FeCl3·6H2O/TMSBr-catalyzed rapid synthesis of dihydropyrimidinones and dihydropyrimidinethiones under microwave irradiation

Article abstract of DOI:10.3390/molecules22091503

An efficient and practical protocol has been developed to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl₃ 6H₂O TMSBr-catalyzed three-component cyclocondensation under microwave irradiation. This approach features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones.

Full text of DOI:10.3390/molecules22091503

molecules
Article
FeCl3·6H2O/TMSBr-Catalyzed Rapid
Synthesis of Dihydropyrimidinones and
Dihydropyrimidinethiones under
Microwave Irradiation
Fei Zhao * ID , Xiuwen Jia, Pinyi Li, Jingwei Zhao, Jun Huang, Honglian Li and Lin Li
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of
Antibiotics, Chengdu University, 168 Hua Guan Road, Chengdu 610052, China; echo19930319@163.com (X.J.);
18349336094@163.com (P.L.); huizi0268616@sina.com.cn (J.Z.); 13183854809@163.com (J.H.);
13281813368@163.com (H.L.); ll18328653533@126.com (L.L.)
* Correspondence: zhaofei@cdu.edu.cn; Tel.: +86-187-8025-5276
Received: 22 August 2017; Accepted: 7 September 2017; Published: 11 September 2017
Abstract: An efficient and practical protocol has been developed to synthesize dihydropyrimidinones
and dihydropyrimidinethiones through FeCl3 6H2O/TMSBr-catalyzed three-component
·
cyclocondensation under microwave irradiation. This approach features high yields, broad
substrate scope, short reaction time, mild reaction conditions, operational simplicity and
easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones
and dihydropyrimidinethiones.
Keywords: FeCl3 6H2O; TMSBr; dihydropyrimidinones; dihydropyrimidinethiones; microwave
·
irradiation
1. Introduction
Dihydropyrimidinones and dihydropyrimidinethiones have received great attention in synthetic
organic chemistry because of their ubiquitous presence in a large number of natural products
and pharmaceutical agents [
alkaloids such as batzelladine A-I [11
a broad spectrum of pharmacological activities such as antibacterial [16], antitumor [17
anti-inflammatory [20], antiviral [21], and antihypertensive activities [22 23]. They are also known
as calcium channel blockers [24 27] and α1A-adrenergic receptor (α1A-AR) antagonists [28 29].
1–
10]. For example, they act as key components in natural marine
13], ptilocaulin [14], and saxitoxin [15]. Moreover, they exhibit
20],
–
–
,
–
,
In addition, dihydropyrimidinones display as a key precursor in the synthesis of pyrimidine bases
which constitute the basic skeleton of nucleic acids [30]. Therefore, an efficient access to these two
structures is highly desirable for both organic synthesis and drug discovery.
The first synthetic method for the preparation of dihydropyrimidinones and
dihydropyrimidinethiones was reported by Biginelli in 1893 [31]. However, this method suffered
from low yields and the usage of strong acids. Consequently, improved procedures, including the
employment of Lewis acid catalysts [32–56], bases [57,58], ionic liquids [59–62], ultrasound irradiation [63],
and nanocomposites [64 66] have been developed. Despite the remarkable achievements made,
–
however, many of these methods still suffer from major or minor drawbacks, such as long reaction
time, harsh reaction conditions, low yields, the stoichiometric requirements of the metal catalysts
and the involvement of expensive or toxic reagents. Therefore, the development of a faster, milder,
high-yielding and environmentally benign approach for the synthesis of dihydropyrimidinones
and dihydropyrimidinethiones is still of great significance. Herein, we present our efforts towards
FeCl3 6H2O/TMSBr- (TMSBr = Bromotrimethylsilane) catalyzed three-component cyclocondensation
·
Molecules 2017, 22, 1503; doi:10.3390/molecules22091503
www.mdpi.com/journal/molecules

Molecules 2017, 22, 1503
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under microwave irradiation to synthesize dihydropyrimidinones and dihydropyrimidinethiones.
Our protocol features high yields, broad substrate scope, short reaction time, mild reaction conditions,
operational simplicity and easy work-up, thus affording a rapid and convenient approach for the
synthesis of dihydropyrimidinones and dihydropyrimidinethiones.
2. Results and Discussion
We began our study by investigating the reaction of 1-tetralone (1a), benzaldehyde (2a
and thiourea (3a) in CH3CN at 90 ◦C in an oil bath for 10 h employing FeCl3
6H2O as the
catalyst, considering the potential of FeCl3 6H2O in Biginelli-like reactions [45 67 68] (Table 1,
entry 1). Pleasingly, the desired product 4a was obtained, albeit with low yield. Considering that
microwave-assisted organic synthesis (MAOS) is time and energy-saving [69 71] and its applications
in Biginelli-like reactions [57 72 81], we then chose this technology to conduct the three-component
)
·
·
, ,
–
,
–
condensation reaction. As a result, a similar yield was obtained under the same catalytic conditions
when the reaction was carried out under microwave irradiation for just 2 h (Table 1, entry 2). Then,
we tried to optimize the reaction conditions under microwave heating. At first, various catalysts
such as ZnCl2, FeSO4
them exhibited a higher catalytic performance than FeCl3
catalyst, a series of additives were added and screened in order to improve the reaction yield (Table 1,
entries 7–12). Both BF3 OEt2 and BBr3 caused no obvious enhancement of the reaction yield (Table 1,
entries 7 and 8). As TMS-X-type (X = Cl, I, OTf) compounds were proved to be efficient reagents which
could significantly promote Biginelli-like reactions [44 45 56 82 102], we then explored the effects of
·
7H2O, CuBr2, and AlCl3 were evaluated (Table 1, entries 3–6), and none of
·
6H2O. Next, employing FeCl3 6H2O as the
·
·
,
, , –
this kind of additive. We found that TMSOTf, TMSCl, TMSBr and TMSI could improve the yield to
different degrees (Table 1, entries 9–12). To our delight, TMSBr was found to be the most efficient
additive, with which product 4a was obtained in 88% yield by filtration (Table 1, entry 11). This
might be because TMSBr could activate the carbonyl group of 1a to promote the reaction [103–105].
Subsequently, a further screening of the solvents revealed that increasing the polarity of the solvent
generally had a positive effect on the reaction yield (Table 1, entry 13–16), and CH3CN displayed as the
best choice to promote the transformation, although ethanol could be an alternative solvent with which
a slight lower yield (84%) was observed (Table 1, entry 16). In addition, solvent-free conditions were
also tested, and only a moderate yield (52%) was obtained because of the recovery of the materials
(Table 1, entry 17). By contrast, a lower yield (80%) was observed when the reaction was heated with
an oil bath for 8 h under the optimal reaction conditions because of the incomplete consumption of
the substrates (Table 1, entry 18), and it took 10 hours to finish the reaction to obtain a comparable
yield (87%) using an oil bath (Table 1, entry 19). These results highlighted the efficiency of microwave
irradiation. In this way, FeCl3 6H2O/TMSBr-catalyzed synthesis of dihydropyrimidinethiones through
·
three-component cyclocondensation under microwave heating was developed.
Table 1. Optimization of the reaction conditions a.
Yield (%) b
Entry
Catalyst
Additive
Solvent
Time
1 c
2
3
4
5
6
7
8
FeCl3·6H2O
FeCl3·6H2O
ZnCl2
-
-
-
-
-
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
38
37
trace
trace
16
18
43
41
FeSO4·7H2O
CuBr2
AlCl3
FeCl3·6H2O
BF3·OEt2
FeCl3·6H2O
BBr3

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Table 1. Cont.
Yield (%) b
Entry
Catalyst
Additive
Solvent
Time
9
10
11
12
13
14
15
16
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
TMSOTf
TMSCl
TMSBr
TMSI
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
TMSBr
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
1,4-Dioxane
EtOH
neat
CH3CN
CH3CN
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
8 h
10 h
65
82
88
73
44
61
71
84
52
80
87
17
18 c
19 c
a
Unless noted, reactions were performed with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), catalyst (0.05 mmol)
and additive (0.5 mmol) in CH3CN (3.0 mL) at 90 ◦C under microwave irradiation (sealed vessel at fixed power,
30 W); Isolated yield; Heated with oil bath; TMSOTf = Trimethylsilyl trifluoromethanesulfonate, TMSCl =
Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, TMSI = Iodotrimethylsilane.
b
c
After determining the optimal reaction conditions, we then examined the general applicability
of this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were easily
prepared in good to high yields by the reaction of ketones, benzaldehydes and thiourea under the
catalysis of FeCl3
groups (Me, MeO) furnished the corresponding products 4b
entries 2–4). The protocol was also compatible with benzaldehydes bearing electron-withdrawing
groups (CN, COOMe) and afforded the desired products 4e 4f in good to high yields (Table 2,
·
6H2O/TMSBr (Table 2). The reactions of benzaldehydes carrying electron-donating
–
4d in 80%–86% yields (Table 2,
–
entries 5 and 6). Halogens (F, Cl, Br) were tolerated well and excellent yields (89%–90%) were
obtained (Table 2, entries 7–9). Subsequently, the substituents on the 1-tetralones were investigated.
As a result, the reactions of 1-tetralones with electron-donating group (MeO), halogen (Br) and
electron-withdrawing group (NO2) on the benzene ring gave the corresponding products 4j–4l in high
yields (Table 2, entries 10–12). In addition, a high yield (89%) was observed when 1-indanone was
subjected to the optimal reaction conditions (Table 2, entries 13).
Table 2. FeCl3·6H2O/TMSBr catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-thiones a.
Yield (%) b
Entry
Ketones (1)
Benzaldehydes (2)
Products (4)
1
88
2
3
86
83

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Table 2. Cont.
Yield (%) b
Entry
Ketones (1)
Benzaldehydes (2)
Products (4)
4
80
5
6
91
76
89
90
90
84
86
92
89
7
8
9
10
11
12
13
a
Reaction conditions:
1
(0.5 mmol),
2
(0.5 mmol), 3a (0.75 mmol), FeCl3 6H2O (0.05 mmol) and TMSBr (0.5 mmol) in
·
CH3CN (3.0 mL) at 90 ◦C for 2 h under microwave irradiation (sealed vessel at fixed power, 30 W); b Isolated yield.
Next, a wide range of structurally diverse ketones, benzaldehydes and urea were subjected to
the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in
high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3,
entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO2, CN)
and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b
–6g in high yields
(Table 3, entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group (MeO),

Molecules 2017, 22, 1503
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halogen (Br) and electron-withdrawing group (NO2) on the benzene ring afforded the corresponding
products 6h 6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were also obtained
–
when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11 and 12), these
findings further broadened the substrate scope of this methodology. It should be noted that the
structures of compounds 4 and 6
were confirmed by 1H-NMR (see Supplementary Files), 13C-NMR
(see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS).
Table 3. FeCl3·6H2O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones a.
Yield (%) b
Entry
Ketones (1)
Benzaldehydes (2)
Products (6)
1
90
2
3
4
5
6
7
8
9
86
91
84
82
90
80
81
83

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Table 3. Cont.
Yield (%) b
Entry
Ketones (1)
Benzaldehydes (2)
Products (6)
10
88
11
12
87
82
a
Reaction conditions:
1
(0.5 mmol),
2
(0.5 mmol), 5a (0.75 mmol), FeCl3 6H2O (0.05 mmol) and TMSBr (0.5 mmol) in
·
CH3CN (3.0 mL) at 90 ◦C for 2 h under microwave irradiation (sealed vessel at fixed power, 30 W); b Isolated yield.
3. Materials and Methods
3.1. General Information
The reagents were purchased from commercial suppliers and used without further purification.
Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness),
visualized by irradiation with UV light (254 nm). Column chromatography was performed using
silica gel FCP 200–300. Melting points were measured with a micro melting point apparatus. Nuclear
magnetic resonance spectra were recorded on a Brucker AMX-300 or 400 or 500 MHz instrument
[TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts per million
(ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low and high-resolution mass
(LRMS and HRMS) were measured by the EI (Electron Ionization) method with a Tsou-EI mass
spectrometer. All the microwave-assisted reactions were performed in sealed tubes (capacity 10 mL)
under a nitrogen atmosphere under a microwave heating system (CEM Discover) at the specified
temperature. A feedback mechanism was involved in the temperature control system, and the reaction
temperature which could be read from the temperature display screen was real-time monitored.
It should be note◦d that a fixed power (30 W) was found to be appropriate to achieve the reaction
temperature (90 C) without overheating since a higher power led to the loss of efficacy of the
temperature control system which resulted in overheating.
3.2. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-thiones (4)
A high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol),
benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl3 6H2O (0.05 mmol) and TMSBr (0.5 mmol) in
·
CH3CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was
heated to 90 ◦C for 2 h under microwave irradiation using a CEM Discover (fixed power, 30 W). After
cooling, the solids which had precipitated out were separated by filtration, and the solids obtained
were washed with CH3CN to give the desired products 4.
4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p.
246–248 ◦C. 1H-NMR (500 MHz, DMSO)
δ
9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35
(m, 2H), 7.34–7.28 (m, 3H), 7.24–7.16 (m, 2H), 7.15 (d, J = 6.6 Hz, 1H), 4.95 (s, 1H), 2.77–2.65 (m, 1H),
2.61–2.52 (m, 1H), 2.22–2.12 (m, 1H), 1.88–1.77 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.28, 142.90,
δ

Molecules 2017, 22, 1503
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135.45, 128.75, 127.98, 127.81, 127.75, 127.64, 127.02, 126.69, 126.38, 121.71, 111.23, 58.51, 27.37, 23.65.
LRMS (EI): 292 (M+); HRMS (EI) calcd. for C18H16N2S (M+) 292.1034, found: 292.1031.
4-p-Tolyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4b): White solid (131.3 mg, 86%), m.p.
230–232 ◦C. 1H-NMR (400 MHz, DMSO)
δ
9.74 (s, 1H), 9.04 (s, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.23–7.15
(m, 7H), 4.90 (s, 1H), 2.71 (dt, J = 15.4, 7.6 Hz, 1H), 2.64–2.53 (m, 1H), 2.28 (s, 3H), 2.23–2.10 (m, 1H),
1.89–1.77 (m, 1H). 13C-NMR (126 MHz, DMSO)
δ 174.15, 139.99, 137.20, 135.43, 129.25, 127.78, 127.75,
127.61, 126.96, 126.59, 126.35, 121.67, 111.37, 58.21, 27.36, 23.62, 20.75. LRMS (EI): 306 (M+); HRMS (EI)
calcd. for C19H18N2S (M+) 306.1191, found: 306.1192.
4-(3,4,5-Trimethoxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4c): White solid (158.6 mg,
◦
1
83%), m.p. 224–226 C. H-NMR (400 MHz, DMSO)
7.31–7.09 (m, 3H), 6.64 (s, 2H), 4.92 (s, 1H), 3.74 (s, 6H), 3.65 (s, 3H), 2.80–2.70 (m, 1H), 2.70–2.58 (m, 1H),
2.29–2.12 (m, 1H), 2.04–1.84 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.21, 152.99, 138.30, 137.12,
δ 9.79 (s, 1H), 9.01 (s, 1H), 7.75–7.53 (m, 1H),
δ
135.51, 127.76, 127.73, 127.60, 126.92, 126.32, 121.65, 111.01, 104.22, 59.99, 58.43, 55.86, 27.39, 23.59.
LRMS (EI): 382 (M+); HRMS (EI) calcd. for C21H22N2O3S (M+) 382.1351, found: 382.1349.
4-O-tolyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4d): White solid (122.9 mg, 80%), m.p.
◦
1
241–242 C. H-NMR (400 MHz, DMSO)
7.33–7.07 (m, 7H), 5.25 (d, J = 2.0 Hz, 1H), 2.76–2.64 (m, 1H), 2.60–2.52 (m, 1H), 2.41 (s, 3H), 2.18–1.99
(m, 1H), 1.77–1.59 (m, 1H). 13C-NMR (126 MHz, DMSO)
173.94, 140.83, 135.64, 135.41, 130.60, 128.42,
δ 9.72 (s, 1H), 8.97 (s, 1H), 7.70 (dd, J = 8.3, 6.4 Hz, 1H),
δ
127.85, 127.71, 127.68, 127.56, 126.74, 126.59, 126.33, 121.62, 111.15, 55.55, 27.28, 23.31, 18.83. LRMS (EI):
306 (M+); HRMS (EI) calcd. for C19H18N2S (M+) 306.1191, found: 306.1193.
4-(3-Nitrilephenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4e): White solid (144.1 mg, 91%),
◦
m.p. 243–244 C. 1H-NMR (400 MHz, DMSO)
δ
9.90 (s, 1H), 9.12 (s, 1H), 7.83–7.78 (m, 1H), 7.73 (s, 1H),
7.72–7.59 (m, 3H), 7.26–7.19 (m, 2H), 7.19–7.13 (m, 1H), 5.09 (s, 1H), 2.78–2.67 (m, 1H), 2.66–2.54 (m, 1H),
2.26–2.14 (m, 1H), 1.90–1.79 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.51, 144.24, 135.50, 131.83,
δ
131.76, 130.51, 130.21, 127.94, 127.61, 127.47, 127.21, 126.31, 121.81, 118.63, 111.50, 110.19, 57.53, 27.22,
23.34. LRMS (EI): 317 (M+); HRMS (EI) calcd. for C19H15N3S (M+) 317.0987, found: 317.0979.
methyl 4-(2-Thioxo-1,2,3,4,5,6-hexahydrobenzo[h]quinazolin-4-yl)benzoate (4f): White solid (133.8 mg, 76%),
m.p. 188–190 ◦C. 1H-NMR (400 MHz, DMSO)
δ
9.86 (s, 1H), 9.17 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.69
(d, J = 6.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.31–7.07 (m, 3H), 5.08 (s, 1H), 3.84 (s, 3H), 2.77–2.67 (m, 1H),
2.63–2.53 (m, 1H), 2.27–2.10 (m, 1H), 1.90–1.72 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.49, 165.99,
δ
147.92, 135.49, 129.73, 129.18, 127.95, 127.66, 127.61, 127.37, 126.99, 126.38, 121.79, 110.49, 58.13, 52.24,
27.31, 23.52. LRMS (EI): 350 (M+); HRMS (EI) calcd. for C20H18N2O2S (M+) 350.1089, found: 350.1085.
4-(4-Fluorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4g): White solid (138.3 mg, 89%),
◦
1
m.p. 242–243 C. H-NMR (400 MHz, DMSO)
7.38–7.32 (m, 2H), 7.24–7.19 (m, 4H), 7.18–7.13 (m, 1H), 4.99 (s, 1H), 2.78–2.66 (m, 1H), 2.64–2.53 (m, 1H),
2.28–2.03 (m, 1H), 1.90–1.72 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.23, 161.77 (d, JC–F = 243.9 Hz),
δ 9.80 (s, 1H), 9.10 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H),
δ
139.13, 135.48, 129.07 (d, JC–F = 8.3 Hz), 127.86, 127.68, 127.64, 126.82, 126.37, 121.76, 115.55 (d, JC–F
= 21.4 Hz), 111.05, 57.66, 27.34, 23.55. LRMS (EI): 310 (M+); HRMS (EI) calcd. for C18H15FN2S (M+)
310.0940, found: 310.0933.
4-(4-Chlorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4h): White solid (146.8 mg, 90%),
◦
1
m.p. 226–228 C. H-NMR (400 MHz, DMSO)
d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.23–7.18 (m, 2H), 7.07 (s, 1H), 4.99 (s, 1H), 2.78–2.66 (m, 1H),
2.67–2.54 (m, 1H), 2.24–2.12 (m, 1H), 1.88–1.75 (m, 1H). 13C-NMR (126 MHz, DMSO)
174.26, 141.74,
δ 9.82 (s, 1H), 9.11 (s, 1H), 7.72–7.64 (m, 1H), 7.46
(
δ
135.43, 132.45, 128.84, 128.70, 127.83, 127.58, 126.87, 126.31, 121.72, 110.69, 57.64, 27.26, 23.46. LRMS
(EI): 326 (M+, Cl35), 328 (M+, Cl37); HRMS (EI) calcd. for C18H15ClN2S (M+) 326.0644, found: 326.0636.
4-(4-Bromophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4i): White solid (166.5 mg, 90%),
◦
1
m.p. 229–230 C. H-NMR (400 MHz, DMSO)
δ 9.82 (s, 1H), 9.12 (s, 1H), 7.73–7.65 (m, 1H), 7.59

Molecules 2017, 22, 1503
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(
d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.24–7.13 (m, 3H), 4.97 (s, 1H), 2.77–2.65 (m, 1H), 2.64–2.54
(m, 1H), 2.27–2.09 (m, 1H), 1.89–1.74 (m, 1H). 13C-NMR (126 MHz, DMSO)
δ 174.27, 142.14, 135.44,
131.63, 129.20, 127.85, 127.59, 126.89, 126.32, 121.73, 121.05, 110.64, 57.72, 27.27, 23.46. LRMS (EI): 370
(M+, Br79), 372 (M+, Br81); HRMS (EI) calcd. for C18H15BrN2S (M+) 370.0139, found: 370.0134.
8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4j): White solid (135.0 mg, 84%),
m.p. 247–248 ◦C. 1H-NMR (400 MHz, DMSO)
δ
9.71 (s, 1H), 9.06 (s, 1H), 7.73–7.55 (m, 1H), 7.38 (dd,
J = 8.9, 5.7 Hz, 2H), 7.34–7.27 (m, 3H), 6.82–6.69 (m, 2H), 4.92 (s, 1H), 3.74 (s, 3H), 2.76–2.63 (m, 1H),
2.63–2.53 (m, 1H), 2.22–2.10 (m, 1H), 1.87–1.72 (m, 1H). 13C-NMR (101 MHz, DMSO)
174.20, 158.91,
δ
143.10, 137.53, 128.74, 127.93, 127.01, 126.53, 123.12, 120.63, 113.97, 110.85, 108.56, 58.51, 55.18, 27.78,
23.62. LRMS (EI): 322 (M+); HRMS (EI) calcd. for C19H18N2OS (M+) 322.1140, found: 322.1139.
9-Bromo-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4k): White solid (159.1 mg, 86%),
◦
m.p. 225–226 C. 1H-NMR (400 MHz, DMSO)
δ
9.97 (s, 1H), 9.12 (s, 1H), 7.96 (s, 1H), 7.42–7.35 (m, 3H),
7.35–7.28 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 4.96 (s, 1H), 2.74–2.63 (m, 1H), 2.60–2.52 (m, 1H), 2.28–2.09
(m, 1H), 1.93–1.74 (m, 1H). 13C-NMR (101 MHz, DMSO)
δ 174.38, 142.67, 134.76, 130.27, 129.94, 129.58,
128.81, 128.07, 127.03, 125.93, 124.67, 119.60, 112.85, 58.44, 26.74, 23.51. LRMS (EI): 370 (M+, Br79), 372
(M+, Br81); HRMS (EI) calcd. for C18H15BrN2S (M+) 370.0139, found: 370.0145.
9-Nitro-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4l): White solid (154.8 mg, 92%), m.p.
◦
1
228–229 C. H-NMR (400 MHz, DMSO)
dd, J = 8.2, 2.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.43–7.37 (m, 2H), 7.36–7.31 (m, 3H), 5.00 (d, J = 2.4 Hz
1H), 2.93–2.81 (m, 1H), 2.72 (ddd, J = 16.0, 9.0, 6.9 Hz, 1H), 2.37–2.15 (m, 1H), 2.02–1.78 (m, 1H).
δ 10.36 (s, 1H), 9.18 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.08
(
,
13C-NMR (101 MHz, DMSO)
122.63, 116.89, 113.98, 58.33, 27.34, 23.02. LRMS (EI): 337 (M+); HRMS (EI) calcd. for C18H15N3O2S
(M+) 337.0885, found: 337.0889.
δ 174.53, 146.49, 143.72, 142.50, 129.21, 128.81, 128.09, 127.06, 125.73,
4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2(5H)-thione (4m): White solid (123.4 mg, 89%), m.p.
◦
1
199–201 C. H-NMR (400 MHz, DMSO)
(
δ
10.82 (s, 1H), 9.07 (s, 1H), 7.96–7.71 (m, 1H), 7.42–7.24
m, 7H), 7.22–7.11 (m, 1H), 5.51 (s, 1H), 3.33 (d, J = 23.8 Hz, 1H), 2.88 (d, J = 23.2 Hz, 1H). 13C-NMR
(126 MHz, DMSO)
δ 174.24, 143.42, 142.26, 136.48, 132.95, 128.76, 127.75, 126.57, 126.40, 125.45, 124.09,
118.84, 115.34, 57.56, 34.92. LRMS (EI): 278 (M+); HRMS (EI) calcd. for C17H14N2S (M+) 278.0878,
found: 278.0877.
3.3. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones (6)
A high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol),
benzaldehydes (0.5 mmol), urea (0.75 mmol), FeCl3 6H2O (0.05 mmol) and TMSBr (0.5 mmol) in
·
CH3CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was
heated to 90 ◦C for 2 h under microwave irradiation using a CEM Discover (fixed power, 30 W). After
cooling, the solids which had precipitated out were separated by filtration, and the solids obtained
were washed with CH3CN to give the desired products 6.
4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6a): White solid (124.1 mg, 90%), m.p. 270–272
1
◦C. H-NMR (400 MHz, DMSO)
δ 8.60 (s, 1H), 7.58 (dd, J = 13.4, 6.3 Hz, 1H), 7.39–7.30 (m, 5H),
7.30–7.24 (m, 1H), 7.25–7.12 (m, 3H), 4.94 (s, 1H), 2.75–2.65 (m, 1H), 2.62–2.52 (m, 1H), 2.19–2.03
(m, 1H), 1.84–1.65 (m, 1H). 13C-NMR (101 MHz, DMSO)
δ 153.49, 144.20, 135.47, 128.85, 128.65, 127.72,
127.67, 127.54, 127.52, 126.95, 126.40, 121.27, 108.16, 59.16, 27.66, 23.58. LRMS (EI): 276 (M+); HRMS (EI)
calcd. for C18H16N2O (M+) 276.1263, found: 276.1260.
4-M-tolyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6b): White solid (124.9 mg, 86%), m.p.
1
273–275 ◦C. H-NMR (400 MHz, DMSO)
δ 8.54 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.27–7.17 (m, 4H),
7.16–7.08 (m, 4H), 4.89 (s, 1H), 2.75–2.65 (m, 1H), 2.62–2.52 (m, 1H), 2.29 (s, 3H), 2.19–2.02 (m, 1H),
1.84–1.67 (m, 1H). 13C-NMR (101 MHz, DMSO)
153.41, 144.19, 137.71, 135.47, 128.87, 128.54, 128.31,
δ

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127.63, 127.54, 127.49, 127.47, 126.39, 124.14, 121.25, 108.17, 59.18, 27.66, 23.56, 21.16. LRMS (EI): 290
(M+); HRMS (EI) calcd. for C19H18N2O (M+) 290.1419, found: 276.1412.
4-(4-Nitrophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6c): White solid (146.1 mg, 91%), m.p.
◦
1
214–216 C. H-NMR (400 MHz, DMSO)
δ 8.71 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.64–7.56 (m, 3H),
7.46 (s, 1H), 7.24–7.11 (m, 3H), 5.14 (s, 1H), 2.77–2.65 (m, 1H), 2.64–2.52 (m, 1H), 2.22–2.09 (m, 1H),
1.81–1.68 (m, 1H). 13C-NMR (126 MHz, DMSO)
δ 153.18, 146.62, 143.71, 143.66, 130.27, 128.66, 127.74,
126.93, 126.78, 122.34, 116.19, 110.97, 58.94, 27.59, 22.92. LRMS (EI): 321 (M+); HRMS (EI) calcd.
for C18H15N3O3 (M+) 321.1113, found: 321.1114.
3-(2-Oxo◦-1,2,3,4,5,6-hexahydrobenzo[h]quinazolin-4-yl)benzonitrile (6d): White solid (127.1 mg, 84%), m.p.
286–287 C. 1H-NMR (400 MHz, DMSO)
δ 8.70 (s, 1H), 7.81–7.73 (m, 2H), 7.68 (s, 1H), 7.65–7.56 (m, 2H),
7.41 (s, 1H), 7.26–7.10 (m, 3H), 5.07 (s, 1H), 2.78–2.66 (m, 1H), 2.64–2.54 (m, 1H), 2.20–2.08 (m, 1H),
1.81–1.69 (m, 1H). 13C-NMR (126 MHz, DMSO)
153.33, 145.69, 135.58, 131.95, 131.62, 130.59, 130.22,
δ
128.64, 128.38, 127.78, 127.64, 126.46, 121.47, 118.86, 111.46, 107.09, 58.35, 27.62, 23.34. LRMS (EI): 301
(M+); HRMS (EI) calcd. for C19H15N3O (M+) 301.1215, found: 301.1210.
4-(4-Fluorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6e): White solid (120.9 mg, 82%), m.p.
◦
1
209–210 C. H-NMR (400 MHz, DMSO)
(s, 1H), 7.25–7.10 (m, 5H), 4.97 (s, 1H), 2.76–2.66 (m, 1H), 2.63–2.53 (m, 1H), 2.19–1.99 (m, 1H), 1.81–1.67
(m, 1H). 13C-NMR (101 MHz, DMSO)
161.58 (d, JC–F = 243.1 Hz), 153.27 (s), 140.43 (s), 135.45 (s),
δ 8.58 (s, 1H), 7.66–7.51 (m, 1H), 7.40–7.32 (m, 2H), 7.30
δ
128.90 (d, JC–F = 8.2 Hz), 128.75 (s), 127.82 (s), 127.51 (s), 126.35 (s), 121.29 (s), 115.35 (d, JC–F = 21.4 Hz),
107.89 (s), 58.30 (s), 27.61 (s), 23.45 (s). LRMS (EI): 294 (M+); HRMS (EI) calcd. for C18H15FN2O (M+)
294.1168, found: 294.1168.
4-(3-Chlorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6f): White solid (140.1 mg, 90%), m.p.
◦
1
279–280 C. H-NMR (400 MHz, DMSO)
7.30 (d, J = 7.4 Hz, 1H), 7.24–7.12 (m, 3H), 4.94 (s, 1H), 2.77–2.65 (m, 1H), 2.63–2.53 (m, 1H), 2.21–2.03
(m, 1H), 1.87–1.70 (m, 1H). 13C-NMR (101 MHz, DMSO)
153.33, 146.67, 135.50, 133.23, 130.68, 128.67,
δ 8.65 (s, 1H), 7.59 (d, J = 6.6 Hz, 1H), 7.42-7.33 (m, 4H),
δ
128.11, 127.66, 127.62, 127.59, 126.77, 126.41, 125.61, 121.36, 107.46, 58.50, 27.62, 23.42. LRMS (EI): 310
(M+, Cl35), 312 (M+, Cl37); HRMS (EI) calcd. for C18H15ClN2O (M+) 310.0873, found: 310.0864.
4-(2-Bromophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6g): White solid (142.7 mg, 80%), m.p.
◦
271–273 C. 1H-NMR (400 MHz, DMSO)
δ
8.67 (s, 1H), 7.63–7.57 (m, 2H), 7.49–7.39 (m, 2H), 7.33 (s, 1H),
7.27–7.16 (m, 3H), 7.16–7.11 (m, 1H), 5.54–5.38 (m, 1H), 2.75–2.64 (m, 1H), 2.59–2.52 (m, 1H), 2.22–2.01
(m, 1H), 1.81–1.58 (m, 1H). 13C-NMR (101 MHz, DMSO)
153.15, 142.77, 135.53, 132.70, 130.12, 129.79,
δ
128.72, 128.64, 128.22, 127.66, 127.55, 126.42, 121.95, 121.38, 107.18, 58.35, 27.55, 22.97. LRMS (EI): 354
(M+, Br79), 356 (M+, Br81); HRMS (EI) calcd. for C18H15BrN2O (M+) 354.0368, found: 354.0366.
8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6h): White solid (124.4 mg, 81%),
◦
m.p. 247–249 C. 1H-NMR (400 MHz, DMSO)
δ
8.54 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39–7.30 (m, 4H),
7.30–7.23 (m, 2H), 6.82–6.67 (m, 2H), 4.90 (s, 1H), 3.74 (s, 3H), 2.75–2.63 (m, 1H), 2.60–2.52 (m, 1H),
2.15–2.03 (m, 1H), 1.80–1.68 (m, 1H). 13C-NMR (101 MHz, DMSO)
158.66, 153.45, 144.37, 137.44,
δ
128.57, 127.55, 127.50, 126.91, 122.59, 121.71, 113.81, 110.81, 105.43, 59.11, 55.10, 28.03, 23.50. LRMS (EI):
306 (M+); HRMS (EI) calcd. for C19H18N2O2 (M+) 306.1368, found: 306.1367.
9-Bromo-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6i): White solid (147.2 mg, 83%), m.p.
◦
277–279 C. 1H-NMR (400 MHz, DMSO)
δ
8.67 (s, 1H), 7.78 (s, 1H), 7.40–7.27 (m, 7H), 7.10 (d, J = 7.9 Hz
,
1H), 4.90 (s, 1H), 2.72–2.61 (m, 1H), 2.59–2.52 (m, 1H), 2.24–2.05 (m, 1H), 1.89–1.65 (m, 1H). 13C-NMR
(101 MHz, DMSO)
δ 153.25, 143.94, 134.73, 131.04, 129.98, 129.48, 128.91, 128.68, 127.74, 126.95, 124.17,
119.62, 109.87, 59.06, 27.02, 23.40. LRMS (EI): 354 (M+, Br79), 356 (M+, Br81); HRMS (EI) calcd. for
C18H15BrN2O (M+) 354.0368, found: 354.0371.
9-Nitro-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6j): White solid (141.1 mg, 88%), m.p.
◦
319–321 C. 1H-NMR (400 MHz, DMSO)
δ 8.99 (s, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.2, 2.2 Hz,

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1H), 7.45–7.40 (m, 1H), 7.40–7.31 (m, 5H), 7.32–7.26 (m, 1H), 4.97 (s, 1H), 2.84 (m, 1H), 2.77–2.64 (m, 1H),
2.27–2.14 (m, 1H), 1.81 (m, 1H). 13C-NMR (126 MHz, DMSO)
δ 153.18, 146.62, 143.71, 143.66, 130.27,
128.66, 127.74, 126.93, 126.78, 122.34, 116.19, 110.97, 58.94, 27.59, 22.92. LRMS (EI): 321 (M+); HRMS (EI)
calcd. for C18H15N3O3 (M+) 321.1113, found: 321.1108.
4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-2(5H)-one (6k): White solid (114.3 mg, 87%), m.p.
◦
1
269–270 C. H-NMR (400 MHz, DMSO)
δ 9.45 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.45–7.20 (m, 8H),
7.20–7.08 (m, 1H), 5.45 (s, 1H), 3.26 (d, J = 22.9 Hz, 1H), 2.78 (d, J = 22.8 Hz, 1H). 13C-NMR (101 MHz,
DMSO)
δ 153.38, 144.46, 142.76, 137.51, 134.82, 128.63, 127.42, 126.40, 126.23, 125.11, 123.95, 118.19,
112.24, 57.18, 34.66. LRMS (EI): 262 (M+); HRMS (EI) calcd. for C17H14N2O (M+) 262.1106, found:
262.1103.
4-Phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-2(5H)-one (6l): White solid (113.8 mg, 82%), m.p.
◦
1
251–252 C. H-NMR (400 MHz, DMSO)
δ 8.91 (s, 1H), 7.63 (dd, J = 7.8, 1.3 Hz, 1H), 7.47 (s, 1H),
7.43–7.27 (m, 5H), 7.24–7.14 (m, 1H), 7.00–6.90 (m, 1H), 6.83–6.75 (m, 1H), 4.98 (s, 1H), 4.74–4.68 (m, 1H),
4.21 (d, J = 13.6 Hz, 1H). 13C-NMR (126 MHz, DMSO)
δ 153.48, 152.99, 143.11, 129.61, 128.78, 127.90,
126.76, 125.17, 121.97, 121.22, 117.40, 115.83, 101.30, 64.80, 56.08. LRMS (EI): 278 (M+); HRMS (EI) calcd.
for C17H14N2O2 (M+) 278.1055, found: 278.1049.
4. Conclusions
In conclusion, we have developed an efficient and practical approach to synthesize
dihydropyrimidinones and dihydropyrimidinethiones through FeCl3 6H2O/TMSBr-catalyzed
·
three-component cyclocondensation under microwave heating. This protocol features high yields,
broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy
work-up. These advantages demonstrate the great potential of this method for the synthesis of
dihydropyrimidinones and dihydropyrimidinethiones. More importantly, our ongoing research has
revealed that the simple derivatives of compounds 4 or 6 are found to be potential EV71 3C protein
inhibitors, which are worthy of further investigation for the development of medical therapies for
hand, foot and mouth disease (HFMD). We anticipate that these important heterocyclic compounds
may find their potent pharmaceutical applications after further exploration.
Supplementary Materials: Supplementary Files (Copies of 1H and 13C-NMR spectra of compounds
available online.
4 and 6) are
Acknowledgments: We gratefully acknowledge financial support from the National Natural Science Foundation
of China (No. 21602022), the Open Project Program of Antibiotics Research and Re-evaluation Key Laboratory of
Sichuan Province (No. ARRLKF15-01), Chengdu University New Faculty Start-up Funding (No. 2081915037) and
the Open Project Program of Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan
Education Department (No. 10Y201711).
Author Contributions: F.Z. conceived and designed the experiments; X.J., P.L., J.Z. and J.H. performed the
experiments; F.Z. analyzed the data; H.L. and L.L. contributed reagents and materials; F.Z. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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