Regiospecific strategies for the synthesis of novel dihydropyrimidinones and pyrimidopyridazines catalyzed by molybdate sulfuric acid

Article abstract of DOI:10.1016/j.tetlet.2014.02.025

The one-pot reactions of aryl glyoxals with acetylacetone and urea using molybdate sulfuric acid (5 mol %) lead to the novel functionalized 5-acetyl-4-(aryloyl)-3,4-dihydropyrimidinones, which readily undergo the Knorr condensation with hydrazines to produce new pyrimido[4,5-d]pyridazines. The present strategies are in accordance with green chemistry principles through the use of a safe and recyclable catalyst under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2014.02.025

Accepted Manuscript
Regiospecific strategies for the synthesis of novel dihydropyrimidinones and
pyrimidopyridazines catalyzed by molybdate sulfuric acid
Bahador Karami, Saeed Khodabakhshi, Sedigheh Akrami, Mahnaz Farahi
PII:
S0040-4039(14)00255-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.025
TETL 44212
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 October 2013
28 January 2014
12 February 2014
Please cite this article as: Karami, B., Khodabakhshi, S., Akrami, S., Farahi, M., Regiospecific strategies for the
synthesis of novel dihydropyrimidinones and pyrimidopyridazines catalyzed by molybdate sulfuric acid,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.02.025
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Graphical Abstract
Regiospecific strategies for the synthesis of
novel dihydropyrimidinones and
pyrimidopyridazines catalyzed by molybdate
sulfuric acid
Leave this area blank for abstract info.
Bahador Karami,* Saeed Khodabakhshi, Sedigheh Akrami, Mahnaz Farahi

1
Tetrahedron Letters
journal homepage: www.els evier.com
Regiospecific strategies for the synthesis of novel dihydropyrimidinones and
pyrimidopyridazines catalyzed by molybdate sulfuric acid
Bahador Karami∗, Saeed Khodabakhshi, Sedigheh Akrami, Mahnaz Farahi
Department of Chemistry, Yasouj University, Yasouj, Iran, Zip Code: 75918-74831
ARTICLE INFO
ABSTRACT
Article history:
Received
The one-pot reactions of aryl glyoxals with acetylacetone and urea using molybdate sulfuric acid
(5 mol%) lead to the novel functionalized 5-acetyl-4-(aryloyl)-3,4-dihydropyrimidinones, which
readily undergo the Knorr condensation with hydrazines to produce new pyrimido[4,5-
d]pyridazines. The present strategies are in accordance with green chemistry principles through
the use of a safe and recyclable catalyst under solvent-free conditions.
Received in revised form
Accepted
Available online
2012 Elsevier Ltd. All rights reserved.
Keywords:
Aryl glyoxal
Pyrimido[4,5-d]pyridazines
Hydrazine
In continuation of our interest on the synthesis of fused
heterocycles,14-16 we herein describe simple and efficient
strategies for the synthesis of new dihydropyrimidinones and
pyrimidopyridazines. The increasing demand for clean syntheses
of fine chemicals has stimulated chemists to explore and develop
new strategies in accordance with green chemistry principles.
The chemistry of heterocyclic compounds containing a
nitrogen atom has been widely studied. Among these,
dihydropyrimidinones are important in biological and
pharmaceutical research.1-3 The most common method for the
synthesis of dihydropyrimidinones and the corresponding
dihydropyrimidine-thiones (DHPMs) is via the Biginelli reaction.
Accordingly, much attention has been paid to the study of the
Biginelli reaction due to the important biological and
pharmaceutical merits of DHPMs.4 For example, functionalized
dihydropyrimidine-2-ones have shown biological activities such
as antibacterial,5 antiviral,6 and antitumour.7 Besides, several
reports on the synthesis and biological evaluation of pyrimido-
fused heterocycles such as pyrimido[4,5-d]pyridazin-8(7H)-
ones,8 pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines,9 and
2,4-diaminopyrido[2,3-d]pyrimidines10 are available in the
literature. Multicomponent reactions (MCRs) are increasingly
emerging as powerful tools for rapidly generating complex
molecules with potential biological properties.11 In addition,
organic synthesis based on green strategies has been widely
investigated because of stringent environmental and economic
regulations.12 Molybdate sulfuric acid (MSA) is a safe, stable,
and recyclable solid acid and, is a suitable catalyst for many
organic reactions. On the other hand, according to green
chemistry principles, the use of low amounts of a recyclable
catalyst and the avoidance of organic solvents are important
factors.13
After several experiments, we found that new aryloyl-3,4-
dihydropyrimidinones 4 could be obtained via a one-pot,
multicomponent reaction of aryl glyoxals 1, urea (2), and
acetylacetone (3) in the presence of molybdate sulfuric acid
(MSA) under solvent-free conditions. Aryl glyoxals 1 were
obtained by selenium dioxide oxidation of the corresponding aryl
ketones.17 Subsequently, compounds 4 were used as suitable 1,4-
diketones for the synthesis of new pyrimido[4,5-d]pyridazines
via the Knorr condensation with hydrazines 5. The reactions were
also catalyzed by MSA under solvent-free conditions (Scheme
1).18,19
By employing these methods, a number of novel fused
heterocycles were obtained (Tables 1 and 2).
The structures and purities of the presented products were
deduced from their FT-IR, elemental analysis, and NMR spectral
1
data. As a representative example, the H NMR (DMSO-d6, 400
MHz) spectrum of 4a exhibited two singlets due to the nitrogen
protons (δ = 10.61 and 10.10), and a doublet (δ = 7.35) and
singlet (δ = 7.20) corresponding to the aromatic protons. The
resonance for the protons of the two methyl groups appeared at δ
= 1.94 as a singlet.
———
∗ Corresponding author. Tel.: +98 7412223048; fax: +98 7412242167; e-mail: karami@mail.yu.ac.ir (B. Karami).

2
Tetrahedron
It is interesting to note that the Knorr reaction proceeded with
the intermediate by urea through a 1,4-addition followed by
dehydration, produces compounds 4. In the second step for the
formation of pyrimido[4,5-d]pyridazines 6, MSA also acts as an
efficient catalyst which can release a proton and activate the δ-
dicarbonyl, thus, the energy of the transition state decreases and
the rate of the nucleophilic displacement increases. After
nucleophilic attack of the hydrazine on the activated carbonyls
and dehydration, the final products 6 are formed.
regiospecificity in this method and only one structural isomer
was formed. During the reaction, no trace was found by thin-
layer chromatography (TLC) of the possible alternative product
7. One of the ways to prove the exclusive formation of adducts 6
rather than adducts 7 was the disappearance of the signal for the
methine hydrogen (usually at δ = 4-7) and the appearance of two
NH signals. For example, in the case of compound 6b, as an
example, the disappearance of the methine hydrogen and the
appearance of two protons for the NH groups were confirmed.
The 1H NMR spectrum of 6b exhibited two sharp singlets
identified as two methyl group protons (δ = 2.05 and 2.08). The
multiplets (δ = 7.15-7.55) corresponded to the protons of the
phenyl groups. The NH protons appeared as two distinct signals
at δ = 10.23 and δ = 10.64. The proton decoupled 13C NMR
spectrum of 6b showed 16 distinct resonances in agreement with
the proposed structure.
Table
1.
Synthesis
of
5-acetyl-4-(aryloyl)-3,4-
dihydropyrimidinones using MSA under solvent-free conditions.
Yielda
Time
Entry
Ar
Product
Mp (ºC)
(%)
(h)
O
OH
OH
O
O
O
O
NH
1
C6H5
70
5
212-214
O
H3C
NH
H3C
CH3
Ar
H3C
4a
+
1
3
O
Cl
NH2
H2N
2
O
2
4-Cl-C6H4
75
4
180-182
O
NH
NH
(i)
O
H3C
H3C
4b
H
H
Ar
O
N
N
H
R
NH2
H2N
R
O
N
5
(i)
5
(i)
O
O
HN
CH3
O
NH
NH
2-naphthyl
3
80
5
165-167
O
CH3
H3C
H3C
4
4c
Ar
Ar
H
N
H
N
Br
O
R
O
N
N
N
N
N
HN
R
O
O
NH
CH3 CH3
4
4-Br-C6H4
85
4
170-172
CH3 CH3
6
O
H3C
NH
7
H3C
4d
(0%)
(100%)
(i): MSA (5 mol%), 80 oC, solvent-free.
NO2
O
S
O
S
NO2
O
O
O
5
4-O2N-C6H4
75
4
195-197
O
NH
NH
MSA: HO
R:
H,
Mo
OH
,
O
O
O
O2N
O
O
H3C
Scheme 1. Synthesis of aryloyl-3,4-dihydropyrimidinones 4 and
pyrimido[4,5-d]pyridazines 6
H3C
4e
a Isolated yield.
It should also be mentioned that the reactions did not proceed
in the absence of the catalyst, even after long reaction times
(about 12 h).
An attempt to prepare compounds 6 in a one-pot process proved
unsuccessful.
A suggested mechanism for the two-step process is shown in
Scheme 2. Protonation of the hydroxyl group of the aryl glyoxal
by the Brønsted acid MSA generates an electrophilic center
which participates in a Knoevenagel condensation to form an
α,β-unsaturated ketone as a reactive intermediate. Interception of

3
CH3 CH3
Table 2. Synthesis of pyrimido[4,5-d]pyridazines using MSA
under solvent-free conditions.
HN
N
NH
Yielda
(%)
Time
O
N
H
Entr
y
Substrate
Product
Mp (ºC)
(min)
7
4e
258-260
79
65
CH3 CH3
NO2
HN
N
NH
O
N
H
6g
1
4a
78
84
83
308-310
60
CH3
CH3
HN
N
N
6a
CH3 CH3
O
N
H
Ph
8
4b
215-217
77
60
HN
N
N
Cl
O
N
H
Ph
2
4a
313-315
6h
60
a Isolated yield.
6b
H
N
O
HN
CH3
NO2
N
N
3
4b
224-226
60
Cl
NO2
6c
CH3 CH3
N
HN
N
O
N
H
Ph
4
4e
275-277
80
65
NO2
6d
CH3 CH3
N
HN
N
O
N
H
Ph
5
4d
212-214
88
50
Br
6e
CH3 CH3
HN
N
NH
O
N
H
6
4c
290-292
85
90
6f
Scheme 2. Suggested mechanism for the synthesis of dihydropyrimidinones
and pyrimidopyridazines using MSA.

4
Tetrahedron
13. Karami, B.; Khodabakhshi, S.; Nikrooz, M. Polycyclic Aromat.
Compd. 2011, 31, 97.
14. Karami, B.; Khodabakhshi, S.; Eskandari, K. Tetrahedron. Lett.
2012, 53, 1445.
Additionally, the activity of the MSA was investigated in the
synthesis of 6a over three runs, during which a small
appreciable loss was observed in the catalytic activity (Figure
1).
15. Karami, B.; Ghashghaee, V.; Khodabakhshi, S. Catal. Commun.
2012, 20, 71.
16. Karami, B.; Eskandari, K.; Khodabakhshi, S. Arkivoc 2012, (ix),
76.
17. Riley H. A.; Gray. A. R. Org. Synth. Coll. 1935, 15, 67.
18. Preparation of 5-acetyl-4-(aryloyl)-3,4-dihydropyrimidinones (4)
A mixture of 1 (1 mmol), 2 (1.5 mmol), 3 (1 mmol), and MSA
(0.05 mmol) was stirred and heated at 80 °C in a preheated oil
bath for the appropriate amount of time. After completion of the
reaction as indicated by TLC (EtOAc/hexane, 1:4), the mixture
was cooled to room temperature, then crystallized from EtOH to
afford the pure product 4. The catalyst was separated by filtration
and washed with Et2O, dried at 70 °C for 45 min, and reused in
another reaction.
5-Acetyl-4-(benzoyl)-6-methyl-3,4-dihydropyrimidinone
Light yellow solid, IR (KBr): 3057, 1720, 1648, 1591, 1448, 1027
(4a).
1
cm-1; H NMR (DMSO-d6, 400 MHz): δ = 10.61 (s, 1H), 10.10 (s,
1H), 7.35 (d, 4H, J = 5.6 Hz), 7.20 (s, 1H), 5.55 (s, 1H), 1.94 (s,
6H); 13C NMR (DMSO-d6, 100 MHz): δ = 193.15, 183.00, 153.88,
129.96, 128.79, 126.50, 124.11, 119.60, 112.66, 103.85, 57.38,
23.25; Anal. Calcd. for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85.
Found: C, 65.31; H, 5.40; N, 10.73.
Figure 1. Recyclability of the MSA catalyst in the synthesis of
6a over three runs.
In summary, we have shown that the three-component
reaction of aryl glyoxals, urea, and acetylacetone catalyzed by
molybdate sulfuric acid provides a simple one-pot entry for the
synthesis of functionalized aryloyl-3,4-dihydropyrimidinones.
Moreover, the aryloyl-3,4-dihydropyrimidinone derivatives
undergo condensation with hydrazines to produce novel
pyrimido[4,5-d]pyridazines. The simple operation and work-up
procedure, compatibility with green chemistry principles, and
high yields of products are notable features of this work. The
presence of transformable functionalities in the products makes
them potentially valuable substrates for further synthetic
manipulations.
19. Preparation of pyrimidopyridazines (6).
A mixture of 4 (1 mmol), 5 (1 mmol) and MSA (0.05 mmol) was
stirred and heated at 80 °C in a preheated oil bath for the
appropriate amount of time. After completion of the reaction as
indicated by TLC (EtOAc/hexane, 1:4), the mixture was dissolved
in hot EtOH and the catalyst was separated by filtration. The
solvent was removed under vacuum and the product was purified
by crystallization from EtOH. The catalyst was washed with Et2O,
dried at 70 °C for 45 min, and reused in another reaction.
4,5-Dimethyl-7,8-diphenylpyrimido[4,5-d]pyridazin-
2(1H,3H,7H)-one (6b). Light yellow solid, IR (KBr): 3450, 3030,
2995, 2990, 2890, 1690, 1650, 1490, 1100 cm-1; 1H NMR
(DMSO-d6, 400 MHz): δ = 10.64 (s, 1H), 10.23 (s, 1H), 7.55-7.50
(m, 4H), 7.43-7.36 (m, 1H), 7.31-7.27 (m, 4H), 7.18-7.15 (m, 1H),
2.08 (s, 3H), 2.05 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ =
154.72, 148.09, 139.75, 138.80, 130.90, 129.72, 129.05, 129.05,
127.85, 126.69, 124.81, 124.56, 119.31, 110.78, 110.76, 12.72,
11.97; Anal. Calcd. for C20H18N4O: C, 72.71; H, 5.49; N, 16.96.
Found: C, 72.95; H, 5.36; N, 16.80.
Acknowledgments
The authors gratefully acknowledge financial support of this
work by Yasouj University, Iran.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at …
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