Multicomponent azide-alkyne cycloaddition catalyzed by impregnated bimetallic nickel and copper on magnetite

Article abstract of DOI:10.1039/c4ra03149k

A new bimetallic catalyst derived from nickel and copper has been used successfully for the first time in the multicomponent reaction of terminal alkynes, sodium azide, and benzyl bromide derivatives. The presence of both metallic species on the surface of magnetite seems to have a positive and synergetic effect. The catalyst loading is the lowest ever published for a catalyst of copper anchored on any type of iron support. The catalyst could be easily removed from the reaction media just by magnetic decantation and it could be reused up to ten times without any negative effect on the initial results. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4ra03149k

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Multicomponent azide–alkyne cycloaddition
catalyzed by impregnated bimetallic nickel and
Cite this: RSC Adv., 2014, 4, 23943
copper on magnetite†
*
Juana M. Perez, Rafael Cano and Diego J. Ramon
´
´
A new bimetallic catalyst derived from nickel and copper has been used successfully for the first time in the
multicomponent reaction of terminal alkynes, sodium azide, and benzyl bromide derivatives. The presence
of both metallic species on the surface of magnetite seems to have a positive and synergetic effect. The
catalyst loading is the lowest ever published for a catalyst of copper anchored on any type of iron
support. The catalyst could be easily removed from the reaction media just by magnetic decantation and
it could be reused up to ten times without any negative effect on the initial results.
Received 8th April 2014
Accepted 21st May 2014
DOI: 10.1039/c4ra03149k
www.rsc.org/advances
the generalization of this approach for the synthesis of inter-
esting polyvalent structures. However, the use of a multicompo-
Introduction
nent approach, generating the azide derivative in situ by
reaction of sodium azide and the corresponding organic
reagent,9c,10b,d–f,11d,f,h,12f,h,14,15b,16 has permitted us to overcome this
problem. On the other hand, we have recently developed a new,
simple and robust method to immobilize different metal oxides17
onto magnetite,18 and we initially decided to apply the copper
impregnated on magnetite catalyst19 to the multicomponent
azide–alkyne cycloaddition reaction.
Although the 1,3-dipolar cycloaddition of azide derivatives and
alkynes dates back to the nineteenth century,1 the pioneer and
seminal works of the Medal2 and Sharpless3 groups on the
copper-catalyzed process were the denitive push for the blos-
soming of this process. This process allowed access to different
1,2,3-triazoles of great interest to different areas of chemistry
and pharmacy, in short reaction times, under mild conditions,
and as only one regioisomer.4
The tremendous success of the homogenous copper(I)
complexes as catalysts has eclipsed the activity of others, such
as those derived from ruthenium, platinum, palladium,5 silver6
or nickel,7 as well as the use of other heterogeneous catalysts.
However, very recently some heterogeneous catalysts have
emerged as an alternative. Thus, the particles of copper,8 or its
oxide derivatives,9 different copper salts supported on char-
coal,10 on organic materials,11 as well as on inorganic supports12
have been tested for this transformation, with copper loading of
these catalysts ranging from 0.5 to 12 mol%. Interestingly, some
of the inorganic supports were based on iron, which permitted
the development of magnetic catalyst and separation, as it
was for the case of copper supported on iron (5 mol%),13 cop-
perferrite (5 mol%),14 or ligand-graed copper on magnetite
(2 mol%).15
Results and discussion
Simple azide–alkyne cycloaddition
Although our ultimate goal was to get a heterogeneous and
recyclable catalyst for the multicomponent version of azide–
alkyne cycloaddition, the study was started with the standard
two-component reaction between ethynylbenzene (1a) and
(azidomethyl)benzene (2a) catalyzed by impregnated copper on
magnetite (Table 1).
Tꢀhe initial reaction was conducted in absence of catalyst at
110 C in water, obtaining aer 7 days a 1 : 1 mixture of both
possible isomers. Then, the reaction was repeated in the pres-
ence of copper catalyst in toluene at 70 ꢀC giving exclusively
1-benzyl-4-phenyl-1H-1,2,3-triazole (3a) in a modest yield (entry
2). Both the decrease and the increase of temperature led to the
formation of a mixture of regioisomers (entries 3 and 4). Then,
the inuence of solvent was examined, nding that the highest
yield was reached in water (entry 10). Under these conditions,
the role of magnetite support was studied and high activity of
the supposed inert material was found (entry 12).
The intrinsic instability of organic azides, mainly those of
low molecular weight, has been an important drawback in
´
´
´
´
Instituto de Sıntesis Organica (ISO), and Departamento de Quımica Organica,
Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain.
E-mail: djramon@ua.es; Fax: +35-965903549; Tel: +35-965903548
† Electronic supplementary information (ESI) available: Particle size distribution
for catalysts, XPS Data and TEM images of new Ni–Cu–Fe3O4 catalyst, as well as
copies of 1H and 13C-NMR for all compounds 3, 9, 11 and 12. See DOI:
10.1039/c4ra03149k
Once the activity of copper catalyst was examined, its recy-
cling was studied. Aer the rst trial, the magnetite was
collected with a magnet, washed with toluene and ethanol, and
dried. The recycled catalyst could be re-used three fold with
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problem of the multicomponent version,9c,10d,e,11d,h,12h,14,15b,16b,c
using benzyl bromide (5a), sodium azide (6) and ethy-
nylbenzene (1a) as reaction model (Table 2). The reaction in
water gave a mixture of expected heterocycle 3a together with its
regioisomer 4a (compare entry 1 in Table 2 and entry 9 in Table
1). This initial trial showed that the change from simple cyclo-
addition to the multicomponent reaction one was not so
simple. Thus, a new optimization process on this multicom-
ponent reaction was carried out, starting by studying the effect
of solvent (entries 1–8 in Table 2). The best result was obtained
in absence of solvent, but a small amount of the product arising
from homocoupling of terminal alkyne was found.19e The
optimal temperature seemed to be 50 ꢀC (entries 8–11), since at
higher temperatures different by-products were formed, and at
lower temperatures a modest yield was achieved. Finally, the
increase of amount of reagents, 5a and 6, increased the yield
(compare entry 12 in Table 2 with entry 9 in Table 1).
Although copper catalysts have been the most used, other
metal catalysts have also shown some activity for this reaction.
For this reason we tested a series of impregnated metal catalyst
in this multicomponent version (Table 3), starting from the
uncatalyzed reaction (entry 1). From all ductile metal oxide, only
nickel and copper catalysts showed activity (entries 2–14).
Then, a series of bimetallic derivatives were studied, nding
that Pd/Cu system19c could render the expected product 3a
(entry 15). Very recently, different bimetallic Ni–Cu/C composite
catalysts20 have been tested in the simple cycloaddition of
azides and terminal alkynes and these results prompted us to
prepare the corresponding bimetallic one impregnated on
magnetite. Its reaction gave the expected product with an
excellent result (entry 16). The decrease of the amount of Ni–Cu
Table 1 Optimization of cycloaddition reaction conditions
Entry
Solvent
T (ꢀC)
t (d)
Yielda 3a (4a) (%)
1b
2
3
4
5
6
7
8
9
H2O
110
70
25
110
70
70
70
70
70
70
70
70
7
2
2
2
2
2
2
2
2
1
2
1
46 (49)
58 (0)
35 (7)
73 (25)
43 (7)
52 (6)
15 (6)
33 (8)
50 (0)
94 (0)
73 (12)
82 (1)
PhMe
PhMe
PhMe
THF
CHCl3
MeCN
DMSO
MeOH
H2O
10
11
12c
H2O
a
Isolated yield aer column chromatography. b Reaction carried out in
absence of catalyst. c Reaction performed using only nanomagnetite (21
mol%).
similar results (82–78%). However, the yield dropped to 35% in
the forth use, keeping this level of results during the following
5 cycles (Fig. 1). The phenomenon of leaching was studied by
ICP-MS analysis of the resulting reaction solution mixture, and
1.1% of the initial amount of copper was detected (0.007% of
iron), which could explained the lost of activity. Moreover, the
TEM images of the recycled catalyst showed a small change in
copper particle size from 7.1 ꢁ 6.5 nm of the fresh prepared Table 2 Optimization of multicomponent cycloaddition process
catalyst to 6.4 ꢁ 5.2 nm for the recycled one, which would not
affect the reactivity of the recycled catalyst. Finally, it should be
pointed out that the BET surface area did not suffer a great
change, from 6.2 m2 gꢂ1 for the initial catalyst to 8.4 m2 gꢂ1 for
the used one, which is practically the same specic area.
Multicomponent cycloaddition processes
Yielda 3a (4a) (%)
Aer nding that copper catalyst was effective in the cycload-
dition between azides and terminal alkynes, we faced the
Entry
Solvent
T (ꢀC)
t (d)
1
2
3
4
5
6
7
8
H2O
PhMe
THF
CHCl3
MeCN
DMSO
MeOH
—
—
—
—
—
70
70
70
70
70
70
70
70
50
25
110
25
3
3
3
3
3
3
3
3
2
3
2
2
57 (13)
33 (0)
21 (4)
19 (1)
16 (0)
25 (3)
32 (25)
69b (0)
71 (0)
38 (0)
53b (6)
83 (0)
9
10
11
12c
a
b
Isolated yield aer column chromatography. 1,4-Diphenylbuta-1,3-
c
diyne was isolated in a 10%. Reaction performed using 2 equiv. of
compounds 5a and 6.
Fig. 1 Recycling of CuO–Fe3O4 catalyst for the cycloaddition.
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Table 3 Optimization of catalyst for multicomponent cycloaddition
improvement of the result obtained by the copper derivative
(compare entries 20, 22 and 24, 25, respectively).
The bimetallic Ni–Cu catalyst could be recycled and reused
tenfold, just by collection of the catalyst with a magnet, washing
with toluene and ethanol, and drying, without any depreciation
in its activity (Fig. 2).
The phenomenon of leaching was studied by ICP-MS analysis
of the resulting reaction solution mixture, and 1.1, and 0.2% of
the initial amount of copper, and nickel, respectively, was
detected (0.006% of iron). The TEM images of the recycled
catalyst showed a small change in the particle size from 3.1 ꢁ 1.7
nm of the freshly prepared catalyst to 4.7 ꢁ 2.4 nm for the
recycled one. Moreover, XPS data analysis of bimetallic catalyst
showed only NiO, CuO and Cu2O species (Fig. 3), which was
conrmed by Auger spectroscopy (see ESI†). However, the recy-
cled one showed the presence of Ni(OH)2 as well as Cu(OH)2.
These small changes, in particle size and the nickel species
seemed not to affect the activity of the bimetallic catalyst, since it
could be reused several times with similar activity.
Entry
Catalyst (mol%)
Yielda 3a (%)
1
2
3
4
5
6
7
8
—
0
0
0
0
5
83
0
0
0
0
0
0
0
b
Fe3O4 (21)
Fe3O4 (21)
c
CoO–Fe3O4 (1.4)
NiO–Fe3O4 (1.0)
CuO–Fe3O4 (0.9)
Ru2O3–Fe3O4 (1.3)
Rh2O3–Fe3O4 (0.4)
PdO–Fe3O4 (1.2)
AgO2–Fe3O4 (1.3)
OsO2–Fe3O4 (0.5)
IrO2–Fe3O4 (0.1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PtO–Fe3O4 (0.5)
Au2O3–Fe3O4 (0.1)
PdO/Cu–Fe3O4 (1.5/0.9)
NiO/Cu–Fe3O4 (0.9/0.9)
NiO/Cu–Fe3O4 (0.2/0.2)
NiO/Cu–Fe3O4 (1.8/1.8)
NiO–Fe3O4 (1.0) + CuO–Fe3O4 (0.9)
CuO (0.9)
NiO (0.9)
Cu(OH)2 (0.9)
Ni(OH)2 (0.9)
NiO (0.9) + CuO (0.9)
Ni(OH)2 (0.9) + Cu(OH)2 (0.9)
0
42
98
15
>99d
87
78
12
58
11
76
62
a
b
Isolated yield aer column chromatography. Powder < 5 mm.
Fig. 2 Recycling of NiO/Cu–Fe3O4 catalyst for the multicomponent
reaction.
c
Powder < 50 nm. d Reaction performed during 24 h.
catalyst had an important detrimental effect, meanwhile its
increase had a marginal benet (compare entries 16–18).
Faced with the excellent result obtained with the bimetallic
nickel–copper catalyst we wondered if the yield was a result of a
simple addition of two independent catalytic sites or was it the
result of some type of synergic effect. To answer that question,
the reaction was repeated using both catalysts (the copper and
the nickel one) with almost the same loading and the result
seemed to be the addition of the activity of both catalysts
(compare entries 5 and 6 with entry 19). Therefore, we believe
that the bimetallic catalyst develops a synergetic effect that
makes it superior to the addition of both parts, although the
nature of this positive interaction is unknown.
Finally, the unsupported metal catalysts were tested. Thus,
the reaction using CuO alone gave the expected product 3a with
a good result (Table 3, entry 20), meanwhile the related nickel
oxide gave a worse result (entry 21). When the reaction was
repeated with the corresponding metal hydroxide derivatives
the yields were slightly lower (entries 22 and 23). The equi-
Fig. 3 X-Ray photoelectron spectroscopy of the fresh NiO/Cu–Fe3O4
molecular mixture of both metallic catalysts did not show any catalyst.
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To know if the reaction took place by the leached copper or compound 3q in a modest yield (entry 17). However, it should be
nickel species to the organic medium, we performed the stan- pointed out that the reactions using less electrophilic reagents
dard multicomponent reaction (Table 3, entry 16). Aer that, such as aliphatic bromide (1-bromododecane) or benzyl chloride,
the catalyst was removed carefully by a magnet at high failed aer seven days under standard conditions, recovering
temperature, and washed with toluene. The solvents of the unchanged the starting alkyne, as well as in the case of using
above solution, without catalyst, were removed under low either an aliphatic substituted alkyne (oct-1-yne).
pressure and alkyne 1a, sodium azide (6) and 4-bromobenzyl
Then, the initial source of benzyl azide was tested (Scheme
alcohol were added to the above residue. The resulting mixture 1). The reaction with benzylic alcohols failed aer six days,
was heated again at 50 ꢀC for 24 h. The analysis of crude recovering unchanged the initial alkyne. The reaction also
mixture, aer hydrolysis, revealed the formation of compound failed using the silyl ether 7b. However, the reaction using
3a in 95% (catalyzed process) and product 3b in less than 1% benzyl mesylate gave a modest yield (35%) aer 2 days reaction
yield by GC-analysis (compare with entry 2 in Table 4). There- time. When the reaction time was increased up to 6 days a
fore, we could exclude that the nal leached copper–nickel reasonable yield was isolated (75%). When the reaction was
species were responsible for the reaction results under the performed with benzyl tosylate (7d) the result was very modest.
standard conditions.
The multicomponent reaction with symmetrical internal
Once the catalytic activity and the recyclability of bimetallic alkynes 8 gave the expected compound 9 with very modest yield
catalyst were proved, the scope of the reaction was tested (Scheme 2). This result highlighted the possible selectivity of
(Table 4). The reaction gave excellent results independently of catalyst, and in order to conrm this, the reaction of benzyl
substituent position on the aromatic ring of the bromide 5 bromide (5a, 2 equiv.), sodium azide (6, 2 equiv.), ethy-
(entries 2–4). The electronic nature of substituent on the nylbenzene (1a, 1 equiv.) and 1,2-diphenylethyne (8a, 1 equiv.)
aromatic ring of the bromide 5 seemed not to have inuenced was performed under standard conditions, nding exclusively
on the results (compare entries 1–7), since the results disagrees the compound 3a (94%) from the analysis of crude mixture.
with the Hammett constants. Also, the reaction was accom-
Once the scope of the reaction was studied, we faced the
plished with akynes 1 with different groups in the aromatic problem of reaction sequentiality. For this proposal, we carried
ring, with no clear correlation of the reached yields with the the reaction with the dibromide derivative 10, and a double
electronic nature of substituents (entries 8–16). The reaction amount of sodium azide (6), obtaining aer six days the azide 11
with 2-(bromomethyl)isoindoline-1,3-dione gave the expected with a moderate yield (Scheme 3).
The GC-MS analysis of crude mixture did not show the
presence of corresponding bis-triazole, with the relate bis-azide
derivative being the main by-product. The isolated azide 11 was
submitted to another cycloaddition process, yielding the
Table 4 Multicomponent cycloaddition
unsymmetrical bis-triazole derivative 12 with good yield. This
approach highlights the possibilities of the catalyst in the
synthesis of different substituted triazoles.
Entry
R1
R2
No
Yielda (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
98
4-BrC6H4
3-BrC6H4
2-BrC6H4
2-MeC6H4
3-MeC6H4
3,5-(MeO)2C6H3
Ph
4-BrC6H4
Ph
Ph
3-MeC6H4
Ph
Ph
3-BrC6H4
3-MeC6H4
Ph
>99
>99
>99b
59b
50
Scheme 1 Multicomponent cycloaddition with benzyl derivatives.
89
4-ClC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-BrC6H4
4-MeOC6H4
3-MeC6H4
3-MeC6H4
3-MeC6H4
C6H4(CO)2N
80b
>99
45b
42b
90
9
10
11
12
13
14
15
16
17
42b
55b
86
49
37b
a
b
Isolated yield aer column chromatography. Reaction performed
during 4 days.
Scheme 2 Multicomponent cycloaddition with internal alkynes.
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on a JASCO 4100LE (Pike Miracle ATR) spectrophotometer.
Mass spectra (EI) were obtained at 70 eV on a Himazdu QP-5000
spectrometer, giving fragment ions in m/z with relative inten-
sities (%) in parentheses. The chromatographic analyses (GLC)
were determined with a Hewlett Packard HP-5890 instrument
equipped with a ame ionization detector and 12 m HP-1
capillary column (0.2 mm diam., 0.33 mm lm thickness, OV-1
stationary phase), using nitrogen (2 mL minꢂ1) as a carrier gas,
Tinjector ¼ 275 ꢀC, Tdetector ¼ 300 ꢀC, Tcolumn ¼ 60 ꢀC (3 min) and
60–270 ꢀC (15 ꢀC minꢂ1), P ¼ 40 kPa. Thin layer chromatography
(TLC) was carried out on Schleicher & Schuell F1400/LS 254
plates coated with a 0.2 mm layer of silica gel; detection by
UV254 light, staining with phosphomolybdic acid [25 g phos-
phomolybdic acid, 10 g Ce(SO4)2$4H2O, 60 mL of concentrated
H2SO4 and 940 mL H2O]. Column chromatography was per-
formed using silica gel 60 of 40–63 mesh. All reagents were
commercially available (Acros, Aldrich, Fluorochem) and were
used as received. The ICP-MS analyses were carried out on a
Thermo Elemental VGPQ-ExCell spectrometer. The Elemental
Analysis was performed on a Elemental Microanalyzer Thermo
Finningan Flash 1112 Series.
Scheme 3 Sequential multicycloaddition process.
General procedure for the preparation of NiO/Cu–Fe3O4
Conclusions
catalyst
To a stirred solution of CuCl2 (1 mmol, 130 mg) and NiCl2$H2O
(1 mmol, 130 mg) in deionized water (120 mL) was added
commercially available Fe3O4 (4 g, 17 mmol, powder < 5 mm,
BET area: 9.86 m2 gꢂ1). Aer 10 minutes at room temperature,
the mixture was slowly basied with NaOH (1 M) until pH
around 13. The mixture was stirred during one day at room
temperature in air. Aer that, the catalyst was ltered and
washed several times with deionized water (3 ꢃ 10 mL). The
We have demonstrated that the new bimetallic catalyst derived
from nickel and copper supported on magnetite was a good
catalyst for the multicomponent reaction of terminal alkynes,
sodium azide, and benzyl bromide derivatives. The presence of
both metallic species on the surface of magnetite seemed to
have a positive and synergetic effect. The catalyst loading was
the lowest ever published for a catalyst of copper anchored on
any type of iron support, and being in the lowest level for any
type of the heterogeneous ones. The catalyst could be easily
removed from the reaction media just by magnetic decantation,
and it could be reused up to ten times without any negative
effect on the initial results.
ꢀ
solid was dried at 100 C during 24 h in a standard glassware
oven, obtaining thereaer the expected catalyst.
General procedures for the preparation of the products
To a stirred solution of sodium azide (6, 2 mmol) and benzyl
halide (5, 2 mmol) were added NiO/Cu–Fe3O4 (50 mg, 0.9 mol%
of Ni and 0.9 mol% of Cu) and the corresponding alkyne (1 or 8,
Experimental
General
ꢀ
1 mmol). The resulting mixture was stirred at 50 C until the
XPS analyses were carried out on a VG-Microtech Mutilab. XRD end of the reaction. The catalyst was removed by a magnet and
analyses were obtained on a BRUKER D-8 ADVANCE diffrac- the resulting mixture was quenched with deionized water and
¨
tometer with Goebel mirror, with a high temperature chamber extracted with AcOEt (3 ꢃ 5 mL). The organic phases were dried
ꢀ
(up to 900 C), with a X-ray generator KRISTALLOFLEX K 760- over MgSO4, followed by evaporation under reduced pressure to
80F (3 kW, 20–60 kV and 5–80 mA). TEM images were obtained remove the solvent. The product was usually puried by chro-
on a JEOL, model JEM-2010 equipped with an X-ray detector matography on silica gel (hexane–ethyl acetate) to give the
OXFORD INCA Energy TEM 100 for microanalysis (EDS). XRF corresponding products 3 or 9 (see ESI†). The chromatographic
analyses were obtained on a PHILIPS MAGIX PRO (PW2400) analyses were determined with a ame ionization detector and
X-ray spectrometer equipped with a rhodium X-ray tube and a a 30 m capillary column (0.32 mm diam. 0.25 mm lm thickness,
beryllium window. BET isotherms were carried out on a HP-5 stationary phase), using nitrogen (2 mL minꢂ1) as carrier
ꢀ
AUTOSORB-6 (Quantachrome), using N2. Melting points were gas, P ¼ 10 psi, T(injector) ¼ 270 C and T(detector) ¼ 300 ꢀC; tR
obtained with a Reichert Thermovar apparatus. NMR spectra values are given under these conditions. Physical and spectro-
were recorded on a Bruker AC-300 (300 MHz for 1H and 75 MHz scopic data, only for new compounds, follow:
for 13C) using CDCl3 as a solvent and TMS as internal standard
1-Benzyl-4-phenyl-1H-1,2,3-triazole (3a).10e White solid; m.p.
for 1H and 13C; chemical shis are given in d (parts per million) 104–108 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3021, 2920, 1450, 1223;
and coupling constants (J) in Hertz. FT-IR spectra were obtained 1H NMR (300 MHz, CDCl3): d 5.57 (s, 2H), 7.3–7.45 (m, 8H), 7.66
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(s, 1H), 7.75–7.8 (m, 2H); 13C NMR (75 MHz, CDCl3): d 54.2, 74%), 281 (14), 266 (41), 252 (10), 239 (32), 236 (19), 209 (21), 208
119.4, 125.7 (2C), 128.0 (2C), 128.1, 128.8 (3C), 129.1 (2C), 130.5, (15), 207 (61), 164 (36), 152 (13), 151 (100), 117 (12), 116 (100), 91
134.7, 148.2; EI-MS m/z: 235 (M+, 22%), 207 (14), 206 (71), 180 (19), 89 (21), 78 (11), 77 (18), 65 (11).
(13), 179 (11), 116 (100), 104 (21), 91 (84), 89 (29), 65 (20), 63 (11).
1-Benzyl-4-(4-chlorophenyl)-1H-1,2,3-triazole (3h).15b White
1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (3b).21 White solid; m.p. 125–127 C (hexane–AcOEt); IR (cmꢂ1): 3060, 1481,
ꢀ
solid; m.p. 150–152 C (hexane–AcOEt); IR (cmꢂ1): 3082, 1489, 1222, 1069; H NMR (300 MHz, CDCl3): d 5.57 (s, 2H), 7.3–7.4
1
ꢀ
1
1221, 1073; H NMR (300 MHz, CDCl3): d 5.5 (s, 2H), 7.17 (d, (m, 7H), 7.65 (s, 1H), 7.72 (d, 3J(H,H) ¼ 8.7 Hz, 2H); 13C NMR (75
3J(H,H) ¼ 8.4 Hz, 2H), 7.3–7.35 (m, 1H), 7.4–7.45 (m, 2H), 7.52 MHz, CDCl3): d 54.3, 60.4, 119.5, 126.9 (2C), 128.1 (2C), 128.8,
(d, 3J(H,H) ¼ 8.4 Hz, 2H), 7.7 (s, 1H), 7.8–7.85 (m, 2H); 13C NMR 129.0 (2C), 129.2 (2C), 133.9, 134.5, 147.1; EI-MS m/z: 271 (M+ +
(75 MHz, CDCl3): d 53.5, 119.4, 122.9, 125.7 (2C), 128.3, 128.8 2, 9%), 269 (M+, 26%), 242 (23), 241 (15), 240 (70), 207 (14), 206
(2C), 129.6 (2C), 130.3, 132.3 (2C), 133.6, 148.4; EI-MS m/z: 315 (27), 179 (29), 152 (36), 151 (10), 150 (100), 125 (10), 123 (25), 104
(M+ + 2, 9%), 313 (M+, 10%), 286 (16), 284 (17), 206 (20), 171 (24), (20), 102 (11), 91 (93), 65 (22).
169 (25), 116 (100), 90 (19), 89 (28).
1-(4-Bromobenzyl)-4-(4-chlorophenyl)-1H-1,2,3-triazole (3i).
1-(3-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (3c).14 White White solid; m.p. 146–150 ꢀC (hexane–AcOEt); IR (cmꢂ1): 1487,
solid; m.p. 85–87 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3084, 1460, 1456, 1227, 1092, 1072; H NMR (300 MHz, CDCl3): d 5.53 (s,
1
1432, 1222, 1046; 1H NMR (300 MHz, CDCl3): d 5.54 (s, 2H), 7.2– 2H), 7.18 (d, J(H,H) ¼ 8.4 Hz, 2H), 7.36 (d, J(H,H) ¼ 8.5 Hz,
7.25 (m, 2H), 7.3–7.35 (m, 1H), 7.4–7.45 (m, 2H), 7.45–7.5 (m, 2H), 7.51 (d, 3J(H,H) ¼ 8.4 Hz, 2H), 7.66 (s, 1H), 7.72 (d, 3J(H,H)
2H), 7.71 (s, 1H), 7.8–7.85 (m, 2H); 13C NMR (75 MHz, CDCl3): d ¼ 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 53.5, 119.5, 123.0,
53.4, 119.5, 123.1, 125.7 (2C), 126.5, 128.3, 128.8 (2C), 130.2, 126.9 (2C), 128.8, 129.0 (2C), 129.6 (2C), 132.3 (2C), 133.5, 133.9,
130.7, 130.9, 131.9, 136.8, 148.3; EI-MS m/z: 315 (M+ + 2, 8%), 147.3; EI-MS m/z: 349 (M+ + 2, 17%), 347 (M+, 13%), 320 (19), 318
313 (M+, 8%), 286 (14), 284 (14), 206 (21), 171 (22), 169 (23), 116 (14), 240 (26), 207 (10), 171 (27), 169 (29), 152 (33), 151 (10), 150
3
3
(100), 90 (20), 89 (29).
(100), 123 (16), 90 (19), 89 (16); HRMS (ESI): m/z calcd for
1-(2-Bromobenzylꢀ)-4-phenyl-1H-1,2,3-triazole (3d).14 White
C
15H11BrClN3: 346.9825; found: 346.9828.
1-Benzyl-4-(2-chloropehnyl)-1H-1,2,3-triazole (3j).22 White
solid; m.p. 101–103 C (hexane–AcOEt); IR (cmꢂ1): 3051, 1459,
1430, 1220, 1043; 1H NMR (300 MHz, CDCl3): d 5.7 (s, 2H), 7.15– solid; m.p. 77–78 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3083, 1461,
1
7.25 (m, 2H), 7.3–7.35 (m, 2H), 7.4–7.45 (m, 2H), 7.62 (dd, 1227, 1056; H NMR (300 MHz, CDCl3): d 5.61 (s, 2H), 7.2–7.45
4
3
4
3J(H,H) ¼ 7.9 Hz, J(H,H) ¼ 1.0 Hz, 1H), 7.78 (s, 1H), 7.82 (d, (m, 8H), 8.12 (s, 1H), 8.22 (dd, J(H,H) ¼ 7.8 Hz, J(H,H) ¼ 1.8
3J(H,H) ¼ 7.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 53.8, 119.8, Hz, 2H); 13C NMR (75 MHz, CDCl3): d 54.2, 123.1, 127.1, 127.9
123.4, 125.7 (2C), 128.2 (2C), 128.8 (2C), 130.1, 130.2, 130.4, (2C), 128.7, 129.0, 129.1 (2C), 129.2, 129.8, 130.1, 131.1, 134.6,
133.2, 134.2, 148.1; EI-MS m/z: 315 (M+ + 2, 12%), 313 (M+, 11%), 144.4; EI-MS m/z: 271 (M+ + 2, 6%), 269 (M+, 17%), 242 (12), 240
208 (12), 207 (59), 206 (93), 184 (11), 171 (31), 169 (32), 117 (11), (36), 206 (40), 179 (30), 152 (28), 150 (87), 123 (14), 104 (26), 102
116 (100), 103 (13), 91 (21), 90 (24), 89 (34), 63 (10).
(10), 91 (100), 65 (19).
1-(2-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (3e).12h White
1-Benzyl-4-(4-bromophenyl)-1H-1,2,3-triazole (3k).6b White
solid; m.p. 98–99 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3096, 1462, solid; m.p. 143–145 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3070, 1477,
1216; 1H NMR (300 MHz, CDCl3): d 2.31 (s, 3H), 5.6 (s, 2H), 7.2– 1449, 1222, 1050; 1H NMR (300 MHz, CDCl3): d 5.56 (s, 2H), 7.3–
7.25 (m, 3H), 7.3–7.35 (m, 2H), 7.35–7.45 (m, 2H), 7.54 (s, 1H), 7.4 (m, 5H), 7.5–7.55 (m, 2H), 7.65–7.7 (m, 3H); 13C NMR (75
7.75–7.8 (m, 2H); 13C NMR (75 MHz, CDCl3): d 19.0, 52.5, 119.2, MHz, CDCl3): d 54.3, 119.5, 122.0, 127.2 (2C), 128.1 (2C), 128.8,
125.6 (2C), 126.7, 128.1, 128.8 (2C), 129.2, 129.4, 130.5, 131.1, 129.1 (2C), 129.4, 131.9 (2C), 134.4, 147.1; EI-MS m/z: 315 (M+ + 2,
132.5, 137.0, 148.0; EI-MS m/z: 249 (M+, 22%), 220 (35), 207 (17), 23%), 313 (M+, 24%), 287 (10), 286 (54), 285 (11), 284 (53), 207
206 (11), 118 (31), 117 (39), 116 (100), 105 (63), 104 (10), 103 (15), (12), 206 (40), 204 (11), 196 (73), 194 (75), 179 (32), 178 (12), 169
89 (23), 79 (14), 77 (21).
(13), 167 (13), 115 (11), 104 (18), 102 (12), 91 (100), 88 (14), 65 (19).
1-(3-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (3f).21 White
4-(4-Bromophenyl)-1-(3-methylbenzyl)-1H-1,2,3-triazole (3l).
solid; m.p. 95–96 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3089, 1464, White solid; m.p. 127–128 C (hexane–AcOEt); IR (cmꢂ1): 3016,
ꢀ
1222; 1H NMR (300 MHz, CDCl3): d 2.34 (s, 3H), 5.52 (s, 2H), 7.1– 1450, 1225, 1069; 1H NMR (300 MHz, CDCl3): d 2.35 (s, 3H), 5.53
7.2 (m, 3H), 7.25–7.45 (m, 4H), 7.66 (s, 1H), 7.8–7.85 (m, 2H); 13
C
(s, 2H), 7.11 (d, 3J(H,H) ¼ 7.3 Hz, 2H), 7.18 (d, 3J(H,H) ¼ 7.3 Hz,
NMR (75 MHz, CDCl3): d 21.3, 54.2, 119.5, 125.1, 125.6 (2C), 1H), 7.28 (d, 3J(H,H) ¼ 7.3 Hz, 1H), 7.52 (d, 3J(H,H) ¼ 8.6 Hz, 2H),
128.1, 128.7, 128.8 (2C), 129.0, 129.5, 130.5, 134.5, 139.0, 148.1; 7.65 (s, 1H), 7.67 (d, J(H,H) ¼ 8.6 Hz, 2H); 13C NMR (75 MHz,
3
EI-MS m/z: 249 (M+, 29%), 221 (13), 220 (61), 206 (36), 179 (20), CDCl3): d 21.3, 54.3, 119.5, 122.0, 125.2, 127.2 (2C), 128.8, 129.0,
118 (14), 117 (17), 116 (100), 105 (66), 103 (14), 89 (24), 79 (13), 77 129.5, 129.6, 131.9 (2C), 134.3, 139.1, 147.1; EI-MS m/z: 329 (M+ +
(20).
2, 24%), 327 (M+, 22%), 300 (34), 298 (36), 286 (27), 284 (26), 220
1-(3,5-Dimethoxybenzyl)-4-phenyl-1H-1,2,3-triazole (3g).12h (21), 207 (22), 196 (70), 194 (76), 193 (27), 178 (12), 169 (12), 167
White solid; m.p. 90–92 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3086, (12), 118 (18), 117 (11), 115 (15), 105 (100), 103 (20), 102 (14), 88
1
1610, 1197; H NMR (300 MHz, CDCl3): d 3.76 (s, 6H), 5.49 (s, (15), 79; elemental analysis calcd for C16H14BrN3: C ¼ 58.55; H ¼
2H), 6.44 (s, 3H), 7.3–7.35 (m, 1H), 7.35–7.4 (m, 2H), 7.68 (s, 1H), 4.30; N ¼ 12.80; found: C ¼ 58.50; H ¼ 4.29; N ¼ 12.69.
7.75–7.8 (m, 2H); 13C NMR (75 MHz, CDCl3): d 54.2, 55.4 (2C),
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole
(3m).15b
100.4, 106.0 (2C), 119.5, 125.6 (2C), 128.1, 128.8 (2C), 130.5, White solid; m.p. 135–136 ꢀC (hexane–AcOEt); IR (cmꢂ1):
136.7, 148.2, 161.2 (2C); EI-MS m/z: 296 (M+ + 1, 13%), 295 (M+, 1455, 1250; 1H NMR (300 MHz, CDCl3): d 3.82 (s, 3H), 5.55
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(s, 2H), 6.93 (d, J(H,H) ¼ 8.9 Hz, 2H), 7.25–7.4 (m, 5H), 7.58 3H), 1.25–1.45 (m, 4H), 1.50–1.7 (m, 4H), 2.55 (t, J(H,H) ¼ 7.6
(s, 1H), 7.72 (d, 3J(H,H) ¼ 8.9 Hz, 2H); 13C NMR (75 MHz, Hz, 2H), 2.67 (t, 3J(H,H) ¼ 7.6 Hz, 2H), 5.39 (s, 2H), 7.0–7.1 (m,
CDCl3): d 54.1, 55.3, 114.2 (2C), 118.6, 123.2, 127.0 (2C), 128.0 6H), 7.2–7.25 (m, 5H), 7.45–7.5 (m, 2H); 13C NMR (75 MHz,
(2C), 128.7, 129.1 (2C), 134.7, 148.0, 159.5; EI-MS m/z: 266 (M+ CDCl3): d 13.9, 14.0, 22.3 (2C), 33.3, 35.3, 35.5, 51.9, 125.1, 126.5
+ 1, 6%), 265 (M+, 35%), 237 (21), 236 (100), 222 (17), 210 (10), (2C), 127.0, 127.5 (2C), 128.0, 128.4 (2C), 128.6 (2C), 129.1 (2C),
209 (20), 206 (19), 194 (10), 193 (10), 179 (16), 160 (11), 146 129.9 (2C), 133.6, 135.5, 142.4, 144.4, 144.5; EI-MS m/z: 423 (M+,
(82), 119 (29), 91 (63), 89 (15), 76 (13), 65 (24).
1-Benzyl-4-(m-tolyl)-1H-1,2,3-triazole (3n).22 White solid; m.p. (72), 209 (13), 208 (18), 207 (100); elemental analysis calcd for
145–146 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3031, 1454, 1220; 1H
29H33N3: C ¼ 82.23; H ¼ 7.85; N ¼ 9.92; found: C ¼ 82.26; H ¼
0%), 361 (16), 360 (69), 359 (24), 328 (13), 283 (18), 282 (20), 281
C
NMR (300 MHz, CDCl3): d 2.38 (s, 3H), 5.58 (s, 2H), 7.12 (d, 7.75; N ¼ 9.89.
3J(H,H) ¼ 7.6 Hz, 1H), 7.25–7.45 (m, 6H), 7.58 (d, 3J(H,H) ¼ 7.6
1-(3-Bromobenzyl)-4,5-diphenyl-1H-1,2,3-triazole (9c). White
Hz, 1H), 7.65–7.7 (m, 2H); 13C NMR (75 MHz, CDCl3): d 21.4, solid; m.p. 70–73 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3054, 1572,
54.2, 119.4, 122.8, 126.3, 128.0 (2C), 128.7, 128.8, 128.9, 129.1 1241; 1H NMR (300 MHz, CDCl3): d 5.37 (s, 2H), 6.97 (d, 3J(H,H)
(2C), 130.3, 134.7, 138.5, 148.3; EI-MS m/z: 249 (M+, 25%), 221 ¼ 7.7 Hz, 1H), 7.1–7.15 (m, 4H), 7.2–7.3 (m, 3H), 7.35–7.6 (m,
(13), 220 (58), 206 (10), 179 (12), 131 (11), 130 (100), 104 (13), 103 6H); 13C NMR (75 MHz, CDCl3): d 51.4, 122.7, 126.2, 126.6 (2C),
(14), 91 (70), 77 (14), 65 (14).
127.6 (2C), 127.8, 128.4 (2C), 129.3 (2C), 129.9, 130.0 (2C), 130.3,
1-(3-Bromobenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (3o).6b White 130.7, 131.4, 133.8, 137.3, 144.6; EI-MS m/z: 391 (M+ + 2, 6%),
solid; m.p. 90–93 ꢀC (hexane–AcOEt); IR (cmꢂ1): 3036, 1429, 389 (M+, 6%), 193 (15), 192 (100), 165 (28), 89 (15); elemental
1
1223, 1084; H NMR (300 MHz, CDCl3): d 2.35 (s, 3H), 5.48 (s, analysis calcd for C21H16BrN3: C ¼ 64.63; H ¼ 4.13; N ¼ 10.77;
2H), 7.1–7.3 (m, 4H), 7.4–7.45 (m, 2H), 7.57 (d, 3J(H,H) ¼ 7.8 Hz, found: C ¼ 64.65; H ¼ 4.17; N ¼ 10.69.
1H), 7.65 (s, 1H), 7.7 (s, 1H); 13C NMR (75 MHz, CDCl3): d 21.3,
1-(20-(Azidomethyl)-[1,10-biphenyl]-2-yl)-4-phenyl-1H-1,2,3-
53.2, 119.5, 122.6, 122.9, 126.2, 126.4, 128.6, 128.9, 130.1, 130.5, triazole (11). Colorless oil; IR (cmꢂ1): 2092, 1242; 1H NMR (300
130.7, 131.7, 136.8, 138.4, 148.3; EI-MS m/z: 329 (M+ + 2, 11%), MHz, CDCl3): d 3.95–4.05 (m, 2H), 5.25–5.35 (m, 2H), 7.15–7.2
327 (M+, 12%), 300 (18), 298 (17), 220 (18), 207 (39), 171 (24), 169 (m, 1H), 7.2–7.3 (m, 3H), 7.35–7.5 (m, 8H), 7.7–7.8 (m, 2H); 13
C
(22), 131 (11), 130 (100), 103 (814), 90 (14), 89 (13).
NMR (75 MHz, CDCl3): d 51.7, 52.3, 119.7, 125.5 (2C), 128.0,
1-(3-Methylbenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (3p). White 128.4 (2C), 128.5, 128.6, 128.7 (2C), 128.9, 129.6, 129.9, 130.1,
solid; m.p. 127–128 C (hexane–AcOEt); IR (cmꢂ1): 3017, 1446, 132.9, 133.5, 139.1 (2C), 147.5; EI-MS m/z: 194 (M+ ꢂ 172, 16%),
ꢀ
1220; 1H NMR (300 MHz, CDCl3): d 2.34 (s, 3H), 2.37 (s, 3H), 5.52 193 (100), 192 (28), 166 (14), 165 (56), 164 (10), 163 (10);
(s, 2H), 7.1–7.2 (m, 4H), 7.25–7.3 (m, 2H), 7.57 (d, 3J(H,H) ¼ 7.8 elemental analysis calcd for C22H18N6: C ¼ 72.11; H ¼ 4.95; N ¼
Hz, 1H), 7.64 (s, 1H), 7.66 (s, 1H); 13C NMR (75 MHz, CDCl3): d 22.94; found: C ¼ 72.12; H ¼ 4.98; N ¼ 22.98.
21.3, 21.4, 54.2, 119.4, 122.7, 125.1, 126.3, 128.6, 128.7, 128.8,
4-(4-Methoxyphenyl)-1-((20-((4-phenyl-1H-1,2,3-triazol-1-yl)-
129.0, 129.5, 130.4, 134.6, 138.4, 139.0, 148.2; EI-MS m/z: 264 methyl)-[1,10-biphenyl]-2-yl)methyl)-1H-1,2,3-triazole (12). Pale
(M+ + 1, 7%), 263 (M+, 35%), 235 (14), 234 (62), 220 (41), 207 (18), yellow oil; IR (cmꢂ1): 1245; 1H NMR (300 MHz, CDCl3): d 3.83 (s,
193 (18), 131 (10), 130 (100), 118 (15), 105 (62), 103 (22), 79 (10), 3H), 5.1–5.25 (m, 2H), 5.3–5.35 (m, 2H), 6.9–6.95 (m, 2H), 7.25–
77 (25); HRMS (ESI): m–z calcd for C17H17N3 263.1422; found: 7.3 (m, 3H), 7.3–7.45 (m, 9H), 7.47 (s, 1H), 7.6–7.65 (m, 2H), 7.7–
263.1414.
7.75 (m, 2H); 13C NMR (75 MHz, CDCl3): d 51.8, 55.3, 60.3, 114.2
2-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)isoindoline-1,3-dione (2C), 114.5, 119.5, 120.4, 123.0, 125.6 (2C), 126.9 (2C), 128.1,
(3q). White solid; m.p. 186–188 ꢀC (hexane–AcOEt); IR (cmꢂ1): 128.6 (2C), 128.7 (2C), 128.8, 129.1, 129.9, 130.0, 130.1, 130.3,
1715; 1H NMR (300 MHz, CDCl3): d 6.26 (s, 2H), 7.25–7.4 (m, 3H), 133.3 (2C), 138.6 (2C), 147.4 (2C), 159.6; EI-MS m/z: 499 (M+ + 1,
7.75–7.85 (m, 4H), 7.9–7.95 (m, 2H), 8.11 (s, 1H); 13C NMR (75 5%), 498 (M+, 14%), 339 (11), 325 (15), 324 (13), 309 (11), 295
MHz, CDCl3): d 49.7, 120.5, 124.1 (2C), 125.8 (2C), 128.3, 128.8 (16), 294 (15), 292 (10), 283 (14), 282 (62), 180 (27), 179 (100), 178
(2C), 130.1, 131.4 (2C), 134.9 (2C), 148.4, 166.5 (2C); EI-MS m/z: (61), 166 (10), 165 (36), 146 (16), 133 (12), 132 (11), 116 (19), 89
304 (M+, 31%), 281 (11), 248 (10), 208 (10), 207 (40), 161 (11), 160 (10); elemental analysis calcd for C31H26N6O: C ¼ 74.68; H ¼
(100), 133 (15), 116 (31), 104 (16), 77 (15), 76 (14); elemental 5.26; N ¼ 16.86; found: C ¼ 74.69; H ¼ 5.28; N ¼ 16.87.
analysis calcd for C17H12N4O2: C ¼ 67.10; H ¼ 3.97; N ¼ 18.41;
found: C ¼ 67.11; H ¼ 3.96; N ¼ 18.42.
1-Benzyl-4,5-diphenyl-1H-1,2,3-triazole (9a).23 White solid;
Acknowledgements
m.p. 109–110 C (hexane–AcOEt); IR (cmꢂ1): 3058, 1449, 1246;
ꢀ
This work was supported by the current Spanish Ministerio de
1H NMR (300 MHz, CDCl3): d 5.41 (s, 2H), 7.0–7.05 (m, 2H), 7.1–
7.15 (m, 2H), 7.2–7.3 (m, 6H), 7.4–7.5 (m, 3H), 7.55–7.6 (m, 2H);
13C NMR (75 MHz, CDCl3): d 52.0, 126.7 (2C), 127.5 (2C), 127.7,
127.8, 128.1, 128.4 (2C), 128.7 (2C), 129.1 (2C), 129.6, 130.1 (2C),
130.9, 133.9, 135.3, 144.5; EI-MS m/z: 311 (M+, 17%), 193 (16),
192 (100), 165 (23), 91 (75), 89 (16).
´
Economıa y Competitividad (CTQ2011-24151) and University of
Alicante. J.M.P. thanks to M.E.C. for a fellowship through the
FPI program. We gratefully acknowledge the polishing of our
English by Mrs Oriana C. Townley.
1-Benzyl-4,5-bis(4-butylphenyl)-1H-1,2,3-triazole (9b). Pale
yellow oil; IR (cmꢂ1): 3030, 1455, 1245; 1H NMR (300 MHz,
CDCl3): d 0.89 (t, 3J(H,H) ¼ 7.3 Hz, 3H), 0.97 (t, 3J(H,H) ¼ 7.3 Hz,
Notes and references
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