Ultrasound-assisted synthesis of dihydropyrimidine-2-thiones

Article abstract of DOI:10.2298/JSC100212057S

Chalcone derivatives were prepared by the condensation of various substituted aryl aldehydes and acetophenone in alkaline ethanol, while pyrimidine- 2-thione derivatives were prepared by the combination of chalcones and thiourea under conventional and ult

Full text of DOI:10.2298/JSC100212057S

J. Serb. Chem. Soc. 76 (5) 679–684 (2011)
UDC 534–8+542.913:547.853+547.286.2
JSCS–4148
Original scientific paper
Ultrasound-assisted synthesis of dihydropyrimidine-2-thiones
*
JAVAD SAFAEI-GHOMI and MOHAMMAD ALI GHASEMZADEH
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan,
51167 Kashan, I. R. Iran
(Received 12 February 2010, revised 9 January 2011)
Abstract: Chalcone derivatives were prepared by the condensation of various
substituted aryl aldehydes and acetophenone in alkaline ethanol, while pyrimi-
dine-2-thione derivatives were prepared by the combination of chalcones and
thiourea under conventional and ultrasonic conditions. Advantages of the ultra-
sound effect were observed and high yields of the products were obtained after
20–30 min sonication. Characterization and structural elucidation of the pro-
ducts was realized based on chemical, analytical and spectral analyses. The re-
sults clearly demonstrated a high efficiency of the ultrasonic systems was
achieved in the chemical processes.
Keywords: chalcone derivatives, ultrasound, pyrimidine-2-thione derivatives.
INTRODUCTION
Heterocyclic compounds have so far been synthesized mainly because of
their wide range of biological activities. These compounds play an important role
in medicinal chemistry, serving as key templates central to the development of
1
numerous important therapeutic agents. Pyrimidine derivatives have found ap-
plication in a wide range of medical applications because of their diverse bio-
2
3
logical activities, such as antimicrobial, antitumor and antifungal activities. In
addition, these compounds are considered to be important for drugs and agricul-
4–6
tural chemicals.
These chemotherapeutic applications of pyrimidine deriva-
tives prompted the present synthesis of some substituted pyrimidines in a facile
pathway.
Multi-component reactions (MCRs) play an important role in combinatorial
chemistry because they enable the synthesis of small drug-like molecules with
several degrees of structural diversity. This reaction tool allows compounds to be
synthesized in a few steps and usually in a one-pot operation. Another typical be-
nefit from these reactions is the simplified purification, because all the reagents
*Corresponding author. E-mail: safaei@kashanu.ac.ir
doi: 10.2298/JSC100212057S
679
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680
SAFAEI-GHOMI and GHASEMZADEH
are incorporated into the final product. The Biginelli reaction is a multiple-com-
ponent chemical reaction that creates dihydropyrimidine from ethyl acetoacetate,
7,8
an aryl aldehyde and urea or thiourea.
Recently, several methods have been reported for the synthesis of pyrimidine
derivatives. One method involves the reaction of aldehydes, ß-dicarbonyl com-
pounds and urea/thiourea in the presence of a catalytic amount of tetrachloro-
9
silane in DMF at ambient temperature. The synthesis of 2-thiopyrimido benz-
imidazole derivatives by the condensation of 4-isothiocyanato-4-methyl-2-penta-
none and 3,3’-diaminobenzidine in absolute methanol under reflux is another me-
10
thod. Pyrimidine derivatives can also be prepared by the reaction of certain
amides with nitriles under electrophilic activation of the amide with 2-chloropyri-
11
dine and trifluoromethanesulfonic anhydride. However, these methods suffer
from drawbacks, such as longer reaction times, complicated workup and low yields.
The present paper describes the synthesis of pyrimidine-2-thione derivatives
under conventional and ultrasonic irradiation by the reaction of chalcones and
thiourea. The effects of ultrasound on organic reactions are attributed to cavita-
tions, a physical process that create, enlarge, and implode gaseous and vaporous
12
cavities in an irradiated liquid. The cavitations induce very high local tempe-
ratures and pressures inside the bubbles (cavities), leading to a turbulent flow in
13
the liquid and enhanced mass transfer. In some reactions, ultrasonic irradiation
allows the process to occur with ease to provide high yields within very short
14–16
times.
EXPERIMENTAL
All melting points are uncorrected and were determined in a capillary tube on a Boetius
melting point microscope. The FTIR spectra were recorded on a Nicolet Magna 550 spec-
1
trometer (KBr). The H-NMR and 13C-NMR spectra were obtained on a Bruker 400 MHz
spectrometer with DMSO-d6 as the solvent using tetramethylsilane (TMS) as the internal
standard. Sonication was performed in an ELO-150 ultrasonic cleaner with a frequency of 46
kHz and a nominal power of 200 W. All reactions were followed and checked by TLC using
n-hexane/ethyl acetate (7:3) as the mobile phase. The spots were visualized using a UV lamp.
The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 ana-
lyzer. The mass spectra were recorded on a Joel D-30 instrument at an ionization potential of
70 eV.
General procedure for the preparation of pyrimidine-2-thione derivatives (3a–h)
Conventional heating. A mixture of chalcone (0.005 mol), thiourea (0.005 mol) and
potassium hydroxide (0.5 g) in ethanol (20 ml) was refluxed with stirring on an oil bath at 70–
–80 °C for the periods indicated in Table I. Subsequently, the reaction mixture was left over-
night and then concentrated under reduced pressure. The solid residue was collected, washed
with water and recrystallized from ethanol.
Ultrasound. All contents were placed in an ultrasonic bath for the periods indicated in
Table I, at 20–25 °C and worked up as described above.
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ULTRASOUND-ASSISTED SYNTHESIS OF DIHYDROPYRIMIDINE-2-THIONES
681
TABLE 1. Preparation of pyrimidines (3) under conventional and ultrasound conditions
Conventional conditions
Ultrasound irradiation
Compound
Time, h
5.5
6
Yield, %
65
Time, min
Yield, %
82
3a
3b
3c
3d
3e
3f
20
22
22
24
26
24
25
29
55
78
80
76
78
6
54
5.5
6
58
60
6
61
75
73
75
3g
3h
6.5
5.5
65
55
RESULTS AND DISCUSSION
Spectral data for the compounds
4,6-Diphenyl-3,4-dihydropyrimidine-2(1H)-thione (3a). Yellow crystals;
17
–1
m.p.: 182–184 °C (lit. m.p. 184 °C). FTIR (KBr, cm ): 3173 (NH), 1644 (C=N),
1
1559, 1478 (C=C), 1183 (C=S). H-NMR (400 MHz, DMSO-d , δ / ppm): 4.86
(1H, d, J = 5.0 Hz, 4–CH), 5.15 (1H, d, J = 5.0 Hz, 5–CH), 6.78–7.29 (10H, m,
Ar–H), 8.85 (1H, bs, NH), 9.60 (1H, bs, NH). C-NMR (100 MHz, DMSO-d , δ /
/ ppm): 55.1, 101.6, 126.3, 126.8, 127.2, 128.85, 129.2, 129.3, 133.8, 134.8,
144.5, 175.4.
6
13
6
4-(2-Methylphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3b). Yel-
low crystals; m.p.: 175–177 °C; Anal. Calcd. for C H N S: C 72.85, H 5.71, N
17 16
2
–1
10.00 %. Found: C 72.75, H 5.80, N 10.15 %. FTIR (KBr, cm ): 3235 (NH),
1642 (C=N), 1566, 1480 (C=C), 1165 (C=S). H-NMR (400 MHz, DMSO-d , δ /
/ ppm): 2.10 (3H, s, CH ), 4.87 (1H, d, J = 5.0 Hz, 4–CH) 5.12 (1H, d, J = 5.0 Hz,
1
6
3
13
5–CH), 6.91–7.30 (9H, m, Ar–H), 8.85 (1H, bs, NH), 9.60 (1H, bs, NH). C-
-NMR (100 MHz, DMSO-d , δ / ppm): 22.3, 56, 101.8, 125.4, 125.8, 127.5,
6
127.9, 128.7, 129.2, 133.4, 133.8, 134.7, 137.5, 144.3, 175.2; MS (EI) (m/z): 280
+
(M ).
4-(3-Methylphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3c). Yel-
low crystals; m.p.: 183–185 °C; Anal. Calcd. for C H N S: C 72.85, H 5.71, N
17 16
2
–1
10.00 %. Found: C 72.88, H 5.77, N 10.10 %. FTIR (KBr, cm ): 3169 (NH),
1640 (C=N), 1575, 1482 (C=C), 1194 (C=S). H-NMR (400 MHz, DMSO-d , δ /
/ ppm): 2.08 (3H, s, CH ), 4.85 (1H, d, J = 5.0 Hz, 4–CH ) 5.15 (1H, d, J = 5.0
1
6
3
Hz, 5–CH ), 6.83–7.31 (9H, m, Ar–H), 8.85 (1H, bs, NH), 9.64 (1H, bs, NH).
13
C-NMR (100 MHz, DMSO-d , δ / ppm): 21.6, 55.1, 101.7, 124, 126.2, 127.3,
6
127.9, 128.6, 129.1, 129.3, 133.75, 134.6, 138.2, 144.5, 177.3. MS (EI) (m/z):
280 (M ).
+
4-(4-Methylphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3d). Yel-
18
–1
low crystals; m.p.: 198–200 C (lit. m.p. 199–200 °C). FTIR (KBr, cm ): 3198
1
(NH), 1644 (C=N), 1566, 1480 (C=C), 1184 (C=S). H-NMR (400 MHz,
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682
SAFAEI-GHOMI and GHASEMZADEH
DMSO-d , δ / ppm): 2.03 (3H, s, CH ), 4.86 (1H, d, J = 5.0 Hz, 4–CH) 5.14 (1H,
6
3
d, J = 5.0 Hz, 5–CH), 6.87–7.29 (9H, m, Ar–H), 8.85 (1H, bs, NH), 9.64 (1H, bs,
13
NH). C-NMR (100 MHz, DMSO-d , δ / ppm): 21.2, 56.0, 102.8, 127.4, 127.9,
6
128.5, 129.5, 130.4, 130.7, 134.9, 138.4, 142.2, 178.1.
4-(2-Methoxyphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3e). White
crystals; m.p.: 178–180°C; Anal. Calcd. for C H N OS: C 68.91, H 5.40, N
17 16
2
–1
9.45 %. Found: C 68.99, H 5.50, N 9.39 %. FTIR (KBr, cm ): 3152 (NH ), 1642
(C=N), 1555, 1479 (C=C), 1182 (C=S). H-NMR (400 MHz, DMSO-d , δ / ppm):
3.60 (3H, s, –OCH ), 5.13 (2H, m, 4–CH, 5–CH), 6.93–7.23 (9H, m, Ar–H), 8.75
(1H, bs, NH), 9.71 (1H, bs, NH). C-NMR (100 MHz, DMSO-d , δ / ppm):
50.2, 56.0, 100.8, 111.5, 121.1, 126.2, 126.9, 128.8, 129.1, 129.2, 132.1, 133.8,
1
6
3
13
6
+
134.8, 155.73, 177.3. MS (EI) (m/z): 296 (M ).
4-(4-Methoxyphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3f). White
19
–1
crystals; m.p.: 123–125 C (lit. m.p. 123–124 °C). FTIR (KBr, cm ): 3149 (NH),
1
1642 (C=N), 1555, 1479 (C=C), 1182 (C=S). H-NMR (400 MHz, DMSO-d , δ /
/ ppm): 3.60 (3H, s, –OCH ), 5.13 (2H, m, 4–CH, 5–CH), 6.79–7.25 (9H, m, Ar–H),
8.62 (1H, bs, NH), 9.60 (1H, bs, NH). C-NMR (100 MHz, DMSO-d , δ / ppm):
50.2, 56.0, 100.8, 111.6, 121.1, 126.2, 128.8, 129.1, 129.2, 132.1, 134.8, 155.8,
178.2.
6
3
13
6
4-(2,4-Dimethoxyphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3g).
White crystals; m.p.: 180–182 °C. Anal. Calcd. for C H N O S: C 66.25, H
18 18
2 2
–1
5.52, N 8.58 %. Found: C 66.29, H 5.43, N 8.67 %. FTIR (KBr, cm ): 3195
(NH), 1644 (C=N), 1581, 1465 (C=C), 1162 (C=S). H-NMR (400 MHz, DMSO-
1
-d , δ / ppm): 3.60 (6H, s, 2’,4’–OCH ), 5.13 (2H, m, 4–CH, 5–CH), 6.83–7.25
6
3
13
(8H, m, Ar–H), 8.60 (1H, bs, NH), 9.63 (1H, bs, NH). C-NMR (100 MHz,
DMSO-d , δ / ppm): 51.1, 58.2, 101.2, 111.2, 121.2, 125.2, 125.9, 127.3, 129.1,
6
+
129.8, 132.6, 134.8, 153.7, 154.6, 177.1. MS (EI) (m/z): 326 (M ).
4-(4-N,N-Dimethylphenyl)-6-phenyl-3,4-dihydropyrimidine-2(1H)-thione (3h).
Yellow crystals; m.p.: 162–164 °C; Anal. Calcd. for C H N S: C 69.91, H
18 19
3
–1
6.14, N 13.9 %. Found: C 70.03, H 6.19, N 13.95 %. FTIR (KBr, cm ): 3196
(NH), 1640 (C=N), 1552, 1475 (C=C), 1191 (C=S). H-NMR (400 MHz, DMSO-
1
-d , δ / ppm): 2.74 (6H, s, N(Me) ), 5.00 (2H, m, 4–CH, 5–CH), 6.83–7.25 (8H, m,
6
2
13
Ar–H), 8.64 (1H, bs, NH), 9.60 (1H, bs, NH). C-NMR (100 MHz, DMSO-d , δ /
/ppm): 56.5, 79.7, 102.0, 112.2, 125.6, 126.3, 128.0, 128.2, 130.3, 134.5, 138.7,
150.5, 176.1. MS (m/z): 309 (M ).
6
+
In the present work, chalcone derivatives 1 were treated with thiourea 2 in
the presence of potassium hydroxide in ethanol to produce the pyrimidine-2-thi-
one derivatives 3. The reaction occurred in two steps: first conjugate addition
took place on the β-position of carbonyl group and then nucleophilic attack on
the carbonyl group followed by dehydration led to the six-membered ring pro-
17,19,20
ducts (Scheme 1).
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ULTRASOUND-ASSISTED SYNTHESIS OF DIHYDROPYRIMIDINE-2-THIONES
683
O
X
S
5
X
KOH
4
+
H2N
NH2
EtOH
U.S
HN
NH
S
2
3
1
3a: X = H
3e: X = 2-OCH3
3f
3b: X = 2-CH3
3c: X = 3- CH3
: X = 4-OCH3
3g
: X = 2,4-OCH3
3h: X = N(Me)2
3d
: X = 4-CH3
Scheme 1. Approach to the synthesis of pyrimidine-2-thiones under ultrasound
irradiation (in 3h N(Me)2 stands for 4-N(Me)2).
Application of ultrasound shortened the reaction time of the generation of
pyrimidines from 6 h under classical conditions to 30 min. In addition, the yields
of the products were improved by 20–30 % in comparison with those obtained by
the thermal heating method (Table I).
Conventional heating of the sonicating reaction mixture to the same (bulk)
temperature did not lead to any significant differences in the yields and times.
In the view of the interest in green chemistry for the synthesis of organic
compounds, an optimized procedure for the preparation of pyrimidine-2-thione
derivatives was developed. These reactions were realized under milder and
cleaner conditions. While with thermal heating these reactions required 6 h at
70–80 °C, the new method was performed at room temperature for shorter times.
CONCLUSIONS
An optimized procedure for the preparation of pyrimidine-2-thione deriva-
tives under mild and clean conditions was described. The advantages of ultra-
sound in chemical reactions, such as shorter reaction times, higher yields and
milder conditions, could be of use in industrial applications in the pharmaceutical
or fine chemical industries.
Acknowledgements. The authors gratefully acknowledge the financial support of this
work by the Research Affairs Office of the University of Kashan, Kashan, I. R. Iran. Dr A. H.
Bamoniri is acknowledged for his help in the preparation of this paper.
И З В О Д
СИНТЕЗА ДИХИДРОПИРИМИДИН-2-ТИОНА УЛТРАОЗВУЧИВАЊЕМ
JAVAD SAFAEI-GHOMI и MOHAMMAD ALI GHASEMZADEH
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, 51167 Kashan, I. R. Iran
Деривати xалкона добијени су кондензацијом различитих супституисаних арил-ал-
дехида и ацетофенона под базним условима у етанолу, а деривати пиримидин-2-тиона
добијени су реакцијом xалкона и тиоурее, под уобичајеним реакционим условима и ултра-
озвучивањем. Уочене су предности ултраозвучивања реакционе смеше, као што су повећање
приноса и добијање производа за краће реакционо време, 20–30 min. Карактеризација и
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684
SAFAEI-GHOMI and GHASEMZADEH
одређивање структуре производа извршено је уобичајеним спектроскопским и аналитичким
методама.
(Примљено 12. фебруара 2010, ревидирано 9. јануара 2011)
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