Multicomponent synthesis and evaluation of new 1,2,3-triazole derivatives of dihydropyrimidinones as acidic corrosion inhibitors for steel

Article abstract of DOI:10.3390/molecules21020250

An efficient one-pot synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones has been developed using two multicomponent reactions. The aldehyde-1,2,3-triazoles were obtained in good yields from in situ-generated organic azides and O-propargylbenzaldehyde. The target heterocycles were synthesized through the Biginelli reaction in which the aldehyde-1,2,3-triazoles reacted with ethyl acetoacetate and urea in the presence of Ce(OTf)3 as the catalyst. The corrosion inhibition of steel grade API 5 L X52 in 1 M HCl by the synthesized compounds was investigated using the electrochemical impedance spectroscopy technique. The measurements revealed that these heterocycles are promising candidates to inhibit acidic corrosion of steel.

Full text of DOI:10.3390/molecules21020250

molecules
Article
Multicomponent Synthesis and Evaluation of New
1,2,3-Triazole Derivatives of Dihydropyrimidinones
as Acidic Corrosion Inhibitors for Steel
Rodrigo González-Olvera 1, Viridiana Román-Rodríguez 1, Guillermo E. Negrón-Silva 1,*,
Araceli Espinoza-Vázquez 2, Francisco Javier Rodríguez-Gómez 2 and Rosa Santillan 3
1
Departamento de Ciencias Básicas, Universidad Autónoma Metropolitana-Azcapotzalco,
Av. San Pablo No. 180, Ciudad de México, C.P. 02200, Mexico; rodrigo_glezo@hotmail.com (R.G.-O.);
vacuidadd@gmail.com (V.R.-R.)
Departamento de Ingeniería Metalúrgica, Facultad de Química, Universidad Nacional Autónoma de México,
2
C.U., Ciudad de México, C.P. 04510, Mexico; arasv_21@hotmail.com (A.E.-V.);
fxavier@hotmail.com (F.J.R.-G.)
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico
3
Nacional, Apartado Postal 14-740, 07000 Ciudad de México, Mexico; rsantill@cinvestav.mx
*
Correspondence: gns@correo.azc.uam.mx; Tel.: +52-55-5318-9593; Fax: +52-55-5318-9000 (ext. 2169)
Academic Editor: Derek J. McPhee
Received: 23 December 2015 ; Accepted: 17 February 2016 ; Published: 22 February 2016
Abstract: An efficient one-pot synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones has
been developed using two multicomponent reactions. The aldehyde-1,2,3-triazoles were obtained
in good yields from in situ-generated organic azides and O-propargylbenzaldehyde. The target
heterocycles were synthesized through the Biginelli reaction in which the aldehyde-1,2,3-triazoles
reacted with ethyl acetoacetate and urea in the presence of Ce(OTf)3 as the catalyst. The corrosion
inhibition of steel grade API 5 L X52 in 1 M HCl by the synthesized compounds was investigated
using the electrochemical impedance spectroscopy technique. The measurements revealed that these
heterocycles are promising candidates to inhibit acidic corrosion of steel.
Keywords: multicomponent synthesis; dihydropyrimidinone; 1,2,3-triazole; corrosion inhibitor; steel
1. Introduction
Multicomponent reactions (MCRs) are one-pot processes in which three or more starting materials
are combined in a single reaction vessel to give a product that incorporates substantial portions
of all the components. MCR processes are of great interest in organic and medicinal chemistry
because of several attributes, including selectivity, atom economy, convergence, versatility, and
molecular complexity [1–6]. In this regard, one example of MCR is the azide-alkyne 1,3-dipolar
cycloaddition between benzyl halides, sodium azide and terminal alkyne to afforded 1,2,3-triazoles [7]
(Scheme 1). Currently, the copper(I)-catalyzed azide-alkyne cycloaddition (also known as the
Click or Huisgen-Meldal-Sharpless reaction) is the most widely used method for the synthesis of
1,4-disubstituted 1,2,3-triazoles from a wide range of organic azides and terminal alkynes [8–10].
Molecules 2016, 21, 250; doi:10.3390/molecules21020250
www.mdpi.com/journal/molecules

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Scheme 1. Multicomponent click reaction.
Recently, 1,2,3-triazole derivatives of carbohydrates, amino acids, maleic acid, and chalcones
have been studied as effective corrosion inhibitors of steel in acidic media (Figure 1) [11–16]
This nitrogen-containing heterocycle is not only used to mitigate corrosion but is also an
important pharmacophore because of its presence in many compounds displaying pharmacological
activities [17–23]. Additionally, our group has reported the multicomponent synthesis and
corrosion inhibitory activity of 1,2,3-triazole derivatives of pyrimidine nucleobases and
2-mercaptobenzimidazole [24–27].
.
Figure 1. Representative 1,2,3-triazoles with corrosion inhibition activity.
The corrosion of steels has received a considerable amount of attention as a result of industrial
concern. API 5 L X52 steel is typically used in pipelines for gas and fuel conduction in the oil
industry [28]. The steel pipelines for hydrocarbon transport are susceptible to corrosion cracking
caused by hydrogen embrittlement and contact with fluids with high concentrations of chlorides [29,30].
One of the available methods to fight corrosion is the use of inhibitors that decrease the corrosion
rates to an acceptable level. Corrosion inhibitors based on organic compounds containing nitrogen,
oxygen, and sulfur atoms as well as
π electrons associated with triple bonds, conjugated double bonds
or aromatic rings are good inhibitors [31]. In this regard, 3,4-dihydropyrimidin-2(1H)-one (DHPM)
is a heterocycle that possesses a wide range of biological activities [32–37]; however, its corrosion
inhibition properties have hardly been studied [38].
Recently, several groups have introduced MCR strategies for the synthesis of heterocycles
containing both dihydropyrimidinone and 1,2,3-triazole rings in their structures [39 45]. In
–
continuation of our work on the development and study of organic corrosion inhibitors, we report
herein a multicomponent synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones and their
evaluation as acidic corrosion inhibitors for API 5 L X52 steel.

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2. Results and Discussion
2.1. Synthesis
For the synthesis of the title compounds, O-propargylbenzaldehyde (2) was first synthesized
from 4-hydroxybenzaldehyde (1) and propargyl bromide in the presence of K2CO3 in acetone under
reflux. After 2.5 h, the desired compound
by crystallization (Scheme 2).
2 was obtained in 91% yield after workup and purification
Scheme 2. Synthesis of O-propargylbenzaldehyde (2).
Based on our previously reported methodology, we then performed the one-pot, three-component
1,3-dipolar cycloaddition reaction between O-propargylbenzaldehyde (
chloride in the presence of Cu(OAc)2 H2O, sodium ascorbate, and 1,10-phenantroline as the catalyst
system in EtOH–H2O (2:1, v/v) at room temperature for 12 h [24 26]. The desired product was
2), sodium azide, and benzyl
¨
–
3
obtained in 78% yield (Table 1, entry 1). As an alternative synthesis for this compound, we also
performed the three-component reaction under microwave irradiation. When the reaction between
the alkyne
the aldehyde-triazole
aldehyde-triazoles
in good yields (Table 1, entries 3–6).
2, sodium azide, and benzyl chloride was performed under microwave irradiation,
˝
3
was obtained in 82% yield after 15 min at 90 C (Table 1, entry 2). The
4–7 were prepared under these established reaction conditions and were obtained
Table 1. One-pot three-component reaction catalyzed by Cu(OAc)2¨ H2O.
Entry a
Compound
X
R
Yield c (%)
1 b
2
3
4
5
3
3
4
5
6
7
Cl
Cl
Cl
Cl
Br
Br
H
H
F
Cl
Br
I
78
82
80
86
75
72
6
a: Reagents:
2
(1.25 mmol), NaN3 (1.38 mmol), and benzyl halide (1.38 mmol); b: The reaction was conducted at
room temperature for 12 h. c: Isolated yields after purification.
The next step of our synthetic strategy for the production of 1,2,3-triazole-DHPMs 8–12 involved
a Biginelli reaction. Many Lewis acids have been reported as efficient catalysts for the Biginelli
reaction [36]. We performed the one-pot, three-component reaction between ethyl acetoacetate, the
corresponding aldehyde-triazoles 3–7, and urea using cerium trifluoromethanesulfonate [Ce(OTf)3]
as a catalyst because of its high efficiency in this multicomponent reaction [46]. The heterocyclic
compounds 8–12 were isolated in 80% to 87% yield (Table 2).

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Table 2. Biginelli reaction catalyzed by Ce(OTf)3.
Entry a
Compound
R
Yield b (%)
1
2
3
4
5
8
9
10
11
12
H
F
Cl
Br
I
80
87
86
85
84
a: Reagents: aldehydes
after purification.
3–7
(0.34 mmol), urea (0.37 mmol), and ethyl aceto-acetate (0.37 mmol); b: Isolated yields
We also investigated another route for the synthesis of the target 1,2,3-triazole-DHPM, which
involved the Biginelli/Click sequence. The preparation of DHPM (13) performed with ethyl
acetoacetate, O-propargylbenzaldehyde (
2
), and urea in the presence of p-TsOH
60 C for 48 h. The desired DHPM (13) was isolated in 82% yield and was used without purification for
the following reaction. The 1H-NMR spectrum of DHPM (13) exhibited a triplet at
= 3.52 ( CH) and
a doublet at = 4.76 (CH2) for the propargyl fragment, whereas signals at = 55.9 (CH2), 78.5 ( CH),
and 79.8 (C
) appeared in the 13C-NMR spectrum (Figure S11). The one-pot, three-component reaction
¨
H2O in EtOH at
˝
δ
”
δ
δ
”
”
between the alkyne (13), 4-bromobenzyl bromide, and sodium azide was performed in the presence of
a copper catalyst to give DHPM-triazole (11) in 86% yield (Scheme 3).
Scheme 3. Synthesis of 1,2,3-triazole-DHPM through the Biginelli/Click sequence.
It is worth noting that the Biginelli reaction and the Click reaction cannot be performed directly in
one step. When all of the reactants—O-propargylbenzaldehyde (2), 4-bromobenzyl bromide, sodium
˝
azide, ethyl acetoacetate and urea—were stirred in EOH–H2O (1:1 v/v) at 90 C for 48 h in the presence
of Cu(OAc)2 H2O (10 mol %), sodium ascorbate, and 1,10-phenantroline, only the aldehyde-triazole
was observed by thin layer chromatography (CH2Cl2–EtOH 95:5 v/v).
The structures of the synthesized heterocycles
12 were confirmed by examination of their 1H-
and 13C-NMR and high-resolution mass spectra. The 1H- and 13C-NMR signals for compounds
12
were assigned with the help of 2D heteronuclear correlation experiments (HSQC and HMBC). The
signals in the 1H-NMR spectra at
= 8.27–8.28 corresponded to the triazolyl hydrogen, which were
supported by the signals in the 13C-NMR spectra at
= 125.0–125.1. The signals for the quaternary
carbon of the triazole ring appeared at
= 143.6–143.6 in the 13C-NMR spectra. These chemical shift
values are consistent with those reported for 1,4-disubstituted 1,2,3-triazoles [24–26].
¨
6
8–
8–
δ
δ
δ

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2.2. Corrosion Inhibition Efficiencies
We employed electrochemical impedance spectroscopy (EIS) to evaluate the activity of compounds
(8–
12) on the corrosion inhibition of API 5 L X52 steel. The Nyquist plots obtained for API 5 L X52 steel
in 1 M HCl solution in the absence and presence of the tested compounds
Figure 2a clearly shows that the steel in 1 M HCl shows one semicircle (Zre~30
that the steel corrosion is mainly controlled by a charge transfer process. In contrast, the corresponding
Nyquist plots obtained for the steel in the acid solution in the presence of 12 (10 ppm) increased
the impedance (Zre) value (Figure 2b), which is generally attributed to the adsorption of the organic
compounds onto the metal surface [16 27]. The electrochemical parameters obtained from fitting the
8–
12 are shown in Figure 2.
Ω
cm2), which indicates
8–
,
recorded EIS data using the appropriate equivalent circuit model (R(Q)R) are listed in Table 3.
40
Compound 8
Compound 9
600
Compound 10
a)
Compound 11
Compound 12
Fifted
30
20
10
0
400
200
0
Fifted
Ajuste
Ajuste
Experimental
Experimental
8.59Hz
947mHz
8.12Hz
134Hz
37.4Hz
967 mHz
0
200
400
600
0
10
20
30
40
Zre
/
Ω − cm2
Zre
/
Ω − cm2
(a)
(b)
Figure 2. Nyquist plots recorded in the following systems: (
X52/1 M HCl +10 ppm of compounds 8–12.
a) API 5 L X52/1 M HCl and (b) API 5 L
Table 3. Electrochemical parameters obtained from experimental impedance data including the
corrosion inhibition efficiencies (IE) at 10 ppm of the organic inhibitor.
CDL/µF¨ cm´2
RCT/Ωcm2
Compound
IE/%
Blank
8
9
10
11
12
310.0
38.0
83.3
34.8
61.9
49.5
30.0
-
618.4
564.9
733.0
573.7
678.9
95.1
94.7
95.9
94.8
95.6
The electrochemical data in Table 3 show that the charge transfer resistance (Rct) values increased,
whereas the double layer capacitance (Cdl) values decreased with addition of compounds 12. A
large Rct value is associated with a slower corrosion rate, whereas the decrease in Cdl can be attributed
to the formation of a protective layer on the metal surface [14 16 27]. It is worth noting that all of the
8–
,
,
compounds exhibited corrosion inhibitory activity with inhibition efficiencies (IE) of approximately 95%
at relatively low concentration values. These compounds provide excellent inhibition activity under
static conditions that is comparable to if not better than those of organic inhibitors that incorporate the
1,2,3-triazole moiety [11–16,25–27].

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3. Experimental Section
3.1. General Information
Commercially available reagents and solvents were used as received. Column chromatography
was performed on Kieselgel silica gel 60 (230–400 mesh). Melting points were determined using
a Fisher-Johns apparatus and are uncorrected. IR spectra were recorded on an Alpha FT-IR/ATR
spectrometer (Bruker, Leipzig, Germany). The NMR spectra (400 MHz for 1H and 100.6 MHz for 13C)
were obtained using a Bruker Ascend-400 spectrometer (Billerica, MA, USA). Chemical shifts (δ) are
given in ppm and coupling constants (J) are given in hertz (Hz). High-resolution mass spectra (HRMS)
were recorded on JMS-SX 102a (JEOL, Tokyo, Japan) and MSD-TOF-1069A (Agilent, Santa Clara, CA,
USA) spectrometers. Microwave irradiation experiments were performed using a Discover System
(CEM Corporation, Matthews, NC, USA) single-mode microwave with standard sealed microwave
glass vials. The reaction temperature was monitored by an IR sensor on the outside wall of the reaction
vial. The electrochemical impedance study was performed at room temperature using a Gill-AC
electrochemical workstation (ACM Instruments, Cark, Cumbria, UK), with a sinusoidal perturbation
signal of
˘
10 mV around Ecorr, within a range of 10´1 Hz to 104 Hz. A saturated Ag/AgCl electrode
was used as the reference, a graphite rod was used as the counter electrode, and the working electrode
was the API 5 L X52 steel sample with an exposed area of approximately 1 cm2 and a chemical
composition (wt %) of C: 0.080, Mn: 1.06, Si: 0.26, Ti: 0.003, V: 0.054, Nb: 0.041, P: 0.019, S: 0.003,
Al: 0.039, Ni: 0.019, Ceq: 0.274, Fe: balance [47], which was prepared prior to each experiment using
standard metallographic procedures. The corrosion inhibition efficiency (IE) was evaluated by means
of electrochemical impedance spectroscopy (EIS) in the API 5 L X52 steel/1 M HCl system containing 0
(blank) or 10 ppm of the organic inhibitor. A simulation of the impedance data recorded was conducted
by means of electrical equivalent circuits and the electrical parameters: charge transfer resistance (Rct)
and double layer capacitance (Cdl) were obtained in this way.
3.2. Product Synthesis and Characterization
4-(Prop-2-ynyloxy)benzaldehyde (2). In a 100 mL round bottom flask equipped with a magnetic stirrer and
a reflux condenser, 4-hydroxybenzaldehyde (
1
, 1.00 g, 8.18 mmol) was dissolved in acetone (20 mL).
Anhydrous potassium carbonate (1.47 g, 10.63 mmol) was then added and the mixture was heated
to reflux for 30 min. After cooling to room temperature, propargyl bromide (1.18 mL, 13.29 mmol,
80 wt.% in toluene) was added slowly and the reaction mixture was heated to reflux for an additional
2 h. The solvent was evaporated under vacuum and the crude reaction mixture was treated with H2O
(15 mL) and extracted with EtOAc (3
ˆ
15 mL). The combined organic phases were dried (Na2SO4)
˝
and then activated charcoal was added and the combined organics were stirred and heated at 40 C for
15 min. After the combined organics were filtered over Celite, which was washed with EtOAc (15 mL),
the solvent was evaporated under vacuum and the crude product was purified by recrystallization
˝
from EtOAc/hexane (1:2 v/v) to afford 1.19 g (91% yield) of
m.p. 75–78 ˝C). 1H-NMR (CDCl3):
= 2.59 (t, J = 2.4 Hz, 1H,
7.10 (d, J = 8.7 Hz, 2H, ArH), 7.87 (d, J = 8.8 Hz, 2H, ArH), 9.91 (s, 1H, CHO). 13C-NMR (CDCl3):
55.9 (OCH2), 76.3 ( CH), 77.5 (C ), 115.2 (2 ArCH), 130.6 (Cipso), 131.9 (2
190.7 (C=O). FT-IR/ATR CH), 2831, 2807, 2749, 2121 (C
cm´1: 3206 (
2
as a white solid, m.p. 75–77 C (Lit. [48
]
δ
”
CH), 4.79 (d, J = 2.4 Hz, 2H, OCH2),
δ
=
”
”
ˆ
ˆ
ArCH), 162.4 (O-Cipso),
C), 1677 (C=O), 1601,
ν
”
”
max
1574, 1504, 1248, 1213, 1168, 1006, 825, 509. HRMS (ESI-TOF) calculated for C10H8O2 + H+: 161.0597;
Found: 161.0599.
4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (
magnetic stirrer, Cu(OAc)2 H2O (11.4 mg, 0.063 mmol, 5 mol%), 1,10-phenanthroline monohydrate
(12.5 mg, 0.063 mmol, 5 mol%), and sodium L-ascorbate (188 mg, 0.95 mmol) were added in EtOH–H2O
(1:1 v/v, 4 mL), followed by stirring for five min at room temperature. Subsequently, alkyne (200 mg,
1.25 mmol), sodium azide (90 mg, 1.38 mmol), and benzyl chloride (0.16 mL, 1.38 mmol) were added to
3). In a 10 mL microwave vial equipped with a
¨
2

Molecules 2016, 21, 250
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˝
the reaction mixture, which was irradiated (5–6 W) at 90 C for 15 min. Afterward, H2O (15 mL) was
added to the reaction mixture and extracted with CH2Cl2 (3 15 mL). The combined organic phases
ˆ
were dried (Na2SO4) and then the solvent was evaporated under vacuum. The crude product was
purified by column chromatography (Hexane/EtOAc 1:1, v/v) and recrystallized from EtOAc/hexane
(1:2, v/v) to afford 300 mg (82% yield) of
1H-NMR (CDCl3):
= 5.26 (s, 2H, OCH2), 5.54 (s, 2H, NCH2), 7.08 (d, J = 8.7 Hz, 2H, ArH), 7.26–7.29
(m, 2H, ArH), 7.36–7.39 (m, 3H, ArH), 7.55 (s, 1H, ArH triazole), 7.82 (d, J = 8.7 Hz, 2H, ArH), 9.88 (s,
1H, CHO). 13C-NMR (CDCl3):
= 54.3 (NCH2), 62.2 (OCH2), 115.0 (2 ArCH), 122.8 (ArCH triazole),
128.2 (2 ArCH), 128.9 (ArCH), 129.2 (2 ArCH), 130.4 (Cipso), 132.0 (2 ArCH), 134.3 (Cipso), 143.6
(Cipso triazole), 163.1 (O-Cipso), 190.8 (C=O). FT-IR/ATR
cm´1: 3143, 3097, 3064, 2963, 2935,
3
as a white solid, m.p. 95–97 ˝C [Lit. [48] m.p.100–103 ˝C].
δ
δ
ˆ
ˆ
ˆ
ˆ
ν
max
2842, 2820, 2760, 1673 (C=O), 1601, 1575, 1240, 1216, 1172, 834, 752. HRMS (ESI-TOF) calculated for
C17H15N3O2 + H+: 294.1237; Found: 294.1240.
4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (
(using the same quantities of Cu(OAc)2 H2O, 1,10-phenanthroline monohydrate, and sodium
L-ascorbate) was followed to obtain compound , employing alkyne (200 mg, 1.25 mmol), NaN3
4). The procedure described above
¨
4
2
(90 mg, 1.38 mmol), and 4-fluorobenzyl chloride (0.16 mL, 1.38 mmol). The crude product was purified
by column chromatography (hexane/EtOAc 1:1 v/v) and recrystallized from EtOAc/hexane (1:2
v/v) to afford 313 mg (80% yield) of the desired product
4 ]
as a white solid, m.p. 89–90 ˝C [Lit. [49
m.p.101–104 C]. 1H-NMR (CDCl3):
7.26–7.30 (m, 2H, ArH), 7.56 (s, 1H, ArH triazole), 7.83 (d, J = 8.8 Hz, 2H, ArH), 9.88 (s, 1H, CHO).
13C-NMR (CDCl3):
= 53.6 (NCH2), 62.2 (OCH2), 115.1 (2 ArCH), 116.2 (d, JCF = 21.8 Hz, 2 ArCH),
122.6 (ArCH triazole), 130.1 (d, JCF = 8.4 Hz, 2 ArCH), 130.2 (d, JCF = 3.3 Hz, Cipso), 130.4 (Cipso),
132.0 (2 ArCH), 143.8 (Cipso triazole), 162.9 (d, JCF = 248.5 Hz, F-Cipso), 163.1 (O-Cipso), 190.7 (C=O).
FT-IR/ATR
cm´1: 3151, 3068, 3038, 2944, 2841, 2759, 1672 (C=O), 1601, 1574, 1456, 1254, 1217,
δ = 5.26 (s, 2H, OCH2), 5.51 (s, 2H, NCH2), 7.04–7.09 (m, 4H, ArH),
˝
δ
ˆ
ˆ
ˆ
ˆ
ν
max
1157, 1032, 823, 501. HRMS (ESI-TOF) calculated for C17H14FN3O2 +H+: 312.1143; Found: 312.1146.
4-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde ( ). The procedure described above
(using the same quantities of Cu(OAc)2 H2O, 1,10-phenanthroline monohydrate, and sodium
L-ascorbate) was followed to obtain compound , employing alkyne (200 mg, 1.25 mmol), NaN3
5
¨
5
2
(90 mg, 1.38 mmol), and 4-chlorobenzyl chloride (222 mg, 1.38 mmol). The crude product was purified
by column chromatography (hexane/EtOAc 1:1, v/v) and recrystallized from EtOAc/hexane (1:2,
v/v) to afford 350 mg (85% yield) of the desired product
m.p.108–110 ˝C]. 1H-NMR (CDCl3):
= 5.26 (s, 2H, OCH2), 5.52 (s, 2H, NCH2), 7.08 (d, J = 8.7 Hz,
2H, ArH), 7.22 (d, J = 8.4 Hz, 2H, ArH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.58 (s, 1H, ArH triazole), 7.83
(d, J = 8.7 Hz, 2H, ArH), 9.88 (s, 1H, CHO). 13C-NMR (CDCl3):
= 53.6 (NCH2), 62.1 (OCH2), 115.1
(2 ˆ ArCH), 122.8 (ArCH triazole), 129.4 (2 ArCH), 129.5 (2 ArCH), 130.4 (Cipso), 132.0 (2
132.8 (Cl-Cipso), 135.0 (Cipso), 143.8 (Cipso triazole), 163.1 (O-Cipso), 190.8 (C=O). FT-IR/ATR
5 ]
as a white solid, m.p. 88–89 ˝C [Lit. [49
δ
δ
ˆ
ˆ
ˆ
ArCH),
´1
ν
max cm
:
3149, 3100, 3055, 2943, 2807, 2744, 1671 (C=O), 1600, 1571, 1160, 992, 833, 806, 772, 501. HRMS (ESI-TOF)
calculated for C17H14ClN3O2 + H+: 328.0847; Found: 328.0845.
4-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (
(using the same quantities of Cu(OAc)2 H2O, 1,10-phenanthroline monohydrate, and sodium
L-ascorbate) was followed to obtain compound , employing alkyne (200 mg, 1.25 mmol), NaN3
6). The procedure described above
¨
6
2
(90 mg, 1.38 mmol), and 4-bromobenzyl bromide (345 mg, 1.38 mmol). The crude product was purified
by column chromatography (hexane/EtOAc 1:1, v/v) and recrystallized from EtOAc/hexane (1:2,
v/v) to afford 355 mg (76% yield) of the desired product
(CDCl3): = 5.26 (s, 2H, OCH2), 5.50 (s, 2H, NCH2), 7.08 (d, J = 8.8 Hz, 2H, ArH), 7.16 (d, J = 8.4 Hz,
2H, ArH), 7.51 (d, J = 8.4 Hz, 2H, ArH), 7.57 (s, 1H, ArH triazole), 7.83 (d, J = 8.8 Hz, 2H, ArH), 9.88 (s,
1H, CHO). 13C-NMR (CDCl3):
= 53.6 (NCH2), 62.2 (OCH2), 115.1 (2 ArCH), 122.7 (ArCH triazole),
123.1 (Br-Cipso), 129.7 (2 ArCH), 130.4 (Cipso), 132.0 (2 ArCH), 132.4 (2 ArCH), 133.3 (Cipso),
143.9 (Cipso triazole), 163.1 (O-Cipso), 190.7 (C=O). FT-IR/ATR
cm´1: 3149, 3100, 3054, 2943, 2807,
6
as a white solid, m.p. 82–84 ˝C. 1H-NMR
δ
δ
ˆ
ˆ
ˆ
ˆ
ν
max

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2746, 1670 (C=O), 1600, 1572, 1249, 1212, 1160, 991, 833, 770, 491. HRMS (ESI-TOF) calculated for
C17H14BrN3O2 + H+: 372.0342; Found: 372.0347.
4-((1-(4-Iodobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (
followed to obtain compound , employing Cu(OAc)2 H2O (5.6 mg, 0.031 mmol), 1,10-phenanthroline
monohydrate (6.1 mg, 0.031 mmol), sodium L-ascorbate (93 mg, 0.47 mmol), alkyne (100 mg,
7). The procedure described above was
7
¨
2
0.62 mmol), NaN3 (44 mg, 0.68 mmol), and 4-iodobenzyl bromide (214 mg, 0.72 mmol). The crude
product was purified by column chromatography (Hexane/EtOAc 1:1 v/v) and recrystallized from
EtOAc/hexane (1:2 v/v) to afford 190 mg (73% yield) of the desired product
7
as a white solid, m.p.
= 5.27 (s, 2H, OCH2), 5.49 (s, 2H, NCH2), 7.03 (d, J = 8.4 Hz, 2H, ArH),
7.08 (d, J = 8.7 Hz, 2H, ArH), 7.56 (s, 1H, ArH triazole), 7.71 (d, J = 8.4 Hz, 2H, ArH), 7.83 (d, J = 8.8 Hz,
2H, ArH), 9.88 (s, 1H, CHO). 13C-NMR (CDCl3):
= 53.7 (NCH2), 62.2 (OCH2), 94.7 (I-Cipso), 115.1
(2 ArCH), 122.7 (ArCH triazole), 129.9 (2 ArCH), 130.4 (Cipso), 132.0 (2 ArCH), 134.0 (Cipso),
138.4 (2 ArCH), 143.9 (Cipso triazole), 163.1 (O-Cipso), 190.7 (C=O). FT-IR/ATR
cm´1: 3154,
˝
85–87 C. 1H-NMR (CDCl3):
δ
δ
ˆ
ˆ
ˆ
ˆ
ν
max
2953, 2919, 2873, 2820, 2799, 2738, 1682 (C=O), 1604, 1579, 1252, 1210, 1154, 1047, 1008, 811, 768. HRMS
(ESI-TOF) calculated for C17H14IN3O2 + H+: 420.0203; Found: 420.0206.
Ethyl 4-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (
8). In a 25 mL round-bottomed flask equipped with a magnetic stirrer, aldehyde-triazole
3
(100 mg, 0.34 mmol), urea (22 mg, 0.37 mmol), ethyl acetoacetate (47
µL, 0.37 mmol), and cerium
trifluoromethanesulfonate (40 mg, 0.068 mmol, 20 mol %) were added in EtOH (2 mL). The reaction
mixture was stirred at room temperature for 3 days. The solvent was evaporated under vacuum
and the crude reaction mixture was purified by column chromatography (CH2Cl2
98:2 v/v) to afford 122 mg (80% yield) of
as a white foam, m.p. 72–75 ˝C [Lit. [41] m.p.131–133 ˝C].
1H-NMR (DMSO-d6):
= 1.09 (t, J = 7.1 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.97 (q, J = 7.1 Hz, 2H, OCH2),
5.09 (s, 1H, CH), 5.10 (s, 2H, OCH2), 5.61 (s, 2H, NCH2), 6.97 (d, J = 8.7 Hz, 2H, ArH), 7.15 (d, J = 8.7 Hz
2H, ArH), 7.30–7.40 (m, 5H, ArH), 7.70 (br, 1H, NH), 8.28 (s, 1H, ArH triazole), 9.18 (br, 1H, NH).
13C-NMR (DMSO-d6):
= 14.6 (OCH2CH3), 18.2 (CH3), 53.3 (NCH2), 53.8 (CH), 59.6 (OCH2CH3), 61.5
(OCH2), 100.0 (C=), 114.9 (2 ArCH), 125.1 (ArCH triazole), 127.9 (2 ArCH), 128.4 (2 ArCH),
128.6 (ArCH), 129.2 (2 ArCH), 136.5 (Cipso), 137.9 (Cipso), 143.5 (Cipso triazole), 148.5 (=CNH), 152.6
(NC=ON), 157.7 (O-Cipso), 165.8 (OC=O). FT-IR/ATR
ÑCH2Cl2/EtOH
8
δ
,
δ
ˆ
ˆ
ˆ
ˆ
ν
max cm´1: 3231, 3098, 2931, 1692 (C=O), 1638,
1507, 1454, 1220, 1174, 1085, 794, 756, 716, 653. HRMS (ESI-TOF) calculated for C24H25N5O4 + H+:
448.1979; Found: 448.1983.
Ethyl 4-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (
employing aldehyde-triazole
0.35 mmol), and cerium trifluoromethanesulfonate (38 mg, 0.064 mmol, 20 mol %). The crude reaction
mixture was purified by column chromatography (CH2Cl2 CH2Cl2/EtOH 98:2 v/v) to afford 130 mg
as a white foam, m.p. 77–80 C. 1H-NMR (DMSO-d6):
= 1.10 (t, J = 7.1 Hz, 3H, CH3),
9). The procedure described above was followed to obtain compound
9,
4
(100 mg, 0.32 mmol), urea (21 mg, 0.35 mmol), ethyl acetoacetate (44
µL,
Ñ
˝
(87% yield) of
9
δ
2.25 (s, 3H, CH3), 3.98 (q, J = 7.1 Hz, 2H, OCH2), 5.10 (s, 3H, CH, OCH2), 5.60 (s, 2H, NCH2), 6.97 (d,
J = 8.6 Hz, 2H, ArH), 7.16 (d, J = 8.1 Hz, 2H, ArH), 7.18–7.23 (m, 2H, ArH), 7.38–7.42 (m, 2H, ArH), 7.67
(br, 1H, NH), 8.27 (s, 1H, ArH triazole), 9.15 (br, 1H, NH). 13C-NMR (DMSO-d6):
δ
= 14.5 (OCH2CH3),
18.2 (CH3), 52.5 (NCH2), 53.8 (CH), 59.6 (OCH2CH3), 61.6 (OCH2), 100.1 (C=), 115.0 (2 ˆ ArCH)
116.0 (d, JCF = 21.6 Hz, 2 ArCH), 125.0 (ArCH triazole), 127.9 (2 ArCH), 130.7 (d, JCF = 8.4 Hz,
2 ˆ ArCH), 132.6 (d, JCF = 3.0 Hz, Cipso), 137.9 (Cipso), 143.6 (Cipso triazole), 148.5 (=CNH), 152.6
,
ˆ
ˆ
´1
:
(NC=ON), 157.7 (O-Cipso), 162.4 (d, JCF = 244.5 Hz, F-Cipso), 165.9 (OC=O). FT-IR/ATR
ν
max cm
3228, 3098, 2928, 1692 (C=O), 1639, 1508, 1455, 1220, 1085, 829, 778. HRMS (ESI-TOF) calculated for
C24H24FN5O4 + H+: 466.1885; Found: 466.1889.
Ethyl 4-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (10). The procedure described above was followed to obtain compound 10
,

Molecules 2016, 21, 250
9 of 13
employing aldehyde-triazole
5
(100 mg, 0.30 mmol), urea (20 mg, 0.33 mmol), ethyl acetoacetate
(42 µL, 0.33 mmol), and cerium trifluoromethanesulfonate (35 mg, 0.060 mmol, 20 mol %). The crude
reaction mixture was purified by column chromatography (CH2Cl2 CH2Cl2/EtOH 98:2, v/v) to
afford 125 mg (86% yield) of 10 as a white solid, m.p. 157–158 ˝C. 1H-NMR (DMSO-d6):
= 1.09 (t,
Ñ
δ
J = 7.1 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.97 (q, J = 7.1 Hz, 2H, OCH2), 5.09 (s, 1H, CH), 5.10 (s, 2H,
OCH2), 5.61 (s, 2H, NCH2), 6.97 (d, J = 8.7 Hz, 2H, ArH), 7.15 (d, J = 8.6 Hz, 2H, ArH), 7.34 (d, J =
8.5 Hz, 2H, ArH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 7.67 (br, 1H, NH), 8.28 (s, 1H, ArH triazole), 9.15
(br, 1H, NH). 13C-NMR (DMSO-d6):
(OCH2CH3), 61.5 (OCH2), 100.0 (C=), 114.9 (2
(2 ArCH), 130.4 (2 ArCH), 133.4 (Cl-Cipso), 135.5 (Cipso), 137.9 (Cipso), 143.5 (Cipso triazole), 148.5
δ
= 14.6 (OCH2CH3), 18.2 (CH3), 52.5 (NCH2), 53.8 (CH), 59.6
ArCH), 125.1 (ArCH triazole), 127.9 (2 ArCH), 129.2
ˆ
ˆ
ˆ
ˆ
(=CNH), 152.6 (NC=ON), 157.7 (O-Cipso), 165.8 (OC=O). FT-IR/ATR
ν
cm´1: 3197, 3085, 2926,
max
1697 (C=O), 1638, 1218, 1172, 1090, 1017, 767. HRMS (ESI-TOF) calculated for C24H24ClN5O4 + H+:
482.1589; Found: 482.1595.
Ethyl 4-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (11). The procedure described above was followed to obtain compound 11
employing aldehyde-triazole (100 mg, 0.27 mmol), urea (18 mg, 0.30 mmol), ethyl acetoacetate (38 L,
0.30 mmol), and cerium trifluoromethanesulfonate (32 mg, 0.054 mmol, 20 mol %). The crude reaction
mixture was purified by column chromatography (CH2Cl2 CH2Cl2/EtOH 98:2, v/v) to afford 120 mg
(85% yield) of 11 as a white solid, m.p. 188–190 ˝C. 1H-NMR (DMSO-d6):
= 1.10 (t, J = 7.1 Hz, 3H,
CH3), 2.25 (s, 3H, CH3), 3.98 (q, J = 7.1 Hz, 2H, OCH2), 5.10 (s, 3H, CH, OCH2), 5.60 (s, 2H, NCH2), 6.97
,
6
µ
Ñ
δ
(d, J = 8.6 Hz, 2H, ArH), 7.15 (d, J = 8.6 Hz, 2H, ArH), 7.28 (d, J = 8.3 Hz, 2H, ArH), 7.58 (d, J = 8.4 Hz
2H, ArH), 7.66 (br, 1H, NH), 8.28 (s, 1H, ArH triazole), 9.14 (br, 1H, NH). 13C-NMR (DMSO-d6):
δ = 14.6 (OCH2CH3), 18.2 (CH3), 52.6 (NCH2), 53.8 (CH), 59.6 (OCH2CH3), 61.6 (OCH2), 100.0 (C=),
,
115.0 (2
(2 ArCH), 135.8 (Cipso), 137.9 (Cipso), 143.6 (Cipso triazole), 148.5 (=CNH), 152.6 (NC=ON), 157.7
(O-Cipso), 165.8 (OC=O). FT-IR/ATR
max cm´1: 3197, 3086, 2925, 1696 (C=O), 1638, 1218, 1089, 826,
766, 656. HRMS (ESI-TOF) calculated for C24H24BrN5O4 + H+: 526.1084; Found: 526.1086.
ˆ
ArCH), 121.9 (Br-Cipso), 125.1 (ArCH triazole), 127.9 (2
ˆ
ArCH), 130.7 (2
ˆ
ArCH), 132.2
ˆ
ν
Ethyl 4-(4-((1-iodobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (12). The procedure described above was followed to obtain compound 12
employing aldehyde-triazole (100 mg, 0.24 mmol), urea (16 mg, 0.26 mmol), ethyl acetoacetate
(33 µL, 0.26 mmol), and cerium trifluoromethanesulfonate (28 mg, 0.048 mmol, 20 mol %). The crude
reaction mixture was purified by column chromatography (CH2Cl2 CH2Cl2/EtOH 98:2, v/v) to
afford 115 mg (83% yield) of 12 as a white solid, m.p. 208–210 C. 1H-NMR (DMSO-d6):
= 1.10 (t, J =
,
7
Ñ
˝
δ
7.1 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.97 (q, J = 7.1 Hz, 2H, OCH2), 5.10 (s, 3H, CH, OCH2), 5.57 (s, 2H,
NCH2), 6.97 (d, J = 8.7 Hz, 2H, ArH), 7.11–7.16 (m, 4H, ArH), 7.70 (br, 1H, NH), 7.75 (d, J = 8.2 Hz,
2H, ArH), 8.28 (s, 1H, ArH triazole), 9.18 (br, 1H, NH). 13C-NMR (DMSO-d6):
δ
= 14.6 (OCH2CH3),
18.2 (CH3), 52.7 (NCH2), 53.8 (CH), 59.6 (OCH2CH3), 61.5 (OCH2), 94.9 (I-Cipso), 100.0 (C=), 114.9
(2 ArCH), 125.1 (ArCH triazole), 127.9 (2 ArCH), 130.7 (2 ArCH), 136.2 (Cipso), 137.9 (Cipso),
138.0 (2 ArCH), 143.5 (Cipso triazole), 148.5 (=CNH), 152.6 (NC=ON), 157.7 (O-Cipso), 165.8 (OC=O).
FT-IR/ATR
ˆ
ˆ
ˆ
ˆ
ν
cm´1: 3212, 3085, 2929, 1692 (C=O), 1638, 1510, 1218, 1090, 765, 658. HRMS (ESI-TOF)
max
calculated for C24H24IN5O4 + H+: 574.0946; Found: 574.0945.
Ethyl 6-methyl-2-oxo-4-(4-(prop-2-ynyloxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (13). In a
100 mL pressure vessel equipped with a magnetic stirrer, aldehyde 2 (160 mg, 1 mmol), urea (72 mg,
1.2 mmol), ethyl acetoacetate (0.14 mL, 1.1 mmol), and p-toluenesul˝fonic acid monohydrate (57 mg,
0.3 mmol) were added in EtOH (3 mL). The mixture was heated at 60 C for 2 days, cooled and poured
into ice/water (15 g), and the precipitate was filtered off and dried. The light yellow solid 13 (260 mg,
82% yield) was used directly for the following reaction. A sample for analysis was recrystallized from
˝
CH2Cl2-hexane (1:2 v/v), which gave a colorless solid, m.p. 159–160 C. 1H-NMR (DMSO-d6):
δ = 1.10
(t, J = 7.1 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.52 (t, J = 2.2 Hz, 1H, CH), 3.99 (q, J = 7.1 Hz, 2H, OCH2),
”

Molecules 2016, 21, 250
10 of 13
4.76 (d, J = 2.1 Hz, 2H, OCH2), 5.10 (d, J = 2.8 Hz, 1H, CH), 6.93 (d, J = 8.6 Hz, 2H, ArH), 7.16 (d, J =
8.6 Hz, 2H, ArH), 7.66 (br, 1H, NH), 9.14 (br, 1H, NH). 13C-NMR (DMSO-d6):
= 14.6 (OCH2CH3),
18.2 (CH3), 53.8 (CH), 55.9 (OCH2), 59.6 (OCH2CH3), 78.5 ( CH), 79.8 (C ), 100.0 (C=), 115.2 (2
ArCH), 127.8 (2 ArCH), 138.3 (Cipso), 148.5 (=CNH), 152.6 (NC=ON), 156.9 (O-Cipso), 165.8 (OC=O).
FT-IR/ATR
δ
”
”
ˆ
ˆ
ν
max cm´1: 3276, 3246, 3114, 2981, 2920, 2115 (C
C), 1704 (C=O), 1650, 1508, 1221, 1175,
”
1093, 1034, 776. HRMS (ESI-TOF) calculated for C17H18N2O4 + H+: 315.1339; Found: 315.1344.
4. Conclusions
In conclusion, we have developed an efficient synthesis of 1,2,3-triazole derivatives of
dihydropyrimidinones by the MCR strategy (Click/Biginelli reactions) in good yields. Consequently,
this MCR strategy is a powerful synthetic tool for the construction of new corrosion inhibitors based on
1,2,3-triazoles and dihydropyrimidinones. EIS measurements showed that the inhibitive capacity for
API 5 L X52 steel in 1 M HCl of the heterocycles 8–12 was comparable or better than that other organic
inhibitors that incorporate the 1,2,3-triazole moiety. Further investigations of these heterocycles as
corrosion inhibitors for steel are in progress and will be reported in due course.
Supplementary Materials: Copies of 1H- and 13C-NMR spectra for compounds
3–13 (Figures S1–S11).
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/2/250/s1.
Acknowledgments: The authors would like to thank Consejo Nacional de Ciencia y Tecnología, CONACyT
(project 181448) for financial support. R. González-Olvera, G.E. Negrón-Silva, A. Espinoza-Vázquez, F.J.
Rodríguez-Gómez and R. Santillan wish to acknowledge the SNI (Sistema Nacional de Investigadores) for
the distinction of their membership and the stipend received. We also wish to thank Maria Eugenia Ochoa, Rebeca
Yépez for the technical assistance, and Geiser Cuéllar for the mass measurements.
Author Contributions: R.G.-O. conceived, designed, and performed the experiments and prepared the manuscript
and the supplementary information; V.R.-R. performed the experiments; G.E.N.-S. provided conceptual
guidance, supervised the project, and edited the manuscript; A.E.-V. and F.J.R.-G. designed and performed
the electrochemical experiments and analyzed the data; R.S. contributed with analysis tools, discussed the NMR
data, and edited the manuscript. All authors read and commented on the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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