Silica-supported perchloric acid (HClO4-SiO2): An efficient catalyst for one-pot synthesis of functionalized tetrahydropyrimidine derivatives

Article abstract of DOI:10.1002/jhet.1017

HClO₄-SiO₂ has been found to be a highly efficient catalyst for the synthesis of substituted tetrahydropyrimidine and bis-tertahydropyrimidine derivatives in good to excellent yields involving the reaction of dimethyl acetylenedicarboxylate, amines/diamines, and formaldehyde. One-pot, atom economy, high-bond forming efficiency, environmentally benign, good yields, and mild reaction conditions are some of the salient features of this multicomponent reaction.

Full text of DOI:10.1002/jhet.1017

1362
Silica-Supported Perchloric Acid (HClO4–SiO2): An Efficient
Catalyst for One-Pot Synthesis of Functionalized
Tetrahydropyrimidine Derivatives
Vol 49
*
Abu T. Khan, Md. Musawwer Khan, Deb Kumar Das, and Mohan Lal
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
*
E-mail: atk@iitg.ernet.in
Received April 21, 2011
DOI 10.1002/jhet.1017
View this article online at wileyonlinelibrary.com.
HClO4–SiO2 has been found to be a highly efficient catalyst for the synthesis of substituted tetrahydropyr-
imidine and bis-tertahydropyrimidine derivatives in good to excellent yields involving the reaction of
dimethyl acetylenedicarboxylate, amines/diamines, and formaldehyde. One-pot, atom economy, high-bond
forming efficiency, environmentally benign, good yields, and mild reaction conditions are some of the salient
features of this multicomponent reaction.
J. Heterocyclic Chem., 49, 1362 (2012).
INTRODUCTION
Owing to the importance of tetrahydropyrimidine derivatives,
a considerable attention has been paid to the synthesis of these
compounds over the years [13,14]. These methods are
associated with certain limitations such as use of expensive
and excess amount of catalyst, long reaction times and drastic
reaction conditions. In addition, the synthesis of bis-tetrahy-
dropyrimidine derivatives using MCRs has not yet been
reported. Therefore, there is a need to develop a synthetic
methodology using a catalyst, which might work under milder
reaction conditions.
HClO4–SiO2 is an inexpensive, nontoxic, reusable, environ-
mentally benign as well as highly efficient catalyst and it has
been utilized for various organic transformations [15]. The use-
fulness of this catalyst has been demonstrated by the authors for
geminal diacylation of aldehydes [16a], tetrahydropyranyla-
tion, oxathioacetalization and thioacetylation [16b], and aza-
Michael reaction [16c]. The efficiency of HClO4–SiO2 was
shown in other one-pot MCRs [17] and its advantage is going
to be explored further. In this article, the authors have reported
the synthesis of substituted tetrahydropyrimidine and bis-tetra-
hydropyramidine derivatives using HClO4–SiO2 as a heteroge-
neous catalyst (Scheme 1).
In recent times, multicomponent reactions (MCRs) have
emerged as an important and promising tool in organic
chemistry for construction of architecturally complex
molecules [1,2]. These reactions have been explored in
the total syntheses of natural products and synthetic building
blocks [2,3]. They avoid time-consuming, expensive processes
for purification of various precursors as well as cumbersome
steps of protection and deprotection of functional groups. In
addition, these reactions are environmentally benign and often
proceed with excellent chemoselectivities [4]. Hence, MCRs
are considered as a new type of “Green Chemistry.” To devise
a new selective cascade, reaction is a challenging task at the
forefront of organic chemistry so the interest in MCRs is in-
creasing gradually. Of late, the authors have developed various
synthetic methodologies using MCR approach to synthesize
new entities leading to chemical and pharmaceutical interest
[5].
Pyrimidine and its analogs are important class of nitrogen
heterocyclic pharmacophores, which are present in many
pharmaceuticals. Some of them are in clinical and preclinical
trial stage and also exhibits interesting biological activities
[6] such as muscarinic agonist activity [7], antiviral activity
[8], anti-inflammatory activity [9], and protein–nucleic acid
interactions [10]. Pyrimidine skeleton is a key structural motif
found in various naturally occurring compounds [11] and they
also serve as building block for various organic synthesis [12].
RESULTS AND DISCUSSION
For the present study, the catalyst HClO4–SiO2 was pre-
pared by following the published reports procedure [17].
© 2012 HeteroCorporation

November 2012 Silica-Supported Perchloric Acid (HClO4–SiO2): An Efficient Catalyst for One-Pot
1363
Synthesis of Functionalized Tetrahydropyrimidine Derivatives
Scheme 1. Synthesis of tetrahydropyrimidine derivatives.
R2
N
R2
N
H2N
NH2
O
R1NH2
( )
R2
n
CO2Me
MeO2C
MeO2C
N
H
H
6
4
3
N
N
( )
n = 2 - 5
N
R1
MeO2C
CO2Me
CO2Me
n
R2NH2
CO2Me
CO2Me
5a-o
1
2
7a-e
(84-96%)
(68-78%)
The reaction of dimethyl acetylenedicarboxylate (DMAD,
1), aniline (2a), and formaldehyde (3) using HClO4–SiO2
as a catalyst at room temperature was examined and it
smoothly converted into the functionalized tetrahydropyri-
midine derivative 5a within 1.5 h giving 95% yield.
The reaction conditions were optimized by varying the
amount of catalyst and stoichiometric ratios of the reactants
(DMAD, aniline, and formaldehyde) to obtain best result in
terms of reaction time and yield (Table 1, entries 1–4). The
optimized amount of catalyst (HClO4–SiO2) was deter-
mined to be 25 mg (0.125 mmol). The optimal amount of
the reactants such as DMAD (1), aniline (2a), and formal-
dehyde (3) was found to be 1.0, 2.0, and 2.5 equiv, respec-
tively. Various solvents namely MeCN, DMF, DCM,
MeOH, EtOH, and H2O were also screened and MeOH
was found to be the best solvent among them (Table 1,
entries 4–9).
the product 5a was obtained in 55% yield using the same
amount of catalyst. These results indicate that the catalyst
and solvent have definite role in the reaction both in terms
of time and yield. This might be due to lack of proper inter-
action between the reactants (Table 1, entry 11).
After optimization of the reaction conditions, the reac-
tion of 4-methylaniline (2 mmol) with DMAD (1 mmol),
formaldehyde (2.5 mmol) using HClO4–SiO2 (25 mg, 2.5
mol %) in methanol was performed. The product 5b was
obtained in 96% yield. The scope of this protocol was in-
vestigated using the same reaction condition for substituted
anilines. Me, Et, MeO, Cl, and Br were the substituents
that was used in these studies. The desired products 5c–i
were obtained in good to excellent yields.
The present method was also tested with aliphatic amines
namely n-butylamine, benzylamine, furfurylamine, and
cyclohexylamine under identical reaction conditions to fur-
nish tetrahydropyrimidines 5j–m in good yields (Table 2,
entries 10–13). It is observed that the aliphatic amines require
shorter reaction time than the aromatic amines.
The reaction was performed without the catalyst in
methanol at room temperature, which gave only 52% yield
after 5 h (Table 1, entry 10). In the case of neat reaction,
Table 1
Screening of reaction conditions for the synthesis of tetrahydropyrimidine 5a.
Entry
Solvent
Amount of Catalyst (in mg)
Molar ratio (1:2:3)
Time (h)
Yielda (%)
1
2
CH3OH
CH3OH
CH3OH
CH3OHb
CH3CN
DMF
DCM
EtOH
H2O
CH3OH
No solvent
25
50
1:2:4
1:2:4
1:2:3
1:2:2.5b
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:2:4
1:2:3
1.5
1.5
1.5
1.5b
2
2.5
2
1.5
2
95
94
95
95b
88
88
76
89
72
52
55
3
25
4b
5
25b
25
25
25
25
25
6
7
8
9
10
11
No catalyst
25
5
5
aIsolated yield.
bThe experimental condition is the best optimized condition for obtaining the product.
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A. T. Khan, M. M. Khan, D. K. Das, and M. Lal
Vol 49
Table 2
Scope of the one‐pot synthesis of tetrahydropyrimidines 5 catalyzed by HClO4–SiO2.
Entry
R1
R2
Time (h)
1.5
Product
Yielda (%)
1
2
3
4
5
5a
95
96
92
91
92
1.5
1.5
2.5
1.5
5b
5c
5d
5e
6
7
8
9
2.0
2.0
2.0
2.0
5f
5g
5h
5i
84
94
88
93
10
1.0
5j
95
(Continues)
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November 2012 Silica-Supported Perchloric Acid (HClO4–SiO2): An Efficient Catalyst for One-Pot
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Synthesis of Functionalized Tetrahydropyrimidine Derivatives
Table 2. (Continued)
Entry
11
R1
R2
Time (h)
1.0
Product
Yielda (%)
5k
92
12
13
1.0
1.5
5l
96
91
5m
14
15
2
2
5n
5o
86
88
aIsolated yield.
The substituent pattern of the pyrimidine ring at posi-
tions 1 and 3 can be altered by changing the sequence of
addition of the amines. The product 5n was obtained when
aniline (2a) was added with DMAD followed by the addi-
tion of benzylamine (2k) and formaldehyde (3), while the
product 5o was isolated by changing the order of the
Table 3
Scope of the one‐pot domino reaction for the synthesis of bis‐tetrahydropyrimidines.
Entry
n
Time (h)
Product
Yielda (%)
1
2
3
4
5
2, 6a
3, 6b
4, 6c
5, 6d
6, 6e
2
2
2
2
2
7a
7b
7c
7d
7e
74
71
76
68
78
aIsolated yields.
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A. T. Khan, M. M. Khan, D. K. Das, and M. Lal
Vol 49
Figure 1. X‐ray crystal structure of 7a (CCDC no. 756205).
amines that is benzylamine was added first followed by
aniline.
confirmed by single X-ray crystallographic data. The
tetrahydropyrimidine ring adopted envelope conformation
and the orientation of two rings are found to be anti to each
other as shown in Figure 1.
The reaction of other aliphatic diamines such as 1,3-diamine
(6b), 1,4-diamine (6c), 1,5-diamine (6d), and 1,6-diamine (6e)
were examined individually with DMAD (1), aniline (2a), and
formaldehyde (3) under the same experimental conditions and
the results are summarized in Table 3.
The synthetic utility of the present protocol was further
extended by synthesizing bis-pyrimidine derivatives. The
reaction of DMAD (1, 2 mmol) with ethylenediamine
(6a, 1 mmol), followed by addition of aniline (2a, 2 mmol)
and formaldehyde (5 mmol) using HClO4–SiO2 (50 mg, 5
mol %) as a catalyst provides a bis-tetrahydropyrimidine
derivative 7a (Table 3, entry 1). The product 7a was
1
fully characterized by H and 13C NMR spectra as well
A plausible mechanism for the formation of tetrahydropyri-
midine 5a involves the initial formation of hydroamination
as elemental analysis. The structure of compound 7a was
Scheme 2. Plausible mechanism for the formation of tetrahydropyrimidine.
CO2Me
NH2
O
MeO2C
MeO2C
HClO4-SiO2
MeOH, rt, 1h
N
2
H
H
N
CO2Me
1
3
5a
H
N
H2C
MeO2C
9
MeO2C
NH
8
Mannich -type reaction
MeO2C
MeO2C
MeO2C
MeO2C
10
nucleophilic addition
reaction
N
H
NH OH2
NH
H2C OH
11
Journal of Heterocyclic Chemistry
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November 2012 Silica-Supported Perchloric Acid (HClO4–SiO2): An Efficient Catalyst for One-Pot
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Synthesis of Functionalized Tetrahydropyrimidine Derivatives
1
Compound 5b. Yellow liquid (365 mg, 96%); H NMR (400
MHz, CDCl3): δ = 2.26 (s, 3 H), 2.30 (s, 3 H), 3.58 (s, 3 H),
3.72 (s, 3 H), 4.22 (s, 2 H), 4.85 (s, 2 H), 6.83 (d, J = 8.4 Hz, 2
H), 6.88 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 8.4 Hz, 2 H), 7.06
(d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 20.5,
21.0, 47.6, 51.4, 52.4, 69.2, 98.9, 118.1, 125.1, 129.8, 129.9,
130.6, 136.4, 140.9, 146.0, 147.0, 164.6, 166.2; IR (KBr):
product 8, which reacts with acid protonated imine 9 to form
intermediate 10 via Mannich-type reaction. The intermediate
10 reacts with acid protonated formaldehyde to give species
11 by nucleophilic addition reaction. Finally, the intermediate
11 undergoes intramolecular SN2 type reaction to furnish the
desired product 5a via elimination of a water molecule as
shown in Scheme 2. All the products 5a–o and 7a–e were char-
acterized by IR, 1H NMR, 13C NMR spectra, and by elemental
analysis.
2949, 2863, 1742, 1698, 1588, 1514, 1434, 1259, 1112 cm−1
Anal. Calcd for C22H24N2O4 (380.45): C, 69.46; H, 6.36; N,
7.36. Found: C, 69.54; H, 6.23; N, 7.12.
;
Compound 5c. Semi solid (376 mg, 92%); 1H NMR (400
MHz, CDCl3): δ = 1.19 0 (t, J = 7.6 Hz, 3 H), 1.21 (t, J = 7.2
Hz, 3 H), 2.53–2.63 (m, 4 H), 3.58 (s, 3 H), 3.73 (s, 3 H), 4.23
(s, 2 H), 4.86 (s, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 6.91
(d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 2 H), 7.09 (d, J =
8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 15.5, 15.9,
28.1, 28.5, 47.8, 51.6, 52.6, 69.3, 99.2, 118.3, 125.3, 128.7,
128.8, 137.3, 141.1, 142.8, 146.3, 147.1, 164.8, 166.4; IR (KBr):
2963, 2872, 1744, 1697, 1588, 1514, 1434, 1260, 1110 cm−1;
Anal. Calcd for C24H28N2O4 (408.50): C, 70.57; H, 6.91; N,
6.86. Found: C, 70.51; H, 6.80; N, 6.66.
CONCLUSION
In conclusion, the efficacy and generality of HClO4–SiO2 as
a versatile catalyst for the synthesis of tetrahydropyrimidines
using DMAD, amines, and formaldehyde have been demon-
strated. In addition, the synthesis of novel bis-tetrahydropyrimi-
dine derivatives has been achieved using aliphatic diamines
under the same experimental conditions. The salient features
of this protocol are good yields, mild reaction conditions,
superior atom economy, environmentally benign, easy accessi-
bility of the catalyst, and its cost effectiveness. These pyrimi-
dine derivatives can be used for other organic transformation
and these reactions are under progress.
Compound 5d. Yellow liquid (378 mg, 91%); 1H NMR
(400 MHz, CDCl3): δ = 2.12 (s, 3 H), 2.20 (s, 3 H), 2.24
(s, 3 H), 2.27 (s, 3 H), 3.52 (s, 3 H), 3.71 (s, 3 H), 4.04
(s, 2 H), 4.32 (d, J = 11.6 Hz, 1 H), 4.49 (d, J = 11.6 Hz, 1 H),
6.78 (d, J = 8.0 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.95
(d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 1 H), 7.14 (d, J =
8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 18.0, 18.1, 20.9,
21.1, 48.8, 51.4, 52.4, 69.8, 96.9, 121.4, 127.1, 127.3, 128.8,
131.7, 132.0, 137.7, 133.9, 136.4, 138.0, 138.8, 146.0, 148.4,
164.9, 166.5; IR (KBr): 2950, 2859, 1744, 1697, 1592, 1502,
1435, 1263, 1111 cm−1; Anal. Calcd for C24H28N2O4 (408.50): C,
70.57; H, 6.91; N, 6.86. Found: C, 70.43; H, 6.79; N, 6.71.
EXPERIMENTAL
Melting points were determined on a Büchi-melting point
apparatus. IR spectra were recorded on Perkin-Elmer 281 IR
1
spectrophotometer. H and 13C NMR spectra were recorded on
1
Varian 400 spectrometer using TMS internal standard; chemical
Compound 5e. Yellow liquid (379 mg, 92%); H NMR (400
1
shifts (δ scale) are reported in parts per million (ppm). H NMR
MHz, CDCl3): δ = 3.56 (s, 3 H), 3.72 (s, 3 H), 3.76 (s, 3 H),
3.77 (s, 3 H), 4.18 (s, 2 H), 4.77 (s, 2 H), 6.76 (d, J = 8.8 Hz, 2
H), 6.81 (d, J = 9.2 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.95
(d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 47.9,
51.5, 52.6, 55.5, 55.7, 70.8, 97.5, 114.4, 114.6, 120.5, 127.5,
136.2, 142.4, 147.7, 154.9, 158.4, 164.7, 166.4; IR (KBr):
spectra are reported in the order: multiplicity, coupling constant
(J value) in hertz (Hz), and no of protons. Elemental analyses
were carried out using Perkin-Elmer 2400 Series II CHNS/O an-
alyzer at the Department of Chemistry, Indian Institute of
Technology, Guwahati. Crystal data were collected with Bruker
Smart Apex-II CCD diffractometer using graphite monochro-
mated MoKα radiation (λ = 0.71073 Å) at 298 K.
2950, 2837, 1742, 1694, 1579, 1511, 1435, 1247, 1110 cm−1
;
Anal. Calcd for C22H24N2O6 (412.45): C, 64.07; H, 5.87; N,
6.79. Found: C, 63.96; H, 5.72; N, 6.48.
General procedure for the synthesis of tetrahydropyrimidine
derivatives 5. A mixture of DMAD (1 mmol) and amines (2 mmol)
in MeOH (3 mL) was stirred at room teperatutre for 10 min. Then
38% formaldehyde solution (200 mg, 2.5 mmol) in methanol (2 mL)
and the catalyst HClO4–SiO2 (25 mg, 1.25 mol%) were added
successively into the reaction vessel. After completion of reaction as
monitored by TLC, methanol was removed and the crude residue
was extracted with dichloromethane (2 × 20 mL). The organic layer
was washed with NaHCO3 solution, brine, and finally with water.
The solvent was removed and crude material was purified by
column chromatography using ethyl acetate/hexane (1:9) as eluent to
give the pure products 5a–o.
1
Compound 5f. Yellow liquid (346 mg, 84%); H NMR (400
MHz, CDCl3): δ = 3.50 (s, 3 H), 3.70 (s, 3 H), 3.71 (s, 3 H),
3.75 (s, 3 H), 4.21 (s, 2 H), 4.80 (br s, 2 H), 6.67–6.71 (m, 2
H), 6.77 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.91
(t, J = 7.6 Hz, 1 H), 6.99 (t, J = 7.6 Hz, 1 H), 7.12 (td, J =
7.2 Hz, J = 2.4 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H); 13C NMR
(100 MHz, CDCl3): δ = 48.0, 51.4, 52.4, 55.5, 55.9, 68.4, 97.4,
111.3, 111.9, 120.4, 120.8, 121.0, 124.0, 128.5, 128.52, 131.7,
137.9, 147.8, 152.2, 155.4, 164.6, 166.4; IR (KBr): 2949, 2838,
1743, 1693, 1581, 1501, 1436, 1264, 1108 cm−1; Anal. Calcd
for C22H24N2O6 (412.45): C, 64.07; H, 5.87; N, 6.79. Found: C,
64.01; H, 5.71; N, 6.63.
1
Compound 5a. Yellow liquid (334 mg, 95%); H NMR (400
MHz, CDCl3): δ = 3.58 (s, 3 H), 3.74 (s, 3 H), 4.27 (s, 2 H),
4.92 (s, 2 H), 6.91 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H),
7.16–7.29 (m, 6 H); 13C NMR (100 MHz, CDCl3): δ = 47.7, 51.7,
52.6, 69.0, 100.7, 118.0, 121.3, 125.2, 126.6, 129.4, 143.8, 146.7,
148.4, 164.7, 166.3; IR (KBr): 2950, 1743, 1697, 1580, 1495,
1261, 1112 cm−1; Anal. Calcd for C20H20N2O4 (352.39): C, 68.17;
H, 5.72; N, 7.95; Found: C, 68.01; H, 5.61; N, 7.73.
Compound 5g. Light yellow solid (396 mg, 94%); mp 128–130°
C; H NMR (400 MHz, CDCl3): δ = 3.61 (s, 3 H), 3.75 (s, 3 H),
4.23 (s, 2 H), 4.85 (s, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.90
(d, J = 8.8 Hz, 2 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.24 (d, J = 8.8 Hz,
2 H); 13C NMR (100 MHz, CDCl3): δ = 47.6, 51.9, 52.9, 69.1,
101.6, 119.3, 126.2, 126.5, 129.4, 129.7, 132.3, 142.2, 146.1,
146.7, 164.4, 165.9; IR (KBr): 2953, 1744, 1688, 1571, 1491,
1
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A. T. Khan, M. M. Khan, D. K. Das, and M. Lal
Vol 49
1266, 1228, 1117 cm−1; Anal. Calcd for C20H18N2O4Cl2
(421.28): C, 57.02; H, 4.30; N, 6.65. Found: C, 56.91; H, 4.19;
N, 6.42.
Compound 5n. Yellow liquid (315 mg, 86%); 1H NMR (400 MHz,
CDCl3): δ = 3.63 (s, 3 H), 3.67 (s, 3 H), 3.71 (s, 2 H), 3.81 (s, 2 H),
4.36 (s, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 1 H),
7.24 (br s, 5 H), 7.30 (t, J = 7.2 Hz, 2 H); 13C NMR (100 MHz,
CDCl3): δ = 48.8, 51.4, 52.6, 56.7, 69.8, 97.3, 124.8, 126.3, 127.5,
128.4, 129.0, 129.3, 137.8 143.7, 145.9, 164.8, 166.8; IR (KBr):
2951, 2860, 1739, 1688, 1582, 1284, 1247, 1109 cm−1; Anal. Calcd
for C21H22N2O4 (366.42): C, 68.84; H, 6.05; N, 7.65. Found: C,
68.72; H, 5.91; N, 7.49.
1
Compound 5h. Yellow liquid (371 mg, 88%); H NMR (400
MHz, CDCl3): δ = 3.65 (s, 3 H), 3.76 (s, 3 H), 4.23 (s, 2 H),
4.87 (s, 2 H), 6.72 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 H), 6.83 (t, J
= 2.0 Hz, 1 H), 6.86 (dq, J = 8.0 Hz, J = 0.8 Hz, 1 H), 6.90
(dq, J = 8.0 Hz, J = 1.2 Hz, 1 H), 7.04 (t, J = 2.4 Hz, 1 H),
7.12 (t, J = 8.0 Hz, 1 H), 7.17 (m, 1 H), 7.22 (t, J = 8.0 Hz, 1
H); 13C NMR (100 MHz, CDCl3): δ = 47.7, 52.0, 52.9, 68.2,
103.4, 115.5, 117.7, 121.3, 122.6, 124.7, 126.7, 130.5, 130.6,
135.2, 135.3, 144.9, 145.6, 149.2, 164.5, 165.9; IR (KBr):
2950, 2843, 1742, 1703, 1591, 1482, 1262, 1114 cm−1; Anal.
Calcd for C20H18N2O4Cl2 (421.28): C, 57.02; H, 4.30; N, 6.65.
Found: C, 56.98; H, 4.17; N, 6.50.
Compound 5i. Light yellow solid (474 mg, 93%); mp 150–152°C;
1H NMR (400 MHz, CDCl3): δ = 3.62 (s, 3 H), 3.75 (s, 3 H), 4.22
(s, 2 H), 4.85 (s, 2 H), 6.75 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz,
2 H), 7.30 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H); 13C NMR
(100 MHz, CDCl3): δ = 47.6, 51.8, 52.9, 68.8, 101.8, 113.7, 119.5,
120.1, 126.3, 132.3, 132.6, 142.7, 145.9, 147.2, 164.4, 165.9; IR
(KBr): 2951, 1744, 1689, 1591, 1568, 1487, 1265, 1227, 1116 cm−1;
Anal. Calcd for C20H18N2O4Br2 (510.20): C, 47.08; H, 3.56; N, 5.49.
Found: C, 47.01; H, 3.42; N, 5.29.
Compound 5o. Yellow liquid (322 mg, 88%); 1H NMR (400 MHz,
CDCl3): δ = 3.73 (s, 3 H), 3.85 (s, 3 H), 4.12 (s, 2 H), 4.21 (s, 2 H),
4.42 (s, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.90 (t, J = 7.6 Hz, 1 H),
7.17–7.24 (m, 4 H), 7.26–7.31 (m, 3 H); 13C NMR (100 MHz,
CDCl3): δ = 46.4, 51.4, 53.0, 54.5, 65.4, 94.8, 117.8, 121.2, 128.0,
128.1, 128.8, 129.3, 135.8, 148.4, 149.0, 165.5, 166.4; IR (KBr):
2963, 2872, 1744, 1697, 1588, 1514, 1260, 1110 cm−1; Anal. Calcd
for C21H22N2O4 (366.42): C, 68.84; H, 6.05; N, 7.65. Found: C,
68.72; H, 5.88; N, 7.48.
General reaction procedure for functionalized bis-
tetrahyropyrimidines 7. A mixture of DMAD (1 mmol) and
diamines (1 mmol) in MeOH (2 mL) was stirred at room teperatutre
for 20 min. Aniline (2 mmol) in MeOH (1 mL) and formaldehyde
(38%, 400 mg, 5 mmol) in methanol (2 mL) were added into it.
Finally, the catalyst silica supported perchloric acid (50 mg, 2.5 mol
%) was added into the reaction vessel. After completion of reaction
as monitored by TLC, the same work up procedure was followed as
above. The products 7a–e were obtained by purification through
column chromatography using ethyl acetate/hexane (1:9) as eluent.
Compound 7a. Light yellow solid (428 mg, 74%); mp 104–106°C;
1H NMR (400 MHz, CDCl3): δ = 2.98 (s, 4 H), 3.71 (s, 6 H), 3.88
(s, 6 H), 4.01 (s, 4 H), 4.44 (s, 4 H), 6.92–6.96 (m, 6 H), 7.25–7.29
(m, 4 H); 13C NMR (100 MHz, CDCl3): δ = 46.3, 50.5, 51.6, 53.3,
67.9, 96.2, 118.1, 121.7, 129.6, 148.2, 148.5, 165.4, 166.2; IR
(KBr): 2949, 1741, 1684, 1575, 1497, 1427, 1270, 1219, 1151, 1097
cm−1; Anal. Calcd for C30H34N4O8 (578.63): C, 62.27; H, 5.92; N,
9.68. Found: C, 62.11; H, 5.83; N, 9.82.
Compound 5j. Yellow liquid (297 mg, 95%); 1H NMR
(400 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H), 0.93 (t, J = 7.2 Hz,
3 H), 1.24–1.32 (m, 2 H), 1.34–1.41 (m, 2 H), 1.47–1.56 (m, 4 H),
2.53 (t, J = 7.6 Hz, 2 H), 3.01 (t, J = 7.6 Hz, 2 H), 3.50 (s, 2 H),
3.64 (s, 3 H), 3.90 (s, 3 H), 3.98 (s, 2 H); 13C NMR (100 MHz,
CDCl3): δ = 13.9, 14.2, 20.0, 20.6, 30.3, 31.4, 48.2, 51.0, 52.6,
52.8, 67.7, 91.1, 148.4, 165.6, 167.1; IR (KBr): 2956, 2870, 1743,
1689, 1582, 1434, 1285, 1249, 1145 cm−1; Anal. Calcd for
C16H28N2O4 (312.41): C, 61.51; H, 9.03; N, 8.97. Found: C,
61.51; H, 8.92; N, 8.81.
1
Compound 5k. Yellow liquid (350 mg, 92%); H NMR (400
MHz, CDCl3): δ = 3.55 (s, 2 H), 3.60 (s, 2 H), 3.65 (s, 3 H),
3.84 (s, 2 H), 3.91 (s, 3 H), 4.16 (s, 2 H), 7.15–7.18 (m, 2 H),
7.22–7.32 (m, 8 H); 13C NMR (100 MHz, CDCl3): δ = 48.4,
51.3, 53.1, 54.4, 57.1, 66.1, 92.2, 127.4, 128.2, 128.24, 128.5,
128.9, 136.3, 138.1, 148.4, 165.8, 167.1; IR (KBr): 2949, 2855,
1740, 1689, 1582, 1434, 1286, 1110 cm−1; Anal. Calcd for
C22H24N2O4 (380.45): C, 69.46; H, 6.36; N, 7.36. Found: C,
69.39; H, 6.25; N, 7.18.
Compound 7b. Yellow liquid (421 mg, 71%); 1H NMR (400 MHz,
CDCl3): δ = 1.48 (t, J = 7.2 Hz, 2 H), 2.90 (t, J = 7.2 Hz, 4 H), 3.69
(s, 6 H), 3.84 (s, 6 H), 4.04 (s, 4 H), 4.36 (s, 4 H), 6.93–6.96
(m, 6 H), 7.28 (t, J = 7.6 Hz, 4 H); 13C NMR (100 MHz, CDCl3):
δ = 28.4, 46.6, 48.6, 51.5, 53.1, 66.5, 95.3, 118.5, 121.8, 129.6,
148.7, 165.5, 166.3; IR (KBr): 2950, 1739, 1689, 1596, 1583, 1435,
1257, 1149 cm−1; Anal. Calcd for C31H36N4O8 (592.65): C, 62.83;
H, 6.13; N, 9.45. Found: C, 62.70; H, 6.02; N, 9.22.
1
Compound 5l. Yellow liquid (350 mg, 96%); H NMR (400
1
MHz, CDCl3): δ = 1.03–1.3 (m, 8 H), 1.35–1.45 (m, 2 H),
1.62–1.92 (m, 10 H), 2.43–2.52 (m, 1 H), 2.97 (tt, J = 11.6 Hz,
J = 4.8 Hz, 1H), 3.54 (s, 2 H), 3.64 (s, 3 H), 3.90 (s, 3 H), 4.01
(s, 2 H); 13C NMR (100 MHz, CDCl3): δ = 25.3, 25.6, 25.9,
26.1, 30.5, 31.4, 45.5, 51.0, 52.8, 59.0, 60.0, 60.2, 92.7, 149.0,
166.0, 166.8; IR (KBr): 2932, 1742, 1688, 1582, 1435, 1287,
1239, 1117 cm−1; Anal. Calcd for C20H32N2O4 (364.49): C,
65.91; H, 8.85; N, 7.69. Found: C, 65.79; H, 8.75; N, 7.53.
Compound 5m. Yellow liquid (328 mg, 91%); 1H NMR (400
MHz, CDCl3): δ = 3.59 (s, 2 H), 3.63 (s, 2 H), 3.65 (s, 3 H), 3.92
(s, 3 H), 4.05 (s, 2 H), 4.19 (s, 2 H), 6.13 (d, J = 3.2 Hz, 1 H),
6.26 (d, J = 3.2 Hz, 1 H), 6.30 (d, J = 3.0 Hz, 1 H), 6.33
(d, J = 3.0 Hz, 1 H), 7.37–7.38 (m, 2 H); 13C NMR (100 MHz,
CDCl3): δ = 46.9, 47.8, 49.2, 51.3, 66.3, 92.5, 109.2, 110.3,
110.8, 142.7, 143.0, 149.9, 151.5, 165.3, 166.9; IR (KBr):
Compound 7c. Yellow liquid (461 mg, 76%); H NMR (400
MHz, CDCl3): δ = 1.24 (br s, 4 H), 2.88 (br s, 4 H), 3.70 (s, 6 H),
3.85 (s, 6 H), 4.05 (s, 4 H), 4.43 (s, 4 H), 6.93 (t, J = 7.6 Hz,
2 H), 6.96 (d, J = 8.8 Hz, 4 H), 7.62 (t, J = 7.6 Hz, 4 H);
13C NMR (100 MHz, CDCl3): δ = 25.9, 46.3, 50.5, 51.3, 52.9,
66.1, 94.0, 118.2, 121.4, 129.4, 148.6, 148.9, 165.3, 166.3; IR
(KBr): 2949, 1739, 1688, 1580, 1434, 1258, 1145 cm−1; Anal.
Calcd for C32H38N4O8 (606.68): C, 63.35; H, 6.31; N, 9.24.
Found: C, 63.21; H, 6.11; N, 9.00.
Compound 7d. Yellow liquid (422 mg, 68%); 1H NMR (400 MHz,
CDCl3): δ = 0.94–0.99 (m, 2 H), 1.25–1.32 (m, 4 H), 2.92 (t, J = 7.6
Hz, 4 H), 3.70 (s, 6 H), 3.85 (s, 6 H), 4.08 (s, 4 H), 4.09 (s, 4 H),
6.94 (t, J = 7.2 Hz, 2 H), 6.98 (d, J = 7.6 Hz, 4 H), 7.28 (t, J = 7.6
Hz, 4 H); 13C NMR (100 MHz, CDCl3): δ = 23.5, 28.8, 46.5, 51.0,
51.4, 53.0, 66.4, 93.9, 118.4, 121.6, 129.5, 148.8, 149.0, 165.4,
166.4; IR (KBr): 2950, 1739, 1687, 1579, 1434, 1257, 1146, 1090
cm−1; Anal. Calcd for C33H40N4O8 (620.70): C, 63.86; H, 6.49; N,
9.03. Found: C, 63.73; H, 6.43; N, 9.21.
2951, 1739, 1688, 1582, 1435, 1284, 1247, 1188, 1109 cm−1
;
Anal. Calcd for C18H20N2O6 (360.37): C, 59.99; H, 5.59; N,
7.77. Found: C, 59.91; H, 5.48; N, 7.61.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Silica-Supported Perchloric Acid (HClO4–SiO2): An Efficient Catalyst for One-Pot
1369
Synthesis of Functionalized Tetrahydropyrimidine Derivatives
[6] (a) Looper, R. E.; Runnegar, M. T. C.; Williams, R. M. Angew
Chem Int Ed 2005, 44, 3879; (b) Kobayashi, J.; Kanda, F.; Ishibashi, M.;
Shigemori, H. J Org Chem 1991, 56, 4574.
Compound 7e. White solid (495 mg, 78%); mp 150–152°C;
1H NMR (400 MHz, CDCl3): δ = 1.01 (br s, 4 H), 1.33 (br s, 4 H),
2.96 (t, J = 7.2 Hz, 4 H), 3.70 (s, 6 H), 3.86 (s, 6 H), 4.09 (s, 4 H),
4.50 (s, 4 H), 6.93 (t, J = 7.2 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 4 H),
7.28 (t, J = 7.6 Hz, 4 H); 13C NMR (100 MHz, CDCl3): δ = 26.3,
29.0, 46.5, 51.2, 51.4, 53.0, 66.4, 93.8, 118.4, 121.5, 129.5, 148.8,
149.1, 165.4, 166.4; Anal. Calcd for C34H42N4O8 (634.73): C,
64.34; H, 6.67; N, 8.83. Found: C, 64.30; H, 6.52; N, 8.69.
[7] (a) Messer, W. S.; Abuh, Y. F.; Liu, Y.; Periyasamy, S.; Ngur,
D. O.; Edgar, M. A. N.; Eissadi, S.; Sbeih, A. A.; Dunbar, P. G.; Roknich,
S.; Rho, T.; Fang, Z.; Ojo, B.; Zhang, H.; Huzl, J. J.; Nagy, P. I. J Med
Chem 1997, 40, 1230. (b) Dunbar, P. G.; Durant, G. J.; Rho, T.;
Ojo, B.; Huzl, J. J.; Smith, D. A.; El-Assadi, A. A.; Sbeih, S.; Ngur, D. O.;
Periyassamy, S.; Hoss, W.; Messer, W. S. Jr. J Med Chem 1994, 37,
2774. (c) Dunbar, P. G.; Durant, G. J.; Fang, Z.; Abuh, Y. F.; El-Assadi,
A. A.; Ngur, D. O.; Periyasamy, S.; Hoss, W. P.; Messer, W. S. J Med
Chem 1993, 36, 842.
[8] (a) Nair, V.; Chi, G.; Ptak, R.; Neamati, N. J Med Chem 2006,
49, 445; (b) Zhou, S.; Kern, E. R.; Gullen, E.; Cheng, Y. C.; Drach, J. C.;
Matsumi, S.; Mitsuya, H.; Zemlicka, J. J Med Chem 2004, 47, 6964.
[9] Chantrapromma, K.; James, S.; Manis, M.; Ganem, B.
Tetrahedron Lett 1980, 21, 2475.
Crystallographic description of 7a. Crystal data were
collected with Bruker Smart Apex-II CCD diffractometer using
graphite monochromated MoKα radiation (λ = 0.71073 Å) at
298 K. Complete crystallographic data of 7a has been deposited
with the Cambridge Crystallographic Data Centre, CCDC no. is
756205. Copies of this information may be obtained free of
charge from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-
1223-336033, e-mail: deposit@ccdc.cam.ac.uk or via: www.
ccdc.cam.ac.uk).
[10] Malin, G.; Iakobashvili, R.; Lapidot, A. J Biol Chem 1999,
274, 6920.
[11] (a) Endo, T.; Tsuda, M.; Fromont, J.; Kobayashi, J. J Nat Prod
2007, 70, 423; (b) Costa, E. V.; Pinheiro, M. L. B.; Xavier, C. M.; Silva, J.
R. A.; Amaral, A. C. F.; Souza, A. D. L.; Barison, A.; Campos, F. R.;
Ferreira, A. G.; Machado, G. M. C.; Leon, L. L. P. J Nat Prod 2006, 69,
292; (c) Lin, Y. L.; Huang, R. L.; Chang, C. M.; Kuo, Y. H. J Nat Prod
1997, 60, 982.
[12] (a) Zamri, A.; Sirockin, F.; Abdallah, M. A. Tetrahedron
1999, 55, 5157; (b) Shutalev, A. D.; Fesenko, A. A.; Cheshkov, D. A.;
Goliguzov, D. V. Tetrahedron Lett 2008, 49, 4099.
[13] (a) Möhrle, H.; Reinhardt, H. W. Arch Pharm 1981, 314, 767;
(b) Cho, H.; Shima, K.; Hayashimatsu, M.; Ohnaka, Y.; Mizuno, A.;
Takeuchi, Y. J Org Chem 1985, 50, 4227; (c) Chanda, K.; Dutta, M. C.;
Karim, E.; Vishwakarma, J. N. J Heterocycl Chem 2004, 41, 627; (d)
Zhao, F.; Liu, J. J Fluorine Chem 2004, 125, 1491.
[14] (a) Qiuhua, Z.; Huanfeng, J.; Jinghao, L.; Min, Z.; Xiujun, W.;
Chaorong Q. Tetrahedron 2009, 65, 4604; (b) Zhang, M.; Jiang, H.; Liu,
H.; Zhu, Q. Org Lett 2007, 9, 4111; (c) Cao, H.; Wang, X.; Jiang, H.; Zhu,
Q.; Zhang, M.; Liu, H. Chem Eur J 2008, 14, 11623.
[15] (a) Chakraborti, A. K.; Gulhane, R. Chem Commun 2003,
1896; (b) Misra, A.; Tiwari, P.; Agnihotri, G. Synthesis 2005, 260; (c)
Kamble, V. T.; Jamode, V. S.; Joshi, N. S.; Biradar, R. A. V.; Deshmukh,
Y. Tetrahedron Lett 2006, 47, 5573; (d) Du, Y.; Wei, G.; Cheng, S.; Hue,
Y.; Linhardt, R. J. Tetrahedron Lett 2006, 47, 307; (e) Agarwal, A.; Rani,
S.; Vankar, Y. D. J Org Chem 2004, 69, 6137; (f) Maheswara, M.;
Siddaiah, V.; Rao, Y. K.; Tzeng, Y. -M.; Sridhar, C. J Mol Catal A Chem
2006, 260, 179; (g) Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.;
Nagarapu, L. J Mol Catal A Chem 2007, 266, 104; (h) Narasimhulu,
M.; Reddy, T. S.; Mahesh, K. C.; Prabhkar, P.; Rao, C. B.; Venkates-
warlu, Y. J Mol Catal A Chem 2007, 266, 114; (i) Kantevri, S.; Bantu,
R.; Nagarapu, L. J Mol Catal A Chem 2007, 269, 53.
Acknowledgment. Md. Musawwer Khan and Mohan Lal are
thankful to UGC and CSIR for their research fellowship. Deb
Kumar Das acknowledges to IIT Guwahati for his research
fellowship. The authors are thankful to DST for providing XRD
facility under the FIST program. The authors are thankful to Dr.
R. Subramanian at IIT Patna for necessary language corrections.
REFERENCES AND NOTES
[1] (a) Schreiber, S. L.; Science 2000, 287, 1964; (b) Snyder,
S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J Am Chem
Soc 2009, 131, 1753; (c) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.;
Pham, S. M.; Zhang, L. J Am Chem Soc 2005, 127, 2836; (d) Trost, B. M.
Angew Chem Int Ed 1995, 34, 259; (e) Trost, B. M. Acc Chem Res 2002,
35, 695.
[2] (a) Tietze, L. F.; Brazel, C. C.; Holsken, S.; Magull, J.; Ringe,
A. Angew Chem Int Ed 2008, 47, 5246; (b) Yang, J. W.; Fonseca, H. M.
T.; List, B. J. Am Chem Soc 2005, 127, 15036; (c) Enders, D.; Hüttl, M.
R. M.; Grondal, C.; Raab, G. Nature 2006, 441, 861.
[3] (a) Zhu, J.; Bienaymé, H.; Multicomponent Reactions; Wiley-VCH:
Weinheim, Germany, 2006; (b) Tietze, L. F.; Brasche, G.; Gericke, K. M.;
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2006; (c) Dömling, A. Chem Rev 2006, 106, 17.
[4] (a) Tietze, L. F. Chem Rev 1996, 96, 115; (b) Enders, D.;
Huettl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861.
[5] (a) Khan, A. T.; Parvin, T.; Choudhury, L. H. J Org Chem
2008, 73, 8398; (b) Khan, A. T.; Parvin, T.; Choudhury, L. H. Eur J
Org Chem 2008, 5, 834; (c) Khan, A. T.; Khan, M. M.; Bannuru, K. K.
R. Tetrahedron 2010, 66, 7762; (d) Khan, A. T.; Lal, M.; Khan, M. M.
Tetrahedron Lett 2010, 51, 4419.
[16] (a) Khan, A. T.; Choudhury, L. H.; Ghosh, S. J Mol Catal A
Chem 2006, 255, 230; (b) Khan, A. T.; Parvin, T.; Choudhury, L. H.
Synthesis 2006, 15, 2497; (c) Khan, A. T.; Ghosh, S.; Choudhury, L. H.
Eur J Org Chem 2006, 9, 2226.
[17] (a) Kumar, A.; Sharma, S.; Maurya, R. A. Tetrahedron Lett
2009, 50, 5937; (b) Reza, S. H.; Asghar, H.; Majid, G. Synth Commun
2008, 38, 3766.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet