One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones catalyzed by Co phthalocyanines: Synthesis, characterization, aggregation behavior and antibacterial activity

Article abstract of DOI:10.1016/j.saa.2016.04.045

The synthesis of a novel phthalonitrile derivative with pyridine-2-thiol and 2,4,6-trimethylphenylamine substituents functionalized groups and its peripherally tetrasubstituted cobalt phthalocyanine and cationic phthalocyanines complexes were reported. Th

Full text of DOI:10.1016/j.saa.2016.04.045

SAA-14408; No of Pages 10
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
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Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
journal homepage: www.elsevier.com/locate/saa
One-pot three-component Biginelli-type reaction to synthesize
3,4-dihydropyrimidine-2-(1H)-ones catalyzed by Co phthalocyanines: Synthesis,
characterization, aggregation behavior and antibacterial activity
Rawdha Medyouni a, Wissal Elgabsi a, Olfa Naouali d, Antonio Romerosa c, Abdullah Sulaiman Al‐Ayed b,
Lasaad Baklouti b,d, Naceur Hamdi a,b,
⁎
a
Heterocyclic and Organometallic Chemistry Laboratory, Higher Institute of Environmental Sciences and Technology, University of Carthage, Hammam-Lif, 2050, Tunisia
Chemistry Department, College of Science and Arts, Qassim University, Al-Rass, Kingdom of Saudi Arabia
Área de Química Inorgánica, Universidad d’Almeria 04120, Almería, Spain
Laboratory of Applied Chemistry and Natural Substances Resources and Environment, Faculty of Sciences, University of Carthage, Zarzouna‐Bizerta, 7021, Tunisia
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel phthalonitrile derivative with pyridine-2-thiol and 2,4,6-trimethylphenylamine substit-
uents functionalized groups and its peripherally tetrasubstituted cobalt phthalocyanine and cationic phthalocy-
anines complexes were reported. The aggregation investigations carried out in different concentrations indicate
that Co Phthalocyanines compounds 3,4 do not have any aggregation behavior for the concentration range of
6 × 10−4–14 × 10−6 M in DMSO. The ion binding properties of Co Phthalocyanines compounds 3,4 show the for-
mation of stable complex with Co2+. In addition 3,4-Dihydropyrimidin-2(1H)-one derivatives were synthesized
by modified Biginelli cyclocondensation reaction catalyzed by MPc as Lewis base. The structures of the synthe-
sized compounds have been successfully characterized by the spectroscopic methods (IR, 1H NMR, 13CNMR,
UV–Vis, mass spectrometry, elemental analysis and NMR 2D). The influence of substrate/catalyst ratio, solvent
was also investigated to find optimal reaction on this synthesis for getting the highest conversion. Different pa-
rameters were examined for finding optimal conditions of catalysis. In addition; the compounds 3–11 were in-
vestigated for antimicrobial activity. Most of them exhibited important antimicrobial activity.
Received 29 November 2015
Received in revised form 24 April 2016
Accepted 25 April 2016
Available online 26 April 2016
Keywords:
Characterization
Complexation
Phthalocyanine
Metallophthalocyanine derivatives
Aggregation
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
yields (20–40%) of the desired products, particularly in case of substitut-
ed aldehydes, and loss of acid sensitive functional groups during the re-
Dihydropyrimidinones and their derivatives have attracted increas-
ing interest owing to their.
action. This has led to multi-step synthetic strategies that produce
somewhat better yields, but which lack the simplicity of the original
one-pot Biginelli protocol [9]. The search for more suitable preparation
of dihydropyrimidinones continues today. Recently, many synthetic
methods for preparing these compounds have been developed to im-
prove and modify this reaction by using Lewis acid catalysts, protic
acids as well as ionic liquids [10–31].
On the others hand Multicomponent reactions (MCRs) have become
an important component of the combinatorial chemistry, as wide varie-
ties of biologically relevant compounds can be produced in a rapid par-
allel synthetic program [32–35]. The high atom economy, convergent
character, operational simplicity, structural diversity and complexity
of molecules are the major advantages associated with the MCRs. Mul-
ticomponent reactions contribute to the requirements of an environ-
mentally friendly process by reducing the number of synthetic steps,
energy consumption and waste production.
therapeutic and pharmaceutical properties, such as antiviral, anti-
bacterial, anti-inflammatory and antitumour activities [1–3]. Recently,
functionalized dihydropyrimidinones have been successfully used as
antihypertensive agents, calcium channel blockers, adrenergic and neu-
ropeptide Y (NPY) antagonists [4,5]. In addition, some alkaloids contain-
ing the dihydropyrimidine core unit which also exhibit interesting
biological properties have been isolated from marine sources [6,7].
One of the famous MCRs is synthesize of Dihydropyrimidinones
(DHPMs) which was first reported by the Italian chemist Pietro Biginelli
N100 years ago; it involves a three-component onepot condensation of
benzaldehyde, ethyl acetoacetate and urea under strongly acidic condi-
tions [8]. However, this method suffers from drawbacks such as low
The scope of the Biginelli reaction has been extended by a long way
by the variation of all building blocks, allowing access to a large number
of multifunctionalzed pyrimidine derivatives with important biological
properties. Therefore synthesis of this type of heterocyclic compounds
⁎
Corresponding author at: Heterocyclic and Organometallic Chemistry Laboratory,
Higher Institute of Environmental Sciences and Technology, University of Carthage,
Hammam-Lif 2050, Tunisia.
E-mail address: naceur.hamdi@isste.rnu.tn (N. Hamdi).
http://dx.doi.org/10.1016/j.saa.2016.04.045
1386-1425/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
catalyzed by Co ..., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2016), http://dx.doi.org/10.1016/j.saa.2016.04.045

2
R. Medyouni et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
Scheme 1. Synthesis of the phthalonitriles 1–2.
has been the focus of much interest from organic and medicinal chem-
istry. Many synthetic methods have been developed and Biginelli reac-
tion has gained an active ongoing research.
Scheme 3. The synthesis of tetracationic metallophthalocyanine 5,6.
As a continuation of our work [36,37], we report here firstly the syn-
thesis and characterization of a new peripherally functionalized
phthalonitrile 1,2 and Co metallophthalocyanines 3,4 and their
quaternized derivatives 5,6 which contain different substituents groups
on peripheral positions in the phthalocyanine framework. Secondly we
report a facile and efficient multicomponent reaction route towards the
synthesis of such multifunctionalized 3.4-dihydropyrimidin-2-ones by
using methalophthalocyanines 3 as a catalyst. On the other hand we re-
port also the binding properties of compounds 3,4 towards Co2+. The
studies were performed by UV–visible spectrophotometry absorption
and by conductimetry.
2. Results and discussion
The phthalonitriles 1 and 2 were obtained via a based catalyzed
(K2CO3) nucleophilic aromatic substitution reaction. The synthetic
routes to novel phthalonitriles 1 and 2 are showed in Scheme 1.
The phthalonitriles 1–2 were characterized by the spectral data (IR,
1H NMR, 13C NMR, mass spectroscopies, elemental analysis and NMR
2D). The characterization data of the new compounds are consistent
with the assigned formula.
In the 1H NMR spectra of compound 1 the aromatic protons appear
at 8.38–8.98, methylic protons appear at 2.02 (s), 2.09 (s) ppm respec-
tively. In 13C NMR, signal at δ149.5 ppm assigned to C4, signal at
δ116.4 is due to C2 carbon. Signals that appeared at 114.5 and 114.8 cor-
respond to the CN carbons. Other signals are in good agreement with
the target compounds.
In addition the compounds 1–5 were investigated for their antimi-
crobial activity. Most of the new compounds exhibited important anti-
microbial activity.
The 1H NMR spectrum of compounds 2 showed a multiplet between
7.33 and 8.52 ppm for aromatic protons. In the mass spectra of com-
pounds 1,2 the presence of molecular ions peaks at m/z = 261 and
237 respectively, confirmed the proposed structures.
Cyclotetramerization of 1 and 2 occurred in the presence of
CoCl2·6H2O to form the desired Cocomplexes: 3 and 4, respectively.
All of these new cobalt phthalocyanines were purified by preparative
thin layer and silica gel column chromatograph. They were obtained
in a yield (55% for 3, 65% for 4) (Scheme 2).
Scheme 2. Synthesis of the Co metallophthalocyanines 3,4.
Scheme 4. UV–Vis spectra of 5 in (DMSO, H2O).
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
catalyzed by Co ..., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2016), http://dx.doi.org/10.1016/j.saa.2016.04.045

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3
of DHPMs. We started our study of the one-pot three-component
Biginelli condensation using CoMPc as the catalyst by examining the
conditions for the reaction using benzaldehyde, ethylacetoacetate and
urea to afford the corresponding DHPM product 7–11 (Scheme 6).
We studied the reaction in different solvents including ethanol, ace-
tonitrile, toluene, dichloromethane, THF and DMC conditions at 120 °C
(Table 1). The best results were obtained in DMC (entry 6).
In order to investigate the scope of these conditions, we have under-
taken the synthesis of different derivatives of 3,4-dihydropyrimidin-
2(1H)-ones (7–11), from a variety of substrates from aromatic alde-
hydes, ethylacetoacetate and urea in the presence of CoMPc 3 as
catalyst.
The benzaldehyde derivatives with substitutions in the aromatic
ring with 4-methyl, 3-methoxy, 4-nitro and 4-N (Me)2 positions were
reacted with urea to furnish a series of products 7–11 (Table 2).
The new compounds 7–11 were characterized by IR, 1H NMR spec-
troscopies and elemental analysis. The analyses are consistent with
the predicted structures as shown in the experimental section.
The 1H NMR spectrum of compound 7 shows a triplet at 1.14 ppm for
the methylic protons (b), whereas the methylic protons (a) appeared at
2.19 ppm, 4.50 ppm attributed to the (Hd), H6 appeared at 5.24 ppm.
The spectrum also shows a multiplet at 7.2–8.5 ppm for the aromatic
protons (Fig. 1).
Scheme 5. UV–Vis spectra of 6 in (DMSO, H2O).
After conversion of phthalonitriles 1,2 into cobalt phthalocyanine der-
ivations, the characteristic CN stretch at 2235 cm−1 and 2233 cm−1 for 1
and 2 disappeared in the IR spectra, indicative of metallophthalocyanine
formation. The characteristic vibration peaks of the Co\\N and C_N ap-
peared at 904, 1520 cm−1 respectively. The 1H NMR spectra of cobalt
phthalocyanines 3 and 4 could not be taken due to the paramagnetic co-
balt (II) centers [38]. The elemental analyses for complexes 3,4 gave sat-
isfactory results that were close to calculated values.
In the UV–vis spectrum of metallo phthalocyanines 3,4, the Q bands
causing by π−π* transitions were observed at 689, 687, 722 and
690 nm respectively [39]. The B bands causing from deeper π levels to
LUMO were observed at: 364, 410, 384, and 414 nm for metallo phtha-
locyanines 3,4.
The pyridine-2-thiol substituent on the complex 4 and 2.4.6-
trimethyl phenylamine on the complex 3 are suitable for conversion
into quaternary ammonium groups and this can increase the products'
solubility in water so, quaternization of metallophthalocyanine com-
plexes 3,4 was achieved by reaction with excess methyl iodide as a
quaternization agent in CHCl3 at room temperature. The yields of the
products were 77% and 80% (Scheme 3).
13C NMR spectroscopic analysis also confirmed structural identity,
with resonances observed at δC 161.7 (O_C ester),
123.1–141.3(Carom), 150.2 (C2), 150.2 (C2),13.7(CH3(a)),
17.3(CH3(b)) ppm (Fig. 2).
Elemental analysis of compound 7 was within the range 0.4% and
fully supported structural assignment.
The suggested mechanism for the Biginelli reaction catalyzed by
MPc is outlined in Schemes 7–9.
Step 1 Formation of Acylimine intermediate: This intermediate is
formed by the reaction between an aldehyde and urea. Scheme 7.
Step 2 Enolisation of ethyl acetoacetate: CoMPc plays the role of a
Lewis base by interaction with electrophilic carbon of aldehyde. The
β–ketoester enolate can be formed by coordinating the aldehyde with
MPc, which promotes deprotonation of the β–ketoester [40] Scheme 8.
Step 3 Condensation of Enol with the Acylimine to give an interme-
diate which undergoes cyclization followed by dehydration to afford the
corresponding dihydropyrimidines. Scheme 9.
Quarternized metal-free 5,6 are very soluble in water as expected.
Infrared spectra of the quarternized complexes 5,6 showed the pres-
ence of C H stretching and bending alkyl groups bands around
2900 cm−1 and 1400 cm−1 respectively, and a CSC stretch between 800
2.2. Aggregation study behaviors of methallophthalocyanines 3,4
Phthalocyanine compounds have a high aggregation tendency due
to the interaction between their 18 electron systems and the aggrega-
tion decreases the solubility of these compounds in solvents. Aggrega-
tion is usually depicted as a coplanar association of rings progressing
from monomer to dimer and higher order complex. It is dependent on
the concentration, nature of the solvent, nature of the substituents,
complexed metal ions and temperature. These compounds, normally
with bulky substituents, possess good solubility, which can facilitate
the purification and characterization processes. The non-aggregated na-
ture can also prevent undesirable effects arising from stacking of mole-
cules [41].Generally the increasing concentration of Pcs leads to
aggregation, which is observed by the position of Q bands, which shift
and 990 cm−1
.
Typical UV–Vis spectra of 5 in DMSO showed a Q band at 677/614 nm
and a B band at 329 nm (Scheme 4). Also UV–Vis spectra of 6 in H2O
showed a Q band at 687/615/ 678 nm and a B band at 351 nm (Scheme 5).
Also UV–Vis spectra of 6 in H2O showed a Q band at 687/615/678 nm
and a B band at 351 nm.
2.1. Catalytic activities of metallophthalocyanine 3,4 (CoMPc)
We are interested in studying Biginelli reaction with the aim to de-
velop an operationally simple method for the synthesis of a large range
Scheme 6. General synthetic scheme of compounds 7–11.
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
catalyzed by Co ..., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2016), http://dx.doi.org/10.1016/j.saa.2016.04.045

4
R. Medyouni et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
Scheme 7. Formation of Acylimine intermediate.
to higher energies by a parallel decrease in the molar absorption. In this
work the aggregation behavior of the metallophthalocyanine com-
plexes 3 and 4 were investigated at different concentrations from
6 × 10−4 to 14 × 10−6 M in DMSO for compounds 3 and 4 in DMSO
(Figs. 3–4).
As the concentration was increased, the intensity of absorption of
the Q band corresponding to monomeric species also increased and
there were no new bands due to the aggregated species for both of
the complexes. Beer–Lambert law was obeyed in the concentrations
ranging from 6 × 10−4–14 × 10−6 M for compound 3 and from for com-
pound 4. It can clearly be concluded that the phthalocyanines deriva-
tives (3 and 4) did not show aggregation in DMSO for the studied
concentrations.
tested with MIC values of 0.625–5 mg/ml. The compounds 5 and 6 ex-
hibited an important antibacterial activity against Micrococcus luteus,
Staphylococcus aureus, Listeria monocytogenes and Polycystis aeruginosa
and antifungal activity against Candida albicans and Candida tropicalis
with an important diameter ranging from 16 to 26 mm. The Compound
7 exhibited the highest in vitro antibacterial activity against M. luteus
with MIC values of 0, 312 mg/ml while the Compound 8 showed a mod-
erate antibacterial activity against M. luteus, S. aureus, L. monocytogenes,
S. Typhimurium and P. aeruginosa with MIC values ranging from 5 to
10 mg/ml.
These results show that the most synthesized compounds have po-
tent inhibitory activities against both Gram-positive and Gram-
negative bacteria and fungi. Thus, they have an effective antimicrobial
potential against food- borne pathogens and clinical microorganisms.
2.3. Antimicrobial activity of compounds 3–11
3. Complexation study
The synthesized compounds (3−11) were evaluated for in vitro an-
timicrobial activity by the well diffusion method. The antimicrobial ac-
tivity of the tested compounds was presented in Table 3 by the
formation of an inhibitory zone. In parallel, the MIC values were
determinated in Table 4. The diameter of the zone of inhibition indicates
the degree of sensitivity of the microorganisms to the compounds the
well contains. It was obtained that, five compounds (5, 6, 7, 8 and 9)
present the best antimicrobial activity with a broad spectrum. The com-
pound 9 showed antimicrobial activity against all bacteria and fungi
The complexation study of cobalt chloride by the free phthalocyanie
3,4 was followed by UV spectrophotometry. In fact, the titration of li-
gand solution in DMSO by a cobalt chloride solution in methanol
shows a decrease of absorbance and a light hypsochromic displacement
of the maximum of absorption (Δλ ≈ 3 nm). The end of complexation
between the phthalocyanine 3,4 and Co2+ is shown by the superposi-
tion of the spectra at approximately a ratio R (R = CM/CL) lower than
5 (see Fig. 5).
Scheme 8. Enolisation of ethyl acetoacetate.
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
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Scheme 9. Suggested mechanism for the Biginelli reaction catalyzed by MPc 3.
In addition, treatment of these spectral data by the digital program
“Letagrop” [42] illustrates the stoichiometries of the formed complexes
and their stability constants. The results show that the complexes
formed in all cases are ML. The determination of stability constant
shows the formation of stable complex (over 3.6 log units), however,
3·Co2+ is more stable than 4·Co2+ (log ᵝ11 (3·Co2+) = 3.77 and
logᵝ11 (4·Co2+) = 3.64) this result is expected given the given the pref-
erence of the N-donor site at cobalt [43].
Most of the new compounds 3–11 exhibited an important antibacte-
rial activity. The Compound 7 exhibited the highest in vitro antibacterial
activity against M. luteus with MIC values of 0, 312 mg/ml while the
Compound 8 showed a moderate antibacterial activity against
M. luteus, S. aureus, L. monocytogenes, S. Typhimurium and P. aeruginosa
with MIC values ranging from 5 to 10 mg/ml.
5. Experimental
In the other hand, the 1:1 stoichiometry of the complexes 3·Co2+
and 4·Co2+) were confirmed by conductimetric studies [44] (Fig. 6).
All reagents were obtained from Fluka and Aldrich.The purity of the
products was tested in each step by TLC (SiO2, CHCl3/MeOH and THF/
MeOH). Melting points were determined using an Electrothermal appa-
ratus and are uncorrected. 1H NMR and 13C NMR spectra were carried
on a Varian Gemini 400 (400 MHz) spectrometer using TMS as internal
standard (δ = 0 ppm). IR spectra were recorded on a Perkin-Elmer 398
Spectrophotometer. MS were recorded on a LC-MS-MS 8030 Shimadzu.
Elemental analyses were performed on Perkin-Elmer 2400 elemental
analyzer, and the values found were within 0.3% of the theoretical
values. The UV spectra were recorded on a Perkin Elmer Lambda 11
spectrophotometer.
4. Conclusion
In the present work, we have presented the synthesis and character-
ized of a new phthalonitriles 1–2 and peripheral and non-peripheral
substituted cobalt phthalocyanine 3 and 4 using spectroscopic methods
(IR, UV–Vis, 1H/13C NMR, two-dimensional, mass spectroscopies, and as
well as elemental analyses).
The cationic derivatives of the phthalocyanines were synthesized by
the reaction of non-ionic phthalocyanines 3,4 and methyl iodide in chlo-
roform. Quaternized derivatives 5,6 exhibited excellent solubility in
water. 3,4 formed a mononuclear complex with cobalt in DMSO solu-
tion. The stability constant is determined by UV spectrophotometry.
The aggregation behaviors of compounds 3 and 4 were investigated.
These phthalocyanines showed monomeric behaviors inTHF for studied
concentration ranges.
5.1. Synthesis of 4-(2.4.6-trimethylphenylamino)phthalonitrile 1
4-nitrophthalonitrile
(0.38
g,
1.92
mmol),
2,4,6-
trimethylphenylamine (0.55 g, 1.92 mmol) and anhydrous DMF
(15 mL) were added to a round bottom flask under a nitrogen atmo-
sphere. A fine powder of anhydrous potassium carbonate (0.8 g,
5.76 mmol) was added to this mixture. The resulting mixture was stirred
at room temperature for 24 h. The crude product was collected by filtra-
tion, washed with distilled water, and then recrystallized. The crude prod-
uct was recrystallized from THF-petroleum ether to afford a white
In addition, a new method for the preparation of substituted
dihydropyrimidinones-DHPMs was discovered that utilizes a multi-
component coupling reaction catalyzed by CoMPc, with a rapid and
high yielding cyclocondensation to afford the corresponding DHPMs.
powder. Yield: 0.77 g (98%). M.p. = 400 °C. IR (KBr pellet) vmax cm−1
:
1305 (C\\N), 1568 (C = C), 2235 (C`N), 3049 (C\\H, aromatic). 1H
NMR (DMSO-d6): 8.38–8.98(m, 5H, Harom), 4.21(s, 1H, NH), 2.02(s, 3H,
Table 1
MPc catalyzed synthesis of dihydropyrimidines in different solvents.
Entry
Solvent
Amount of MPc mol%)
Time (h)
Yield (%)
Table 2
Synthesis of dihydropyrimidines 7‐11 in different solvents.
1
2
3
4
5
6
7
8
9
Ethanol
Acetonitrile
Toluene
Dichloromethane
THF
DMC
DMC
DMC
DMC
10
10
10
10
10
10
15
20
5
16
16
16
16
16
8
8
8
8
10
10
30
22
25
62
54
50
52
Substrat
MPc
DHPM Time Solvant Amount of Yield
(h)
MPc mol%) (%)
Benzaldehyde
4-CH3-Benzaldehyde
3-methoxyBenzaldehyde Co(II)Pc
4-nitro-Benzaldehyde
4-N(Me)2-Benzaldehyde Co(II)Pc
Co(II)Pc
Co(II)Pc
7
8
9
3
4
2
2
3
CH3CN
EtOH
DMC
DMC
DMF
2
2
1
1
2
78
92
96
92
85
Co(II)Pc 10
5
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Fig. 1. 1HNMR spectrum of compound 7 (DMSO, 300 MHz).
CH3(a)), 2.09(s, 6H, CH3(b,c)), 2.08(s, 3H, CH3). 13CNMR(DMSO-
d6,75 MHz)δ:17.5(C(a,b)),
5.2. Synthesis of 4-(pyridine-2-ylsulfanyl) phthalonitrile 2
19.9(Cb),114.5(CN),114.8(CN),116.4(C2),
120.0(C2′),120.5(C6′),123.9(C4′),128.2(C3′,5′),
128.3(C3),128.6(C5),135.4(C6),141.3(C11),149.5(C4).
MS (LCMS-MS) m/z: Calc. 261.3; Found: 261.3. Anal. Calc. for C17H15N3:
C, 78.135%; H, 5.786; N, 16.080, Found: C, 78.1; H, 5.6; N, 16.0%.
The synthesis of 2 was similar to 1 but the mixture was stirred for
72 h; pyridine-2-thiol (0.55 g, 1.92 mmol) was employed instead of
2,4,6-trimethylphenylamine. The amounts of the other reagents were
4-nitrophthalonitrile, 1 g (5.55 mmol) and anhydrous potassium car-
bonate, 2 g (13.88 mmol).
Fig. 2. 13CNMR spectrum of compound 7 (DMSO, 75 MHz).
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FT-IR (KBr) n, cm-1: 3020 (C-Harom); 1403 (C\\C); 1250 (C\\N);
1602 (C_C); 1520 (C_N); 904 (Co\\N).
UV/Vis (DMSO, λmax nm (log ɛ)): 345 (4.780), 642 (4.863), 687
(5.082).
Calc. for C68H60N12Co: C, 73.964%; H, 5.477%, N, 15.222%; Found: C,
73.8; H, 5.4, N 15.1.
5.3.2. Co(II)pc (4)
Yield: (65%).
M.p. = 330 °C.
FT-IR (KBr) ν, cm−1: 3048 (C-Harom); 1420 (C\\C); 1292 (C\\N);
1620 (C_C); 1564 (C_N); 914 (Co\\N).
UV/Vis (DMSO, λmax nm (log ɛ)): 345 (4.90), 620 (4.69), 679(5.21).
Calc. for C52H28N12S4Co: C 61.957%; H, 2.800%,N 16.674% Found: C
61.8; H, 2.6, N16.5;
Fig. 3. The aggregation behavior of phthalocyanine 3 in DMSO.
5.4. General procedure for the synthesis of quaternized
metallophthalocyanines (5,6)
Yield: 0.77 g (85%) M.p. = 370 °C. IR spectrum (cm−1): 3077 (Ar-
CH), 2233 (C\\N), 1601 (C\\C), 1263 (C-O-C), 1568 (C_C), 3049
(C\\H, aromatic). 1H NMR (DMSO-d6): 7.33–8.52(m, Har, 7H).
The methallophthalocyanines were dissolved in chloroform (10 ml)
and excess amount of methyl iodide was added to these solutions. The
reaction mixtures were stirred at ambient temperature for two days.
The green precipitates were filtered off, washed with ethanol, acetone,
diethyl ether and chloroform and dried.
13CNMR(DMSO-d6,75
MHz)δ:
113.5(C2),115.9
(CN),116.2(C1),123.2(C2’),
125.3(C4′),134.7(C6),136.3(C4),138.7(C3′),
141.3(C5),150.8(C5′),154.8(C1′). MS (LCMS-MS) m/z: Calc. 237.2;
Found: 237.2. Calc. for C13H7N3S: C, 65.804%; H, 2.974%; N, 17.709%,
Found: C, 65.8; H, 2.9; N, 17.7%.
5.4.1. Q Co(II)pc (5)
Elution solvent system: chloroform: methanol (100:3) as eluent.
Yield: (77%).
5.3. General procedure for synthesis of metallophthalocyanines 3,4
M.p. = 338 °C.
FT-IR (KBr) n, cm-1: 1520 (C = N), 1602 (C = C), 1250 (C\\N), 1403
(C\\C), 904 (Co\\N).
UV–vis (DMSO): λmax, nm (log ε): 629 (4.70), 690 (5.05), 316 (4.61),
388 (4.91).
Compound (1) (0.24 mmol) or compound 2 (0.24 mmol) N,N-
dimethylaminoethanol (DMAE) (4 ml), 1,8-diazabicyclo [4.5.0]undec-
7-ene (DBU) (3 drops) and (0.06 mmol) of CoCl2·6H2O were added in
s shlink tube. The mixture was heated at reflux temperature of 170 °C
for 24 h under N2 atmosphere. Then the mixture was left for cooling
at room temperature then treated with ethylacetate to precipitate the
product which was then filtered off and suddenly washed with water.
The green solid product was washed with hot ethanol and hot acetic
acid and dried in vaccum. The raw product was purified by chromatog-
raphy of silica gel column.
5.4.2. Q Co(II)pc (6)
Elution solvent system: chloroform: methanol (100:3) as eluent.
Yield: (80%).
M.p. = 335 °C.
FT-IR (KBr) n, cm-1: 1565 (C = N), 1620 (C = C), 1292 (C\\N), 1420
(C\\C), 914 (Co\\N).
UV–vis (DMSO): λmax, nm (log ε): 629 (4.70), 690 (5.05), 316 (4.61),
388 (4.91).
Calc. for C56H40I4N12S4Co: C 46.465%; H, 2.785%,N 11.611% Found:
C 46.6; H, 2.9, N11.5.
5.3.1. Co(II)pc (3)
Elution solvent system: chloroform: methanol (100:3) as eluent.
Yield: (55%).
M.p. = 315 °C.
5.5. General procedure for preparation of the 7–11
A solution of ethyl acetoacetate (1 mmol), aldehyde (1 mmol) and
urea, MPc (0.24 mmol), in DMC (2 mmol) was heated at 120 °C for ap-
propriate duration of time (Table 1). The progress of the reaction was
checked by TLC (chloroform/petroleum 2/1) and after completion of
the reaction, the mixture was diluted with EtOH/H2O (2/1) and then
the crude product was recrystallized from EtOH (96%) to afford the
pure product.
5.5.1. 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5–carbox-
ylate 7
Yield: (96%).
M.p. = 320 °C.
1HNMR (DMSO-d6,300 MHz)δ ppm: 1.04 (t, 3H, CH3(a)); 2.14 (s, 3H,
CH3(b)); 3.81 (q, 2H, Hd); 6.75 (s, 1H, H3); 6.86 (s, 1H, H1); 6.99 (s, 1H,
H6);
13CNMR(DMSO-d6,75 MHz) δ ppm: 13.6 (CH3(b)); 16.58 (CH3(a));
52.4 (Cb); 60.6 (Cd); 109.6 (C5); 140.7 (C4); 159.6 (CO ester); 156.5
(C2), 128.5–145.1(Carom).
Fig. 4. The aggregation behavior of phthalocyanine 4 in DMSO.
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
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R. Medyouni et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
Fig. 5. UV absorption spectra on complexation of Co2+ with (a) 3 and (b) 4 in DMSO (0 ≤ RM/L ≤ 2.3) at 25 °C.
Calc. for C14H1503N2 C 9.827%; H, 88.536%, N 1.637% Found: C 9.7;
5.5.5.
4-(4-Dimethylaminophenyl)-6-methyl-2-oxo-1,2,3,4-
H, 88.4, N1.5;
tetrahydropyrimidine-5–carboxylate 11
Yield: (85%).
5.5.2. 4-(3-Methylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5–carboxylate 8
M.p. = 310 °C.
1HNMR (DMSO-d6, 300 MHz)δ ppm: 1.2 (t, 3H, CH3(c)); 2.12 (s, 3H,
CH3(b)); 2.10 (s, 6H, N(CH3)2); 3.65 (q, 2H, Hd); 5.95 (s, 1H, H6); 8.64 (s,
1H, H3); 7.50 (s, 1H, H1); 6.73–7.36(m,5H, Harom).
13CNMR(DMSO-d6,75 MHz)δ ppm: 16.4 (N(CH3)2); 14.5 (CH3(b));
42.4 (CH3(a)); 52.8 (C6); 60.,2 (Cd); 109.3 (C5); 141.2 (C4); 159.7
(COester); 156.3 (C2); 126.6–138.4(Carom).
Yield: (92%).
M.p. = 220 °C.
1HNMR (DMSO-d6,300 MHz)δ ppm: 2.14 (s,3H, (CH3(b)); 1.2 (s, 3H,
(CH3(c)); 3.4 (s, 3H, CH3(a));4.5 (s, 2H, Hd); 6.72 (s, 1H, H3); 7.2–8.5 (m,
5H, Harom); 7.96 (s, 1H, H6).
13CNMR(DMSO-d6,75 MHz) δ ppm: 13.6 (CH3); 16.5 (CH3(b)); 42.1
(CH3(a)); 52.4 (C6); 60.6 (Cd); 109.6 (C5); 140.7 (C4); 159.6 (COester);
156.5 (C2); 127.5–139.4(Carom).
5.6. Antimicrobial activities
Calc. for C15H1703N2 C 9.360%; H, 89.184%,N 1.455% Found: C 9.4;
H, 89.2, N 1.5;
5.6.1. Microorganisms and growth conditions
Bacterial strains: Gram-positive bacteria (Micrococcus luteus LB
14110, Staphylococcus aureus ATCC 6538, Listeria monocytogenes ATCC
19117 and Agrobacterium tumefaciens), Gram-negative bacteria
(Salmonella Typhimurium ATCC 14028 and Pseudomonas aeruginosa
ATCC 49189) were used as indicator microorganisms for the
5.5.3.
4-(3-Methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5–carboxylate 9
Yield: (96%).
M.p. = 310 °C.
1HNMR (DMSO-d6,300 MHz)δ ppm: 1.04 (t, 3H, CH3(c)); 2.14 (s, 3H,
CH3(b)); 3.46 (s, 3H, CH3(a)); 3.81 (q, 2H, Hd); 5.97 (s, 1H, Hb); 6.75 (dd,
1H, H6’); 6.86 (s, 1H, H2’); 6.99 (dd, 1H, H4’); 7.24 (dd, 1H, H5’); 7.48 (s,
1H, H1); 8.68 (s, 1H, H3).
13CNMR (DMSO-d6,75 MHz)δ ppm: 55.6 (OCH3); 16.3 (CH3(b));
42.4 (CH3(a)); 52.6 (C6); 60.2 (Cd); 109.8 (C5); 141.7 (C4); 159.6
(COester); 156.8 (C2); 128.4–140.2(Carom).
Calc. for C15H1704N2 C 9.356%; H, 89.190%,N 1.455% Found: C 9.4;
H, 89.2, N1.5.
5.5.4. 4-(4-Nitrophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5–carboxylate 10
Yield: (92%).
M.p. = 310 °C.
1HNMR (DMSO-d6, 300 MHz)δ ppm: 1.2 (t, 3H, CH3(c)); 2.12 (s, 3H,
CH3(b)); 3.81 (q, 2H, Hd); 5.97 (s, 1H, H6); 8.68 (s, 1H, H3); 7.48 (s, 1H,
H1); 6.75–7.26(m,5H, Harom).
13CNMR(DMSO-d6,75 MHz)δ ppm: 14.8 (CH3(b)); 42.6 (CH3(a));
52.6 (C6); 60.2 (Cd); 109.3 (C5); 141.2 (C4); 159.7 (COester); 156.3
(C2); 126.6–138.4(Carom).
Calc. for C14H1405N3 C 10.339%; H, 87.077%,N 2.584% Found: C
10.4; H, 87.2, N2.6.
Fig. 6. Conductometric titration in the case of 3 with Co2+
.
Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
catalyzed by Co ..., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2016), http://dx.doi.org/10.1016/j.saa.2016.04.045

R. Medyouni et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
9
Table 3
Antimicrobial activity spectrum of the synthesized compound.
Table 4
Determination of the Minimum Inhibitory Concentrations (MICs) expressed in mg/ml.
Microrganism indicator
Compounds
Inhibition zone (mm)
Microorganism indicator
Compounds
MIC(mg/ml)
Micrococcus luteus
LB 14110
3
4
5
6
7
8
9
10
11
3
4
5
26
26
22
14
16
18
13
14
21
25
23
–
Micrococcus luteus
3
4
5
6
7
8
9
10
11
3
4
5
5
5
LB 14110
0.3125
10
1.25
5
0.4125
4
4
Staphylococcus aureus
ATCC 6538
Staphylococcus aureus
5
5
–
ATCC 6538
6
7
8
9
10
11
3
4
5
14
18
17
12
13
23
16
20
–
6
7
8
9
10
11
3
4
5
5
2.5
–
5
10
–
Listeria monocytogenes
ATCC 19117
Listeria monocytogenes
2.5
5
–
ATCC 19117
6
7
8
9
10
11
3
13
20
19
18
17
14
–
6
7
8
9
10
11
3
5
0.625
–
2.5
5
1.32
5
Agrobacterium tumefaciens
Salmonella Typhimurium
4
5
–
–
ATCC 14028
4
5
10
–
6
7
8
9
10
11
3
4
5
–
6
7
8
9
10
11
3
4
5
10
5
19
17
14
13
12
12
12
–
2.5
5
1.25
–
Salmonella typhimurium
ATCC 14028
Pseudomonas aeruginosa
5
5
–
ATCC 49189
6
7
8
9
10
11
3
4
5
6
7
8
9
10
11
3
4
5
12
19
16
14
13
12
16
16
–
12
20
22
18
16
14
22
12
–
6
7
8
9
10
11
3
4
5
6
7
8
9
10
11
3
4
5
10
2.5
–
5
10
1.32
2.5
5
Pseudomonas aeruginosa
ATCC 49189
Candida albicans
10
5
–
–
2.3
–
2.1
2.5
5
Candida tropicalis
R2 CIP203.
Candida albicans
–
6
–
6
–
7
8
9
10
11
3
4
5
6
7
8
9
10
11
10
12
13
16
14
20
16
–
7
8
9
10
11
5
2.5
5
1.32
–
Candida tropicalis
R2 CIP203.
antibacterial activity assays. Antifungal activity was determined against
the Candida albicans and Candida tropicalis R2 CIP203.
–
15
14
13
14
–
The bacterial strains using as indicator microorganisms were grown
overnight in LB media under aerobic conditions and constant agitation
(200 rpm) at 30 °C for M. luteus LB14110, L. monocytogenes ATCC
19117, and A. tumefaciens, and at 37 °C for S. aureus ATCC 6538, S.
Typhimurium ATCC 14028 and P. aeruginosa ATCC 49189, and then
diluted 1:100 in LB media and incubated for 5 h under constant agi-
tation (200 rpm) at the appropriate temperature. C. tropicalis R2
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10
R. Medyouni et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 165 (2016) xxx–xxx
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Please cite this article as: R. Medyouni, et al., One-pot three-component Biginelli-type reaction to synthesize 3,4-dihydropyrimidine-2-(1H)-ones
catalyzed by Co ..., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2016), http://dx.doi.org/10.1016/j.saa.2016.04.045