Catalyst free synthesis of fused pyrido[2,3-d]pyrimidines and pyrazolo[3,4-b]pyridines in water

Article abstract of DOI:10.1016/j.cclet.2012.08.009

A one-pot, three-component condensation reaction of an aldehyde, benzoyl acetonitrile (3-oxo-3-phenylpropane nitrile) and 6-amino-1,3-dimethylpyrimidine- 2,4(1H,3H)-dione or 3-methyl-1-phenyl-1H-pyrazol-5-amine in water to give fused pyrido[2,3-d]pyrimidi

Full text of DOI:10.1016/j.cclet.2012.08.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1149–1152
www.elsevier.com/locate/cclet
Catalyst free synthesis of fused pyrido[2,3-d]pyrimidines and
pyrazolo[3,4-b]pyridines in water
*
Abbas Rahmati , Zahra Khalesi
Department of Chemistry, University of Isfahan, P.O. Box 81746, 73441 Isfahan, Iran
Received 26 June 2012
Available online 21 September 2012
Abstract
A one-pot, three-component condensation reaction of an aldehyde, benzoyl acetonitrile (3-oxo-3-phenylpropane nitrile) and 6-
amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione or 3-methyl-1-phenyl-1H-pyrazol-5-amine in water to give fused pyrido[2,3-
d]pyrimidines and pyrazolo[3,4-b]pyridines in high yields without any catalyst, is described.
# 2012 Abbas Rahmati. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aminopyrazole; Aqueous media; 3-Methyl-1-phenyl-1H-pyrazol-5-amine; Pyrazolo[3,4-b]pyridine
Development of environmentally benign and clean synthetic procedure is one of the goals of organic synthesis [1].
In this way during the last two decades, water has been used as a green medium for organic reactions [2]. Because the
use of water as solvent has several benefits; water is a cheap, plentiful, nontoxic, nonflammable, safe, neutral and
natural solvent [3–6]. Also, one-pot multi-component reaction (MCR) strategies offer significant advantages over
conventional linear-type syntheses by virtue of their convergence, productivity, facile execution and high yield [7].
Recently one-pot multi component have been used in drug discovery programs [8–12]. Therefore, the importance of
accomplish of the MCRs in water and/or without any harmful organic solvents have been reported [13,14].
Pyrido[2,3-d]pyrimidine ring system is the main part of structure in a number of biologically active compounds
which have antibacterial [15], anticancer [16], antipyretic [17], analgesic and anti-inflammatory [18], inhibitors of
mTOR kinase [19], tyrosine kinase inhibitor [20,21] and adenosine kinase inhibitor [22] as well as anti-tumor
activities [23]. As a consequence of the above reasons the synthesis of pyrido[2,3-d]pyrimidines compounds have been
attracted great attention and several methods were reported for synthesis of these compounds [24–34]. Pyrazolo[3,4-
b]pyridines rings have also displayed in wide range of biological and pharmaceutical activates [35]. Hence, the
preparation of these compounds has been attracted great attention and numerous methods have been reported [36–40].
In spite of the potential utility of aforementioned routes for the synthesis of pyrido[2,3-d]pyrimidines and
pyrazolo[3,4-b]pyridines compounds, many of these methods involve toxic and strong acidic/basic conditions, long
reaction times and low yields as well as use of toxic organic reagents or catalysts. Therefore, to resolve these problems
and limitations, the development of a new and efficient reaction with high catalytic activity, short reaction time and
* Corresponding author.
E-mail address: a.rahmati@sci.ui.ac.ir (A. Rahmati).
1001-8417/$ – see front matter # 2012 Abbas Rahmati. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.08.009

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A. Rahmati, Z. Khalesi / Chinese Chemical Letters 23 (2012) 1149–1152
simple workup for the preparation of pyrido[2,3-d]pyrimidines and pyrazolo[3,4-b]pyridines under neutral, mild and
practical conditions is of great interest.
In continuing our interest in MCRs [41] herein we wish to report a one-pot, an efficient approach for the synthesis of
pyrido[2,3-d]pyrimidines and pyrazolo[3,4-b]pyridines; by three-component reaction of benzoyl acetonitrile (1),
aminouracil (2) or 3-methyl-1-phenyl-1H-pyrazol-5-amine (3), and an aldehyde (4) in water in the absence of any
catalyst (Schemes 1).
In order to optimize the reaction conditions, we carried out the reaction of benzoyl acetonitrile (1) with 6-amino-
1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2) and 4-bromobenzaldehyde (4b) in water in the absence of catalyst in
24 h at room temperature. The results showed that the reaction could proceed as well. After, in order to obtain the best
temperature, this reaction was carried out at various temperatures ranging from 25 to 90 8C under similar conditions in
water. As disclose in Table 1, the maximum yield was observed at 90 8C (entry 6). Therefore, this temperature was
chosen as the reaction temperature for all further reactions. At next step, the reaction was performed in different times,
the results showed that amount of products at 8 h is maximum; the results of optimization process are summarized in
Table 1.
After that, optimum conditions were obtained a variety of aldehydes were used for the scope and generality of this
method (Scheme 2) and the results were listed in Table 2. It is demonstrated that all the aldehydes that used to give the
product of pyrido[2,3-d]pyrimidines 5a–h with satisfactory yields, and all the reactions were very clean. In order to
further ability of method 3-methyl-1-phenyl-1H-pyrazol-5-amine (3) were used instead of aminouracil. The result
showed that reaction could proceed as well as amino uracil. Then different aldehydes was tested with 3-methyl-1-
phenyl-1H-pyrazol-5-amine (3) in the presence of 3-oxo-3-phenylpropanenitrile in these conditions and pyrazolo[3,4-
b]pyridines 6a–c were obtained in excellent yields (Table 2).
In this study, we have successfully applied benzoyl acetonitrile in reaction with amino uracil or aminopyrazole
using different aldehydes for one-pot three-component synthesis of pyrido[2,3-d]pyrimidine and pyrazolo[3,4-
b]pyridine derivatives in water at 90 8C. The mild reaction conditions, less expensive of reaction medium, operational
simplicity, environmental friendliness, and high yields are the advantages of the protocol. The present method may
find some value in organic synthesis, because it is operationally very simple and the starting materials are readily
available.
General procedure for the synthesis of compounds (4a–h and 6a–c): A solution of 3-oxo-3-phenyl propanenitrile
(1 mmol), aldehyde (1 mmol), amino uracil or 5-amino-3-phenyl-pyrazol (1 mmol) was heated in water (5 mL) for
8 h at 90 8C. After completion of the reactions, which has been followed by TLC, the reaction mixturewas filtered and
the pure products were obtained. In some of cases pure products were obtained by extra recrystallization from
methanol.
1,3-Dimethyl-2,4-dioxo-7-phenyl-5-(3-methoxylphenyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carboni-
1
trile (5h): White crystals, mp: 163À165 8C. IR (KBr, cmÀ1): 3064, 2930, 2223, 1716, 1669, 1555, 1476. H NMR
(400 MHz, DMSO-d6): d 3.30 (s, 3H, OCH3), 3.77 (s, 3H, NCH3), 3.78 (s, 3H, NCH3), 6.75 (t, 1H, J = 2.0 Hz,
CHarom), 6.80 (ddd, 1H, J = 7.6 Hz, J = 1.6 Hz, J = 0.8 Hz, CHarom), 6.99 (ddd, 1H, J = 8.4 Hz, J = 2.6 Hz, J = 0.8 Hz,
CHarom), 7.39 (t, 1H, J = 8.0 Hz, CHarom), 7.49–7.52 (m, 3H, 3CHarom), 7.96 (dd, 2H, J = 4.0 Hz, J = 0.8 Hz,
2CHarom). 13C NMR (100.61 MHz, DMSO-d6): d 162.74, 158.70, 158.52, 158.04, 152.16, 150.65, 137.77, 136.41,
131.11, 129.30, 129.20, 128.61, 119.76, 116.27, 113.72, 113.49, 107.04, 103.76, 55.11, 30.04, 28.21. MS m/z (%): 398
(43) [M+], 397 (35), 383 (5), 141 (26), 107 (39), 105 (49), 77 (60), 57 (100), 44 (57), 43 (92), and 42 (64). Anal. calcd.
for C23H18N4O3: C, 69.34; H, 4.55; N, 14.06. Found: C, 69.30; H, 5.07; N, 14.34.
Scheme 1. Synthesis of pyrido[2,3-d]pyrimidines and pyrazolo[3,4-b]pyridines.

A. Rahmati, Z. Khalesi / Chinese Chemical Letters 23 (2012) 1149–1152
1151
Table 1
Optimization of reaction conditions for synthesis of pyrido[2,3-d]pyrimidines (5b).a
Experimental number
Temperature (8C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
25
40
70
90
90
90
90
90
24
24
24
24
16
8
74
84
93
97
97
97
91
65
4
1
a
4-Bromo benzaldehyde(1 mmol), amino uracil (1 mmol), and 3-oxo-3-phenylpropanenitrile (1 mmol).
Scheme 2. Various aldehydes.
Table 2
Synthesis of pyrido[2,3-d]pyrimidines 5a–h and pyrazolo[3,4-b]pyridine 6a–c in water.a
aEntry
CH-acid
Aldehyde
Product
Isolated yield (%)
1
2
2
2
2
2
2
2
2
2
3
3
3
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
90
97
86
83
93
82
84
96
98
96
95
3
4
5
6
7
4g
4h
4c
4i
5g
5h
6a
6b
6c
8
9
10
11
4e
a
Aldehyde (1 mmol), amino uracil or aminopyrazole (1 mmol), and 3-oxo-3-phenylpropanenitrile (1 mmol).
Acknowledgment
We gratefully acknowledge the financial support of the Research Council of the University of Isfahan.
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