Synthesis of 4,5-disubstituted-1H-1,2,3-triazoles

Article abstract of DOI:10.1007/s00706-019-02463-x

Abstract: Two-step procedure, a palladium catalyzed Sonogashira cross-coupling reaction of aroyl chlorides with aryl acetylenes, and 1,3-dipolar cycloaddition of the 1,3-diarylprop-2-yn-1-ones with sodium azide under catalyst free conditions achieved the

Full text of DOI:10.1007/s00706-019-02463-x

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-019-02463-x
ORIGINAL PAPER
Synthesis of 4,5‑disubstituted‑1H‑1,2,3‑triazoles
Djenisa H. A. Rocha1,2 · Diana C. G. A. Pinto2 · Artur M. S. Silva2
Received: 12 April 2019 / Accepted: 12 June 2019
© Springer-Verlag GmbH Austria, part of Springer Nature 2019
Abstract
Two-step procedure, a palladium catalyzed Sonogashira cross-coupling reaction of aroyl chlorides with aryl acetylenes, and
1,3-dipolar cycloaddition of the 1,3-diarylprop-2-yn-1-ones with sodium azide under catalyst free conditions achieved the
synthesis of aryl(4-aryl-1H-1,2,3-triazol-5-yl)methanones in moderate-to-good chemical yields (30–90%). The procedures
allowed the synthesis of 4,5-disubstituted-1H-1,2,3-triazol scafolds containing electron-neutral, -withdrawing, or -donat-
ing groups.
Graphic abstract
Keywords Alkyne · Cycloaddition · NMR spectroscopy · Heterocycles
Introduction
pharmacophore. The 1,2,3-triazole heterocycles are well-
known privileged medicinal scafolds because of their signif-
icant biological activities such as antifungal [4], antibacte-
rial [5], anti-infammatory [6], anti-HIV [7], and anti-cancer
[8–10] properties. Signifcant eforts have been made in the
last few years towards the design, synthesis, and evaluation
of various 1,2,3-triazole based molecules as anti-cancer
agents [11]. Among diverse C-4 substituents at 1,2,3-triazole
ring, the p-substituted phenyl led to increased antiprolifera-
tive activity compared to aliphatic branched or unbranched
C-4 side chains. Moreover, halophenyl-substituted 1,2,3-tria-
zolyl in bioactive hybrids contributed to strong cytostatic
activity in hepatocellular carcinoma cells [12]. The 1,2,3-tri-
azole moieties disubstituted at C-4 and C-5 demonstrated
excellent anti-cancer efect against a panel of 60 human can-
cer [13] and antifungal activities [14]. Some example of the
most active compounds is represented in Fig. 1.
Heterocyclic compounds, more precisely fve-membered
rings containing heteroatoms of nitrogen, such as triazole,
pyrazole, oxazole, imidazole, and thiazole, are structural
motifs that often play an important role in biochemical
process. Among them 1,2,3-triazole based heterocycles
have been well exploited for the generation of many bio-
active molecules as well as pharmaceuticals [1–3]. The
1,2,3-triazole moiety does not exist in nature; still, it has
gained paramount interest, because this ring is a remarkable
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-019-02463-x) contains
supplementary material, which is available to authorized users.
* Djenisa H. A. Rocha
djenisa@ua.pt
The 1,2,3-triazole derivatives are also key synthetic inter-
mediates in many industrial applications such as supramo-
lecular chemistry [15], polymers [16], pigments [17], metal
chelators [18], and other areas [19–21]. Triazoles can be
used as linker and show bioisosteric efects on peptide link-
age, aromatic ring, and double bonds [22]. Some unique
1
Department of Chemistry, CICECO-Aveiro Institute
of Materials, University of Aveiro, 3810-193 Aveiro,
Portugal
2
Department of Chemistry and QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
Vol.:(0123456789)
1 3

D. H. A. Rocha et al.
Fig. 1 Example of di- and
tri-substituted triazoles with
therapeutic efects
features like hydrogen bond formation, dipole–dipole, and
π-stacking interactions of triazole compounds have increased
their importance in medicinal chemistry as they improved
their solubility and their ability to bind with the biological
targets [3, 23, 24].
become an aim of great interest to chemists in the last years
[34, 35]. The frst step of our transformation involved the
Sonogashira reaction in homogenous phase [(PPh3)2PdCl2/
CuI] and/or heterogenous phase (Pd/C), using a terminal
alkyne derivative 5a–5c and aroyl chlorides 4a–4c with
diferent substituents (electron-neutral, -withdrawing, or
-donating groups) to obtain the 1,3-diarylprop-2-yn-1-ones
6a–6i) [36–38] (Scheme 2). The 1,3-diarylprop-2-yn-1-one
6a was obtained in 80% yield by homogenous phase (proce-
dure I) (Table 1, entry 1), while, by procedure II, the yield
was half (41%). Having in mind these results, the synthesis
of compounds 6b–6i was done using the conditions estab-
lished in procedure I.
Due to 1,2,3-triazoles versatilities and biological potential
above-mentioned, synthetic strategies toward their synthesis
had been a subject of intense research. The most common
reaction consists in 1,3-dipolar cycloaddition also known
as Huisgen cycloaddition, between azides and terminal
alkynes [25]. The other common approach is a copper(I)-
catalyzed version of azide-alkyne cycloaddition reaction
(CuAAC), resulted in the production of many 1,4-disubsti-
tuted 1,2,3-triazoles in very high yields [26]. Despite recent
advances in synthetic methods toward N-unsubstituted
4,5-disubstituted-1H-1,2,3-triazoles [27–32], protocols
afording these compounds, especially if the substituents are
aromatic or include aromatic rings, are still in demand. Our
contribution to the feld has been in design, synthesis, and
reactivity studies of diferent substituents (electron-neutral,
-withdrawing, or -donating groups) on the aryl rings in the
1,3-dipolar cycloaddition reaction of internal alkynes with
sodium azide. A procedure that allows the synthesis of nitro
derivatives and that is less expensive was achieved.
The derivatives 6a, 6b, 6d, and 6e (Table 1, entries 1, 2,
4, and 5) were obtained in good yields using the procedure I.
For the synthesis of compounds having electron-withdraw-
ing group (NO2) 6c, 6f–6i, it was necessary some modifca-
tion in the reaction conditions. In the cases of derivatives
6f and 6h, it was only necessary to perform the reaction at
45 °C (Table 1, entries 6 and 9). The synthesis of compound
6i was done under heterogeneous and homogeneous phase
at room temperature and at 45 °C; however, the obtained
yields (<20%) were always lower than the yields obtained
under homogeneous phase at room temperature (Table 1,
entry 10). For derivatives 6c and 6g, the best results were
obtained using procedure II (Table 1, entry 3 and entry 8).
Alonso et al. [39] demonstrated that using different
sources of palladium as pre-catalyst for the copper-free
acylation of terminal alkynes with diferent carboxylic acid
chlorides in toluene in the presence of three equivalents
of triethylamine (TEA) as base, giving the corresponding
ynones in good yields. They also showed that the coupling
reaction of aroyl chlorides such as 4-chlorobenzoyl and
Results and discussion
Bearing in mind the above-mentioned facts we envisage
the use of Sonogashira cross-coupling reaction to obtain
1,3-diarylprop-2-yn-1-ones 6 [Scheme 1, step (A)], followed
by their 1,3-dipolar cycloaddition with sodium azide giving
aryl(5-aryl-1H-1,2,3-triazol-4-yl)methanones 7 [Scheme 1,
step (B)].
The original Sonogashira reaction requires a copper(I)
salt as a co-catalyst in combination with the palladium
source. Although essential for the efectiveness, the usage
of copper as a co-catalyst in Pd/Cu catalyzed Sonogashira
reaction entails several drawbacks including the applica-
tion of environmentally unfriendly reagents, the formation
of undesirable alkyne homocoupling side products, and the
necessity of strict oxygen exclusion in the reaction mixture
[33]. For these reasons, Cu-free Sonogashira reaction has
Scheme 1
1 3

Synthesis of 4,5-disubstituted-1H-1,2,3-triazoles
Scheme 2
Table 1 Reaction time and yields in the synthesis of 1,3-diarylprop-
2-yn-1-ones 6a–6i
better yields failed. It can be inferred that the presence of
this withdrawing group in both reagents diminished their
reactivity towards the cross-coupling reaction. The 1,3-diar-
ylprop-2-yn-1-ones 6a–6i characterization by 1H NMR spec-
tra only reveals the signals corresponding to the aromatic
protons. On the other hand, the 13C NMR spectra signals
are much more elucidative of the compound structure, and
at ca. δ = 87 and 93 ppm, the signal characteristics of the
triple bond’s carbons were assigned to C-2 and C-3, and at
ca. 178 ppm, the signal due to the carbonyl carbon.
Entry Compounds Substituents Substituents Yield/% Time/h
R
R1
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
6g
6g
6h
6i
H
H
H
OCH3
OCH3
OCH3
NO2
NO2
NO2
NO2
H
80
90
82
60
86
80
20
50
70
40
3a
OCH3
NO2
H
OCH3
NO2
H
H
OCH3
NO2
19a
3b
22a
18a
3c
The next reaction step involves a 1,3-dipolar cycloaddi-
tion reaction of the above-mentioned 1,3-diarylprop-2-yn-
1-ones 6a–6i with sodium azide in DMF (Scheme 3). This
1,3-dipolar cycloaddition is one of the most-described meth-
odologies towards the synthesis of 1,2,3-triazoles deriva-
tives [42–46], and nonetheless, we would like to emphasize
that, in this case, the products are obtained without the use
of any catalyst, which naturally makes the procedure more
economical.
3a
3b
8.5c
2.6a
aProcedure I
bProcedure II
cProcedure I at 45 °C
First, we tried the synthesis of phenyl(5-phenyl-1H-1,2,3-
triazol-4-yl)methanone (7a) using the conventional heating,
and after 17 h of reaction, it was observed a complete dis-
appearance of 6a by thin-layer chromatography (TLC) and
4-nitrobenzoyl chlorides with phenylacetylene afording
good yields at 110 °C. Chen and Li [40] also reported that
toluene could be used as solvent of 4-nitrobenzoyl chloride
leading to increase of Sonogashira coupling yield using
(PPh3)2PdCl2/CuI. Other authors also studied different
sources of palladium and conclude that they can infuence
the yield of nitro derivatives [41]. Therefore, we believe that
the reaction conditions, solvent and temperature, and catalyst
system are responsible for the best yields obtained in case of
derivatives 6c and 6g.
1
the formation of 7a. The H NMR spectrum confrms the
formation of the desired product 7a in very good yield (78%;
Table 2, entry 1).
The same reaction was tried using the microwave irradia-
tion (120 °C for 30 min, at 500 W) as heating source, and
again, the desired product 7a was obtained, but in lower
yield (64%). These results led the use of conventional heat-
ing to obtain the other derivatives 7b–7i (Table 2). Under
the conventional heating, some nitro derivatives 7c, 7g, and
7i yielded the expected products in lower yields (Table 2,
entries 3, 9, 11, and 12), and consequently, the microwave
irradiation was tried as an alternative.
A careful analysis of Table 1 shows that the substituents
have a great impact in the reaction conditions and time, for
instance the presence of methoxy groups enlarge the reaction
time (Table 1, entries 2, 4, and 5), whereas the presence of
nitro groups involves mostly the modifcation of the reaction
conditions (Table 1, entries 3, 6, and 8). Moreover, nitro
groups tend to lower the yields and, in some cases (Table 1,
entry 10), all the attempts to obtain the compounds with
Microwave technology has already been applied in many
felds and its efect on accelerating chemical reactions was
largely studied [47, 48]. The advantages is that the use of
1 3

D. H. A. Rocha et al.
Scheme 3
Table 2 Reaction time and yields in the synthesize of 1,2,3-triazole
derivatives 7a–7i
Entry Compounds Substituents Substituents Yield/% Time/h
R
R1
1
2
3
4
5
6
7
8
7a
7b
7c
7c
7d
7e
7f
H
H
H
H
OCH3
OCH3
OCH3
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
78
88
44
64
68
90
85
60
30
85
33
40
30
45
17
22
OCH3
NO2
NO2
H
OCH3
NO2
H
H
H
OCH3
OCH3
NO2
NO2
21
(a)
(b)
0.5a
15
Fig. 2 The most important HMBC signals
16
16
5
7g
7g
7g
7h
7h
7i
The 1H NMR spectra of aryl(5-aryl-1H-1,2,3-triazol-4-yl)-
methanones 7a–7i1 only reveal the aromatic protons signals.
On the other hand, the 13C NMR spectra signals reveal the
presence of signals at ca δ=159 and 148 ppm, correspond-
ing to carbon C-4 and C-5 resonances of the 1,2,3-triazole
ring. The signal at ca 188 ppm confrms the presence of the
carbonyl group.
9
16
10
11
12
13
14
0.5a
17
0.75a
25
7i
1a
aThe product was obtained using microwave irradiation (500 W,
120 °C)
The HMBC correlations observed in the spectrum of
1,3-diarylprop-2-yn-1-one 6b (Fig. 2a) and aryl(5-aryl-1H-
1,2,3-triazol-4-yl)methanone 7f (Fig. 2b) not only confrmed
the depicted structures but also allowed the assignment of
all protons and carbons resonances. The main correlations
in the case of 1,3-diarylprop-2-yn-1-ones are the correlation
between the protons H-2′-6′ and carbon C-1 and between
protons H-2″, 6″ and carbons C-3 and C-4″ (Fig. 2a). In
the case of aryl(5-aryl-1H-1,2,3-triazol-4-yl)methanones,
the main correlations are between the protons H-2′-6′ and
carbons C-1 and C-4′ and between the protons H-2″, 6″ and
carbons C-5 and C-4″ (Fig. 2b).
MW in synthetic process such as clean-and-green, environ-
ment friendly chemistry, high yield, reduced reaction time,
and product selectivity leads the application of this method
in 1,3-dipolar cycloaddition [43, 44]. Here in, microwave
irradiation was performed to shorten reaction time and
increased the reaction yields of the products obtained in low
yield under conventional heating.
As can be seen in Table 2 (entries 4, 10, 12, and 14), the
change of the heating source from conventional to micro-
wave irradiation was a success in the case of derivatives 7c,
7g–7i. Under MW irradiation, the heating proceeds directly
inside mixture, the rapid orientation, and reorientation of the
molecules, which contribute for the stabilization/activation
of the benzenic ring and subsequent favor the interaction of
the internal alkyne with the azide.
1
Due to the prototropy of 1,2,3-triazoles, the name of structures 7a–
7i can be aryl(5-aryl-1H-1,2,3-triazol-4-yl)methanones or aryl(4-aryl-
1H-1,2,3-triazol-5-yl)methanones. Herein, we used the former one to
be coherent with the number system presented in Table 2.
1 3

Synthesis of 4,5-disubstituted-1H-1,2,3-triazoles
taken in 10 cm3 ethyl acetate and the water residue was
removed over Na2SO4. The purifcation was done by col-
umn chromatography using a (9:1) mixture of light petro-
leum and dichloromethane as eluent.
Conclusion
In summary, a simply and efcient protocol for the synthe-
sis of 1,2,3-triazoles with unusually 4,5-disubstituted pat-
tern was described. The protocol herein discussed allowed
the synthesis of several derivatives in overall yields above
50%, starting from commercial and readily available rea-
gents. 1,2,3-Triazoles with electron-neutral, -withdrawing,
and -donating groups were prepared and can quite useful
for the construction of a small focused library. Although
the presence of nitro groups lowered the overall yield, it
should be emphasized that the use of microwave irradia-
tion as a source of energy allowed the synthesis of the
desired products in moderate–good yields (41–85%).
Procedure II
A mixture of 0.94 mg alkyne 2c (6.37 mmol), 1.8 cm3 tri-
ethylamine (12.74 mmol), and Pd/C (1 mol %) in 2 cm3 dry
toluene was stirred at room temperature under a nitrogen
atmosphere for 30 min. The corresponding acyl chloride
4a (0.89 cm3, 7.64 mmol) in dry toluene was added and
the solution was heated at 110 °C. The excess of catalyst
was removed by fltration and the solution was washed with
water (3×5 cm3). The solid was taken in 10 cm3 ethyl ace-
tate and the water residue was removed over Na2SO4. The
purifcation was done by column chromatography using light
petroleum as eluent, and then, a 9:1 mixture of light petro-
leum and ethyl acetate was obtained the 3-(4-nitrophenyl)-
1-phenylprop-2-yn-1-one 6c.
Experimental
All reagents were commercially available and used with-
out further purification. Column chromatography was
performed on silica gel 60 Merck 0.032–0.063 mm and
0.063–0.200 mm and preparative thin-layer chromatog-
raphy (TLC) on silica gel 60 GF254 from Merck. The
solvents were commercially available first grade and
distillate. Melting points were obtained using a Büchi
melting point B-540. Microwave equipment was Ethos
MicroSYNTH Labstation (Milestone Inc) using an optic
fber sensor to control the temperature. The NMR spec-
tra were recorded using Avance 300 and 500 spectrom-
1,3‑Diphenylprop‑2‑yn‑1‑one (6a) [39, 49, 51, 52] White
1
solid; yield: 115.4 mg (80%); m.p.: 48–51 °C; H NMR
(300.13 MHz, CDCl3): δ = 8.23 (dd, J = 1.5, 8.2 Hz, 2H,
H-2′, 6′), 7.70 (dd, J=1.5, 8.2 Hz, 2H, H-2″, 6″), 7.63 (br
dd, J = 7.4, 8.2 Hz, 1H, H-4′), 7.54 (brd, J = 7.2 Hz, 2H,
H-3′, 5′), 7.48 (m, 1H, H-4″), 7.44 (br d, J = 7.2 Hz, 2H,
H-3″, 5″) ppm; 13C NMR (75.47 MHz, CDCl3): δ=178.0
(C-1), 136.9 (C-1′), 134.1 (C-4′), 133.1 (C-2″, 6″), 130.8
(C-4″), 129.6 (C-2′, 6′), 128.7 (C-3″, 5″), 128.6 (C-3′, 5′),
120.1 (C-1″), 93.1 (C-3), 86.9 (C-2) ppm; MS (ESI+): m/z
(%)=207 ([M+H]+, 75), 229 ([M+Na]+, 90).
1
eters operating at 300.13 MHz and 500.13 MHz for H
and 75.47 MHz and 125.76 MHz for 13C, respectively,
with tetramethylsilane (TMS) as the internal standard. The
chemical shifts are reported as δ values (ppm) and cou-
pling constants (J) in Hz. High-resolution mass spectra
were performed at the LTQ Orbitrap XLTM Hybrid Ion
Trap-Orbitrap Mass Spectrometer.
3‑(4‑Methoxyphenyl)‑1‑phenylprop‑2‑yn‑1‑one (6b) [50–
52] Brown solid; yield: 148.8 mg (90%); m.p.: 70–72 °C;
1H NMR (300.13 MHz, CDCl3): δ=8.23 (brd, J=8.0 Hz,
2H, H-2′, 6′), 7.65 (dd, J=2.0, 9.0 Hz, 2H, H-2″, 6″), 7.60–
7.64 (m, 1H, H-4′), 7.53 (brd, J=8.0 Hz, 2H, H-3′, 5′), 6.95
(dd, J=2.0, 9.0 Hz, 2H, H-3″, 5″), 3.87 (s, 3H, 4″-OCH3)
ppm; 13C NMR (75.47 MHz, CDCl3): δ=178.1 (C-1), 161.7
(C-4″), 137.0 (C-1′), 135.1 (C-2″, 6″), 133.9 (C-4′), 129.5
(C-2′, 6′), 128.5 (C-3′, 5′), 114.4 (C-3″, 5″), 111.9 (C-1″),
94.3 (C-3), 86.9 (C-2), 55.4 (4″-OCH3) ppm; MS (ESI+):
m/z (%)=237 ([M+H]+, 87), 259 ([M+Na]+, 45); FT-MS
(ESI): m/z calcd for C16H13O2 ([M+H]+) 237.0916, found
237.0900.
Synthesis of 1,3‑diarylprop‑2‑yl‑1‑ones 6a–6i
Procedure I
8.9 mg Bis[triphenylphosphine]palladium(II) dichlo-
ride (2 mol%) and 1.2 mg copper(I) iodide (1 mol%)
were added to a mixture of the appropriate alkyne 5a–5c
(0.7 mmol) and aroyl chloride 4a–4c (0.84 mmol) in tri-
ethylamine (35.9 mmol). The mixture was stirred at room
temperature under nitrogen atmosphere. At the end (see
Table 1 for reaction time), the mixture was evicted over
ice/water (15 cm3/20 g). Diluted HCl (20%) was added to
the reaction mixture and the solid fltrated. The solid was
3‑(4‑Nitrophenyl)‑1‑phenylprop‑2‑yn‑1‑one (6c) [39] Brown
solid; yield: 131.2 mg (82%); m.p.: 144–145 °C; 1H NMR
(300.13 MHz, CDCl3): δ 8.30 (dd, J = 2.1, 9.0 Hz, 2H,
H-3″, 5″), 8.21 (dd, J=1.2, 8.3 Hz, 2H, H-3′, 5′), 7.85 (dd,
J=2.1, 9.0 Hz, 2H, H-2″, 6″), 7.65–7.71 (m, 1H, H-4′), 7.55
(brd, J=8.3 Hz, 2H, H-2′, 6′) ppm; 13C NMR (75.47 MHz,
1 3

D. H. A. Rocha et al.
CDCl3): δ=177.7 (C-1), 148.6 (C-4″), 136.3 (C-1″), 134.7
(C-4′), 133.7 (C-2′, 6′), 129.7 (C-3″, 5″), 128.8 (C-2″, 6″),
126.8 (C-1′), 123.8 (C-3′, 5′), 95.7 (C-3), 89.2 (C-2) ppm;
MS (ESI+): m/z (%)=252 ([M+H]+, 22); FT-MS (ESI): m/z
calcd for C15H10NO3 ([M+H]+) 252.0655, found 252.0642.
(%)=281 ([M]+, 100), 282 ([M+H]+, 80); FT-MS (ESI): m/z
calcd for C15H10NO3 ([M+H]+) 252.0655, found 252.0642.
3‑(4‑Methoxyphenyl)‑1‑(4‑nitrophenyl)prop‑2‑yn‑1‑one (6h,
C16H12NO4) Brown solid; yield: 137.8 mg (70%); m.p.: 141–
142 °C; 1H NMR (300.13 MHz, CDCl3): δ=8.37 (brs, 4H,
H-2′, 3′, 5′, 6′), 7.68 (d, J=8.9 Hz, 2H, H-2″, 6″), 6.97 (d,
1‑(4‑Methoxyphenyl)‑3‑phenylprop‑2‑yn‑1‑one (6d) [39,
52] Brown solid; yield: 99.2 mg (60%); m.p.: 99–100 °C; 1H
NMR (300.13 MHz, CDCl3): δ=8.21 (dd, J=2.3, 9.3 Hz,
2H, H-2′, 6′), 7.68 (dd, J=1.5, 8.0 Hz, 2H, H-2″, 6″), 7.41–
7.47 (m, 3H, H-3″, 4″, 5″), 7.00 (dd, J = 2.4, 9.3 Hz, 2H,
H-3′, 5′), 3.91 (s, 3H, 4′-OCH3) ppm; 13C NMR (75.47 MHz,
CDCl3): δ = 176.7 (C-1), 164.5 (C-4′), 132.9 (C-2″, 6″),
132.0 (C-2′, 6′), 130.6 (C-4″), 130.3 (C-1′), 128.6 (C-3″,
5″), 120.3 (C-1″), 113.9 (C-3′, 5′), 92.3 (C-3), 86.9 (C-2),
55.6 (4′-OCH3) ppm; MS (ESI+): m/z (%)=237 ([M+H]+,
87), 259 ([M+Na]+, 45).
J=8.9 Hz, 2H, H-3″, 5″), 3.86 (s, 3H, 4″-OCH3) ppm; 13
C
NMR (75.47 MHz, CDCl3): δ=175.6 (C-1), 162.3 (C-4″),
150.8 (C-4′), 141.3 (C-1′), 135.5 (C-2″, 6″), 130.3 (C-2′, 6′),
123.8 (C-3′, 5′), 114.5 (C-3″, 5″), 111.1 (C-1″), 96.9 (C-3),
86.9 (C-2), 55.5 (4″-OCH3) ppm; MS (ESI+): m/z (%)=252
([M+H]+, 35), 274 ([M+Na]+, 15); FT-MS (ESI): m/z calcd
for C16H12NO4 ([M+H]+) 282.0761, found 282.0746.
1,3‑Bis(4‑nitrophenyl)prop‑2‑yn‑1‑one (6i, C15H8N2O5) Brown
1
solid; yield: 82.9 mg (40%); m.p.: 125–127 °C; H NMR
(300.13 MHz, CDCl3): δ = 8.39 (d, J = 2.5 Hz, 4H, H-3′,
5′, 3″, 5″), 8.33 (dd, J=2.5, 9.0 Hz, 2H, H-2′, 6′), 7.87 (dd,
J=2.5, 9.0 Hz, 2H, H-2″, 6″) ppm; 13C NMR (75.47 MHz,
CDCl3): δ=175.4 (C-1), 151.1 (C-4′), 148.8 (C-4″), 140.4
(C-1′), 133.9 (C-2″, 6″), 130.5 (C-2′, 6′), 125.9 (C-1″), 124.1
(C-3″, 5″), 123.5 (C-3´,5′), 91.1 (C-3), 89.0 (C-2) ppm; MS
(ESI+): m/z (%)=296 ([M]+, 100).
1,3‑Bis(4‑methoxyphenyl)prop‑2‑yn‑1‑one (6e) [51] Yel-
low solid; yield: 160.3 mg (86%); m.p.: 79–80 °C; 1H NMR
(300.13 MHz, CDCl3): δ = 8.19 (d, J = 8.9 Hz, 2H, H-2′,
6′), 7.64 (d, J=8.9 Hz, 2H, H-2″, 6″), 6.99 (d, J=8.9 Hz,
2H, H-3′, 5′), 6.94 (d, J = 8.9 Hz, 2H, H-3″, 5″), 3.91 (s,
3H, 4″-OCH3), 3.87 (s, 3H, 4′-OCH3) ppm; 13C NMR
(75.47 MHz, CDCl3): δ=176.8 (C-1), 164.3 (C-4′), 161.5
(C-4″), 135.0 (C-2″, 6″), 131.8 (C-2′, 6′), 130.4 (C-1″),
114.4 (C-3′, 5′), 113.8 (C-3″, 5″), 112.1 (C-1′), 93.4 (C-3),
86.8 (C-2), 55.6 (4′-OCH3), 55.4 (4″-OCH3) ppm; MS
(ESI+): m/z (%)=267 ([M+H]+, 80), 289 ([M+Na]+, 100).
Synthesis of aryl(5‑aryl‑1H‑1,2,3‑triazol‑4‑yl)‑
ketones 7a–7i
Sodium azide (0.087 mg, 1.34 mmol) was added a solu-
tion of the appropriate 1,3-diarylprop-2-yn-1-one 6a–6i
(0.67 mmol) in 7 cm3 DMF. The mixture was stirred at
120 °C under nitrogen atmosphere until the consumption
of the starting material. At the end, the mixture was evicted
over ice/water (15 cm3/20 g). Diluted HCl (20%) was added
to the reaction mixture and the solid fltrated. The solid was
taken in 10 cm3 ethyl acetate and the water residue was
removed over Na2SO4. In case of 7b and 7e, the compound
was obtained by recrystallization in ethanol and the other
derivatives by column chromatography using as eluent light
petroleum and ethyl acetate (8:2).
1‑(4‑Methoxyphenyl)‑3‑(4‑nitrophenyl)prop‑2‑yn‑1‑one
(6f, C16H12NO4) Yellow solid; yield: 157.5 mg (80%); m.p.:
158–160 °C; 1H NMR (300.13 MHz, CDCl3): δ=8.30 (d,
J=9.0 Hz, 2H, H-3″, 5″), 8.18 (d, J=9.0 Hz, 2H, H-2′, 6′),
7.83 (d, J=9.0 Hz, 2H, H-2″, 6″), 7.01 (d, J=9.0 Hz, 2H,
H-3′, 5′), 3.92 (s, 3H, 4′-OCH3) ppm; 13C NMR (75.47 MHz,
CDCl3): δ=174.5 (C-1), 165.0 (C-4′), 148.3 (C-4″), 133.5
(C-2″, 6″), 132.1 (C-2′, 6′), 129.6 (C-1′), 127.0 (C-1″), 123.8
(C-3″, 5″), 114.1 (C-3′, 5′), 95.0 (C-3), 88.3 (C-2) ppm; MS
(ESI+): m/z (%)=282 ([M+H]+, 100), 304 ([M+Na]+, 15);
FT-MS (ESI): m/z calcd for C16H12NO4 ([M+H]+) 282.0761,
found 282.0746.
Phenyl(5‑phenyl‑1H‑1,2,3‑triazol‑4‑yl)methanone (7a)
1
[32] White solid; yield: 78%; m.p.: 94–96 °C; H NMR
1‑(4‑Nitrophenyl)‑3‑phenylprop‑2‑yn‑1‑one (6g) [39,
52] Brown solid; yield: 87.9 mg (50%); m.p.: 162–163 °C;
1H NMR (300.13 MHz, CDCl3): δ = 8.39 (s, 4H, H-2′, 3′,
5′, 6′), 7.72 (dd, J = 1.6, 7.0 Hz, 2H, H-2″, 6″), 7.52 (dd,
J = 1.6, 7.4 Hz, 1H, H-4″), 7.48 (dd, J = 1.6, 7.0 Hz, 2H,
H-3″, 5″) ppm; 13C NMR (75.47 MHz, CDCl3): δ=175.9
(C-1), 150.9 (C-4′), 141.0 (C-1′), 133.3 (C-2″, 6″), 131.4
(C-4″), 130.4 (C-2′, 6′), 128.9 (C-3″, 5″), 123.9 (C-3′, 5′),
119.4 (C-1″), 95.4 (C-3), 86.5 (C-2) ppm; MS (ESI+): m/z
(300.13 MHz, CDCl3): δ=8.09 (brd, J=8.3 Hz, 2H, H-2′,
6′), 7.76–7.81 (m, 2H, H-3′, 5′), 7.62 (ddd, J = 2.0, 7.0,
8.3 Hz, 1H, H-4′), 7.49 (brd, J=8.0 Hz, 2H, H-2″, 6″), 7.40–
7.46 (m, 3H, H-3″, 4″, 5″) ppm; 13C NMR (75.47 MHz,
CDCl3): δ=187.8 (C=O), 159.0 (C-4),148.0 (C-5), 137.0
(C-1′), 133.8 (C-1″), 133.5 (C-4′), 130.4 (C-2′, 6′), 129.6
(C-4″), 128.8 (C-3″, 5″), 128.6 (C-3′, 5′), 128.4 (C-2″,
6″) ppm; MS (ESI+): m/z (%) = 250 ([M+H]+, 13), 272
([M+Na]+, 100); FT-MS (ESI): m/z calcd for C15H12N3O
([M+H]+) 250.0975, found 250.0964.
1 3

Synthesis of 4,5-disubstituted-1H-1,2,3-triazoles
[5‑(4‑Methoxyphenyl)‑1H‑1,2,3‑triazol‑4‑yl]phenylmetha‑
none (7b, C16H13N3O2) Yellow solid; yield: 164.7 mg (88%);
m.p.: 258–260 °C; 1H NMR (300.13 MHz, CDCl3): δ=8.10
(brd, J=7.2 Hz, 2H, H-2′, 6′), 7.77 (dd, J=2.5, 9.3 Hz, 2H,
H-2″, 6″), 7.58–7.62 (m, 1H, H-4′), 7.48 (t, J = 7.5 Hz,
2H, H-3′, 5′), 6.98 (dd, J=2.5, 9.3 Hz, 2H, H-3″, 5″), 3.85
(s, 3H, 4″-OCH3) ppm; 13C NMR (75.45 MHz, CDCl3):
δ = 187.8 (C=O), 160.7 (C-4″), 146.3 (C-5), 141.0 (C-4),
137.2 (C-1′), 133.3 (C-4′), 130.5 (C-2′, 6′), 130.2 (C-2″, 6″),
128.3 (C-3′, 5′), 120.2 (C-1″), 114.0 (C-3″, 5″), 55.3 (4″-
OCH3) ppm; MS (ESI+): m/z (%)=280 ([M+H]+, 40), 302
([M+Na]+, 100); FT-MS (ESI): m/z calcd for C16H13N3O2
([M+H]+) 280.1026, found 280.1018.
m/z calcd for C17H15N3NaO3 ([M+Na]+) 332.1006, found
332.0990.
(4‑Methoxyphenyl)[5‑(4‑nitrophenyl)‑1H‑1,2,3‑triazol‑4‑yl]‑
methanone (7f, C16H13N4O4) Brown solid; yield: 184.6 mg
(85%); m.p.: 172–175 °C; 1H NMR (300.13 MHz, CDCl3):
δ=8.27 (d, J=9.0 Hz, 2H, H-3″, 5″), 8.11 (d, J =9.0 Hz,
2H, H-2′, 6′), 8.04 (d, J = 9.0 Hz, 2H, H-2″, 6″), 6.98 (d,
J = 9.0 Hz, 2H, H-3′, 5′), 3.90 (s, 3H, 4′-OCH3) ppm; 13C
NMR (75.47 MHz, CDCl3): δ=174.2 (C=O), 164.3 (C-4′),
148.0 (C-4″), 146.2 (C-5), 138.7 (C-4), 135.9 (C-1′), 132.9
(C-2′, 6′), 129.6 (C-2″, 6″), 129.5 (C-1″), 123.6 (C-3″,
5″), 113.8 (C-3′, 5′), 55.6 (4′-OCH3) ppm; MS (ESI+):
m/z (%)=347 ([M+Na]+, 98); FT-MS (ESI): m/z calcd for
C16H13N4O4 ([M+H]+) 325.0931, found 325.0921.
[5‑(4‑Nitrophenyl)‑1H‑1,2,3‑triazol‑4‑yl]phenylmethanone
(7c, C15H11N4O3) Brown solid; yield: 126.2 mg (64%); m.p.:
198–200 °C; 1H NMR (300.13 MHz, CDCl3): δ=8.32 (dd,
J=2.2, 9.2 Hz, 2H, H-3″, 5″), 8.03–8.08 (m, 4H, H-2′, 6′,
2″, 6″), 7.71 (t, J=7.4 Hz, 1H, H-4′), 7.57 (t, J=7.6 Hz, 2H,
H-3′, 5′) ppm; 13C NMR (75.47 MHz, CDCl3): δ = 187.7
(C=O), 147.5 (C-4″), 144.9 (C-5), 136.9 (C-1′), 135.9
(C-1″), 133.6 (C-4′), 130.2 (C-2″, 6″), 129.7 (C-2′, 6′), 128.5
(C-3′, 5′), 123.6 (C-3″, 5″) ppm; MS (ESI+): m/z (%)=317
([M+Na]+, 12); FT-MS (ESI): m/z calcd for C15H11N4O3
([M+H]+) 295.0826, found 295.0818.
(4‑Nitrophenyl)(5‑phenyl‑1H‑1,2,3‑triazol‑4‑yl)methanone
(7g, C15H11N4O3) Brown solid; yield: 167.5 mg (85%);
m.p.: 136–138 °C; 1H NMR (300.13 MHz, CDCl3): δ=8.40
(m, 4H, H-2′, 3′, 5′, 6′), 7.94 (m, 2H, H-2″, 6″), 7.52 (m,
3H, H-3″, 4″, 5″) ppm; 13C NMR (125.77 MHz, CDCl3):
δ = 186.9 (C=O), 151.0 (C-4′), 147.2 (C-5), 143.6 (C-1′),
141.8 (C-4), 132.3 (C-2′, 6′), 130.4 (C-4″), 130.3 (C-1″),
129.8 (C-3″, 5″), 129.2 (C-2″, 6″), 124.0 (C-3′, 5′) ppm;
MS (ESI+): m/z (%) = 295 ([M+H]+, 12), 317 ([M+Na]+,
45); FT-MS (ESI): m/z calcd for C15H11N4O3 ([M+H]+)
295.0826, found 295.0818.
(4‑Methoxyphenyl)(5‑phenyl‑1H‑1,2,3‑triazol‑4‑yl)metha‑
none (7d, C16H13N3O2) Brown solid; yield: 127.2 mg
(68%); m.p.: 117–118 °C; 1H NMR (300.13 MHz, CDCl3):
δ=8.12 (brd, J=8.9 Hz, 2H, H-2′, 6′), 7.76–7.80 (m, 2H,
H-2″, 6″), 7.40–7.44 (m, 3H, H-3″, 4″, 5″), 6.95 (brd,
J = 8.9 Hz, 2H, H-3′, 5′), 3.88 (s, 3H, 4′-OCH3) ppm; 13C
NMR (125.77 MHz, CDCl3): δ=186.5 (C=O), 163.9 (C-4′),
144.7 (C-5), 141.5 (C-4), 132.9 (C-2′, 6′), 129.8 (C-1′),
129.3 (C-4″), 128.7 (C-3″, 5″), 128.5 (C-2″, 6″), 113.6
(C-3′, 5′), 55.5 (4′-OCH3) ppm; MS (ESI+): m/z (%)=280
([M+H]+, 40), 302 ([M+Na]+, 100); FT-MS (ESI): m/z
calcd for C16H13N3O2 ([M+H]+) 280.1026, found 280.1020.
[5‑(4‑Methoxyphenyl)‑1H‑1,2,3‑triazol‑4‑yl](4‑nitrophenyl)‑
methanone (7h, C16H13N4O4) Brown solid; yield: 71.7 mg
(33%) m.p.: 144–146 °C; 1H NMR (300.13 MHz, CDCl3):
δ = 8.33 (s, 4H, H-2′, 3′, 5′, 6′), 7.80 (d, J = 8.8 Hz, 2H,
H-2″, 6″), 7.01 (d, J = 8.8 Hz, 2H, H-3″, 5″), 3.87 (s, 3H,
4″-OCH3) ppm; 13C NMR (125.77 MHz, CDCl3): δ=185.7
(C=O), 161.2 (C-4″), 150.1 (C-4′), 146.3 (C-5), 142.3
(C-1′), 131.4 (C-2′, 6′), 130.4 (C-2″, 6″), 123.3 (C-3′, 5′),
119.4 (C-1″), 114.2 (C-3″, 5″), 55.4 (4″-OCH3) ppm; MS
(ESI+): m/z (%) = 347 ([M+Na]+, 98); FT-MS (ESI): m/z
calcd for C16H13N4O4 ([M+H]+) 325.0931, found 325.0921.
(4‑Methoxyphenyl)[5‑(4‑methoxyphenyl)‑1H‑1,2,3‑tria‑
zol‑4‑yl]methanone (7e, C17H15N3O3) Yellow solid; yield:
186.5 mg (90%); m.p.: 170–172 °C; 1H NMR (300.13 MHz,
CDCl3): δ = 7.82 (dd, J = 1.9, 9.0 Hz, 2H, H-2′, 6′), 7.47
(dd, J=1.9, 9.0 Hz, 2H, H-2″, 6″), 6.94 (dd, J=1.9, 9.0 Hz,
2H, H-3″, 5″), 6.91 (dd, J=1.9, 9.0 Hz, 2H, H-3′, 5′), 3.89
(s, 3H, 4′-OCH3), 3.86 (s, 3H, 4″-OCH3) ppm; 13C NMR
(75.47 MHz, CDCl3): δ=184.3 (C=O), 166.1 (C-4′), 162.1
(C-4″), 143.4 (C-5), 135.7 (C-4), 133.5 (C-2′, 6′), 130.5
(C-2″, 6″), 127.0 (C-1′), 115.1 (C-3″, 5″), 115.0 (C-1″),
114.6 (C-3′, 5′), 55.8 (4′-OCH3), 55.6 (4″-OCH3) ppm;
MS (ESI+): m/z (%) = 310 ([M+H]+, 60); FT-MS (ESI):
(4‑Nitrophenyl)[5‑(4‑nitrophenyl)‑1H‑1,2,3‑triazol‑4‑yl]‑
methanone (7i, C15H9N5O5) Brown oil; yield: 68.2 mg
1
(30%); H NMR (300.13 MHz, CDCl3): δ = 8.37 (br d,
J=8.9 Hz, 2H, H-3′, 5′), 8.34 (brd, J=8.9 Hz, 2H, H-3″, 5″),
8.32 (brd, J=8.9 Hz, 2H, H-2′, 6′), 8.13 (brd, J=8.9 Hz, 2H,
H-2″, 6″) ppm; 13C NMR (MHz, CDCl3): δ=185.6 (C=O),
153.1 (C-5), 150.4 (C-4′), 148.4 (C-4″), 141.7 (C-1′), 141.8
(C-4), 135.2 (C-1″), 131.2 (C-2′, 6′), 130.0 (C-3′, 5′), 123.5
(C-3″, 5″), 123.0 (C-2″, 6″) ppm; MS (ESI+): m/z (%)=340
([M+H]+, 12).
1 3

D. H. A. Rocha et al.
24. Astruc D, Liang L, Rapakousiou A, Ruiz J (2012) Acc Chem Res
45:630
Acknowledgements Thanks are due to FCT/MEC for the fnancial
support to the QOPNA research Unit (FCT UID/QUI/00062/2013),
through national founds and where applicable co-fnanced by the
FEDER, within the PT2020 Partnership Agreement, and to the Portu-
guese NMR Network. D. H. A. Rocha also thanks FCT for her Ph.D.
Grant (SFRH/BD/68991/2010).
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