Phenylphosphinic acid-catalyzed synthesis of 6-unsubstituted dihydropyrimidinones under solvent-free conditions

Article abstract of DOI:10.1002/hc.21327

Phenylphosphinic acid is found to catalyze the three-component condensation of an aldehyde, enaminone, and urea or thiourea to afford the corresponding 6-unsubstituted dihydropyrimidinones in high to excellent yields. This methodology is simple and fast s

Full text of DOI:10.1002/hc.21327

Received: 15 October 2015
DOI: 10.1002/hc.21327
Revised: 26 May 2016
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S H O R T C O M M U N I C AT I O N
Phenylphosphinic acid-catalyzed synthesis of 6-unsubstituted
dihydropyrimidinones under solvent-free conditions
Heshmatollah Alinezhad1
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Mahmood Tajbakhsh1
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Mahboobeh Zare2
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Mahboobeh Mousavi1
1Department of Organic Chemistry, Faculty of
Chemistry, University of Mazandaran, Babolsar,
Iran
2Department of Basic Science, Faculty of
Science and Herbs, Amol University of Special
Modern Technologies, Amol, Iran
Abstract
Phenylphosphinic acid is found to catalyze the three-component condensation of an
aldehyde, enaminone, and urea or thiourea to afford the corresponding 6-unsubstituted
dihydropyrimidinones in high to excellent yields. This methodology is simple and
fast synthetic route for the preparation of interesting class of heterocycles.
Correspondence
Heshmatollah Alinezhad, Department of
Organic Chemistry, Faculty of Chemistry,
University of Mazandaran, Babolsar, Iran.
E-mail: heshmat@umz.ac.ir.
For these reasons, we decided to pursue solvent-less
synthesis of 6-unsubstituted dihydropyrimidinones from
aldehydes, enaminones, and ureas/thiourea in the presence
1
INTRODUCTION
|
Dihydropyrimidinones (DHPMs) have been the subject of
chemical and biological studies[1] due to their wide spec-
trum of biological and therapeutic properties including anti-
inflammatory,[2] anticancer,[3] and calcium channel blocker.[4]
One of the most common procedures for the synthesis of
dihydropyrimidinones was reported by Biginelli using three-
component reaction of aromatic aldehydes, β-ketoesters, and
urea.[5] Recently, several improved protocols for the synthe-
sis of dihydropyrimidinones have been reported by modifi-
cation of classical Biginelli reaction using new catalysts,[6]
ionic liquids,[7] and microwave[8] and ultrasound irradiation[9]
and extending its substrate scope.[10] Enaminones are highly
reactive building blocks in the synthesis of heterocyclic com-
pounds.[11] In the last decade, Wan[12] and co-workers devel-
oped a protocol for the synthesis of 6-unsubstituted DHPMs
by employing enaminone as the active methylene donor,
aldehyde and urea/thiourea. However, few studies have used
enaminones as a substrate,[13–16] which lead to large number
of multifunctionalized pyrimidinones. Using organic solvents
and excess amount of catalyst, moderate yields and long reac-
tion time have been described in most cases. Organocatalysis
is an important area of research in recent years because they
are usually robust, inexpensive, readily available, low toxic,
and high tolerance to molecular oxygen and traces of water.[17]
Reactions which are carried out in solvent-free conditions are
often rapid, regio- or chemoselective with high yields, and
have environmental and economic advantages.[18]
of phenylphosphinic acid as an organocatalyst. The results
obtained in this investigation are reported herein (Scheme 1).
2
RESULTS AND DISCUSSION
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In this study, we initially optimized the reaction conditions
using 4-nitrobenzaldehyde (1 mmol), phenyl enaminone
(1 mmol), and urea (1.2 mmol) as model substrates under
solvent-free conditions (Table 1). As it is clear from this
table, the best result was obtained when the reaction was car-
ried out in the presence of 5 mol% of phenylphosphinic acid
at 120°C (Table 1, entry 6).
In order to show the generality of this reaction, we syn-
thesized different 6-unsubstituted DHPMs using variety
of aldehydes with enaminones and ureas or thiourea under
solvent-free conditions (Table 2). As shown in Table 2, vari-
ous aromatic aldehydes bearing electron-withdrawing groups
and electron-donating groups reacted with enaminones and
urea in the presence of phenylphosphinic acid under solvent-
free conditions at 120°C to give 6-unsubstituted DHPMs in
excellent yields (Table 2, entries 2–14). This reaction was
also successfully performed with N-substituted urea. 4-(4-
Nitrophenyl)-5-phenylmethanone-yl-3,4-dihydropyrimidin-
2(1H) was isolated in high yield when N-methyl urea, phe-
nyl enaminone, and 4-nitro benzaldehyde were employed
(Table 2, entry 15). However, aliphatic aldehydes, such as
isobutyraldehyde, resulted in a very low product yield of 15%
Contract grant sponsor: Research Council University of Mazandaran.
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Heteroatom Chemistry 2016; 1–5
wileyonlinelibrary.com/journal/hc
© 2016 Wiley Periodicals, Inc.
1

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AlinezhAd et Al.
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O
4
EXPERIMENTAL
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R1
H
X
O
R3
P H
OH
R1
NH
Materials were purchased from Fluka and Merck companies.
Enaminones were prepared according to the reported proce-
dure.[19] Products were characterized by comparison of their
N
H
NH2
O
O
N
R2
R2
spectroscopic data (IR, H NMR, 13C NMR, and MS) and
1
Solvent free
1200C
N
X
R3
R1= Aryl
R2= Aryl
X= O, S
physical properties with those of authentic samples.
R3= H, Me
General procedure for the synthesis of DHPMs 4a–v.
Aldehyde (1 mmol), enaminone (1 mmol), and urea or
thiourea (1.2 mmol) were ground with phenylphosphinic
acid (5 mol%) in a pestle mortar at 120°C under solvent-free
conditions for 20 min. The reaction mixture was then cooled
to room temperature and water (5 mL) was added to the mix-
ture. The catalyst was dissolved in water and filtered for sep-
aration of the crude product. The residue was washed twice
with 5 mL of water. Then, product was purified by recrystal-
lization procedure in EtOH/H2O.
SCHEME 1 Solvent-less synthesis of 6-unsubstituted
dihydropyrimidinones
(Table 2, entries 16). The investigation of this method indi-
cated that reaction of thiourea with aromatic aldehydes and
various enaminones afforded corresponding thio-derivatives
of dihydropyrimidinones under optimum reaction conditions
(Table 2, entries 16–22).
Mechanistically,[11] the reaction may be done via N-
acyliminium ion formation by acid-catalyzed condensation
of aldehyde and urea. Subsequently, addition of the enam-
inone to this iminium followed by condensation affords
6-unsubstituted DHPM (Scheme 2).
4.1
Spectral data for unknown
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products are as follows
4-(4-Cyanophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4f). IR νmax 905, 1157, 1214,
1
1375, 1446, 1611, 1655, 1695, 2229, 3330, 3211. H NMR
(DMSO–d6, 400 MHz): δ 5.50 (d, 1H, J = 2.8 Hz), 7.07 (d,
1H, J = 6 Hz), 7.43–7.55 (m, 7H), 7.84 (d, 2H, J = 8.4 Hz),
7.99 (s, 1H), 9.48 (d, 1H, J = 5.2 Hz). 13C NMR (DMSO–d6,
100 MHz): δ 53.7, 110.7, 111.8, 119.1, 128.0, 128.5, 131.5,
133.1, 138.7, 142.9, 149.6, 151.4, 191.9. ESI-MS: m/z 303.1
([M]+).
3
CONCLUSIONS
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In summary, we have developed simple, efficient, and environ-
mentallyfriendlyapproachforthepreparationof6-unsubstituted
DHPMs by three-component cyclocondensation of various
aldehydes, enaminones, and thiourea or substituted- and unsub-
stituted urea in the presence of phenylphosphinic acid as an
organocatalyst. The reactions are solvent less, fast, and the
yields of the products are excellent in most cases.
4-(2-Iodophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4g). IR νmax 1075, 1155, 1214,
1
1368, 1441, 1620, 1656, 1702, 2929, 3224, 3401. H NMR
TABLE 1 Optimization reaction conditions for the synthesis of dihydropyrimidinones
NO2
O
O
O
O
NH
H
Phenylphosphinic acid
N
N
H
O
H2N
NH2
O2N
1
3
2
4d
Entry
Mol% of catalyst
Temperature (°C)
Time (min)
Yield (%)a
1
2
3
4
5
6
5
5
80
100
120
120
120
120
20
20
20
20
20
20
55
80
97
90
88
40
5
10
3
-
aYields refer to isolated products.

AlinezhAd et Al.
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TABLE 2 Synthesis of 6-unsubstituted dihydropyrimidinones in the presence of phenylphosphinic acida
R1
O
O
X
O
NH
R2
Phenylphosphinic acid
Solvent free
R3
N
R2
N
X
R1
N
H
NH2
H
R3
3
1
2
4
Entry
R1
C6H5
R2
X/R3
Product
Yield (%)b
M.p. °C[ref]
1
H
H
H
H
H
H
H
H
H
H
H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/H
O/Me
O/H
S/H
S/H
S/H
S/H
S/H
S/H
S/H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
93
91
90
97
94
97
91
92
90
95
92
95
93
94
83
15
91
89
87
92
90
93
90
282–284[13]
232–234[12]
229–231[12]
251–253[12]
286–288[12]
264–265
2
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
3-O2N C6H4
4-NCC6H4
2-IC6H4
3
4
5
6
7
202–205
8
4-BrC6H4
255–257
9
3-MeOC6H4
4-ClC6H4
175–177
10
11
12
13
14
15
15c
16
17
18
19
20
21
22
257–260
2-Cl, 5-O2NC6H3
4-NC6H4
201–202
4-NO2
4-NO2
4-NO2
H
166–168
3-MeOC6H4
4-O2NC6H4
4-O2NC6H4
(CH3)2CHCH2
C6H5
238–240
195–198
223–225[12]
232–234[12]
278–280[12]
279–281[12]
266–268[12]
269–271[12]
283–285[12]
235–238
H
H
4-MeC6H4
4-MeOC6H4
4-ClC6H4
H
H
H
4t
4-BrC6H4
H
4u
4v
4x
2-Cl, 5-NO2C6H3
4-Me C6H4
H
NO2
235–237[12]
aReactions were performed using benzaldehydes (1 mmol), enaminones (1 mmol), ureas/thiourea (1.2 mmol), and phenylphosphinic acid (5 mol%) at 120°C for 20 min
without solvent.
bYields refer to isolated products.
cReaction was performed for 120 min.
(DMSO–d6, 400 MHz): δ 5.71 (d, 1H, J = 1.6 Hz), 7.01–
7.08 (m, 2H), 7.40–7.53 (m, 7H), 7.79 (s, 1H), 7.83 (d, 1H,
J = 7.6 Hz), 9.42 (d, 1H, J = 4.4). 13C NMR (DMSO–d6,
100 MHz): δ 59.3, 99.7, 112.4, 128.5, 128.8, 129.2, 129.5,
130.0, 131.4, 138.9, 139.8, 142.6, 145.8, 150.8, 191.7. ESI-
MS: m/z 403.0 ([M-1]+).
4-(4-Bromophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4h). IR νmax 905, 1153, 1202,
1370, 1485, 1574, 1613, 1654, 1700, 2924, 3280. 1H NMR
(DMSO–d6, 400 MHz): δ 5.41 (d, 1H, J = 2.4 Hz), 7.03
(d, 1H, J = 6 Hz), 7.29 (d, 2H, J = 8.4 Hz), 7.43–7.53 (m,
5H), 7.54 (d, 2H, J = 8.4 Hz), 7.92 (s, 1H), 9.41 (d, 1H,
J = 4.8 Hz). 13C NMR (DMSO–d6, 100 MHz): δ 53.3,
112.4, 120.9, 128.4, 128.8, 129.2, 131.4, 131.8, 138.8,
142.3, 142.4, 143.8, 151.4, 191.9. ESI-MS: m/z 356.1
([M]+).
4-(3-Methoxyphenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4i). IR νmax 899, 1153, 1201,
1
1254, 1371, 1452, 1489, 1608, 1651, 1702, 2927, 3275. H
NMR (DMSO–d6, 400 MHz): δ 3.74 (s, 3H), 5.41 (d, 1H,
J = 2.4 Hz), 6.84 (d, 1H, J = 8.0 Hz), 6.88 (s, 1H), 6.91
(d, 1H, J = 7.6 Hz), 7.03 (t, 1H, J = 2.8 Hz), 7.28 (t, 1H,
J = 7.6 Hz), 7.44–7.55 (m, 5H), 7.88 (s, 1H), 9.34 (d, 1H,
J = 5.2 Hz). 13C NMR (DMSO–d6, 100 MHz): δ 53.5, 55.4,
112.7, 112.8, 112.9, 118.8, 128.4, 128.8, 130.1, 131.4, 138.9,
142.2, 145.9, 151.7, 159.7, 192.0. ESI-MS: m/z 308.2 ([M]+).
4-(4-Chlorophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4j). IR νmax 906, 1204, 1247,
1325, 1370, 1446, 1488, 1616, 1654, 1698, 2925, 3127, 3274.
1H NMR (DMSO–d6, 400 MHz): δ 5.43 (s, 1H), 7.03 (t, 1H,
J = 2.8 Hz), 7.35–7.53 (m, 9H), 7.91 (s, 1H), 9.40 (d, 1H,
J = 4.8 Hz). 13C NMR (DMSO–d6, 100 MHz): δ 53.3, 112.4,

4
AlinezhAd et Al.
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O
N
Ar
H+
OH
N
Ar
X
H
O
N
Ar
H+
O
X
H
O
N
Ar
H
H
-H+
NH
NH2
N
Ar
H N NH2
Ar
+
2
NH
Ar
Ar
X
H2N
X= O or S
X
H2N
O HAr
O
Ar
NH
NH
Ar
SCHEME 2 Plausible mechanism
for the synthesis of 6-unsubstituted
dihydropyrimidinone derivatives
-NH(Me)2
Ar
X
N
N
H
N
H
X
128.4, 128.8, 128.9, 131.4, 132.4, 138.9, 142.2, 142.4, 143.4,
151.4, 151.5, 191.9. ESI-MS: m/z 312.0 ([M]+).
1217, 1348, 1422, 1521, 1599, 1631, 1700, 1796, 1868, 2923,
3394, 3568. 1H NMR (DMSO–d6, 400 MHz): δ 5.56 (d, 1H,
J = 3.2 Hz), 7.13 (d, 1H, J = 6.4 Hz), 7.62 (d, 2H, J = 8.8 Hz),
7.71 (d, 2H, J = 8.8 Hz), 8.12 (s, 1H), 8.23–8.29 (m, 4H), 9.77
(d, 1H, J = 4.8 Hz). 13C NMR (DMSO–d6, 100 MHz): δ 53.4,
111.6, 124.0, 124.3, 124.6, 128.3, 129.6, 129.7, 144.5, 147.4,
151.1, 151.3, 190.3. ESI-MS: m/z 368.0 ([M]+).
4-(2-Chloro-5-nitrophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4k). IR νmax 742, 833, 910,
1049, 1132, 1156, 1219, 1251, 1346, 1445, 1525, 1616, 1657,
1701, 2925, 3308, 3411. 1H NMR (DMSO–d6, 400 MHz): δ
5.93 (d, 1H, J = 2.4 Hz), 7.16 (s, 1H), 7.46–7.56 (m, 5H),
7.76 (d, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 2.8 Hz), 8.15 (d,
1H, J = 2.8 Hz), 8.21 (d, 1H, J = 2.8 Hz), 9.51 (s, 1H). 13C
NMR (DMSO–d6, 100 MHz): δ 52.9, 110.4, 124.4, 128.5,
128.8, 131.5, 138.6, 139.5, 142.7, 143.5, 147.0, 150.7, 191.7.
ESI-MS: m/z 359.1 ([M + 2]+).
4-(2-Chloro-5-nitrophenyl)-5-phenylmethanone-yl-3,4-
dihydropyrimidin-2(1H)-thione (4v). IR νmax 736, 827, 932,
1050, 1135, 1203, 1256, 1345, 1472, 1525, 1560, 1634, 1664,
1
3088, 3169, 3351. H NMR (DMSO–d6, 400 MHz): δ 5.96
(s, 1H), 6.96 (d, 1H, J = 5.2 Hz), 7.45–7.55 (m, 5H), 7.79 (d,
1H, J = 8.8 Hz), 8.17 (d, 1H, J = 8.8 Hz), 8.21 (s, 1H), 9.82
(s, 1H), 10.67 (d, 1H, J = 4.4 Hz). 13C NMR (DMSO–d6,
100 MHz): δ 53.0, 111.6, 124.7, 125.3, 128.6, 128.9, 131.8,
131.9, 138.1, 138.9, 139.7, 141.7, 147.0, 174.2, 191.9. ESI-
MS: m/z 373.0 ([M]+).
4-(4-Cyanophenyl)-5-(4-nitrophenyl)-methanone-yl-
3,4-dihydropyrimidin-2(1H)-one (4l). IR νmax 852, 913,
1216, 1318, 1349, 1434, 1522, 1559, 1601, 1630, 1700,
1
2230, 2925, 3368. H NMR (DMSO–d6, 400 MHz): δ 5.51
(d, 1H, J = 2.8 Hz), 7.54 (d, 2H, J = 6.4 Hz), 7.71 (d, 2H,
J = 8.8 Hz), 7.84 (d, 2H, J = 8.4 Hz), 8.07 (s, 1H), 8.25 (d
2H, (d, 1H, J = 8.8 Hz), 9.74 (d, 1H, J = 5.2 Hz). 13C NMR
(DMSO–d6, 100 MHz): δ 53.6, 110.8, 119.1, 124.05, 128.05,
129.7, 133.1, 144.50, 144.55, 149.0, 149.4, 151.2, 190.3.
ESI-MS: m/z 348.1 ([M]+).
ACKNOWLEDGMENT
Financial support by the Research Council University of
Mazandaran is acknowledged.
4-(3-Methoxyphenyl)-5-(4-nitrophenyl)-methanone-yl-
3,4-dihydropyrimidin-2(1H)-one (4m). IR νmax 851, 926,
1155, 1253, 1321, 1349, 1489, 1523, 1615, 1670, 1701,
REFERENCES
1
2936, 3105, 3282. H NMR (DMSO–d6, 400 MHz): δ 3.38
[1] a) J. P. Wan, Y. Pan, Mini Rev. Med. Chem. 2012, 12, 337; b) J. P. Wan, Y.
Liu, Synthesis 2010, 23, 3943.
[2] Y. S. Sadanandam, M. M. Shetty, P. V. Diwan, Eur. J. Med. Chem. 1992, 27,
87.
[3] A. Matsuda, H. Hattori, M. Tanaka, T. Sasaki, Bioorg. Med. Chem. Lett.
1996, 6, 1887.
[4] G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, D. J. Dimarco, J.
Gougoutas, A. Hedberg, M. Malley, J. P. Mccarthy, R. Zhang, S. Mareland,
J. Med. Chem. 1995, 38, 119.
(s, 3H), 5.40 (d, 1H, J = 2.8 Hz), 6.84–6.89 (m, 2H), 6.92 (d,
1H, J = 7.6 Hz), 7.07 (d, 1H, J = 5.6 Hz), 7.28 (t, 1H), 7.71
(d, 2H, J = 8.4 Hz), 7.96 (s, 1H), 8.27 (d, 2H, J = 8.8 Hz),
9.60 (d, 1H, J = 5.2 Hz). 13C NMR (DMSO–d6, 100 MHz): δ
53.4, 55.4, 112.5, 112.9, 118.8, 124.0, 129.71, 129.75, 130.2,
143.9, 144.7, 145.7, 148.9, 151.5, 159.8, 190.3. ESI-MS: m/z
353.2 ([M]+).
[5] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
[6] a) G. Shao, Chin. J. Synth. Chem. 2004, 12, 325; b) A. Lengar, C. O. Kappe,
Org. Lett. 2004, 6, 771.
4-(4-Nitrophenyl)-5-(4-nitrophenyl)-methanone-yl-3,4-
dihydropyrimidin-2(1H)-one (4n). IR νmax 421, 743, 854, 1110,

AlinezhAd et Al.
5
|
[7] A. V. Narsaiah, A. K. Basak, K. Nagaiah, Synthesis 2004, 8, 1253.
[8] J. Wannberg, D. Dallinger, C. O. Kappe, M. Larhed, J. Comb. Chem., Perkin
Trans. 2005, 7, 574.
[9] J. S. Yadav, B. V. S. Reddy, K. B. Reddy, S. R. Kavuda, R. P. Attaluri, J.
Chem. Soc. 1939, 2001, 1.
[10] a) M. A. Kolosov, V. D. Orlov, Zh. Org. Farm. Khim. 2005, 3, 17; b) C. D.
Bailey, C. E. Houlden, G. L. J. Bar, G. C. Lloyd-JonesK. I. Booker-Milburn.
Chem. Commun. 2007, 28, 2932.
[12] J. P. Wan, Y. J. Pan, Chem. Commun. 2009, 19, 2768.
[13] E. S. Darwish, I. A. Abdelhamid, M. A. Nasra, F. M. Abdel-Gallil, D. H.
Fleita, Helv. Chim. Acta 2010, 93, 1204.
[14] S. M. Al-Mousawi, M. A. El-Apasery, M. H. Elnagdi, Molecules 2010, 15, 58.
[15] H. M. E. Hassaneen, I. A. Abdelhamid, Curr. Org. Synth. 2013, 10, 974.
[16] J. Wan, C. Wang, Y. Pan, Tetrahedron 2011, 67, 922.
[17] D. L. Silva, S. A. Fernandes, A. A. Sabino, A. Fatima, Tetrahedron Lett.
2011, 52, 6328.
[11] a) J. P. Wan, Y. Zhou, S. Cao, J. Org. Chem. 2014, 79, 9872; b) J. P. Wan,
S. Zhong, Y. Liu, Synthesis 2015, 47, 3611; c) J. P. Wan, S. Cao, Y. Liu, J.
Org. Chem. 2015, 80, 9028; d) J. P. Wan, Y. Zhou, Y. Liu, S. Sheng, Green
Chem. 2016, 18, 402.
[18] H. Alinezhad, M. Tajbakhsh, M. Zare, Monatsh. Chem. 2012, 143, 947.
[19] Y. Sun, A. Hienzsch, J. Grasser, E. Herdtweck, W. R. J. Thiel, Organomet.
Chem. 2006, 691, 291.