Ecofriendly synthesis of tetrahydropyrimidine derivatives in aqueous medium under ultrasonic irradiation

Article abstract of DOI:10.1080/00397911.2011.582218

A simple, efficient, and ecofriendly procedure was developed for the synthesis of 2-substituted 1,4,5,6-tetrahydropyrimidine derivatives catalyzed by N-bromosuccinimide using ultrasonic irradiation in aqueous medium. Prominent advantages of this new method are good yields, aqueous medium, short reaction times, and easy workup procedure. The compounds were characterized by infrared, NMR, liquid chromatography-mass spectrometry, and elemental analyses.

Full text of DOI:10.1080/00397911.2011.582218

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EcoFriendly Synthesis of
Tetrahydropyrimidine Derivatives in
Aqueous Medium Under Ultrasonic
Irradiation
Valasani Koteswara Rao a , Boppudi Hari Babu , Kilaru Raveendra
Babu a , Doddaga Srinivasulu a & Chamarthi Naga Raju a
a Department of Chemistry , Sri Venkateswara University , Tirupati ,
India
Accepted author version posted online: 11 Nov 2011.Published
online: 18 Jul 2012.
To cite this article: Valasani Koteswara Rao , Boppudi Hari Babu , Kilaru Raveendra Babu ,
Doddaga Srinivasulu & Chamarthi Naga Raju (2012) EcoFriendly Synthesis of Tetrahydropyrimidine
Derivatives in Aqueous Medium Under Ultrasonic Irradiation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:22, 3368-3376,
DOI: 10.1080/00397911.2011.582218
To link to this article: http://dx.doi.org/10.1080/00397911.2011.582218
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Synthetic Communications1, 42: 3368–3376, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.582218
ECOFRIENDLY SYNTHESIS OF
TETRAHYDROPYRIMIDINE DERIVATIVES IN AQUEOUS
MEDIUM UNDER ULTRASONIC IRRADIATION
Valasani Koteswara Rao, Boppudi Hari Babu,
Kilaru Raveendra Babu, Doddaga Srinivasulu, and
Chamarthi Naga Raju
Department of Chemistry, Sri Venkateswara University, Tirupati, India
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and ecofriendly procedure was developed for the synthesis of
2-substituted 1,4,5,6-tetrahydropyrimidine derivatives catalyzed by N-bromosuccinimide
using ultrasonic irradiation in aqueous medium. Prominent advantages of this new method
are good yields, aqueous medium, short reaction times, and easy workup procedure. The
compounds were characterized by infrared, NMR, liquid chromatography–mass spec-
trometry, and elemental analyses.
Keywords Aqueous medium; green synthesis; NBS; tetrahydropyrimidines; ultrasound
irradiation
INTRODUCTION
Pyrimidine derivatives are widely used as chemotherapeutic agents for the
treatment of various diseases resulting from different microorganisms. Many useful
drugs containing these skeletal structures with diverse biological activities have
now emerged and are widely used against tumors and viral diseases and have been
found to possess antibacterial,[1] anti-inflammatory,[2] and insecticidal activities.[3]
Pyrimidine derivatives such as pyrimethamine and trimethoprim are well known
to inhibit the enzyme dihydrofolate reductase, thereby blocking the reduction to
tetrahydrofolic acid from its dihydro precursor, an essential coenzyme in nucleic acid
synthesis.
Received March 27, 2011.
Address correspondence to Chamarthi Naga Raju, Department of Chemistry, Sri Venkateswara
University, Tirupati 517502, India. E-mail: rajuchamarthi10@gmail.com
3368

TETRAHYDROPYRIMIDINE DERIVATIVES
3369
Scheme 1. Synthetic route of tetrahydropyrimidine.
In addition, the pyrimidine moiety is found in various synthetic pharmaceuti-
cals displaying a broad spectrum of biological activity including antitumor,[4]
antipyretic,[5] analgesic,[6] antihistaminic,[7] PDE4 inhibitory,[8] adenosine kinase
inhibitory,[9] tyrosine kinase inhibitory,[10] and diuretic[11,12] activities.
However, many of the synthetic protocols reported so far[13,14] suffer from
disadvantages such as requirement of anhydrous conditions, use of toxic organic
solvents, harsh reaction conditions, prolonged reaction times, and use of metals
and expensive reagents. Therefore, the development of a synthetic protocol that is
cost-effective and safe and uses environmentally friendly reagents is desirable.
In view of this, there is a need to develop techniques that promote green chem-
istry concepts when compared with conventional methods. Energy conservation and
waste minimization are considered processing aids for ultrasounic applications.[15]
Many synthetically useful reactions utilize the energy provided by ultrasound. The
influence of ultrasound on organic reactions is due to cavitation, a physical process
that creates, enlarges, and implodes gaseous and vaporous cavities in an irradiated
liquid, thus enhancing the mass transfer.[15a,16,17]
Use of water as solvent in organic reactions is a green method, as it is readily
available, inexpensive, and nontoxic.[18] It is also nonflammable and environmentally
benign, providing opportunities for clean processing and pollution prevention. Per-
forming organic reactions in an aqueous medium has attracted great attention in
recent decades, as organic reactions often display unique reactivity and selectivity
because of their hydrophobic effects.[18]
The method for forming 2-substituted-1,4,5,6-tetrahydropyrimidines under
ultrasonic irradiation offers several advantages including faster reaction rates, better
conversion, easy workup, and excellent yields. The primary objective of ultrasounic
application is to decrease reaction times compared with conventional methods. The
products were obtained in 14–25 min compared to conventional methods, which
require long agitation at high temperature for completion of the reaction.
RESULTS AND DISCUSSION
In continuation of our work to develop new and ecofriendly synthetic
methodologies, we herein report a green, facile, and efficient method for the
synthesis of 2-substituted-1,4,5,6-tetrahydropyrimidines (3a–s) catalyzed by
N-bromosuccinimide (NBS) under ultrasonic irradiation at 65–70 ꢀC in 14–25 min
(Scheme 1).
In the present work, our intention was to avoid toxic organic solvents or inert
atmospheres by taking a 1:1.2 mol ratio mixture of aldehyde and 1,3-diamino

3370
V. K. RAO ET AL.
Table 1. Synthesis of tetrahydropyrimidine
Method A
Method B
Mp (ꢀC)b
Time
(min)
Yield
(%)a
Time
(h)
Yield
(%)a
Entry
R
Product
Found
Reported
1
3a
17
95
92
82
90
4
82
78
70
76
133–134
128–130
169–171
141–143
132–134[14]
2
3
4
3b
3c
3d
15
16
20
3.2
2.3
2.5
—
169–171[14]
—
5
6
7
3e
3f
18
20
25
87
89
90
6
6
6
72
70
68
115–117
139–140
160–162
—
139–141[19]
—
3g
8
9
3h
3i
3j
18
16
16
85
86
85
4
2
5
80
77
72
143–144
128–129
142–143
144–145[19]
127–130[19]
—
10
11
12
3k
31
17
22
92
94
10
80
81
148–151
151–153
—
—
10
10
13
3m
19
91
76
139–141
139–141[20]
(Continued )

TETRAHYDROPYRIMIDINE DERIVATIVES
3371
Table 1. Continued
Method A
Method B
Mp (ꢀC)b
Time
(min)
Yield
(%)a
Time
(h)
Yield
(%)a
Entry
R
Product
Found
Reported
14
3n
14
92
94
86
8
78
80
75
184–186
184–186[20]
15
16
3o
3p
14
20
6
161–163
135–136
—
10
136–137[13]
17
3q
21
90
11
78
138–140
—
18
19
3r
3s
14
18
89
85
6
7
75
73
130–131
142–143
130[13]
—
Notes. Method A, ultrasonic irradiation; method B, conventional.
aIsolated yields.
bAll the melting points were matched with the reported data.
propane. The reaction was carried out at 65–70 ꢀC for 14–25 min, in the presence of
1.2 mol of NBS as a catalyst using water as solvent at 50 kHz under sonication.
A wide range of substituted and structurally diverse aldehydes was used to
synthesize the title compounds in good yields. For an obvious examination of the
influence of ultrasound irradiation in this transformation, comparison of the reaction
under two methods, ultrasound irradiation at ambient temperature (method A) and
reflux conditions (method B), was performed. As illustrated in Table 1, method A is
comparatively better than method B in both yield and especially reaction times.
Using these optimized conditions, we initiated our investigation into the aro-
matic aldehydes with 1,3-diamino propane in presence of the NBS, and the results
are summarized in Table 1. Various aromatic=heterocyclic aldehydes reacted with
1,3-diaminopropane to give the corresponding 2-substituted-1,4,5,6-tetrahydropyri-
midines. In the presence of both electron-releasing groups such as methoxy and
electron-withdrawing groups such as nitro, the corresponding 2-substituted-1,4,5,6-
tetrahydropyrimidines were obtained in moderate to very good yields. The presence

3372
V. K. RAO ET AL.
of an electron-releasing group at the para position such as methoxy resulted in the
greatest yield of pyrimidine (entry 1) in both method A and method B, whereas
the presence of an electron-withdrawing group such as nitro at the para position
reduced the yield of the corresponding pyrimidine to 82% (entry 3).
The presence of an electron-releasing methoxy group at the meta position
decreased the yield of the reaction (entries 10), whereas the nitro group at the meta
position increased the yield of the reaction (entry 2).
We were pleased to note that under our optimized reaction conditions, hetero-
cyclic aldehydes also reacted with 1,3-diamino propane to afford the corresponding
pyrimidine derivatives.
The present method does not require toxic or anhydrous organic solvents to
prepare 3a–s compared with conventional methods. The transformations were carried
out with good yields without any significant amounts of undesirable side products.
All the products were characterized by NMR, infrared (IR), and mass spectrometry
(MS) and also by comparison with authentic samples. A wide range of aromatic=
heterocyclic aldehydes were employed, and all the title compounds (3a–s) were
obtained in good yields. (Table 1, method A, entries 1–19), and both electron-
withdrawing and electron-releasing substituents reacted with the same ease.
To evaluate the applicability of this method, we also concentrated our study by
using different aldehydes (Table 1). The results reveal that the high ability of this
method is proved undoubtedly for the synthesis of tetrahydropyrimidine derivatives
with different substituents at the 2-position.
CONCLUSION
In conclusion, we have reported the preparation of 2-substituted-1,4,5,6-
tetrahydropyrimidines using an efficient and environmentally benign synthetic
protocol. The simplicity, use of water instead of organic solvents as reaction medium,
good yields (82–95%), short reaction times (14–25 min), and ultrasonic irradiation
make this synthetic protocol highly attractive and ecofriendly in nature.
EXPERIMENTAL
Chemicals were procured from Sigma-Aldrich, Merck, and Lancaster and used
as such without further purification. Melting points (mp) were determined using a cali-
brated thermometer on a Buchi melting-point apparatus B-545. They are expressed in
degrees centigrade (ꢀC) and are uncorrected. Thin-layer chromatography (TLC) was
performed using Merck silica-gel 60 F254 precoated plates (0.25 mm) and visualized
by ultraviolet (UV) fluorescence lamp. Silica gel (particle size 100–200 mesh) was used
for chromatography. 1H NMR and 13C NMR spectra were recorded on a Bruker 400-
MHz instrument. 1H NMR spectra were reported using Me4Si (d 0.0 ppm) as internal
standard. 13C NMR were reported relative to CDCl3 (d 77.16 ppm) and dimethylsulf-
oxide (DMSO-d6), d 48.5 ppm. Fourier transform (FT–IR spectra were recorded on a
Nicolet 6700 specꢀtrometer and are reported in wave numbers (cmꢁ1). Optical rota-
tions (in degrees, ) were recorded in methanol on a Perkin-Elmer model 241 polar-
imeter at the sodium D line. Liquid chromatography (LC) mass spectra were
recorded on a Jeol S ꢂ 102 DA=600 mass spectrometer.

TETRAHYDROPYRIMIDINE DERIVATIVES
3373
General Procedure for the Synthesis of Pyrimidine Derivatives
A mixture of 4-methoxy benaldehyde 1 (1.0 mmol) and 1,3-diamino propane 2
(1.2 mmol) in water (12 mL) was added to reaction flask with the aid of an adapter
attached to the reaction glass container, and the mixture was sonicated for 2 min.
Later, NBS (1.2 mmol) was added to the mixture and the reaction temperature
was raised to 65–70 ꢀC and sonicated for 17 min (Scheme 1). Then the reaction mix-
ture was cooled to room temperature, and aqueous NaOH (20%) was added to the
reaction mixture. Finally, the solution was extracted with ethyl acetate (3 ꢂ 15 mL),
and the combined organic layers were washed with water (2 ꢂ 10 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure to afford the
2-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (3a) with excellent purity. The
same experimental procedure was adopted for the preparation of the remaining title
compounds (3b–s).
Selected Data
2-(4-Nitrophenyl)-1,4,5,6-tetrahydropyrimidine (3b). Yield 86%, mp 128–
ꢁ1
1
130 ꢀC; IR (KBr) cm : 3352 (N-H), 1624 (C N); H NMR (400 MHz, DMSO-d6) d
1.81–1.86 (m, 2H, CH2), 3.50 (t, J ¼ 5.7 Hz, 4H, 2 ꢂ CH2), 5.51 (br s, 1H, NH),
7.90–8.02 (m, 3H, Ar). 13C NMR (125 MHz, DMSO-d6) d 20.2, 39.5, 40.2, 124.5
(2C), 132.6 (2C), 140.1, 151.2, 155.8. APCI: m=z 206 [M þ 1], Anal. calcd for
C11H14N2O: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.47; H, 5.35; N, 20.42.
=
2-(2,4-Dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine (3d). Yield 90%,
ꢁ1
1
mp 141–143 ꢀC; IR (KBr) cm : 3328 (N-H), 1626 (C N); H NMR (400 MHz,
DMSO-d6) d 1.81–1.85 (m, 2H, CH2), 3.48 (t, J ¼ 8.0 Hz, 4H, 2 ꢂ CH2), 4.42 (br s,
1H, NH), 7.01 (d, J ¼ 8.6 Hz, 1H, Ar), 7.27–7.33 (m, 2H, Ar). 13C NMR
(125 MHz, DMSO-d6) d 20.5, 40.2, 55.8, 101.2, 102.9, 106.7, 131.2, 156.7, 161.4,
163.9. APCI: m=z 206 [M þ 1], Anal. calcd. for C12H16N2O2: C, 65.43; H, 7.32; N,
12.72. Found: C, 65.37; H, 7.27; N, 12.68.
=
2-(2,4-Dichlorophenyl)-1,4,5,6-tetrahydropyrimidine (3e). Yield 87%, mp
ꢁ1
1
115–117 ꢀC; IR (KBr) cm : 3298 (N-H), 1622 (C N); H NMR (400 MHz, DMSO-
d6) d1.85–1.91 (m, 2H, CH2), 3.48 (t, J ¼ 8.0 Hz, 4H, 2 ꢂ CH2), 4.42 (br s, 1H, NH),
7.05–7.08 (m, 1H, Ar), 7.31–7.36 (m, 2H, Ar). APCI: m=z 228 [Mþ], 229 [M þ 1], 230
[M þ 2], 232 [M þ 4], 196, 161, 127, 99. Anal. calcd. for C10H10Cl2N2: C, 52.42; H,
4.40; N, 12.23. Found: C, 52.36; H, 4.37; N, 12.19.
=
2-(2,3-Dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine (3g). Yield 90%:
ꢁ1
1
mp 160–162 ꢀC; IR (KBr) cm : 3355 (N-H), 1628 (C N); H NMR (300 MHz,
DMSO-d6) d 1.78–1.86 (m, 2H, CH2), 3.52 (t, J ¼ 5.7 Hz, 4H, 2 ꢂ CH2), 3.78 (s,
6H, OCH3), 5.02 (br s, 1H, NH), 7.22–7.42 (m, 3H, Ar). APCI: m=z 220 [M þ 1].
Anal. calcd. for C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C, 65.37; H,
7.28; N, 12.67.
=
2-(3-Methoxyphenylꢁ)-11,4,5,6-tetrahydropyrimidine (3j). Yield 85%, mp
142–143 ꢀC; IR (KBr) cm : 3323 (N-H), 1630 (C N); 1H NMR (400 MHz,
=
DMSO-d6) d 1.91–1.94 (m, 2H, CH2), 3.50 (t, J ¼ 5.7 Hz, 4H, 2 ꢂ CH2), 3.79 (s,

3374
V. K. RAO ET AL.
3H, OCH3), 5.09 (br s, 1H, NH), 7.24 (d, J ¼ 8.2 Hz, 1H, Ar), 7.26–7.30 (m, 2H, Ar),
7.36 (d, J ¼ 7.7 Hz, 1H, Ar).13C NMR (125 MHz, DMSO-d6) d 20.2, 40.2 (2C), 55.8,
110.6, 111.4, 121.1, 128.2, 132.0, 156.7, 160.4. APCI: m=z 191[M þ 1]. Anal. calcd. for
C11H14N2O: C, 69.45; H, 7.42; N, 14.73. Found: C, 69.40; H, 7.34; N, 14.69.
2-(Pyridin-4-ylꢁ)-11,4,5,6-tetrahydropyrimidine (3 l). Yield 94%, mp 151–
1
153 ꢀC; IR (KBr) cm : 3322 (N-H), 1626 (C N); H NMR (400 MHz, DMSO-d6)
=
d 1.83–1.88 (m, 2H, CH2), 3.51 (t, J ¼ 5.6 Hz, 4H, 2 ꢂ CH2), 4.83 (br s, 1H, NH),
7.18 (m, 4H, Ar). APCI: m=z 162 [M þ 1], Anal. calcd. for C9H11N3: C, 67.06; H,
6.88; N, 26.07. Found: C, 67.0; H, 6.84; N, 26.02.
2-(1H-Pyrrol-2-yl)-1,4,5,6-tetrahydropyrimidine (3m). Yield 91%, mp 124–
ꢁ1
1
126 ꢀC; IR (KBr) cm : 3325 (N-H), 1631 (C N); H NMR (400 MHz, DMSO-d6)
d1.87–1.91 (m, 2H, CH2), 3.48 (t, J ¼ 8.0 Hz, 4H, 2 ꢂ CH2), 5.02 (br s, 1H, NH),
7.08–7.16 (m, 2H, Ar), 7.28–7.32 (m, 1H, Ar), 7.51 (s, NH). APCI: m=z 150
[M þ 1], Anal. calcd. for C8H11N3: C, 64.40; H, 7.43; N, 28.16. Found: C, 64.35; H,
7.39; N, 28.12.
=
2-(5-Bromothiophen-2-ꢁy1l)-1,4,5,6-tetrahydropyrimidine (3o). Yield 95%,
1
mp 161–163 ꢀC; IR (KBr) cm : 3324 (N-H), 1621 (C N); H NMR (400 MHz,
=
DMSO-d6) 1.82–1.88 (m, 2H, CH2), 3.48 (t, J ¼ 5.7 Hz, 4H, 2 ꢂ CH2), 7.06–7.10
(m, 1H, Ar), 7.20–7.24 (m, 1H, Ar). APCI: m=z 245 [M þ 1].
2-(2-Bromophenyl)-1,4,5,6-tetrahydropyrimidine (3p). Yield 86%, mp
ꢁ1
144–146 ꢀC; IR (KBr) cm : 3338 (N-H), 1622 (C N); 1H NMR (400 MHz,
=
DMSO-d6) d 1.83–1.88 (m, 2H, CH2), 3.48 (t, J ¼ 5.8 Hz, 4H, 2 ꢂ CH2), 4.83 (br s,
1H, NH), 7.20 (d, J ¼ 8.0 Hz, 1H, Ar), 7.27–7.31 (m, 2H, Ar), 7.41 (d, J ¼ 7.7 Hz,
1H, Ar). 13C NMR (125 MHz, DMSO-d6) d 20.5, 42.2 (2C), 120.7, 127.3, 129.9,
130.2, 132.7, 139.3, 155.3. APCI: m=z calcd. for C10H12BrN2 [M þ H]þ 239.
2-(2-Chloro-6-fluorophenyl)-1,4,5,6-tetrahydropyrimidine
(3q). Yield
89%, mp 138–140 ꢀC; IR (KBr) cm : 3358 (N-H), 1624 (C N); 1H NMR
(300 MHz, DMSO-d6) d 1.81–1.86 (m, 2H, CH2), 3.48 (t, J ¼ 5.7 Hz, 4H, 2 ꢂ CH2),
5.02 (br s, 1H, NH), 7.72–8.01 (m, 3H, Ar). APCI: m=z 214 [M þ 2], 213 [M þ 1],
212 [Mþ], 195, 179, 161, 145, 99. Anal. calcd. for C10H10ClFN2: C, 56.48; H, 4.74;
N, 13.17. Found: C, 56.41; H, 4.70; N, 13.14.
ꢁ1
=
3-(1,4,5,6-Tetrahydropyrimidin-2-yl)-1h-indole (3s). Yield 85%, mp 142–
ꢁ1
1
143 ꢀC; IR (KBr) cm : 3352 (N-H), 1625 (C N); H NMR (400 MHz, DMSO-d6)
d 1.82–1.87 (m, 2H, CH2), 3.61 (t, J ¼ 6.3 Hz, 4H, 2 ꢂ CH2), 5.15 (br s, 1H, NH),
7.01 (d, J ¼ 8.2 Hz, 1H, Ar), 7.27–7.35 (m, 4H, Ar). 13C NMR (125 MHz, DMSO-
d6) d 20.3, 40.4 (2C), 110.4, 111.1, 120.3, 121.5, 121.7, 126.3, 130.5, 137.1, 154.7.
APCI: m=z 200 [M þ 1]. Anal. calcd. for C12H13N3: C, 72.33; H, 6.58; N, 21.09.
Found: C, 72.27; H, 6.54; N, 21.04.
=
ACKNOWLEDGMENT
The authors express their thanks to BRNS (DAE), BARC, Mumbai, India, for
sanctioning a research project (2007=37=46=BRNS=2916).

TETRAHYDROPYRIMIDINE DERIVATIVES
3375
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