Synthesis of bis(1,2,3-triazole) functionalized quinoline-2,4-diones ?

Article abstract of DOI:10.3390/molecules23092310

Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title

Full text of DOI:10.3390/molecules23092310

molecules
Article
Synthesis of Bis(1,2,3-Triazole) Functionalized
Quinoline-2,4-Diones †
1
David Milic´evic´ , Roman Kimmel 1, Martin Gazvoda 2, Damijana Urankar 2, Stanislav Kafka 1,
*
and Janez Košmrlj 2,
*
1
Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlin, 760 01 Zlin, Czech Republic;
david.milicevic@gmail.com (D.M.); r.kimmel@centrum.cz (R.K.)
Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
martin.gazvoda@fkkt.uni-lj.si (M.G.); damijana.urankar@fkkt.uni-lj.si (D.U.)
Correspondence: kafka@utb.cz (S.K.); janez.kosmrlj@fkkt.uni-lj.si (J.K.);
Tel.: +420-57-603-1115 (S.K.); +386-1-479-8558 (J.K.)
2
*
†
Dedicated to Professor Oldrˇich Paleta on his 80th birthday.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 25 June 2018; Accepted: 4 September 2018; Published: 10 September 2018
Abstract: Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on
quinolone nitrogen atom, which are available by the previously described four step synthesis starting
from aniline, were exploited as intermediates in obtaining the title compounds. The procedure
involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned
intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF)
in presence of a potassium carbonate and the subsequent formation of a second triazole ring by
copper catalyzed cyclisation reaction with azido compounds. The products were characterized by
1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of
the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC,
1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts
at the natural abundance level of 15N isotope.
Keywords: click chemistry; azido group; quinoline-2,4(1H,3H)-diones; propargyl group;
bis(1,2,3-triazole)
1. Introduction
The 1,4-disubstituted-1,2,3-triazole heterocyclic motif has become an exceedingly popular
structure finding applications in a broad range of areas including materials, biomaterials,
metallopharmaceuticals, supramolecular chemistry, chemical sensing and catalysis, to name just
a few [
ligand scaffold, not only because of simplicity and reliability in its preparation, but also due to
a variety of coordination modes offering [ ]. Owing to the discovery of copper(I)-catalyzed
1,3-cycloaddition of terminal alkynes with organic azides, the CuAAC click reaction, the preparation
of 1,4-disubstituted-1,2,3-triazole is facilitated in mild and modular fashion [ ]. Although
1]. In coordination and organometallic chemistry, for example, it became an important
2–6
7,8
this “click triazole” has become a part of a broad range of molecules, its association with
quinoline-2,4-diones remains largely underdeveloped. Apart from our recent publication on
3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione derivatives (1, Figure 1) [9], to the best of our
knowledge, other 1,2,3-triazole functionalized quinoline-2,4-diones are unprecedented.
As part of our endeavor in quinoline-2,4-dione chemistry [10] as well as functional click
triazoles [11
,12] and their applications [13], we became interested in the synthesis of bis(1,2,3-triazole)
functionalized quinoline-2,4-diones
2
that may potentially serve as functional scaffolds in coordination
Molecules 2018, 23, 2310; doi:10.3390/molecules23092310
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2310
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chemistry, molecular sensing and biochemistry. It is noteworthy that many compounds with
the quinoline-2,4-dione structure were isolated from fungi, bacteria and plants, possessing broad
range of interesting biological activities in vitro and in vivo
[
10]. Herein we report an approach to
1
quinoline-2,4-diones unsymmetrically substituted with two click triazoles, an extensive H, 13C,
and 15N NMR spectral analyses, and a preliminary investigation of their chelating properties
towards arene-ruthenium.
N
N
N
R2
O
R2
N
O
N
R1
N
R1
N
O
N
H
O
N
R3
N
N
2
1
Figure 1. A general structure of 1,2,3-triazole quinoline-2,4-diones
counterparts 2 (right).
1 (left) and the bis(1,2,3-triazole)
2. Results and Discussion
We reasoned that the desired bis(1,2,3-triazole) functionalized quinoline-2,4-diones
obtained via previously described 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione derivatives
2
could be
as
1
synthetic intermediates (Scheme 1). The latter were prepared in a four-step reaction sequence starting
from aniline, which upon treatment with diethyl 2-methylmalonate and diethyl 2-phenylmalonate
initially afforded the corresponding 4-hydroxyquinolin-2(1H)-ones 3a and 3b
sulfuryl chloride into 3-methyl- and 3-phenyl-3-chloroquinolin-2,4(1H,3H)-diones 4a
followed by the nucleophilic displacement of the chlorine atoms with sodium azide, gave 3-methyl-
[14]. Chlorination with
[
15] and 4b 16],
[
and 3-phenyl- substituted 3-azidoquinoline-2,4(1H,3H)-diones 5a and 5b [16]. Then we began with
copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC).
Scheme 1. Preparation of bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2.
Although a large variety of reaction conditions have been developed for the CuAAC reaction [17
,18],
our previous work in this field has shown that for 3-azidoquinoline-2,4(1H,3H)-diones a combination
of copper(II) sulfate pentahydrate and elemental copper (CuSO4/Cu0) in dimethyl sulfoxide (DMSO)
provided results that were superior to other combinations. Adopting those previous results in
this work some additional optimizations of the reaction conditions were carried out with 5a and
phenylacetylene (6a) as the model substrates. Screening through the reaction solvents indicated that
N,N-dimethylformamide (DMF) is even more efficient than DMSO, providing the desired target
compound 1a in shorter reaction times. The influence of the amount of granular copper to the
course of the reaction between 5a and equimolar amount of 6a in DMF was also briefly investigated.
While keeping the loading of CuSO4
elemental copper was varied from 380 mol % to 100 mol %. The results are summarized in Table 1.
·
5H2O constant at 10 mol % relative to 5a, the amount of the

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Table 1. The Effect of Granular Copper to the Conversion of 5a into 1a a.
N
O
N
Ph
O
N3
Ph
Ph
N
6a
Ph
Cu, CuSO4
DMF, rt
N
H
O
N
H
O
5a
1a
Yield b (%)
Entry
Cu0 (mmol)
Reaction Time (h)
1
2
3
4
3.8
3
2
0.75
0.75
1
98
91
89
1
25
82 c
a
Reaction conditions: 5a (1 mmol), phenylacetylene (1 mmol), and CuSO4
·
5H2O (0.1 mmol), DMF (4 mL), rt.
The reaction time was determined by thin-layer chromatography (TLC) monitoring of the reaction mixture.
b
c
Refers to the yield of isolated pure product. Complete consumption of 5a was not reached.
Based on the above, in a general procedure, a mixture of 3-azidoquinoline-2,4(1H,3H)-dione
, 1.0 mmol), a slight excess of terminal alkyne (1.05 mmol), CuSO4 5H2O (0.12 mmol), and granular
copper (2.0 mmol) in DMF (2.3 mL) was stirred at room temperature, in the presence of air. In addition
(5
6
·
to phenylacetylene (6a), propargyl alcohol (6b) was selected as the acetylene partner. The reactions
were completed within 30 min. As indicated in Table 2, the products
1 were obtained in excellent yields.
By using a more standard CuSO4 5H2O/L-ascorbic acid catalyst in CH2Cl2/water biphasic system, the
·
cycloaddition between 5a and 6a required substantially longer reaction time (48 h) to achieve a similar
yield of the product 1a as compared to the above CuSO4/Cu0/DMF conditions (Entries 1 and 2).
Table 2. Preparation of compounds 1.
N
R2
O
R2
O
N
N3
R1
N
6
R1
Cu, CuSO4
DMF, rt
N
H
O
N
H
O
5
1
Entry
Azide 5
R1
Acetylene 6
R2
Product 1
Yield a
1
2
3
4
5
5a
5a
5b
5a
5b
Me
Me
Ph
Me
Ph
6a
6a
6a
6b
6b
Ph
Ph
Ph
1a
1a
1b
1c
95
83 b
86
99
98
CH2OH
CH2OH
1d
a
b
Refers to percent yield of pure (by TLC and IR) isolated product.
acid/CH2Cl2/water conditions, 48 h reaction time.
Employing CuSO4 5H2O/L-ascorbic
·
Prior to the introduction of propargyl group at the N1 nitrogen atom of the
quinoline-2,4(1H,3H)-dione ring in , the primary hydroxyl groups at 1c and 1d were protected by
1
acetylation by using acetic anhydride in pyridine as shown in Scheme 2. The corresponding acetates
1e and 1f were obtained in 84–85% yields.
N
N
N
N
O
O
OH
OAc
N
N
Ac2O, Py
R1
R1
N
H
O
N
H
O
1c (R1 = Me)
1d (R1 = Ph)
1e (R1 = Me), 84%
1f (R1 = Ph), 85%
Scheme 2. Preparation of compounds 1e and 1f.

Molecules 2018, 23, 2310
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Alkylation of compounds 1a
,
b,
e
,f
with propargyl group was carried out by using 1.5 equivalent of
propargyl bromide (6c) and 3 equivalents of potassium carbonate in DMF. These reactions proceeded
smoothly within 45 min at room temperature. The yields are given in Table 3.
Table 3. Preparation of compounds 7.
N
N
R2
Br
N
R2
O
N
O
N
N
6c
R1
R1
K2CO3
DMF, rt
N
O
N
H
O
1
7
Entry
1
R1
R2
6
Yield of 7 (%) a
1
2
3
4
1a
1b
1e
1f
Me
Ph
Me
Ph
Ph
Ph
CH2OAc
CH2OAc
6c
6c
6c
6c
7a, 96
7b, 79
7c, 81
7d, 63
a
Refers to percent yield of pure (by TLC and IR) isolated product.
Although N-alkylation of the lactam group usually takes place preferentially in
quinoline-2,4(1H,3H)-diones [10], the competitive O-alkylation has been documented in similar
systems [19]. The N1 position of thus introduced propargyl group in
7 was confirmed by 2D NMR
spectroscopy in particular by the presence of the long-range correlations between the propargyl
methylene protons and carbon atoms C-8a and C-2 in the 1H-13C HMBC spectra (in 7a
N1 nitrogen atom in the 1H–15N gs-HMBC spectrum (in 7a).
,c,d) as well as
As the last step of the reaction sequence shown in Scheme 1, monotriazoles
a second cycloaddition with selected azides to give the expected bis-triazoles
azidobenzene (8b) and tetrazolo[1,5-a]pyridine (8c) were selected as the reaction partners. Whereas
benzyl azide (8a) and azidobenzene (8b) readily reacted into the desired products 2a,b,d,e,g,h,j,k
7
were submitted to
8
2. Benzyl azide (8a),
at room temperature, tetrazolo[1,5-a]pyridine (8c), a synthetic equivalent for 2-azidopyridine (8c’),
required harsher reaction conditions (Table 4). This can be explained by the tetrazolyl form in which
compound 8c exists predominantly at room temperature [11]. As the proportion of the azido isomer
◦
increases at elevated temperature, the reactions with 8c were conducted at 100 C, to afford compounds
2c,f,i,l in good yields.
In this case too, some standard click catalyst/solvent combinations were briefly evaluated.
The cycloaddition between acetylene 7c and benzyl azide (8a) with CuSO4 5H2O/Na-ascorbate
·
(or L-ascorbic acid) pair in CH2Cl2/water and t-BuOH/water solvent systems required prolonged
reaction times, providing lower yields of the product 2d as compared to the CuSO4/Cu0/DMF
conditions (compare Entries 4–7). In the case of t-BuOH/water the presence of water in the reaction
mixture turned the reactants and products into a gummy material that stuck to the reaction vessel and
the magnetic stirring bar, impeding the reaction from going to completion, as already noticed for click
reactions with highly hydrophobic reagents [20].
In principle, the “click-propargylation-click” reaction sequence at 3-azidoquinoline-2,4-diones
could be altered, providing the target bis-(1,2,3-triazole) functionalized products via bifunctional
azidoethynyl quinoline-2,4-dione intermediate as shown in Scheme 3. This would allow
5
2
9
orthogonal sequential synthetic strategies for accessing bis(1,2,3-triazole) functionalized materials [21].
We briefly explored this possibility by treating 3-azido-1-propargylquinoline-2,4-dione derivative
9a with phenylacetylene (6a) or benzyl azide (8a) under the above mentioned CuSO4/Cu0/DMF
conditions. The corresponding monotriazoles 7a (16%) and 10a (42%), respectively, were obtained in
moderate yields.

Molecules 2018, 23, 2310
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Table 4. Preparation of compounds 2.
◦
Entry
2
R1
R2
R3
t ( C)
Time (h)
Yield a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
b
c
d
d
d
d
e
f
g
h
i
j
k
l
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Bn
Ph
2-Py
Bn
Bn
Bn
Bn
Ph
2-Py
Bn
Ph
23
23
100
23
23
23
23
23
100
23
23
1
1
0.5
0.5
4
48
45
2
1
1
1
0.75
2
97
99
93
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
CH2OAc
Ph
Ph
Ph
CH2OAc
CH2OAc
CH2OAc
96
85 b
81 c
45 d
92
85
92
94
57
97
93
85
Ph
Ph
Ph
Ph
2-Py
Bn
Ph
100
23
23
0.5
0.5
Ph
2-Py
100
a
b
Refers to percent yield of pure (by TLC and IR) isolated product. Employing CH2Cl2/water/CuSO4
·
5H2O/
Na-ascorbate conditions. c Employing t-BuOH/water/CH3CN/CuSO4
t-BuOH/water/CuSO4·5H2O/L-ascorbic acid conditions.
·
5H2O/Na-ascorbate conditions. d Employing
Scheme 3. An alternative approach to bis(1,2,3-triazole) functionalized quinoline-2,4-diones
2
through
a “propargylation-click-click” reaction sequence.
The compounds 2a
–
l
were characterized by 1H, 13C and, with the exception of 2a
,
g,
h
, also by 15
N
NMR spectroscopy. The corresponding resonances were assigned on the basis of gradient-selected
2D NMR experiments including 1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC and 1H–15N
gs-HMBC. For the atom numbering scheme, see Figure 2. Some characteristic spectral features are
discussed below.

Molecules 2018, 23, 2310
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Figure 2. Selected ring and atom numbering along with the chemical shift data (mean values rounded
up to whole numbers are provided).
The 13C and 15N chemical shifts for triazole rings
with those reported previously [11].
A and D (Tables 5 and 6) are in a good agreement
To preliminarily assess the applicability of bis-triazole compounds
examine their coordination abilities to arene-ruthenium. NMR experiment was designed in which
compound 2b and equimolar amount of ruthenium (0.5 equiv of [RuCl( -Cl)(
6-p-cymene)]2) were
2 as ligands, we decided to
µ
η
mixed in CDCl3 in NMR tube at room temperature. CDCl3 was selected as the reaction solvent in
place of the coordinative DMSO-d6 to avoid possible interference with the metal center (Scheme 4).
The reaction mixture was monitored by time dependent 1H NMR spectroscopy indicating an instant
change in the resonances for 2b and p-cymene ligands upon mixing to form a new set of resonances
that remained unchanged over several days. As shown in Figures 3 and 4, both proton and carbon
NMR resonances were severely broadened suggesting the presence of a dynamic process in the
solution, presumably an equilibrium with the starting ligand, which can result from a relatively
weak ligand-to-metal interaction. Unfortunately, broad NMR resonances prevented an unambiguous
structure determination of the product [Ru–Cym]-2b through the 2D NMR techniques due to overlap as
well as lack of several indicative crosspeaks in the spectra, especially in 1H–15N gs-HMBC. Nevertheless,
the analysis of the available NMR data tentatively suggested the coordination of both 1,2,3-triazole
rings to the Ru–Cym unit as indicated in Scheme 4. Although the coordination properties of the
1,2,3-triazole nitrogen atom N2 are weak, some of us have previously shown that such chelates can be
greatly stabilized through an assistance of auxiliary ligand [22].
Table 5. Selected 1H, 13C and 15N NMR chemical shifts in ppm for compounds 1 and 7.
1a
1b
1c
1d
7a
7b
7c
7d
Quinolone
N1
C2
C3
–
–
–
–
–
–
134.4
167.8
72.8
–
168.5
72.2
166.8
80.0
168.7
71.9
166.8
79.7
167.7
72.6
165.8
79.6
165.8
80.0
C4
C4a
C5
C6
C7
190.7
117.4
127.7
123.5
137.3
117.0
141.6
188.9
119.2
127.6
123.5
137.0
116.7
140.5
190.8
117.5
127.6
123.3
137.1
116.9
141.6
189.0
119.2
127.5
123.4
136.9
116.7
140.6
189.7
119.0
128.2
124.2
137.3
116.7
140.8
187.5
121.0
129.2
124.6
136.9
115.8
140.6
189.6
119.2
128.0
124.0
137.1
116.6
140.7
187.7
120.9
127.8
124.2
136.7
116.3
140.0
C8
C8a
Ring A
N1A
N2A
N3A
C4A
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
247.9
363.4
354.0
141.5
126.0
8.46
–
–
–
145.8
122.4
8.89
145.3
123.4
8.49
147.4
123.7
8.26
146.8
124.8
7.77
145.9
122.5
8.89
146.0
122.3
7.26
140.9
127.1
8.15
C5A
H5A

Molecules 2018, 23, 2310
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Table 6. Selected 1H, 13C and 15N NMR chemical shifts in ppm for compounds 2.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
Quinolone
N1
C2
C3
–
136.3
168.3
73.0
135.8
168.5
73.0
138.7
168.2
71.6
138.7
168.3
71.5
135.3
168.6
73.3
–
–
137.5
166.6
80.4
140.4
166.6
79.6
140.4
166.9
79.6
138.9
166.6
79.7
168.2
72.8
166.2
80.1
166.4
80.3
C4
C4a
C5
C6
C7
190.0
119.1
128.1
123.9
137.2
116.7
141.5
190.0
119.2
128.1
124.0
137.3
116.8
141.6
189.9
119.3
128.1
123.9
137.2
116.6
141.4
189.4
119.2
129.3
124.6
137.8
116.9
141.7
189.4
119.2
129.4
124.7
137.8
116.8
141.7
189.9
119.4
127.9
123.8
137.0
116.5
141.3
188.2
120.9
127.9
124.0
136.8
116.7
140.8
188.2
120.9
127.9
124.1
136.8
116.7
140.7
188.1
120.9
127.9
124.0
136.8
116.5
140.5
187.9
120.9
129.0
124.6
137.2
116.8
141.1
187.9
120.9
129.1
124.7
137.4
116.7
140.9
187.9
121.0
129.1
124.6
137.2
116.6
141.2
C8
C8a
Ring A
N1A
N2A
N3A
C4A
–
–
–
248.9
363.2
347.1
146.0
122.5
8.87
248.9
363.4
347.1
146.0
122.5
8.87
248.4
361.6
355.2
142.3
124.2
7.78
248.8
–
355.5
142.3
124.1
7.86
247.6
363.7
353.4
141.6
126.1
8.47
–
–
–
–
–
–
248.7
367.4
347.2
145.4
123.4
8.58
249.8
365.1
356.9
140.9
126.4
7.08
249.9
–
357.2
140.9
126.4
7.14
249.7
–
357.1
140.9
126.4
7.13
145.9
122.5
8.87
145.4
123.4
8.51
145.4
123.5
8.54
C5A
H5A
Ring D
N1D
N2D
N3D
C4D
–
–
–
255.7
358.1
353.4
143.3
121.8
8.75
260.5
358.6
356.9
143.2
120.6
8.82
250.4
362.6
350.0
142.9
123.5
7.55
256.3
–
351.9
143.2
121.7
8.10
260.0
361.9
356.5
143.2
120.6
8.82
–
–
–
–
–
–
260.4
–
357.7
143.0
120.8
8.81
250.4
362.9
350.5
142.9
123.5
7.58
256.3
–
352.9
143.2
121.8
8.05
261.2
–
355.8
143.0
121.0
8.63
142.2
123.8
8.16
141.9
124.2
8.24
142.9
122.3
8.83
C5D
H5D
Ru
Cl
1/2
Cl
N
O
CH3
Cl
Cl
N
O
N
Ru
N
N
N
O
CH3
O
Cl
N
N
N
N
Ru
CDCl3
NMR experiment
N
N
N
N
2b
[Ru−Cym]-
2b
Scheme 4. Reaction of 2b with [RuCl(
[Ru–Cym]-2b complex.
µ
-Cl)(η
6-p-cymene)]2 with tentatively proposed structure of the
Figure 3. Aromatic region of 1H NMR spectra of: (
[RuCl(µ-Cl)(η6-p-cymene)]2 (21 mM) in CDCl3 immediately after dissolution.
a) 2b in CDCl3, and (b) a mixture of 2b (42 mM) and

Molecules 2018, 23, 2310
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Figure 4. Aromatic region of 13C NMR spectra of: (
and [RuCl(µ-Cl)(η6-p-cymene)]2 (21 mM) in CDCl3.
a) 2b in CDCl3, and (b) a mixture of 2b (42 mM)
Attempts to unambiguously determine the structure of [Ru–Cym]-2b by variable temperature
NMR techniques, as well as to grow crystals suitable for X-ray, failed. All of the above also applies to
compounds 2g and 2h that were also preliminarily tested in [Ru–Cym] coordination.
3. Materials and Methods
3.1. General Experimental Methods
The reagents and solvents were used as obtained from the commercial sources.
Compounds 3a
[14], 3b [14], and 5b [15], as well as benzyl azide (8a) [23], azidobenzene
(8b) [11], and tetrazolo[1,5-a]pyridine (8c) [24] were prepared as described in the literature.
Column chromatography was carried out on Fluka Silica gel 60 (particle size 0.063–0.2 mm, activity acc.
Brockmann and Schodder 2–3). Melting points were determined on the microscope hot stage, Kofler,
PolyTherm, manufacturer Helmut Hund GmbH, Wetzlar and are uncorrected. TLC was carried out on
pre-coated TLC sheets ALUGRAM® SIL G/UV254 for TLC, MACHEREY-NAGEL. NMR spectra were
recorded with a Bruker Avance III 500 MHz NMR instrument operating at 500 MHz (1H), 126 MHz
(13C) and 51 MHz (15N) at 300 K. Proton spectra were referenced to TMS as internal standard, in some
cases to the residual signal of DMSO-d5 (at δ 2.50 ppm) or CHCl3 (at δ 7.26 ppm). Carbon chemical
shifts were determined relative to the 13C signal of DMSO-d6 (39.52 ppm) or CDCl3 (77.16 ppm).
15N chemical shifts were extracted from 1H–15N gs-HMBC spectra (with 20 Hz digital resolution in the
indirect dimension and the parameters adjusted for a long-range 1H–15N coupling constant of 5 Hz)
determined with respect to external nitromethane and are corrected to external ammonia by addition
of 380.5 ppm. Nitrogen chemical shifts are reported to one decimal place as measured of the spectrum,
however, the data should not be considered to be more accurate than
resolution limits of the experiment. Chemical shifts are given on the
±
0.5 ppm because of the digital
scale (ppm). Coupling constants
δ
(J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet) or br (broadened). Infrared spectra were recorded on FT-IR spectrometer Alpha (Bruker
Optik GmbH Ettlingen, Ettlingen, Germany) using samples in potassium bromide disks and only
the strongest/structurally most important peaks are listed. Electron impact mass spectra (EI) were
recorded on a Shimadzu QP–2010 instrument at 70 eV. HRMS spectra were recorded with Agilent
6224 Accurate Mass TOF LC/MS system with electrospray ionization (ESI). Elemental analyses (C, H,
N) were performed with FlashEA1112 Automatic Elemental Analyser (Thermo Fisher Scientific Inc.,
Waltham, MA, USA).

Molecules 2018, 23, 2310
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3.2. General Procedure for the Synthesis of 3-Chloroquinoline-2,4(1H,3H)-Diones 4 (Scheme 1)
The 3-Chloroquinoline-2,4(1H,3H)-diones 4a
[
15] and 4b
[16], were prepared from
4-hydroxyquinolin-2(1H)-ones 3a [14] and 3b [14], respectively, according to the procedures described
in the literature.
3-Chloro-3-methylquinoline-2,4(1H,3H)-dione (4a). Compound 4a (19.71 g, 94.0 mmol, 94%) was
prepared from 3a (17.52 g, 100 mmol). Yellow crystals, m.p. 178–181 ◦C (benzene), m.p. [15] 172 ◦C
(acetic acid—water); Rf = 0.52 (30% ethyl acetate in chloroform); 1H NMR (500 MHz, CDCl3)
δ
1.99 (s,
3H), 7.06 (d, 1H, J = 8.0 Hz), 7.22 (dd, 1H, J = 7.6, 7.6 Hz), 7.59–7.66 (m, 1H), 8.02 (d, 1H, J = 7.7 Hz),
9.41 (s, 1H); 13C NMR (126 MHz, CDCl3)
21.2, 62.8, 116.7, 118.1, 124.5, 129.1, 136.8, 139.6, 169.2, 188.4;
δ
IR (cm−1):
ν 3203, 3072, 3004, 2940, 1709, 1674, 1614, 1600, 1486, 1439, 1379, 1239, 770, 440; MS (EI) m/z
(%): 212 (4, [M + 3]+), 211 (33, [M (37Cl)]+), 210 (17, [M + 1]+), 209 (100, [M (35Cl)]+), 208 (18), 175 (15),
+
174 (36), 146 (68), 128 (17), 120 (18), 119 (59), 92 (32), 91 (15); HRMS (ESI+): m/z calcd for C10H9ClNO2
[M + H]+ 210.0316, found 210.0313. Anal. Calcd for C10H8ClNO2 (209.63): C, 57.30; H, 3.85; N, 6.68%.
Found: C, 57.18; H, 3.83; N, 6.61%.
3-Chloro-3-phenylquinoline-2,4(1H,3H)-dione (4b). Compound 4b (26.08 g, 96.0 mmol, 96%) was
◦
prepared from 3b (23.73 g, 100 mmol). Pale yellow needles, m.p. 182–185 C (benzene), m.p. [16
]
178–180 ◦C (ethanol); Rf = 0.57 (30% ethyl acetate in chloroform). H NMR (500 MHz, CDCl3)
δ
7.04
1
(d, 1H, J = 8.0 Hz, H-8), 7.18 (ddd, 1H, J = 7.8, 7.4, 0.7 Hz, H-6), 7.33–7.39 (m, 3H, H-3C, H-4C, H-5C),
7.51–7.54 (m, 2H, H-2C, H-6C), 7.55 (ddd, 1H, J = 7.3, 6.5, 1.5 Hz, H-7), 7.97 (dd, 1H, J = 7.8, 1.2 Hz,
H-5), 9.82 (s, 1H, H-1); 13C NMR (126 MHz, CDCl3)
δ
74.9 (C-3), 116.9 (C-8), 118.7 (C-4a), 124.7 (C-6),
127.4 (C-2C, C-6C), 129.1 (C-5), 129.2 (C-3C, C-5C), 129.8 (C-4C), 134.6 (C-1C), 137.0 (C-7), 139.4 (C-8a),
168.8 (C-2), 187.9 (C-4); IR (cm−1):
3201, 3138, 3082, 2992, 2926, 1716, 1680, 1613, 1595, 1485, 1365,
ν
755, 743, 690; MS (EI) m/z (%): 273 (7, [M (37Cl)]+), 271 (21, [M (35Cl)]+), 238 (12), 237 (80), 236 (100),
218 (10), 120 (63), 119 (19), 92 (34), 89 (10), 77 (12), 76 (10), 65 (14), 63 (10); HRMS (ESI+): m/z calcd for
C15H11ClNO2+ [M + H]+ 272.0473, found 272.0480. Anal. Calcd for C15H10ClNO2 (271.70): C, 66.31;
H, 3.71; N, 5.16%. Found: C, 66.07; H, 3.62; N, 5.29%.
3.3. General Procedure for the Synthesis of 3-Azidoquinoline-2,4(1H,3H)-Diones 5 (Scheme 1)
To a stirred solution of the 3-chloroquinoline-2,4(1H,3H)-dione
4 (40 mmol) in DMF (200 mL),
sodium azide (3.90 g, 60 mmol) was added in small portions during 10 min. The reaction mixture was
stirred in darkness for additional 2 h and then poured into ice-water (1.5 L). The precipitated solid was
filtered, washed with water and dried at 50 ◦C in darkness, which afforded product
to TLC and 1H NMR spectrum, which was crystallized from benzene.
5, pure according
3-Azido-3-methylquinoline-2,4(1H,3H)-dione (5a). Compound 5a (8.47 g, 39.2 mmol, 98%) was
◦
prepared from 4a (8.39 g, 40.0 mmol). Colorless needles, m.p. 158–161 C (benzene, 87% yield
1
of recrystallization); Rf = 0.30 (30% ethyl acetate in chloroform). H NMR (500 MHz, CDCl3)
δ
1.86 (s,
3H, CH3), 7.11 (d, 1H, J = 8.0 Hz, H-8), 7.22 (dd, 1H, J = 7.4, 7.4 Hz, H-6), 7.60–7.67 (m, 1H, H-7), 7.98 (d,
1H, J = 7.3 Hz, H-5), 9.86 (s, 1H, H-1); 13C NMR (126 MHz, CDCl3)
23.6 (CH3), 70.0 (C-3), 116.9 (C-8),
118.0 (C-4a), 124.6 (C-6), 128.6 (C-5), 137.2 (C-7), 140.0 (C-8a), 171.6 (C-2), 191.7 (C-4); IR (cm−1):
3202,
δ
ν
3078, 3005, 2936, 2108, 1708, 1682, 1614, 1598, 1485, 1392, 1284, 1156, 755, 612; MS (EI) m/z (%): 217 (0.24,
[M + 1]+), 216 (2, [M]+), 147 (15), 120 (11), 119 (100), 92 (35), 91 (11), 64 (12); HRMS (ESI+): m/z calcd
+
for C10H9N4O2 [M + H]+ 217.0720, found 217.0724. Anal. Calcd for C10H8N4O2 (216.20): C, 55.55; H,
3.73; N, 25.91%. Found: C, 55.44; H, 3.72; N, 25.98%.
3-Azido-3-phenylquinoline-2,4(1H,3H)-dione (5b). Compound 5b (10.90 g, 39.2 mmol, 98%) was
prepared from 4b (10.87 g, 40.0 mmol). Colorless needles, m.p. 186–189 ◦C (benzene, 96% yield of
◦
recrystallization); m.p. [
1H NMR (500 MHz, CDCl3)
(m, 3H, H-3C, H-4C, H-5C), 7.48–7.53 (m, 2H, H-2C, H-6C), 7.54 (ddd, 1H, J = 7.7, 7.7, 1.6 Hz, H-7),
9] 173–181 C (benzene); Rf = 0.33 (38% ethyl acetate in petroleum ether);
δ
6.98 (d, 1H, J = 8.1 Hz, H-8), 7.16 (dd, 1H, J = 7.6, 7.6 Hz, H-6), 7.38–7.43

Molecules 2018, 23, 2310
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7.93 (dd, 1H, J = 7.8, 1.6 Hz, H-5), 9.30 (s, 1H, H-1); 13C NMR (126 MHz, CDCl3)
δ
78.0 (C-3), 116.7 (C-8),
119.5 (C-4a), 124.6 (C-6), 127.3 (C-2C, C-6C), 128.6 (C-5), 129.8 (C-3C, C-5C), 130.4 (C-4C), 132.6 (C-1C),
136.9 (C-7), 139.4 (C-8a), 170.2 (C-2), 189.9 (C-4); 15N NMR (51 MHz, CDCl3)
δ
133.4 (N-1); IR (cm−1):
ν
3244, 2105, 1718, 1705, 1685, 1611, 1484, 1356, 1256, 877, 773, 744, 702, 611, 525; MS (EI) m/z (%): 250 (7,
[M
−
N2]+), 236 (8, [M
−
N3]+), 147 (28), 120 (14), 119 (100), 104 (15), 92 (32), 77 (10), 76 (10), 64 (14);
HRMS (ESI+): m/z calcd−for C15H11N2O2+ [M
−
N2 + H]+ 251.0815, found 251.0818. HRMS (ESI
−
):
−
−
−
m/z calcd for C15H9N4O2 [M
−
H] 277.0731, found 277.0732; calcd for C15H9N2O2 [M
−
N2
−
H]
249.0670, found 249.0671. Anal. Calcd for C15H10N4O2 (278.27): C, 64.74; H, 3.62; N, 20.13%. Found: C,
64.54; H, 3.56; N, 20.38%.
3.4. General Procedure for the Synthesis of 3-(1H-1,2,3-Triazol-1-yl)Quinoline-2,4(1H,3H)-Diones 1a–d by
Employing CuSO4/Cu0/DMF Conditions (Table 2, Entries 1 and 3–5)
A solution of phenylacetylene (6a) (1.287 g, 12.6 mmol) or propargyl alcohol (6b) (706
mg, 12.6 mmol) in DMF (4 mL) was added dropwise to a vigorously stirred mixture of
3-azidoquinoline-2,4(1H,3H)-dione
5
(12 mmol), CuSO4 5H2O (300 mg, 1.2 mmol), granular copper
·
(1.5 g, 24 mmol) and DMF (24 mL). The reaction mixture was stirred in darkness for 30 min.
Afterward, (NH4)2CO3 (3.5 g, 36 mmol) and water (12 mL) were added to the resulting brown-black
suspension and the stirring was continued for 10 min. The reaction mixture was subjected to column
chromatography with silica gel (15 g, column diameter of 1 cm) as a stationary phase, and 10% ethanol
in chloroform as a mobile phase. Combined fractions containing yellow eluate were washed with
saturated aqueous NH4Cl (5
afford pure products 1a–d, which were recrystallized from ethanol for analyses.
×
50 mL), dried (Na2SO4), and concentrated under reduced pressure to
3-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (1a). Colorless solid, m.p.
217–219 ◦C (ethanol); Rf = 0.35 (30% ethyl acetate in chloroform); 1H NMR (500 MHz, DMSO-d6)
δ
2.15 (s, 3H, CH3), 7.22–7.27 (m, 2H, H-6, H-8), 7.33–7.39 (m, 1H, H-4B), 7.45–7.50 (m, 2H, H-3B, H-5B),
7.73–7.79 (m, 1H, H-7), 7.83–7.90 (m, 3H, H-5, H-2B, H-6B), 8.89 (s, 1H, H-5A), 11.48 (s, 1H, H-1); 13
NMR (126 MHz, DMSO-d6)
23.1 (CH3), 72.2 (C-3), 117.0 (C-8), 117.4 (C-4a), 122.4 (C-5A), 123.5 (C-6),
125.1 (C-2B, C-6B), 127.7 (C-5), 128.0 (C-4B), 129.0 (C-3B, C-5B), 130.6 (C-1B), 137.3 (C-7), 141.6 (C-8a),
C
δ
145.8 (C-4A), 168.5 (C-2), 190.7 (C-4); IR (cm−1):
ν 3137, 2911, 1714, 1683, 1612, 1483, 1430, 1386, 1355,
1238, 1023, 808, 759, 690, 594; MS (EI) m/z (%): 319 (2, [M + 1]+), 318 (8, [M]+), 117 (14), 116 (100),
102 (12), 89 (14); HRMS (ESI+): m/z calcd for C18H15N4O2 [M + H]+ 319.1190, found 319.1188. Anal.
+
Calcd for C18H14N4O2 (318.33): C, 67.91; H, 4.43; N, 17.60%. Found: C, 67.80; H, 4.47; N, 17.89%.
3-Phenyl◦-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (1b). Colorless solid, m.p.
◦
280–283 C (ethanol); m.p. [
9
] 274–277 C (ethanol); Rf = 0.37 (30% ethyl acetate in chloroform);
1H NMR (500 MHz, DMSO-d6)
δ 7.12 (d, 1H, J = 8.1 Hz, H-8), 7.16–7.20 (m, 1H, H-6), 7.31–7.37 (m, 1H,
H-4B), 7.40–7.47 (m, 4H, H-3B, H-5B, H-2C, H-6C), 7.49–7.55 (m, 3H, H-3C, H-4C, H-5C), 7.62–7.67 (m,
1H, H-7), 7.80–7.84 (m, 2H, H-2B, H-6B), 7.86 (dd, 1H, J = 7.8, 1.4 Hz, H-5), 8.49 (s, 1H, H-5A), 11.68 (s,
1H, H-1); 13C NMR (126 MHz, DMSO-d6)
δ
80.0 (C-3), 116.7 (C-8), 119.2 (C-4a), 123.4 (C-5A), 123.5
(C-6), 125.2 (C-2B, C-6B), 127.6 (C-5), 128.0 (C-4B), 128.9 (C-2C, C-6C), 129.0 (C-3B, C-5B), 129.6 (C-3C,
C-5C), 129.9 (C-1C), 130.5 (C-1B), 130.6 (C-4C), 137.0 (C-7), 140.5 (C-8a), 145.3 (C-4A), 166.8 (C-2), 188.9
(C-4); IR (cm−1):
ν 3275, 3169, 1721, 1690, 1613, 1595, 1486, 1452, 1353, 854, 771, 756, 699, 666, 607;
MS (EI) m/z (%): 381 (2, [M + 1]+), 380 (8, [M]+), 247 (13), 237 (15), 236 (56), 220 (13), 218 (13), 120 (11),
117 (10), 116 (100), 102 (15), 92 (10), 89 (15), 77 (14); HRMS (ESI+): m/z calcd for C23H17N4O2+ [M + H]+
381.1346, found 381.1341. Anal. Calcd for C23H16N4O2 (380.40): C, 72.62; H, 4.24; N, 14.73%. Found: C,
72.40; H, 4.23; N, 14.90%.
3-(4-(Hydroxymethy◦l)-1H-1,2,3-triazol-1-yl)-3-methylquinoline-2,4(1H,3H)-dione (1c). Colorless
1
solid, m.p. 188–189 C (ethanol); Rf = 0.35 (30% ethyl acetate in chloroform); H NMR (500 MHz,
DMSO-d6)
δ 2.08 (s, 3H, CH3), 4.55 (d, 2H, J = 5.6 Hz, CH2), 5.28 (t, 1H, J = 5.6 Hz, OH), 7.18–7.25 (m,
2H, H-6, H-8), 7.69–7.76 (m, 1H, H-7), 7.83 (dd, 1H, J = 8.1, 1.4 Hz, H-5), 8.26 (s, 1H, H-5A), 11.39 (s, 1H,

Molecules 2018, 23, 2310
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H-1); 13C NMR (126 MHz, DMSO-d6)
δ
23.1 (CH3), 55.0 (CH2), 71.9 (C-3), 116.9 (C-8), 117.5 (C-4a), 123.3
(C-6), 123.7 (C-5A), 127.6 (C-5), 137.1 (C-7), 141.6 (C-8a), 147.4 (C-4A), 168.7 (C-2), 190.8 (C-4); IR (cm−1):
ν
3148, 2992, 2919, 1729, 1682, 1613, 1486, 1378, 1345, 1235, 1189, 1009, 751, 667, 590; MS (EI) m/z (%):
273 (2, [M + 1]+), 272 (13, [M]+), 185 (68), 175 (89), 174 (45), 146 (100), 128 (58), 120 (70), 119 (75), 92 (66),
91 (39), 77 (39), 65 (37), 55 (39), 42 (79); HRMS (ESI+): m/z calcd for C13H13N4O3+ [M + H]+ 273.0982,
found 273.0981. Anal. Calcd for C13H12N4O3 (272.26): C, 57.35; H, 4.44; N, 20.58%. Found: C, 57.20; H,
4.42; N, 20.83%.
3-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione dimethylformamide
solvate (1d·DMF). Colorless solid, m.p. 139–143 ◦C (ethanol); m.p. [
9
] 116–135 ◦C (benzene); Rf = 0.27
(10% ethanol in chloroform); 1H NMR (500 MHz, DMSO-d6)
δ 4.53 (d, 2H, J = 5.7 Hz, CH2), 5.22 (t, 1H,
J = 5.7 Hz, OH), 7.09 (d, 1H, J = 8.1 Hz, H-8), 7.13–7.18 (m, 1H, H-6), 7.36–7.42 (m, 2H, H-2C, H-6C),
7.47–7.53 (m, 3H, H-3C, H-4C, H-5C), 7.59–7.65 (m, 1H, H-7), 7.77 (s, 1H, H-5A), 7.83 (dd, 1H, J = 7.8, 1.3
Hz, H-5), 11.60 (s, 1H, H-1); 13C NMR (126 MHz, DMSO-d6)
δ
55.0 (CH2), 79.7 (C-3), 116.7 (C-8), 119.2
(C-4a), 123.4 (C-6), 124.8 (C-5A), 127.5 (C-5), 128.8 (C-2C, C-6C), 129.6 (C-3C, C-5 C), 130.2 (C-1C), 130.5
(C-4C), 136.9 (C-7), 140.6 (C-8a), 146.8 (C-4A), 166.8 (C-2), 189.0 (C-4); IR (cm−1):
ν 3392, 3136, 2926,
1724, 1692, 1654, 1613, 1485, 1438, 1353, 857, 769, 752, 665, 603; MS (EI) m/z (%): 335 (0.8, [M + 1]+), 334
(4, [M]+), 305 (37), 275 (18), 249 (30), 247 (27), 237 (50), 236 (100), 218 (35), 208 (18), 180 (20), 120 (33),
104 (23), 92 (23), 77 (34); HRMS (ESI+): m/z calcd for C18H15N4O3 [M + H]+ 335.1139, found 335.1138.
+
Anal. Calcd for C21H21N5O4 (407.42): C, 61.91; H, 5.20; N, 17.19%. Found: C, 61.89; H, 5.24; N, 17.28%.
3.5. Synthesis of Compound 1a by Employing CuSO4·5H2O/L-Ascorbic Acid/CH2Cl2/Water Conditions
(Table 2, Entry 2)
To a solution of azide 5a (162 mg, 0.75 mmol) and phenylacetylene (6a) (153 mg, 1.5 mmol)
in dichloromethane (8 mL) a solution of L-ascorbic acid (106 mg, 0.60 mmol) in water (4 mL),
and a solution of CuSO4
reaction mixture was stirred in darkness at room temperature for 48 h. The reaction mixture was
extracted with chloroform (5 30 mL). The combined organic layers were dried (Na2SO4), filtered,
·
5H2O (15 mg, 0.06 mmol) in water (4mL) were added. The two-phase
×
and evaporated to dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel
(30 g) column chromatography using 38% ethyl acetate in hexane as eluent, affording compound 1a
(199 mg, 63 mmol 83%).
3.6. General Procedure for the Synthesis of (1-(2,4-Dioxo-1,2,3,4-Tetrahydroquinolin-3-yl)-1H-1,2,3-Triazol-
4-yl)Methyl Acetates 1e,f (Scheme 2)
Acetic anhydride (12 mL, 12.9 g, 126 mmol) was added to a light yellow solution of compound
1c or 1d (6 mmol) in pyridine (18 mL) under stirring during 2 min. The reaction mixture was stirred
for 1 h, followed by evaporation of volatiles under reduced pressure. The remaining pyridine was
removed by co-distillation with ethanol (6
×
40 mL). The residue was triturated with water (300 mL)
to form a white precipitate which was collected by filtration on a sintered glass filter with suction,
washed with water to neutral and dried to give acetates 1e or 1f. The crude product was recrystallized
from the solvent indicated below.
(1-(3-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (1e).
Compound 1e (1.58 g, 5.04 mmol, 84%) was prepared from 1c (1.63 g, 6.0 mmol). Pale yellow solid,
◦
m.p. 145–148 C (ethyl acetate); Rf = 0.33 (5% ethanol in chloroform); 1H NMR (500 MHz, DMSO-d6)
δ
2.06 (s, 3H, COCH3), 2.09 (s, 3H, C-3–CH3), 5.16 (s, 2H, CH2), 7.19–7.26 (m, 2H, H-6, H-8), 7.70–7.77 (m,
1H, H-7), 7.83 (dd, 1H, J = 8.0, 1.4 Hz, H-5), 8.45 (s, 1H, H-5A), 11.40 (s, 1H, H-1); 13C NMR (126 MHz,
DMSO-d6)
125.8 (C-5A), 127.6 (C-5), 137.1 (C-7), 141.4 (C-4A), 141.6 (C-8a), 168.6 (C-2), 170.1 (COCH3), 190.7
(C-4); 15N NMR (51 MHz, DMSO-d6) 133.5 (N-1), 248.7 (N-1A), 354.1 (N-3A), 362.9 (N-2A); IR (cm−1):
3467, 3249, 3148, 2920, 1722, 1685, 1613, 1485, 1439, 1384, 1355, 1239, 1028, 759, 666; MS (EI) m/z (%):
δ 20.6 (COCH3), 23.2 (C-3–CH3), 57.1 (CH2), 72.4 (C-3), 116.9 (C-8), 117.5 (C-4a), 123.3 (C-6),
δ
ν

Molecules 2018, 23, 2310
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315 (2, [M + 1]+), 314 (11, [M]+), 244 (22), 201 (22), 175 (71), 174 (31), 146 (43), 128 (26), 120 (25), 119 (27),
+
92 (24), 55 (20), 43 (100), 42 (26); HRMS (ESI+): m/z calcd for C15H15N4O4 [M + H]+ 315.1088, found
315.1087. Anal. Calcd for C15H14N4O4 (314.30): C, 57.32; H, 4.49; N, 17.83%. Found: C, 57.32; H, 4.59;
N, 17.58%.
(1-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (1f).
Compound 1f (1.92 g, 5.1 mmol, 85%) was prepared from 1d (2.01 g, 6.0 mmol). Colorless crystals, m.p.
130–134 ◦C (ethanol, 80% yield of recrystallization); Rf = 0.40 (5% ethanol in chloroform); 1H NMR
(500 MHz, DMSO-d6) δ 2.04 (s, 3H, CH3), 5.13 (s, 2H, CH2), 7.09 (d, 1H, J = 8.1 Hz, H-8), 7.13–7.18 (m,
1H, H-6), 7.35–7.42 (m, 2H, H-2C, H-6C), 7.46–7.54 (m, 3H, H-3C, H-4C, H-5C), 7.59–7.65 (m, 1H, H-7),
7.83 (dd, 1H, J = 7.8, 1.3 Hz), 8.07 (s, 1H, H-5A), 11.62 (s, 1H, H-1); 13C NMR (126 MHz, DMSO-d6)
δ
20.7 (CH3), 57.1 (CH2), 79.9 (C-3), 116.7 (C-8), 119.3 (C-4a), 123.4 (C-6), 127.0 (C-5A), 127.5 (C-5), 128.8
(C-2C, C-6C), 129.6 (C-3C, C-5C), 130.0 (C-1C), 130.6 (C-4C), 136.9 (C-7), 140.5 (C-8a), 140.8 (C-4A), 166.8
(C-2), 170.1 (COCH3), 188.8 (C-4); IR (cm–1):
ν 3501, 3155, 2920, 1722, 1707, 1686, 1614, 1594, 1484, 1358,
1252, 1229, 1063, 857, 759; MS (EI) m/z (%): 377 (1, [M + 1]+), 376 (6, [M]+), 306 (16), 289 (18), 288 (54),
263 (15), 237 (50), 236 (100), 218 (34), 180 (14), 141 (14), 120 (24), 92 (14), 77 (19), 43 (16); HRMS (ESI+):
m/z calcd for C20H17N4O4+ [M + H]+ 377.1244, found 377.1241.
3.7. General Procedure for the Synthesis of 3-(1H-1,2,3-Triazol-1-yl)-1-(prop-2-yn-1-yl)Quinoline-2,4(1H,3H)-
Diones 7 (Table 3)
The mixture of the appropriate compound 1a,b,e,f (8.00 mmol), potassium carbonate (3.32 g,
24 mmol), and DMF (40 mL) was stirred for 40 min. During this time, the original yellow color of the
suspension changed to orange. Afterwards, under continued stirring, an 80% solution of propargyl
bromide (6c) in toluene (1.78 g, 12 mmol) diluted with DMF (20 mL) was added dropwise during 1 min
and stirring was continued for 90 min. Then the mixture was reduced in vacuo and then toluene (50 mL)
was added and the whole evaporated in vacuo at 50 ◦C. This was repeated seven times in order to
remove traces of DMF. The residual light brown solid was suspended in chloroform (100 mL) and the
suspension was acidified with 0.5 M HCl, whereas carbon dioxide was evolved owing to decomposition
of unreacted potassium carbonate. The formed emulsion was diluted with water, organic phase was
separated and aqueous phase was extracted with chloroform (5
combined, dried (Na2SO4), filtered and taken down in vacuo. The residual solid TLC pure product was
crystallized from a suitable solvent. The yields of prepared compounds 7 are given in Table 3.
×
40 mL). The organic phases were
3-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(prop-2-yn-1-yl)quinoline-2,4(1H,3H)-dione
Colorless crystals, m.p. 187–189 ◦C (benzene); Rf = 0.63 (30% ethyl acetate in chloroform); 1H NMR
(500 MHz, DMSO-d6) 2.16 (s, 3H, CH3), 3.39 (dd, 1H, J = 2.3, 2.3 Hz, C CH), 4.90 (dd, 1H, J = 18.1,
2.3 Hz, N-1–CH ), 4.97 (dd, 1H, J = 18.1, 2.3 Hz, N-1–CH
), 7.34–7.42 (m, 2H, H-6, H-4B), 7.48 (dd, 2H,
J = 7.7, 7.7 Hz, H-3B, H-5B), 7.61 (d, 1H, J = 8.4 Hz, H-8), 7.84–7.89 (m, 2H, H-2B, H-6B), 7.89–7.95 (m,
1H, H-7), 8.00 (dd, J = 7.7, 1.5 Hz, H-5), 8.89 (s, 1H, H-5A); 13C NMR (126 MHz, DMSO-d6)
23.3 (CH3),
32.7 (N-1–CH2), 72.6 (C-3), 75.4 (C CH), 78.2 (C
CH), 116.7 (C-8), 119.0 (C-4a), 122.5 (C-5A), 124.2
(C-6), 125.1 (C-2B, C-6B), 128.1 (C-4B), 128.2 (C-5), 129.0 (C-3B, C-5B), 130.5 (C-1B), 137.3 (C-7), 140.8
(7a).
δ
≡
α
β
δ
≡
≡
(C-8a), 145.9 (C-4A), 167.7 (C-2), 189.7 (C-4); IR (cm−1):
ν 3261, 3173, 2122, 1713, 1678, 1601, 1469, 1427,
1381, 1368, 1353, 1306, 1189, 769, 754; MS (EI) m/z (%): 357 (2, [M + 1]+), 356 (8, [M]+), 259 (10), 128 (11),
+
117 (16), 116 (100), 102 (17), 90 (11), 89 (16), 77 (10), 76 (10); HRMS (ESI+): m/z calcd for C21H17N4O2
[M + H]+ 357.1346, found 357.1342. Anal. Calcd for C21H16N4O2 (356.38): C, 70.77; H, 4.53; N, 15.72%.
Found: C, 70.81; H, 4.58; N, 15.82%.
3-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(prop-2-yn-1-yl)quinoline-2,4(1H,3H)-dione
Colorless crystals, m.p. 232–234 ◦C (ethanol); Rf = 0.69 (30% ethyl acetate in chloroform); 1H NMR
(500 MHz, CDCl3) 2.34 (dd, 1H, J = 2.4, 2.4 Hz), 4.51 (dd, 1H, J = 17.8, 2.3 Hz), 5.37 (dd, 1H, J = 17.8,
(7b).
δ
2.3 Hz), 7.23 (dd, 1H, J = 7.6, 7.6 Hz), 7.26 (s, 1H), 7.27–7.31 (m, 1H), 7.32–7.40 (m, 3H), 7.43–7.51 (m,
3H), 7.51–7.56 (m, 2H), 7.62–7.69 (m, 1H), 7.73–7.81 (m, 2H), 8.05 (dd, 1H, J = 7.7, 1.4 Hz); 13C NMR

Molecules 2018, 23, 2310
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(126 MHz, CDCl3)
δ
33.6, 73.6, 76.9, 79.6, 115.8, 121.0, 122.3, 124.6, 126.0, 128.1, 128.8, 129.0, 129.2, 130.0,
130.1, 130.7, 131.3, 136.9, 140.6, 146.0, 165.8, 187.5; IR (cm−1):
ν 3197, 2983, 2118, 1716, 1680, 1603,
1468, 1448, 1304, 1039, 870, 760, 752, 694; MS (EI) m/z (%): 419 (13, [M + 1]+), 418 (75, [M]+), 390 (43),
287 (22), 286 (31), 285 (89), 276 (25), 275 (100), 274 (28), 259 (70), 248 (46), 235 (53), 145 (52), 116 (95),
+
44 (99); HRMS (ESI+): m/z calcd for C26H19N4O2 [M + H]+ 419.1503, found 419.1502. Anal. Calcd for
C26H18N4O2: C, 74.63; H, 4.34; N, 13.39%. Found: C, 74.45; H, 4.40; N, 13.43%.
(1-(3-Methyl-2,4-dioxo-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl
◦
acetate (7c). Colorless crystals, m.p. 159–161 C (ethyl acetate); Rf = 0.29 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
δ
2.06 (s, 3H, COCH3), 2.10 (s, 3H, C-3–CH3), 3.37 (dd,
CH), 4.84 (dd, 1H, J = 18.1, 2.4 Hz, N-1–CH ), 4.95 (dd, 1H, J = 18.1, 2.4 Hz,
), 5.17 (s, 2H, OCH2), 7.37 (dd, 1H, J = 7.5, 7.5 Hz, H-6), 7.58 (d, 1H, J = 8.4 Hz, H-8), 7.87–7.93
(m, 1H, H-7), 7.96 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.46 (s, 1H, H-5A); 13C NMR (126 MHz, DMSO-d6)
20.6 (COCH3), 23.4 (C-3–CH3), 32.6 (N-1–CH2), 57.1 (OCH2), 72.8 (C-3), 75.3 (C CH), 78.2 (C CH),
116.6 (C-8), 119.2 (C-4a), 124.0 (C-6), 126.0 (C-5A), 128.0 (C-5), 137.1 (C-7), 140.7 (C-8a), 141.5 (C-4A),
167.8 (C-2), 170.1 (COCH3), 189.63 (C-4); 15N NMR (51 MHz, DMSO-d6) 134.4 (N1), 247.9 (N-1A),
3256, 3152, 2122, 1721, 1687, 1604, 1471, 1383, 1306, 1246, 1194,
1H, J = 2.4, 2.4 Hz, C
N-1–CH
≡
α
β
δ
≡
≡
δ
354.0 (N-3A), 363.4 (N-2A); IR (cm−1):
ν
1053, 1008, 756; MS (EI) m/z (%): 353 (3, [M + 1]+), 352 (12, [M]+), 213 (69), 212 (34), 184 (19), 156 (32),
146 (17), 130 (19), 129 (21), 128 (22), 77 (17), 57 (16), 55 (23), 43 (100), 42 (17); HRMS (ESI+): m/z calcd
+
for C18H17N4O4 ([M+H]+): 353.1244, found 353.1246. Anal. Calcd for C18H16N4O4 (352.34): C, 61.36;
H, 4.58; N, 15.90%. Found: C, 61.27; H, 4.64; N, 15.87%.
(1-(2,4-Dioxo-3-phenyl-1-(prop-2-yn-1-yl)-1,2,3,4◦-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl
1
acetate (7d). Colorless crystals, m.p. 210–214 C; Rf = 0.66 (5% ethanol in chloroform); H NMR
(500 MHz, DMSO-d6)
2.3 Hz, N-1–CH ), 5.09–5.20 (m, 3H, N-1–CH
(m, 4H, H-8, H-3C, H-4C, H-5C), 7.73–7.79 (m, 1H, H-7), 7.92 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.15 (s, 1H,
H-5A); 13C NMR (126 MHz, DMSO-d6)
20.6 (COCH3), 33.1 (N-1–CH2), 57.1 (OCH2), 75.5 (C CH),
77.9 (C
CH), 80.0 (C-3), 116.3 (C-8), 120.9 (C-4a), 124.2 (C-6), 127.1 (C-5A), 127.8 (C-5), 128.6 (C-2C,
C-6C), 129.5 (C-3C, C-5C), 129.9 (C-1C), 130.7 (C-4C), 136.7 (C-7), 140.0 (C-8a), 140.9 (C-4A), 165.8 (C-2),
δ
2.05 (s, 3H, COCH3), 3.41 (dd, 1H, J = 2.4, 2.3 Hz, C
≡
CH), 4.80 (dd, 1H, J = 18.0,
α
β
, OCH2), 7.24–7.32 (m, 3H, H-6, H-2C, H-6C), 7.41–7.51
δ
≡
≡
170.1 (COCH3), 187.7 (C-4); IR (cm−1):
ν 3227, 3152, 2116, 1736, 1715, 1683, 1602, 1467, 1379, 1303, 1251,
1036, 764, 747, 694; MS (EI) m/z (%): 415 (2, [M + 1]+), 414 (7, [M]+), 313 (26), 275 (72), 274 (63), 246 (28),
235 (31), 218 (29), 217 (30), 156 (26), 130 (29), 105 (22), 104 (29), 103 (22), 43 (100); HRMS (ESI+): m/z
+
calcd for C23H19N4O4 [M + H]+ 415.1401, found 415.1403. Anal. Calcd for C23H18N4O4: C, 66.66; H,
4.38; N, 13.52%. Found: C, 66.45; H, 4.39; N, 13.35%.
3.8. General Procedure for the Synthesis of Bis-Triazoles 2a,b,d,e,g,h,j,k by Employing CuSO4/Cu0/DMF
Conditions (Table 4, Entries 1, 2, 4, 8, 10, 11, 13 and 14)
A solution of azidobenzene (8b, 197 mg, 1.65 mmol) or (azidomethyl)benzene (8a, 220 mg,
1.65 mmol) in DMF (4 mL) was added to a vigorously stirred mixture of the appropriate
N-propargylquinoline-2,4(1H,3H)-dione
7
(1.5 mmol), CuSO4 5H2O (38 mg, 0.15 mmol) and granular
·
copper (191 mg, 3.05 mmol) in DMF (5 mL). The reaction mixture was stirred in darkness at room
temperature for the time given in Table 4. The color of the mixture became brown-black. Then,
(NH4)2CO3 (432 mg, 4.5 mmol) and water (2 mL) were added to the reaction mixture and the stirring
was continued for 10 min. The reaction mixture was poured into a narrow (1 cm in diameter) column
of silica gel (15 g). The organic portion was eluted with 10% ethanol in chloroform (approximately
150 mL). The yellow eluate was washed with saturated aqueous NH4Cl (50 mL), dried over anhydrous
sodium sulfate, filtered, and the solvent was removed by rotary evaporation in vacuo. The TLC pure
product thus prepared, with the exception of compounds 2d,e,k, was crystallized from suitable solvent.
The yields of prepared compounds 2 are given in Table 4.

Molecules 2018, 23, 2310
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1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-3-methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4
◦
(1H,3H)-dione (2a). Colorless crystals, m.p. 202–204 C (ethanol); Rf = 0.40 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
δ 2.18 (s, 3H, CH3), 5.24 (d, 1H, J = 16.2 Hz, N-1–CHα),
5.49 (d, 1H, J = 16.2 Hz, N-1–CHβ
), 5.58 (s, 2H, N-1D–CH2), 7.24–7.29 (m, 2H, H-2E, H-6E), 7.29–7.40
(m, 5H, H-6, H-4B, H-3E, H-4E, H-5E), 7.49 (dd, 2H, J = 7.7, 7.7 Hz, H-3B, H-5B), 7.67 (d, 1H, J = 8.5 Hz,
H-8), 7.79–7.90 (m, 3H, H-7, H-2B, H-6B), 7.96 (dd, 1H, J = 7.7, 1.4 Hz, H-5), 8.16 (s, 1H, H-5D), 8.87 (s,
1H, H-5A); 13C NMR (126 MHz, DMSO-d6) 23.4 (CH3), 38.7 (N-1–CH2), 52.8 (N-1D–CH2), 72.8 (C-3),
δ
116.7 (C-8), 119.1 (C-4a), 122.5 (C-5A), 123.8 (C-5D), 123.9 (C-6), 125.1 (C-2B, C-6B), 127.9 (C-2E, C-6E),
128.0 (C-4B), 128.1 (C-5), 128.1 (C-4E), 128.7 (C-3E, C-5E), 129.1 (C-3B, C-5B), 130.6 (C-1B), 136.0 (C-1E),
137.2 (C-7), 141.5 (C-8a), 142.2 (C-4D), 145.9 (C-4A), 168.2 (C-2), 190.0 (C-4); IR (cm−1):
ν 3137, 3128,
1711, 1673, 1600, 1471, 1387, 1051, 768, 761, 718, 694; MS (EI) m/z (%): 490 (2, [M + 1]+), 489 (6, [M]+),
289 (13), 145 (17), 144 (16), 117 (11), 116 (44), 91 (100), 90 (10), 89 (12); HRMS (ESI+): m/z calcd for
C28H24N7O2+ [M + H]+ 490.1986, found 490.1981. Anal. Calcd for C28H23N7O2 (489.53) C, 68.70; H,
4.74; N, 20.03. Found: C, 68.71; H, 4.78; N, 20.36.
3-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-((1-phen◦yl-1H-1,2,3-triazol-4-yl)methyl)quinoline-2,4
(1H,3H)-dione (2b). Colorless crystals, m.p. 194–197 C (benzene); Rf = 0.48 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
5.62 (d, 1H, J = 16.4 Hz, N-1–CH
δ 2.23 (s, 3H, CH3), 5.33 (d, 1H, J = 16.4 Hz, N-1–CHα),
β
), 7.31–7.39 (m, 2H, H-6, H-4B), 7.45–7.52 (m, 3H, H-3B, H-5B, H-4E),
7.55–7.62 (m, 2H, H-3E, H-5E), 7.70 (d, 1H, J = 8.5 Hz, H-8), 7.82–7.91 (m, 5H, H-7, H-2B, H-6B, H-2E,
H-6E), 7.98 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.75 (s, 1H, H-5D), 8.87 (s, 1H, H-5A); 13C NMR (126 MHz,
DMSO-d6) δ
23.4 (CH3), 38.7 (N-1–CH2), 73.0 (C-3), 116.8 (C-8), 119.2 (C-4a), 120.2 (C-2E, C-6E), 121.8
(C-5D), 122.5 (C-5A), 124.0 (C-6), 125.2 (C-2B, C-6B), 128.1 (C-4B), 128.1 (C-5), 128.8 (C-4E), 129.1 (C-3B,
C-5B), 129.9 (C-3E, C-5E), 130.6 (C-1B), 136.5 (C-1E), 137.3 (C-7), 141.6 (C-8a), 143.3 (C-4D), 146.0 (C-4A),
168.3 (C-2), 190.0 (C-4); 15N NMR (51 MHz, DMSO-d6)
δ
136.3 (N1), 248.9 (N-1A), 255.7 (N-D-1), 347.1
3275, 1721, 1690, 1613, 1485, 1353, 854,
(N-3A), 353.4 (N-3D), 358.1 (N-2D), 363.2 (N-2A); IR (cm−1):
ν
771, 756, 698, 666, 607, 520; MS (EI) m/z (%): 476 (3, [M + 1]+), 475 (8, [M]+), 289 (14), 145 (12), 131 (11),
130 (100), 129 (18), 128 (11), 116 (56), 104 (12), 103 (16), 102 (12), 89 (12), 77 (69); HRMS (ESI+): m/z
calcd for C27H22N7O2+ [M + H]+ 476.1829, found 476.1825. Anal. Calcd for C27H21N7O2 (475.50): C,
68.20; H, 4.45; N, 20.62%. Found: C, 68.48; H, 4.53; N, 20.60%.
(1-(1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-
◦
1,2,3-triazol-4-yl)methyl acetate (2d). Colorless powder, m.p. 69–82 C; Rf = 0.42 (30% ethyl acetate
1
in chloroform); H NMR (500 MHz, CDCl3),
δ
2.09 (s, 3H, COCH3), 2.12 (s, 3H, C-3–CH3), 5.25 (s,
), 5.51 (d, 1H, J = 14.8 Hz,
), 7.23–7.26 (m, 3H, H-6, H-2E, H-6E), 7.32–7.38 (m, 3H, H-3E, H-4E, H-5E), 7.55 (s, 1H,
H-5D), 7.73 (ddd, 1H, J = 8.7, 7.1, 1.6 Hz, H-7), 7.78 (s, 1H, H-5A), 7.82 (d, 1H, J = 8.4 Hz, H-8), 8.02 (dd,
2H, OCH2), 5.33 (s, 2H, N-1-CH2), 5.45 (d, 1H, J = 14.8 Hz, N-1D–CH
α
N-1D–CH
β
1H, J = 7.7, 1.6 Hz, H-5); 13C NMR (126 MHz, CDCl3)
δ 21.1 (COCH3), 23.5 (C-3–CH3), 39.5 (N-1–CH2),
54.5 (N-1D–CH2), 57.7 (OCH2), 71.6 (C-3), 116.9 (C-8), 119.2 (C-4a), 123.5 (C-5D), 124.2 (C-5A), 124.6
(C-6), 128.3 (C-2E, C-6E), 129.0 (C-4E), 129.3 (C-3E, C-5E), 129.3 (C-5), 134.4 (C-1E), 137.8 (C-7), 141.7
(C-8a), 142.3 (C-4A), 142.9 (C-4D), 168.2 (C-2), 171.1 (COCH3), 189.4 (C-4); 15N NMR (51 MHz, CDCl3)
δ
138.7 (N-1), 248.4 (N-1A), 250.4 (N-1D), 350.0 (N-3D), 355.2 (N-3A), 361.6 (N-2A), 362.6 (N-2D); IR
(cm−1):
ν 3143, 2930, 1739, 1717, 1679, 1602, 1470, 1384, 1243, 1186, 1050, 1028, 765, 721, 664; MS (EI)
m/z (%): 486 (0.3, [M + 1]+), 485 (1, [M]+), 144 (18), 91 (100), 43 (24); HRMS (ESI+): m/z calcd for
C25H24N7O4+ [M + H]+ 486.1884, found 486.1884.
(1-(3-Methyl-2,4-dioxo-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-
1,2,3-triazol-4-yl)methyl acetate (2e). Colorless powder, m.p. 78–97 ◦C; Rf = 0.25 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, CDCl3)
δ 2.10 (s, 3H, COCH3), 2.20 (s, 3H, C-3–CH3), 5.27 (s, 2H,
OCH2), 5.42 (d, 1H, J = 15.8 Hz, N-1–CHα), 5.52 (d, 1H, J = 15.8 Hz, N-1–CHβ), 7.27–7.30 (m, 1H, H-6),
7.41–7.47 (m, 1H, H-4E), 7.49–7.55 (m, 2H, H-3E, H-5E), 7.69–7.74 (m, 2H, H-2E, H-6E), 7.76 (ddd, 1H,
J = 8.1, 7.7, 1.6 Hz, H-7), 7.85 (d, 1H, J = 7.3 Hz, H-8), 7.86 (s, 1H, H-5A), 8.05 (dd, 1H, J = 7.8, 1.5 Hz,

Molecules 2018, 23, 2310
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H-5), 8.10 (s, 1H, H-5D); 13C NMR (126 MHz, CDCl3)
δ
21.0 (COCH3), 23.4 (C-3–CH3), 39.5 (N-1-CH2),
57.7 (OCH2), 71.5 (C-3), 116.8 (C-8), 119.2 (C-4a), 120.6 (C-2E, C-6E), 121.7 (C-5D), 124.1 (C-5A), 124.7
(C-6), 129.1 (C-4E), 129.4 (C-5), 129.9 (C-3E, C-5E), 136.9 (C-1E), 137.8 (C-7), 141.7 (C-8a), 142.3 (C-4A),
143.2 (C-4D), 168.3 (C-2), 171.1 (COCH3), 189.4 (C-4); 15N NMR (51 MHz, CDCl3)
δ
138.7 (N-1), 248.8
(N-1A), 256.3 (N-1D), 351.9 (N-3D), 355.5 (N-3A); IR (cm−1):
ν 3145, 2926, 1740, 1717, 1681, 1601, 1470,
1384, 1242, 1184, 1046, 761, 691, 664; MS (EI) m/z (%): 472 (0.9, [M + 1]+), 471 (3, [M]+), 303 (20), 302
(17), 131 (13), 130 (100), 129 (14), 77 (44), 43 (25); HRMS (ESI+): m/z calcd for C24H22N7O4+ [M + H]+
472.1728, found 472.1726.
1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-3-phenyl-3-(◦4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4
(1H,3H)-dione (2g). Colorless crystals, m.p. 142–145 C (ethanol); Rf = 0.42 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
N-1D–CH2), 5.63 (d, 1H, J = 15.8 Hz, N-1–CH
δ
5.15 (d, 1H, J = 15.8 Hz, N-1–CH
α), 5.62 (s, 2H,
β
), 7.22–7.50 (m, 14H, H-6, H-3B, H-4B, H-5B, H-2C, H-3C,
H-4C, H-5C, H-6C, H-2E, H-3E, H-4E, H-5E, H-6E), 7.68 (d, 1H, J = 7.8 Hz, H-8), 7.73 (ddd, 1H, J = 8.5,
7.1, 1.7 Hz, H-7), 7.80–7.83 (m, 2H, H-2B, H-6B), 7.92 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.24 (s, 1H, H-5D),
8.51 (s, 1H, H-5A); 13C NMR (126 MHz, DMSO-d6) 39.2 (N-1–CH2), 52.8 (N-1D–CH2), 80.1 (C-3), 116.7
δ
(C-8), 120.9 (C-4a), 123.4 (C-5A), 124.0 (C-6), 124.2 (C-5D), 125.2 (C-2B, C-6B), 127.9 (C-5), 128.0 (C-4C,
C-2E, C-6E), 128.2 (C-4B),128.7 (C-1C), 128.8 (C-3E, C-5E), 129.0 (C-3B, C-5B), 129.4 (C-2C, C-6C), 129.8
(C-1B), 130.5 (C-3C, C-5C, C-4E), 136.0 (C-1E), 136.8 (C-7), 140.8 (C-8a), 141.9 (C-4D), 145.4 (C-4A), 166.2
(C-2), 188.2 (C-4); IR (cm−1):
ν 3434, 3138, 3062, 1716, 1678, 1601, 1468, 1375, 1307, 1035, 870, 761, 724,
695; MS (EI) m/z (%): 552 (1, [M + 1]+), 551 (3, [M]+), 289 (23), 236 (11), 145 (18), 144 (17), 116 (31), 104
(10), 91 (100), 89 (11), 77 (16); HRMS (ESI+): m/z calcd for C33H26N7O2 [M + H]+ 552.2142, found
+
552.2133. Anal. Calcd for C33H25N7O2 (551.60): C, 71.86; H, 4.57; N, 17.78%. Found: C, 71.58; H, 4.58;
N, 17.73%.
3-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)quinoline-2,4
◦
(1H,3H)-dione (2h). Colorless crystals, m.p. 152–157 C (ethanol); Rf = 0.54 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
δ 5.33 (d, 1H, J = 16.1 Hz, N-1–CHα), 5.71 (d, 1H, J = 16.1
Hz, N-1–CHβ
), 7.25–7.29 (m, 1H, H-6), 7.32–7.48 (m, 8H, H-3B, H-4B, H-5B, H-2C, H-3C, H-4C, H-5C,
H-6C), 7.48–7.53 (m, 1H, H-4E), 7.58–7.64 (m, 2H, H-3E, H-5E), 7.70 (d, 1H, J = 8.2 Hz, H-8), 7.72–7.77
(m, 1H, H-7), 7.81–7.85 (m, 2H, H-2B, H-6B), 7.88–7.93 (m, 2H, H-2E, H-6E), 7.95 (dd, 1H, J = 7.7, 1.5 Hz,
H-5), 8.54 (s, 1H, H-5A), 8.83 (s, 1H, H-5D); 13C NMR (126 MHz, DMSO-d6)
δ 39.0 (N-1–CH2), 80.3
(C-3), 116.7 (C-8), 120.2 (C-2E, C-6E), 120.9 (C-4a), 122.3 (C-5D), 123.5 (C-5A), 124.1 (C-6), 125.2 (C-2B,
C-6B), 127.9 (C-5), 128.0 (C-4B), 128.9 (C-4E), 128.9 (C-2C, C-6C), 129.0 (C-3B, C-3B), 129.4 (C-3C, C-5C),
129.9 (C-1C), 130.0 (C-3E, C-5E), 130.5 (C-4C), 130.6 (C-1B), 136.5 (C-1E), 136.8 (C-7), 140.7 (C-8a), 142.9
(C-4D), 145.4 (C-4A), 166.4 (C-2), 188.2 (C-4); IR (cm−1):
ν 3447, 3142, 3060, 1716, 1679, 1600, 1468, 1449,
1375, 1305, 1040, 871, 758, 693; MS (EI) m/z (%): 538 (1, [M + 1]+), 537 (3, [M]+), 366 (14), 262 (10), 236
(17), 145 (29), 131 (10), 130 (100), 129 (19), 128 (11), 118 (10), 116 (38), 104 (14), 103 (17), 102 (13), 90 (12),
+
89 (15), 77 (71), 51 (12); HRMS (ESI+): m/z calcd for C32H24N7O2 ([M+H]+) 538.1986, found 538.1976.
Anal. Calcd for Anal. calcd for C32H23N7O2 (537.57) C, 71.50; H, 4.31; N, 18.24%. Found: C, 71.22; H,
4.32; N, 17.94%.
(1-(1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-
1H-1,2,3-triazol-4-yl)methyl acetate (2j). Colorless powder, m.p. 188–194 ◦C (ethanol); Rf = 0.41 (30%
1
ethyl acetate in chloroform); H NMR (500 MHz, CDCl3)
δ
2.04 (s, 3H, CH3), 5.17 (s, 2H, OCH2),
5.21 (d, 1H, J = 15.6 Hz, N-1–CH
N-1–CH
α
), 5.43 (d, 1H, J = 14.8 Hz, N-1D–CH
α
), 5.51 (d, 1H, J = 15.6 Hz,
β
), 5.55 (d, 1H, J = 14.8 Hz, N-1D–CH ), 7.08 (s, 1H, H-5A), 7.18 (ddd, 1H, J = 7.5, 7.5, 0.8 Hz,
β
H-6), 7.23–7.29 (m, 4H, H-3C, H-5C, H-2E, H-6E), 7.29–7.33 (m, 2H, H-2C, H-6C), 7.34–7.39 (m, 3H, H-3E,
H-4E, H-5E), 7.38–7.44 (m, 1H, H-4C), 7.58 (s, 1H, H-5D), 7.63 (ddd, 1H, J = 8.4, 7.4, 1.7 Hz, H-7), 7.75 (d,
1H, J = 8.3 Hz, H-8), 7.99 (dd, 1H, J = 7.7, 1.7 Hz, H-5); 13C NMR (126 MHz, CDCl3)
δ 21.0 (CH3), 39.9
(N-1–CH2), 54.5 (N-1D–CH2), 57.6 (OCH2), 79.6 (C-3), 116.8 (C-8), 120.9 (C-4a), 123.5 (C-5D), 124.6
(C-6), 126.4 (C-5A), 128.3 (C-2E, C-6E), 128.7 (C-2C, C-6C), 129.0 (C-5), 129.1 (C-4E), 129.4 (C-3E, C-5E),

Molecules 2018, 23, 2310
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129.7 (C-1C), 130.0 (C-3C, C-5C), 131.3 (C-4C), 134.5 (C-1E), 137.2 (C-7), 140.9 (C-4A), 141.1 (C-8a), 142.9
(C-4D), 166.6 (C-2), 171.0 (COCH3), 187.9 (C-4); 15N NMR (51 MHz, CDCl3) 140.4 (N-1), 249.8 (N-1A),
3142, 2927, 1740, 1717,
δ
250.4 (N-1D), 350.5 (N-3D), 356.9 (N-3A), 362.9 (N-2D), 365.1 (N-2A); IR (cm−1):
ν
1679, 1602, 1469, 1377, 1244, 768, 749, 714, 697; MS (EI) m/z (%): 548 (0.1, [M + 1]+), 547 (0.3, [M]+), 347
+
(13), 289 (13), 144 (14), 105 (10), 104 (13), 91 (100), 43 (29); HRMS (ESI+): m/z calcd for C30H26N7O4
[M + H]+ 548.2041, found 548.2032.
(1-(2,4-Dioxo-3-phenyl-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-
◦
1H-1,2,3-triazol-4-yl)methyl acetate (2k). Colorless powder, m.p. 93–105 C; Rf = 0.42 (30% ethyl
acetate in chloroform); 1H NMR (500 MHz, CDCl3)
δ 2.05 (s, 3H, CH3), 5.19 (s, 2H, OCH2), 5.42 (d, 1H,
J = 15.7 Hz, N-1–CHα), 5.55 (d, 1H, J = 15.7 Hz, N-1–CHβ
), 7.14 (s, 1H, H-5A), 7.20 (ddd, 1H, J = 7.6, 7.6,
0.8 Hz, H-6), 7.38–7.49 (m, 6H, H-2C, H-3C, H-4C, H-5C, H-6C, H-4E), 7.49–7.55 (m, 2H, H-3E, H-5E),
7.66 (ddd, 1H, J = 8.5, 7.3, 1.7 Hz, H-7), 7.68–7.72 (m, 2H, H-2E, H-6E), 7.76 (d, 1H, J = 8.4 Hz, H-8),
8.03 (dd, 1H, J = 7.8, 1.5 Hz, H-5), 8.05 (s, 1H, H-5D); 13C NMR (126 MHz, CDCl3)
δ 21.0 (CH3), 39.8
(N-1-CH2), 57.6 (OCH2), 79.6 (C-3), 116.7 (C-8), 120.7 (C-2E, C-6E), 120.9 (C-4a), 121.8 (C-5D), 124.7
(C-6), 126.4 (C-5A), 128.9 (C-2C, C-6C), 129.1 (C-5), 129.2 (C-4E), 129.9 (C-1C), 130.0 (C-3E, C-5E), 130.2
(C-3C, C-5C), 131.4 (C-4C), 136.9 (C-1E), 137.4 (C-7), 140.9 (C-4A), 140.9 (C-8a), 143.2 (C-4D), 166.9 (C-2),
171.0 (COCH3), 187.9 (C-4); 15N NMR (51 MHz, CDCl3)
δ
140.4 (N-1), 249.9 (N-1A), 256.3 (N-1D), 352.9
3146, 2962, 1741, 1718, 1681, 1600, 1468, 1376, 1243, 1043, 762, 693,
(N-3D), 357.2 (N-3A); IR (cm−1):
ν
665, 608; MS (EI) m/z (%): 534 (0.2, [M + 1]+), 533 (0.6, [M]+), 366 (12), 365 (11), 262 (12), 131 (11), 130
(100), 129 (19), 128 (12), 104 (14), 103 (16), 99 (18), 77 (62), 44 (17), 43 (52); HRMS (ESI+): m/z calcd for
C29H24N7O4+ [M + H]+ 534.1884, found 534.1882.
3.9. General Procedure for the Synthesis of Bis-Triazoles 2c,f,i,l by Employing CuSO4/Cu0/DMF Conditions
(Table 4, Entries 3, 9, 12 and 15)
A mixture of the appropriate N-propargylquinoline-2,4(1H,3H)-dione
7 (1.5 mmol),
tetrazolo[1,5-a]pyridine (189 mg, 1.58 mmol), CuSO4
·
5H2O (38 mg, ◦0.15 mmol), granular copper
(191 mg, 3.05 mmol) and DMF (9 mL) was heated in darkness to 95–105 C (oil bath) for the time given
in Table 4, whereas the color of the mixture changed from brown-black to dark green. The mixture
was then allowed to cool to room temperature. Subsequently, (NH4)2CO3 (432 mg, 4.5 mmol) and
water (2 mL) were added and after stirring for 15 min, the mixture was poured into a narrow (1 cm
diameter) column of silica gel (15 g). The organic portion was eluted from the column with 10% ethanol
in chloroform. The yellow eluate was washed with saturated aqueous NH4Cl (50 mL), dried over
anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in vacuo. In the
cases of 2c
,i, the residue, which was TLC pure compound, was crystallized from suitable solvent. In
the cases of 2f
,
l
, the residue was purified by chromatography on silica gel column using chloroform as
eluent. The yields of prepared compounds 2 are given in Table 4.
3-Methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)quinoline-
2,4(1H,3H)-dione (2c). Colorless crystals, m.p. 188–191 ◦C (benzene); Rf = 0.29 (30% ethyl acetate in
chloroform); 1H NMR (500 MHz, DMSO-d6)
5.58 (d, 1H, J = 16.5 Hz, N-1–CH
δ 2.23 (s, 3H, CH3), 5.42 (d, 1H, J = 16.5 Hz, N-1–CHα),
β
), 7.28–7.40 (m, 2H, H-6, H-4B), 7.43–7.51 (m, 2H, H-3B, H-5B),
7.51–7.57 (m, 1H, H-5E), 7.64 (d, 1H, J = 8.4 Hz, H-8), 7.78–7.90 (m, 3H, H-7, H-2B, H-6B), 7.99 (d, 1H,
J = 7.5 Hz, H-5), 8.07–8.17 (m, 2H, H-3E, H-4E), 8.54–8.61 (m, 1H, H-6E), 8.82 (s, 1H, H-5D), 8.87 (s, 1H,
H-5A); 13C NMR (126 MHz, DMSO-d6)
δ
23.4 (CH3), 38.7 (N-1–CH2), 73.0 (C-3), 113.7 (C-3E), 116.6
(C-8), 119.3 (C-4a), 120.6 (C-5D), 122.5 (C-5A), 123.9 (C-6), 124.5 (C-5E), 125.2 (C-2B, C-6B), 128.1 (C-4B),
128.1 (C-5), 129.1 (C-3B, C-5B), 130.5 (C-1B), 137.2 (C-7), 140.3 (C-4E), 141.4 (C-8a), 143.2 (C-4D), 146.0
(C-4A), 148.4 (C-2E), 149.0 (C-6E), 168.5 (C-2), 189.9 (C-4); 15N NMR (51 MHz, DMSO-d6)
δ
135.8 (N-1),
248.9 (N-1A), 260.5 (N-1D), 284.9 (N-1E), 347.1 (N-3A), 356.9 (N-3D), 358.6 (N-2D), 363.4 (N-2A); IR
(cm−1):
3426, 3126, 2972, 1706, 1674, 1601, 1471, 1378, 1310, 1232, 1041, 777, 764; MS (EI) m/z (%): 477
(2, [M + 1]+), 476 (7, [M]+), 289 (11), 145 (14), 132 (14), 131 (96), 116 (50), 102 (10), 90 (10), 89 (13), 79 (20),
ν

Molecules 2018, 23, 2310
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78 (100), 77 (10), 51 (10); HRMS (ESI+): m/z calcd for C26H21N8O2 [M + H]+ 477.1782, found 477.1773.
+
Anal. Calcd for C26H20N8O2 (476.48) C, 65.54; H, 4.23; N, 23.52%. Found: C, 65.68; H, 4.21; N, 23.63%.
(1-(3-Methyl-2,4-dioxo-1-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-
3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (2f). Colorless powder, m.p. 69–82 ◦C; Rf = 0.29 (30% ethyl
acetate in chloroform); 1H NMR (500 MHz, DMSO-d6)
δ
2.06 (s, 3H, COCH3), 2.18 (s, 3H, C3–CH3),
5.17 (d, 1H, J = 12.7 Hz, O–CH
α
), 5.20 (d, 1H, J = 12.7 Hz, O–CH ), 5.41 (d, 1H, J = 16.5 Hz, N-1–CH ),
β
α
5.53 (d, 1H, J = 16.5 Hz, N-1–CHβ), 7.31 (dd, 1H, J = 7.4, 7.4 Hz, H-6), 7.54 (dd, 1H, J = 8.8, 4.5 Hz,
H-5E), 7.59 (d, 1H, J = 8.5 Hz, H-8), 7.77–7.83 (m, 1H, H-7), 7.96 (dd, 1H, J = 7.7 Hz, J = 1.6 Hz, H-5),
8.08–8.14 (m, 2H, H-3E, H-4E), 8.47 (s, 1H, H-5A), 8.55–8.59 (m, 1H, H-6E), 8.82 (s, 1H, H-5D); 13C NMR
(126 MHz, DMSO-d6) δ 20.6 (COCH3), 23.5 (C3–CH3), 38.7 (N-1–CH2), 57.2 (OCH2), 73.3 (C-3), 113.7
(C-3E), 116.5 (C-8), 119.4 (C-4a), 120.6 (C-5D), 123.8 (C-6), 124.4 (C-5E), 126.1 (C-5A), 127.9 (C-5), 137.0
(C-7), 140.2 (C-4E), 141.3 (C-8a), 141.6 (C-4A), 143.2 (C-4D), 148.3 (C-2E), 148.9 (C-6E), 168.6 (C-2), 170.1
(COCH3), 189.9 (C-4); 15N NMR (51 MHz, DMSO-d6) 135.3 (N1), 247.6 (N-1A), 260.0 (N-1D), 284.7
δ
(N-1E), 353.4 (N-3A), 356.5 (N-3D), 361.9 (N-2D), 363.7 (N-2A); IR (cm−1):
ν 3152, 1741, 1718 1681, 1600,
1471, 1384, 1314, 1242, 1183, 1038, 782, 756, 663; MS (EI) m/z (%): 473 (0.7, [M + 1]+), 472 (2, [M]+),
304 (27), 303 (26), 302 (17), 132 (13), 131 (100), 79 (22), 78 (100), 43 (21); HRMS (ESI+): m/z calcd for
C23H21N8O4 [M + H]+ 473.1680, found 473.1684. Anal. Calcd for C23H20N8O4
57.38; H, 4.40; N, 23.27%. Found: C, 57.39; H, 4.36; N, 23.47%.
·
12 H2O (472.46): C,
+
3-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)quinoline-
◦
2,4(1H,3H)-dione (2i). Colorless crystals, m.p. 188–192 C (benzene); Rf = 0.50 (30% ethyl acetate
1
in chloroform); H NMR (500 MHz, DMSO-d6)
δ
5.44 (d, 1H, J = 16.3 Hz, N-1–CH
), 7.26 (dd, 1H, J = 7.5, 7.5 Hz, H-6), 7.32–7.40 (m, 3H, H-4B, H-2C, H-6C),
α), 5.67 (d, 1H,
J = 16.3 Hz, N-1–CH
β
7.41–7.52 (m, 5H, H-3B, H-5B, H-3C, H-4C, H-5C), 7.52–7.61 (m, 2H, H-8, H-5E), 7.68–7.75 (m, 1H, H-7),
7.78–7.86 (m, 2H, H-2B, H-6B), 7.96 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.09–8.16 (m, 2H, H-3E, H-4E), 8.58 (s,
1H, H-5A), 8.60 (ddd, 1H, J = 4.8, 1.3, 1.3 Hz, H-6E), 8.81 (s, 1H, H-5D); 13C NMR (126 MHz, DMSO-d6)
δ
39.1 (N-1–CH2), 80.4 (C-3), 113.7 (C-3E), 116.5 (C-8), 120.8 (C-5D), 120.9 (C-4a), 123.4 (C-5A), 124.0
(C-6), 124.5 (C-5E), 125.2 (C-2B, C-6B), 127.9 (C-5), 128.0 (C-4B), 128.9 (C-2C, C-6C), 129.0 (C-3B, C-5B),
129.4 (C-3C, C-5C), 130.0 (C-1C), 130.5 (C-4C), 130.6 (C-1B), 136.8 (C-7), 140.2 (C-4E), 140.5 (C-8a), 143.0
(C-4D), 145.4 (C-4A), 148.3 (C-2E), 149.0 (C-6E), 166.6 (C-2), 188.1 (C-4); 15N NMR (51 MHz, DMSO-d6)
δ
137.5 (N1), 248.7 (N-1A), 260.4 (N-1D), 284.8 (N-1E), 347.2 (N-3A), 357.7 (N-3D), 367.4 (N-2A); IR (cm−1):
ν
3418, 2973, 1718, 1679, 1596, 1477, 1467, 1450, 1049, 1031, 773, 766, 757, 701; MS (EI) m/z (%): 539 (1,
[M + 1]+), 538 (3, [M]+), 236 (11), 145 (16), 132 (14), 131 (100), 116 (32), 91 (11), 89 (11), 79 (15), 78 (85), 77
(13); HRMS (ESI+): m/z calcd for C31H23N8O2 [M + H]+ 539.1938, found 539.1932. Anal. calcd for
+
C31H22N8O2 (538.19): C, 69.13; H, 4.12; N, 20.81%. Found: C, 68.91; H, 4.17; N, 20.66%.
(1-(2,4-Dioxo-3-phenyl-1-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-
3-yl)-1H-1,2,3-triazol-4-yl)methyl acetate (2l). Colorless powder, m.p. 93–102 ◦C; Rf = 0.18 (30% ethyl
acetate in chloroform); 1H NMR (500 MHz, CDCl3)
1H, J = 15.8 Hz, N-1–CH
δ
2.05 (s, 3H, COCH3), 5.19 (s, 2H, OCH2), 5.30 (d,
α
), 5.71 (d, 1H, J = 15.8 Hz, N-1–CH
β
), 7.13 (s, 1H, H-5A), 7.19 (dd, 1H, J = 7.5,
7.5 Hz, H-6), 7.36 (dd, 1H, J = 7.3, 4.9 Hz, H-5E), 7.38–7.42 (m, 2H, H-3C, H-5C), 7.42–7.48 (m, 3H, H-2C,
H-4C, H-6C), 7.63 (ddd, 1H, J = 8.3, 7.4, 1.6 Hz, H-7), 7.70 (d, 1H, J = 8.4 Hz, H-8), 7.88–7.95 (m, 1H,
H-4E), 8.02 (dd, 1H, J = 7.8, 1.5 Hz, H-5), 8.15 (d, 1H, J = 8.2 Hz, H-3E), 8.47–8.53 (m, 1H, H-6E), 8.63
(s, 1H, H-5D); 13C NMR (126 MHz, CDCl3)
δ 21.0 (COCH3), 39.9 (N-1–CH2), 57.6 (OCH2), 79.7 (C-3),
113.9 (C-3E), 116.6 (C-8), 121.0 (C-4a), 121.0 (C-5D), 124.0 (C-5E), 124.6 (C-6), 126.4 (C-5A), 128.9 (C-2C,
C-6C), 129.1 (C-5), 129.7 (C-1C), 130.2 (C-3C, C-5C), 131.3 (C-4C), 137.2 (C-7), 139.3 (C-4E), 140.9 (C-4A),
141.2 (C-8a), 143.0 (C-4D), 148.9 (C-6E), 149.0 (C-2E), 166.6 (C-2), 171.0 (COCH3), 187.9 (C-4); 15N NMR
(51 MHz, CDCl3)
δ
138.9 (N-1), 249.7 (N-1A), 261.2 (N-1D), 285.1 (N-1E), 355.8 (N-3D), 357.1 (N-3A); IR
(cm−1):
ν
3155, 2926, 1741, 1718, 1682, 1599, 1470, 1375, 1313, 1243, 1034, 779, 697, 665; MS (EI) m/z (%):
535 (0.4, [M + 1]+), 534 (0.7, [M]+), 132 (14), 131 (100), 79 (19), 78 (93), 44 (11), 43 (31); HRMS (ESI+):
m/z calcd for C28H23N8O4+ [M + H]+ 535.1837, found 535.1846.

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3.10. Synthesis of Bis-Triazole 2d by Employing CH2Cl2/Water/CuSO4·5H2O/Na-Ascorbate Conditions
(Table 4, Entry 5)
To a solution of acetylene 7c (132 mg, 0.375 mmol) and azide 8a (52.4 mg, 0.394 mmol) in
dichloromethane (6.5 mL) a solution of sodium ascorbate (59.5 mg, 0.3 mmol) in water (5.5 mL),
and a solution of CuSO4 5H2O (7.5 mg, 0.03 mmol) in water (1 mL) were added. The two-phase
·
liquid reaction mixture was stirred in darkness at room temperature until the compound 7c reacted
completely according to TLC analysis (4 h). The reaction mixture was diluted with water (50 mL) and
extracted with chloroform (4
×
30 mL). The combined organic layers were dried (Na2SO4), filtered,
and evaporated to dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel
(25 g) column chromatography using 67% ethyl acetate in petroleum ether as eluent, affording product
2d (155 mg, 0.32 mmol, 85%).
3.11. Synthesis of Bis-Triazole 2d by Employing t-BuOH/Water/CH3CN/CuSO4·5H2O/Na-Ascorbate
Conditions (Table 4, Entry 6)
To a mixture of acetylene 7c (264 mg, 0.75 mmol), azide 8a (105 mg, 0.79 mmol) and t-BuOH
(3.5 mL) a solution of Na-ascorbate (30 mg, 0.15 mmol) in water (2.5 mL), and a solution of CuSO4 5H2O
·
(4 mg, 0.02 mmol) in water (1 mL) were added. The reaction mixture was stirred in darkness at room
temperature for 9 h. Then a solution of Na-ascorbate (89 mg, 0.45 mmol) in water (1 mL), and a solution
of CuSO4 5H2O (11 mg, 0.044 mmol) in water (1 mL) and t-BuOH (2 mL) were added. The reaction
·
mixture was stirred for additional 20 h. The resulting sticky sediment that formed in the course of the
reaction was dissolved by addition of acetonitrile (3 mL) to the reaction mixture. The reaction mixture
was stirred for additional 19 h. Although the azide and acetylene coupling partners were still present
in the reaction mixture, as judged by TLC analysis, the reaction was stopped by the addition of water
(50 mL) and extracted with chloroform (4
×
30 mL). The combined organic layers were dried (Na2SO4),
filtered, and evaporated to dryness. The residue was dissolved in chloroform and subjected to silica
gel (35 g) column chromatography using 67% ethyl acetate in petroleum ether as eluent, affording
regenerated starting acetylene 7c (48 mg, 0.14 mmol, 18%) and product 2d (295 mg, 0.61 mmol, 81%).
3.12. Synthesis of Bis-Triazole 2d by Employing t-BuOH/Water/CuSO4·5H2O/L-Ascorbic Acid Conditions
(Table 4, Entry 7)
To a mixture of acetylene 7c (264 mg, 0.75 mmol) and azide 8a (105 mg, 0.79 mmol) a solution
of L-ascorbic acid (13 mg, 0.074 mmol) and CuSO4
and t-BuOH (3.5 mL) were added. The reaction mixture was stirred in darkness at room temperature.
After 8.5 h and 22 h of stirring additional portions of L-ascorbic acid/CuSO4 5H2O/water/t-BuOH
·
5H2O (2 mg, 0.008 mmol) in water (3.5 mL),
·
(40 mg, 0.23 mmol/6 mg, 0.02 mmol/1 mL/1 mL and 53 mg, 0.3 mmol/7.5 mg, 0.03 mmol/1 mL/1 mL,
respectively) were added. Although after stirring for additional 23 h (total reaction time 45 h),
TLC analysis indicated the presence of azide and acetylene starting compounds, the heterogeneous
reaction mixture (a sticky sediment was formed) was diluted with water and extracted with chloroform
(5
×
50 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to
dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel (35 g) column
chromatography using 33% ethyl acetate in petroleum ether as eluent, affording regenerated starting
acetylene 7c (114 mg, 0.32 mmol, 43%) and product 2d (165 mg, 0.34 mmol 45%).
3.13. 3-Azido-3-methyl-1-(prop-2-yn-1-yl)Quinoline-2,4(1H,3H)-Dione (9a) (Scheme 3)
A mixture of the azide 5a (649 mg, 3.0 mmol) and potassium carbonate (1.24 g, 9 mmol) in DMF
(15 mL) was stirred at room temperature in darkness for 40 min. Propargyl bromide (6c, 80% solution
in toluene, 669 mg, 4.5 mmol) diluted with DMF (7 mL) was added dropwise under stirring during
1 min. The reaction mixture was stirred for 6 h, during which time it turned yellow, diluted with
cold water (200 mL) and extracted with chloroform (5
dried (Na2SO4), filtered, and evaporated to dryness. Trace amounts of DMF were removed by five
×
50 mL). The combined organic layers were

Molecules 2018, 23, 2310
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◦
subsequent co-destilations in vacuo at 50 C with toluene (30 mL). The residual yellow oil was dissolved
in chloroform (5 mL) and chromatographed on column silica gel (35 g) using chloroform as eluent,
affording product 9a (717 mg, 2.82 mmol, 94%, dried in vacuo to constant weight) as off-white oily
material, that was pure by TLC (Rf = 0.57; chloroform); 1H NMR (500 MHz, CDCl3)
δ 1.79 (s, 3H), 2.29
(dd, 1H, J = 2.5, 2.5 Hz), 4.67 (dd, 1H, J = 17.8, 2.5 Hz), 4.98 (dd, 1H, J = 17.8, 2.5 Hz), 7.26 (ddd, 1H,
J = 7.7, 7.4, 0.8 Hz), 7.35 (d, 1H, J = 8.3 Hz), 7.71 (ddd, 1H, J = 8.3, 7.4, 1.7 Hz), 8.02 (dd, 1H, J = 7.7,
1.7 Hz); 13C NMR (126 MHz, CDCl3)
δ 23.6, 32.7, 70.7, 73.4, 77.1, 115.8, 119.6, 124.4, 129.0, 136.9, 140.8,
169.1, 191.1; IR (cm−1):
ν
3241, 2980, 2138, 2107, 1711, 1678, 1603, 1471, 1383, 1366, 1305, 1285, 1260,
1218, 762; HRMS (ESI+): m/z calcd for C13H11N4O2 [M + H]+ 255.0877, found 255.0877; calcd for
+
C13H11N2O2+ [M − N2 + H]+ 227.0815, found 227.0814.
3.14. Synthesis of Triazole 7a from Phenylacetylene (6a) and Compound 9a (Scheme 3)
A mixture of compound 9a (286 mg, 1.13 mmol), phenylacetylene (6a) (230 mg, 2.25 mmol),
CuSO4 5H2O (28 mg, 0.11 mmol) and granular copper (143 mg, 2.25 mmol) in DMF (5 mL) was stirred
in darkness at room temperature for 60 min. To the resulting brown-green suspension (NH4)2CO3
(324 mg, 3.38 mmol) and water (3 mL) were added and stirring was continued for 10 min. The resulting
mixture was diluted with 10% ethanol in chloroform (10 mL). The organic layer was separated
and the aqueous layer was extracted with chloroform (3
were passed through a narrow (1 cm in diameter) column of silica gel (13 g) and the column was
subsequently washed with 10% ethanol in chloroform (210 mL) using overpressure to the top of the
×
10 mL). The combined organic layers
column. The yellow eluate was washed with saturated aqueous NH4Cl (1
×
50 mL) and distilled
water (1 50 mL), dried (Na2SO4), filtered, and evaporated to dryness. Trace amounts of DMF were
×
removed by five subsequent co-destilations in vacuo at 50 ◦C with toluene (40 mL). The residue was
chromatographed on a column of silica gel (30 g) using 38% ethyl acetate in hexane. The resulting
white solid (88 mg) was crystallized from benzene affording triazole 7a (66 mg, 0.19 mmol, 16%),
which was identified with the compound 7a described above.
3.15. 3-Azido-1-((1-Benzyl-1H-1,2,3-Triazol-4-yl)Methyl)-3-Methylquinoline-2,4(1H,3H)-Dione (10a)
(Scheme 3)
A mixture of acetylene 9a (254 mg, 1.0 mmol), (azidomethyl)benzene (8a) (266 mg, 2.0 mmol),
CuSO4 5H2O (25 mg, 0.1 mmol) and granular copper (127 mg, 2.0 mmol) in DMF (10 mL) was stirred
·
at room temperature for 21 h. Then (NH4)2CO3 (288 mg, 3.0 mmol) and water (3 mL) were added
and the stirring was continued for 10 min. The resulting mixture was poured into a narrow (1 cm in
diameter) column of silica gel (13 g). The organic portion was eluted with 10% ethanol in chloroform
(190 mL). The yellow eluate was washed with saturated aqueous NH4Cl (50 mL) and water (50 mL),
dried (Na2SO4), filtered, and evaporated t◦o dryness. Trace amounts of DMF were removed by six
subsequent co-destilations in vacuo at 50 C with toluene (30 mL). The residue was dissolved in
chloroform (5 mL) and chromatographed on silica gel (35 g) column using gradually 38% and 50%
ethyl acetate in petroleum ether as mobile phase, affording product 10a (164 mg, 0.42 mmol, 42%) as
a white solid, m.p. 42–47 ◦C; Rf = 0.21 (38% ethyl acetate in petroleum ether); 1H NMR (500 MHz,
CDCl3)
1H, J = 14.8 Hz), 7.16–7.28 (m, 3H), 7.32–7.39 (m, 3H), 7.54 (s, 1H), 7.67 (ddd, 1H, J = 8.3, 7.4, 1.6 Hz),
7.77 (d, 1H, J = 8.4 Hz), 7.96 (dd, 1H, J = 7.7, 1.5 Hz); 13C NMR (126 MHz, CDCl3)
23.6, 39.1, 54.5,
70.6, 116.6, 119.5, 123.5, 124.3, 128.3, 128.8, 129.0, 129.3, 134.3, 137.1, 141.4, 143.0, 169.8, 191.3; IR (cm−1):
δ 1.73 (s, 3H), 5.20 (d, 1H, J = 15.6 Hz), 5.31 (d, 1H, J = 15.6 Hz), 5.45 (d, 1H, J = 14.8 Hz), 5.49 (d,
δ
ν
3137, 3033, 2980, 2106, 1713, 1676, 1602, 1489, 1469, 1379, 1336, 1279, 1223, 765, 724; HRMS (ESI+):
m/z calcd for C20H18N7O2 [M + H]+ 388,1516, found 388.1514. Anal. Calcd for C20H17N7O2 (387.39):
+
C, 62.01; H, 4.42; N, 25.31%. Found: C, 61.74; H, 4.77; N, 25.15%.

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4. Conclusions
We have developed
a
methodology for accessing bis(1,2,3-triazole) functionalized
quinoline-2,4-diones in which the triazole heterocycles are present in substituents at positions
1 and 3 of the quinoline scaffold. Preliminary investigation has revealed that these compounds are
potential multidentate ligands for arene-ruthenium.
Supplementary Materials: The following are available online: 1H NMR and 13C NMR spectra of all
new compounds.
Author Contributions: D.M. performed the experiments. The manuscript was prepared through the contributions
of R.K., M.G., D.U., S.K., and J.K.
Funding: The authors acknowledge the financial support from (internal grants No. IGA/FT/2018/007,
funded from the resources of specific university research) and the Slovenian Research Agency (Research Core
Funding Grant P1-0230, Project J1-8147, and Project J1-9166).
Acknowledgments: Tereza Dostálová and Lovro Kotnik participated in this study in their undergraduate projects.
Their contributions are gratefully acknowledged.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of all compounds are available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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