been widely used for the synthesis
2
of 3,4-dihydropyrimidin-2-(1H)-one derivatives with important therapeutic and pharmacological
3
behaviors such as HIV gp-120-CD4 inhiditors, calcium channel blockers, α-adrenergic and neuropeptide
4
5
6
Y antagonists, antihypertensive agents, antitumor, antibacterial and anti-inflammatory activity. The
scope of this pharmacophore has been further increased by the identification of monastrol as a novel

768
HETEROCYCLES, Vol. 65, No. 4, 2005
cell-permeable lead molecule for the development of new anticancer drugs that containing a
7
dihydropyrimidinone core. Thus the development of facile and environmentally friendly synthetic
methods towards dihydropyrimidinones, constitutes an active area of investigation in organic synthesis.
The most well-known method for the preparation of these compounds (Biginelli reaction) limits to the
direct condensation of aldehydes as a precursor with β-dicarbonyls and urea in the presence of different
8
-10
Lewis acids. Therefore, expansion of this method which can be applied to a number of substrates with
different natures, from the viewpoint of total synthesis for the preparation of new dihydropyrimidinone
derivatives, is highly desirable.
RESULTS AND DISCUSSION
In 1985, Ireland and co-worker reported a one-pot scheme in which an aldehyde was generated using
1
1
Swern oxidation conditions from alcohols and trapped in situ by the Wittig reagent. This procedure
alleviated the necessity of isolating the intermediate aldehyde and vastly improved the yield. In the
1
2
13
14
course of our work on the ability of Bi(III) salts, we found the oxidative and catalytic behaviors of
Bi(NO . 5H O in organic transformations. These results prompted us to focus our work on the using of
3
)
3
2
primary alcohols instead of aldehyde in Biginelli reaction.
Two paths can be considered for the conversion of primary alcohols to their dihydropyrimidinones: Path
1
(traditional manner) that containing of: (1) oxidation of the alcohols to their aldehydes (2) isolation of
the aldehydes (3) purification of the aldehydes and (4) utility of the aldehydes in the condensation
reaction.
However, in path 2, these steps can be done in one-pot transformation (a short cut manner) and the
intermediate aldehyde trapped without isolation. This procedure alleviated the necessity of isolating the
intermediate aldehyde and vastly improved the yield.
To investigate the utility of Bi(NO ) .5H O in a one-pot reaction, benzyl alcohol was treated with
3
3
2
3 3 2
Bi(NO ) .5H O followed immediately by addition of ethyl acetoacetate and urea at reflux conditons.
Regardless of reaction times, no dihydropyrimidinone was achieved.
However, the alcohol with Bi(NO ) .5H O in acetonitrile in a traditional manner could be converted to
3
3
2
the corresponding DHPM in 40 % yield (path 1). Next, with further investigation we found that true
one-pot reaction was also possible. Benzyl alcohol was treated with Bi(NO .5H O in acetonitrile and
3
)
3
2
allowed to react at reflux conditions. Once the oxidation was complete, as determined by TLC, the
mixture of ethyl acetoacetate and urea was added and allowed to stir at 70 °C (path 2). Treatment of the
alcohol with this new one-pot oxidation-cyclocondensation procedure led to a dramatic doubling of the
yield (82 %) of the DHPMs as compared to the overall yield obtained in the traditional process where
after oxidation of the alcohol, the aldehyde is isolated and purified before the subsequent cyclocondensation.

HETEROCYCLES, Vol. 65, No. 4, 2005
769
Therefore, we now report the development of methodology utilizing Bi(NO
3
)
3
.5H
2
O in the one-pot
oxidation-cyclocondensation of alcohols to their DHPMs in acetoniltrile (Scheme 1, Method A).
R1
O
2
R C
(
(
a) Bi(NO ) . 5H O
NH
3
3
2
1
R CH OH
2
2
b) (H N) CO, CH COCH COR
2
2
3
2
O
H C
N
H
3
1
R = Alkyl or Aryl
2
R = CH or OC H
3
2
5
Method A = CH CN as solvent
3
Method B = TBAB as solvent
Scheme 1
To the best of our knowledge no report is available in the literature using primary alcohols as precursors
for Biginelli reaction. The generality of this process was demonstrated by the wide range of primary
alcohols. This method is a short cut for conversion of primary alcohols to their dihydropyrimidinones
(
Table 1).
a
Table 1. Formation of dihydropyrimidinones from primary alcohols with
Bi(NO
3
)
3
.5H
2
O in CH
3
CN (Method A)
1
2
b
Entry
R
R
Time(min) Yield /% Ref.
1
C
p-CH
m-CH
p-HOC
o-HOC
m- HOC
p- FC
p- ClC
o- ClC
o- BrC
2,4-Cl
H
OC
OC
OC
OC
OC
OC
OC
H
H
H
H
H
H
H
40
30
85
90
100
80
40
100
60
90
82
91
79
81
78
79
83
89
80
77
84
77
76
14
14
9
9
9
14
14
14
8
6
5
2
2
2
2
2
2
2
5
5
5
5
5
5
5
2
3
4
5
6
7
8
9
1
1
1
1
3
OC
OC
6
H
4
3
6
H
4
6
H
H
4
6
4
6
H
4
6
H
4
6
H
4
OC H5
2
6
H
4
OC
OC
OC
OC
OC
2
2
2
2
2
H
5
H
5
H
5
H
5
H
5
0
1
2
3
6
H
4
8
2
C
6
H
3
100
190
210
14
14
14
2 6 4
m- NO C H
p- NO C H
2 6 4
O
1
4
5
OC
2
2
H
5
5
105
100
70
80
9
8
O
O
S
1
OC
H
1
6
OC
2
H
5
140
78
9
1
1
7
8
C
6
H
5
CH
CH
3
45
30
83
82
14
14
3 6 4
p-CH OC H
3

770
HETEROCYCLES, Vol. 65, No. 4, 2005
Table 1. (continued)
1
2
b
Entry
R
R
Time(min) Yield /% Ref.
1
2
9
0
m-CH
p-HOC H
6 4
3
OC
6
H
4
CH
CH
CH
3
3
3
40
40
70
72
9
9
O
2
1
60
84
9
O
2
2
2
2
2
2
2
2
a
2
3
4
5
6
7
8
9
p- FC
o- ClC
o- BrC
2,4-Cl
6
H
4
CH
CH
CH
CH
CH
CH
OC
OC
3
3
3
3
3
3
2
2
40
65
30
60
30
30
25
30
89
70
91
79
90
92
93
91
9
9
9
9
9
9
9
9
6
H
4
6
H
4
2
6 3
C H
CH
CH
CH
CH
3
3
3
3
(CH
(CH
(CH
(CH
2
)
)
)
)
3
2
3
2
CH
CH
CH
CH
2
2
2
2
2
2
2
H
H
5
5
1
13
All products were characterized with H NMR, C NMR, IR spectra and comparison of their
b
physical and spectral data with those samples in the literatures; Total time (oxidation +
cyclocondensation reactions)
As shown in Table 1, one-pot treatment of a variety of primary alkyl or aryl alcohols with
Bi(NO .5H O in acetonitrile afforded the corresponding DHPMs in good to high yields. The use of
large amounts of Bi(NO .5H O is also found to be not fruitful and does not increase the yields.
3
)
3
2
3
)
3
2
In this procedure several functional groups like chloro, bromo, hydroxyl, methoxy and nitro on aryl
alcohols do survive during the course of the reaction (Table 1, Entries 1-25). Acid sensitive alcohols such
as piperonyl alcohol also work well without the formation of any side products (Table 1, Entries 14, 21).
Interestingly we found that primary aliphatic alcohols were produced DHPMs in excellent yields (Table
14
1
, Entries 26-29) against to the alkyl aldehydes that we did not achieve these products previously.
1
5
Due to the growth in interest for using of ionic liquid as novel reaction media, and as a part of our
research on utility of tetrabutyl ammonim bromide (TBAB) as an ionic liquid in organic
1
8
transformation, we were also interested to carry out this reaction in a one-pot manner using
Bi(NO .5H O immobilized on TBAB (Scheme 1, Method B).
3
)
3
2
The experimental procedure for this transformation is remarkably straightforward and does not require
the use of toxic organic solvents or inert atmospheres. We have found that treatment of primary benzyl
alcohols, carrying either electron-withdrawing or electron-donating groups, afforded the dihydro-
pyrimidinones in high yields in short reaction times (Table 2). Another important aspect is that various
functionalities such as ether, halide, nitro, etc., survived under the present reaction conditions. On the
other hand acid-sensitive groups such as cinnamyl alcohol are also reacted in high yields without the
formation of any side products (Table 2, Entry 6). However, under the same reaction conditions, primary
aliphatic alcohols such as 1-propanol reacted sluggishly and the product yield was much lower than those
3 3 2
obtained with benzylic alcohols (Table 2, Entry 20). Also it was found that Bi(NO ) .5H O-TBAB (Method

HETEROCYCLES, Vol. 65, No. 4, 2005
771
3 3 2 3
B) was a more effective (both in reaction times and yields of the products) than Bi(NO ) .5H O-CH CN
(
Method A) in the one-pot transformation of benzyl alcohols to their DHPMs.
a
Table 2. Formation of dihydropyrimidinones from primary alcohols with
3 3 2
Bi(NO ) .5H O-TBAB (Method B)
1
2
Entry
R
R
Time
Yield /%
Ref.
b
(
min)
1
2
3
4
5
6
7
8
9
C
6
H
5
OC
2
2
H
5
5
20
20
20
22
65
30
30
30
55
50
55
100
115
135
20
32
33
97
96
94
84
80
85
93
86
80
79
84
93
82
80
92
88
81
76
86
12
14
14
14
9
p-CH
p-CH
p-HOC
o-HOC
3
C
OC
6
H
4
OC
H
3
6
H
4
OC H5
2
6
H
H
4
OC
OC
2
H
H
5
9
6
4
2
5
C
6
H
5
CH=CH
OC H5
2
14
14
14
8
p- FC
p- ClC
o- ClC
o- BrC
2,4-Cl
6
H
4
OC
2
H
5
6
H
4
OC H5
2
6
H
4
OC
OC
2
H
H
5
10
11
12
13
14
15
16
17
18
19
20
a
6
H
4
2
5
8
2
C
6
H
H
3
OC H5
2
14
14
14
14
14
9
14
9
14
9
p- NO
2
C
6
4
OC
OC
2
H
H
5
m- NO
o- NO
p-CH
p- FC
p- ClC
2,4-Cl
p- NO
3 2 2 2
CH (CH ) CH
2 6 4
C H
2
5
2
C
6
H
4
OC H5
2
3
C
6
H
4
OCH
OCH
OCH
3
3
3
6
H
4
6
H
4
2
C
C
6
H
H
3
OCH3
60
100
150
2
6
4
OCH
OCH
1
3
3
13
All products were characterized with H NMR, C NMR, IR spectra and comparison of their
In conclusion, we have demonstrated for the first time a new, straightforward, efficient and
environmentally friendly procedure for the one-pot conversion of primary alcohols to their
dihydropyrimidinones under neutral conditions in two media. The reaction can be carried out
conveniently and proceeds with good to high yield and purity. In addition, high chemoselectivity, easy
work-up and using of low cost, low toxicity and easy handling of reagent, specially in the case of
3 3 2
Bi(NO ) .5H O-TBAB as a new and environmentally friendly oxidative-catalytic media, are worthy
advantages of this method. On the other hand, this procedure would expand the tools available to
chemists to perform Biginelli reactions on sensitive or volatile aldehydes.
EXPERIMENTAL

772
HETEROCYCLES, Vol. 65, No. 4, 2005
General Procedure for the Conversion of Primary Alcohols to Their Dihydropyrimidinones in
Acetonitrile Promoted by Bi(NO .5H O (Method A)
To a solution of primary alcohol (1 mmol) in acetonitrile (2 mL) was added Bi(NO
3
)
3
2
3 3 2
) .5H O (0.63 g, 1.3
mmol) and the mixture was allowed to stir under reflux conditions as verified by TLC (usually 2-8 h).
After the reaction was completed, urea (0.09 g, 1.5 mmol) and the β-dicarbonyl compound (2 mmol)
were added and the reaction mixture was stirred under reflux conditions for the appropriate time
according to Table 1. The progress of the reaction was monitored by TLC and after completion hot
ethanol (10 mL) was added. The mixture was filtered and the filterate was cooled until the product was
crystallized. The product was washed with a cooled mixture of (1:1) water/ethanol and then dried. The
pure product was purified by recrystallization from ethanol (95%) in 70-93 % yields.
General Procedure for the Conversion of Primary Alcohols to Their Dihydropyrimidinones in Molten
3 3 2
TBAB Promoted by Bi(NO ) .5H O (Method B)
3 3 2
To the mixture of primary alcohol (1 mmol) in molten TBAB (0.16 g, 0.5 mmol), Bi(NO ) .5H O (0.53 g,
ο
1
.1 mmol) was added. The reaction mixture was stirred at 50 C for 5 min. After completion of the
oxidation step, the β-dicarbonyl compound (1.2 mmol) and urea (0.09 g, 1.5 mmol) were added and the
ο
mixture was stirred magnetically at 90 C for 15 min (the progress of the reaction was followed by TLC).
When the reaction was completed, hot ethanol (20 mL) was added and the suspension was filtered. The
filtrate was cooled until the product was crystallized. The solid product was separated and recrystallised
from ethanol (95%) to afford the pure product (12-97%).
ACKNOWLEDGEMENTS
The authors thank the Razi University Research Council for the support of this work.
REFERENCES
1.
2.
3.
H. Z. S. Huma, R. Halder, S. S. Kalra, J. Das, and J. Iqbal, Tetrahedron Lett., 2002, 43, 6485; M. C.
Bagley, J. W. Cale, and J. Bower, Chem. Commun., 2002, 1682; D. Dallinger, N. Y. Gorobets, and C. O.
Kappe, Org. Lett., 2003, 5, 1205; U. Bora, A. Saikia, and R. C. Boruah, Org. Lett., 2003, 5, 435;
P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360; P. Wipf and A. Cunningham, Tetrahedron. Lett. 1995, 36,
7819; A. Studer, P. Jeger, P. Wipf, and D. P. Curran, J. Org. Chem., 1997, 62, 2917; C. O. Kappe, Acc.
Chem. Res., 2000, 33, 879.
B. Snider, J. Chen, A. D. Patil, and A. Freyer, Tetrahedron Lett., 1996, 37, 6977; A. D. Patil, N. V.
Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer, C. De Brosse, S. Mai, A. Truneh, D. J. Faulkner, B.
Carte, A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W. Westley, and B. C. M. Potts, J. Org. Chem.,

HETEROCYCLES, Vol. 65, No. 4, 2005
773
1
995, 60, 1182.
4
.
.
G. C. Ronyar, S. D. Kinball, B. Beyer, G. Cucinotta, J. D. Dimarco, J. Gougoutas, A. Hedberg, M.
Malley, J. P. McCarthy, R. Zhang, and S. Moreland, J. Med. Chem., 1995, 38, 119.
G. J. Grover, S. Dzwonczyk, D. M. McMullen, C. S. Normadinam, P. G. Sleph, and S. J. Moreland, J.
Cardiovasc. Pharmacol., 1995, 26, 289.
5
6
7
.
.
C. O. Kappe, Tetrahedron, 1993, 49, 6937 and references cited therein.
T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, and T. J. Mitchison, Science,
1
999, 286, 971.
8
.
.
X. Fan, X. Zhang, and Z. Yongmin, J. Chem. Res. (S), 2002, 436; Ch. V. Reddy, M. Mahesh, P. V. K.
Raju, T. R. Babu, and V. V. N. Reddy, Tetrahedron Lett., 2002, 43, 2657; J. Lu and Y. Bai, Synthesis,
2
002, 466; T. Jin, S. Zhang, J. Guo, and T. Li, J. Chem. Res. (S), 2002, 37.
9
P. Salehi, M. Dabiri, M. A. Zolfigol, and M. A. Bodagh Ford, Tetrahedron Lett., 2003, 44, 2889; R.
Varala, M. M. Alam, and S. R. Adapa, Synlett, 2003, 67; K. Kiran, G. S. Reddy, Ch. Srinivas Reddy, J. S.
Yadav, and G. Sabitha, Synlett, 2003, 858. A. S. Paraskar, G. K. DewKar, and A. Sudalai, Tetrahedron
Lett., 2003, 44, 3305; D. Subhas Bose, L. Fatima, and H. B. Mereyala, J. Org. Chem., 2003, 68, 587; K.
R. Reddy, Ch. V. Reddy, M. Mahesh, P. V. K. Raju and V. V. N. Reddy, Tetrahedron Lett., 2003, 44,
8
173.
1
0. S. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, and Q. Zhuang, Synlett, 2004, 537; M. Gohain, D. Prajapati
and J. S. Sandhu, Synlett, 2004, 235; D. S. Bose, R. K. Kumar, and L. Fatima, Synlett, 2004, 279.
1. R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
1
1
2. I. Mohammadpoor-Baltork, H. Aliyan, and A. R. Khosropour, Tetrahedron, 2001, 57, 5851; I.
Mohammadpoor-Baltork and A. R. Khosropour, Monatsh. Chem., 2002, 133, 189; M. M. Khodaei, A.
R. Khosropour, and S. J. Hoseini Jomor, J. Chem. Res. (S), 2003, 10, 638; A. R. Khosropour, M. M.
Khodaei, and K. Ghozati, Chem. Lett., 2004, 304; A. R. Khosropour, M. M. Khodaei, and M.
Kookhazadeh, Tetrahedron Lett., 2004, 45, 1725.
13. M. M. Khodaei, I. Mohammadpoor-Baltork, and K. Nikoofar, Bull. Korean Chem. Soc., 2003, 24, 885.
14. M. M. Khodaei, A. R. Khosropour, and M. Beygzadeh, Synth. Commun., 2004, 34, 1551.
15. A. R. Khosropour, M. M. Khodaei, and K. Ghozati, Chem. Lett., 2004, 1378; J. S. Yadav, B. V. S.
Reddy, A. K. Basak, and A. Venkat Narsaiah, Tetrahedron Lett., 2003, 44, 1047; B. Ganchegui, S.
Bouquillon, F. Henin, and J. Muzart, Tetrahedron Lett., 2002, 43, 6641; B. C. Ranu, A. Das, and S.
Samanta, J. Chem. Soc., Perkin Trans. 1, 2002, 1520; K. Selvakumar, A. Zapt, and M. Beller, Org. Lett.,
2
002, 4, 3031.
1
6. M. M. Khodaei, A. R. Khosropour, and K. Ghozati, Tetrahedron Lett., 2004, 45, 3525; M. M. Khodaei,
A. R. Khosropour, and M. Kookhazadeh, Synlett, 2004, 1980.