An efficient and recyclable L-proline triflate ionic liquid catalyst for one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones via the multi-component Biginelli reaction

Article abstract of DOI:10.24820/ARK.5550190.P011.096

A simple, efficient, and environmentally-friendly process has been developed for the synthesis of L-proline triflate ionic liquid (L-ProTfO) from L-proline and triflic acid using ultrasound irradiation. The combination of L-proline triflate ionic liquid t

Full text of DOI:10.24820/ARK.5550190.P011.096

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An efficient and recyclable L-proline triflate ionic liquid catalyst for one-pot
synthesis of 3,4-dihydropyrimidin-2(1H)-ones via the multi-component Biginelli
reaction
Khan Manh Hua, Phuong Hoang Tran*, and Thach Ngoc Le*
Department of Organic Chemistry, Faculty of Chemistry, University of Science, Vietnam National University, Ho
Chi Minh City 700000, Vietnam
Email: lenthach@yahoo.com, thphuong@hcmus.edu.vn
Received 10-25-2019
Accepted 12-11-2019
Published on line 02-02-2020
Abstract
A simple, efficient, and environmentally-friendly process has been developed for the synthesis of L-proline
triflate ionic liquid (L-ProTfO) from L-proline and triflic acid using ultrasound irradiation. The combination of L-
proline triflate ionic liquid technology with microwave energy represents an attractive and rapid alternative to
the conventional acid-base-catalyzed thermal process. The current method has several advantages, including
high yield, short reaction time, and work-up simplicity. In addition, the L-proline triflate ionic liquid could be
recycled and reused four times without a noticeable decrease in catalytic activity.
Keywords: Biginelli reaction, ultrasonic irradiation, microwave irradiation, L-proline triflate, solvent-free
conditions
DOI: https://doi.org/10.24820/ark.5550190.p011.096
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Introduction
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have attracted increasing interest due to their
diverse therapeutic and pharmacological activities, such as calcium-channel blocking, antihypertensive,
antifungal, antibacterial, antiviral, anti-inflammatory, and anticancer properties.1-3 Some of them have been
successfully used as calcium-channel blockers, antihypertensive agents, and α1a-antagonists.4, 5 Several
alkaloids isolated from marine sources whose molecular structures contain the dihydropyrimidinone unit also
exhibit interesting biological activities.1 The Biginelli reaction involves a three-component, one-pot
condensation of benzaldehyde, β-keto ester, and urea under strongly acidic conditions.1 However, some
methods often require harsh conditions, long reaction times, expensive catalysts, and volatile organic
solvent.5-13 The search for new, efficient, and green catalysts is still being actively pursued.
Ionic liquids (ILs) have attracted interest as powerful alternatives to volatile organic solvents and catalysts
due to their negligible vapor pressure, thermal stability, designability, nonflammability, wide range of
solubility and ease of recycling.14-18 Some ionic liquids have been used as catalysts for the synthesis of
dihydropyrimidinones.19-22 Low yields and long reaction times, however, have limited the applicability of these
ionic liquids. The use of acidic-ionic liquids in the Biginelli reaction under microwave irradiation has been
studied sparsely in the literature.23-26 The preparation of these acidic-ionic liquids usually required a two-step
procedure via zwitterions, and the purification of ionic liquids was not easily achieved.
The utility of microwave irradiation (MW) and ultrasound activation to assist organic reactions has been
studied extensively. The prominent features of these techniques are significant rate enhancement, short
reaction time, energy savings, high yields with high selectivity. A large number of papers have previously
reported the application of MW and ultrasound irradiation in the synthesis of heterocyclic compounds. 27-33
In the present study, an easily synthesizable and cost-effective L-proline triflate ionic liquid was prepared
from L-proline and triflic acid using ultrasonic irradiation technology. This ionic liquid was used as an efficient
and green catalyst for the Biginelli reaction under solvent-free conditions. The Biginelli reaction was carried
out using both conventional heating methods and microwave energy for comparison.
Results and Discussion
In our current work, an efficient pathway for the synthesis of L-ProTfO, an α-amino acid-based IL from L-
proline (1) and triflic acid (2), has been developed under ultrasonic irradiation (Scheme 1).34 For the first time,
L-ProTfO has been used as an efficient and green catalyst for the Biginelli reaction under solvent-free
conditions.
Scheme 1. Synthesis of L-proline triflate using ultrasonic irradiation.
As seen from Table 1, the reaction between L-proline and triflic acid is exothermic; it was performed at
ambient temperature (30 oC). The control experiment without sonication resulted in a slightly lower yield
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while aso requiring a longer time (Table 1: entries 3, 6). The most significant effect of ultrasound irradiation is
that, by passing its waves through a liquid medium, which causes the generation of energy provided by
cavitation, resulting in the formation, and subsequent collapse, of the bubble which liberates considerable
energy in a short period of time. This is also a green protocol for the efficient synthesis of L-proline triflate
because this process used water as the only solvent, thereby avoiding toxic organic solvents, and used a green
method, ultrasonic irradiation.
Table 1. Preparation results of L-proline triflate under ultrasonic irradiation
Entry
Temperature (oC)
Time (min)
Yield (%)a
1
2
3
4
5
6b
30
30
30
30
30
30
2
3
4
5
6
80
90
99
99
99
98
60
a Isolated yield.
b Without ultrasonic irradiation.
L-proline triflate was used to catalyze the Biginelli reaction to prepare 3,4-dihydropyrimidin-2(1H)-one
(DHPM) under conventional heating and microwave irradiation for the first time (Scheme 2).
Scheme 2. The Biginelli synthesis of DHPM.
Initially, we began our investigation by using benzaldehyde (4), ethyl acetoacetate (5), and urea (6) for the
o
model reaction. As shown in Table 2, when the reaction was carried out at 70 C in the presence of L-proline
triflate (10 mo%), the yields increased from 57% to 72% when the reaction time was increased from 1.0 to 1.5
h. When the reaction time was prolonged beyond 1.5 h, however,the product yield did not increase (Table 2,
entries 1-4). The molar ratio of reagents and reaction temperatures were also investigated. The best yield
obtained was 88% yield (Table 2, entry 9).
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Table 2. Synthesis of DHPM under solvent-free conventional heating
Cmpds 4:5:6
(molar ratio)
1:1:1
L-ProTfO
(mol%)
10
Temperature Time Yield
Entry
(oC)
70
70
70
70
60
80
90
80
80
80
80
80
80
(h)
1.0
1.5
2.0
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
(%)a
57
72
72
71
60
75
70
78
88
80
65
80
75
1
2
3
4
5
6
7
8
9
10
11
12
13
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
10
10
10
10
10
10
10
10
10
5
15
20
1:1:1.5
1:1:2.0
1:1:2.5
1:1:2.0
1:1:2.0
1:1:2.0
aIsolated yield.
Next, we focused on trying to lower the reaction time using microwave irradiation instead of conventional
heating. As seen from Table 3, in comparison with conventional heating, microwave irradiation is a more
efficient and environmentally-friendly tool because of the shorter reaction times and resulting energy savings.
The best yield was 90% following only 10 min (Table 3, Entry 9). Under the same reaction conditions, the
conventional heating method resulted in extremely poor yield (Table 3, entry 14).
Table 3. Synthesis of DHPM under solvent-free microwave irradiation
Cmpds 4:5:6
(molar ratio)
1:1:1
L-ProTfO
(mol%)
10
Temperature
Time
(min)
5
10
15
20
10
10
10
10
10
10
10
10
10
10
Yield
(%)a
59
74
74
72
64
77
70
80
90
83
70
82
77
20
Entry
(oC)
70
70
70
70
60
80
90
80
80
80
80
80
80
80
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
10
10
10
10
10
10
10
10
10
5
15
20
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1.5
1:1:2.0
1:1:2.5
1:1:2.0
1:1:2.0
1:1:2.0
1:1:2.0
10
aIsolated yield.
bConventional heating.
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With the optimized conditions in hand, a variety of aldehydes were investigated. The results are
summarized in Table 4. Both electron-withdrawing and electron-donating groups on the aldehyde aryl ring
were investigated and found to be reactive. Ortho- and para- electron-donating groups on the aldehyde aryl
ring produced the desired products, o-Cl (7e), p-Cl (7g), o-Br (7h), p-Br (7j), o-Me (7l), o-MeO (7m), and m-
MeO-p-OH (7o), in similarly high yields, albeit lower than the product yield of benzaldehyde. In addition, ortho
and para electron-withdrawing groups on the aldehyde aryl ring produced the desired products, o-F (7b), p-F
(7d), p-NO2 (7k), in excellent yields, and higher than the product yield of benzaldehyde. m-Substituted
aldehydes, including m-Cl (7f), m-Br (7i), m-OH (7n) provided the desired products in lower yield than
benzaldehyde. m-Fluorobenzaldehyde provided the desired product in high yield due to the electron-
withdrawing nature of fluorine.
Table 4. Synthesis of DHPMs catalyzed by L-proline triflate under solvent-free conditionsa
Time
(min)
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Yield
(%)b
90
96
92
94
86
90
88
85
89
88
97
89
86
92
87
Mp (oC)
Entry Product
R
Found
Ref.
1
2
3
4
5
7a
7b
7c
7d
7e
7f
H
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-Br
3-Br
207-208
235-236
209-210
182-184
221-223
193-195
213-214
205-206
184-186
224-225
209-211
213-215
200-202
184-186
238-240
207-20832
235-23729
209-2117
182-18433
222-2231
192-19333
214-21532
205-20734
185-18633
225-22610
210-21132
213-2159
200-2029
184-18632
239-24032
6
7
8
9
7g
7h
7i
10
11
12
13
14
15
7j
7k
7l
7m
7n
7o
4-Br
4-NO2
4-Me
4-MeO
3-OH
3-MeO-4-OH
aReaction conditions: aldehyde (2.5 mmol), ethyl acetoacetate (2.5 mmol), urea (5.0
mmol) and L-ProTfO (0.6625 g) and microwave irradiation.
bIsolated yield.
The recovery and reuse of L-proline triflate in the Biginelli synthesis were investigated in the model
reaction. The reusability of IL is presented in Table 5. A little loss of the catalytic activity was observed after
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the fourth cycle. These results show that the L-proline triflate catalyst can be reused at least four times
without significant loss of the activity.
Table 5. Recycling results of L-proline triflate in the Biginelli reactiona
Entry
Cycles
Yield (%)
1
2
3
4
1
2
3
4
90
90
90
89
aReaction conditions: aldehyde (2.5 mmol), ethyl
acetoacetate (2.5 mmol), urea (5.0 mmol) and L-ProTfO
(0.6625 g) under solvent-free microwave irradiation for
10 min.
bIsolated yield.
Conclusions
In summary, we have developed the use of ultrasonic irradiation for the synthesis of L-proline triflate for the
first time. The method offers several advantages, including mild reaction conditions, short reaction times, easy
isolation, and excellent yields. L-proline triflate was shown to be an efficient, clean, and environmentally-
friendly catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones from aromatic aldehydes under solvent-
free microwave irradiation. This is also the first time that L-proline triflate was used for the Biginelli reaction.
The catalyst can be easily recovered and reused several times without a noticeable decrease in reactivity.
Experimental Section
General. All solvents and chemicals used in the experiments were commercially available from Merck, Aldrich,
and were used without further purification unless otherwise stated. Products were characterized by melting
point (Buchi B-545), and 1H and 13C NMR (Bruker Advance, 500 MHz) spectroscopy. Ultrasonic bath (BRANSON
1510) and microwave oven Discover (CEM) were used for the syntheses.
General procedure for the synthesis of L-proline triflate (3) under ultrasonic irradiation
L-Proline (1 mmol, 0.115 g) was dissolved in water (1 mL) and cooled in an ice-salt bath (0-5 C). Then triflic
o
acid (1mmol, 0.15 g) was added dropwise with stirring for 5 min. The reaction was carried out under
o
ultrasound irradiation at room temperature. Upon completion, water was removed under vacuum at 70 C.
The product was extracted with diethyl ether (5 x 10 mL) to remove non-ionic residues. The combined organic
layers were evaporated under vacuum to afford the pure L-proline triflate as a white solid (0.262 g, 99% yield).
1H NMR (D2O) δ(ppm): 2.08-2.14 (m, 2H), 2.19-2.26 (m, 1H), 2.45-2.52 (m, 1H), 3.41-3.52 (m, 2H), 4.45-4.48
(m, 1H). 13C NMR (D2O) δ(ppm): 26.0, 30.9, 48.9, 62.3, 118.5, 126.1, 174.5.
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General procedure for recycling L-proline triflate
After completion of the Biginelli reaction, the mixture was washed with cold water. The filtrate included L-
o
proline and urea. Afterwards, water was removed from the mixture using a rotary evaporator at 70 C. The
crude product was extracted with acetone (3 x 20 mL) to remove urea. The combined organic layers were
collected and concentrated to afford the recycled catalyst.
General procedure for the synthesis of 5-ethoxycarbonyl-4-substituted-phenyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (7a-o). A mixture of the respective aldehyde (2.5 mmol), 1,3-dicarbonyl
compound (2.5 mmol), urea (5.0 mmol), and L-ProTfO (0.6625 g, 10 mol%) was added? into a round-bottom
flask. The mixture was stirred and activated by conventional-heating or microwave-irradiation methods. Cold
water (15 mL) was added and stirred for 10 min. The product was filtered and washed with water (3x15 mL)
and recrystallized from ethanol to afford the pure product in almost quantitative yield. The filtrate was
extracted with diethyl ether to remove organic residues and to recover the L-proline triflate.
5-Ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7a). White solid (0.234 g, 90% yield),
o
1
m.p. 207-208 C. H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.23 (s, 3H), 3.97 (q, 2H, J 7.0 Hz), 5.13 (d,
1H, J 1.5 Hz), 7.21-7.29 (m, 3H), 7.29-7.32 (m, 2H), 7.69 (s, 1H), 9.14 (s, 1H). 13C NMR (DMSO-d6) δ(ppm): 14.0,
17.7, 54.0, 59.1, 99.3, 126.2, 127.2, 128.3, 144.8, 148.3, 152.1, 165.3.[1]
5-Ethoxycarbonyl-4-(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7b). White solid (0.267 g,
o
96% yield),, m.p. 235-236 C.1H NMR (DMSO-d6) δ(ppm): 1.01 (t, 3H, J 7.0 Hz), 2.25 (s, 3H), 3.90 (q, 2H, J 7.0
Hz), 5.44 (s, 1H), 7.10-7.15 (m, 2H), 7.23-7.30 (m, 2H), 7.66 (s, 1H), 9.23 (s, 1H). 13C NMR (DMSO-d6) δ(ppm):
14.3, 18.2, 49.1, 59.6, 98.0, 115.8, 125.0, 129.4, 129.8, 132.1, 149.4, 152.0, 158.9-160.8, 165.5.[2]
5-Ethoxycarbonyl-4-(3-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7c). White solid (0.256 g,
o
1
92% yield), m.p. 209-210 C. H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.24 (s, 3H), 3.98 (q, 2H, J 7.0
Hz), 5.15 (d, 1H, J = 3.5 Hz), 6.79-7.08 (m, 3H), 7.34-7.38 (m, 1H), 7.76 (s, 1H), 9.22 (s, 1H). 13C NMR (DMSO-d6)
δ(ppm): 14.5, 18.3, 54.0, 59.8, 99.2, 113.5, 114.5, 122.7, 131.0, 148.1, 149.4, 152.5, 161.6-163.5, 165.7.[3]
5-Ethoxycarbonyl-4-(4-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7d). White solid (0.261 g,
o
1
94% yield), m.p. 182-184 C. H NMR (DMSO-d6) δ(ppm): 1.07 (t, 3H, J 7.0 Hz), 2.23 (s, 3H), 3.96 (q, 2H, J 7.0
Hz), 5.13 (s, 1H), 7.130 (t, 2H, J 9.0 Hz), 7.24 (t, 2H,J 9.0 Hz), 7.73 (s, 1H), 9.21 (s, 1H). 13C NMR (DMSO-d6)
δ(ppm): 14.5, 18.3, 53.8, 59.7, 99.6, 115.5, 115.7, 128.7, 128.5, 141.6, 149.0, 152.4, 160.8-162.8, 165.7.[4]
5-Ethoxycarbonyl-4-(2-clorophenyl-)6-methyl-3,4-dihydropyrimidin-2(1H)-one (7e). White solid (0.253 g, 86%
yield), m.p. 221-223. 1H NMR (DMSO-d6) δ(ppm): 0.97 (t, 3H, J 7.0 Hz), 2.28 (s, 3H), 3.88 (q, 2H, J 7.0 Hz), 5.62
(d, 1H, J 3.0 Hz), 7.23-7.27 (m, 1H), 7.30 (d, 2H, J 4.0 Hz), 7.38 (d, 1H,J 9.0 Hz), 7.66 (s, 1H), 9.24 (s, 1H). 13C
NMR (DMSO-d6) δ(ppm): 14.4, 18.2, 52.0, 59.5, 98.4, 128.2, 129.3, 129.5, 129.9, 132.2, 142.2, 149.8, 151.8,
165.4.[5]
5-Ethoxycarbonyl-4-(3-clorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7f). White solid (0.265 g, 90%
o
1
yield), m.p. 193-195 C. H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.24 (s, 3H), 3.98 (q, 2H, J 7.0 Hz),
5.14 (d, 1H, J 3.5 Hz), 7.19 (d, 1H, J 7.5 Hz), 7.23 (s, 1H), 7.73 (d, 1H, J 9.0 Hz), 7.35 (t, 1H, J 9.0 Hz), 7.76 (s, 1H),
9.24 (s, 1H). 13C NMR (DMSO-d6) δ(ppm): 14.5, 18.3, 54.1, 59.8, 99.1, 125.4, 126.7, 127.7, 131.0, 133.4, 147.7,
149.4, 152.4, 165.6.[4]
5-Ethoxycarbonyl-4-(4-clorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7g). White solid (0.259 g, 88%
o
1
yield), m.p. 213-214 C. H NMR (DMSO-d6) δ(ppm): 1.07 (t, 3H, J 7.0 Hz), 2.23 (s, 3H), 3.96 (q, 2H, J 7.0 Hz),
5.12 (s, 1H), 7.23 (d, 2H, J 10.5 Hz), 7.37 (d, 2H, J 9.0 Hz), 7.76 (s, 1H), 9.23 (s, 1H). 13C NMR (DMSO-d6) δ(ppm):
14.5, 18.3, 53.9, 59.7, 99.2, 128.7, 128.9, 132.3, 144.3, 149.2, 152.4, 165.7.[1]
5-Ethoxycarbonyl-4-(2-bromophenyl-)6-methyl-3,4-dihydropyrimidin-2(1H)-one (7h). White solid (0.287 g,
o
1
85% yield), m.p. 205-206 C. H NMR (DMSO-d6) δ(ppm): 0.98 (t, 3H, J 7.0 Hz), 2.29 (s, 3H), 3.89 (q, 2H, J 7.0
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Hz), 5.60 (s, 1H, J 1,5 Hz), 7.17 (t, 1H, J 7.0 Hz), 7.29-7.34 (m, 2H), 7.55 (d, 1H, J 7.5 Hz), 7.65 (s, 1H), 9.24 (s,
1H). 13C NMR (DMSO-d6) δ(ppm): 14.4, 18.1, 54.5, 59.5, 98.8, 122.8, 128.9, 129.2, 129.8, 133.1, 149.7, 151.7,
165.4.[6]
5-Ethoxycarbonyl-4-(3-bromophenyl-)6-methyl-3,4-dihydropyrimidin-2(1H)-one (7i). White solid (0.301 g,
o
1
89% yield), m.p. 184-186 C. H NMR (DMSO-d6) δ(ppm): 1.09 (t, 3H, J 7.0 Hz), 2.24 (s, 3H), 3.98 (q, 2H, J 7.0
Hz), 5.13 (d, 1H, J 3.0 Hz), 7.22 (d, 1H, J 8.0 Hz), 7.29 (t, 1H, J 8.0 Hz), 7.38 (s, 1H), 7.43 (d, 1H, J 9.0 Hz), 7.76 (s,
1H), 9.24 (s, 1H). 13C NMR (DMSO-d6) δ(ppm): 14.5, 18.3, 54.1, 55.8, 99.1, 122.0, 125.7, 129.6, 130.6, 131.3,
147.9, 149.4, 152.4, 165.6.[4]
5-Ethoxycarbonyl-4-(4-bromophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7j). White solid (0.297 g,
o
1
88% yield), m.p. 224-225 C. H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.23 (s, 3H), 3.97 (q, 2H, J 7.0
Hz), 5.11 (d, 1H, J 3.0 Hz), 7.17 (d, 2H, J 7.5 Hz), 7.51 (d, 2H, J 10.5 Hz), 7.73 (s, 1H), 9.21 (s, 1H). 13C NMR
(DMSO-d6) δ(ppm): 14.5, 18.3, 54.0, 59.7, 99.3, 120.8, 129.0, 131.8, 144.7, 149.2, 152.4, 165.7.[7]
5-Ethoxycarbonyl-4-(4-nitrophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7k). Yellow solid (0.296 g, 97%
o
1
yield), m.p. 209-0211 C. H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.25 (s, 3H), 3.98 (q, 2H, J 7.0 Hz),
5.27 (s, 1H), 7.49 (d, 2H, J 9.0 Hz), 7.86 (s, 1H), 8.20 (d, 2H, J 9.0 Hz), 9.32 (s, 1H). 13C NMR (DMSO-d6) δ(ppm):
14.5, 18.3, 54.2, 59.9, 98.7, 124.3, 128.1, 147.2, 147.9, 152.2, 152.5, 165.5.[1]
5-Ethoxycarbonyl-4-(4-methylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7l). White solid (0.244 g,
89% yield), m.p. 213-215 oC. 1H NMR (DMSO-d6) δ(ppm): 1.08 (t, 3H, J 7.0 Hz), 2.22 (s, 3H), 2.24 (s, 1H), 3.96 (q,
2H, J 7.0 Hz), 5.09 (s, 1H), 7.10 (s, 4H), 7.67 (s, 1H), 9.14 (s, 1H). 13C NMR (DMSO-d6) δ(ppm): 14.6, 18.2, 21.1,
54.1, 59.6, 99.9, 126.6, 129.4, 136.8, 142.4, 148.6, 152.7, 165.8.[8]
5-Ethoxycarbonyl-4-(4-methoxylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7m). White solid (0.249 g,
86% yield), m.p. 200-202 oC. 1H NMR (DMSO-d6) δ(ppm): 1.09 (t, 3H, J 7.0 Hz), 2.22 (s, 3H), 3.70 (s, 1H), 3.96 (q,
2H, J 7.0 Hz), 5.07 (d, 1H, J 3.0 Hz), 6.86 (d, 2H, J 10.5 Hz), 7.13 (d, 2H, J 10.5 Hz), 7.63 (s, 1H), 9.17 (s, 1H). 13C
NMR (DMSO-d6) δ(ppm): 14.6, 18.2, 53.8, 55.8, 59.6, 100.1, 114.2, 127.9, 137.5, 148.5, 152.6, 158.9, 165.8.[8]
5-Ethoxycarbonyl-4-(3-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7n). Yellow solid (0.254 g,
o
1
92%), m.p. 184-186 C. H NMR (DMSO-d6) δ(ppm): 1.12 (t, 3H, J 7.0 Hz), 2.25 (s, 3H), 4.01 (q, 2H, J 7.0 Hz),
5.09 (s, 1H), 6.64 (d, 1H, J 7.5 Hz), 6.68 (t, 2H, J 7.5 Hz), 7.10 (t, 1H, J 7.5 Hz), 7.66 (s, 1H), 9.12 (s, 1H), 9.37 (s,
1H). 13C NMR (DMSO-d6) δ(ppm): 14.0, 17.7, 53.8, 59.2, 99.5, 113.1, 114.2, 116.9, 129.2, 146.2, 147.9, 152.2,
157.3, 165.3.[1]
5-Ethoxycarbonyl-4-(3-methoxy-4-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (7o). Yellow
o
1
solid (0.266 g, 87%), m.p. 238-240 C. H NMR (DMSO-d6) δ(ppm): 1.10 (t, 3H, J 7.0 Hz), 2.21 (s, 3H), 3.70 (s,
1H), 3.98 (q, 2H, J 7.0 Hz), 5.04 (s, 1H), 6.59 (d, 1H, J 9.0 Hz), 6.68 (d, 1H, J = 10.5 Hz), 6.78 (s, 1H), 7.61 (s, 1H),
8.88 (s, 1H), 9.10 (s, 1H). 13C NMR (DMSO-d6) δ(ppm): 14.6, 18.2, 54.0, 56.1, 59.6, 100.1, 111.4, 115.8, 118.8,
136.4, 146.3, 147.7, 148.3, 152.7, 165.9.[1]
Supplementary Material
Spectral data and copies of spectra of compounds are provided in the supplementary material file available on
the Publisher’s web site.
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References
1. Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439.
https://doi.org/10.1021/cr800296p
2. Desai, N. C.; Trivedi, A. R.; Khedkar, V. M. Bioorg. Med. Chem. Lett. 2016, 26, 4030.
https://doi.org/10.1016/j.bmcl.2016.06.082
3. Xue, H.; Zhao, Y.; Wu, H.; Wang, Z.; Yang, B.; Wei, Y.; Wang, Z.; Tao, L. J. Am. Chem. Soc. 2016, 138, 8690.
https://doi.org/10.1021/jacs.6b04425
4. Ali, F.; Khan, K. M.; Salar, U.; Iqbal, S.; Taha, M.; Ismail, N. H.; Perveen, S.; Wadood, A.; Ghufran, M.; Ali, B.
Bioorg. Med. Chem. 2016, 24, 3624.
https://doi.org/10.1016/j.bmc.2016.06.002
5. Hang, Z.; Zhu, J.; Lian, X.; Xu, P.; Yu, H.; Han, S. Chem. Commun. 2016, 52, 80.
https://doi.org/10.1039/C5CC07880F
6. Li, P.; Regati, S.; Butcher, R. J.; Arman, H. D.; Chen, Z.; Xiang, S.; Chen, B.; Zhao, C. G. Tetrahedron Lett.
2011, 52, 6220.
https://doi.org/10.1016/j.tetlet.2011.09.099
7. Safari, J.; Gandomi-Ravandi, S. J. Iran. Chem. Soc. 2014, 12, 147.
https://doi.org/10.1007/s13738-014-0468-9
8. Khademinia, S.; Behzad, M.; Alemi, A.; Dolatyari, M.; Sajjadi, S. M. RSC Adv. 2015, 5, 71109.
https://doi.org/10.1039/C5RA11432B
9. Lin, J.; Abroshan, H.; Liu, C.; Zhu, M.; Li, G.; Haruta, M. J. Catal. 2015, 330, 354.
https://doi.org/10.1016/j.jcat.2015.07.020
10. Ren, X.; Yang, B.; Zhao, Y.; Zhang, X.; Wang, X.; Wei, Y.; Tao, L. Polymer 2015, 64, 210.
https://doi.org/10.1016/j.polymer.2015.02.033
11. Saikia, M.; Bhuyan, D.; Saikia, L. Appl. Catal. A: Gen. 2015, 505, 501.
https://doi.org/10.1016/j.apcata.2015.05.021
12. Dalil Heirati, S. Z.; Shirini, F.; Shojaei, A. F. RSC Adv. 2016, 6, 67072.
https://doi.org/10.1039/C6RA11201C
13. Pal, T. K.; De, D.; Senthilkumar, S.; Neogi, S.; Bharadwaj, P. K. Inorg. Chem. 2016, 55, 7835.
https://doi.org/10.1021/acs.inorgchem.6b00154
14. Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111, 3508.
https://doi.org/10.1021/cr1003248
15. Niedermeyer, H.; Hallett, J. P.; Villar-Garcia, I. J.; Hunt, P. A.; Welton, T. Chem. Soc. Rev. 2012, 41, 7780.
https://doi.org/10.1039/c2cs35177c
16. Martins, M. A.; Frizzo, C. P.; Tier, A. Z.; Moreira, D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2014, 114,
PR1.
https://doi.org/10.1021/cr500106x
17. Amarasekara, A. S. Chem. Rev. 2016, 116, 6133.
https://doi.org/10.1021/acs.chemrev.5b00763
18. Goossens, K.; Lava, K.; Bielawski, C. W.; Binnemans, K. Chem. Rev. 2016, 116, 4643.
https://doi.org/10.1021/cr400334b
19. Jiajian Peng; Deng, Y. Tetrahedron Lett. 2001, 42 5917.
https://doi.org/10.1016/S0040-4039(01)01139-X
20. Azizi, N.; Dezfuli, S.; Hahsemi, M. M. TheScientificWorldJournal 2012, 2012, 908702.
Page 9
©AUTHOR(S)

Arkivoc 2019, vi, 0-0
Hua, K. M. et al.
https://doi.org/10.1100/2012/908702
21. Safari, J.; Zarnegar, Z., New J. Chem. 2014, 38, 358.
https://doi.org/10.1039/C3NJ01065A
22. Zarnegar, Z.; Safari, J. J. Nanopart. Res. 2014, 16, 2509.
https://doi.org/10.1007/s11051-014-2509-9
23. Fu, R.; Yang, Y.; Ma, X.; Sun, Y.; Li, J.; Gao, H.; Hu, H.; Zeng, X.; Yi, J.Molecules 2017, 22, 1531
https://doi.org/10.3390/molecules22091531
24. Sharma, N.; Kumar Sharma, U.; Kumar, R.; Richa; Kumar Sinha, A.RSC Adv. 2012, 2, 10648.
https://doi.org/10.1039/c2ra22037g
25. Singh, V.; Kaur, S.; Ratti, R.; Kad, G. L.; Singh, J. Indian J. Chem. B 2010, 49B, 611.
26. Arfan, A.; Paquin, L.; Bazureau, J. P. Russian J. Org. Chem. 2007, 43, 1058.
https://doi.org/10.1134/S1070428007070202
27. Kappe, C. O. Angew Chem. Int. Ed. Engl. 2013, 52, 7924.
https://doi.org/10.1002/anie.201304368
28. Kappe, C. O.; Dallinger, D. Mol. Divers. 2009, 13, 71.
https://doi.org/10.1007/s11030-009-9138-8
29. Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794.
https://doi.org/10.1039/c0gc00823k
30. Zbancioc, G.; Mangalagiu, II; Moldoveanu, C. Ultrason. Sonochem. 2015, 23, 376.
https://doi.org/10.1016/j.ultsonch.2014.10.028
31. Zbancioc, G.; Zbancioc, A. M.; Mangalagiu, II. Ultrason. Sonochem. 2014, 21, 802.
https://doi.org/10.1016/j.ultsonch.2013.09.012
32. Gaudino, E. C.; Tagliapietra, S.; Mantegna, S.; Cravotto, G. Chem. Heterocycl. Com. 2017, 52, 856.
https://doi.org/10.1007/s10593-017-1979-y
33. Wu, Z.; Borretto, E.; Medlock, J.; Bonrath, W.; Cravotto, G. ChemCatChem 2014, 6, 2762.
https://doi.org/10.1002/cctc.201402221
34. Li, J.; Lin, S.; Dai, J.; Su, W. J. Chem. Res. 2010, 34, 196.
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©AUTHOR(S)