Multicomponent click synthesis of 1,2,3-triazoles from epoxides in water catalyzed by copper nanoparticles on activated carbon

Article abstract of DOI:10.1021/jo2016339

Copper nanoparticles on activated carbon have been found to effectively catalyze the multicomponent synthesis of Β-hydroxy-1,2,3-triazoles from a variety of epoxides and alkynes in water. The catalyst is easy to prepare, reusable at a low copper loading (

Full text of DOI:10.1021/jo2016339

ARTICLE
pubs.acs.org/joc
Multicomponent Click Synthesis of 1,2,3-Triazoles from Epoxides in
Water Catalyzed by Copper Nanoparticles on Activated Carbon§
Francisco Alonso,*,† Yanina Moglie,† Gabriel Radivoy,‡ and Miguel Yus*,†
†Departamento de Química Orgꢀanica, Facultad de Ciencias and Instituto de Síntesis Orgꢀanica (ISO), Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
‡Departamento de Química, Instituto de Química del Sur (INQUISUR-CONICET), Universidad Nacional del Sur, Avenida Alem 1253,
8000 Bahía Blanca, Argentina
S Supporting Information
b
ABSTRACT: Copper nanoparticles on activated carbon have been found to
effectively catalyze the multicomponent synthesis of β-hydroxy-1,2,3-triazoles
from a variety of epoxides and alkynes in water. The catalyst is easy to prepare,
reusable at a low copper loading (0.5 mol %), and exhibits higher catalytic activity
than some commercially available copper sources. The regio- and stereochem-
istry of the reaction has been revised and unequivocally established on the basis of
X-ray crystallographic analyses. An NMR experiment has been implemented for
the rapid and unmistakable determination of the regiochemistry of the process. Some mechanistic aspects of the reaction have been
also undertaken which unveil the participation of copper(I) acetylides.
’ INTRODUCTION
moiety which is also present in peptide surrogates of HIV-1
protease inhibitors.15 The pioneering work in this field involved
The Huisgen 1,3-dipolar cycloaddition of azides and alkynes1
has become a synthetic cornerstone since the paramount dis-
covery by the groups of Meldal2 and Sharpless3 of its copper(I)-
catalyzed version (CuAAC).4 The superb reliability of the
CuAAC reaction has increasingly attracted the attention from a
diverse range of the areas of chemistry.5 As a result, a plethora of
methods have been developed around this reaction with the aim
to increase efficiency. Among them, we consider of special
interest those which combine three important aspects in modern
synthetic organic chemistry, namely, (a) multicomponent
synthesis;6 the in situ generation of organic azides in the presence
of the alkyne (three-component alkyneꢀazide cycloaddition)
minimizes hazards derived from the isolation and handling of the
former, avoiding the time-consuming and waste generation of an
additional synthetic step; (b) heterogeneous catalysis,7 especially
involving metal nanoparticles,8 which offers several advantages
over the homogeneous counterpart, such as easy recovery, easy
recycling, and enhanced stability of the catalyst; and (c) reactions
in water,9 the solvent used by nature for biological chemistry
which can make synthetic processes cheaper, safer, and greener.
In this regard, some reports on the copper-catalyzed multi-
component synthesis of triazoles from organic halides in water,
using heterogeneous catalysts, have appeared in the literature.10
The azidolysis of epoxides11 and the CuAAC have in common
some inherent attributes which perfectly fit the set of stringent
criteria required for click chemistry, in the terms coined by
Sharpless et al.12 Therefore, it is not surprising that, in recent
years, an increasing interest emerged on the multicomponent
synthesis of 1,2,3-triazoles through the in situ generation of
azidoalcohols and further cycloaddition with alkynes.13,14 The
resulting products possess a 1-(hydroxyethyl)-1H-1,2,3-triazole
homogeneous catalysis with CuSO4 5H2O (10 mol %)/sodium
3
ascorbate (20 mol %)/H2O,13a CuI (5 mol %)/PEG-400,13b and
Cu(OAc)2 H2O (10 mol %)/H2O.13c Although the reactions
3
were carried out in one pot, the whole process was sequential;
therefore, the formation of the azidoalcohol needed monitoring
before the addition of the alkyne. It is worthy to note the one-pot
enantioselective biocatalytic azidolysis of aromatic epoxides,
linked to the dipolar cycloaddition with alkynes, reported by
the group of Feringa.16 Some heterogeneous catalytic systems
have been developed recently, including porphyrinatocopper
nanoparticles on activated multiwalled carbon nanotubes
(5 mol %)/H2O,14a Cu[N2,N6-bis(2-hydroxyphenyl)pyridine-
2,6-dicarboxamidate]H2O (5 mol %)/ascorbic acid (20 mol %)/
H2O,14b and copper(I)-modified zeolites (8 mol %)/H2O.14c In
these cases, the catalyst could be easily recovered exhibiting a
high recycling capability. Despite the fact of the mild reaction
conditions generally applied, there are still some issues that need
improvement in order to make the processes more effective: (a)
the regioselectivity, which is not always as high as desired; (b) the
purification of products, some methodologies requiring column
chromatography; (c) to reduce the amounts of copper in
solution should be also a priority, particularly for biological
applications; and (d) the long and tedious procedures usually
required for the heterogenization of copper, which preclude the
widespread utilization of this type of catalysts. We can conclude
that easy-to-prepare and versatile heterogeneous copper catalysts
Received: August 4, 2011
Published: September 06, 2011
r
2011 American Chemical Society
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Scheme 1. 1,3-Dipolar Cycloaddition of Organic Azides and
Terminal Alkynes Catalyzed by Unsupported Copper
Nanoparticles
Scheme 3. General Conditions for the Multicomponent
Synthesis of Triazoles from Epoxides
Scheme 2. Multicomponent Synthesis of 1,2,3-Triazoles
from Organic Halides, Aryldiazonium Salts, and Aromatic
Amines Catalyzed by Copper Nanoparticles Supported on
Activated Carbon
azidolysis of epoxides and 1,3-dipolar cycloaddition with alkynes.
Special attention is dedicated to the regio- and stereochemical
course of the reaction, a topic that has not been properly
addressed hitherto and that has led to an incorrect assignment
of the reaction products. An NMR experiment for the determi-
nation of the regioselectivity of the reaction and some mechan-
istic studies are also presented.
’ RESULTS AND DISCUSSION
Preparation of the Catalyst. The copper catalyst was readily
available by mixing activated carbon with a recently prepared
suspension of CuNPs. The latter was obtained in a few minutes
from anhydrous copper(II) chloride, lithium metal, and a catalytic
amount of DTBB (10 mol %) in THF at room temperature. In
contrast with most heterogeneous catalysts, our catalyst was ready
for use as prepared, after filtration and drying, without any further
pretreatment. The catalyst was fully characterized by different
means, which revealed the presence of oxidized spherical nano-
particles (Cu2O and CuO) dispersed on the active carbon support
with an average size of ca. 6 ( 2 nm.21
Multicomponent Synthesis of Triazoles from Epoxides
and Alkynes in Water. All reactions were performed with 0.5
mol % of CuNPs/C, the copper loading being 10-fold lower than
the lowest previously published by others.13,14,16 Preliminary
experiments with styrene oxide, phenylacetylene, and sodium
azide in water allowed us to select a reaction temperature of
70 °C as the most convenient in order to achieve high conver-
sions. A control experiment under the above conditions but in
the presence of only activated carbon (without copper) gave no
trace of the corresponding triazole after 24 h. This result confirms
the essential role of copper and practically discards any catalytic
effect of the support. A series of commercially available epoxides
and alkynes were subjected to the azidolysisꢀcycloaddition
process in water at 70 °C (Scheme 3, Table 1).
We first studied the reaction of alkyl-substituted epoxides with
phenylacetylene (Table 1, entries 1ꢀ4). The monosubstituted
epoxides bearing an alkyl and alkenyl chain 1a and 1b reacted
relatively fast, affording triazoles 3aa and 3ba, respectively, in
high yields (Table 1, entries 1 and 2). Glycidyl phenyl ether (1c)
also reacted nicely, whereas the 1,1-disubstituted vinyl oxirane 1d
furnished a 5:1 mixture of E/Z diastereoisomers (Table 1, entries
3 and 4). Bicyclic epoxides derived from cyclic olefins were
shown to be more reluctant to react. For instance, higher
temperature was necessary to get a high yield in the transforma-
tion of cyclohexene oxide (1e) into hydroxytriazole 3ea (Table 1,
entry 5). Moreover, cyclooctane oxide (1f) remained unchanged
even after prolonged heating (Table 1, entry 6). This result,
however, is not so unexpected since the azidolysis of cyclooctane
oxide was already described as problematic by others.22
that can contribute to the advancement of the multicomponent
synthesis of triazoles from epoxides in water are welcome.
Our interest on the preparation and reactivity of active metals
and nanoparticles17 led us to the generation of a form of active
copper [obtained from CuCl2 2H2O, metal lithium, and a
3
catalytic amount of 4,40-di-tert-butylbiphenyl (DTBB) in THF
at room temperature] and its application to the reduction of
manifold organic functionalitites.18 We discovered that copper
nanoparticles (CuNPs) were formed either from CuCl2 2H2O
3
or anhydrous CuCl2 under the aforementioned conditions.
Trying to expand the use of these nanoparticles,19 we were
immersed in the field of click chemistry in 2009. We found out
that 10 mol % of unsupported CuNPs catalyzed the 1,3-dipolar
cycloaddition of organic azides and terminal alkynes in remark-
able short reaction times (Scheme 1).20 The presence of
triethylamine was, however, mandatory for the reaction to occur,
and the CuNPs could not be reused since they underwent
dissolution. A second generation of catalysts was introduced by
immobilization of the CuNPs on different inorganic supports. In
particular, we developed a highly versatile catalyst, consisting of
oxidized copper nanoparticles on activated carbon (CuNPs/C),
for the multicomponent synthesis of 1,2,3-triazoles from organic
halides, aryldiazonium salts, and anilines in water (Scheme 2).21
One example of other azide precursors, such as an epoxide and
alkene, was also reported. We wish to present herein our results
on the performance and scope of the CuNPs/C in the domino
Then we explored the reactivity of aryl-substituted oxiranes
with phenylacetylene (Table 1, entries 7ꢀ10). Both styrene
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Table 1. Multicomponent Synthesis of Hydroxytriazoles from Epoxides Catalyzed by CuNPs/C in Watera
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), NaN3 (1.1 mmol), CuNPs/C (0.5 mol %), H2O, 70 °C. b Isolated yield. c E/Z 5:1. d Reaction at 100 °C.
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Scheme 4. Computer-Estimated 1H and 13C NMR Chemical
Shifts (in ppm) for 3aa and 4aa
Figure 1. Plot showing the X-ray structure and atomic numbering for
compound 3aa.
oxide (1g) and 4-chlorostyrene oxide (1h) exhibited similar
reactivity, providing the corresponding triazoles in good yields
(Table 1, entries 7 and 8) and with opposite regioselectivity to
that displayed by the alkyl-substituted oxiranes (Table 1, entries
1ꢀ3). The meso-epoxide 1i and racemic 1j gave rise to the 1,
2-diphenyl-2-hydroxyethyl-substituted triazoles 3ia and 3ja
(Table 1, entries 9 and 10). In these cases, longer reaction
times were required and lower yields than the average were
recorded. The methodology was proven to be equally effective
for alkyl- and cycloalkyl-substituted alkynes, such as oct-1-yne
(2b) and cyclohexylacetylene (2c), which manifested the same
reactivity pattern (Table 1, entries 11 and 12). The presence of a
heterocyclic moiety in the alkyne (2d) was compatible with the
reactions conditions leading to the pyridyl-substituted product
3gd (Table 1, entry 13). The reaction of 1,3-diethynylbenzene
(2e) with the enantiomerically pure (R)-1g produced the structu-
rally interesting C2-symmetric bis(hydroxytriazole) 3ge in high
yield (Table 1, entry 14). Finally, a triazole bearing two nonaro-
matic substituents (3bf) was obtained from unsaturated epoxide
1b and hex-1-yne (2f) in moderate yield at 70 °C and good yield at
100 °C (Table 1, entry 15).
Regio- and Stereochemistry of the Reaction. It must be
highlighted that the multicomponent synthesis of hydroxytria-
zoles catalyzed by CuNPs/C was regiospecific with regard to
both the azidolysis of the epoxide and the 1,3-dipolar cycloaddi-
tion of the in situ generated azidoalcohols with terminal alkynes.
In the latter case, and in contrast with some other method-
ologies,13a,14c the 1,4-disubstituted 1,2,3-triazoles were the only
products observed, with no trace of the regioisomeric 1,5-
disubstituted 1,2,3-triazoles being detected. The attention de-
voted by some research groups to the regiochemistry of the
cycloaddition has been to the detriment of the analysis of the
regioselectivity in the oxirane ring opening. The fact that some of
the results have been misunderstood has had, consequently, a
confusing effect on the reader. We would like to address this
subject by taking advantage of the crystalline nature of the
triazoles synthesized. We have selected some examples to
unequivocally assign both the regio- and stereochemistry of the
products on the basis of X-ray crystallography.
Figure 2. Intermolecular hydrogen bonding between molecules of 3aa
in the crystal. The hydrogen atoms, except the hydroxyl group hydrogen
atoms, have been omitted for clarity.
awkward due to the overlapping of the chemical shifts and the
identical multiplicity of CH-Het and CH2-Het in both regio-
isomers. A DEPT 135° experiment, however, would be helpful
in the case of the 13C NMR spectrum. X-ray crystallographic
analysis23 demonstrated that triazole 3aa derived from the
nucleophilic attack of the azide ion to the less hindered position
of the oxirane ring (Figure 1). This result is in agreement with the
previously reported azidolysis of alkyl-monosubstituted oxiranes.22
Interestingly, intermolecular hydrogen bonding was observed in
the crystal structure of 3aa (Figure 2). The fact that the (R)-3aa
and (S)-3aa enantiomers alternate positions within the same
molecular raw favors the formation of hydrogen bonds between
the OH and the 2-N or 3-N of the triazole unit, with the two latter
also participating in an alternate manner. The hydrogen bonds were
unsymmetrical, with the hydrogen being covalently bonded to the
oxygen and hydrogen bonded to the nitrogen.24 In all cases,
constant values of 2.12 Å for the OH N bond (hydrogen-to-
3 3 3
nitrogen distance) and 2.98 Å for the OꢀH N bonds (oxygen-
3 3 3
to-nitrogen distance) were measured.
The reaction with isoprene monoepoxide (1d) was particu-
larly interesting because it provided the regioisomer 3da, arising
from an SN20 process, as a 5:1 E/Z diastereomeric ratio
(Scheme 5, eq 3). Contrary to this behavior, a lack of regios-
electivity was reported for both the uncatalyzed and palladium-
catalyzed azidolyses of 1d (Scheme 5, eqs 1 and 2);25 equilibra-
tion between the tertiary and primary allylic azides occurs, with
the primary reacting selectively because of steric reasons, as
noted by the group of Sharpless and Fokin.26
Cyclohexene oxide (1e) gave, as expected and published by
others,13,14 the trans-β-hydroxytriazole 3ea, the stereochemistry
being deduced from the 1H NMR coupling constants of the ring
protons. The synthesis of triazoles from styrene oxide, however,
is rather controversial and requires careful examination and
Concerning the monosubstituted oxiranes, the β-hydroxytria-
zole derived from oct-1-ene oxide (3aa) was used as a model
compound for this study. The 1H and 13C NMR chemical shifts
of the key nuclei involved in the regiochemical outcome were
computer estimated for 3aa and its regioisomer 4aa (Scheme 4).
1
According to these values, an assignment based on the H and
proton-decoupled 13C NMR spectra might be somewhat ambig-
uous. The assignment of the 1H NMR signals must be especially
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Scheme 5. Azidolysis and Domino AzidolysisꢀCycloaddition of Epoxide 1d
Scheme 6. Computer-Estimated 1H and 13C NMR Chemical
Shifts (in ppm) for 3ga and 7ga
accomplished. We applied our methodology to both cis- and
trans-stilbene oxide (Table 1, entries 9 and 10). In these cases, the
stereochemistry of the ring opening also followed the pattern of a
sole SN2 mechanism, as confirmed by the X-ray structure of the
triazole 3ia derived from cis-stilbene oxide (1i) (Figure 4).
NMR Experiments. We next searched for a fast and reliable
way to ascertain the regiochemistry of the multicomponent
synthesis of triazoles from monosubstituted epoxides once it
was confirmed by X-ray crystallography. We believed that the 1H
NMR signal of the OH of the triazoles 3 could be used as an
adequate probe for this purpose whenever it is visible and does
not overlap other signals. The idea was to use a solvent which
allowed detecting the coupling of the OH with the protons
attached to the α-carbon atom. In this way, the OH of secondary
alcohols, produced by nucleophilic attack on the less hindered
position of the oxirane ring, would manifest as a doublet (d).
On the other hand, the OH of primary alcohols, obtained by
nucleophilic ring opening at the most substituted position,
should be brought into view as a doublet of doublets (dd), given
that the two methylene protons (CH2OH) are diastereotopic.
This information is not so evident from Table 1, where the OH
was normally described as either a singlet or a multiplet. An
array of deuterated solvents was tested using triazole 3ga as a
model compound, with the position of the OH signal being
identified by the addition of D2O to the sample (Figure 5). In
principle, DMSO-d6 does not seem to be an appropriate
solvent because the OH appears as a broad singlet due to
the rapid exchange of the proton, probably favored by the
trace of water contained in the solvent which is difficult to
eliminate. This proton shows up as a triplet in CD3CN at 3.40
ppm, although strictly it must be a partially overlapped
doublet of doublets. No OH peak, except that of residual
water present in commercial CDCl3 or in the sample, was
observed when using this solvent as received. However, when
the CDCl3 was previously passed through a short silica
column, a clear dd was displayed in the spectrum. In this case,
the CHCH2 moiety evolved from three dd with wet CDCl3
into a dd (5.67 ppm) and two ddd (4.63 and 4.23 ppm) with
anhydrous CDCl3. The spectrum recorded in CD3CN pointed
out a similar trend for this moiety.
interpretation of the spectroscopic data. As depicted in Scheme 6,
the key protons resulting from the regiochemistry of the reaction
appear within a near range of chemical shifts for regioisomers
3ga and 7ga. Furthermore, the CH2O and CHN are practically
indistinguishable by 13C NMR in 3ga, making dubious any
assignment unless a sample of the regioisomer 7ga is available
for comparison. Table 2 shows the inconsistency of the melting
1
point and H and 13C NMR data reported by different groups
with the structure proposed; that is, similar melting point and
NMR data are correlated with different regioisomers or totally
unlike data appear for the same regioisomer. In order to disclose
the regio- and stereochemical course of our multicomponent
synthesis of triazoles from aryl-substituted oxiranes, enantio-
merically pure styrene oxide (R)-1g was allowed to react with
sodium azide and phenylacetylene (2a) under the standard
conditions. The β-hydroxytriazole attained was derivatized to
the corresponding mesylate (S)-8, and its regiochemistry and
absolute stereochemistry were unequivocally established by
X-ray crystallography (Figure 3). We can, therefore, assert that
the process is regiospecific, with the exclusive attack of nitrogen
occurring to the benzylic position of the oxirane, and stereo-
specific, through a typical SN2 pathway (i.e., with inversion of the
configuration).
To the best of our knowledge, the multicomponent synthesis
of 1,2,3-triazoles from the stilbene oxides has been never
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Table 2. Reported Data in the Literature for Regioisomers 3ga and 7ga
mp (°C)
1H NMR (ppm)a
13C NMR (ppm)b
57.3, 71.9
structure
ref
131
158
3ga
3ga
3ga
7ga
7ga
13a
DMSO-d6: 4.40 (q), 4.63 (dd), 5.05 (m), 5.65 (d)
CDCl3/DMSO-d6: 4.15 (m), 4.40 (m), 5.03 (t), 5.80 (dd)
CDCl3: 3.62 (s), 4.15 (dd), 4.56 (dd), 5.60 (dd)
CDCl3: 3.61 (s), 4.46 (q), 4.65 (d), 5.24 (d)
13b
13c
126
64.7, 67.3
57.6, 72.3
14a, 14b
156.5
16
a Chemical shifts correspond to the CH2CH moiety (one 1H each) and OH (in italics, tentatively assigned by us). b Chemical shifts correspond to the
CH2CH moiety.
Figure 4. Synthesis of triazole 3ia and plot showing its X-ray structure
and atomic numbering.
The experiments described above are conclusive enough to be
utilized as a tool in the unmistakable determination of the
Figure 3. Synthesis of triazole (S)-3ga and plot showing the X-ray
structure and atomic numbering for compound (S)-8.
regiochemistry of the title reaction. Therefore, we are now in a
position to assess the structure assignment of the β-hydroxy-
triazoles reported in the literature (Table 2). Structures in refs
13a and 13c are right, although only based on the melting point
and 1H NMR data, respectively. Reference 13b is wrong, and the
product obtained by the authors is 7ga instead of 3ga. Refer-
ences 14a and 14b are also wrong; in these publications, the
authors prepared compound 3ga instead of 7ga, and accord-
ingly, the structures drawn for the twelve14a and fifteen14b
examples of β-hydroxytriazoles derived from styrene oxide are
incorrect. Finally, ref 16 is right. In our opinion, these findings
open a new debate about which factors govern the regioselec-
tivity in the step of the azidolysis of the epoxide for every
particular case, as it is known that both regioisomers are
accessible for aryl epoxides.
A parallel study was undertaken, using the secondary alcohol
3aa as a model molecule, with the solvents which better exhibited
the multiplicity of the OH above (Figure 6). Disappointingly,
neither wet nor anhydrous CDCl3 was a useful solvent, with the
OH being manifested in both cases as a broad singlet. In contrast,
CD3CN enabled the OH signal to be resolved as a well-defined
doublet. Therefore, CD3CN was considered to be the solvent of
choice for the 1H NMR spectra of both primary and secondary
alcohols. It was gratifying to see that all triazoles synthesized in
this article, which were subjected to the above experiment,
displayed the aforementioned NMR patterns for the hydroxy
group, that is, a triplet (J ∼ 6.0 Hz) for primary alkyl, a doublet
(J ∼ 5.5 Hz) for secondary alkyl, and a doublet (J ∼ 9.0 Hz) for
secondary benzyl β-hydroxyalcohols (see the Experimental Sec-
tion for details).
Stability and Recycling of the Catalyst. The catalyst was
handled in air, and all of the experiments were carried out without
air exclusion; these are advantages that make the process
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Figure 7. Recycling of the CuNPs/C in the synthesis of the triazole 3ga.
Figure 5. 1H NMR region for the CHCH2OH moiety of 3ga in
different solvents.
Table 3. Three-Component Synthesis of β-Hydroxytriazoles
from Epoxides Catalyzed by Different Copper Catalystsa
entry
catalyst
Cu
mol (%)
t (h)
yield (%)b
1
2
3
4
5
6
7
8
10
10
10
10
1
24
24
24
24
24
24
24
8
0
0
CuO
Cu2O
CuCl
50
79
77
64
20
93
CuCl
CuCl2
CuCl2
CuNPs/C
10
1
0.5
Figure 6. 1H NMR region for the NCH2CHOH moiety of 3aa in
different solvents.
a Reaction conditions: 1g (1 mmol), 2a (1 mmol), NaN3 (1.1 mmol),
catalyst in H2O at 70 °C. b Yield determined by 1H NMR of the
reaction crude.
operationally simple. Furthermore, in all cases, the progress of
the reaction could be followed visually. Once the reaction ended,
a nearly spherical solid piece at the surface of a transparent and
colorless solution was observed, where the triazole was in the core
of the solid covered by the catalyst.21b It is worthwile mentioning
that, despite the fact that a small amount of catalyst was utilized, it
could be easily recovered by filtration (after treating with ethyl
acetate) and reused. We noted a progressive decrease in the isolated
yield of triazole 3ga along four consecutive cycles (Figure 7). The
copper in the aqueous solution from the first to the second cycle
was detected to be 80 ppb (ICP-MS), which practically rules out
any loss of catalytic activity by metal leaching. However, a loss of
catalyst mass of approximately 2 mg was measured after each cycle.
This amount, retained by the fitted glass filter during filtration,
represents a 10% of the starting amount of catalyst (20 mg) in the
first cycle and larger in the subsequent cycles. This fact could
account for the tendency observed in the recycling experiments.
Nevertheless, a fair isolated yield of 70% was recorded after the
fourth cycle. We must remark that the aforementioned aqueous
solution obtained after filtration (with 80 ppb Cu) was proven to be
totally inactive in the three-component synthesis of triazole
3ga. Although this experiment points to a process of heterogeneous
nature, we cannot dismiss that the support acts as a reservoir
for metal species that leach into solution and readsorb (the
releaseꢀrecapture mechanism). This kind of process, however,
has been mainly proven to occur for nanoparticle suspensions of the
catalytically active group VIII transition metals.27 More recently,
significant leaching of copper metal was observed in the Cu/C-
catalyzed cycloaddition of benzyl azide and phenylacetylene in
acetone under continuous flow conditions (170 °C, 20 bar,
1.5 mL minꢀ1).28
Comparison with Other Catalysts. We work on the principle
that any laboratory-made catalyst should be more efficient than
commercially available catalysts used for the same purpose.
Otherwise, it is difficult to economically justify the time, materi-
als, and human resources employed during its preparation.
Taking into account this premise, we undertook a comparative
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Scheme 7. Deuterium-Labeling Experiments in the CuNPs/
C-Catalyzed Multicomponent Synthesis of β-Hydroxytriazole
3ga
recently, it has been disclosed that defect sites on CuNPs can
induce intense dissociation of water to form atomic oxygen,
which might somehow participate in the redox mechanism of the
reaction.29 This fact, together with the large surface-to-volume
ratio of the nanocatalyst and its distribution on the support, could
account for the behavior of the CuNPs/C when compared with
the commercial bulk catalysts.
Some Mechanistic Aspects. The general mechanism for the
CuAAC has been a subject of intense debate.30 The principal
discussion arises from whether copper acetylides or copper
π-complexes are the real intermediates. On the other hand,
although the formation a molecular copper(I) triazolide complex
has been often postulated, only Straub et al. isolated this type of
complex as a direct evidence for the existence of such structures
as intermediates in the click reaction.30d Final protonolysis of this
type of intermediate would render the triazole product. Recently,
we have experimentally demonstrated (based on different ob-
servations, specific reactions, and deuteration experiments) that
copper(I) acetylides are the true intermediate species in the
CuAAC involving unsupported CuNPs in the presence of
triethylamine and THF as solvent.20b To the best of our knowl-
edge, however, this kind of research has been tackled neither for
supported CuNPs nor for the multicomponent synthesis of
triazoles from epoxides. In order to gain an insight into the
mechanism of the title reaction, we carried out two deuteration
experiments with styrene oxide (1g) and phenylacetylene (2a)
(Scheme 7): (a) the reaction with deuterated phenylacetylene
2a-d1 afforded the nondeuterated triazole 3ga; (b) the reaction
with nondeuterated phenylacetylene (2a) in D2O led to triazole
3ga-d1 with 90% deuterium incorporation. The participation of
copper π-complexes would yield 3ga-d1 in experiment (a)
because the Cspꢀdeuterium bond would not dissociate in any
step of the catalytic cycle. Therefore, these results suggest that
both copper(I) phenylacetylide and the corresponding copper-
(I) β-hydroxytriazolide are the true intermediates in this
methodology.31
Scheme 8. Deuteration Experiments in the Ionization of
Terminal Alkynes 2a and 2g36
Another aspect which remains unclear in the CuAAC is how
the copper(I) acetylide is generated. We demonstrated that the
formation of phenylacetylide was favored when triethylamine was
present in an organic solvent, such as THF.20b Inaqueous solvents,
however, the scenario is different and requires a thorough survey.
In a recent mechanistic study,30g it was invoked that sodium
ascorbate functions as a base to deprotonate the terminal alkyne in
a 1:1 t-BuOH/H2O solvent mixture. The ionization constant
values, however, do not seem to support this assertion as, if the
case, ascorbate (pKa = 4.04)32 should deprotonate water (pKa =
13.995)32 rather than phenylacetylene (pKa = 20.0).33 Since our
catalytic system is simply composed of CuNPs/C and water, with
no base, a series of labeling experiments were conducted in order
to study how feasible the ionization of terminal alkynes in water
was (Scheme 8). It was very interesting to prove that, despite the
ΔpKa between phenylacetylene and water, ionization of phenyla-
cetylene in D2O readily occurred at room temperature with
quantitative incorporation of deuterium (Scheme 8, eq a). This
method of preparation of deuteriophenylacetylene (2a-d1) is
much more convenient than the classical one through the corre-
sponding Grignard derivative.34 The less acidic dodec-1-yne (2g)
was not as prone to ionization as phenylacetylene either at room
temperature or at 70 °C (Scheme 8, eq b). Control experiments
with the different components of our catalytic system brought to
light that neither sodium azide nor the support exerted any
ionization effect on 2g (Scheme 8, eqs c and d). We were delighted
study on the reactivity of the CuNPs/C with different commer-
cially available copper sources (Table 3). The standard condi-
tions were applied to the reaction of styrene oxide (1g), sodium
azide, and phenylacetylene (2a) at different catalyst loading.
Copper metal and CuO were inactive (Table 3, entries 1 and 2,
respectively), whereas Cu2O gave rise to the expected triazole
3ga in 50% yield (Table 3, entry 3). CuCl was the best of the
commercial catalysts, albeit prolonged heating was necessary and
the conversion was not as high as desirable (Table 3, entries 4 and
5). The conversion dropped for CuCl2, especially when reducing
the catalyst loading to 1 mol % (Table 3, entries 6 and 7).
Therefore, the nanosized character of our catalyst seems to play a
decisive role in its high performance (Table 3, entry 8). Very
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ARTICLE
to observe quantitative incorporation of deuterium in the presence
of the CuNPs (Scheme 8, eq e). Furthermore, the same outcome
was obtained with commercial copper(I) chloride, with the
concomitant formation of a yellow solid that could be ascribed
to the respective copper(I) acetylide (Scheme 8, eq f). This solid
was not observed in experiment (e) (Scheme 8) due to the lower
amount of copper present in a black suspension and/or to the fact
that the copper acetylide remains anchored to the heterogeneous
catalyst. In view of these results, it seems reasonable to propose
that, in the absence of base, CuNPs enhance the acidity of the
terminal alkyne in water, by coordination to the carbonꢀcarbon
triplebond,35 enablingtheformationof the corresponding copper-
(I) acetylide. This finding highlights the double role that CuNPs
can play in the base-free CuAAC and, in particular, in the multi-
component synthesis of β-hydroxytriazoles from epoxides.
coupling constants (J) in hertz. Infrared analysis was performed with a
spectrophotometer equipped with an ATR component; wavenumbers
are given in cmꢀ1. Mass spectra (EI) were obtained at 70 eV; and
fragment ions in m/z with relative intensities (%) in parentheses. HRMS
analyses were also carried out in the electron impact mode (EI) at 70 eV.
Column chromatography was performed using silica gel 60 of 40ꢀ60
μm (hexane/EtOAc as eluent). 1H and 13C NMR data were estimated
with the ACD/Laboratories 6.0 program.
Typical Procedure for the Preparation of CuNPs/C: Anhy-
drous copper(II) chloride (135 mg, 1 mmol) was added to a suspension
of lithium (14 mg, 2 mmol) and 4,40-di-tert-butylbiphenyl (DTBB, 27
mg, 0.1 mmol) in THF (2 mL) at room temperature under an argon
atmosphere. The reaction mixture, which was initially dark green, rapidly
changed to black, indicating that the suspension of CuNPs was formed.
This suspension was diluted with THF (18 mL) followed by the addition
of the activated carbon (1.28 g). The resulting mixture was stirred for 1 h
at room temperature, filtered, and the solid successively washed with
water (20 mL) and THF (20 mL) and dried under vacuum.
’ CONCLUSION
General Procedure for the CuNP/C-Catalyzed Synthesis of
β-Hydroxytriazoles from Epoxides in Water: NaN3 (72 mg, 1.1
mmol), the epoxide (1 mmol), and the alkyne (1 mmol) were added to a
suspension of CuNPs/C (20 mg, 0.5 mol % Cu) in H2O (2 mL). The
reaction mixture was warmed to 70 °C and monitored by TLC until total
conversion of the starting materials. Water (30 mL) was added to the
resulting mixture, followed by extraction with EtOAc (3 ꢁ 10 mL). The
collected organic phases were dried with anhydrous MgSO4, and the
solvent was removed in vacuo to give the corresponding triazoles 3,
which did not require any further purification. Only triazoles (S)-3ga
and (S,S0)-3ge were submitted to column chromatography in order to
get an accurate optical rotation.
We have demonstrated for the first time that copper nano-
particles can catalyze the multicomponent synthesis of triazoles
from epoxides. A wide range of β-hydroxytriazoles have been
synthesized from epoxides, sodium azide, and terminal alkynes in
water with CuNPs/C as catalyst at low metal loading (0.5 mol %).
The methodology developed is regiospecific with respect to both
the azidolysis of the epoxide and the 1,3-dipolar cycloaddition as
follows: (a) monoalkyl-substituted oxiranes give rise to second-
ary β-hydroxytriazoles; (b) an SN20 mechanism governs the
regiochemistry for vinyl epoxides; (c) monoaryl-substituted
oxiranes lead to primary β-hydroxytriazoles with inversion of
the configuration; and (d) 1,4-disubstituted triazoles are solely
formed. The regio- and stereochemistry have been unequivocally
established on the basis of X-ray crystallographic analysis. More-
over, we realized that three of the six publications dealing with
this topic have mistakenly assigned the regiochemistry of the
1-(4-Phenyl-1H-1,2,3-triazol-1-yl)octan-2-ol37 (3aa): White
solid; Rf 0.55 (hexane/EtOAc, 3:2); mp 125.5ꢀ127.0 °C; 1H NMR (300
MHz, CD3CN) δ 8.12 (s, 1H), 7.85 (d, 3J(H,H) = 7.8 Hz, 2H; ArꢀH),
7.44 (t, 3J(H,H) = 7.8 Hz, 2H; ArꢀH), 7.34 (t, 3J(H,H) = 7.8 Hz, 1H;
ArꢀH), 4.43 (dd, 2J(H,H) = 14.0 Hz, 3J(H,H) = 3.5 Hz, 1H; CHHN),
4.27 (dd, 2J(H,H) = 14.0 Hz, 3J(H,H) = 7.6 Hz, 1H; CHHN),
4.00ꢀ3.88 (m, 1H; CHO), 3.47 (d,3J(H,H) = 5.4 Hz, 1H; OH),
1.53ꢀ1.15 (m, 10H; 5 ꢁ CH2), 0.88 (t, 3J(H,H) = 6.6 Hz, 3H;
CH3); 13C NMR (75 MHz, CD3CN) δ 147.4 (NCCH), 130.2 (ArC),
128.8, 128.1, 125.6 (5 ꢁ ArCH), 121.1 (CHN), 70.5 (CHO), 56.2
(CH2N), 34.4, 31.7, 29.1, 25.4, 23.0 [(CH2)5], 14.0 (CH3); IR (neat) ν~
693, 771, 828, 983, 1089, 1142, 1227, 1464, 1602, 2854, 2915, 3135,
3229; MS (70 eV) m/z (%) 273 (20) [M+], 146 (33), 132 (25), 118
(13), 117 (100), 105 (10), 103 (18), 102 (32), 89 (10), 77 (10), 69 (24),
55 (18), 43 (15), 41 (13); HRMS (EI) m/z calcd for C16H23N3O
273.1841, found 273.1850.
1
products. A simple H NMR experiment in CD3CN has been
proposed to rapidly and reliably disclose the regiochemical
outcome in this type of reaction. In addition, the catalyst could
be recycled, with negligible leaching, and reused along four
cycles, providing excellent-to-good yields of the product. Finally,
deuteration experiments unveiled the double role played by the
CuNPs (i.e., alkyne activation for the acetylide formation and
catalysis for the 1,3-dipolar cycloaddition) as well as the very
likely participation of copper(I) acetylides and triazolides as
reaction intermediates.
1-(4-Phenyl-1H-1,2,3-triazol-1-yl)hex-5-en-2-ol (3ba): White
solid; Rf 0.43 (hexane/EtOAc, 1:1); mp 104.9ꢀ107.9 °C; 1H NMR (400
MHz, CD3CN) δ 8.11 (s, 1H), 7.86 (d, 3J(H,H) = 7.5 Hz, 2H; ArꢀH),
7.44 (t, 3J(H,H) = 7.5 Hz, 2H; ArꢀH), 7.34 (t, 3J(H,H) = 7.5 Hz, 1H;
ArꢀH), 5.93ꢀ5.81 (m, 1H; CHdCH2), 5.06 (dd, 3J(H,H) = 12.9 Hz,
2J(H,H) = 1.2 Hz, 1H; CHHdCH), 4.98 (dd, 3J(H,H) = 7.8 Hz, 2J(H,
H)=1.2Hz, 1H; CHHdCH), 4.45 (dd, 2J(H,H) = 14.0Hz, 3J(H,H) = 3.6
’ EXPERIMENTAL SECTION
General: Anhydrous copper(II) chloride (97%, Aldrich), lithium
powder (MEDALCHEMY S.L.), DTBB (4,40-di-tert-butylbiphenyl,
Aldrich), activated charcoal (Norit CA1, Aldrich), and sodium azide
were commercially available. All of the starting materials, deuterated
solvents, and other reagents were commercially available of the best
grade and were used without further purification. THF was dried in a
solvent purification system using an alumina column. Mesylation of
(S)-3ga to give (S)-8 was done following a standard procedure. Melting
points are uncorrected. Optical rotations were measured using a
polarimeter with a thermally jacketted 5 cm cell at approximately
20 °C. Concentrations (c) are given in g/100 mL and [α] values are
given in units of 10ꢀ1 deg cm2 gꢀ1. NMR spectra were recorded at 300
2
3
Hz, 1H; CHHN), 4.30 (dd, J(H,H) = 14.0, J(H,H) = 7.6 Hz, 1H;
3
CHHN), 4.03ꢀ3.93 (m, 1H; CHO), 3.27 (d, J(H,H) = 5.6 Hz, 1H;
OH), 2.30ꢀ2.10 (m, 4H; 2 ꢁ CH2); 13C NMR (100 MHz, CD3CN) δ
147.7 (NCCH), 139.3 (CHdCH2), 132.3 (ArC), 129.9, 128.8, 126.3
(5 ꢁ ArCH), 122.6 (CHN), 115.4 (CH2dCH), 70.2 (CHO), 56.8
(CH2N), 34.3, 30.3(2 ꢁ CH2); IR (neat) ~ν 693, 771, 832, 921, 983, 1097,
1227, 1443, 1472, 1639, 2919, 2939, 3143, 3241; MS (70 eV) m/z (%)
243 (20) [M+], 214 (15), 158 (215), 156 (130), 146 (26), 132 (10), 130
(33), 118 (12), 117 (100), 105 (16), 104 (10), 103 (34), 102 (55), 91
(10), 90 (15), 89 (22); HRMS (EI) m/z calcd for C14H17N3O 243.1372,
found 243.1350.
1
or 400 MHz for H NMR and 75 or 100 MHz for 13C NMR; peak
assignments were done on the basis of DEPT experiments, chemical
shift estimation, and the information obtained from the X-ray crystal-
lographic analysis; chemical shifts are given in (δ) parts per million and
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1-Phenoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-ol14b
138 (18), 137 (10), 117 (23), 116 (100), 102 (18), 91 (15), 89 (23);
HRMS (EI) m/z calcd for C16H14ClN3O 299.0825, found 299.0830.
(1S*,2S*)-1,2-Diphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
ethanol (3ia): White solid; Rf 0.63 (hexane/EtOAc, 1:1); mp
209.0ꢀ212.0 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H;
NCHdC), 7.87 (d, 3J(H,H) = 7.2 Hz, 2H; ArꢀH), 7.49ꢀ7.39 (m, 4H;
ArꢀH), 7.37ꢀ7.30 (m, 3H; ArꢀH), 7.25ꢀ7.17 (m, 6H; ArꢀH), 6.04
(d, 3J(H,H) = 4.8 Hz, 1H; NCHCH), 5.97 (d, 3J(H,H) = 8.7 Hz, 1H;
1
(3ca): Pale yellow solid; mp 125.0ꢀ127.0 °C; H NMR (400 MHz,
CD3CN) δ 8.15 (s, 1H), 7.86 (d, 3J(H,H) = 7.5 Hz, 2H; ArꢀH), 7.44 (td,
4
3J(H,H) = 7.5 Hz, J(H,H) = 1.6 Hz, 2H; ArꢀH), 7.40ꢀ7.17 (m, 3H;
ArꢀH), 7.08ꢀ6.72 (m, 3H; ArꢀH), 4.66 (dd, 2J (H,H) = 14.1 Hz, 3J (H,
H) = 3.8 Hz, 1H; CHHN), 4.52 (dd, 2J(H,H) = 14.1, 3J (H,H) = 7.6 Hz,
1H; CHHN), 4.43ꢀ4.27 (m, 1H; CHO), 4.09ꢀ3.87 (m, 2H; CH2O), 3.75
(d, 3J(H,H) = 5.4 Hz, 1H; OH); 13C NMR (100 MHz, CD3CN) δ 159.6
(NCCH), 147.8, 132.1 (2 ꢁ ArC), 130.5, 129.9, 128.9, 126.3, 122.8, 122.0
(10 ꢁ ArCH), 115.5 (NCCH), 70.1 (CH2O), 69.5 (CHO), 53.9 (CH2N).
(E)-2-Methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)but-2-en-1-ol26
[(E)-3da]: Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.74ꢀ7.66 (m, 3H;
2 ꢁ ArꢀH, CHN), 7.35 (t, 3J(H,H) = 7.2 Hz, 2H; ArꢀH), 7.31ꢀ7.23
(m, 1H; ArꢀH), 5.70 (t, 3J(H,H) = 7.6 Hz, 1H; CHdCCH3), 4.92 (d,
3J(H,H) = 7.2 Hz, 2H; CH2N), 4.06 (br s, 2H; CH2O), 1.67 (s, 3H; CH3);
13C NMR (100 MHz, CDCl3) δ 147.5 (NCCH), 142.3 (CH3CdCH),
130.2 (ArC), 128.6, 127.9, 125.4 (5 ꢁ ArCH), 119.4 (NCCH), 115.9
(CHdCCH3), 66.5 (CH2O), 47.4 (CH2N), 13.7 (CH3).
OH), 5.58 (dd, 3J(H,H) = 8.7 Hz, 3J(H,H) = 4.8 Hz, 1H; CHO); 13
C
NMR (75 MHz, DMSO-d6) δ 146.0 (NCCH), 141.6, 137.2, 130.9 (3 ꢁ
ArC), 128.9, 128.4, 128.2, 128.0, 127.9, 127.8, 127.5, 127.2, 125.1 (15 ꢁ
ArCH), 121.2 (NCCH), 74.3 (CHO), 70.5 (NCHCH); IR (neat) ν~ 697,
750, 771, 1048, 1207, 1231, 1435, 1455, 2854, 2923, 3029, 3082, 3429;
MS (70 eV) m/z (%) 341 (0.3) [M+], 236 (15), 235 (85), 207 (20), 206
(100), 180 (11), 179 (12), 178 (21), 130 (10), 116 (16), 107 (10), 105
(20), 102 (23), 91 (10), 79 (15), 77 (28); HRMS (EI) m/z calcd for
C22H19N3O 341.1528, C15H13N3 235.1109, found 235.1136.
(1S*,2R*)-1,2-Diphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
ethanol (3ja): White solid; Rf 0.68 (hexane/EtOAc, 1:1); mp 206.5ꢀ
211.0 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H; NCHdC), 7.72
(d, 3J(H,H) = 8.5 Hz, 2H; ArꢀH), 7.66 (d, 3J(H,H) = 8.5 Hz, 2H; ArꢀH),
7.44ꢀ7.12 (m, 11H; ArꢀH), 5.98 (d, 3J(H,H) = 4.8 Hz, 1H; NCHCH),
5.89 (d, 3J(H,H) = 9.0 Hz, 1H; OH), 5.54 (dd, 3J(H,H) = 9.0 Hz, 3J(H,
H) = 4.8 Hz, 1H; CHO); 13C NMR (75 MHz, DMSO-d6) δ 146.3
(NCCH), 142.3, 137.9, 130.9 (3 ꢁ ArC), 129.2, 128.9, 128.6, 128.4, 128.2,
128.1, 127.9, 127.2, 125.3 (15 ꢁ ArCH), 121.1 (NCCH), 74.0 (CHO),
69.8 (NCHCH); IR (neat) ~ν 701, 746, 766, 1451, 2850, 2919, 3078, 3123,
3421; MS (70 eV) m/z (%) 341 (0.3) [M+], 236 (15), 235 (89), 207 (19),
206 (100), 179 (10), 178 (20), 130 (10), 116 (14), 107 (11), 105 (21), 102
(22), 79 (14), 77 (26); HRMS (EI) m/z calcd for C22H19N3O 341.1528,
C15H13N3 235.1109, found 235.1092.
(Z)-2-Methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)but-2-en-1-ol26
1
[(Z)-3da]: Yellow oil; H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H;
CHN), 7.74ꢀ7.66 (m, 2H; ArꢀH), 7.39ꢀ7.31 (m, 2H; ArꢀH),
7.31ꢀ7.23 (m, 1H; ArꢀH), 5.45 (t, 3J(H,H) = 7.5 Hz, 1H; CHdCCH3),
5.01 (d, 3J(H,H) = 7.5 Hz, 2H; CH2N), 4.26 (br s, 2H; CH2O), 1.77
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3) δ 147.5 (NCCH), 142.5
(CH3CdCH), 130.2 (ArC), 128.6, 127.9, 125.4 (5 ꢁ ArCH), 119.7,
119.2 (NCCH, CHdCCH3), 60.9 (CH2O), 47.2 (CH2N), 21.5 (CH3).
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclohexanol13a,30e (3ea):
1
White solid; mp 167.8ꢀ171.8 °C; H NMR (300 MHz, DMSO-d6) δ
8.58 (s, 1H; NCHdC), 7.85 (d, 3J(H,H) = 7.5 Hz, 2H; ArꢀH), 7.45 (t,
3J(H,H) = 7.5 Hz, 2H; ArꢀH), 7.32 (dt, 3J(H,H) = 7.5 Hz, 4J(H,H) =
3
1.2 Hz, 1H; ArꢀH), 5.00 (d, J(H,H) = 5.8 Hz, 1H; OH), 4.24 (ddd,
3J(H,H) = 12.1 Hz, 3J(H,H) = 9.9 Hz, 3J(H,H) = 4.2 Hz, 1H; CH2CHN),
3.85ꢀ3.65 (m, 1H; CHO), 2.13ꢀ1.11 (m, 8H; 4 ꢁ CH2); 13C NMR
(75 MHz, DMSO-d6) δ 145.6 (NCCH), 131.2 (ArC), 128.9, 127.6, 122.9
(5 ꢁ ArCH), 120.5 (NCCH), 71.3 (CHO), 66.0 (CHN), 34.7, 31.9, 24.4,
23.9 (4 ꢁ CH2).
2-(4-Hexyl-1H-1,2,3-triazol-1-yl)-2-phenylethanol13a (3gb):
Pale yellow solid; mp 64.2ꢀ66.3 °C; 1H NMR (300 MHz, CD3CN) δ
7.60 (s, 1H; NCHdC), 7.42ꢀ7.26 (m, 5H; ArꢀH), 5.68 (dd, 3J(H,H) =
8.7 Hz, 3J(H,H) = 4.8 Hz, 1H; CHCH2), 4.40ꢀ4.28, 4.15ꢀ4.03 (2 m,
3
3
2H; CH2), 3.32 (t, J(H,H) = 5.9 Hz, 1H; OH), 2.53 (t, J(H,H) =
7.7 Hz, 2H; CH2CN), 1.69ꢀ1.55 (m, 2H; CH2), 1.37ꢀ1.23 (m, 6H; 3 ꢁ
CH2), 0.81 ppm (t, 3J(H,H) = 7.0 Hz, 3H; CH3); 13C NMR (75 MHz,
CD3CN) δ 152.1 (NCCH), 137.8 (ArC), 129.7, 129.5, 128.4 (5 ꢁ
ArCH), 121.3 (NCCH), 66.7 (CHCH2), 65.3 (CH2O), 35.1, 29.3, 28.9,
26.3, 22.4 (5 ꢁ CH2), 13.9 (CH3).
2-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanol13a,c (3ga):
Pale yellow solid; Rf 0.63 (hexane/EtOAc, 3:7); mp 125.0ꢀ127.0 °C;
1H NMR (300 MHz, CD3CN) δ 8.26 (s, 1H; NCHdC), 7.86 (d, 3J(H,
3
H) = 7.3 Hz, 2H; ArꢀH), 7.44 (t, J(H,H) = 7.3 Hz, 2H; ArꢀH),
7.40ꢀ7.31 (m, 6H; ArꢀH), 5.80 (dd, 3J(H,H) = 8.7 Hz, 3J = 4.7 Hz,
1H; CHCH2), 4.46ꢀ4.36, 4.21ꢀ4.12 (2 m, 2H; CH2), 3.40 (t, 3J(H,
H) = 6.5 Hz; 1H, OH); 13C NMR (75 MHz, CD3CN) δ 147.8
(NCCH), 138.1, 131.9 (2 ꢁ ArC), 129.9, 129.8, 129.5, 128.9, 128.2,
126.4 (10 ꢁ ArCH), 121.6 (NCCH), 67.6 (CHCH2), 64.7 (CH2); IR
(neat) ν~ 685, 700, 713, 757, 1026, 1050, 1079, 1148, 1212, 1361, 1436,
1457, 1497, 2939, 3032, 3087, 3123, 3478; MS (70 eV) m/z (%) 265
(22) [M+], 207 (14), 206 (86), 178 (17), 146 (10), 117 (30), 116
(100), 104 (42), 103 (40), 102 (17), 91 (17), 90 (11), 89 (27), 77 (26).
(S)-2-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanol
[(S)-3ga]: The same physical and spectroscopic data as described for
racemic 3ga; [α]20D +14.5 (c 1.0, CHCl3); HRMS (EI) m/z calcd for
C16H15N3O 265.1215, found 265.1213.
2-(4-Cyclohexyl-1H-1,2,3-triazol-1-yl)-2-phenylethanol
(3gc): White solid; Rf 0.48 (hexane/EtOAc, 3:7); mp 128.2ꢀ131.8 °C;
1H NMR (300 MHz, CD3CN) δ 7.60 (s, 1H; NCHdC), 7.42ꢀ7.26 (m,
5H; ArꢀH), 5.68 (dd, 3J(H,H) = 8.7 Hz, 3J(H,H) = 4.8 Hz, 1H;
NCHCH2), 4.40ꢀ4.28, 4.15ꢀ4.03 (2 m, 2H; CH2O), 3.32 (t, 3J(H,H) =
5.9 Hz, 1H; OH), 2.77ꢀ2.65 (m, 1H; CH2CHCH2), 1.83ꢀ1.65 (m, 4H;
2 ꢁ CH2CH2CH), 1.46ꢀ1.34 (m, 4H; 2 ꢁ CH2CH2CH), 1.29ꢀ1.18
ppm [m, 2H; (CH2)2CH2(CH2)2]. 13C NMR (75 MHz, CD3CN) δ
153.4 (NCCH), 138.5 (ArC), 129.8, 129.4, 128.2 (5 ꢁ ArCH), 120.9
(NCCH), 65.0 (CH2O), 64.7 (NCHCH2), 36.1 (CH2CHCH2), 33.8,
26.9, 26.8 [(CH2)5]; IR (neat) ~ν 697, 756, 889, 1067, 1448, 2849, 2923,
3061, 3117, 3233; MS (70 eV) m/z (%) 271 (23) [M+], 213 (18), 212
(100), 149 (21), 130 (12), 123 (10), 122 (14), 121 (64), 109 (12), 104
(37), 103 (72), 95 (14), 94 (12), 93 (12), 91 (58), 81 (17), 80 (39), 79
(27), 78 (10), 77 (36), 69 (10), 67 (27), 65 (11), 56 (13), 55 (18), 43
(13), 41 (21); HRMS (EI) m/z calcd for C16H21N3O 271.1685, found
271.1685.
2-(4-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
ethanol (3ha): White solid; Rf 0.65 (hexane/EtOAc, 3:7); mp
139.6ꢀ142.1 °C; 1H NMR (300 MHz, CD3CN) δ 8.21 (s, 1 H; NCHd
C), 7.8 (d, 3J(H,H) = 7.5 Hz, 2H; ArꢀH), 7.46ꢀ7.27 (m, 7H; ArꢀH),
5.76 (dd, 3J(H,H) = 9.0 Hz, 3J(H,H) = 3.0 Hz, 1H; CHCH2),
3
4.39ꢀ4.27, 4.17ꢀ4.07 (2 m, 2H; CH2), 3.38 (t, J(H,H) = 6.0 Hz,
2-Phenyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanol
(3gd): White solid; Rf 0.26 (hexane/EtOAc, 1:9); mp 112.7ꢀ115.3 °C;
1H NMR (300 MHz, CD3CN) δ 8.52ꢀ8.47 (m, 1H; ArꢀH), 8.35 (s,
1H; OH); 13C NMR (75 MHz, CD3CN) δ 148.0 (NCCH), 137.0,
134.8, 131.9 (3 ꢁ ArC), 130.1, 129.8, 129.7, 129.0, 126.4 (9 ꢁ ArCH),
121.7 (NCCH), 66.8 (CHCH2), 64.6 (CH2); IR (neat) ν~ 691, 730, 764,
819, 1015, 1050, 1092, 1223, 1432, 1460, 1492, 2938, 3085, 3331; MS
(70 eV) m/z (%): 301 (4) [M+ + 2], 299 (13) [M+], 242 (16), 240 (41),
3
1H; NCHdCN), 8.02 (dt, J(H,H) = 7.8 Hz, 4J(H,H) = 1.1 Hz, 1H;
3
4
ArꢀH), 7.76 (td, J(H,H) = 7.8 Hz, J(H,H) = 1.8 Hz, 1H; ArꢀH),
7.34ꢀ7.27 (m, 4H; ArꢀH), 7.21 (ddd, 3J(H,H) = 7.5 Hz, 3J(H,H) = 5.0 Hz,
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The Journal of Organic Chemistry
ARTICLE
4J(H,H) = 1.2 Hz, 1H; ArꢀH), 5.77 (dd, 3J(H,H) = 8.7 Hz, 3J(H,H) =
4.7 Hz, 1H; CHCH2), 4.43ꢀ4.32, 4.17ꢀ4.06 (2 m, 2H; CH2), 3.44
ppm (t, 3J(H,H) = 6.0 Hz, 1H; OH); 13C NMR (75 MHz, CD3CN) δ
151.4 (NCCHN), 150.6 (ArCH), 148.8, 138.0 (2 ꢁ ArC), 137.9, 129.8,
129.5, 128.2, 123.8, 123.5 (8 ꢁ ArCH), 120.6 (NCCHN), 67.7
(NCHCH2), 64.6 ppm (CH2); IR (neat) ν~ 704, 727, 783, 846, 1004,
1057, 1077, 1084, 1200, 1209, 1235, 1246, 1310, 1422, 1475, 1602, 2845,
2906, 3134; MS (70 eV) m/z (%) 266 (15) [M+], 235 (21), 208 (17),
207 (100), 180 (28), 118 (34), 119 (29), 105 (13), 104 (36), 103 (44),
91 (25), 90 (12), 79 (13), 78 (29), 77 (28), 51 (13); HRMS (EI) m/z
calcd for C15H14N4O 266.1168, found 266.1164.
(2S,2S0)-2,20-[4,40-(1,3-Phenylene)bis(1H-1,2,3-triazole-4,
1-diyl)]bis(2-phenylethanol) [(S,S0)-3ge]: White solid; Rf 0.35
(hexane/EtOAc, 1:4); mp 74.5ꢀ79.1 °C; [α]20D +10.6 (c 1.0, CHCl3);
1H NMR (300 MHz, CD3CN) δ 8.33 (s, 2H, 2 ꢁ NCHdC), 8.31 (t,
4J(H,H) = 1.8 Hz, 1H; ArꢀH), 7.81 (dd, 3J(H,H) = 7.8 Hz, 4J(H,H) =
1.8 Hz, 2H; ArꢀH), 7.48 (t, 3J(H,H) = 7.8 Hz, 1H; ArꢀH), 7.40ꢀ7.33
(m, 10H; ArꢀH), 5.82 (dd, 3J(H,H) = 8.7 Hz, 3J(H,H) = 4.5 Hz, 2H;
2 ꢁ CHCH2), 4.48ꢀ4.38, 4.22ꢀ4.13 (2 m, 4H; 2 ꢁ CH2), 3.54 (t,
3J (H,H) = 5.8 Hz; 2H, 2 ꢁ OH); 13C NMR (75 MHz, CD3CN) δ 147.6
(2 ꢁ NCCH), 138.0, 132.6 (4 ꢁ ArC), 130.5, 129.8, 129.5, 128.2, 125.8,
123.3 (14 ꢁ ArCH), 121.9 (2 ꢁ NCCH), 67.7 (2 ꢁ CHCH2), 64.7 (2 ꢁ
CH2); IR (neat) ν~ 695, 759, 792, 1052, 1230, 1372, 1455, 2924, 3133,
3309; MS (70 eV) m/z (%) 452 (23) [M+], 394 (13), 347 (12), 304
(18), 303 (65), 291 (12), 286 (35), 273 (11), 258 (11), 257 (22), 245
(26), 244 (19), 243 (12), 230 (12), 217 (12), 216 (11), 202 (10), 184
(38), 171 (30), 155 (23), 154 (20), 140 (13), 128 (13), 121 (27), 115
(10), 104 (27), 103 (100), 91 (29), 89 (10), 79 (14), 77 (49); HRMS
(EI) m/z calcd for C26H24N6O2 452.1961, found 452.1958.
(S)-2-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl meth-
anesulfonate [(S)-8]: White solid; Rf 0.51 (hexane/EtOAc, 1:1); mp
1
184.1ꢀ186.1 °C; [α]20 ꢀ7.2 (c 0.4, acetone); H NMR (300 MHz,
D
CD3CN) δ 8.25 (s, 1H; NCHdC), 7.89ꢀ7.81 (m, 2H; ArꢀH),
3
3
7.49ꢀ7.31 (m, 8H; ArꢀH), 6.11 (dd, J (H,H) = 9.6, J (H,H) = 4.8
Hz, 1H; CHCH2), 5.17 (dd, 2J(H,H) = 11.0 Hz, 3J(H,H) = 9.3 Hz, 1H;
CHHO), 4.84 (dd, 2J(H,H) = 11.0 Hz, 3J(H,H) = 4.8 Hz, 1H; CHHO),
2.99 (s, 3H; CH3);13CNMR(75MHz, CD3CN) δ148.9 (NCCH), 136.5,
132.1 (2 ꢁ ArC), 130.8, 130.6, 130.4, 129.7, 128.9, 127.0 (10 ꢁ ArCH),
122.4 (NCCH), 71.2 (CHCH2), 64.7 (CH2), 38.1 (CH3); IR(neat) ~ν 694,
762, 813, 881, 966, 993, 1169, 1182, 1343, 2922, 3023; MS (70 eV) m/z
(%) 343 (6) [M+], 236 (13), 206 (16), 117 (11), 116 (59), 105 (13), 104
(100), 103 (27), 102 (11), 91 (26), 89 (16), 80 (14), 78 (12); HRMS (EI)
m/z calcd for C17H17N3O3S 343.0991, C9H11O3S 199.0429, found
199.0441.
1-Deuteriododec-1-yne (2g-d1): Yellow liquid; Rf 0.83 (hexane);
1H NMR (400 MHz, CDCl3) δ 2.18 (t, 3J(H,H) = 7.2 Hz, 2H; CH2C),
3
1.52 (quintet, J(H,H) = 7.1 Hz 2H; CH2CH2C), 1.43ꢀ1.34 (m, 2H;
CH2CH2CH2C), 1.32ꢀ1.19 [m, 12H; (CH2)6CH3], 0.88 (t, 3J(H,H) =
6.8 Hz, 3H; CH3); 13C NMR (100 MHz, CCl3D) δ 84.3 (t, 2J(C,D) = 27.8
Hz, CtCD), 67.8 (t, 1J(C,D) = 149.4 Hz, DCtC), 31.9, 29.6, 29.5, 29.3,
29.1, 28.8, 28.5, 22.7, 18.4 (9 ꢁ CH2), 14.1 (CH3); IR (film) ~ν 721, 1464,
2597, 2854, 2923; MS (70 eV) m/z (%) 167 (0.1) [M+], 110 (13), 97 (16),
96 (46), 95 (12), 83 (43), 82 (100), 81 (38), 80 (15), 70 (11), 69 (39), 68
(48), 67 (48), 57 (16), 56 (19), 55 (48), 54 (17); HRMS (EI) m/z calcd
for C12H21D 167.1784, C11H18D 152.1550, found 152.1535.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of
1-(4-n-Butyl-1H-1,2,3-triazol-1-yl)hex-5-en-2-ol (3bf): Yel-
low oil; Rf 0.61 (hexane/EtOAc, 1:4); 1H NMR (300 MHz, CD3CN) δ
7.40 (s, 1H; NCHdC), 5.72 (ddt, 3J(H,H) = 17.2 Hz, 3J(H,H) = 10.3
Hz, 3J(H,H) = 6.6 Hz, 1H; CHdCH2), 4.92 (dq, 3J(H,H) = 17.1, 2J(H,
H) = 4J(H,H) = 1.4 Hz, 1H; CHHdCH), 4.80 (dq, 3J(H,H) = 10.3 Hz,
3J(H,H) = 10.4 Hz, 2J(H,H) = 4J(H,H) = 1.4 Hz, 1H; CHHdCH), 4.22
(dd, 2J(H,H) = 14.0 Hz, 3J(H,H) = 3.6 Hz, 1H; CHHN), 4.08 (dd, 2J(H,
S
b
triazoles 3; CIF files of the X-ray crystallographic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: falonso@ua.es, yus@ua.es.
3
H) = 14.0 Hz, J(H,H) = 7.4 Hz, 1H; CHHN), 3.85ꢀ3.73 (m, 1H;
CHO), 3.24 (d, 3J(H,H) = 5.4 Hz, 1H; OH), 2.53 (t, 3J(H,H) = 7.7 Hz,
2H, CH2CN), 2.13ꢀ1.93 (m, 2H; CH2CHdCH2), 1.72ꢀ1.56 (m, 6H;
CH2CH2CHO, CH2CH2CH3), 0.81 (t, 3J(H,H) = 7.2 Hz, 3H; CH3);
13C NMR (75 MHz, CD3CN) δ 148.4 (NCCH), 139.3 (CHdCH2),
123.2 (NCCH), 115.3 (CH2dCH), 70.3 (CHO), 56.4 (CH2N), 34.4,
32.4, 30.2, 25.8, 22.9 (5 ꢁ CH2), 14.1 (CH3); IR (neat) ν~ 910, 994,
1053, 1133, 1219, 1456, 1551, 1640, 2859, 2931, 3077, 3289; MS (70
eV) m/z (%) 223 (11) [M+], 181 (10), 168 (11), 166 (11), 152 (23),
139 (17), 138 (33), 126 (27), 110 (61), 98 (23), 97 (11), 96 (23), 95
(11), 94 (10), 83 (18), 82 (36), 81 (82), 80 (21), 79 (22), 69 (20), 68
(53), 67 (27), 57 (28), 56 (17), 55 (63), 54 (40), 53 (19), 44 (17), 43
(100), 42 (17), 41 (91); HRMS (EI) m/z calcd for C12H21N3O
223.1685, found 223.1683.
’ ACKNOWLEDGMENT
This work was generously supported by the Spanish Ministerio
de Ciencia e Innovaciꢀon (MICINN; CTQ2007-65218 and
Consolider Ingenio 2010-CSD2007-00006), the Generalitat
Valenciana (GV; PROMETEO/2009/039), and FEDER. Y.M.
acknowledges the ISO of the Universidad de Alicante for a grant.
’ DEDICATION
§Dedicated to Professor Francisco Palacios on the occasion of his
60th birthday.
5-Deuterio-2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
ethanol (90% D) (3ga-d1): Yellow solid; Rf 0.66 (hexane/EtOAc,
1:4); mp 122.4ꢀ124.4 °C; 1H NMR (300 MHz, CD3CN) δ 7.88ꢀ7.83
(m, 2H; ArꢀH), 7.48ꢀ7.30 (m, 8H; ArꢀH), 5.80 (dd, 3J(H,H) = 8.7
Hz, 3J(H,H) = 4.8 Hz, 1H; CHCH2), 4.47ꢀ4.36, 4.21ꢀ4.11 (2 m, 2H;
’ REFERENCES
(1) (a) Huisgen, R.; Szeimies, G.; Moebius, L. Chem. Ber. 1965,
98, 4014. (b) Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
(2) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
3
CH2), 3.43 (t, J(H,H) = 6.2 Hz, 1H; OH); 13C NMR (75 MHz,
CD3CN) δ 147.8 (NCCH), 138.1, 132.0 (2 ꢁ ArC), 129.9, 129.8, 129.5,
128.9, 128.2, 126.4 (10 ꢁ CH), 121.6 (t, 1J(C,D) = 58.1 Hz, CD), 67.7
(CHCH2), 64.7 (CH2); IR (neat) ν~ 692, 724, 754, 768, 776, 1024, 1051,
1220, 1455, 1475, 1606, 3029, 3060, 3301; MS (70 eV) m/z (%): 266
(28) [M+], 208 (14), 207 (81), 206 (11), 179 (13), 147 (11), 118 (28),
117 (100), 116 (11), 105 (10), 104 (55), 103 (52), 91 (23), 90 (12), 89
(23), 77 (31), 51 (10); HRMS (EI) m/z calcd for C16H14DN3O
266.1278, found 266.1279.
(3) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(4) For reviews, see: (a) Bock, V. D.; Hiemstra, H.; van Maarseveen,
J. H. Eur. J. Org. Chem. 2006, 51. (b) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952. (c) Appukkuttan, P.; Van der Eycken, E. Eur. J.
Org. Chem. 2008, 1133. (d) Kappe, C. O.; Van der Eycken, E. Chem. Soc.
Rev. 2010, 39, 1280. (e) Finn, M. G.; Fokin, V. V. In Catalysis without
8404
dx.doi.org/10.1021/jo2016339 |J. Org. Chem. 2011, 76, 8394–8405

The Journal of Organic Chemistry
ARTICLE
Precious Metals; Morris Bullock, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2010; pp 235ꢀ260.
(21) (a) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Adv. Synth.
Catal. 2010, 352, 3208. (b) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M.
Org. Biomol. Chem. 2011, 9, 6385.
(22) See, for instance:(a) Yadollahi, B.; Danafar, H. Catal. Lett. 2007,
113, 120. (b) Kiasat, A. R.; Badri, R.; Zargar, B.; Sayyahi, S. J. Org. Chem.
2008, 73, 8382.
(23) CCDC-827722 (3aa), 827723 (3ia), and 827724 [(S)-8]
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(24) For a review on the hydrogen bond in the solid state, see:
Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48.
(25) Tenaglia, A.; Waegell, B. Tetrahedron Lett. 1988, 29, 4851.
(26) Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V.
J. Am. Chem. Soc. 2005, 127, 13444.
(5) For recent reviews, see for instance: (a) Click Chemistry for
Biotechnology and Materials Science; Lahann, J., Ed.; John Wiley & Sons:
Hoboken, NJ, 2009. (b) For a special issue on applications of click
chemistry, see: Finn, M. G., Fokin, V., Eds.; Chem. Soc. Rev. 2010, 39, Issue 4.
(c) Quin, A.; Lam, J. W. Y.; Tang, B. Z. Chem. Soc. Rev. 2010, 39, 2522.
(6) For recent reviews, see: (a) Kumaravel, K.; Vasuki, G. Curr. Org.
Chem. 2009, 13, 1820. (b) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009,
13, 1766. (c) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian
J. 2010, 5, 2318. (d) For a review on asymmetric multicomponent
reactions from our group, see: Ramꢀon, D. J.; Yus, M. Angew. Chem., Int.
Ed. 2005, 44, 1602.
(7) (a) Supported Metals in Catalysis; Anderson, J. A., Fernꢀandez
García, M., Eds.; Imperial College Press: London, 2005. (b) For a
review, see: Kaneda, K.; Ebitani, K.; Mizugaki, T.; Mori, K. Bull. Chem.
Soc. Jpn. 2006, 79, 981. (c) Design of Heterogeneous Catalysts: New
Approaches Based on Synthesis, Characterization and Modelling; Ozkan,
U. S., Ed.; Wiley-VCH: Weinheim, Germany, 2009.
(27) For a review, see: Durꢀan Pachꢀon, L.; Rothenberg, G. Appl.
Organomet. Chem. 2008, 22, 288.
(28) Fuchs, M.; Goessler, W.; Pilger, C.; Kappe, C. O. Adv. Synth.
Catal. 2010, 352, 323.
(8) For recent reviews, see: (a) Sun, J.; Bao, X. Chem.—Eur. J. 2008,
14, 7478. (b) White, R. J.; Luque, R.; Budarin, V. L.; Clark, J. H.;
Macquarrie, D. J. Chem. Soc. Rev. 2009, 38, 481. (c) Campelo, J. M.;
Luna, D.; Luque, F.; Marinas, J. M.; Romero, A. A. ChemSusChem 2009,
2, 18. (d) De Rogatis, L.; Cargnello, M.; Gombac, V.; Lorenzut, B.;
Montini, T.; Fornasiero, P. ChemSusChem 2010, 3, 24. (e) For primary
work on the application of copper nanoparticles in the CuAAC, see:
Durꢀan Pachꢀon, L.; van Maarseveen, J. H.; Rothenberg, G. Adv. Synth.
Catal. 2005, 347, 811.
(9) For recent reviews, see: (a) Chanda, A.; Fokin, V. V. Chem. Rev.
2009, 109, 725. (b) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
(10) (a) Laksmi Kantam, M.; Swarna Jaya, V.; Sreedhar, B.; Mohan
Rao, M.; Choudary, B. M. J. Mol. Catal. A 2006, 256, 273. (b) Sharghi,
H.; Khalifeh, R.; Doroodmand, M. M. Adv. Synth. Catal. 2009, 351, 207.
(c) Bꢀenꢀeteau, V.; Olmos, A.; Boningari, T.; Sommer, J.; Pale, P.
Tetrahedron Lett. 2010, 51, 3673.
(29) Chen, C.-S.; Lai, T.-W.; Chen, C.-C. J. Catal. 2010, 273, 18.
(30) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(b) Ahlquist, M.; Fokin, V. V. Organometallics 2007, 26, 4398. (c)
Straub, B. F. Chem. Commun. 2007, 3868. (d) Nolte, C.; Mayer, P.;
Straub, B. F. Angew. Chem., Int. Ed. 2007, 46, 2101. (e) Chassaing, S.;
Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. Chem.—Eur. J.
2008, 14, 6713. (f) Buckley, B. R.; Dann, S. E.; Harris, D. P.; Heaney, H.;
Stubbs, E. C. Chem. Commun. 2010, 46, 2274. (g) Buckley, B. R.; Dann,
S. E.; Heaney, H. Chem.—Eur. J. 2010, 16, 6278. (h) Cantillo, D.;
Avalos, M.; Babiano, R.; Cintas, P.; Jimꢀenez, J. L.; Palacios, J. C. Org.
Biomol. Chem. 2011, 9, 2952.
(31) Very recent deuterium experiments in the reaction of benzyl
azide and phenylacetylene, employing copper(II) sulfate and ascorbate
in H2O/t-BuOH, are also consistent with the intermediacy of copper(I)
phenylacetylide.30h
ꢀ
(11) For a review, see: Amantani, D.; Fringuelli, F.; Piermatti, O.;
Tortoioli, S.; Vaccaro, L. ARKIVOC 2002, xi, 293.
(12) For a review, see: Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004.
(32) Handbook of Chemistry and Physics, 85th ed.; Lide, D. R., Ed.;
CRC Press: Boca Raton, FL, 2004; pp 8ꢀ46 and 8ꢀ51.
(33) Lin, A. C.; Chiang, Y.; Dahlberg, D. B.; Kresge, A. J. J. Am. Chem.
Soc. 1983, 105, 5380.
(13) (a) Yadav, J. S.; Subba Reddy, B. V.; Madhusudhan Reddy, G.;
Narasimha Chary, D. Tetrahedron Lett. 2007, 48, 8773. (b) Kumaraswamy,
G.; Ankamma, K.; Pitchaiah, A. J. Org. Chem. 2007, 72, 9822. (c) Rajender
Reddy, K.; Uma Maheswari, C.; Rajgopal, K.; Lakshmi Kantam, M. Synth.
Commun. 2008, 38, 2158.
(34) Stoffer, J. O.; Strait, D. R.; Filger, D. L.; Lloyd, E. T.; Crain, C.
J. Org. Chem. 1978, 43, 1812.
(35) (a) Siemsen, P.; Livingstone, R. C.; Diederich, F. Angew. Chem.,
Int. Ed. 2000, 39, 2632. (b) Thathagar, M. B.; Beckers, J.; Rothenberg, G.
Green Chem. 2004, 6, 215.
(14) (a) Sharghi, H.; Beyzavi, M. H.; Safavi, A.; Doroodmand,
M. M.; Khalifeh, R. Adv. Synth. Catal. 2009, 351, 2391. (b) Sharghi,
H.; Hosseini-Sarvari, M.; Moeini, F.; Khalifeh, R.; Beni, A. S. Helv. Chim.
Acta 2010, 93, 435. (c) Boningari, T.; Olmos, A.; Reddy, B. M.; Sommer,
J.; Pale, P. Eur. J. Org. Chem. 2010, 6338.
(15) Brik, A.; Alexandratos, J.; Lin, Y.-C.; Elder, J. H.; Olson, A. J.;
Wlodawer, A.; Goodsell, D. S.; Wong, C.-H. ChemBioChem 2005, 6, 1167.
(16) Campbell-Verduyn, L. S.; Szymaꢀnski, W.; Postema, C. P.;
Dierckx, R. A.; Elsinga, P. H.; Janssen, D. B.; Feringa, B. L. Chem.
Commun. 2010, 46, 898.
(36) All reactions in Scheme 8 were stirred overnight. Neither the
reaction time nor the temperature was optimized. Room temperature or
the standard temperature of 70 °C used along the article was applied.
(37) Szymanski, W.; Postema, C. P.; Tarabiono, C.; Berthiol, F.;
Campbell-Verduyn, L.; de Wildeman, S.; de Vries, J. G.; Feringa, B. L.;
Janssen, D. B. Adv. Synth. Catal. 2010, 352, 2111.
(17) For reviews, see: (a) Alonso, F.; Radivoy, G.; Yus, M. Russ.
Chem. Bull., Int. Ed. 2003, 52, 2563. (b) Alonso, F.; Yus, M. Chem. Soc.
Rev. 2004, 33, 284. (c) Alonso, F.; Yus, M. Pure Appl. Chem. 2008, 80,
1005. (d) Alonso, F.; Riente, P.; Yus, M. Acc. Chem. Res. 2011, 44,
379.
(18) (a) Alonso, F.; Vitale, C.; Radivoy, G.; Yus, M. Synthesis
2003, 443. (b) Alonso, F.; Moglie, Y.; Radivoy, G.; Vitale, C.; Yus, M.
Appl. Catal. A 2004, 271, 171. (c) Radivoy, G.; Alonso, F.; Moglie, Y.;
Vitale, C.; Yus, M. Tetrahedron 2005, 61, 3859.
(19) For a recent contribution, see: Alonso, F.; Melkonian, T.;
Moglie, Y.; Yus, M. Eur. J. Org. Chem. 2011, 2524.
(20) (a) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Tetrahedron
Lett. 2009, 50, 2358. (b) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Eur.
J. Org. Chem. 2010, 1875.
8405
dx.doi.org/10.1021/jo2016339 |J. Org. Chem. 2011, 76, 8394–8405