Facile one-pot three-component synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones under ultrasonic irradiation

Article abstract of DOI:10.1080/00397911.2019.1652759

We developed a facile one-pot procedure for the synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thione under ultrasonic irradiation. The method is based on a three components reaction of aldehydes, ketones, and thiourea under basic conditions affordin

Full text of DOI:10.1080/00397911.2019.1652759

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Facile one-pot three-component synthesis of 4,6-
diaryl-3,4-dihydropyrimidine-2(1H)-thiones under
ultrasonic irradiation
Shymaa A. Abbass, Gamal A. I. Moustafa, Heba A. Hassan & Gamal El-Din A.
Abuo-Rahma
To cite this article: Shymaa A. Abbass, Gamal A. I. Moustafa, Heba A. Hassan & Gamal
El-Din A. Abuo-Rahma (2019): Facile one-pot three-component synthesis of 4,6-diaryl-3,4-
dihydropyrimidine-2(1H)-thiones under ultrasonic irradiation, Synthetic Communications, DOI:
10.1080/00397911.2019.1652759
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https://doi.org/10.1080/00397911.2019.1652759
Facile one-pot three-component synthesis of
4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones under
ultrasonic irradiation
Shymaa A. Abbassa, Gamal A. I. Moustafaa,b, Heba A. Hassana, and
Gamal El-Din A. Abuo-Rahmaa
b
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt; Department
of Chemistry, University of Southampton, Highfield, UK
ABSTRACT
ARTICLE HISTORY
Received 19 June 2019
We developed a facile one-pot procedure for the synthesis of 4,6-
diaryl-3,4-dihydropyrimidine-2(1H)-thione under ultrasonic irradiation.
The method is based on a three components reaction of aldehydes,
ketones, and thiourea under basic conditions affording isolated
yields of up to 95% within a reaction time of 30–90 min.
KEYWORDS
Biginelli reaction; 4,6-diaryl-
3,4-dihydropyrimidine-
2(1H)-thiones; multi-
component reactions; one-
pot synthesis; ultrasound
GRAPHICAL ABSTRACT
Introduction
Pyrimidines are among the most prominent heterocyclic compounds that exhibit a
range of significant pharmacological and herbicidal activities.[1,2] They are found in
many bioactive natural products as well as numerous nucleoside and non-nucleoside
analogs. Pyrimidine derivatives are also important chemical scaffolds in synthetic
organic chemistry. In particular, dihydropyrimidine (DHPM) derivatives have been
reported to exert a range of interesting biological activities.[1,3] Recent reports indicated
that the potent cytotoxic activity of some 4,6-diaryl-3.4-dihydropyrimidine-2(1H)-thione
derivatives could be attributed to their structural analogy to combretastatin A-4
(Figure 1).[4–6] Accordingly, the design of efficient synthetic routes to this class of com-
pounds has attracted considerable attention from various research groups.
CONTACT Gamal A. I. Moustafa
g.a.i.moustafa@soton.ac.uk
Department of Medicinal Chemistry, Faculty of
Pharmacy, Minia University, Minia-61519, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

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S. A. ABBASS ET AL.
Figure 1. Cytotoxic 4,6-diaryl-3,4-dihydropyriimidine-2(1H)-thiones and their structural analogy to
combretastatin A-4.
Traditionally, these 4,6-disubstituted-pyrimidines have been prepared by cycloconden-
sation of chalcones with thiourea under the ultrasound,[7] microwave,[8] or refluxing
conditions in basic media.[9–12] Notably, these syntheses require the formation and iso-
lation of chalcones before conducting the cyclization step. Alternatively, they can be
prepared by one-pot procedure under microwave[13] or refluxing condition.[14] As part
of an ongoing project in our group aiming for the design of important bioactive com-
pounds derived from 4,6-diaryl dihydropyrimidine-2-thiones, we envisioned the possi-
bility of preparing these compounds in a one-pot protocol from aldehyde and ketone
derivatives with thiourea under ultrasound irradiations without the need to isolate the
intermediate chalcones. Notably, the one-pot protocol using ultrasound irradiation has
been successfully applied to similar Biginelli type reactions to prepare substituted pyri-
midines.[15–17] The one-pot multicomponent reactions have several advantages over the
stepwise approaches in terms of efficiency, product purity as well as time and atom
economy.[1,18–21]
The ultrasound technique is broadly used in organic synthesis as a green and eco-
friendly method. The ultrasound wave induces cavitations in the reaction mixture as the
molecules oscillate around themselves and create a great number of cavitation bubbles
that enlarge rapidly and subsequently undergo violent collapse. This collapse increases
the temperature of the reaction mixture that is enough to cross the activation energy
barrier and the reaction occurs.[1,18,22] In this paper, we report our endeavor to synthe-
size a number of 4,6-diaryl-3.4-dihydropyrimidine-2(1H)-thiones in a one-pot procedure
under ultrasonic irradiation.
Results and discussion
Initially, we attempted to prepare the target dihydropyrimidines 1–11 by the conven-
tional one-pot reaction of aromatic aldehydes, acetophenones, and thiourea in ethanolic
KOH under refluxing conditions, however, the reaction required longer times (>16 hr)
leading to poor chemical yields and several byproducts. Therefore, we opted to conduct
the reaction under ultrasound irradiation as a green and ecofriendly method (Table 1).
After short optimization of the reaction conditions, we were delighted to get the max-
imum chemical yields under irradiation for 30–90 min at 50 ꢀC (Table 1). At room tem-
perature, inferior chemical yields were obtained even after prolonged reaction time.
Under the optimized conditions, a variety of un/substituted dihydropyrimidines were

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Table 1. One-pot synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2-(1H)thiones 1–11.
1
Reaction
%
Reaction
%
Entry
1
Products
Entry
7
Products
time (min)
Yield
time (min)
Yield
40
50
94
89
50
40
93
84
2
8
3
4
5
30
60
50
91
85
89
9
50
80
90
88
80
78
10
11
6
30
95
Scheme1. Plausible mechanism for the formation of the target 4,6-diaryl-3,4-dihydropyrimidine-
2-thiones.
efficiently obtained in yields of up to 95%. However, vanillin and nitrobenzaldehydes
were not suitable substrates for this reaction. A plausible reaction mechanism is
depicted in Scheme 1.[10,11] We believe the reaction commences with the formation of
chalcones A which are readily attacked by the deprotonated thiourea via a 1,4-attack.
Thereafter, intramolecular cyclization and subsequent dehydration delivered the target
compounds. The mechanism supports our observation that aldehydes and ketones

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S. A. ABBASS ET AL.
having electron-donating groups required somewhat longer reaction times that is attrib-
uted to the slower formation of intermediate chalcones or the slower rate of subsequent
cyclization (Table 1, entries 10, 11). On the other hand, aldehydes and ketones bearing
electron-withdrawing groups reacted faster owing to the rapid formation of chalcones
and the rapid cyclization as well (entries 3, 6).
Conclusion
A green and efficient ultrasound-assisted one-pot three-component reaction for the syn-
thesis of 4,6-diaryl-3,4-dihydropyrimidine-2-(1H)thiones has been developed. The
method affords up to 95% yield in only 30–90 min under mild heating. Further explor-
ation of the method to the synthesis of highly functionalized heterocycles is ongoing.
Experimental section
General procedure for the synthesis of dihydropyrimidine-2-thiones 1–11
In a round-bottomed flask, a mixture of the appropriate acetophenone (8 mmol), appro-
priate aromatic aldehyde (8 mmol), thiourea (12 mmol) and potassium hydroxide
(80 mmol) in ethanol (20 ml) were placed in an ultrasonic bath at 50 ꢀC for 30–90 min.
After completion of the reaction, as monitored by TLC, the reaction volume was
reduced to its half under vacuum and then poured into crushed ice. The produced pre-
cipitate was filtered off, washed with water, and dried. Crystallization from ethanol
afforded the pure products (1–11). Yields: (78–95%).
4,6-Diphenyl-3,4-dihydropyrimidine-2(1H)-thione 1.[10]
Off-white shiny crystals, yield ¼ 94%, mp ¼ 182–184 ꢀC (reported mp ¼ 182–184 ꢀC);
1H NMR (300 MHz, CDCl3) d: 7.76 (s, 1H, NH), 7.38 (s, 5H, Ar–H), 7.36 (s, 5H,
Ar–H), 7.07 (s, 1H, NH), 5.26 (s, 1H, H-4), 5.18 (s, 1H, H-5). 13C NMR (75 MHz,
CDCl3) d: 174.75, 141.81, 133.49, 132.82, 129.12, 128.70, 128.56, 128.16, 126.47, 124.77,
100.19, 56.74. Data are in good agreement with those reported.[10]
1
Supplementary data (copies of H and 13C NMR spectra of all the synthesized com-
pounds) associated with this article can be found via the “Supplementary Content” sec-
tion of this article’s webpage.
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