A straightforward and sustainable synthesis of 1,4-disubstituted 1,2,3-triazoles: Via visible-light-promoted copper-catalyzed azide-alkyne cycloaddition (CuAAC)

Article abstract of DOI:10.1039/c7ra06390c

A simple and green synthesis of 1,4-disubstituted 1,2,3-triazoles through the effective reduction of copper(ii) assisted by organic dyes and promoted by visible light was developed. This reaction was performed under very mild conditions, using water as solvent, under a non-inert atmosphere, with low catalyst precursor loading, and in the absence of any additive. Copper and solvent recycling was successfully achieved at least three times without loss of efficiency. In addition, a safer one-step one-pot procedure was designed with very good yield.

Full text of DOI:10.1039/c7ra06390c

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A straightforward and sustainable synthesis of 1,4-
disubstituted 1,2,3-triazoles via visible-light-
promoted copper-catalyzed azide–alkyne
cycloaddition (CuAAC)†
Cite this: RSC Adv., 2017, 7, 33967
*
Luciana C. Schmidt
Willber D. Castro-Godoy,
Adrian A. Heredia,
´
*
and Juan E. Arguello
¨
A simple and green synthesis of 1,4-disubstituted 1,2,3-triazoles through the effective reduction of
copper(II) assisted by organic dyes and promoted by visible light was developed. This reaction was
performed under very mild conditions, using water as solvent, under a non-inert atmosphere, with low
catalyst precursor loading, and in the absence of any additive. Copper and solvent recycling was
successfully achieved at least three times without loss of efficiency. In addition, a safer one-step one-pot
procedure was designed with very good yield.
Received 7th June 2017
Accepted 28th June 2017
DOI: 10.1039/c7ra06390c
rsc.li/rsc-advances
It is widely demonstrated that Cu(I) is the catalytically active
species which leads to the exclusive formation of 1,4-disubsti-
tuted 1,2,3-triazole in CuAAC reactions.13 Several copper sources
Introduction
Over the past decades, interest in the synthesis of 1,2,3-triazoles
has signicantly increased. Although these ve-membered
heterocycles are not normally found in nature, several and
interesting biological activities have been attributed to them.1
They are stable against numerous reaction conditions, such as
oxidation, hydrolysis and reduction, turning them into an
amide mimetic group.2 On the other hand, they can interact
with molecules through hydrogen bonding and dipole–dipole
interactions.3 Due to these particular properties, they are
increasingly employed in several areas of chemistry such as new
drug discovery,4 biochemistry,5 dendrimers,6 polymer chem-
istry,7 and materials science.8 Currently, the copper-catalyzed
azide–alkyne cycloaddition (CuAAC) is the method most
commonly used for the synthesis of 1,2,3-triazoles.9 This reac-
tion was developed simultaneously by Sharpless10 and Meldal,11
and allowed affording exclusively the 1,4-disubstituted
regioisomer.
CuAAC reactions are within the group of reactions dened by
Sharpless as “click”.12 These reactions are easy to carry out, have
a broad synthetic scope, high yield and specicity, are easily
puried, do not generate secondary products or are harmful to
the environment or health, require starting materials available
and easily handled, and can oen be developed in benign
solvents such as water or alcohols.
can be used: for example, elemental copper either in wire form
or nanoparticles;14 or Cu(0) combined with a source of Cu(II) to
promote comproportionation.15 Other methodologies directly
employ a Cu(I) source; yet, an inert atmosphere is oen required
to avoid cation oxidation. In these cases, the addition of
nitrogenous base or a ligand is needed to stabilize active Cu(I)
and prevent its oxidation or disproportionation.16 In addition,
the use of organic solvents such as MeCN, THF, dichloro-
methane, and toluene is oen required. Despite that, the in situ
Cu(I) formation at the expense of a Cu(II) source is the most
simple and convenient method. This methodology ensures
a high concentration of Cu(I) throughout the reaction. The most
widespread catalytic system is CuSO4 (as a Cu(II) source) and
sodium ascorbate (as a reducing agent). The limitation is shown
when aerobic conditions are employed in aqueous media,
where the oxidation of Cu(I) to the inactive Cu(II) species is
favoured. To overcome this drawback, larger amounts of Cu(II)
(5–20 mol%) and ascorbate, up to ve times the amounts of
Cu(II), must be employed. In addition, the use of reducing
agents such as sodium ascorbate is limited in biological
systems, since it could affect protein chains17 and DNA struc-
ture.18 To deal with this issue, protocols where Cu(I) species are
generated in situ by the photoinduced reduction of Cu(II) have
been developed. This allows the application of CuAAC not only
in biological environments, but also in materials science,
thanks to the perfect spatial and temporal control offered by
these methodologies.19 Generally, two ways of using the light to
promote reduction of Cu(II) salts are reported: (i) irradiating
with UV light (or visible light to a lesser extent) metal complexes
´
´
INFIQC, Universidad Nacional de Cordoba, CONICET, Departamento de Quımica
´
´
´
Organica, Facultad de Ciencias Quımicas, X5000HUA Cordoba, Argentina. E-mail:
aheredia@fcq.unc.edu.ar; jea@fcq.unc.edu.ar
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data and copies of 1H and 13C NMR spectra for all the products
(3a–r). See DOI: 10.1039/c7ra06390c
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which contain nitrogenous or carboxylates ligands;20 and (ii)
using a photoinitiator, which fragments under irradiation.21
Other methodologies reported are less widespread, but more
benecial since they use visible light exclusively.22 In these
Table 1 Optimization and control reactions
cases, an organic chromophore23 or
a transition metal
complex24 is employed, which can be reduced by a donor
sacricial reagent, usually triethylamine (TEA), when electron-
ically excited by light. The reduced species can transfer one
electron to Cu(II) cation and Cu(I) species is thus generated
triggering CuAAC reaction. The present work represents a novel
example in the use of organic dyes and visible light to assist the
reduction of Cu(II) ions, merging the concepts of photoredox25
and transition metal catalysis applied to the synthesis of 1,4-
disubstituted 1,2,3-triazoles. This new protocol is carried out in
water as solvent, under air atmosphere, at room temperature,
and in short reaction times. In addition, a lower catalyst loading
is used in comparison to conventional CuAAC protocols, and
additives such as bases, proton source, sophisticated ligands,
and copper complexes or nanostructures are not required.
[Cu(II)]
(mol%)
hv
(nm)
Time
(h)
Yield 3ab
(%)
Entrya
Dye (mol%)
1
2
3
4
5
6
7
8
EY (5)
—
EY (5)
EY (5)
CuSO4 (5)
CuSO4 (5)
—
530
530
530
—
1
58
Traces
—
15
15
15
1
2
2
2
2
2
2
CuSO4 (5)
CuSO4 (1)
CuSO4 (0.4)
CuSO4 (0.4)
CuSO4 (0.4)
CuSO4 (0.4)
CuSO4 (0.4)
Cu(NO3)2 (0.4)
Cu(OAc)2 (0.4)
CuCl2 (0.4)
CuCl2 (0.1)
Traces
66 (56)c
86
EY (1)
530
530
467
530
530
625
530
530
530
530
EY (0.4)
FL (0.4)
RB (0.4)
R6G (0.4)
MB (0.4)
EY (0.4)
EY (0.4)
EY (0.4)
EY (0.1)
49 (31)d
67
9
5
10
11
12
13
14
21 (13)d
82
2
2
2
68
95
71
Results and discussion
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), water (2 mL),
b
c
room temperature, ambient air. Isolated yield. Reaction performed
under nitrogen. d Reaction irradiated with green LED (530 nm).
We set out benzylazide 1a and phenylacetylene 2a as model
reagents in water as solvent to test the CuAAC reaction. Some
copper(II) salts were used as a copper source, and organic dyes
as a visible light-promoted reducing agent (Chart 1). Prelimi-
narily, we found that eosin Y disodium salt (EY) promoted an (530 nm) for 1 h to give 3a in 58% yield (Table 1, entry 1).
efficient photochemical reduction of Cu(II) to Cu(I) which Subsequently, control experiments were performed at consid-
aerward participated as catalyst in the copper-catalyzed azide– erably longer reaction times. The absence of the organic dye,
alkyne cycloaddition reaction, yielding the 1,4-disubstituted copper source, or irradiation inhibited the formation of 3a,
1,2,3-triazoles 3a as unique product. Thus, optimization and since under these conditions the Cu(I) active species fails to
control reactions were performed (Table 1).
form (Table 1, entries 2–4).
In the starting condition, Cu(II) and organic dye were initially
When catalyst precursor loading was decreased to 1%,
used at 5 mol%. The mixture was placed under green-LED light a slight improvement in yield of 3a to 66% was observed (Table
1, entry 5); whereas in inert N2 atmosphere, no signicant
advantages against aerobic conditions were noticed. Since
a decrease in catalyst precursor loading showed a slight
improvement in yield of 3a, Cu(II) salt was reduced to 0.4% and
irradiation time was increased to 2 h. In these conditions, 3a
was obtained in 86% yield (Table 1, entry 6).
Other organic dyes such as uorescein (FL), rose bengal (RB),
rhodamine 6G (R6G), and methylene blue (MB) were tested
(Chart 1, Table 1, entries 7–10). The best results were obtained
when the mixtures were irradiated at the wavelength whose
organic dye shows maximum absorption. The formation of Cu(I)
was assisted more efficiently by EY where the best yield for 3a
was observed. The absence of 3a was noticed when R6G was
used (Table 1, entry 9), attributed to two possible reasons: (i)
inability to form Cu(I) from Cu(II) due to the negligible inter-
system crossing quantum yield (FISC ¼ 0.002),26 or (ii) absence
of free carboxyl groups which could act as ligands of the cata-
lytically active cations.27 Then, other Cu(II) sources such as
Cu(NO3)2, Cu(OAc)2, and CuCl2 were used (Table 1, entries 11–
13 respectively). CuCl2 was the most efficient, giving an excel-
lent isolated yield of 3a (95%). Even though the effect of the
counterion in the copper source should be negligible in the
Chart 1 Structures of organic dyes employed for the optimizing
reactions conditions.
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CuAAC reaction, our results suggested that the in situ photoin-
duced reduction of Cu(II) is indeed affected by the anions. This
effect is reasonable by considering that ligands with
a pronounced tendency to complex with metal ions consider-
ably reduces the reduction potential of the Cu(II)/Cu(I) redox
couple.28 Under these conditions, and if the entire amount of
Cu(II) would be reduced to Cu(I) by EY, a TON (turn over
number) of at least 240 would be obtained, which is much
higher than the TONs of most CuAAC reactions carried out in
conventional systems. Finally, when
a catalyst precursor
loading of 0.1 mol% was tested (Table 1, entry 14), 3a was
afforded in 71% yield (TON ¼ 710). This proves the high effi-
ciency of our system, since acceptable yields can be obtained
using the smallest catalyst amount that we could use.
On the other hand, the presence of certain additives was also
tested to improve efficiency, reducing, for instance, irradiation
time. Organic and inorganic bases and acids (and their
combination) were employed to assist the deprotonation or
protonation steps in CuAAC reaction.9 However, a signicant
inhibition was found when triethylamine (TEA) and trietha-
nolamine (TEOA), or its combination with AcOH at 5 mol%,
were used. When TEOA or TEOA/AcOH was employed, 3a was
obtained in around 14% yield, whereas a quantitative recovery
of substrates was noticed when TEA or TEA/AcOH was
employed. A decrease in yield of 3a (65%) was observed when
the inorganic base K2CO3 (2 mol%) was used. To improve the
solubility of substrates, organic co-solvents such as ethanol, iso-
propanol, tert-butanol, and PEG 300 were evaluated; however,
3a was not detected under these conditions.
To study the reaction scope, benzyl, phenacyl, alkyl and aryl
azides, as well as aryl, and alkyl terminal alkynes were tested
under optimized conditions. Scheme 1 shows triazoles obtained
by this methodology. For some substrates, experimental condi-
tions were slightly modied so as to improve reaction yields.
The reaction between 1a and 2a gave an excellent yield of 3a
in 95% under standard conditions as mentioned above
(condition A, Scheme 1). Less than 50% yield was observed
when the irradiation time was 2 h for the other benzylic azides,
but was considerably improved when the irradiation time was
duplicated. Thus, triazoles achieved from benzyl azides with
a methyl (3b), methoxy (3c), nitro (3e), and cyano (3f) group in
their aromatic ring showed very good to excellent yields (73–
100%). Triazoles from benzyl azides with iodine (3d) and tri-
uoromethyl (3g) substituent were obtained close to 50% yield,
(condition A, Scheme 1). In all cases, a satisfactory mass balance
was found even when yields were not quantitative, in these
cases unreacted starting material and no by-products were
detected.
Scheme 1 Synthesis of 1,4-disubstituted 1,2,3-triazoles via visible-
light promoted CuAAC reaction. Reaction conditions: acondition A:
organic azide 1 (0.25 mmol), terminal alkyne 2 (0.25 mmol), CuCl2 (0.4
mol%), EY (0.4 mol%) in water (2 mL) irradiated with green LED (530
nm) for the time in parenthesis indicated. Isolated yields were re-
ported. bCondition B: idem condition A, except that 0.4 mL of water
were used instead of 2 mL. cCondition C: reaction performed in two
steps: a mixture of CuCl2 (0.4 mol%) and EY (0.4 mol%) was irradiated
for 1 h, then organic azide and terminal alkyne were added and stirred
for 4 h in the dark.
To obtain triazoles with a phenacyl moiety, a reduced group
of a-azidoacetophenones was employed. Under standard
conditions, only 3i could be isolated in a very good yield (91%),
whereas 3h and 3j were detected in traces with a partial
consumption of the corresponding organic azide. However,
with an increase in concentration of about ve times (0.4 mL
nal volume) very good yields were obtained for 3h and 3j, 70%
Furthermore, alkyne 2a was tested with two aliphatic azides,
and 86% respectively aer 4 h of irradiation (condition B, n-octyl azide, and 3-azidopropylphthalimide. For the former,
Scheme 1).
triazole 3k was obtained in 97% yield in 4 h under condition B.
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However, for the latter, 3l was not found under any of the above this dye does not have a formal charge under the reaction
conditions, and a partial consumption of the corresponding conditions,29 and could be removed from the aqueous layer
organic azide was observed. In the substrate with a strong aer each cycle. In addition, since our system does not involve
electron-withdrawing group, a reduction event from the elec- the use of ligands or additives, bare Cu(I) species is not stable
tronically excited eosin (EY*) could take place,25a protecting under aerobic conditions, thus a new addition of EY is required
Cu(II) and avoiding the formation of Cu(I) catalytically active to promote photoreduction in the next cycle.
species. Despite this, reduction products from these azides were
Organic azides with a medium and high molecular weight
not observed by GC-MS. For this reason, the reaction between 3- are stable in aqueous media and air, although storage at low
azidopropylphthalimide and 2a was performed in two steps temperatures is advised to avoid decomposition. Aliphatic
(condition C, Scheme 1): a rst step in presence of light, where azides are more stable than aromatic, vinyl or those attached to
a mixture of CuCl2 (0.4 mol%) and EY (0.4 mol%) was irradiated a carbonyl group. While they are mostly easily handled, low
with green-LED light in 0.4 mL of water for 1 h, to achieve in situ molecular weight azides could be volatile, unstable, and even
formation of the Cu(I) catalytically active species; and a second explosive, hindering their store and handle. Accordingly,
step under the dark, where the substrates were added, stirring methodologies that avoid the manipulation of organic azides
at room temperature and without irradiation (dark condition) have been reported by in situ generation in a one-pot proce-
for additional 4 h. Under two-step reaction conditions, 3l was dure.30 These methods are environmentally friendly since they
obtained in 75% isolated yield. Similarly, phenacyl azides were avoid synthesis steps and their isolation, reducing waste and
retested under condition C but 3h and 3j showed no improve- ensuring greater safety. Here, we could perform the synthesis of
ment. Unfortunately, the phenacyl azides with nitro and cyano 3a by a one-step one-pot procedure, using benzyl bromide (4),
group on their aromatic ring (not shown in Scheme 1) failed to sodium azide (5) and phenylacetylene (2a), in presence of CuCl2
achieve their corresponding triazoles, even under two-step and EY, under standard conditions (Scheme 3). In a rst
reaction conditions. Aromatic azide with no substituents in its approximation, 0.25 mmol of 4 was placed in the presence of
aromatic ring (phenyl azide) was used to obtain 3m in 85% a slight excess of 5 (1.1 equiv.). In this case, the complete
yield. When the aromatic azide had a methoxy group (4- consumption of 4, concomitant with a quantitative formation of
methoxyphenyl azide), the corresponding triazole was isolated 1a but the absence of 3a, was observed when the mixture was
in 88% yield (3n) (condition B, Scheme 1).
irradiated for more than 5 h (Scheme 3a). The one-pot proce-
On the other hand, different terminal alkynes were also dure was then repeated but using 0.25 mmol of 5 and 1.1 equiv.
employed. When ortho-methoxyazidobenzene was used, of 4, where the NaN3 was the limiting reagent. Fortunately, the
a quantitative yield of 3o was obtained under condition A. For desired triazole 3a was obtained in 88% yield (Scheme 3b). The
the aryl acetylene with the methoxy group at para position, tri- one-pot reaction was also performed on a gram scale (with
azole 3p was achieved in 77% yield under condition B. When 2- 5 mmol of NaN3). Unlike smaller-scale reactions, in the large-
ethynylaniline was used as terminal alkyne, 3q was isolated in scale one-pot reaction, 8 mL of water were employed and the
89% yield under standard conditions. Finally, propargylic mixture was irradiated for 8 h. Under these conditions 3a was
alkyne 3-phenoxy-1-propyne reacted with 1a to give 3r in an isolated in 80% yield (Scheme 3c).
excellent 100% yield.
The mechanism of 1,4-disubstituted 1,2,3-triazole formation
Recycling of catalyst and solvent reaction was also studied. by cycloaddition reaction from organic azides and terminal
The substrate models 1a and 2a were used for this assay. Aer alkynes catalyzed by Cu(I) is well known and accepted by organic
the rst cycle (irradiation for 2 h with green-LED light), 3a was chemists.13 For this reason, some research groups have centred
extracted with diethyl ether and a new charge of substrates was on nding Cu(I) catalytic systems, designing and synthesizing
added again to the aqueous layer. The yield of the second highly sophisticated metal complexes which stabilize the metal,
catalytic cycle dropped dramatically when aqueous layer was avoiding its oxidation and modulating its reactivity. On the
not treated; however, when 0.4 mol% of EY was added again other hand, other methodologies adopt more stable and
aer extraction and before a new catalytic cycle, recycling was cheaper Cu(II) sources, whereas the use of a reducing agent is
possible up to three times without considerable yield loss necessary for Cu(I) formation. In the latter case, the amount of
(Scheme 2). EY could not be recovered since a large amount of
Scheme
2 Reusability of copper catalyst and solvent in CuAAC
reaction.
Scheme 3 Synthesis of 3a via a one-pot one-step procedure.
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reducing agent is oen higher than Cu(II). In our system,
Summing up, based on our experimental evidence, active
reducing agent is the EY dye, which is electronically excited by Cu(I) formation pathway is shown in oxidative quenching cycle
visible light (530 nm) forming 3EY* aer the inter system (a) in Scheme 4, as well as the pathways where Cu(I) species are
crossing (ISC), nally promoting Cu(II) reduction (oxidative converted into inactive Cu(II). Based on thermodynamic
3
quenching cycle (a) in Scheme 4). The lack of reactivity in the grounds EY* is able to reduce Cu(II) to Cu(I), generating EYc+,
singlet excited state of EY (1EY*) was tested by uorescence with a very exergonic Gibbs free energy change ðDGEꢁ TÞ close to
experiments, where a modication of the quantum uorescence ꢀ29 kcal molꢀ1 (DE ¼ 1.26 V), under the Rehm–Weller
yield (FF) was not found with successive addition of Cu(II). We approximation.32 Oxidized EY does not interfere in the normal
also observed that R6G could not be able to give Cu(I) from progress of CuAAC reaction, except when the amount of Cu(II) is
Cu(II), since the energy absorbed during irradiation was entirely higher than EY. When 1a and 2a were placed in the presence of
emitted by uorescence as its FISC is close to zero. Thus 3R6G* 0.8 mol% of CuCl2 and 0.4 mol% EY (Cu(II) in excess), yield of 3a
cannot be formed and reduction of Cu(II) is not achieved. On the was strongly affected (13%), probably by a back electron transfer
other hand, thermal electron transfer was ruled out, since EY reaction. However, when 0.4 mol% of CuCl2 and 0.8 mol% of EY
UV-Vis spectra did not show signicant changes with the were used, 3a was obtained in 92% yield. Thus, the amount of
addition of CuCl2 in water and 3a was neither observed under EY needs to be equimolar (or higher) than Cu(II). Reduction was
dark conditions (Table 1, entry 4). Furthermore, results shown favoured and the subsequent Cu(I) oxidation was apparently
in Scheme 3(a) suggest that Cu(II) reduction occurs from the inhibited. On the other hand, carboxylic groups in EY could act
triplet state (3EY*) since, when a strong triplet quencher such as as ligands allowing stabilization and activity modulation of
ꢀ
N3 anion is present,31 the Cu(II) photoreduction step to Cu(I) is Cu(I) in CuAAC reaction.25
not favoured and CuAAC is not carried out (reductive quenching
cycle (b) in Scheme 4). Molecular oxygen (O2) dissolved in water
is also a potential EY* quencher, but its concentration (0.26
Conclusions
3
mM) is lower than excess azide ions and Cu(II) concentrations in The use of organic dyes as a Cu(II) reducing agent by photoredox
standard condition shown in Scheme 3 (12.5 mM and 0.5 mM reactions which promote Cu(I) production for its application in
respectively). An energy transfer quenching is possible by O2 CuAAC reaction was reported as a novel methodology in the
(giving 1O2 which does not affect CuAAC reaction nor products), synthesis of 1,4-disubstituted 1,2,3-triazoles in this work. This
where EY ground state is recovered.
protocol is environmentally friendly and respects several green
ꢀ
When N3 ions are present, formation of cycloaddition chemistry principles: water is used as a renewable and non-toxic
products is totally suppressed, since these anions could be able solvent, avoiding the use of organic solvents; the amount of
to give EYcꢀ from 3EY* by electron-transfer quenching. Simi- catalyst precursor (and organic dye as a reducing agent) is much
larly, an important drop in the triazole yield was evidenced lower than that found in conventional methodologies (TON ¼
when TEA (or TEOA) was added as additive since these amines 710); metal and solvent can be recycled for up to three times
are also electron donors (cycle (b) in Scheme 4). Even Cu(I) could without a considerable loss of efficiency; visible light through
be formed at the expense of EYcꢀ by electron transfer to Cu(II) in LED is used, which is inexpensive and safer compared with
the presence of TEA, TEOA or N3ꢀ. Dissolved oxygen could also methodologies which employ UV light to promote Cu(II)
be reduced to superoxide (O2cꢀ) and subsequent formation of reduction; and lack of additives such as bases, ligands, proton
H2O2 promoted Cu(I) deactivating through its oxidation dis- sources, phase transfer agents, and sacricial reducers,
favouring CuAAC reaction (cycle (b) in Scheme 4).
improving the atom economy. In addition, an efficient one-step
one-pot procedure was designed and carried out on a small and
large scale with very good results, avoiding synthesis step and
the handling of organic azides that could be hazardous.
Experimental
Synthetic procedures
General experimental procedure for the synthesis of 1,4-
disubstituted 1,2,3-triazoles via visible-light promoted CuAAC
reaction in one step. Condition A. The reactions were carried
out in a 10 mL glass vial, equipped with a rubber septum and
a magnetic stirrer. Organic azide (1, 0.25 mmol), terminal
alkyne (2, 0.25 mmol), and 1.6 mL of water were added. 200 mL
EY (5 mM) and 200 mL CuCl2 (5 mM) were added and the
mixture was irradiated with green-LED (530 nm) and stirred
under air atmosphere for the time indicated. Ethyl acetate (10
mL) and a saturated solution of NaHCO3 (10 mL) were added
and the mixture was stirred. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (2 ꢂ 10
Scheme 4 Plausible mechanism of Cu(I) formation.
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mL). The combined organic extract was dried over anhydrous (62.3 mg, 75% yield). Mp ¼ 146.5–147.1 ꢁC. 1H NMR (400 MHz,
Na2SO4 and the products were isolated from the crude reaction CDCl3): d ¼ 2.38 (q, J ¼ 6.6 Hz, 2H), 3.78 (t, J ¼ 6.6 Hz, 2H), 4.45
mixture by ash column chromatography (silica gel, eluting (t, J ¼ 6.6 Hz, 2H), 7.31 (t, J ¼ 7.5 Hz, 1H), 7.40 (t, J ¼ 7.5 Hz, 2H),
with 1 : 1 pentane/dichloromethane (50 mL) and 1 : 1 7.69–7.71 (m, 2H), 7.80–7.84 (m, 4H), 7.97 (s, 1H). 13C NMR (100
dichloromethane/ethyl acetate (50 mL)).
MHz, CDCl3): d ¼ 29.5, 35.2, 48.0, 120.4, 123.5, 125.9, 128.2,
General experimental procedure for the synthesis of 1,4- 128.9, 130.8, 132.0, 134.3, 147.8, 168.5. HRMS EI [M+] calcd for
disubstituted 1,2,3-triazoles via visible-light promoted CuAAC
reaction in one step. Condition B. The reactions were carried
out in a 10 mL glass vial, equipped with a rubber septum and
a magnetic stirrer. Organic azide (1, 0.25 mmol), terminal
alkyne (2, 0.25 mmol). 200 mL EY (5 mM) and 200 mL CuCl2 (5
mM) were added and the mixture was irradiated with green-LED
(530 nm) and stirred under air atmosphere for the time indi-
cated. Ethyl acetate (10 mL) and a saturated solution of NaHCO3
(10 mL) were added and the mixture was stirred. The organic
layer was separated and the aqueous layer was extracted with
ethyl acetate (2 ꢂ 10 mL). The combined organic extract was
dried over anhydrous Na2SO4 and the products were isolated
from the crude reaction mixture by ash column
chromatography.
C19H16N4NaO2: 355.1165, found 355.1181.
Acknowledgements
This work was supported by Consejo Nacional de Inves-
´
´
´
´
´
tigaciones Cientıcas y Tecnicas (CONICET), Secretarıa de
´
Ciencia y Tecnologıa de la Universidad Nacional de Cordoba
(SeCyT – UNC) and Ministerio de Ciencia, Tecnologıa e
´
Innovacion Productiva (MinCyT). Argentina. W. D. C.-G. and A.
A. H. gratefully acknowledge the receipt of a fellowship from
CONICET.
Notes and references
General experimental procedure for the synthesis of 1,4-
disubstituted 1,2,3-triazoles via visible-light promoted CuAAC
reaction in two steps. Condition C. The reactions were carried
out in a 10 mL glass vial, equipped with a rubber septum and
a magnetic stirrer. A mixture of 200 mL EY (5 mM) and 200 mL
CuCl2 (5 mM) was irradiated with green-LED (530 nm) and
stirred under air atmosphere for 1 h. Organic azide (1, 0.25
mmol) and terminal alkyne (2, 0.25 mmol) were then added and
the mixture was stirred in dark for 4 h. Ethyl acetate (10 mL) and
a saturated solution of NaHCO3 (10 mL) were added and the
mixture was stirred. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 ꢂ 10 mL). The
combined organic extract was dried over anhydrous Na2SO4 and
the products were isolated by ash column chromatography.
Experimental procedure for the synthesis of 3a via one-step
one-pot procedure. The reactions were carried out in a 10 mL
glass vial, equipped with a rubber septum and a magnetic
stirrer. Benzyl bromide (4, 0.275 mmol), NaN3 (5, 0.25 mmol),
and phenyl acetylene (2a, 0.25 mmol) were added and
a suspension was observed when water (1.6 mL), 200 mL EY (5
mM) and 200 mL CuCl2 (5 mM) were added. The mixture was
irradiated with green-LED (530 nm) and stirred under air
atmosphere for 2 h. Ethyl acetate (10 mL) and a saturated
solution of NaHCO3 (10 mL) were added and the mixture was
stirred. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (2 ꢂ 10 mL). The combined
organic extract was dried over anhydrous Na2SO4 and 3a was
isolated by ash column chromatography.
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Synthetic procedure and characterization data for novel 2-(3-
(4-phenyl-1H-1,2,3-triazol-1-yl)propyl)isoindoline-1,3-dione (3l).
Following the general procedure for the reaction in two steps, 2-
(3-azidopropyl)isoindoline-1,3-dione (57.5 mg, 0.25 mmol) and
phenyl acetylene (2a, 25.5 mg, 0.25 mmol) were placed in a glass
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