An effective Biginelli-type synthesis of 1-methoxy-3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2015.06.041

Abstract The ternary condensation of N-methoxyurea, aldehydes, and 1,3-dicarbonyl compounds, resulting in novel 1-methoxy-3,4-dihydropyrimidin-2(1H)-ones has been examined. Commonly used reaction conditions and catalysts (EtOH/HCl, HOAc, DMF) proved to be

Full text of DOI:10.1016/j.tetlet.2015.06.041

Accepted Manuscript
An effective Biginelli-type synthesis of 1-methoxy-3,4-dihydropyrimi-
din-2(1H)-ones
Maksim A. Kolosov, Olesia G. Kulyk, Muataz J.K. Al-Ogaili, Valeriy D. Orlov
PII:
S0040-4039(15)01034-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.041
TETL 46433
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
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8 June 2015
13 June 2015
Please cite this article as: Kolosov, M.A., Kulyk, O.G., Al-Ogaili, M.J.K., Orlov, V.D., An effective Biginelli-type
synthesis of 1-methoxy-3,4-dihydropyrimidin-2(1H)-ones, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.06.041
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Graphical Abstract
An effective Biginelli-type synthesis of 1-
methoxy-3,4-dihydropyrimidin-2(1H)-ones
Maksim A. Kolosov, Olesia G. Kulyk, Muataz J. K. Al-Ogaili and Valeriy D. Orlov

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An effective Biginelli-type synthesis of 1-methoxy-3,4-dihydropyrimidin-2(1H)-ones
Maksim A. Kolosov , Olesia G. Kulyk, Muataz J. K. Al-Ogaili and Valeriy D. Orlov
Department of Organic chemistry, V.N.Karazin Kharkiv National University, Svobody sq., 4, 61022, Kharkiv, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The ternary condensation of N-methoxyurea, aldehydes and 1,3-dicarbonyl compounds,
resulting in novel 1-methoxy-3,4-dihydropyrimidin-2(1H)-ones has been examined. Commonly
used reaction conditions and catalysts (EtOH/HCl, HOAc, DMF) proved to be unsuitable and we
found that the DMF–TMSCl system was the best catalyst. Similarly, the reaction of ureas with
4-chlorobenzaldehyde and 1,3-cyclohexanedione using the DMF/TMSCl system afforded
3,4,7,8-tetrahydroquinazolin-2,5(1H,6H)-diones, while other catalyst systems resulted in the
formation of product mixtures. In addition, we have developed an effective and simple protocol
for the synthesis of N-(methoxy)urea.
Available online
Keywords:
Biginelli reaction
3,4-dihydropyrimidin-2(1H)-ones
N-(methoxy)urea
2009 Elsevier Ltd. All rights reserved.
TMSCl
3,4,7,8-tetrahydroquinazolin-2,5(1H,6H)-diones
The Biginelli reaction has emerged as an extremely popular
tool in synthetic organic chemistry over the last few years.1 This
ternary condensation of urea (thiourea), aldehydes and 1,3-
dicarbonyl compounds results in the formation of 3,4-
dihydropyrimidin-2(1H)-ones (DHPMs).2 The latter have been
reported to exhibit a wide range of biological activities and are
analogs of unsymmetrical dihydropyridines such as amlodipine
and nimodipine.3 Moreover, the Biginelli reaction allows the
introduction of up to five different substituents on the DHPM
ring in one step, making it an important method for
straightforward functionalization.4
synthesis of the target 1-alkoxyDHPMs. Thus, the main target of
the present research was to study the possibility of introducing N-
(methoxy)urea to the Biginelli reaction using conditions which
had previously been successfully used in the syntheses of 1-
unsubstituted, 1-alkyl and 1-aryl-DHPMs.1a,6 Herein, we wish to
report the results of our study on the Biginelli DHPM synthesis
with N-(methoxy)urea.
There are three main approaches to the synthesis of Biginelli
DHPMs.1-5 The first one is classical and consists of the ternary
condensation of ureas, aldehydes and 1,3-dicarbonyl compounds
under varying conditions using alcohol/strong acid systems,8
HOAc,8a,9 DMF,10 DMF/TMSCl (Scheme 1).6,11 The second
approach, proposed by Atwal, proceeds via the NaHCO3–
promoted two-component reaction of urea with 2-methylene 1,3-
dicarbonyls.12 The third approach developed by Shutalev is the
ternary reaction of aldehydes, urea and sulfinic acids, followed
by amidoalkylation of 1,3-dicarbonyl compounds and subsequent
ring closure.13 The last approach does not have general
applicability and can only be used in cases where labile/reactive
substrates (or products) demand acid-free/mild conditions.
Though the first two approaches each have their limitations and
drawbacks, we selected them for our studies.
While certainly a useful method for DHPM synthesis, the
Biginelli reaction has attracted the attention of hundreds of
scientists all over the world. Unfortunately, much of the attention
has focused on the most popular topic of investigation of the
effect (e.g. the influence of solvents, conditions or catalysts,
microwave irradiation, ultrasonication) on the yields of the
Biginelli DHPMs.1d,5 In most cases, no new compounds have
been synthesized, and only new conditions and catalysts have
been examined.
Nevertheless, several mechanistic details still remain unclear
and several significant steps have been made in the Biginelli
DHPM synthesis. For example, N-arylureas and 1N,3N-
dialkylureas were recently successfully used in the Biginelli
reaction,6 thus providing entrance to previously unknown N-
functionalized DHPMs.1a,7 Additionally, we noted that no
attempts to introduce N-(alkoxy)ureas in the Biginelli reaction
had been made at the present time.
The question to be solved was whether the alpha-effect, steric
h—in—dra—nce and lability of the N-alkoxy group would allow the
 Corresponding author. Tel.: +38-057-707-5613; fax: +38-057-705-0241; e-mail: kolosov@univer.kharkov.ua

2
Tetrahedron
Scheme 2. Synthesis of N-(methoxy)urea and 1-
methoxyDHPMs.
Scheme 1. Common approaches to the synthesis of Biginelli
DHPMs.
Thus, we initially examined whether 1-methoxyDHPMs 2
could be obtained either by the classical Biginelli reaction of
N-(methoxy)urea 1 with benzaldehyde and ethyl acetoacetate
(Scheme 2, routes a–d), or through the Atwal modification
starting from ethyl 2-benzylidene-3-oxobutanoate 3 (Scheme 2,
routes e and f). The starting N-(methoxy)urea 1 could easily be
obtained in three steps from acetophenone oxime, as depicted in
Scheme 2. The method was highly effective and suitable for the
synthesis of other N-(alkoxy)ureas.
Figure 1. Identified components from the reaction mixture
of the TMSCl-DMF-catalyzed synthesis of DHPM 2.
In each case, after reaction completion (TLC), analysis of the
residue by 1H NMR, TLC and MS revealed that in the cases a, b
and c DHPM 2 had not been formed. Moreover, we failed to
obtain 1-MeO-DHPM 4 by the reaction of 4-nitrobenzaldehyde
with N-(methoxy)urea 1 and ethyl acetoacetate in AcOH. The
reaction of 4-nitrobenzaldehyde is usually known to give good
results in the Biginelli reaction;14 however, the only isolated
reaction product was 4-nitrobenzaldehyde O-methyloxime 5.15
Trace amounts of the target DHPM 2 were detected in the cases
of e and f, and route d gave the best result with more than 25 %
of DHPM 2 being observed in the mixture. The components of
this reaction mixture were isolated by column chromatography
and identified (Fig. 1).
Inspired by the success of the preliminary studies, we then
examined the TMSCl–DMF promoted model reaction of
N-(methoxy)urea 1 with benzaldehyde and N-(4-chlorophenyl)-
acetoacetamide 6.6 When TMSCl was added in a 6-fold excess,
dihydropyridine-5-carboxamide 7 was isolated in 20 % yield
(Entry 1). To optimize the reaction conditions, various molar
ratios of the reagents, temperatures and reaction times were
examined (Table 1). It was found, that an increase in the
temperature, reaction time and amount of TMSCl (entries 2, 3, 8)
reduced the yield of the target compound. At the same time,
utilization of a small excess of benzaldehyde and a 3-fold excess
of N-methoxyurea (entries 4-7) considerably increased the yield.
Clearly the large excess of N-methoxyurea required was because
of its instability (the formation of O-methyloximes see below).
Despite the low yield of compound 2, these preliminary
results seemed to be important since very little is known about N-
alkoxypyrimidines and the DMF–TMSCl system was selected as
a good starting point for further studies.
The optimum amounts of TMSCl, reaction time and reagent
ratio were determined from the experiments corresponding to
entries 1, 3–7, while entries 2 and 8 demonstrated that increased
temperature did not facilitate, but suppressed, the formation of
DHPM 7. The best yield (68 %) of DHPM 7 was obtained by
carrying out the reaction at room temperature for 48 h using a 3-
fold excess of N-(methoxy)urea 1 with respect to the β-keto
amide 6, 1.2 eq. of benzaldehyde and a 6-fold excess of TMSCl
(Entry 6). It was noteworthy that in most cases the formation of
benzaldehyde O-methyloxime was detected. Clearly this was
formed by decomposition of starting N-(methoxy)urea 1 followed
by
condensation
of
O-methylhydroxylamine
with
benzaldehyde.16

3
Table 1. Optimization of the reaction conditionsa
using 1,3-cyclohexanedione as a 1,3-dicarbonyl component
showed that the reaction was often complicated by side reactions
leading to the formation of mixtures.18 In fact, the reaction of
urea, 4-chlorobenzaldehyde and 1,3-cyclohexanedione in AcOH,
DMF or EtOH/conc. HCl afforded mixtures of the target
quinazoline 17 along with acridine 19 and/or xanthene 18
(Scheme 3).
Molar ratio 1 :
PhCHO : 6 :
Time
(h)
Temperature
(°C)
Entry
1
Yield of 7b (%)
TMSCl
1 : 1 : 1 : 6
1 : 1 : 1 : 6
48
1
r. t.
30
20
1
80
2
tracesc
1
100
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
50
15
168
48
48
48
48
24
24
3
4
5
6
7
1 : 1 : 1 : 10
1 : 1.5 : 1 : 6
2 : 1 : 1 : 6
tracesc
12
28
3 : 1.2 : 1 : 6
6 : 1.2 : 1 : 6
68
43
Scheme 3. The reaction of ureas with 4-chlorobenzaldehyde
and 1,3-cyclohexanedione.
8
6 : 1.2 : 1 : 6
29
r. t.
a Optimized reaction conditions are in bold.
We found that the TMSCl–DMF-promoted reaction of
b Yields are for pure compounds recrystallized from EtOAc.
c Only traces of DHPM 7 were detected by 1H NMR after evaporation of
EtOAc from the reaction mixture.
N-(methoxy)urea
1
with 4-chlorobenzaldehyde and 1,3-
cyclohexanedione proceed smoothly to give 1-methoxy-
3,4,7,8-tetrahydroquinazolin-2,5(1H,6H)-dione 20 in 66% yield.
In addition, unsubstituted urea and N-methylurea reacted under
the same conditions to afford pure quinazolines 17 and 21,
respectively, in low to modest yields.
The obtained results prompted us to study the scope and
possible limitations of the reaction. Having an optimized protocol
in hand, we examined the reaction of N-(methoxy)urea 1 with
other aldehydes and 1,3-dicarbonyl compounds17 and the results
are summarized in Table 2.
The mass spectra of DHPM-5-carboxamides 7, 10–16 showed
a molecular ion signal of low intensity (except for the spectrum
of compound 14 which possessed no M+ signal) as well as the
signals of fragmentation ions ([M – Ar]+, [M – OMe]+, [M –
NHAr]+). The mass spectra of DHPM-5-carboxylates 2, 8 and 5-
keto-DHPMs 9, 17, 21, 22 showed molecular ion M+ signals of
high intensity. Finally, the obtained N-methoxy compounds were
found to be rather stable at room temperature, exhibiting no
change in their spectral data after several months.
Table 2. The results of the TMSCl–DMF-catalyzed ternary
condensation of various aldehydes and 1,3-dicarbonyls with
N-(methoxy)urea 1.
In conclusion, we have showed the DMF–TMSCl system to
be the catalyst of choice for the synthesis of 1-methoxy-DHPMs
starting from N-(methoxy)urea providing several new DHPMs in
moderate yields. The DMF–TMSCl system also proved to be an
effective catalyst for the Biginelli-type reaction of 1,3-
cyclohexanedione with 4-chlorobenzaldehyde and ureas
Entry
Product
R
Ar
Yields
(%) a
1
2
OEt
Ph
32
19b
40
78
54
65
38
68
61
75
2
8
OEt
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-FC6H4
3
9
Me
(including
N-(methoxy)urea)
leading
to
3,4,7,8-tetrahydroquinazolin-2,5(1H,6H)-diones. In addition, a
facile and effective protocol for the synthesis of N-(methoxy)urea
was developed.
4
10
11
12
13
14
15
16
4-ClC6H4NH
4-ClC6H4NH
4-ClC6H4NH
4-ClC6H4NH
4-ClC6H4NH
4-ClC6H4NH
4-ClC6H4NH
5
6
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-NO2C6H4
3-NO2C6H4
Acknowledgments
7
8
We thank V. V. Vashchenko, E. V. Vashchenko, V. I.
Musatov (STC ―Institute for Single Crystals‖ NAS of Ukraine),
L. V. Vasilenko (V. N. Karazin Kharkiv National University),
Enamine Ltd. for spectroscopic measurements and V. V.
Dotsenko (Kuban State University) for fruitful discussions.
9
10
a Yields are for pure compounds recrystallized from EtOAc.
b After purification by column chromatography.
References and notes
Next, we studied the reaction of N-(methoxy)urea 1 with 4-
chlorobenzaldehyde and 1,3-cyclohexanedione under the same
conditions. A survey of the literature on the Biginelli reaction
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4
Tetrahedron
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aldehyde (1.42 mmol) and 1,3-dicarbonyl (1.18 mmol) in dry
DMF (minimal amount, approx. 10-20 mL), TMSCl (0.77 g, 7.08
mmol) was added dropwise. The mixture was sonicated at room
temperature for 1 h to dissolve the starting materials. The resulting
mixture was allowed to stir for 48 h and then poured into water
(100 mL). The suspension was extracted with EtOAc (3 × 30 mL),
the combined extracts were washed with water (3 × 30 mL) and
dried over Na2SO4. The solvent was removed under reduced
pressure to yield the crude products, which were recrystallized
from EtOAc to give pure compounds 2, 7, 8, 10–17, 20, 21
(compound 9 was purified by column chromatography).
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hydropyrimidine-5-carboxylate (2). White solid, mp: 126–128 °C;
1
IR, νmax, cm–1 (KBr): 1629, 1682, 1715 (br), 2990, 3342 cm–1; H
NMR (DMSO-d6, δH, J, Hz): 8.23 (1Н, br. d, J 3.6, N(3)H), 7.16–
7.41 (5Н, m, Ph), 5.14 (1H, d, J 3.6, C(4)H), 4.03 (2H, q, J 7.0,
OCH2CH3), 3.70 (3Н, s, ОСН3), 2.45 (3Н, s, С(6)СН3), 1.11 (3H,
t, J 7.0, OCH2CH3); 13C NMR (DMSO-d6, δC): 164.97, 150.71,
150.32, 143.00, 128.60, 127.58, 126.10, 100.59, 64.14, 59.90,
52.62, 14.06, 13.27; MS (EI) m/z (I, %): 290 (M+, 43), 259 (74),
246 (100), 213 (43), 144 (41). Anal. Calcd. for
С15H18N2O4 (290.31): С, 62.06; H, 6.25; N, 9.65%. Found: C,
62.11; H, 6.32; N, 9.50 %.
4-(4-Chlorophenyl)-1-methoxy-3,4,7,8-tetrahydroquinazoline-
2,5(1H,6H)-dione (20). Yield 66 %, white solid, mp 176–178 °C;
IR, νmax, cm–1 (KBr): 1629, 1718, 2939, 3126, 3198 (br), 3251 (br)
cm–1; 1H NMR (DMSO-d6, δH, J, Hz): 8.28 (1H, br. d, J 3.6,
N(3)H), 7.37 (2Н, d, J 8.6, ArH), 7.24 (2H, d, J 8.6, ArH), 5.16
(1H, d, J 3.4, C(4)H), 3.77 (3Н, s, ОСН3), 2.55–2.78 (2Н, m,
СН2), 2.16–2.32 (2Н, m, СН2), 1.76–2.07 (2Н, m, СН2); 13C NMR
(DMSO-d6, δC): 193.31, 155.62, 150.14, 142.04, 131.97, 128.54,
127.97, 108.10, 64.53, 49.74, 35.60, 22.78, 20.60; m/z (EI, 70 eV):
306 (M[35Cl]+, 18), 275 (100), 217 (25), 195 (9), 162 (6), 127 (14).
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Supplementary Material
Supplementary data (synthetic protocols, 1H and 13C NMR, IR
and mass-spectra) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.
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