Preparation of 4,6-Diaryl-3,4-dihydropyrimidine-2(1H)-thiones in an ionic liquid

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Organic Preparations and Procedures
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Preparation of 4,6-Diaryl-3,4-
dihydropyrimidine-2(1H)-thiones in an
Ionic Liquid
Javad Safaei-Ghomi a & Mohammad Ali Ghasemzadeh a
a Department of Organic Chemistry, Faculty of Chemistry, University
of Kashan, 51167, Kashan, I. R. Iran
Version of record first published: 05 Nov 2012.
To cite this article: Javad Safaei-Ghomi & Mohammad Ali Ghasemzadeh (2012): Preparation of 4,6-
Diaryl-3,4-dihydropyrimidine-2(1H)-thiones in an Ionic Liquid, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 44:6, 527-531
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Organic Preparations and Procedures International, 44:527–531, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.730944
OPPI BRIEFS
Preparation of
4,6-Diaryl-3,4-dihydropyrimidine-2(1H)-thiones
in an Ionic Liquid
Javad Safaei-Ghomi and Mohammad Ali Ghasemzadeh
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan,
51167 Kashan, I. R. Iran
Pyrimidine derivatives have a wide range of medicinal application because of their diverse
biological activities, such as anti-microbial,1 anti-tumor, and anti-fungal activities;2 they are
also considered to be important for drugs and agricultural chemicals.3–5 Many of the recent
methods reported for the synthesis of pyrimidine derivatives6–11 suffer from drawbacks such
as long reaction times, complicated work-up, unsafe reaction conditions, and low yields.
Over the past decade, ionic liquids have been received increasing attention in organic
chemistry because of their environmentally benign nature, high polarity, and good thermal
stability. Often shorter reaction times, high yields, cleaner reaction products, and high se-
lectivity are observed in ionic liquid as reaction media.12,13 In continuation of our studies on
the application of ionic liquids media,14–16 we found that 1-n-(butyl)-3-methylimidazolium
bromide ([bmim]Br) has several advantages over other ionic liquids.17,18 The use of
[bmim]Br have been reported in reactions such as oxidation of thiols,19 alkyl arenes,
and alcohols;20,21 the preparation of phenacyl esters22 and of 3-acetoacetylcoumarin
derivatives;23 and the demethylation of methyl aryl ethers.24 This reagent is safe, easy
handled, environmentally benign, and presents fewer disposal problems. The present in-
vestigation describes the preparation of pyrimidine-2-thione derivatives 3 in [bmim]Br.
Received August 19, 2011.
Address correspondence to Javad Safaei-Ghomi, Department of Organic Chemistry, Faculty of
Chemistry, University of Kashan, 51167 Kashan, I. R. Iran. E-mail: safaei@kashanu.ac.ir
527

528
Safaei-Ghomi and Ghasemzadeh
Application of the ionic liquid as solvent and catalyst at room temperature shortened
the reaction time of the generation for pyrimidines from 6 h under classical conditions25,27
to 40–50 min (see Table 1) and the yields improved 20%–30% as compared with the base
heating method.25,27 The spectrometric data of products are shown in Table 2. These results
can be explained by the catalytic and coordinative properties of [bmim]Br as previously
discussed.29–32
Michael addition between α,β-unsaturated carbonyl compounds and nucleophiles may
be performed by the use of activated vinyl compounds bearing alkyl or aryl groups. Thus
the reaction between thiourea and chalcones containing various substituents was carried
out in both common and ionic liquids media. Table 1 shows that chalcones bearing both
electron-withdrawing and electron-donating groups afforded the corresponding pyrimidine-
2-thiones. However, with R = o- or p-nitro groups, the yields were poor even after a
prolonged time and the work-up was complicated compared with chalcones bearing other
substituents.
Experimental Section
All melting points are uncorrected and were determined in capillary tubes on Boetius melt-
ing point microscope. FT-IR spectra were recorded on a Nicolet Magna 550 spectrometer
(KBr). [bmim]Br was purchased from Fluka. 1H NMR and 13C NMR spectra were obtained
on Bruker 400 MHZ spectrometer in dimethyl sulfoxide-d6 (DMSO-d6) as solvent using
tetramethylsilane (TMS) as an internal standard; the chemical shift values are in δ. All reac-
tions were monitored and checked by thin layer chromatography (TLC) using hexane/ethyl
acetate (7:3) and spots were examined using a UV lamp.
Table 1
Preparation of Pyrimidines (3) under Base and Ionic Liquid Conditions
Cmpd
mp(◦C)
lit. mp
Base-Catalyzed
Time (h) Yield (%)
5.5 68
In [bmim]Br
Time (min)
Yield (%)
3a
3b
3c
3d
3e
3f
182–184
175–177
183–185
196–198
123–124
162–164
192–194
180–182
18425
—–a
—–b
197–19826
123–12427
—–c
193–19428
181–18228
40
45
42
42
45
45
35
30
92
85
88
90
87
88
95
95
6
6
6
6
6
5
5
64
66
66
60
60
70
72
3g
3h
aAnal. Calcd. For C17H16N2S: C, 72.82; H, 5.75; N, 9.99; S, 11.44. Found: C, 72.88; H, 5.66; N,
10.05; S, 11.35.
bAnal. Calcd. For C17H16N2S: C, 72.82; H, 5.75; N, 9.99; S, 11.44. Found: C, 72.83; H, 5.76; N,
10.01; S, 11.38.
cAnal. Calcd. For C18H19N3S: C, 69.87; H, 6.19; N, 13.58; S, 10.36. Found: C, 69.93; H, 6.15; N,
13.55; S, 10.33.

4,6-Diaryl-3,4-dihydropyrimidine-2(1H)-thiones
529
Table 2
Spectroscopic Data of Compounds 3b, 3c, 3f
Cmpd
IR
(Cm−1
1H NMR
13C NMR
)
(δ)
(δ)
3b
3255 (NH), 1677
(C N), 1165 (C S)
2.1 (s, 3H, CH3), 4.87 (d,
1H, 4-CH) 5.12 (d, 1H,
5-CH C CH), 6.91–7.30
(m, 9H, Ar-H), 8.85 (bs,
1H, NH), 9.60 (bs, 1H,
NH).
22.3, 56, 101.8, 125.45,
125.8, 127.5, 127.9,
128.7, 129.2, 133.4,
133.8, 134.7, 137.5,
144.3, 175.2
3c
3f
3169 (NH), 1667
(C N), 1194 (C S)
2.08 (s, 3H, CH3), 4.85 (d,
1H, 4-CH) 5.15 (d, 1H,
5-CH), 6.83–7.31 (m,
9H, Ar-H), 8.85 (bs, 1H,
NH), 9.64 (bs, 1H, NH).
2.74 (s, 6H, N(Me)2), 5 (m,
2H, 4-CH, 5-CH),
6.83–7.25 (m, 8H,
Ar-H), 8.64 (bs, 1H,
NH), 9.60 (bs, 1H, NH)
21.6, 55.1, 101.7, 124,
126.2, 127.3, 127.9,
128.6, 129.1, 129.3,
133.75, 134.6, 138.2,
144.5, 177.3
56.52, 79.67, 102.04,
112.22, 125.64, 126.26,
127.98, 128.19, 130.29,
134.46, 138.7, 150.54,
176.12
3196 (NH), 1666
(C N), 1191 (C S)
General Procedures for the Synthesis of Pyrimidine-2-thiones 3a–3h
Base-catalyzed Method: A mixture of chalcone (5 mmol), thiourea (0.38 g, 5 mmol), and
potassium hydroxide (0.5 g) in ethanol (20 ml) was refluxed (magnetic stirring) on oil bath
at 70◦C–80◦C for 6 h. The reaction mixture was left standing for overnight and then was
concentrated under reduced pressure. The solid obtained was collected, washed with water,
and recrystallized from ethanol.
[bmim]Br Method: A mixture of chalcone (5 mmol), thiourea (0.38 g, 5 mmol), and
[bmim]Br (0.763 g, 3.5 mmol) was stirred at room temperature for the period of time shown
in Table 1. After completion of the reaction as indicated by TLC using hexane/ethyl acetate
(7:3), the reaction mixture was extracted with ether (3 × 10 ml). The organic layer was
evaporated under reduced pressure and the product was recrystallized from ethanol. The
immiscible ionic liquid phase was recovered and heated for 3 h under vacuum (1 mbar) for
further uses. The best results were obtained with a ratio of [1:1:0.7] mmols of chalcone,
thiourea, and [bmim]Br.
General Procedure for the Large-scale Synthesis of 4,6-Diphenyl-3,4-dihydro-
pyrimidine-2(1H)-thione (3a) by the [bmim]Br Method: To a 500 ml round-bottomed
flask equipped with a large stir bar was added 1,3-diphenyl-2-propen-1-one (1a) (20.8 g,
0.1 mol), thiourea (7.6 g, 0.1 mol), and [bmim]Br (15.26 g, 0.07 mol). The reaction mix-
ture was stirred at room temperature for 2 h. Progress of the reaction was continuously
monitored by TLC using hexane/ethyl acetate (7:3). After the reaction was completed, the
mixture was extracted with ether (3 × 50 ml). The organic layer was evaporated under

530
Safaei-Ghomi and Ghasemzadeh
vacuum and the solid obtained was recrystallized from ethanol to produce 20.5 g (77%) of
pure product (3a). The catalyst was recovered as mentioned in previous procedure.
Acknowledgment
The authors are grateful to the University of Kashan for supporting this work by grant no.
65384/II.
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