One-pot two-step synthesis of N3-functionalized 3,4-dihydropyrimidinones in the presence of TMSCl

Article abstract of DOI:10.3987/COM-10-11968

Novel 3,4-dihydropyrimidinones modified with N3-alkyloxymethyl, aminomethyl, arylsulfonylmethyl, and azidomethyl groups can be regioselectively obtained over their isomeric N1 compounds in good yields by reaction of 3,4-dihydropyrimidinones with paraforma

Full text of DOI:10.3987/COM-10-11968

HETEROCYCLES, Vol. 81, No. 8, 2010
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HETEROCYCLES, Vol. 81, No. 8, 2010, pp. 1827 - 1841. © The Japan Institute of Heterocyclic Chemistry
Received, 30th April, 2010, Accepted, 14th June, 2010, Published online, 14th June, 2010
DOI: 10.3987/COM-10-11968
ONE-POT TWO-STEP SYNTHESIS OF N3-FUNCTIONALIZED 3,4-
DIHYDROPYRIMIDINONES IN THE PRESENCE OF TMSCl
Zheng-Jun Quan,* Rong-Guo Ren, Yu-Xia Da, Zhang Zhang, Xiao-Dong Jia,
Cai-Xia Yang, and Xi-Cun Wang*
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of
Education, China, Gansu Key Laboratory of Polymer Materials, College of Che-
mistry and Chemical Engineering, Northwest Normal University, Anning East
Road 967#, Lanzhou, Gansu 730070, China
Tel./Fax: +86-931-7971971
E-mail: wangxicun@nwnu.edu.cn, quanzj@nwnu.edu.cn
Abstract – Novel 3,4-dihydropyrimidinones modified with N3-alkyloxymethyl,
aminomethyl, arylsulfonylmethyl, and azidomethyl groups can be regioselectively
obtained over their isomeric N1 compounds in good yields by reaction of 3,4-
dihydropyrimidinones with paraformaldehyde and alcohol, amine, sodium benze-
nesulfinate, and sodium azide, respectively, by a one-pot two-step strategy in the
presence of chlorotrimethylsilane. The advantages of this method are the simple
procedure, the high regioselectivity of the products, no requirement for a base cat-
alyst, and the mild reaction conditions.
INTRODUCTION
In past decades, dihydropyrimidinones (DHPMs) and their derivatives have attracted considerable interest
due to their heterocyclic scaffold1-8 and interesting pharmacological properties. They form the underlying
structure for many clinically important substances, such as calcium channel modulators, antihypertensives,
α1a adrenergic agonists, mitotic kinesin inhibitors, and hepatitis B virus replication suppressors.9-11
Among DHPM derivatives, most of the pharmacologically attractive forms are N3-substituted analogues.3
The N-alkylation of dihydropyrimidin-2-ones is one way of functionalizing the ring to achieve important

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HETEROCYCLES, Vol. 81, No. 8, 2010
bioactive properties. Most N-alkylated pyrimidin-2-ones are obtained from SN2 displacement of an
electrophile, such as a diazoalkane,12 alkyl halide,13-15 alkyl sulfate, and alkyl phosphate,16 with the
pyrimidine reacting as the nucleophile. Generally, most nucleophilic reactions17 involving N-alkylation of
pyrimidinones yield N1-alkylated products.18
The classical method for the preparation of N3-substituted DHPMs, which employs a base-mediated
alkylation of S-alkylated or O-alkylated pyrimidinones, results in protected N3-alkylated
dihydropyrimidines.19 An alternative for this reaction is the “Atwal modification” of the Biginelli
condensation.20, 21 Kappe et al. have reported the synthesis of N3-acylated DHPMs by acylation of
DHPMs with ethyl chloroformate and N,N-dimethylcarbamoyl chloride22 or with anhydrides.23 Reaction
of DHPMs with a base (LDA or n-BuLi) followed by quenching with electrophiles, resulted in a mixture
of N1 and N3 position products.24, 25 N3-Acetoxymethyl26 DHPM has also been synthesized by standard
acylation reaction of acetyl chloride with N3-hydroxylmethylated DHPM, which was produced by
treating DHPM with aqueous formaldehyde and potassium carbonate at reflux temperature for 48 h.27 The
N-alkyl-pyrimidin-2-ones were also generated by the cyclocondensation of 4-alkoxy-1,1,1-trihalo-3-
alken-2-ones with methyl and allylureas and the N-alkylation of 4-(trihalomethyl)-pyrimidin-2-ones with
methyl iodide and allyl bromide.28 DHPMs could be regioselectively substituted at the N3 position by
aza-Michael addition reactions of DHPMs to α,β-ethylenic compounds.29,30 N3,S-Dimethylated 1,6-
dihydropyrimidine has also been prepared by the reaction of 3,4-dihydropyrimidine-2-thiones with
dimethyl carbonate.31
Unfortunately, these strategies suffer from the disadvantage that the procedures need to be carried out in
harsh conditions such as high temperature with long reaction time and/or in the presence of strong base.
Sometimes unexplained low selectivity in the position of N3 to N1 also occurs. To the best of our
knowledge, a comparative study on the synthesis of DHPM derivatives, including addition of
alkyloxymethyl, arylsulfonylmethyl, and azidomethyl groups at the N3 position of the pyrimidine ring by
a one-pot multi-component reaction, has not yet been carried out. In this article, we present a convenient
approach for the preparation of N3 functionalized DHPM derivatives that involves addition of
alkyloxymethyl, aminomethyl, arylsulfonylmethyl, and azidomethyl groups under mild conditions and in
the absence of a base catalyst. This was performed by treatment of DHPMs with paraformaldehyde and
chlorotrimethylsilane (TMSCl), followed by reactions with various substrates such as alcohols,
morpholine, sodium benzenesulfinate, and sodium azide.

HETEROCYCLES, Vol. 81, No. 8, 2010
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RESUSTS AND DISCUSSIONS
Initially, experiments were carried out for the optimal reaction conditions using the reaction for 2a as a
typical reaction. A mixture of DHPM (1a) with TMSCl and paraformaldehyde in dichloromethane was
stirred for 24 h. The mixture subsequently was added to methanol for another 4 h to give N3-
methoxymethyl DHPM (2a). The catalysts, solvents, and reaction temperature greatly influenced the
product yield. Use of 2.0 equiv of TMSCl with 5 equiv of paraformaldehyde in CH2Cl2 at 35 oC afforded
2a in 73% yield; however, in the case of 2.5 equiv of TMSCl, the yield of 2a increased to 82%.
Increasing the amount of TMSCl to 3 equiv led to isolation of 2a in a lower yield (60 %). Different
solvents also influenced the reaction yield, as the reaction worked well in CH2Cl2 and THF; however, the
product 2a was not detected when MeCN, TFA, p-TSA, HCl, acetic acid, FeCl3, and CuCl2 were used as
catalysts. Thus, we decided to use 2.5 equiv of TMSCl and 5 equiv of paraformaldehyde in CH2Cl2 at 35
oC as the optimal reaction conditions for the preparation of N3 substituted DHPMs.
Table 1. Reactions of DHPMs with TMSCl, paraformaldehyde and alcoholsa
O
Ar
O
Ar
1) (CH2O)n, TMS-Cl
2) ROH
EtO
Me
NH
EtO
Me
N
OR
N
H
1
O
N
H
O
2a-h
Entry
Ar
R
Product
2a
Isolated Yield(%)
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
Et
82
85
75
88
90
84
71
65
p-MeO-C6H4
p-Cl-C6H4
C6H5
2b
2c
2d
p-MeO-C6H4
p-Cl-C6H4
C6H5
Et
2e
Et
2f
i-Pr
2g
C6H5
Me3C
2h
a Reaction conditions: (1) DHPM (1 mmol), (CH2O)n (5 mmol), TMS-Cl (2.5 mmol), CH2Cl2 (5 mL), 35
oC, 24 h; (2) ROH (3 mmol), 35 oC, 4 h.
Under optimal conditions, other N3-methoxymethyl DHPMs (2b-c) were prepared in good yields (Table 1,

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HETEROCYCLES, Vol. 81, No. 8, 2010
entries 1-3). We then investigated other alcohols, such as ethanol, isopropanol, and tert-butyl alcohol as
substrates and the corresponding N3-alkyloxymethyl DHPMs were obtained (Table 2, entries 4-8). 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 2 h
resulted (entry 8).
Table 2. Reaction of DHPM with paraformaldehyde and morpholinea
O
Ar
O
Ar
(CH2O)n, TMS-Cl
EtO
Me
NH
EtO
Me
N
N
O
N
H
1
O
HN
O
N
H
O
3a-e
Entry
Ar
Product
Isolated Yield(%)
Method A
Method B
Method C
1
2
3
4
5
C6H5
3a
3b
3c
3d
3e
90
88
85
86
92
94
90
87
87
92
89
85
80
87
86
p-MeO-C6H4
p-Me-C6H4
p-Cl-C6H4
p-Br-C6H4
a Reaction conditions: Method A: (1) DHPM (1 mmol), (CH2O)n (5 mmol), TMS-Cl (2.5 mmol), CH2Cl2 (5
mL), 35 oC, 24 h; (2) morpholine (2 mmol), 35 oC, 4 h. Method B: DHPM (1 mmol), (CH2O)n (5 mmol),
o
TMS-Cl (0.5 mmol), morpholine (1 mmol), MeOH (3 mmol), 80 C, 8 h. Method C: DHPM (1 mmol),
(CH2O)n (5 mmol), AcOH (0.5 mmol), morpholine (3 mmol), MeOH (5 mL), 80 oC, 8 h.
To expand the scope and limitation of this one-pot reaction, we then investigated amine, sodium
benzenesulfinate, and sodium azide as substrates in the reaction. The reaction between DHPM,
paraformaldehyde, and morpholine in the presence of TMSCl was studied and good yields of DHPM
derivatives 3a-e were obtained (Method A) (Table 2). Reactions for 3a-e were more efficient than
alcohols and gave higher yields. We postulated that this reaction was performed by the three-component
reaction of DHPMs, formaldehyde, and morpholine in the presence of TMSCl. As expected, the direct
treatment of DHPMs 1 and formaldehyde with morpholine in methanol in the presence of TMSCl
(Method B) or acetic acid (Method C), with refluxing for 8 h, resulted in the formation of compounds 3a-

HETEROCYCLES, Vol. 81, No. 8, 2010
1831
e with higher yields than those of the two-step reactions (Method A). However, N3-alkyloxymethyl
DHPM (2) could not be obtained by method B or C. Therefore, we could presumably assume that the
reaction for compounds 3a-e was performed via the Mannich reaction32 that started with the dehydration
of the amine with formaldehyde to give an imine ion, which reacted with DHPMs to afford the products
3a-e.
Table 3. Reactions of DHPMs with TMSCl, paraformaldehyde and sodium saltsa
O
Ar
O
Ar
1) (CH2O)n, TMS-Cl
2) RNa
O
EtO
Me
NH
EtO
Me
N
R
N
H
1
N
H
O
4, 5
Entry
Ar
R
Product
4a
Yield(%)b
1
C6H5
C6H5SO2
76
85
80
70
79
86
70
72
72
70
74
75
2
C6H5
p-Me-C6H4SO2
C6H5SO2
p-Me-C6H4SO2
C6H5SO2
p-Me-C6H4SO2
C6H5SO2
p-Me-C6H4SO2
N3
4b
4c
3
p-MeO-C6H4
p-MeO-C6H4
p-Me-C6H4
p-Me-C6H4
p-NO2-C6H4
p-NO2-C6H4
C6H5
4
4d
4e
5
6
4f
7
4g
8
4h
5a
9
10
11
12
p-MeO-C6H4
p-Me-C6H4
p-Cl-C6H4
N3
5b
5c
N3
N3
5d
a Reaction conditions: (1) DHPM (1 mmol), (CH2O)n (5 mmol), TMS-Cl (2.5 mmol), CH2Cl2 (5 mL), 35
oC, 24 h; (2) NaR (3 mmol), 35 oC, 8-12 h.
b Isolated yields based on DHPMs.
Consistent with previous studies, replacing alcohol with sodium benzenesulfinate or 4-
methylphenylsulfinic acid sodium salt allowed the reactions to proceed smoothly and afforded the desired

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HETEROCYCLES, Vol. 81, No. 8, 2010
products 4a-h in high yields (Table 3). However, this reaction needed a longer reaction time (second step
with 12 h), which was probably due to the poor solubility of sodium benzenesulfinate in CH2Cl2. The
electronic effects of the substituents on the aromatic rings of DHPMs 1 are not important. In the presence
of a nitro group at the aromatic rings of DHPMs 1, the yields such as 4g and 4h were not apparently
lower (Table 2, entries 7 and 8).
Finally, we observed that the readily available and stable DHPMs offered themselves for introduction of
an azido group at the N3 position of pyrimidine ring. The reactions for the synthesis of compounds 5a-d
were smoothly carried out by the procedures described above, using sodium azide as substrate instead of
alcohol (Table 3, entries 9-12). However, the yields of 5a–d were moderate to good with longer reaction
time (second step with 8 h), which perhaps due to the poor reactivity of sodium azide.
The structures of the N3-functionalized dihydropyrimidinones were determined by 1H NMR, H,H-COSY,
and two-dimensional HMBC NMR experiments, using 2a as a model compound. The structures of com-
pounds 2g and 5b were unambiguously confirmed by X-ray crystallography, revealing the N3 selectivity
products N3-(isopropylmethyl)-3, 4-dihydropyrimidine-2-ones (2g), N3-(morpholinomethyl)-3, 4-
dihydropyrimidine-2-ones (3c) and N3-(azidomethyl)-3, 4-dihydropyrimidine-2-ones (5b), which con-
firmed the structures of the obtained products.33
Scheme 1. Plausible reaction mechanism
Cl
H2
C
O
Ar
O
Ar
O
Ar
-TMSOH
EtO
Me
N
Cl
OTMS
EtO
N
EtO
Me
NH
H
CH2=OTMSCl
N
H
9
O
Me
N
H
7
O
N
H
1
O
6
NuH
Cl
O
Ar
O
Ar
NuH
(CH2O)n + TMSCl
EtO
Me
N
Nu
EtO
N
N
O
Me
N
H
O
H
2,4,5
8
We postulate that the reaction starts with the reaction of paraformaldehyde with TMSCl to give 6, which
then reacts with DHPM to afford the crucial intermediate N3-chloromethylation DHPM (9) by two

HETEROCYCLES, Vol. 81, No. 8, 2010
1833
possible pathways forming ammonium ion (7) or iminium ion (8). Subsequently, 9 reacts with the various
nucleophiles (alcohols, benzenesulfinic acid sodium salt, and sodium azide) to give the N3-
functionalization DHPMs 2,4,5 (Scheme 1). Although neither of the intermediates 6 or 9 was isolated,
intermediate 9 was detected by LC-MS; the other intermediate was not detected.
In conclusion, a variety of N3-substituted DHPMs were regioselectively prepared through a one-pot two-
step reaction between of 3,4-dihydropyrimidinones, paraformaldehyde, chlorotrimethylsilane, and various
substrates. To the best of our knowledge, the methodology described herein affording the novel
functionalized DHPM products has not been reported previously. Furthermore, the desired compounds
contain N3CH2- group, which increases the diversity of the molecule and can allow preparation of other
interesting libraries. Synthesis and screening of desired compounds based on DHPM scaffolds may lead
to the discovery of interesting biological activities.
EXPERIMENTAL
All reagents were obtained commercially and used without further purification. Melting points were de-
termined on an XT-4 electrothermal micromelting point apparatus and 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. Elemental analyses were performed on a Carlo-Erba
1106 Elemental Analysis instrument. Mass-spectra were recorded on a TRACE DSQ instrument. Com-
pounds 1 were prepared following the reported methods.34
General procedure for compounds 2a-h. To a suspension of 3,4-dihydropyrimidinone (1.0 mmol), para-
formaldehyde (5.0 mmol), and CH2Cl2 (5 mL), TMSCl (2.5 mmol) were added and the reaction mixture
o
was stirred at 35 C for 24 h. Alcohol (3 mmol) was then added and the reaction mixture was stirred for
an additional 4 h until the reaction was complete (monitored by TLC). After reaction completion, the sol-
id was filtered and the filtrate was quenched with saturated aqueous NaHCO3 solution (10 mL). The
aqueous phase was extracted with CH2Cl2 (15 mL) and the combined organic phase was washed with
brine (15 mL), dried over Na2SO4, and concentrated. Purification by crystallization from aq. EtOH
(EtOH: H2O = 4:1) afforded N3-substituted 3,4-dihydropyrimidinone (2a-h).
o
1
2a: Yield 82%; mp 157-159 C. H NMR (400 MHz, CDCl3): δ = 9.05 (bs, 1H, NH), 7.38-7.26 (m, 5H,
HAr), 5.33 (s, 1H, 4-CH), 5.19 (d, J = 10.4 Hz, 1H, NCHH), 4.22 (d, J = 10.4 Hz, 1H, NCHH), 4.12-4.07
13
(m, 2H, OCH2CH3), 3.32 (s, 3H, OCH3), 2.37 (s, 3H, 6-CH3), 1.22-1.18 (m, 3H, OCH2CH3). C NMR
(100 MHz, CDCl3): δ = 165.5, 153.6, 146.3, 144.7, 128.5, 127.9, 127.4, 102.1, 75.6, 59.9, 57.9, 55.9, 18.3,

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HETEROCYCLES, Vol. 81, No. 8, 2010
14.1. MS: m/z = 304 (M+). Anal. Calcd for C16H20N2O4 (304.14): C 63.14, H 6.62, N 9.20. Found: C
63.30, H 6.72, N 9.08.
o
1
2b: Yield 85%; mp 150-152 C. H NMR (400 MHz, CDCl3): δ = 8.58 (bs, 1H, NH), 7.30-7.26 (m, 2H,
HAr), 6.84-7.80 (m, 2H, HAr), 5.43 (s, 1H, 4-CH), 5.15 (d, J = 10.4 Hz, 1H, NCHH), 4.18 (d, J = 10.4 Hz,
1H, NCHH), 4.14-4.05 (m, 2H, OCH2CH3), 3.77 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 2.36 (s, 3H, 6-CH3),
1.26-1.18 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 165.5, 159.2, 153.4, 145.8, 133.9, 128.6,
113.8, 102.4, 75.4, 59.9, 57.3, 55.9, 55.2, 18.9, 14.1. MS: m/z = 334 (M+). Anal. Calcd for C17H22N2O5
(334.15): C 61.07, H 6.63, N 8.38. Found: C 61.25, H, 6.54, N 8.51.
o
2c: Yield 75%; mp 144-146 C. 1H NMR (400 MHz, CDCl3): δ = 8.50 (bs, 1H, NH), 7.32-7.28 (m, 2H,
HAr), 7.27-7.7.25 (m, 2H, HAr), 5.45 (s, 1H, 4-CH), 5.14 (d, J = 10.4 Hz, 1H, NCHH), 4.32 (d, J = 10.4
Hz, 1H, NCHH), 4.12-4.06 (m, 2H, OCH2CH3), 3.28 (s, 3H, OCH3), 2.36 (s, 3H, 6-CH3), 1.23-1.16 (m,
3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 165.3, 153.1 146.1, 140.2, 133.8, 128.8, 128.7, 102.0,
75.7, 60.2, 57.4, 56.0, 18.5, 14.2, MS: m/z = 338 (M+). Anal. Calcd for C16H19ClN2O4 (338.10): C 56.72,
H 5.65, N 8.27. Found: C 56.91, H, 5.74, N 8.13.
o
2d: Yield 88%; mp 172-174 C. 1H 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. MS: m/z = 318
(M+). Anal. Calcd for C17H22N2O4 (318.16): C 64.13, H 6.97, N 8.80. Found: C 63.95, H 6.88, N 8.91.
o
1
2e: Yield 90%; 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 (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. MS:
m/z = 348 (M+). Anal. Calcd for C18H24N2O5 (348.17): C 62.05, H 6.94, N 8.04. Found: C 62.21, H 6.88,
N 8.25.
o
1
2f: Yield 84%; 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-
13
CH3), 1.26-1.20 (m, 3H, OCH2CH3), 1.18-1.12 (m, 3H, OCH2CH3). C 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. MS: m/z =
352 (M+), 354 (M+2). Anal. Calcd for C17H21ClN2O4 (352.12): C 57.87, H 6.00, N 7.94. Found: C 58.01,

HETEROCYCLES, Vol. 81, No. 8, 2010
1835
H 6.08, N 7.81.
1
2g: Yield 71%; mp 127-129 oC. H 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-
13
1.18 (m, 6H, CH(CH3)2), 1.07-1.05 (m, 3H, OCH2CH3). C 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. MS: m/z = 332
(M+). Anal. Calcd for C18H24N2O4 (332.17): C 65.04, H 7.28, N 8.43. Found: C 65.21, H 7.40, N 8.32.
1
2h: yield 65%; mp 142-144 oC. H 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. MS: m/z = 346 (M+), 348 (M+2). Anal. Calcd for C19H26N2O4 (346.19): C 65.87, H 7.56, N
8.09. Found: C 65.91, H 7.50, N 8.21.
General procedure compounds 3a-e. Method A: To a suspension of 3,4-dihydropyrimidinone (1.0
mmol), paraformaldehyde (5.0 mmol), and CH2Cl2 (5 mL), TMSCl (2.5 mmol) was added and the reac-
tion mixture was stirred at 35 oC for 24 h. Morpholine (3 mmol) was then added and the reaction mixture
was stirred for an additional 4 h until the reaction was complete (monitored by TLC). After reaction com-
pletion, the solid was filtered and the filtrate was quenched with saturated aqueous NaHCO3 solution (10
mL). The aqueous phase was then extracted with CH2Cl2 (15 mL) and the combined organic phase was
washed with brine (15 mL), dried over Na2SO4, and concentrated. Purification by crystallization from aq.
EtOH (EtOH: H2O = 6:1) afforded N3-morpholinomethyl 3,4-dihydropyrimidinone (3a-e).
Method B: A mixture of 3,4-dihydropyrimidinone (1.0 mmol), paraformaldehyde (5.0 mmol), TMSCl
(0.5 mmol), and morpholine (3.0 mmol) in MeOH (5 mL) was refluxed under stirring for 8 h. The work-
up was same as mentioned in Method A, giving compounds 3a-d.
Method C: A mixture of 3,4-dihydropyrimidinone (1.0 mmol), paraformaldehyde (5.0 mmol), AcOH (0.5
mmol), and morpholine (3.0 mmol) in MeOH (5 mL) was refluxed under stirring for 8 h. The work-up
was same as mentioned in Method A, giving compounds 3a-d.
o
1
3a: Yield 90%; mp 176-178 C. H NMR (400 MHz, CDCl3): δ = 8.73 (bs, 1H, NH), 7.35-7.24 (m, 5H,
HAr), 5.59 (s, 1H, 4-CH), 4.24 (d, J = 12.0 Hz, 1H, NCHH), 4.17-4.08 (m, 2H, OCH2CH3), 3.72-3.66 (m,
4H, Hmorpholino), 3.42 (d, J = 12.0 Hz, 1H, NCHH), 2.62-2.57 (m, 2H, Hmorpholino), 2.49-2.44 (m, 2H, Hmor-
pholino), 2.35 (s, 3H, 6-CH3), 1.26-1.20 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 165.7, 153.9,

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HETEROCYCLES, Vol. 81, No. 8, 2010
146.3, 141.7, 128.5, 127.8, 127.2, 101.9, 66.8, 65.7, 60.0, 58.2, 50.8, 18.4, 14.2. MS: m/z = 359 (M+).
Anal. Calcd for C19H25N3O4 (359.18): C 63.49, H 7.01, N 11.69. Found: C 63.33, H 7.10, N 11.82.
3b: Yield 88%; mp 198-200 oC. 1H NMR (400 MHz, CDCl3): δ = 7.65 (bs, 1H, NH), 7.25 (d, J = 8.8 Hz,
2H, HAr), 6.82 (d, J = 8.8 Hz, 2H, HAr), 5.54 (s, 1H, 4-CH), 4.51 (d, J = 12 Hz, 1H, NCHH), 4.14-4.09 (m,
2H, OCH2CH3), 3.78 (s, 3H, CH3O), 3.74-3.69 (m, 4H, Hmorpholino), 3.39 (d, J = 12 Hz, 1H, NCHH), 2.61-
2.56 (m, 2H, Hmorpholino), 2.49-2.44 (m, 2H, Hmorpholino), 2.33 (s, 3H, 6-CH3), 1.26-1.21 (m, 3H, OCH2CH3).
13C NMR (100 MHz, CDCl3): δ = 165.8, 159.2, 153.3, 145.5, 133.8, 128.4, 113.8, 102.5, 66.9, 65.6, 60.1,
57.6, 55.2, 50.9, 18.7, 14.2. MS: m/z = 389 (M+). Anal. Calcd for C20H27N3O5 (389.20): C 61.68, H 6.99,
N 10.79. Found: C 61.85, H 7.10, N 10.92.
3c: Yield 85%, mp 202-204 oC. 1H NMR (400 MHz, CDCl3): δ = 8.36 (bs, 1H, NH), 7.25 (m, 2H, HAr),
7.10 (m, 2H, HAr), 5.55 (s, 1H, 4-CH), 4.52 (d, J = 12.0 Hz, 1H, NCHH), 4.14-4.11 (m, 2H, OCH2CH3),
3.70-3.68 (m, 4H, Hmorpholino), 3.40 (d, J = 12.0 Hz, 1H, NCHH), 2.57 (m, 2H, Hmorpholino), 2.48 (m, 2H,
13
Hmorpholino), 2.35 (s, 3H, 6-CH3), 2.32 (s, 3H, CH3), 1.25-1.18 (m, 3H, OCH2CH3). C NMR (100 MHz,
CDCl3) δ = 165.7, 153.9, 146.4, 140.9, 137.5, 129.2, 127.1, 101.6, 66.8, 65.6, 59.9, 57.9, 50.9, 21.1, 18.5,
14.2. MS: m/z = 373 (M+). Anal. Calcd for C20H27N3O4 (373.20): C 64.32, H7.29, N 11.25. Found: C
64.45, H 7.40, N 11.12.
1
3d: Yield 86%; mp 197-199 oC. H NMR (400 MHz, CDCl3): δ = 7.81 (bs, 1H, NH), 7.30-7.21 (m, 4H,
HAr), 5.58 (s, 1H, 4-CH), 4.49 (d, J = 12 Hz, 1H, NCHH), 4.15-4.10 (m, 2H, OCH2CH3), 3.67-3.66 (m,
4H, Hmorpholino), 3.37 (d, J = 12 Hz, 1H, NCHH), 2.59-2.56 (m, 2H, Hmorpholino), 2.46-2.43 (m, 2H, Hmorpho-
13
lino), 2.27 (s, 3H, 6-CH3), 1.25-1.18 (m, 3H, OCH2CH3). C NMR (100 MHz, CDCl3): δ = 165.5, 153.2,
146.0, 140.1., 133.7, 128.7, 128.6, 101.9, 66.9, 65.8, 60.2, 57.5, 50.8, 18.7, 14.2. MS: m/z = 393 (M+).
Anal. Calcd for C19H24ClN3O4 (393.15): C 57.94, H 6.14, N 10.67. Found: C 57.61, H 6.20, N 10.43.
o
1
3e: Yield 92%; mp 212-214 C H NMR (400 MHz, CDCl3): δ = 8.43 (bs, 1H, NH), 7.44-7.42 (m, 2H,
HAr), 7.27-7.21 (m, 2H, HAr), 5.57 (s, 1H, 4-CH), 4.50 (d, J = 12.0 Hz, 1H, NCHH), 4.15-4.12 (m, 2H,
OCH2CH3), 3.70-3.67 (m, 4H, Hmorpholino), 3.39 (d, J = 12 Hz, 1H, NCHH), 2.60-2.56 (m, 2H, Hmorpholino),
13
2.47-2.44 (m, 2H, Hmorpholino), 2.33(s, 3H, 6-CH3), 1.26-1.22 (m, 3H, OCH2CH3). C NMR (100 MHz,
CDCl3): δ = 165.5, 153.6, 146.4, 140.7, 131.6, 129.0, 121.8, 101.6, 66.8, 65.7, 60.2, 57.6, 50.8, 18.5, 14.2.
MS: m/z = 437 (M+). Anal. Calcd for C19H24BrN3O4 (437.10): C 52.06, H 5.52, N 9.59. Found: C 52.20,
H 5.63, N 9.50.
General procedure compounds 4a-h: To a suspension of 3,4-dihydropyrimidinone (1, 1.0 mmol),
paraformaldehyde (5.0 mmol, 5.0 equiv), and CH2Cl2 (5 mL), TMSCl (2.5 mmol, 2.5 equiv) were added
and the reaction mixture was stirred at 35 oC for 24 h. Sodium benzenesulfinate (3 mmol) was then added

HETEROCYCLES, Vol. 81, No. 8, 2010
1837
and the reaction mixture was stirred for an additional 12 h. The work-up was same as mentioned in above
processes, giving compounds 4a-h.
4a: Yield 76%; mp 193-194 oC. 1H NMR (400 MHz, CDCl3): δ = 7.96-7.94 (m, 2H, HAr), 7.68-7.55 (m,
3H, HAr), 7.35-7.27 (m, 5H, HAr), 5.67 (s, 1H, 4-CH), 5.30 (d, J = 14.4 Hz, 1H, NCHH), 4.14-4.05 (m, 2H,
13
OCH2CH3), 3.95 (d, J = 14.4 Hz, 1H, NCHH), 2.27 (s, 3H, 6-CH3), 1.24-1.12 (m, 3H, OCH2CH3). C
NMR (100 MHz, CDCl3): δ = 164.9, 151.8, 145.2, 139.9, 137.5, 134.2, 129.2, 128.9, 128.8, 128.7, 128.5,
127.6, 127.3, 102.2, 64.0, 60.5, 60.3, 18.3, 14.1. MS: m/z = 414 (M+). Anal. Calcd for C21H22N2O5S
(414.12): C 60.85, H 5.35, N 6.76. Found: C 61.00, H 5.43, N 6.88.
4b: Yield 85%; mp 206-207 oC. 1H NMR (400 MHz, CDCl3): δ = 7.85-7.81 (m, 3H, HAr), 7.36-7.26 (m,
6H, HAr), 5.65 (s, 1H, 4-CH), 5.28 (d, J = 14.4 Hz, 1H, NCHH), 4.14-4.04 (m, 2H, OCH2CH3), 3.93 (d, J
= 14.4 Hz, 1H, NCHH), 2.44 (s, 3H, CH3), 2.26 (s, 3H, 6-CH3), 1.26-1.18 (m, 3H, OCH2CH3). 13C NMR
(100 MHz, CDCl3): δ = 164.9, 151.9, 145.4, 145.3, 140.0, 134.6, 129.9, 128.9, 128.8, 128.7, 127.6, 102.2,
64.0, 60.5, 60.2, 21.7, 18.3, 14.1. MS: m/z = 428 (M+). Anal. Calcd for C22H24N2O5S (428.14): C 61.67, H
5.65, N 6.54. Found: C 61.52, H 5.57, N 6.41.
1
4c: Yield 80%; mp 195-197 oC H NMR (400 MHz, CDCl3): δ = 8.08 (br, 1H, NH), 7.95-7.93 (m, 2H,
HAr) 7.67-7.65 (m, 1H, HAr), 7.58-7.54 (m, 2H, HAr), 7.27-7.18 (m, 2H, HAr), 6.85-6.83 (m, 2H, HAr), 5.58
(s, 1H, 4-CH), 5.28 (d, J = 14.4 Hz, 1H, NCHH), 4.11-4.06 (m, 2H, OCH2CH3), 3.96 (d, J = 14.4 Hz, 1H,
13
NCHH), 3.78 (s, 3H, OCH3), 2.22 (s, 3H, CH3), 1.22-1.18 (m, 3H, OCH2CH3). C NMR (100 MHz,
CDCl3): δ = 164.9, 159.7, 152.3, 145.2, 137.6, 134.1, 132.1, 129.2, 128.8, 128.7, 114.0, 102.2, 63.9, 60.1,
59.9, 55.2, 18.1, 14.1. MS: m/z = 444 (M+). Anal. Calcd for C22H24N2O6S (444.14): C 59.45, H 5.44, N
6.30; Found: C 61.61, H 5.52, N 6.42.
1
4d: Yield 70%; mp 194-196 oC. H NMR (400 MHz, CDCl3): δ = 8.28 (br, 1H, NH), 7.82-7.80 (m, 2H,
HAr) 7.36-7.34 (m, 2H, HAr), 7.20-7.17 (m, 2H, HAr), 6.84-6.82 (m, 2H, HAr), 5.56 (s, 1H, 4-CH), 5.27 (d,
J = 14.4 Hz, 1H, NCHH), 4.13-4.03 (m, 2H, OCH2CH3), 3.99 (d, J = 14.4 Hz, 1H, NCHH) 3.78 (s, 3H,
OCH3), 2.44 (s, 3H, CH3), 2.23 (s, 3H, CH3) 1.25-1.18 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3):
δ = 165.0, 159.7, 152.2, 145.3, 145.1, 134.7, 132.1, 129.9, 128.9, 128.7, 127.6, 114.1, 102.2, 67.0, 63.9,
60.0, 55.2, 21.7, 18.1, 14.1. MS: m/z = 458 (M+). Anal. Calcd for C23H26N2O6S (458.15): C 60.25, H 5.72,
N 6.11. Found: C 60.37, H 5.81, N 6.02.
o
1
4e: Yield 79%; mp 197-199 C. H NMR (400 MHz, CDCl3): δ = 7.95-7.93 (m, 2H, HAr), 7.92 (br, 1H,
NH), 7.69-7.65 (m, 1H, HAr), 7.58-7.54 (m, 2H, HAr), 7.16-7.11 (m, 4H, HAr), 5.60 (s, 1H, 4-CH), 5.28 (d,
J = 14.4 Hz, 1H, NCHH), 4.13-4.04 (m, 2H, OCH2CH3), 3.96 (d, J = 14.4 Hz, 1H, NCHH), 2.33 (s, 3H,
CH3), 2.23 (s, 3H, 6-CH3), 1.22-1.19 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 164.9, 151.9,

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HETEROCYCLES, Vol. 81, No. 8, 2010
145.1, 138.5, 137.6, 136.9, 134.2, 129.5, 129.2, 128.8, 127.5, 102.3, 64.0, 60.2, 21.1, 18.3, 14.1. MS: m/z
= 428 (M+). Anal. Calcd for C22H24N2O5S (428.14): C 61.67, H 5.65, N 6.54. Found: C 61.80, H 5.58, N
6.43.
o
1
4f: Yield 86%; mp 196-198 C. H NMR (400 MHz, CDCl3): δ = 7.82-7.80 (m, 1H, HAr), 7.36-7.26 (m,
6H, HAr), 7.17-7.10 (m, 1H, HAr), 5.60 (s, 1H, 4-CH), 5.29 (d, J = 14.4 Hz, 1H, NCHH), 4.13-4.04 (m, 2H,
OCH2CH3), 3.93 (d, J = 14.4 Hz, 1H, NCHH), 2.44 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.26 (s, 3H, 6-CH3),
1.24-1.18 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 164.9, 151.7, 145.4, 145.1, 138.5, 137.0,
136.9, 134.6, 129.9, 129.5, 128.9, 127.6, 102.3, 64.0, 60.5, 21.8, 21.7, 18.3, 14.1. MS: m/z = 442 (M+).
Anal. Calcd for C23H26N2O5S (442.16): C 62.42, H 5.92, N 6.33. Found: C 62.60, H 5.83, N 6.45.
4g: Yield 70%; mp 166-168 oC. 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.4 Hz, 2H, HAr), 7.94 (d, J
= 8.4 Hz, 2H, HAr), 7.70 (br, 1H, NH), 7.60-7.57 (m, 3H, HAr), 7.26-7.24 (m, 2H, HAr), 5.87 (s, 1H, 4-CH),
5.34 (d, J = 14.4 Hz, 1H, NCHH), 4.17-4.11 (m, 2H, OCH2CH3), 3.85 (d, J = 14.4 Hz, 1H, NCHH), 2.29
13
(s, 3H, 6-CH3), 1.26-1.22 (m, 3H, OCH2CH3). C NMR (100 MHz, CDCl3): δ = 164.4, 151.5, 148.0,
147.0, 146.1, 137.2, 134.5, 129.4, 128.8, 128.5, 124.2, 101.5, 64.1, 60.7, 59.9. 18,6, 14.2. MS: m/z = 459
(M+). Anal. Calcd for C21H21N3O7S (459.11): C 54.89, H 4.61, N 9.15. Found: C 54.99, H 4.72, N 9.02.
4h: Yield 72%; mp 208-210 oC. 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2H, HAr), 7.80 (d, J
= 8.4 Hz, 2H, HAr), 7.50-7.48 (m, 2H, HAr), 7.38-7.30 (m, 2H, HAr), 7.27 (br, 1H, NH), 5.88 (s, 1H, 4-CH),
5.32 (d, J = 14.4 Hz, 1H, NCHH), 4.15-4.11 (m, 2H, OCH2CH3), 3.83 (d, J = 14.4 Hz, 1H, NCHH), 2.46
(s, 3H, CH3), 2.31 (s, 3H, 6-CH3), 1.25-1.21 (m, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 164.4
151.6 147.9 147.0 146.2 145.7 134.3 130.0 128.7 128.5 124.2 101.4 64.1 60.6 59.8 21.8 18.5 14.1 MS:
m/z = 473 (M+). Anal. Calcd for C22H23N3O7S (473.13): C 55.80, H 4.90, N 8.87. Found: C 55.92, H 4.99,
N 8.75.
General procedure compounds 5a-d: To a suspension of 3,4-dihydropyrimidinone (1.0 mmol),
paraformaldehyde (5.0 mmol), and CH2Cl2 (5 mL), TMSCl (2.5 mmol) were added and the reaction
o
mixture was stirred at 35 C for 24 h. Sodium azide (3 mmol) was then added and the reaction mixture
was stirred for an additional 8 h. The work-up was same as mentioned in above processes, giving
compounds 5a-d.
1
5a: Yield 72%; 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

HETEROCYCLES, Vol. 81, No. 8, 2010
1839
= 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. MS: m/z = 315 (M+).
Anal. Calcd for C15H17N5O3 (315.13): C 57.13, H 5.43, N 22.21. Found: C 57.25, H 5.25, N 22.07.
o
1
5b: Yield 74%; mp 184-186 C. H NMR (400 MHz, CDCl3): δ = 8.15 (br, 1H, NH), 7.28-7.25 (m, 2H,
HAr), 6.86-6.83 (m, 2H, HAr), 5.39 (s, 1H, 4-CH), 5.16 (d, J = 12.4Hz, 1H, NCHH), 4.24 (d, J = 12.4Hz,
1H, NCHH), 4.22-4.06 (m, 2H, OCH2CH3), 3.78 (s, 3H, OCH3), 2.36 (s, 3H, 6-CH3), 1.26-1.120 (m, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 165.2 159.5, 153.0, 145.2, 133.4, 128.6, 114.0, 102.5, 60.8,
60.2, 59.7, 55.2, 18.5, 14.2. MS: m/z = 345 (M+). Anal. Calcd for C16H19N5O4 (345.14): C 55.64, H 5.55,
N 20.28. Found: C 55.50, H 5.41, N 20.39.
1
5c: Yield 70%; mp 176-178 oC. H NMR (400 MHz, CDCl3): δ = 8.51 (br, 1H, NH), 7.26-7.23 (m, 2H,
HAr), 7.14-7.12 (m, 2H, HAr), 5.40 (s, 1H, 4-CH), 5.16 (d, J = 12.4Hz, 1H, NCHH), 4.17 (d, J = 12.4Hz,
1H, NCHH), 4.09-4.05 (m, 2H, OCH2CH3), 2.35 (s, 3H, CH3), 2.33 (s, 3H, 6-CH3), 1.26-1.120 (m, 3H,
13
OCH2CH3). C NMR (100 MHz, CDCl3): δ = 165.3, 153.3, 145.6, 138.3, 138.2, 129.4, 127.2, 102.3,
60.9, 60.1, 60.0, 21.1, 18.4, 14.1. MS: m/z = 329 (M+). Anal. Calcd for C16H19N5O3 (329.15): C 58.35, H
5.81, N 21.26. Found: C 58.25, H 5.69, N 21.39.
1
5d: Yield 75%; mp 180-182 oC. H NMR (400 MHz, CDCl3): δ = 8.35 (br, 1H, NH), 7.30-7.26 (m, 4H,
HAr), HAr), 5.42 (s, 1H, 4-CH), 5.10 (d, J = 12.8Hz, 1H, NCHH), 4.30 (d, J = 12.8Hz, 1H, NCHH),4.13-
4.07 (m, 2H, OCH2CH3), 2.35 (s, 3H, 6-CH3), 1.25-1.120 (m, 3H, OCH2CH3). 13C NMR (100 MHz,
CDCl3): δ = 165.0, 153.0, 145.9, 139.9, 134.2, 128.9, 128.7, 102.0, 61.1, 60.3, 59.8, 18.5, 14.2. MS: m/z =
349 (M+). Anal. Calcd for C15H16ClN5O3 (349.09): C 51.51, H 4.61, N 20.01. Found: C 51.42, H 4.53, N
20.17.
ACKNOWLEDGMENT
We are thankful for the financial support from the National Nature Science Foundation of China (No.
20902073), the Natural Science Foundation of Gansu Province (No. 096RJZA116), and Scientific and
Technological Innovation Engineering program of Northwest Normal University (nwnu-kjcxgc-03-64).
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graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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