Synthesis of substituted pyrimidinones catalyzed by boric acid and glycerol in aqueous medium

Article abstract of DOI:10.1080/00397911.2011.602497

An expeditious one-pot synthesis of substituted pyrimidinone derivatives with aromatic aldehydes, cyclopentanone, and urea (or thiourea) was developed with boric acid (10mol%) and glycerol (0.1mL) in aqueous medium at 45-50 C. The methodology is simple, h

Full text of DOI:10.1080/00397911.2011.602497

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Synthesis of Substituted Pyrimidinones
Catalyzed by Boric Acid and Glycerol in
Aqueous Medium
Chhanda Mukhopadhyay a & Arup Datta a
a Department of Chemistry, University of Calcutta, Kolkata, India
Accepted author version posted online: 13 Feb 2012.Version of
record first published: 02 Nov 2012.
To cite this article: Chhanda Mukhopadhyay & Arup Datta (2013): Synthesis of Substituted
Pyrimidinones Catalyzed by Boric Acid and Glycerol in Aqueous Medium, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:3, 438-449
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Synthetic Communications1, 43: 438–449, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.602497
SYNTHESIS OF SUBSTITUTED PYRIMIDINONES
CATALYZED BY BORIC ACID AND GLYCEROL IN
AQUEOUS MEDIUM
Chhanda Mukhopadhyay and Arup Datta
Department of Chemistry, University of Calcutta, Kolkata, India
GRAPHICAL ABSTRACT
Abstract An expeditious one-pot synthesis of substituted pyrimidinone derivatives with aro-
matic aldehydes, cyclopentanone, and urea (or thiourea) was developed with boric acid
(10 mol%) and glycerol (0.1 mL) in aqueous medium at 45–50 ꢀC. The methodology is
simple, highly efficient, and high yielding. The idea behind this methodology is that boric
acid, being a weak acid, behaves as a strong acid in presence of glycerol in aqueous medium.
Keywords Aqueous medium; boric acid; glycerol; substituted pyrimidinone derivatives
INTRODUCTION
Recently, organic synthesis in aqueous medium[1,2] without using organic
solvents has become one of the most important topics in organic chemistry to meet
environmental demands.[3,4] Performing organic synthesis in the aqueous phase is
highly challenging from both synthetic and environmental viewpoints. Apart from
being environmentally friendly, water possesses some unique properties (such as
being nontoxic, available in large quantities, cheap, nonflammable, and nonhazar-
dous) that are different from other solvents, thus making it a very good reaction
medium for organic synthesis.
The pyrimidinone skeleton is an integral part of many natural or synthetic
bioactive materials.[5] Pyrimidinones containing specific functional groups exhibit
Received May 6, 2011.
Address correspondence to Chhanda Mukhopadhyay, Department of Chemistry, University of
Calcutta, 92 APC Road, Kolkata 700009, India. E-mail: cmukhop@yahoo.co.in
438

SUBSTITUTED PYRIMIDINONE SYNTHESIS
439
Figure 1. A fused pyrimidine-thione with an arylidene moiety.
specific biological properties. Fused pyrimidinones containing an arylidene skeleton
behave as potential antitumor agents.[6] A new series of 3,5-bis(arylidene)-4-piperi-
dones, as chalcone analogs carrying a variety of aryl and heteroaryl groups, pyra-
zolo[4,3-c]pyridines, pyrido[4,3-d]pyrimidines and pyrido[3,2-c]pyridines, carrying
an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin
isosteres, were synthesized and screened for their in vitro antiviral and antitumor
activities at the National Cancer Institute (NCI).[6] Therefore, the synthesis of this
type of pyrimidinone moiety is always a great challenge. A specific example of such
a fused pyrimidine-thione with an arylidene moiety is given in Fig. 1.
RESULTS AND DISCUSSION
The classical three-component Biginelli condensation involves an aldehyde, a
b-keto ester, and urea or thiourea, mainly under acidic conditions.[7,8] This reaction
could be extended by variation of the b-keto ester or cyclic b-diketones with cyclo-
pentanone. The aim of our work is to design a pyrimidinone skeleton (Fig. 2) posses-
sing an arylidene functional group.
Very few cases of earlier instances for the synthesis of pyrimidinone derivatives
exist where Biginelli-type condensation was done by the reaction of a,a0-
bis(arylidene)cycloalkanones with urea or thiourea. In majority of the cases, either
a strong Brønsted acid such as HCl[9] or strong Brønsted base such as KOH or
sodium alkoxide[10] has been used for the reaction. Recently, the following two meth-
odologies have been developed: (a) using stoichiometric amount of TMSCl in
dimethylformamide (DMF) = MeCN as solvent[11,12] or (b) using ytterbium chloride
as catalyst.[13] Even then, some drawbacks exist in these systems such as use of
(a) strong acids, which leads to cleavage of sensitive functional groups, (b) toxic
Figure 2. A pyrimidinone skeleton possessing an arylidene functional group.

440
C. MUKHOPADHYAY AND A. DATTA
Scheme 1. Synthesis of dihydropyrimidinone derivatives with boric acid and glycerol in aqueous medium.
solvents, and (c) moisture-sensitive reagents. As a result, the search for a new catalyst
for this Biginelli-type reaction is still actively pursued. Therefore, we report here an
efficient, mild, highly convenient, and smooth procedure for the synthesis of substi-
tuted pyrimidinone derivatives by three-component coupling of aromatic aldehydes,
cyclopentanone, and urea or thiourea using boric acid and glycerol in aqueous
medium (Scheme 1).
Boric acid and glycerol form a boron chelate complex (BCC) in water
(Scheme 2). Although boric acid is a weak acid, its complex with polyhydroxy com-
pounds such as glycerol is stronger because of chelate formation and release of Hþ
ions in the aqueous medium. It is because of this that boric acid behaves as a strong
acid in the presence of glycerol in aqueous medium.[14]
On examination of Table 1 we find that 10 mol% (Table 1, entry 4) of boric acid
was the optimum amount to get maximum yield of the product. When the mol% of
boric acid was gradually increased to 30% (Table 1, entry 6), the isolated yield
remained the same.
On examination of Table 2, we find that temperature has a pronounced effect
on the yield of the pyrimidinone derivatives. The optimum temperature for this reac-
tion was found to be 45–50 ꢀC (Table 2, entry 4).
The effect of the amount of glycerol at 45–50 ꢀC was investigated on the stan-
dard reaction with 4-bromobenzaldehyde, cyclopentanone, and urea, and the results
are summarized in Table 3. The amount of glycerol plays a significant role on the
yield of the reaction. The yield of the pyrimidinone was maximum when the reaction
Scheme 2. Formation of boron chelate complex (BCC complex) in water.

SUBSTITUTED PYRIMIDINONE SYNTHESIS
441
Table 1. Optimization of the amount of boric acid for the synthesis of pyrimidinone derivatives with p-
bromobenzaldehyde, cyclopentanone, and urea
Entry
Amount of boric acid (mol%)
Yield (%) (isolated)
1
2
3
4
5
6
—
2
—
50
70
85
85
85
5
10
20
30
was carried out with 0.1 mL of glycerol (Table 3, entry 3). On increasing the amount
of glycerol, the yield of the product did not increase further. Therefore the optimized
reaction conditions were boric acid (10 mol%), glycerol (0.1 mL), and 45–50 ꢀC.
Once the reaction conditions for the standard reaction was optimized,
three-component reactions of various aromatic aldehydes with cyclopentanone
and urea or thiourea were examined, and results are presented in Table 4.
Table 2. Effect of temperature on the synthesis of pyrimidinone derivatives with p-bromobenzaldehyde,
cyclopentanone, and urea
Entry
Temperature (ꢀC)
Yield (%) isolated
1
2
3
4
5
6
25–30
30–35
35–40
45–50
50–60
60–80
55
72
79
85
82
80

442
C. MUKHOPADHYAY AND A. DATTA
Table 3. Optimization of the amount of glycerol for the synthesis of pyrimidinone derivatives at with
boric acid (10 mol%) and water (5 mL) at 45–50 ꢀC with p-bromobenzaldehyde, cyclopentanone, and urea
Entry
Glycerol (mL)
Yield (%) isolated
1
2
3
4
5
6
7
8
0.00
0.05
0.1
0.2
0.3
0.4
0.5
0.6
–
58
85
85
85
85
80
82
Aromatic aldehydes with electron-donating groups required longer reaction
time to produce the substituted pyrimidinones, probably because of lower electrophi-
licity of the aldehyde carbonyl. Stronger electron-withdrawing group possessing
aldehydes produce the products in greater yields compared to ortho-substituted ones
where the yield was less because of some steric hindrance. In general, thiourea
required more time for completion of the reaction than urea.
Probable Mechanisms
This reaction can proceed by two possible mechanisms, path A and path B
(Scheme 3). In path A, initially a crossed aldol condensation takes place between
cyclopentanone and aldehyde, followed by Michael addition of urea, to ultimately
form pyrimidinone derivatives. In path B, the aryl aldehydes react with urea or thio-
urea to form the aryl-imine intermediates, which then react with arylidene cyclopen-
tanone to give the final product.
EXPERIMENTAL
Pyrimidinone Derivative Formation
A
mixture of 4-bromobenzaldehyde (1.6 mmol), and cyclopentanone
(0.8 mmol), and urea (1 mmol) [or thiourea (1 mmol)] in the presence of boric acid
(10 mol%), glycerol (0.1 mL), and water (5 mL) was heated at 45–50 ꢀC in a water
bath for the specified time period (Table 4) untill the thin-layer chromatography
(TLC) showed the absence of the starting aldehyde. The reaction mixture was cooled

SUBSTITUTED PYRIMIDINONE SYNTHESIS
443
Table 4. Synthesis of varieties of pyrimidinone derivatives with boric acid (10 mol%) and glycerol
(0.1 mL) in water (5 mL) at 45–50 ꢀC
Yield (%)[references]
(isolated)
Entry
Products
Time (h)
1
4
80[12]
2
8
74[12]
3
6
85[13]
4
6
83[12]
5
4.5
78[12]
(Continued )

444
C. MUKHOPADHYAY AND A. DATTA
Table 4. Continued
Yield (%)[references]
(isolated)
Entry
Products
Time (h)
6
5
75[13]
7
4
84[12]
8
5
72[12]
9
4
86[12]
10
7
82[13]
(Continued )

SUBSTITUTED PYRIMIDINONE SYNTHESIS
445
Table 4. Continued
Yield (%)[references]
(isolated)
Entry
Products
Time (h)
11
10
72
12
12
78[12]
13
13
80[12]
14
12
62[13]
15
8
70[12]
(Continued )

446
C. MUKHOPADHYAY AND A. DATTA
Table 4. Continued
Yield (%)[references]
(isolated)
Entry
Products
Time (h)
16
7
72[12]
17
7
78[12]
18
8
73[12]
and filtered. The crude product (solid) was washed with 2 mL water for dissolution
of additional boric acid and glycerol that might adhere to the product. The crude
product was then directly recrystallized from EtOH. All products were identified
by relevant spectroscopic data.
(4-Bromobenzylidene)-4-(4-bromophenyl)-3,4,6,7-tetrahydro-
1cyclopenta[d] pyrimidin-2(5H)-one (Table 4, Entry 3)
Mp 220–221 ꢀC (lit.[13] mp 221–222 ꢀC); IR (KBr) 3400, 3216, 1899, 1708, 1560,
1480, 1071, 820 cmꢁ1 1H (300 MHz, DMSO-d6): d 1.98–2.03 (1 H, m, HCH),
;
2.38–2.42 (1 H, m, HCH), 2.79–2.82 (2 H, m, CH2), 5.18 (1 H, s, CHNH), 6.64 (1
H, s, NH), 7.24–7.59 (9 H, m, ArH and CH ), 8.84 (1 H, s, NH); 13C (75 MHz,
=
DMSO-d6): d 28.3, 28.5, 56.8, 115.8, 118.8, 118.9, 120.6, 128.5, 129.9, 131.2, 131.4,
136.2, 136.5, 140.2, 142.6, 153.3.

SUBSTITUTED PYRIMIDINONE SYNTHESIS
447
Scheme 3. Probable mechanisms of pyrimidinone derivative formation with boric acid and glycerol.
7-(4-Cyanobenzylidene)-4-(4-cyanophenyl)-3,4,6,7-tetrahydro-1H-
cyclopenta [d]pyrimidin-2(5H)-one (Table 4, Entry 6)
Mp 224–226 ꢀC (lit.[13] mp 222–225 ꢀC); IR (KBr) 3419, 3318, 2232, 1676,
;
1599, 1506, 1460, 851 cmꢁ1 1H (300 MHz, DMSO-d6): d 1.96–2.08 (1H, m,
HCH), 2.45–2.47 (1 H, m, HCH), 2.83–2.92 (2 H, m, CH2), 5.34 (1 H, s, CHNH),
=
6.75 (1 H, s, NH), 7.36 (1 H, s, CH ), 7.40–7.51 (4 H, m, Ph), 7.72–7.90 (4 H, m,
Ph), 8.90 (1 H, s, NH); 13C (75 MHz, DMSO-d6): d 28.2, 28.6, 57.1, 107.9, 110.4,
115.8, 118.7, 118.9, 119.9, 127.5, 128.0, 132.1, 132.7, 136.5, 142.4, 142.9, 148.3,
152.9.
4-(Naphthalen-1-yl)-7-(naphthalen-1-ylmethylene)-3,4,6,7-
tetrahydro-1h-cyclopenta[d]pyrimidin-2(5h)-one (Table 4, Entry 10)
Mp 236–238 ꢀC (lit.[13] mp 238–240 ꢀC) ; IR (KBr) 3465, 3417, 1665, 1606,
1523, 1468, 767 cmꢁ1 1H (300 MHz, DMSO-d6): d 1.76–1.83 (1 H, m, HCH),
;
2.43–2.45 (1 H, m, HCH), 2.66–2.88 (2 H, m, CH2), 6.04 (1 H, s, CHNH),
7.26–8.45 (15 H, m, ArH and CH ), 9.24 (1 H, s, NH); 13C (75 MHz, DMSO-d6):
=
d 28.3, 28.5, 30.6, 112.6, 119.12, 123.1, 124.2, 124.4, 124.5, 125.3, 125.5, 125.7,
126.3, 126.5, 127.6, 127.8, 128.3, 128.6, 128.7, 130.2, 130.4, 131.4, 133.5, 133.7,
133.9, 136.1, 140.4, 153.3.

448
C. MUKHOPADHYAY AND A. DATTA
7-(2,5-Dimethoxybenzylidene)-4-(2,5-dimethoxyphenyl)-
3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one
(Table 4, Entry 11)
Mp: 242 ꢀC (EtOAc-EtOH), white solid; IR (KBr): 2943, 1677, 1496, 1215 and
1
1040 cmꢁ1; H NMR (300 MHz, DMSO-d6) d: 8.76 (s, 2H, 2NH), 6.86–6.63 (m,7H,
=
0
0
0
2C3 -H, 2C4 -H, 2C6 -H and CH), 5.41 (s, 1H, C4-H), 3.69, 3.68 (2 s, 6H, 2 ꢂ OMe),
3.65, 3.64 (two singlets merged together, 6H, 2 ꢂ OMe), 2.69–2.68 (m, 2H, -CH2),
2.36–2.30 (m, 1H, HCH), 2.0–1.95 (m, 1H, HCH); 13C NMR (75 MHz, DMSO-
=
d6) d: 153.8 (C O), 153.6 (C-OMe), 152.9 (C-OMe), 150.9 (C-OMe), 150.1
=
(C-OMe), 139.4 (C7=C4a), 136.2 (C4a=C7), 132.52 (C7a), 127.5 ( C-C1 ), 118.1
0
=
0
(C1 ), 113.9 (ArC), 113.6 (ArC), 112.3 (ArC), 112.1 (ArCþ C-H), 112.0 (ArC),
111.3 (ArC), 56.1, 56.0, 55.4, 55.3 (4 ꢂ OMe), 51.1 (C4), 28.2, 28.2 (C5 and C6). Anal.
calcd. for C24H26N2O5: C, 68.23; H, 6.20; N, 6.66. Found: C, 68.11; H, 6.35, N,
6.80%.
7-(4-Methylbenzylidene)-4-(4-methylphenyl)-3,4,6,7-tetrahydro-1H-
cyclopenta [d]pyrimidin-2(5H)-thione (Table 4, Entry 14)
Mp 192–193 ꢀC (lit.[13] mp 190–191 ꢀC); IR (KBr) 3390, 1688, 1560, 1506, 1460,
1
852 cmꢁ1; H (300 MHz, DMSO-d6): d 2.04–2.06 (1 H, m, HCH), 2.30 (6 H, s,
OCH3), 2.38–2.45 (1 H, m, HCH), 2.70–2.83 (2 H, m, CH2), 5.16 (1 H, s, CHNH),
=
6.88 (1 H, s, NH), 7.12–7.26 (8 H, m, ArH), 8.90 (1 H, s, CH ), 10.02 (1 H, s, NH);
13C (75 MHz, DMSO-d6): d 20.8, 27.7, 28.5, 57.7, 117.6 120.4, 126.4, 127.9, 129.1,
129.2, 133.7, 134.9, 135.6, 136.9, 137.2, 139.5, 174.2.
CONCLUSION
Herein we report the expeditious synthesis of pyrimidinone derivatives by boric
acid and glycerol in an aqueous medium. This simple method is a highly efficient,
low-cost, and high-yielding technique that avoids hazardous and toxic organic sol-
vents both for reaction medium and for purification processes. Therefore, this meth-
odology will definitely prove beneficial in both academia and industry.
ACKNOWLEDGMENTS
We thank the CAS Instrumentation Facility, University of Calcutta, for
spectral data. We also acknowledge a grant received from the University Grants
Commission Major Project, F. No. 37-398=2009.
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449
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