A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines and their anti-bacterial activity

Article abstract of DOI:10.1016/j.ejmech.2008.10.018

The first simple and efficient approach towards one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines has been developed by three component condensation of aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochloride in alkaline ethanol

Full text of DOI:10.1016/j.ejmech.2008.10.018

European Journal of Medicinal Chemistry 44 (2009) 2651–2654
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl
pyrimidines and their anti-bacterial activity
*
M.B. Deshmukh, S.M. Salunkhe, D.R. Patil, P.V. Anbhule
Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first simple and efficient approach towards one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl
pyrimidines has been developed by three component condensation of aromatic aldehydes, ethyl cya-
noacetate and guanidine hydrochloride in alkaline ethanol. The synthesized compounds evaluated for
their anti-bacterial activity against Gram-positive and Gram-negative bacteria. The some of the
compounds showed excellent zone of inhibition against tested bacteria.
Received 23 July 2008
Received in revised form
16 October 2008
Accepted 20 October 2008
Available online 26 October 2008
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords:
Amino-pyrimidine
Anti-bacterial activity
Escherichia coli
Staphylococcus aureus
1. Introduction
aldehydes, ethyl acetoacetate and urea in alcohol using strong
mineral acid [8]. These Biginelli compounds possess several phar-
The development of simple synthetic routes for widely used
organic compounds from readily available reagents is one of the
major tasks in organic synthesis. Now days, the one step methods
involving three-component condensation are popular in synthetic
organic chemistry for the synthesis of heterocyclic compounds. The
one step methods are more convenient as compared with multi-
step, since they require shorter reaction time and gives higher yield
with easy workup.
Heterocycles are ubiquitous to among pharmaceutical
compounds [1]. Pyrimidine moiety is an important class of N-
containing heterocycles widely used as key building blocks for
pharmaceutical agents. It exhibits a wide spectrum of pharmaco-
phore as it acts as bactericidal, fungicidal [2], analgesic [3], anti-
hypertensive [4] and anti-tumor agents [5]. Among these;
thiouracils are similarly used as for anti-inflammatory and virucidal
agents [6]. Also, preclinical data from literature survey indicate
continuing research in polysubstituted pyrimidine as potential
anti-tumor agents [7]. The biological and synthetic significance
places this scaffold at a prestigious position in medicinal chemistry
research.
maceutical properties like anti-bacterial, anti-viral, anti-inflam-
matory, anti-hypertensive and anti-tumor agents [9,10].
The scope of the original Biginelli reaction was gradually
extended by variation of all three building blocks, allowing access
to a large number of multifunctionalized dihydropyrimidones. The
several protocols and different reaction conditions have been
employed to improve the yield of Biginelli reaction [11–14].
Although, various methods are reported concerning the
synthesis of pyrimidine derivatives, few one-pot syntheses [15,16]
have been published using aromatic aldehydes, ethyl cyanoacetate
and thiourea.
As per our ongoing research program aimed at the development
of newer synthetic methodologies for widely used heterocyclic
compounds [17,18] inspired us to synthesize 2,6-diamino-4-phenyl
pyrimidine-5-carbonitrile.
In this communication, we have been reporting the first
synthesis of said compounds by three-component condensation of
aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochlo-
ride in ethanol under alkaline medium and their anti-bacterial
activity.
Sci. P. Biginelli in 1893 reported one-step synthesis of 3,4-
dihydropyrimidin-2(1H)-one by three-component condensation of
2. Results and discussion
As per our best knowledge, there is no method involving the one
step synthesis of said pyrimidine compounds using aromatic
aldehydes, ethyl cyanoacetate and guanidine hydrochloride. As
* Corresponding author. Tel.: þ09423717717; fax: þ0231 2692333.
E-mail address: prashantchem2000@yahoo.co.in (P.V. Anbhule).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.10.018

2652
M.B. Deshmukh et al. / European Journal of Medicinal Chemistry 44 (2009) 2651–2654
a case study, the equimolar mixtures of 3-chloro benzaldehyde
(10 mmol), ethyl cyanoacetate (10 mmol) and NaOH (0.4 g in 5 ml
water) in 25 ml ethanol were stirred mechanically for 10 min, fol-
lowed by addition of guanidine hydrochloride (10 mmol). The
reaction mixture was then refluxed till completion. After the
completion of the reaction as monitored by TLC, the reaction
mixture was poured in ice-cooled water and neutralized by 1:1 HCl
to get the desired product. The separated solid was filtered, washed
with distilled water to remove all the acid and finally, recrystallised
from ethanol to get the pure product.
and Staphylococcus aureus are common bacteria causing food
poisoning. Therefore we have selected these two bacteria for the
screening work. The results i.e. zone of inhibition have been
introduced in Table 2.
The method exploited works well with variety of aromatic
aldehydes as well as heteroaromatic aldehydes to afford corre-
sponding polysubstituted pyrimidine in excellent yields.
We reasoned that the electron donating as well as electron
withdrawing groups present in aryl aldehydes does not alter the
theme of the method in terms of yield and reaction time. The
physical and analytical data have been given in Table 1
In case of p-anisaldehyde, we were unable to get desired
product. The proton NMR spectrum of corresponding compound
showed four doublets, indicating the formation of 4-(4-
methoxy)-phenyl-5-cyano-6-oxo hexahydro-2-iminopyrimidine.
The same reaction was also carried out for the aliphatic alde-
hydes like crotonaldehyde but we did not succeed to get the
desired product.
Against Gram positive (Entry d)
Against Gram Negative (Entry d)
Anti-bacterial activity against S.aureus(Entry d)
800
700
600
500
400
300
200
100
0
1
2
3
zone of inhibition
4
5
2.1. Anti-bacterial activity
The anti-bacterial study of the synthesized compounds shows
good to excellent activity against tested Gram-positive and Gram-
negative bacteria. Among these, interestingly, the 2-amino-5-
cyano-6-hydroxy-4-phenyl pyrimidine found to be selectively
active against Gram-positive S. aureus bacteria and also noted that
the substituent on the aromatic aldehydes reduces the biological
property.
The anti-bacterial activity was studied by selecting Gram-posi-
tive and Gram-negative bacteria via agar well diffusion method.
The solutions were prepared in five different concentrations: (a)
750 ppm (b) 500 ppm (c) 250 ppm (d) 100 ppm and (e) 50 ppm.
2.2. Agar well diffusion method
In this method, the solution of testing compound was added in
a well in the solidified agar layer in a petri dish and zone of inhi-
bition is measured after 24 h.
2.3. General procedure for the synthesis of desired compounds
About 10–15 g of molten agar was spread into each sterilized
petri dish by taking the usual precautions to avoid the contami-
nations. All the petri dishes were marked in a specific way. Sterile
cork borer was used to make well. The agar plates were inoculated
with the suspension of particular organism by spread plate
technique.
Finally, the agar well plates were filled with 0.5 ml of the test
solution. After the addition of the tested samples, the plates were
kept in freeze for diffusion and incubated at 37 ꢀC for 1 h. The zone
of inhibition if any was then measured in mm for the particular
compound and specific organism.
The equimolar mixture of aromatic aldehyde, (10 mmol), ethyl
cyanoacetate (10 mmol) and NaOH (0.4 g in 5 ml water) in 25 ml
ethanol was stirred mechanically for at least 10 min, then guani-
dine hydrochloride (10 mmol) was added to the above reaction
mixture and reaction mixture was refluxed till completion of
reaction as monitored by TLC. After the completion of reaction,
the reaction mixture was poured into ice-cooled water and
neutralized by 1:1 HCl to get the desired product. The separated
solid was filtered, washed with little distilled water to remove
acid. Finally, the crude product was purified by recrystallisation
from ethanol to get pure product in almost quantitative yield
(Scheme 1).
All the microbial strains used were of non-invasive species of
their genera and thus applicable for analytical work. Escherichia coli
2.4. Experimental part
Table 1
Synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines (a–l).
The melting points of products were taken in open capillary
and are found to be uncorrected. All above products have been
fully characterized by IR, proton NMR, 13C NMR spectroscopy and
mass spectrometry as well as elemental analysis. The data found
were in consistent with the proposed structure. The proton NMR
and 13C spectra were recorded in DMSO-d6 solvent on Brucker
400 MHz spectrometer using tetramethyl silane as internal stan-
dard. The reaction was monitored by TLC using silica gel 60-F 254
plates.
Sr. No. (Entry)
Aryl aldehyde
Time (h)
Yield (%)a
a
b
c
d
e
f
g
h
i
4-N, N–(CH3) 2-C6H4
3-NO2–C6H4
3,4-(OCH3)2–C6H3
C6H5–
C6H4–CH]CH–
3-ClC6H4
4-OCH3C6H4
2-NO2C6H4
3,4,5-(OCH3) 3-C6H2
4-OHC6H4
Thiophene2-aldehyde
2-ClC6H4
1.0
1.0
1.5
1.5
1.5
1.5
2.5
2.0
2.0
1.5
2.5
3.0
92
94
92
90
92
95
90
88
89
93
83
79
j
k
l
2.5. Spectroscopic data of representative compounds
2.5.1. 2-Amino-6-hydroxy-4-(4-N,N-dimethylaminophenyl)-pyrimi-
dine-5-carbonitrile (entry a). M.p.: 215 ꢀC. IR (KBr): 3434, 2924,
2215, 1661, 1611, 1565, 1293, 1190, 1171, 813 cmꢁ1. PMR (DMSO-d6)
a
Yields refer to pure products.

M.B. Deshmukh et al. / European Journal of Medicinal Chemistry 44 (2009) 2651–2654
2653
Table 2
Zone of inhibition against Escherichia coli and Staphylococcus aureus.
Entry
E. coli
S. aureus
Conc. in ppm
Conc. in ppm
50
–
–
–
–
–
–
–
–
100
–
–
–
–
–
–
–
–
250
4 mm
–
–
–
7 mm
4 mm
–
500
7 mm
–
–
–
9 mm
7 mm
–
750
11 mm
–
–
–
12 mm
11 mm
–
50
–
–
–
100
–
–
–
250
7 mm
4 mm
–
15 mm
–
–
–
–
–
500
750
a
b
c
d
e
f
g
h
i
9 mm
8 mm
–
15 mm
5 mm
–
11 mm
14 mm
–
10 mm
12 mm
18 mm
9 mm
5 mm
5 mm
15 mm
13 mm
11 mm
13 mm
14 mm
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3 mm
5 mm
9 mm
12 mm
10 mm
8 mm
9 mm
9 mm
j
k
l
–
–
–
–
–
–
–
–
–
6 mm
–
8 mm
10 mm
–
10 mm
5 mm
6 mm
5 mm
d
3.0 (s, 6H, N–(CH3)2), 6.80–6.82 (dd, 2H, Ar-H J ¼ 8.0 Hz), 7.91–7.93
2.5.5. 2-Amino-6-hydroxy-4-(cinnamyl)-pyrimidine-5-carbonitrile
(dd, 2H, Ar-H J ¼ 8.0 Hz), 8.05 (s, 1H, OH), 13.23 (s, 2H, NH2). 13C
(entry e). M.p.: 196 ꢀC. IR (KBr): 3324, 2934, 2823, 2225,1690, 1650,
NMR (DMSO-d6)
d
40.17, 93.5, 110.9, 111.6, 117.7, 118.4, 133.4, 153.4,
1560, 1284, 1085, 690 cmꢁ1. PMR (DMSO-d6)
d 7.25 (d, 1H, Ar–
153.7, 164.7. Mþ 255, C, H, and N analyses: C 61.12 (61.17), H 5.15
(5.13), N 27.42 (27.43).
CH]CH), 7.30 (d, 2H, Ar-H), 7.48 (br. s, 3H, Ar-H), 7.59 (s, 2H, NH2),
7.63 (s, 1H, –OH), 8.0 (d, 1H, Ar–CH]CH–). 13C NMR (DMSO-d6)
d
103.4, 113.9, 123.0, 127.1, 128.2, 128.8, 129.2, 131.6, 134.5, 150.4,
2.5.2. 2-Amino-6-hydroxy-4-(3-nitro-phenyl)-pyrimidine-5-carbon-
itrile (entry b). M.p.: 176 ꢀC. IR (KBr): 3400, 2924, 2854, 2223,
1632, 1611, 1529, 1351, 1101, 1171, 809, 740 cmꢁ1. PMR (DMSO-d6)
157.2, 166.8. Mþ 238.
2.5.6. 2-Amino-6-hydroxy-4-(3-chlorophenyl)-pyrimidine-5-carbon-
d
3.6 (s, 2H, NH2), 7.0 (s, 1H, OH), 7.37–7.39 (dd, 1H, Ar-H,
J ¼ 8.0 Hz), 8.11–8.13 (dd, 1H, Ar-H, J ¼ 8.0 Hz), 8.52 (m, 1H, Ar-H),
8.62 (s, 1H, Ar-H). 13C NMR (DMSO-d6)
121.4, 122.8, 123.3, 124.6,
itrile (entry f). M.p.: 170 ꢀC. IR (KBr): 3334, 3231, 2958, 2513, 2229,
1694, 1562, 1427, 1294, 1090, 786, 687 cmꢁ1. PMR (DMSO-d6)
d 3.3
d
(br. s, 2H, NH2), 7.60 (m, 1H, Ar-H), 7.69–7.70 (dd, 1H, Ar-H
126.7, 127.9, 130.8, 133.0, 134.4, 135.2, 136.5, 140.7, 147.6, 148.3,
152.0. Mþ 257, C, H, and N analyses: C 51.32 (51.37), H 2.15 (2.74),
N 27.19 (27.23).
J ¼ 4.0 Hz), 8.00–8.01 (dd, 1H, Ar-H J ¼ 4.0 Hz), 8.10 (s, 1H, OH), 8.35
(s, 1H, Ar-H). 13C NMR (DMSO-d6)
d 105.8, 115.6, 128.8, 129.9, 131.0,
132.4, 133.6, 133.8, 152.6, 162.8. Mþ 246, C, H, and N analyses: C
53.52 (53.57), H 2.84 (2.86), N 22.69 (22.71).
2.5.3. 2-Amino-6-hydroxy-4-(3,4-dimethoxyphenyl)-pyrimidine-5-
carbonitrile (entry c). M.p.: 240 ꢀC. IR (KBr): 3473, 3233, 2924, 2222,
1717, 1677, 1592, 1510, 1428, 1260, 1167, 1008, 811, 778 cmꢁ1. PMR
2.5.7. 4-(4-Methoxy)-phenyl-6-oxo hexahydro-2-iminopyrimidine-
5-carbonitrile (entry g). M.p.: 224 ꢀC. IR (KBr): 3337, 2937, 2844,
2224, 1694, 1590, 1590, 1429, 1263, 1177, 1071, 837, 686 cmꢁ1. PMR
(DMSO-d6)
d 3.4 (br. s, 2H, NH2), 3.79 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 7.15–7.17 (dd, 1H, Ar-H, J ¼ 8.0 Hz), 7.67–7.69 (dd, 1H, Ar-H,
(DMSO-d6)
1H, Benzylic H), 7.15 (dd, 1H, CN–H), 7.8 (dd, 2H, Ar-H), 8.15 (dd, 2H,
Ar-H), 8.25 (br. s, 1H, C]NH). 13C NMR (DMSO-d6)
55.4, 55.7, 84.1,
99.8, 113.6, 114.8, 116.6, 117.3, 124.1, 127.8, 130.2, 133.2, 153.8, 155.9,
161.3, 161.6, 163.2, 163.7, 169.3. Mþ 244.
d 2.5 (s, 1H, NH), 3.8 (s, 3H, OCH3), 3.9 (s, 1, NH), 7.05 (dd,
J ¼ 8.0 Hz), 7.74 (s, 1H, Ar-H), 8.23 (s, 1H, OH). 13C NMR (DMSO-d6)
d
55.48, 55.83, 99.7, 111.8, 112.7, 116.7, 124.1, 126.4, 148.7, 153.2,
d
154.0, 163.6. Mþ 272, C, H, and N analyses: C 57.32 (57.35), H 4.45
(4.44), N 20.56 (20.58).
2.5.4. 2-Amino-6-hydroxy-4-(phenyl)-pyrimidine-5-carbonitrile
(entry d). M.p.: (175 ꢀC). IR (KBr): 3473, 3233, 2850, 2221, 1693,
1605, 1577, 1427, 1286, 1170, 1081, 753, 690 cmꢁ1. PMR (DMSO-d6)
2.5.8. 2-Amino-6-hydroxy-4-(2-nitrophenyl)-pyrimidine-5-carbon-
itrile (entry h). M.p.: 214 ꢀC. IR (KBr): 3415, 3010, 2223, 1601, 1556,
1428, 1091, 835, 757, cmꢁ1. PMR (DMSO-d6)
d
7.80 (m, 1H, Ar-H),
d
2.9 (s, 1H, OH), 3.5 (br. s, 2H, NH2), 7.18 (m, 5H, Ar-H). 13C NMR
7.9–8.0 (m, 2H, Ar-H), 8.3 (dd,1H, Ar-H), 8.75 (br. s,1H, OH),14.4 (br.
(DMSO-d6)
d
126.2, 126.6, 128.1, 128.8, 129.1, 130.3, 135.6, 143.2. Mþ
s, 2H, NH2). 13C NMR (DMSO-d6)
d 108.7, 114.6, 125.1, 128.3, 130.5,
212, C, H, and N analyses: C 62.20 (62.26), H 3.75 (3.80), N 26.39
(26.40).
132.2,134.6,147.2,153.9,162.3. Mþ 257, C, H, and N analyses: C 51.30
(51.37), H 2.50 (2.74), N 27.22 (27.23).
R'
CHO
NaOH, EtOH
Reflux
CN
OH
NH
NH2. HCl
N
NC
CH2
COOC2H5
+
+
H2N
H2N
N
R'
R'= -Cl, NO2, -OMe, -OH,
Scheme 1.

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M.B. Deshmukh et al. / European Journal of Medicinal Chemistry 44 (2009) 2651–2654
2.5.9. 2-Amino-6-hydroxy-4-(3,4,5-trimethoxy)-phenyl-pyrimidine-
5-carbonitrile (entry i). M.p.: 170 ꢀC. IR (KBr): 3429, 2939, 2838,
1666, 1591, 1507, 1462, 1240, 1126, 1004, 836 cmꢁ1. PMR (DMSO-d6)
Acknowledgement
Authors thank the Indian Institute of Science, Bangalore for
providing the spectral analysis and KLE’s pharmacy college, Bel-
gaon for screening the samples.
d
3.8 (br. s, 9H, –OCH3), 6.0–6.6 (m, 2H, two Ar-H) 6.7 (s, 1H, OH), 7.3
(br. s, 2H, NH2). 13C NMR (DMSO-d6)
d 56.2, 60.8, 105.5, 109.0, 132.4,
138.0, 153.1. Mþ 302, C, H, and N analyses: C 55.62 (55.63), H 4.84
(4.67), N 18.51 (18.53).
References
2.5.10. 2-Amino-6-hydroxy-4-(4-hydroxyphenyl)-pyrimidine-5-car-
bonitrile (entry j). M.p.: 240 ꢀC. IR (KBr): 3307, 3233, 2924, 2231,
1672, 1562, 1510, 1435, 1288, 1175, 842, 736 cmꢁ1. PMR (DMSO-d6)
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6.92–6.94 (dd, 2H, Ar-H, J 8.0 Hz), 7.94–7.96 (dd, 2H, Ar-H,
J ¼ 8.0 Hz), 8.09 (s, 1H, OH), 10.58 (s, 1H, Ar-OH), 13.7 (br. s, 2H,
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d 98.4, 115.8, 116.3, 116.8, 122.6, 132.0,
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(entry k). M.p.: 240 ꢀC. IR (KBr): 3420, 3177, 2924, 2214, 1647, 1530,
1494, 1422 cmꢁ1. PMR (DMSO-d6)
d, 6.96 (br. s, 1H, –OH), 7.25–7.26
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J ¼ 4.0 Hz), 11.60 (br. s, 2H, NH2). Mþ 218.
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1596, 1494, 1485, 1418, 1260 cmꢁ1. PMR (DMSO-d6) 2.49 (br. s, 2H,
–NH2), 7.55–7.69 (m, 3H, Ar-H), 8.08–8.11 (d, 1H, Ar-H), 8.48 (s,
1H, –OH). 13C NMR (DMSO-d6) 90.07, 108.09, 115.8, 120.02, 127.88,
129.81, 134.51, 145.79, 149.99, 156.38, 162.49 and 176.00. Mþ 246,
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(22.71).
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3. Conclusion
The straightforward approach, simplicity and first one-step
method make it an interesting approach for the synthesis of said
compounds. All the synthesized compounds are new one as per our
knowledge. The anti-bacterial study of the synthesized compounds
shows good to excellent activity against tested Gram-positive and
Gram-negative bacteria. Among these, interestingly, the 2-amino-
5-cyano-6-hydroxy-4-phenyl pyrimidine found to be selectively
active against Gram-positive bacteria is the main findings of this
article.
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