PEG-OSO3H as an efficient catalyst in the synthesis of n3-functionalized 3.4-dihydropyrimidinone and quinazolinone derivatives

Article abstract of DOI:10.3987/COM-17-13659

PEG-OSO₃H-catalyzed three-component reaction of 3,4-dihydropyrimidones and quinazolinone with paraformaldehyde and various reagents for synthesis of N3-functionalized 3,4-dihydropyrimidone and quinazolinone derivatives is described. 2-Hydroxy-s

Full text of DOI:10.3987/COM-17-13659

HETEROCYCLES, Vol. 94, No. 6, 2017
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HETEROCYCLES, Vol. 94, No. 6, 2017, pp. 1027 - 1039. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 24th January, 2017, Accepted, 27th April, 2017, Published online, 8th May, 2017
DOI: 10.3987/COM-17-13659
PEG-OSO3H AS AN EFFICIENT CATALYST IN THE SYNTHESIS OF
N3-FUNCTIONALIZED
3.4-DIHYDROPYRIMIDINONE
AND
QUINAZOLINONE DERIVATIVES
Liang-Jie Yang, 1,2 Jin-Ge Luo, 2 and Xi-Cun Wang 2*
1
School of Resource and Environmental Science, Key Laboratory of Western
China's Environmental Systems, Lanzhou University, Lanzhou 730000, China
2
Laboratory of Eco-Environment-Related Polymer Materials, Ministry of
Education, Gansu Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu
730070, People’s Republic of China. E-mail: wangxicun@nwnu.edu.cn
Abstract
–
PEG-OSO3H-catalyzed
three-component
reaction
of
3,4-dihydropyrimidones and quinazolinone with paraformaldehyde and various
reagents for synthesis of N3-functionalized 3,4-dihydropyrimidone and
quinazolinone
derivatives
is
reacts
described.
with
2-Hydroxy-substituted
aldehydes giving
3,4-dihydropyrimidone
benzo[e]pyrimido[1,6-c][1,3]oxazines. This paper explores the versatility and
effectiveness of polymer bound sulfonic acids as catalysts in different C-N and
C-O bonds formation reactions. The reactions were completed in short times, and
the products were obtained in good to excellent yields. The catalysts activity and
recyclability were investigated completely.
INTRODUCTION
3,4-Dihydropyrimidinones (DHPMs) and their derivatives are central subunits in a broad range of
medicinal agents, which display interesting pharmacological and biological activities, such as calcium
channel modulators, α1a adrenergic agonists, mitotic kinesin inhibitors, and hepatitis B virus replication
inhibitors.1-7 Among DHPM derivatives, most of the pharmacologically attractive forms are
N3-substituted analogues.8 The N-alkylation of dihydropyrimidin-2-ones is one way of functionalizing the
ring to achieve important bioactive properties. Most N-alkylated pyrimidin-2-ones are obtained from SN2
displacement of an electrophile with the pyrimidine reacting as the nucleophile.9 In 2010, we examined

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HETEROCYCLES, Vol. 94, No. 6, 2017
chlorotrimethylsilane (TMSCl) mediated reactions between DHPM with paraformaldehyde and various
reagents for the preparation of N3-functionalized DHPMs.10 These reactions were performed in one-pot
two-step procedures by treatment of DHPMs with paraformaldehyde and chlorotrimethylsilane (TMSCl),
followed by reactions with substituted alcohols, benzoic acids, and acetic acid, respectively. We became
interested in whether these reactions were possible in one-step reaction from DHPM with
paraformaldehyde and alcohols using acid catalyst.
PEGs are soluble in many, mostly polar solvents (including water) and insoluble in a few nonpolar solvents
(hexanes, diethyl ether, tert-butyl methyl ether). Because of this solubility profile, PEG and its derivatives
are considered as ideal supports. In addition, it also combines the advantageous features of homogeneous
catalysis such as high reactivity, lack of diffusion phenomena and analytical simplicity.11 We previously
reported the preparation and utilization of polyethylene glycol (PEG)-bound sulfonic acid (PEG-OSO3H)
and polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported sulfonic acid in the Biginelli, Mannich,
Beckmann rearrangement, multicomponent reactions and conversion of carbohydrates into
5-hydroxymethylfurfural.12-15 Recently, the PEG-OSO3H has been used in several organic
transformations.16-23
In this paper, we wish to report a one-step procedure for N3 functionalized 3,4-dihydropyrimidinone
derivatives and benzo[e]pyrimido[1,6-c][1,3]oxazines by
a
selective reaction between
3,4-dihydropyrimidinones, aldehydes, and nucleophiles (such as alcohols, sodium azide, phenol and
4-methylbenzenethiol) using PEG-OSO3H as catalyst.
RESULTS AND DISCUSSION
Initially, we chose the reaction of DHPM 1a, paraformaldehyde and EtOH as a typical reaction to optimize
the reaction conditions (Scheme 1). An extensive investigation of arrange of solvents was carried out. The
reaction between 1a (1 mmol), paraformaldehyde (4 mmol) and EtOH (3 mL) using PEG-OSO3H (0.6 g,
0.2 mmol) as catalyst could occur in DMF, MeCN, 1,4-dioxane, THF, toluene and dichloromethane to give
2a respectively in yield of 58%, 60%, 65%, 68%, 74% and 78%. Interestingly, the yield of 2a (86%) was
obtained when ethanol itself as the solvent. Lower yields were obtained when the load of catalyst was
reduced, such as 0.3 g (0.1 mmol) of catalyst yielding the product 2a in 61%. Subsequently, we screened
different temperatures and found that the temperature has a significant effect on the yield of the reaction. At
room temperature, the product 2a was not detected and at 60 oC, low yield (63%) of 2a was obtained even
the reaction time was prolonged to 24 h. Thus, we decided to use 1 mmol of 1a, 4 equiv of
o
paraformaldehyde and PEG-OSO3H (0.6 g, 0.2 mmol) in EtOH (3 mL) at 80 C as the optimal reaction
conditions for the preparation of N3-ethoxymethyl DHPM. To evaluate the usefulness of PEG-SO3H, the
comparison experiments using TMSCl, H2SO4, TsOH, phosphowolframic acid and phosphomolybdic acid

HETEROCYCLES, Vol. 94, No. 6, 2017
1029
as a catalyst instead of PEG-OSO3H by a one-step protocol were carried out. TMSCl, H2SO4, HClꢀꢁTsOH,
phosphowolframic acid and phosphomolybdic acid could catalyze the reaction albeit in a lower efficacy
resulted the product 2a in yield of 25%, 35%, 26%, 40% and 45%, respectively. Finally, the
silica-supported sulfonic acid was also applied as catalyst and 75% yield of 2a was obtained. These
indicated that PEG-OSO3H with mild acidity acts simultaneously as an acid catalyst and as a
catalyst promoting the release of formaldehyde from paraformaldehyde and subsequently capturing the
released formaldehyde.
Scheme 1. Three-component reaction of DHPM 1a, paraformaldehyde and EtOH
With these results in hand we then explored the scope and generality of present three-component reaction
using PEG-OSO3H as catalyst (Table 1). Firstly, we investigated other alcohols, such as methanol,
propanol, isopropanol, n-butyl alcohol and tert-butyl alcohol as a nucleophile and the corresponding
N3-alkyloxymethyl DHPMs were obtained (Table 1, entries 2-8). In general, N3-substituted DHPMs were
generated with primary, secondary and tertiary aliphatic alcohol substrates. In fact, when using tert-butyl
alcohol as a nucleophile substrate, a lower yield of product 2f resulted (entry 6). Sulfur-containing
analogues of DHPMs 1 also exhibited a good reactivity yielding the desired products (entries 9-10).
Consistent with previous studies, replacing alcohol with 4-methylbenzenethiol or 4-methoxyphenol
allowed the reactions to proceed smoothly and afforded the desired products in high yields (entries 11-12).
1
The products’ H NMR and 13C NMR data were identical to those reported in the literature.10
Subsequently, we expanded the nuleophiles of this one-pot reaction such as acetic acid, sodium acetate,
benzoic acid, morpholine, sodium benzenesulfinate and sodium azide. However, no products were
detected except for a lower yield of an azido group at the N3 position of pyrimidone ring. However, some
limitations were noted in case of aryl aldehydes, which were unreactive in this reaction instead of
paraformaldehyde.
Table 1. Synthesis of DHPM derivatives catalyzed by PEG-OSO3H

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HETEROCYCLES, Vol. 94, No. 6, 2017
Entry
Ar
X
O
O
O
O
O
O
O
O
S
RXH
Product
2a
Isolated Yield (%)
1
Ph
EtOH
86
78
76
69
72
61
88
83
78
76
83
80
2
Ph
MeOH
PrOH
2b
2c
3
Ph
4
Ph
i-PrOH
n-BuOH
t-BuOH
EtOH
2d
2e
5
Ph
6
Ph
2f
7
4-MeO-Ph
2g
8
4-Cl-Ph
Ph
EtOH
2h
2i
9
PrOH
10
11
Ph
S
i-PrOH
2j
Ph
O
O
2k
2l
12
Ph
a
Conditions: DHPMs (1 mmol), (CH2O)n (4 mmol), alcohol (3 mL), PEG-OSO3H (0.6 g, 0.2 mmol), 80
oC, 8 h.
These promising results promoted us to apply this reaction to other more complicated substrate
quinazolinones and their sulfur-containing analogues. To our delight, substrates 3 were also able to
transform into the corresponding products 4 in good yields (Table 2, entries 1-7).
Table 2. Synthesis of quinazolinone derivatives catalyzed by PEG-OSO3H
Entry
1
Ar
Ph
X
O
R
Product
Yield/%
83
Et
4a
2
3
4
5
Ph
Ph
Ph
Ph
O
S
S
S
Pr
78
85
81
76
4b
4c
4d
4e
Et
Pr
i-Pr

HETEROCYCLES, Vol. 94, No. 6, 2017
1031
6
7
4-MeO-Ph
4-Cl-Ph
S
S
Et
Et
86
76
4f
4g
a Conditions: quinazlinones (1 mmol), (CH2O)n (4 mmol), ROH (3 mL), PEG-OSO3H (0.6 g, 0.2 mmol),
80 oC, 8 h.
Based on these results, the reactions between DHPM substituted with 2-hydroxy on the aromatic ring and
propionaldehyde, butyraldehyde, 3-methylbutanal were examined, and to our delight, the reactions gave
the cyclized product 3,4,6,11b-tetrahydrobenzo[e]pyrimido[1,6-c][1,3]oxazines (7a, 7b, 7c) with high
yields (Scheme 2).
Scheme 2. Reaction of 2-hydroxy-substituted DHPM with aliphatic aldehydes
We finally turn to test the aliphatic aldehydes instead of paraformaldehyde in the three-component
reaction. The reaction between 3,4-dihydropyrimidinone (1a), isobutyraldehyde (5d) and methanol in
THF at 60 °C was tested using PEG-OSO3H as the catalyst. To our great surprise, no any
three-component product was detected and after purification of the reaction mixture, a
dehydration-isomerization product N3-(2-methylprop-1-en-1-yl) substituted product 8 was isolated in
70% yield (Scheme 3).
Scheme 3. The reaction of 3,4-dihydropyrimidinone with isobutyraldehyde
In order to check the recyclability of the catalyst, the reaction for 2a was tested. The yields of 2a were
80%, 80%, 76%, 70, 65% and 30% in the second to sixth reuses, respectively. At the end of the reaction,
the resulting mixture was cooled, quenched to ice water and filtrated, and then the solution was extracted
with dichloromethane (3×10 mL). The white PEG-OSO3H catalyst can be obtained by adding cooled
anhydrous ether into the concentrated organic phase. The recovered catalyst can be used directly in the
next run.

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HETEROCYCLES, Vol. 94, No. 6, 2017
CONCLUSIONS
In conclusion, we have developed novel and efficient synthetic methods to prepare N3-functionalized
DHPMs, and benzo[e]pyrimido[1,6-c][1,3]oxazines by the selectivity reactions between DHPMs,
aldehydes with alcohols, 4-methoxyphenol and 4-methylbenzenethiol using PEG-OSO3H as inexpensive,
and reusable catalysts. Moreover, the simplicity and higher efficiency make this method particularly
attractive.
EXPERIMENTAL
Melting points were determined on an XT-4 electrothermal micromelting point apparatus and the
thermometer was uncorrected. NMR spectra were recorded at 400 (1H) and 100 (13C) MHz, respectively,
on a Varian Mercury plus-400 instrument using CDCl3 as solvent and TMS as internal standard.
Mass-spectra were recorded on a TRACE DSQ instrument. All commercially available substrates were
used as received. TLC was performed on 5×10cm aluminum plates coated with silica gel 60F-254 in an
appropriate solvent. All reagents were obtained commercially and used without further purification.
PEG-OSO3H were prepared according to our previous procedures.12
General procedure for the preparation of compounds 2 and 4 using PEG-OSO3H as catalyst
A mixture of 3,4-dihydropyrimidinone 1 (1 mmol), paraformaldehyde (4 mmol) and PEG-OSO3H (0.6 g,
0.2 mmol–SO3H) in EtOH (5.0 mL) was stirred at 80 oC for 8 h. After completion monitored by TLC, the
resulting mixture was cooled and quenched to ice water. Then the precipitation was filtered off and
purified by silica gel column chromatography eluted with EtOAc/petroleum ether (1:5) to afford the pure
product.
Ethyl
1-(ethoxymethyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate
(2a).10a White solid; mp 165-167 oC; 1H NMR (400 MHz, CDCl3) δ 8.47 (br s, 1H, NH), 7.39-7.26 (m, 5H,
HAr ), 5.50 (s, 1H, 4-CH), 5.23 (d, J = 10.8 Hz, 1H, NCHH), 4.39 (d, J = 10.4 Hz, 1H, NCHH), 4.14-4.06
(m, 2H, OCH2CH3), 3.62-3.55 (m, 1H, OCH2CH3), 3.46-3.39 (m, 1H, OCH2CH3), 2.36 (s, 3H, 6-CH3),
1.26-1.19 (m, 3H, OCH2CH3), 1.14 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ 165.5,
153.2, 146.0, 141.8, 128.5, 127.9, 127.4, 102.3, 74.2, 63.8, 60.0, 58.0, 18.4, 14.9, 14.2. MS: m/z = 318
(M+). Anal. Calcd for C17H22N2O4 (318): C, 64.13; H, 6.97; N, 8.80. Found: C, 63.95; H, 6.88; N, 8.91.
Ethyl 3-(methoxymethyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2b).10a
o
1
White solid; mp 172-174 C. H NMR (400 MHz, CDCl3): δ 8.12 (bs, 1H, NH), 7.35-7.27 (m, 5H, HAr),
5.93 (d, J = 10.0 Hz, 1H, NCHH), 5.68 (s, 1H, 4-CH), 4.66 (d, J = 10.0 Hz, 1H, NCHH), 4.19-4.12 (m,
2H, OCH2CH3), 3.68-3.64 (m, 1H, OCH2CH3), 3.56-3.52 (m, 1H, OCH2CH3), 2.36 (s, 3H, 6-CH3),
13
1.27-1.23 (m, 3H, OCH2CH3), 1.19-1.15 (m, 3H, OCH2CH3). C NMR (100 MHz, CDCl3): δ 176.5,
165.2, 142.3, 140.5, 128.7, 128.3, 127.1, 103.7, 79.2, 64.6, 60.4, 57.2, 18.1, 14.9, 14.2.

HETEROCYCLES, Vol. 94, No. 6, 2017
1033
Ethyl 1-(propoxymethyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate (2c).
White solid; mp 142-144 oC; 1H NMR (400 MHz, CDCl3) δ 8.60 (br s, 1H, NH), 7.39-7.27 (m, 5H, HAr),
5.52 (s, 1H, 4-CH), 5.24 (d, J = 10.0 Hz, 1H, NCHH), 4.38 (d, J = 10.8 Hz, 1H, NCHH), 4.13-4.07 (m,
2H, OCH2CH3), 3.50-3.45 (m, 1H, OCH2CH2CH3), 3.37-3.31 (m, 1H, OCH2CH2CH3), 2.36 (s, 3H,
6-CH3), 1.57-1.51 (m, 2H, OCH2CH2CH3), 1.23-1.19 (m, 3H, OCH2CH3), 0.88-0.91 (m, 3H,
13
OCH2CH2CH3). C NMR (100 MHz, CDCl3) δ 165.5, 153.3, 146.1, 141.7, 128.5, 127.9, 127.4, 102.2,
74.2, 70.3, 60.0, 57.7, 22.6, 18.4, 14.1, 10.5. MS: m/z = 332 (M+). Anal. Calcd for C18H24N2O4 (332.17):
C, 65.04; H, 7.28; N, 8.43. Found: C, 64.85; H, 7.18; N, 8.31.
Ethyl 3-(isopropoxymethyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(2d).10a White solid; mp 127-129 oC. 1H NMR (400 MHz, CDCl3): δ 8.56 (bs, 1H, NH), 7.39-7.32 (m, 3H,
HAr), 7.31-7.32 (m, 2H, HAr), 5.53 (s, 1H, 4-CH), 5.26 (d, J = 10.4 Hz, 1H, NCHH), 4.34 (d, J = 10.4 Hz,
1H, NCHH), 4.13-4.07 (m, 2H, OCH2CH3), 3.74-3.68 (m, 1H, OCHCH3CH3 ), 2.35 (s, 3H, 6-CH3),
1.26-1.18 (m, 6H, CH(CH3)2), 1.07-1.05 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ 165.5,
153.3, 146.1, 141.9, 128.5, 127.9, 127.4, 102.2, 71.9, 68.8, 59.9, 57.7, 22.7, 21.4, 18.4, 14.2.
Ethyl 1-(butoxymethyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate (2e).
White solid; mp 111-113 oC; 1H NMR (400 MHz, CDCl3) δ 7.69 (br s, 1H, NH), 7.38-7.28 (m, 5H, HAr),
5.51 (s, 1H, 4-CH), 5.23 (d, J = 10.4 Hz, 1H, NCHH), 4.36 (d, J = 10.4 Hz, 1H, NCHH), 4.13-4.07 (m,
2H, OCH2CH3), 3.54-3.48 (m, 1H, OCH2CH2CH2CH3), 3.39-3.36 (m, 1H, OCH2CH2CH2CH3), 2.36 (s,
3H, 6-CH3), 1.53-1.44 (m, 2H, OCH2CH2CH2CH3), 1.37-1.32 (m, 2H, OCH2CH2CH2CH3), 1.22 (t, J =
13
7.2 Hz, 3H, OCH2CH3), 0.89 (t, J = 7.2 Hz, 3H, OCH2CH2CH2CH3). C NMR (100 MHz, CDCl3) δ
165.4, 152.8, 145.7, 141.6, 128.5, 128.0, 127.3, 102.5, 74.3, 68.1, 60.1, 57.7, 31.5, 19.2, 18.6, 14.2, 13.8.
MS: m/z = 346 (M+). Anal. Calcd for C19H26N2O4 (346.19): C, 65.87; H, 7.56; N, 8.09. Found: C, 65.93;
H, 7.48; N, 8.18.
Ethyl 3-(tert-butoxymethyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(2f).10a White solid; mp 142-144 oC. 1H NMR (400 MHz, CDCl3): δ 8.76 (bs, 1H, NH), 7.38-7.24 (m, 5H,
HAr), 5.60 (s, 1H, 4-CH), 5.40 (d, J = 10.0 Hz, 1H, NCHH), 4.12 (d, J = 10.0 Hz, 1H, NCHH), 4.10-4.06
(m, 2H, OCH2CH3), 2.32(s, 3H, CH3), 1.29-1.19 (m, 9H, CH3), 1.18-1.14 (m, 3H, OCH2CH3). 13C NMR
(100 MHz, CDCl3): δ 165.6, 152.7, 146.3, 141.8, 128.4, 127.9, 127.5, 102.0, 74.1, 67.9, 59.9, 57.0, 28.0,
18.4, 14.2.
Ethyl
3-(ethoxymethyl)-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
o
1
carboxylate (2g).10a White solid; mp 134-136 C. H NMR (400 MHz, CDCl3): δ 8.51 (bs, 1H, NH),
7.30-7.27 (m, 2H, HAr), 6.83-6.81 (m, 2H, HAr), 5.45 (s, 1H, 4-CH), 5.34 (d, J = 10.4 Hz, 1H, NCHH),
4.35 (d, J = 10.4 Hz, 1H, NCHH), 4.11-4.05 (m, 2H, OCH2CH3), 3.80 (s, 3H, OCH3), 3.61-3.57 (m, 1H,
OCH2CH3), 3.52-3.42 (m, 1H, OCH2CH3), 2.37 (s, 3H, CH3), 1.24-1.16 (m, 6H, OCH2CH3×2). 13C NMR

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HETEROCYCLES, Vol. 94, No. 6, 2017
(100 MHz, CDCl3): δ 165.5, 153.3, 145.9, 138.9, 137.7, 129.1, 127.3, 102.4, 73.9, 63.8, 60.0, 57.6, 21.1,
18.4, 14.9, 14.2.
Ethyl
4-(4-chlorophenyl)-3-(ethoxymethyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
o
1
carboxylate (2h).10a White solid; mp 175-177 C. H NMR (400 MHz, CDCl3): δ 8.69 (bs, 1H, NH),
7.33-7.26 (m, 4H, HAr), 5.48 (s, 1H, C4-CH), 5.19 (d, J = 10.8 Hz, 1H, NCHH), 4.37 (d, J = 10.8 Hz, 1H,
NCHH), 4.15-4.06 (m, 2H, OCH2CH3), 3.59-3.53 (m, 1H, OCH2CH3 ), 3.43-3.39 (m, 1H, OCH2CH3),
2.36 (s, 3H, 6-CH3), 1.26-1.20 (m, 3H, OCH2CH3), 1.18-1.12 (m, 3H, OCH2CH3). 13C NMR (100 MHz,
CDCl3): δ 165.3, 153.2, 146.3, 140.4, 133.7, 128.8, 128.6, 101.9, 74.2, 63.8, 60.1, 57.4, 18.4, 14.8, 14.2.
Ethyl 1-(propoxymethyl)-4-methyl-2-thioxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate
o
1
(2i). White solid; mp 108-110 C; H NMR (400 MHz, CDCl3) δ 8,29 (br s, 1H, NH), 7.34-7.27 (m, 5H,
HAr), 5.97 (d, J = 10.4 Hz, 1H, NCHH), 5.70 (s, 1H, 4-CH), 4.64 (d, J = 10.0 Hz, 1H, NCHH), 4.18-4.13
(m, 2H, OCH2CH3), 3.54-3.43 (m, 2H, OCH2CH2CH3), 2.37 (s, 3H, 6-CH3), 1.60-1.54 (m, 2H,
13
OCH2CH2CH3), 1.25 (t, J = 7.2 Hz, 3H, OCH2CH3), 0.93 (t, J = 7.2 Hz, 3H, OCH2CH2CH3). C NMR
(100 MHz, CDCl3) δ 176.4, 165.2, 142.5, 140.4, 128.7, 128.3, 127.1, 103.6, 79.2, 70.7, 60.4, 56.9, 22.7,
18.0, 14.1, 10.5. MS: m/z = 348 (M+). Anal. Calcd for C18H24N2O3S (348.15): C, 62.04; H, 6.94; N, 8.04.
Found: C, 62.12; H, 7.01; N, 8.09.
Ethyl
1-(isopropoxymethyl)-4-methyl-2-thioxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-ꢀ
o
1
carboxylate (2j). White solid; mp 80-82 C; H NMR (400 MHz, CDCl3) δ 8.01 (br s, 1H, NH),
7.34-7.27 (m, 5H, HAr), 6.00 (d, J = 10.8 Hz, 1H, NCHH), 5.74 (s, 1H, 4-CH), 4.62 (d, J = 10.4 Hz, 1H,
NCHH), 4.19-4.14 (m, 2H, OCH2CH3), 3.86-3.80 (m, 1H, OCHCH3CH3), 2.36 (s, 3H, 6-CH3), 1.28-1.24
13
(m, 3H, OCH2CH3), 1.22 (d, J = 6.0 Hz, 3H, CH3CHCH3), 1.13 (d, J = 6.0 Hz, 3H, CH3CHCH3). C
NMR (100 MHz, CDCl3) δ 176.2, 165.2, 142.4, 140.4, 128.8, 128.3, 127.0, 103.6, 76.7, 69.9, 60.4, 56.7,
22.8, 21.5, 18.1, 14.2. MS: m/z = 348 (M+). Anal. Calcd for C18H24N2O3S (348.15): C, 62.04; H, 6.94; N,
8.04. Found: C, 62.12; H, 7.01; N, 8.09.
Ethyl
1-(p-tolylthiomethyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate
o
1
(2k).10a White solid; mp 147-149 C; H NMR (400 MHz, CDCl3) δ 8.56 (br s, 1H, NH), 7.40-7.09 (m,
9H, HAr), 5.61 (s, 1H, 4-CH), 5.54 (d, J = 13.6 Hz, 1H, NCHH), 4.12-4.03 (m, 2H, OCH2CH3), 3.83 (d, J
= 14.0 Hz, 1H, NCHH), 2.31 (s, 3H, Ar-CH3), 2.27 (s, 3H, 6-CH3), 1.20 (t, J = 7.2 Hz, 3H, OCH2CH3).
13C NMR (100 MHz, CDCl3) δ 165.4, 152.3, 146.0, 141.0, 137.8, 132.6, 129.9, 129.7, 128.5, 128.1, 127.5,
101.4, 59.9, 58.0, 49.6, 21.1, 18.2, 14.1.
Ethyl
1-((4-methoxyphenoxy)methyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-
o
1
carboxylate (2l). White solid; mp 175-177 C; H NMR (400 MHz, CDCl3) δ 8.63 (br s, 1H, NH),
7.43-6.62 (m, 9H, HAr), 5.48 (s, 1H, 4-CH), 4.72 (d, J = 14.8 Hz, 1H, NCHH), 4.15-4.03 (m, 2H,
OCH2CH3), 3.90 (d, J = 14.8 Hz, 1H, NCHH), 3.74 (s, 3H, Ar-OCH3), 2.33 (s, 3H, 6-CH3), 1.23-1.19 (m,

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13
3H, OCH2CH3). C NMR (100 MHz, CDCl3) δ 165.2, 154.4, 152.6, 149.7, 145.0, 141.3, 128.7, 128.3,
127.6, 122.2, 118.0, 117.0, 115.1, 102.3, 61.0, 60.2, 55.8, 45.7, 18.4, 14.2. MS: m/z = 396 (M+). Anal.
Calcd for C22H24N2O5 (396.17): C, 66.65; H, 6.10; N, 7.07. Found: C, 66.78; H, 6.06; N, 7.16.
Ethyl 3-(azidomethyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2m).10a
1
White solid; mp 136-138 oC. H NMR (400 MHz, CDCl3): δ 8.24 (br, 1H, NH), 7.35-7.26 (m, 5H, HAr),
5.54 (s, 1H, 4-CH), 5.17 (d, J = 12.0Hz, 1H, NCHH), 4.26 (d, J = 12.0Hz, 1H, NCHH), 4.11-4.08 (m, 2H,
OCH2CH3), 2.37 (s, 3H, 6-CH3), 1.23-1.19 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ 165.2,
152.9, 145.5, 141.2, 128.8, 128.4, 127.3, 102.4, 60.9, 60.3, 60.2, 18.5, 14.1.
3-(Ethoxymethyl)-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione
(4a).
White solid; mp 168-170 oC; 1H NMR (400 MHz, CDCl3): δ 8.67 (br s, 1H, NH), 7.40-7.25 (m, 5H, HAr),
5.61 (s, 1H, 4-CH), 5.28 (d, J = 10.4 Hz, 1H, NCHH), 4.35 (d, J = 10.4 Hz, 1H, NCHH), 3.56-3.54 (m,
1H, OCH2CH3), 3.46-3.45 (m, 1H, OCH2CH3), 2.43-2.18 (m, 4H, 6-CH2, 8-CH2), 1.15 (t, J = 7.2 Hz, 3H,
13
OCH2CH3), 1.11 (s, 3H, CH3), 0.95 (s, 3H, CH3). C NMR (100 MHz, CDCl3) δ 193.6, 153.2, 149.4,
141.2, 128.6, 127.9, 127.1, 110.1, 74.4, 63.9, 56.1, 50.3, 40.0, 32.8, 29.3, 27.2, 14.9. MS: m/z = 328 (M+).
Anal. Calcd for C19H24N2O3 (328.18): C, 69.49; H, 7.37; N, 8.53. Found: C, 69.61; H, 7.42; N, 8.42.
3-(Propoxymethyl)-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione
(4b).
White solid; mp 166-168 oC; 1H NMR (400 MHz, CDCl3): δ 8.96 (br s, 1H, NH), 7.40-7.23 (m, 5H, HAr),
5.61 (s, 1H, 4-CH), 5.28 (d, J = 10.0 Hz, 1H, NCHH), 4.35 (d, J = 10.0 Hz, 1H, NCHH), 3.47-3.32 (m,
2H, OCH2CH2CH3), 2.43-2.13 (m, 4H, 6-CH2, 8-CH2), 1.57-1.51 (m, 2H, OCH2CH2CH3), 1.10 (s, 3H,
CH3), 0.95 (s, 3H, CH3), 0.89 (t, J = 7.2 Hz, 3H, OCH2CH2CH3). 13C NMR (100 MHz, CDCl3) δ 193.6,
153.4, 149.6, 141.2, 128.6, 127.9, 127.1, 110.0, 74.6, 70.3, 55.9, 50.3, 39.9, 32.8, 29.2, 27.2, 22.7, 10.6.
MS: m/z = 342 (M+). Anal. Calcd for C20H26N2O3 (342.19): C, 70.15; H, 7.65; N, 8.18. Found: C, 70.26;
H, 7.62; N, 8.26.
3-(Ethoxymethyl)-7,7-dimethyl-4-phenyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4c).
White solid; mp 153-155 oC; 1H NMR (400 MHz, CDCl3): δ 7.98 (br s, 1H, NH), 7.36-7.28 (m, 4H, HAr),
5.98 (d, J = 10.4 Hz, 1H, NCHH), 5.76 (s, 1H, 4-CH), 4.63 (d, J = 10.0 Hz, 1H, NCHH), 3.65-3.49 (m,
2H, OCH2CH3), 2.43-2.17 (m, 4H, 6-CH2, 8-CH2), 1.18 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.11 (s, 3H, CH3),
0.93 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 193.9, 176.7, 145.2, 140.1, 128.8, 128.2, 126.9, 110.9,
79.6, 64.8, 55.5, 50.3, 39.6, 32.9, 29.3, 27.1, 15.0. MS: m/z = 344 (M+). Anal. Calcd for C19H24N2O2S
(344.16): C, 66.25; H, 7.02; N, 8.13. Found: C, 66.37; H, 7.10; N, 8.02.
3-(Propoxymethyl)-7,7-dimethyl-4-phenyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4d).
White solid; mp 148-150 oC; 1H NMR (400 MHz, CDCl3): δ 8.73 (br s, 1H, NH), 7.36-7.26 (m, 5H, HAr),
5.99 (d, J = 10.4 Hz, 1H, NCHH), 5.77 (s, 1H, 4-CH), 4.62 (d, J = 10.4 Hz, 1H, NCHH), 3.55-3.42 (m,
2H, OCH2CH2CH3), 2.44-2.17 (m, 4H, 6-CH2, 8-CH2), 1.59-1.52 (m, 2H, OCH2CH2CH3), 1.11 (s, 3H,

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HETEROCYCLES, Vol. 94, No. 6, 2017
CH3), 0.93 (s, 3H, CH3), 0.89 (t, J = 7.2 Hz, 3H, OCH2CH2CH3). 13C NMR (100 MHz, CDCl3) δ 193.9,
176.7, 145.5, 140.1, 128.8, 128.2, 126.9, 110.8, 79.5, 71.0, 55.3, 50.3, 39.4, 32.9, 29.2, 27.1, 22.7, 10.5.
MS: m/z = 358 (M+). Anal. Calcd for C20H26N2O2S (358.17): C, 67.01; H, 7.31; N, 7.81. Found: C, 67.13;
H, 7.27; N, 7.94.
3-(Isopropoxymethyl)-7,7-dimethyl-4-phenyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one
o
1
(4e). Light yellow solid; mp 118-120 C; H NMR (400 MHz, CDCl3): δ 8.59 (br s, 1H, NH), 7.36-7.24
(m, 5H, HAr), 6.03 (d, J = 10.4 Hz, 1H, NCHH), 5.81 (s, 1H, 4-CH), 4.59 (d, J = 10.4 Hz, 1H, NCHH),
3.83-3.77 (m, 1H, OCH(CH3)2), 2.43-2.17 (m, 4 H, 6-CH2, 8-CH2), 1.19 (d, J = 6.0 Hz, 3H, CH3CHCH3),
1.14 (d, J = 6.0 Hz, 3H, CH3CHCH3), 1.10 (s, 3H, CH3), 0.93 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)
δ 193.9, 176.4, 145.5, 140.1, 128.8, 128.2, 126.9, 110.7, 77.5, 70.4, 55.1, 50.3, 39.4, 32.9, 29.2, 27.2, 22.8,
21.7. MS: m/z = 358 (M+). Anal. Calcd for C20H26N2O2S (358.17): C, 67.01; H, 7.31; N, 7.81. Found: C,
67.12; H, 7.28; N, 7.93.
3-(Ethoxymethyl)-4-(4-methoxyphenyl)-7,7-dimethyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6
o
1
H)-one (4f). Light yellow solid; mp 161-163 C; H NMR (400 MHz, CDCl3): δ 8.64 (br s, 1H, NH),
7.28-6.82 (m, 4H, HAr), 5.96 (d, J = 7.6 Hz, 1H, NCHH), 5.69 (s, 1H, 4-CH), 4.59 (d, J = 7.2 Hz, 1H,
NCHH), 3.79 (s, 3H, Ar-OCH3), 3.67-3.52 (m, 2H, OCH2CH3), 2.43-2.16 (m, 4H, 6-CH2, 8-CH2),
1.27-1.23 (m, 3H, OCH2CH3), 1.21 (s, 3H, CH3), 0.94 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 194.1,
176.4, 159.4, 145.3, 145.2, 132.4, 128.3, 114.1, 110.9, 79.2, 64.7, 54.9, 50.3, 39.3, 32.9, 29.3, 27.1, 15.0.
MS: m/z = 374 (M+). Anal. Calcd for C20H26N2O3S (374.17): C, 64.14; H, 7.00; N, 7.48. Found: C, 64.25;
H, 6.97; N, 7.59.
3-(Ethoxymethyl)-4-(4-chlorophenyl)-7,7-dimethyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-
o
1
one (4g). Light yellow solid; mp 179-181 C; H NMR (400 MHz, CDCl3): δ 8.55 (br s, 1H, NH),
7.31-7.27 (m, 4H, HAr), 5.95 (d, J = 10.4 Hz, 1H, NCHH), 5.74 (s, 1H, 4-CH), 4.63 (d, J = 10.0 Hz, 1H,
NCHH), 3.64-3.50 (m, 2H, OCH2CH3), 2.44-2.17 (m, 4H, 6-CH2, 8-CH2), 1.18 (t, J = 6.8 Hz, 3H,
13
OCH2CH3), 1.11 (s, 3H, CH3), 0.92 (s, 3H, CH3). C NMR (100 MHz, CDCl3) δ 193.9, 176.6, 145.6,
138.7, 134.1, 129.0, 128.3, 110.4, 79.5, 64.9, 54.8, 50.2, 39.4, 32.9, 29.3, 27.0, 14.9. MS: m/z = 378 (M+),
380 (M+2). Anal. Calcd for C19H23ClN2O2S (378.12): C, 60.23; H, 6.12; N, 7.39. Found: C, 60.35; H,
6.07; N, 7.46.
Ethyl
6-methyl-3-(2-methylprop-1-en-1-yl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
o
1
carboxylate (6a). White solid, mp 151-153 C, yield: 70%. H NMR (400 MHz, CDCl3): δ 8.90 (s, 1H),
7.38-7.24 (m, 5H), 5.61 (s, 1H), 5.30 (s, 1H), 4.12-4.08 (m, 2H), 2.37 (s, 3H), 1.71 (s, 3H), 1.61 (s, 3H),
13
1.21 (t, J = 7.2, 3H). C NMR (100 MHz, CDCl3): δ 165.6, 152.7, 147.1, 141.3, 133.9, 128.4, 127.6,
127.0, 120.6, 101.4, 61.9, 59.9, 22.1, 18.4, 18.0, 14.1. MS: m/z 314 (M+). Anal. Calcd for C18H22N2O3
(314.38): C 68.77, H 7.05, N 8.91. Found: C 68.70, H 7.08, N 8.87.

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General procedure for the synthesis of products 7a-c
A mixture of 2-hydroxy-substituted 3,4-dihydropyrimidinone (1, 1 mmol), propionaldehyde (4a, 1.5
mmol) and PEG-OSO3H (0.6 g) in THF (3.0 mL) was stirred at 65 oC for 6 h. After completion monitored
by TLC, the resulting mixture was cooled and quenched to ice water. Then the precipitation was filtered
off and purified by silica gel column chromatography eluted with EtOAc/petroleum ether (1:5) to afford
the pure product 7.
Ethyl
6-ethyl-2-methyl-4-oxo-3,4,6,11b-tetrahydrobenzo[e]pyrimido[1,6-c][1,3]oxazine-1-
carboxylate (7a). White solid; mp 246-248 oC; yield: 87%; 1H NMR (400 MHz, CDCl3): δ 8.46 (br s, 1H,
NH), 7.17-6.80 (m, 4H, HAr), 6.15 (t, J = 7.2 Hz, 1H, OCHN), 5.62 (s, 1H, CH), 4.35-4.23 (m, 2H,
OCH2CH3), 2.36 (s, 3H, 2-CH3), 2.10-1.86 (m, 2H, CH2CH3), 1.31 (t, J = 7.2 Hz, 3H, CH2CH3), 1.04 (t, J
= 7.2 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ 166.3, 154.1, 152.4, 148.2, 128.8, 124.6, 124.4,
120.3, 117.1, 98.3, 82.8, 60.4, 47.4, 25.0, 18.6, 14.4, 8.8. MS: m/z = 316 (M+). Anal. Calcd for
C17H20N2O4 (316): C, 64.54; H, 6.37; N, 8.86. Found: C, 64.63; H, 6.35; N, 8.94.
Ethyl
2-methyl-4-oxo-6-propyl-3,4,6,11b-tetrahydrobenzo[e]pyrimido[1,6-c][1,3]oxazine-1-
carboxylate (7b). White solid; mp 185-187 oC; yield: 85%; 1H NMR (400 MHz, CDCl3): δ 8.33 (br s, 1H,
NH), 7.26-6.79 (m, 4H, HAr), 6.24 (t, J = 7.2 Hz, 1H, OCHN), 5.64 (s, 1H, CH), 4.35-4.24 (m, 2H,
OCH2CH3), 2.36 (s, 3H, 2-CH3), 2.04-1.83 (m, 2H, CH2CH2CH3), 1.54-1.47 (m, 2H, CH2CH2CH3), 1.33
13
(t, J = 7.2 Hz, 3H, CH2CH2CH3), 1.01 (t, J = 7.2 Hz, 3H, OCH2CH3). C NMR (100 MHz, CDCl3): δ
166.3, 154.0, 152.4, 148.1, 128.8, 124.6, 124.4, 120.3, 117.2, 98.4, 81.5, 60.4, 47.5, 33.8, 18.6, 17.8, 14.4,
13.7. MS: m/z = 330 (M+). Anal. Calcd for C18H22N2O4 (330.16): C, 65.44; H, 6.71; N, 8.48. Found: C,
65.52; H, 6.68; N, 8.55.
Ethyl
6-isobutyl-2-methyl-4-oxo-3,4,6,11b-tetrahydrobenzo[e]pyrimido[1,6-c][1,3]oxazine-1-ꢀ
carboxylate (7c). White solid; mp 180-182 oC; yield: 81%; 1H NMR (400 MHz, CDCl3): δ 8.29 (br s, 1H,
NH), 7.26-6.79 (m, 4H, HAr), 6.33 (t, J = 6.8 Hz, 1H, OCHN), 5.65 (s, 1H, CH), 4.35-4.25 (m, 2H,
OCH2CH3), 2.36 (s, 3H, 2-CH3), 1.90-1.78 (m, 3H, CH2CH(CH3)2), 1.33 (t, J = 6.8 Hz, 3H, OCH2CH3),
13
1.24-0.98 (m, 6H, CH2CH(CH3)2). C NMR (100 MHz, CDCl3): δ 166.3, 153.9, 152.4, 148.1, 128.8,
124.7, 124.2, 120.3, 117.2, 98.5, 80.4, 60.4, 47.5, 40.3, 24.2, 22.9, 22.2, 18.6, 14.4. MS: m/z = 344 (M+).
Anal. Calcd for C19H24N2O4 (344.17): C, 66.26; H, 7.02; N, 8.13. Found: C, 66.35; H, 7.05; N, 8.21.
Ethyl 4-methyl-1-(2-methylprop-1-enyl)-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-5-carboxylate
o
(8). White solid, yield: 70%, mp 151-153 C. 1H NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 7.38-7.24 (m,
5H), 5.61 (s, 1H), 5.30 (s, 1H), 4.12-4.08 (m, 2H), 2.37 (s, 3H), 1.71 (s, 3H), 1.61 (s, 3H), 1.21 (t, J = 7.2,
13
3H). C NMR (100 MHz, CDCl3): δ 165.6, 152.7, 147.1, 141.3, 133.9, 128.4, 127.6, 127.0, 120.6,
101.4, 61.9, 59.9, 22.1, 18.4, 18.0, 14.1. MS: m/z 314 (M+). Anal. Calcd for C18H22N2O3 (314): C 68.77,
H 7.05, N 8.91. Found: C 68.70, H 7.08, N 8.87.

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HETEROCYCLES, Vol. 94, No. 6, 2017
ACKNOWLEDGEMENTS
We are thankful for the financial support from the National Natural Science Foundation of China (No.
41501176).
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