Copper-catalyzed huisgen 1,3-dipolar cycloaddition under oxidative conditions: Polymer-assisted assembly of 4-acyl-1-substituted-1,2,3-triazoles

Article abstract of DOI:10.1021/jo400800j

We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the thermodynamic instability of copper(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne-azide cycloaddition.

Full text of DOI:10.1021/jo400800j

Article
pubs.acs.org/joc
Copper-Catalyzed Huisgen 1,3-Dipolar Cycloaddition under
Oxidative Conditions: Polymer-Assisted Assembly of 4‑Acyl-1-
Substituted-1,2,3-Triazoles
Paula M. Diz,†,‡ Alberto Coelho,*,†,‡ Abdelaziz El Maatougui,†,‡ Jhonny Azuaje,†,‡ Olga Caamano,‡
̃
§
,†,‡
́
Alvaro Gil, and Eddy Sotelo*
‡
†Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Department of Organic Chemistry, Faculty of
§
Pharmacy, and Institute of Ceramics, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
S
* Supporting Information
ABSTRACT: We herein document the first example of a
reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition
under oxidative conditions. The combined use of two polymer-
supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-
5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the
thermodynamic instability of copper(I) species toward
oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-
dipolar cycloadditions in the presence of an oxidant agent.
This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-
substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne−azide cycloaddition.
derivatives, have shown to preserve the reliability of the
reaction in challenging applications.1,6 These agents stabilize
Cu(I) (shielding catalytic species from interactions that lead to
degradation), thus enabling the reaction to work under aerobic
conditions, thereby reducing the catalyst loading and
preventing oxidative damage of biomolecules.1 Such a scenario
has stimulated the emergence of copper-immobilized catalytic
systems, particularly of those based on polymeric matrices
incorporating Cu(I)-stabilizing chelates.1,7
In the context of a program to develop polymer-assisted
methodologies enabling the rapid assembly of privileged
structures, libraries of pharmacologically relevant 4-acyl-1-
substituted-1,2,3-triazoles (5)8 were required. CuAAC-based
approaches targeting this chemotype (Figure 1) employ azides
(2) and either acetylenic carbinols (1) or ynones (3) as
dipolarophiles, both strategies requiring an additional oxidation
step to generate the ketone function (either at the starting
propynol 1 or the 1,2,3-triazolic intermediate 4) that must
necessarily be carried out as a separate step.8 Accordingly, we
speculated on the feasibility of a direct pathway to access 4-acyl-
1-substituted-1,2,3-triazoles (5) starting from azides 2 and
propynols 1 by performing CuAAC in the presence of an
oxidant reagent that is able to selectively transform the hydroxyl
group into a ketone function, without affecting the performance
of the catalytic process. Being aware that instability of Cu(I)
species precluded the viability of such a strategy employing
conventional homogeneous catalysts, and building upon
Cohen’s “wolf and lamb” principle,9 which states that resins
INTRODUCTION
■
By virtue of its regiospecificity, reliability, and experimental
simplicity, the Cu(I)-catalyzed alkyne−azide cycloaddition
(CuAAC)1 has emerged as the flagship of click chemistry,2 a
synthetic paradigm of remarkable practical and environmental
significance that has found applications in diverse areas.3
Independently, Medal4 and Sharpless5 introduced the copper-
catalyzed Huisgen cycloaddition, highlighting its regiospecific-
ity, substrate scope, and tremendous acceleration of the
reaction. These seminal papers proposed alternative approaches
to overcome the thermodynamic instability of Cu(I), thus
providing the currently established experimental procedures to
perform CuAAC:1 by employing Cu(I) salts [e.g., copper(I)
iodide] in combination with ligands and/or bases, or the in situ
generation of Cu(I) from copper(II) salts [e.g., copper(II)
sulfate pentahydrate], either by comproportionation with
copper metal or employing a sacrificial reducing agent (typically
sodium ascorbate) that constantly reduces Cu(II) to Cu(I),
maintaining high levels of catalytically active species. The
simplicity and robustness of the reaction, notwithstanding the
instability of Cu(I) oxidation state, generally impose strict
experimental conditions aimed to minimize the impact of
oxidant species. Accordingly, reliable CuAAC protocols,
employing Cu(I) halides, are performed under anaerobic
conditions, while those taking place under a weakly reductive
reaction medium (sodium ascorbate) do not require an inert
atmosphere. Despite extensive practical validation of the
transformation,1,3 the development of CuAACs in the presence
of oxidant agents remains a methodological challenge.
Although CuAAC is effectively catalyzed under “ligand-free”
Received: April 15, 2013
conditions,1 diverse ligands, particularly some heterocyclic
© XXXX American Chemical Society
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Figure 1. CuAAC-based pathways targeting 4-acyl-1-substituted-1,2,3-triazoles (5).8
with mutually incompatible functionality do not interact with
each other and may be used together to achieve one-pot
transformations that would not be possible employing their
soluble phase counterparts, it was reasoned that the combined
use of two polymer-supported reagents10 (e.g., a heterogenized
Cu(I) chelating catalytic system and a mild oxidant reagent
grafted to a polymeric matrix) would be able to overcome the
Figure 2. Structure of herein employed polymer-supported reagents.
previously stated limitations.
Herein, we document a polymer-assisted approach enabling
reliable Cu(I)-catalyzed alkyne−azide cycloadditions under
oxidative conditions. Our findings, in addition to providing
an efficient, environmentally friendly, and shortened pathway to
access 4-acyl-1-substituted-1,2,3-triazoles 5, emphasize the
potential of heterogeneous CuAACs in comparison to their
homogeneous counterparts, reveal novel facets of the trans-
formation, and consequently, expand their scope. To the best of
our knowledge, this is the first report describing a Cu(I)-
catalyzed alkyne−azide cycloaddition in the presence of an
oxidant reagent, and the implementation of such a trans-
formation provides theoretical, as well as practical, connotations
that go beyond the direct access to 1,2,3-triazoles 5 starting
from azides (2) and propynols (1).
PS-TBD-Cu(I),13 negligible leaching of the metal was verified
by ICP-MS analysis (of solvent and isolated products),
confirming that the excellent stabilizing/chelating profile of
the TBD framework guarantees that copper species remain
fixed on the solid support, which would enable minimizing its
exposition to oxidant agents. A search among supported
reagents able to efficiently oxidize alcohols under mild
conditions highlighted the tailored reactivity and selectivity
profiles elicited by polymeric matrices incorporating the 2-
iodoxybenzoic acid scaffold (IBX).14 Among this reagent’s
family, polystyrene IBX amide15 (7, 0.5−1.0 mmol/g) was
selected (Figure 2), which is a stable (air- and moisture-
tolerant) and highly efficient reagent that is able to rapidly (2−
5 h) and selectively transform activated alcohols into the
corresponding ketones or aldehydes at room temperature.15c
The first stage of the study consisted of a brief verification
that candidates 6 and 7 constitute highly competent supported
reagents for each single step; to this end, 1-phenylprop-2-yn-1-
ol (1a), 1-phenylprop-2-yn-1-one (3a), and benzyl azide (2a)
were employed as model substrates (Scheme 1). These
experiments were also aimed at exploring the key experimental
parameters in order to reach proof of concept (e.g., solvent
compatibility, reaction temperature, as well as the equivalents of
each supported reagent required for optimal performance in
reasonable reaction times). The obtained results were
consistent with previous data, validating the robustness of the
supported reagents (6 and 7) for the tested transformations
[alcohol oxidation (1a → 3a, 4a → 5a), as well as CuAAC (1a
+ 2a → 4a, 3a + 2a → 5a)], affording 1,2,3-triazoles 4a and 5a
in nearly quantitative yields. The optimized conditions
(Scheme 1) require a slight excess of both polymer-supported
reagents [2 equiv of PS-TBD/Cu (≈3 mol % Cu) and 3 equiv
for PS-IBX-amide] to ensure a complete conversion of the
reactants at room temperature in reasonable times (8−10 h for
CuAAC and 2−5 h for alcohol oxidation). Although the effect
of the solvent does not seem to be particularly critical (DMF,
CHCl3, and DCM are eligible), DMF was preferred for further
optimization due to its generality and excellent swelling of
RESULTS AND DISCUSSION
■
Because the feasibility and practical interest of the proposed
pathway rely heavily on the robustness and compatibility of the
polymer-supported reagents employed, particularly for the
CuAAC catalyst, we have focused on a comprehensive survey of
candidates exhibiting not only excellent efficiency and
selectivity but also optimal performance on challenging reaction
environments and the recyclability criteria. Among the plethora
of heterogeneous catalysts described for CuAAC,11 it became
apparent that copper chelates derived from amine-based
heterocyclic ligands grafted to polymeric matrices6,7 were
ideally suited for this application. These catalytic systems have
been shown to prevent oxidative dimerization pathways when
performing CuAAC under oxidative environments.1,12 The
heterocyclic moiety stabilizes catalytically active copper species,
shielding them from interactions that lead to degradation,
simultaneously exhibiting significant efficacy as copper
scavengers. Attending to its effectiveness, robustness, and
polyvalent roles, the polystyrene-based 1,5,7-triazabicyclo-
[4,4,0]dec-5-ene (TBD) framework-copper chelate [PS-TBD-
Cu, (6)]13 seemed to us to be a good candidate for proof of
concept (Figure 2). While the presence of homogeneous
copper species was detected during CuAAC experiments with
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Scheme 1. Polymer-Assisted Step-Wise Synthesis of 4-Acyl-1-benzyl-1,2,3-triazoles
polystyrene-based matrices. When the superior reactivity profile
exhibited by electron-deficient acetylenes toward 1,3-dipolar
cycloadditions,16 and particularly some precedents describing
its participation in the Huisgen reaction,16 were taken into
account, the role of the polymer-supported copper catalyst
within the transformation was validated. With this aim, 1-
phenylprop-2-yn-1-one (3a) and benzyl azide (2a) were
combined under identical experimental conditions to those
previously studied (but in the absence of the catalyst). These
experiments failed to afford the 4-benzoyl-1-benzyl-1,2,3-
triazole (5a), verifying conversion levels below 10% after 48
h of reaction, which unequivocally validated that the supported
copper species (PS-TBD/Cu) play a key role during the
observed transformation. It should be noted that, as expected,
attempts to perform the tandem process delivering 5a under
conventional homogeneous conditions [employing Dess−
Martin or IBX reagents as oxidants and Cu(I) species in
combination with established CuAAC ligands (e.g., DIPEA or
TBTA)]1 failed, producing complex mixtures.
Equipped with robust polymer-supported candidates (6 and
7), putatively fulfilling the requirements of the designed
pathway, we proceeded to assess the feasibility of the Cu(I)-
catalyzed alkyne−azide cycloaddition under oxidative con-
ditions. Equimolecular amounts (0.5 mmol) of 1-phenylprop-2-
yn-1-ol (1a) and benzyl azide (2a) were added to a
preincubated solution (DMF) containing PS-IBX-amide (3
equiv) and PS-TBD/Cu (2 equiv, i.e. 3 mol % Cu)13, and the
mixture was submitted to orbital stirring at room temperature
under either anaerobic or aerobic conditions. Gratifyingly, it
was verified that complete consumption of the reactants
occurred within 24 h, and the reaction regioselectively afforded
4-benzoyl-1-benzyl-1,2,3-triazole (5a) in excellent yields (90−
92%), irrespective of whether the cycloaddition was performed
under aerobic or anaerobic atmosphere. Full conversion and
high purity were observed for the transformation in the
following solvents: DMF, CHCl3, and acetonitrile.
byproducts derived from oxidative coupling pathways (e.g., bis-
acetylenic compounds, 5,5′-bistriazoles, or 5-alkynyl-1,2,3-
triazoles)12 when CuAAC was performed under oxidant
conditions, thus confirming the appropriateness of the herein
documented approach. The absence of bis-acetylenic com-
pounds or enynes (derived from Glaser or Strauss reactions)
suggests that, notwithstanding the presence of polymer-
supported oxidant (PS-IBX-amide), cupric species are not
substantially formed. This is likely due to the excellent chelating
profile of the TBD framework that scavenges copper species
from solution and shields catalytic species from degradation.
The polymeric nature of the catalyst could also contribute to
such a chemoselective behavior because the formation of
copper acetylides on the solvated polymeric matrix thoroughly
prevents the occurrence of cross-coupling reactions.1 In a
similar fashion, the nonappearance of oxidative dimeric
compounds 5,5′-bistriazoles or 5-alkynyl-1,2,3-triazoles, which
are byproduct compounds generally afforded when performing
CuAAC transformations under mild oxidative conditions,12
should be necessarily related to the following: (a) the use of
two polymeric reagents effectively prevents capture and
oxidative pathways on triazolyl copper intermediates [since
both reactive species are linked to different resins], and (b) as
recently demonstrated,12 the use of catalytic systems consisting
of copper coordination forms a complex with nitrogenated
ligands, inhibits oxidative dimerization exclusively, and affords
targeted 1,2,3-triazoles.
The availability of authentic samples of 1-phenylprop-2-yn-1-
one (3a) and triazole 4a enabled us to detect both
intermediates in the reaction mixture, which confirmed that
both pathways are simultaneously operating during the tandem
process (Figure 3). Briefly, the CuAAC of azide (2) and the 1-
substituted-prop-2-yn-1-ol (1) afforded the triazolic carbinol
intermediate (4) that was subsequently oxidized and generated
the target structure (5). Alternatively, the oxidation of the
starting 1-substituted-prop-2-yn-1-ol (1) generated an ynone
intermediate (3) that was transformed into 4-acyl-1-benzyl-
1,2,3-triazole 5 by the CuAAC with benzyl azide.
A brief screening of the reaction to assess the effect of
lowering copper loadings (1.5 and 2 mol %) revealed a similar
performance, albeit requiring longer reaction time (24−48 h),
while a similar study for the equivalents of PS-IBX-amide
confirmed that a minimum of 3 equiv is required. An exhaustive
scrutiny of the reaction mixture revealed the nonappearance of
In an attempt to evaluate the importance of the supported
ligand (PS-TBD/Cu) on the tandem process, 1-phenylprop-2-
yn-1-ol (1a) and benzyl azide (2a) were reacted under
previously optimized experimental conditions (Scheme 1),
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Table 1. Representative 1,2,3-Triazoles Obtained Employing
Optimized Conditions
Figure 3. Alternative operating pathways.
but we used the polymeric version of two established ligands
for CuAAC (TBTA7a and DIPEA1), instead of using PS-
TBTA/Cu. These experiments highlighted the supreme
stabilization provided by heterocyclic ligands (TBD and
TBTA), both of which exhibited similar reactivity and
comparable yields (87−90%). Conversely, the use of PS-
DIPEA/Cu produced lower yields (46%) and the concomitant
formation of byproducts.
Having established the feasibility of the proposed method for
the model system, a preliminary assessment of the robustness
and scope of the developed methodology was performed by
recurring to a set of assorted dipolarophiles (1a−l) and benzyl
azide (2a). We were pleased to observe that the conditions
described in Scheme 2 led to a smooth cycloaddition, which
Scheme 2. Polymer-Assisted One-Pot Synthesis of 4-Acyl-1-
benzyl-1,2,3-triazoles
exclusively afforded 4-acyl-1-benzyl-1,2,3-triazoles (5). The
structures of the obtained compounds are depicted in Table
1. It can be seen that the reaction allows a thorough variation
(electronic as well as steric) in the acetylenic partner, thus
generating 1,2,3-triazoles incorporating diverse acyl residues at
position 4 (compounds 5a−l). It is noteworthy to highlight that
the reaction remains successful for dipolarophiles incorporating
hindered aromatic residues (e.g., 2-Cl or 2,6-Cl). The use of
propargyl alcohol was similarly successful, enabling the
introduction of a formyl group at position 4 of the heterocycle
without observing the formation of overoxidation products.
The purity of the crude isolated adducts was generally higher
than 90%, as determined by LC-MS analysis, and the
compounds that did not reach this level were purified by
preparative chromatography.
captured by an organic azide that is generated in situ from an
appropriate halide and sodium azide. Encouraged by the
efficiency of the new pathway herein described (Scheme 2), and
to further evaluate its potential conceptual and practical
connotations, we wondered if it would be possible to observe
a polymer-assisted three-component assembly of 4-acyl-1-
A serious limitation of the copper-mediated Huisgen
cycloaddition in drug discovery programs arises from the
relatively low abundance of commercially available azides.1
Such a drawback is generally overcome by developing three-
17
component transformations,
where the dipolarophile is
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Scheme 3. Polymer-Assisted One-Pot Synthesis of 4-Acyl-1-substituted-1,2,3-triazoles
substituted-1,2,3-triazoles (5), starting from acetylenic carbinols
(1), halides (8), and sodium azide (Scheme 3). Such a
transformation would combine, in a one-pot sequence, the in
situ generation of the organic azide (2), a copper-mediated
Huisgen 1,3-dipolar cycloaddition, and the oxidation of the
alcoholic residue [either at the starting propynol (1) or the
heterocycle (4)]. While the dual role of PS-TBD/Cu
[consisting of copper species immobilized on a highly effective
chelating/stabilizing basic residue (TBD)] facilitates the
implementation of three-component approaches,13 some
studies have described the IBX ability to transform halides
into their corresponding carbonyl compounds18 (DMSO, 65
°C). We anticipated a critical issue that could have potentially
affected the feasibility of the projected pathway (Scheme 3). To
address a potential issue, the reaction of two representative
halides (8a, b) with PS-IBX-amide (3−5 equiv) in DMF was
studied (at room temperature and 40 °C, respectively). We
were pleased to observe that halides 8a, b remained unaltered
under the evaluated conditions, even when combining a large
excess (4 equiv) of PS-IBX-amide at 40 °C. These results
provided a solid foundation for the feasibility of the planned
reaction sequence.
The feasibility of the designed polymer-assisted three-
component transformation (Scheme 3) was assessed employing
1-(4-chlorophenyl)prop-2-yn-1-ol (1b), sodium azide, and two
model halides [benzyl bromide (8a) and ethyl bromoacetate
(8b)]. Process optimization involved a study examining the
optimal alkyne/halide/sodium azide ratio, solvent, and temper-
ature, as well as variable equivalents of the polymeric reagents
(6 and 7). All reactions were performed under aerobic
conditions by adding the reactants to a preincubated slurry of
the polymer-supported reagents and submitting the reaction
mixture to vigorous orbital stirring at room temperature. A
slight excess of sodium azide, in combination with DMF as
reaction medium, was critical to achieve a complete conversion
in reasonable reaction times (18−24 h). After we refined the
experimental parameters, it was verified that, in the presence of
PS-TBD/Cu (3 equiv) and PS-IBX-amide (5 equiv), 1-(4-
chlorophenyl)prop-2-yn-1-ol (1b), sodium azide, and the
selected halides were smoothly and regiospecifically converted
to the corresponding 4-(4-chlorobenzoyl)-1-substituted-1,2,3-
triazoles (5b and 5m), resulting in a satisfactory yield (79 and
70%, respectively, Table 2). The reaction performed well at
room temperature, and the optimal alkyne/halide/azide ratio
was 1.0/1.0/1.5. As observed in previous experiments (Scheme
1), a scrutiny of the reaction mixture confirmed excellent
selectivity with an absence of subproducts derived from Glaser-
type homocoupling or oxidative dimerization.
in Table 2, the reaction was not influenced by either the
electronic or steric variations of the reacting substrates, being
broadly successful for both variable components (i.e.,
dipolarophiles and halides). A significant structural variation
was well-tolerated in the halide, as exemplified by a range of
alkyl, benzyl, and heteroaryl halides, as well as dipolarophiles
(covering aliphatic and aromatic series). It should be noted that
the transformation was not limited to aryl or alkylpropynols,
but it also tolerated propargyl alcohol as the acetylenic partner
(that successfully afforded carbaldehydes with somewhat
satisfactory yield). The information contained in Table 2
enabled the scope of this mild and efficient procedure to be
evaluated, exemplifying its contribution in terms of rapid access
to hitherto unexplored diversity spaces. This simple method
preserves the reliability of the previously developed approach,
while maximizing the diversity space for position 1 of the 1,2,3-
triazole core.
The success achieved (Schemes 2 and 3) provides
unequivocal validation of the reliability of the herein proposed
Cu(I)-catalyzed alkyne−azide cycloaddition under oxidative
conditions. Nonetheless, a critical analysis reveals that the
practical implementation of the concept underexploits advan-
tages derived from the polymeric nature of 6 and 7. According
to one of the basic principles of Green Chemistry,19 catalytic or
recyclable reagents are superior to stoichiometric reagents.
Thus, in addition to its efficacy and robustness, the recyclability
of polymer-supported reagents constitutes a remarkable feature,
with practical and environmental implications. Although
efficiently affording targeted compounds, the experimental
protocols described in Schemes 2 and 3 [consisting of the
addition of reactants to a mixture of both supported reagents (6
and 7) in DMF] precluded the separation, regeneration, and
potential reuse of 6 and 7 in newer transformations;
accordingly, we focused on the development of practical
protocols enabling us to recycle and reuse 6 and 7. The
polymer-supported reagents herein employed elicit different
recycling potentials, while PS-TBD/Cu (6) can be recycled
after a simple washing and drying protocol;13 conversely, the
reuse of PS-IBX-amide (7) requires an oxidative activation
step.15b Two alternative scenarios achieving this goal were
devised: the first one is based on the compartmentalization of
the polymer-supported reagents, and the second is based on the
implementation of a continuous-flow process. Considering its
versatility and experimental simplicity, we have chosen the
compartmentalization approach, in which one of the reactants
(or catalysts) remains physically separated by permeable
containers (e.g., membranes or capsules), guaranteeing
retention of the encapsulated substrate, while allowing smooth
transport of solvent, reactants, and products. Such a strategy
has recently become an attractive approach pursuing the largely
elusive goal of recycling homogeneous catalysts (i.e., function-
Having optimized the performance of the catalytic system for
the model examples, the scope of the three-component reaction
on a number of assorted substrates was examined. As observed
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Table 2. Representative 1,2,3-Triazoles Obtained Employing Optimized Conditions
alized dendritic catalyst systems).20 According to the require-
ments of our reaction setup and inspired by the pioneer
Houghten’s “tea bag” method,21 an experimental protocol was
designed by confining both polymer-supported reagents in
mesh bags, enabling the circulation of solvents and reactants,
while isolating both polymeric reagents. The practical
implementation of the compartmentalization strategy is
illustrated in Figure 4.
For a preliminary validation of the tea bag compartmental-
ization protocol, the required amount of each polymer-
supported reagent was encapsulated into polypropylene mesh
bags and then placed into a vial containing a DMF solution of
the model reactants [1-phenylprop-2-yn-1-ol (1a) and benzyl
azide (2a)]. Subsequently, the reaction mixture was submitted
to orbital stirring at room temperature. Under these conditions,
the substrates (1a and 2a) would migrate into the membrane
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0.5−1.0 mmol/g, PS-DIPEA, 3 mmol/g, Tentagel-TBTA, 0.17 mmol/
g) were purchased from commercial sources. Acetylenic carbinols were
prepared according to the literature22 or purchased from commercial
sources. Organic extracts were dried with anhydrous Na2SO4. The
reactions were monitored by TLC, and purified compounds each
showed a single spot. Unless stated otherwise, UV light and/or iodine
vapor was used for the detection of compounds. The synthesis and
purification of all compounds were accomplished using the equipment
routinely available in organic chemistry laboratories. Most of the
preparative experiments were performed in coated vials on an organic
synthesizer with orbital stirring. Purification of isolated products was
carried out by column chromatography. Compounds were routinely
characterized by spectroscopic and analytical methods. Melting points
were determined on a melting point apparatus and are uncorrected.
The chemical structures of the obtained compounds were charac-
terized by nuclear magnetic resonance spectroscopy (1H and 13C) and
high-resolution mass spectra (HRMS). Unless otherwise quoted,
NMR spectra were recorded in CDCl3. Chemical shifts are given as δ
values against tetramethylsilane as the internal standard, and J values
are given in Hz. Inductively coupled plasma mass spectroscopy (ICP-
MS) analysis of compounds 5a and 5b was performed on a Varian
820-MS spectrometer (after microwave-assisted digestion of the
samples).
Representative Procedure for the Immobilization of Copper
Species on Polystyrene-Supported TBD (PS-TBD). To a solution
of 18 mg of CuI in 35 mL of MeCN was added 1.0 g of PS-TBD
(loading 2.6 mmol/g), and the suspension was vigorously stirred
under orbital stirring at room temperature for 24 h. The resulting
supported catalyst was filtered through a fritted syringe, washed
(DCM, diethyl ether), and dried under vacuum for 8 h at room
temperature. Copper loading (0.28%) was determined by wavelength
dispersive X-ray fluorescence spectrometry (WD-XRF).13
Representative Procedure for the Synthesis of 4-Acyl-1-
substituted-1,2,3-triazoles. Method A: A mixture of the acetylenic
carbinol (0.189 mmol) and the organic azide (0.189 mmol) in DMF
(2 mL) was added to a vial containing a slurry of the polymer-
supported reagents [PS-TBD/Cu (0.378 mmol) and PS-IBX-amide
(0.567 mmol)] in DMF (3 mL). The reaction mixture was submitted
to orbital stirring at room temperature, until reactions reached
completion (12−24 h). The polymer-supported catalysts were filtered
through a fritted syringe in a 12-channel vacuum manifold and washed
with DCM and THF. The filtrate was evaporated to give a residue that
afforded the corresponding substituted 1,2,3-triazoles after recrystal-
lization or chromatographic purification.
Representative Procedure for the Three-Component Syn-
thesis of 4-Acyl-1-substituted-1,2,3-triazoles. Method B: A
mixture of sodium azide (0.283 mmol), alkyl halide (0.189 mmol), and
the corresponding acetylenic carbinol (0.189 mmol) in DMF (2 mL)
was added to a vial containing a slurry of the polymer-supported
reagents [PS-TBD/Cu (I) (0.567 mmol) and PS-IBX-amide (0.945
mmol)] in DMF (3 mL). The reaction mixture was submitted to
orbital stirring at room temperature, until reactions reached
completion (18−24 h). The polymer-supported catalysts were filtered
through a fritted syringe in a 12-channel vacuum manifold and washed
with DCM and THF. The filtrate was evaporated to give a solid or
residue that afforded the corresponding substituted 1,2,3-triazoles after
recrystallization or chromatographic purification.
Representative Procedure for the Synthesis of 4-Acyl-1-
substituted-1,2,3-triazoles. Method C (Click Chemistry in a Tea
Bag):21 A mixture of the acetylenic carbinol (0.189 mmol) and the
organic azide (0.189 mmol) in DMF (2 mL) was added to a vial
containing the supported reagents encapsulated in polypropylene
mesh bags [PS-TBD/Cu(I) (0.378 mmol) and PS-IBX-amide (0.567
mmol)]. The reaction mixture was submitted to orbital stirring at
room temperature, until reactions reached completion (24−36 h). The
bags were removed, suspended in DCM, and washed with DCM and
THF. The filtrate was evaporated to give a solid or residue that
afforded the corresponding substituted 1,2,3-triazoles after recrystal-
lization or chromatographic purification.
Figure 4. Illustration of the compartmentalization experiments.
Polypropylene mesh bag containing PS-TBD/Cu and PS-IBX-amide
(left). Both encapsulated reagents enclosed into a vial containing a
DMF solution of the reactants (right).
bags, in which they interact with the catalytically active copper
species, or the oxidant, and would be converted into the
corresponding 1,2,3-triazole or ketone. The success of the
designed pathway was confirmed 36 h later, when it was
observed that the reactants (1a and 2a) were thoroughly
transformed into 4-benzoyl-1-benzyl-1,2,3-triazole (5a) with an
excellent yield (84%). Notably, a similar experimental design
employing ethyl bromoacetate and sodium azide also validated
the feasibility of the compartmentalization protocol for the
three-component reaction, affording comparable results (e.g.,
yields and reaction times).
Once the practicability of the tea bag compartmentalization
approach was validated, we determined that it effectively
enabled the straightforward separation and recycling of both
polymer-supported reagents, making it possible to perform the
washing and activation (for PS-IBX-amide with oxone) of the
polymeric materials in the polypropylene mesh bag. The
recycled polymeric materials were employed in new experi-
ments (e.g., synthesis of compounds 5a−c and 5m−p) without
dramatic yield loss for at least five reaction cycles for PS-TBD
and two new experiments for PS-IBX-amide. In addition to its
catalytic efficacy and recyclability, the leaching of metal to the
reaction media is a key subject to be considered during the
development of novel heterogeneous catalytic systems. In an
attempt to provide preliminary data on this issue, the copper
content of two representative 4-acyl-1,2,3-triazoles (5a and 5b)
was determined employing inductively coupled plasma mass
spectroscopy (ICP-MS). These experiments evidenced negli-
gible (parts per billion) release of copper to the products
(11.2563 0.2141 and 10.2869 0.15587 ppb, respectively),
which is in agreement with previous observations.13
In summary, we have documented the first example of a
reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition
under oxidative conditions. The application of Cohen’s “wolf
and lamb” principle, combining two polymeric reagents (PS-
TBD/Cu and PS-IBX-amide), overcomes the thermodynamic
instability of copper(I) species toward oxidation, enabling
reliable CuAAC not only under aerobic conditions but also in
the presence of a well-known oxidant agent. This polymer-
assisted pathway, not feasible under conventional homogeneous
conditions, provides a direct assembly of 4-acyl-1-substituted-
1,2,3-triazoles contributing to the expansion of the reliability
and scope of the Huisgen 1,3-dipolar cycloaddition under
previously unexplored conditions.
EXPERIMENTAL SECTION
Commercially available starting materials and reagents were purchased
and used without further purification from freshly opened containers.
Polymer-supported reagents (PS-TBD, 2.6 mmol/g, PS-IBX-amide,
■
G
dx.doi.org/10.1021/jo400800j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1-Benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone, 5a:
White solid; mp 117−118 °C (lit 115−116 °C);23 Method A, yield
90% (44 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.41 (d, J = 7.0
Hz, 2H), 8.15 (s, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.3 Hz,
2H), 7.42−7.38 (m, 3H), 7.34−7.28 (m, 2H), 5.61 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ (ppm) 185.6, 143.9, 136.5, 133.6, 133.2, 130.6,
129.3, 129.2, 128.4, 128.3, 128.2, 54.5; HRESIMS calcd for
C16H13N3NaO (M+) 286.0951, found 286.0954.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-chlorophenyl)methanone,
5b: White solid; mp 158−160 °C; Method A, yield 89% (39 mg);
Method B, yield 78% (34 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm)
8.26 (d, J = 8.5 Hz, 2H), 7.99 (s, 1H), 7.33−7.30 (m, 2H), 7.26−7.23
(m, 3H), 7.23−7.14 (m, 2H), 5.44 (s, 2H); 13C NMR (CDCl3, 75
MHz) δ (ppm) 184.1, 148.2, 139.8, 134.7, 133.5, 132.1, 129.4, 129.2,
128.7, 128.4, 128.3, 54.5; HRESIMS calcd for C16H12ClN3NaO (M+)
320.0561, found 320.0564.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(cyclohexyl)methanone, 5j:
Yellow solid; mp 112−114 °C; Method A, yield 92% (44 mg); H
1
NMR (CDCl3, 300 MHz) δ (ppm) 7.93 (s, 1H), 7.42−7.38 (m, 3H),
7.32−7.27 (m, 2H), 5.55 (s, 2H), 3.59−3.50 (m, 1H), 1.97−1.94 (m,
2H), 1.84−1.70 (m, 3H), 1.55−1.52 (m, 2H), 1.48−1.40 (m, 2H),
1.36−1.22 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 198.5,
133.6, 129.3, 129.1, 128.3, 128.2, 125.7, 54.4, 46.7, 28.6, 25.9, 25.6;
HRESIMS calcd for C16H19N3NaO (M+) 292.1420, found 292.1423.
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethanone, 5k: Yellow solid;
mp 85−86 °C (lit. 90 °C);24 Method A, yield 92% (65 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 7.77 (s, 1H), 7.24−7.12 (m, 5H), 5.39 (s,
2H), 2.51 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 192.8, 133.5,
129.3, 129.1, 128.3, 125.1, 125.0, 54.5, 27.1; HRESIMS calcd for
C11H11N3NaO (M+) 224.0794, found 224.0800.
1-Benzyl-1H-1,2,3-triazole-4-carbaldehyde, 5l: Colorless oil;
1
Method A, yield 79% (64 mg); Method B, yield 75% (61 mg); H
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2-chlorophenyl)methanone,
NMR (CDCl3, 300 MHz) δ (ppm) 10.07 (s, 1H), 8.01 (s, 1H), 7.37−
7.35 (m, 3H), 7.29−7.25 (m, 2H), 5.56 (s, 2H); 13C NMR (CDCl3, 75
MHz) δ (ppm) 184.9, 148.0, 133.3, 129.3, 129.2, 128.3, 125.1, 54.5;
HRESIMS calcd for C10H9N3NaO (M+) 210.0638, found 210.0629.
Ethyl 2-[4-(4-Chlorobenzoyl)-1H-1,2,3-triazol-1-yl]acetate,
5m: White solid; mp 163−165 °C; Method B, yield 70% (30 mg);
1H NMR (CDCl3, 300 MHz) δ (ppm) 8.37 (d, J = 8.6 Hz, 2H), 8.35
(s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 5.18 (s, 2H), 4.23 (q, J = 7.1 Hz,
2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ (ppm)
183.9, 165.5, 148.2, 139.9, 134.6, 132.0, 129.9, 128.7, 62.8, 50.9, 14.04;
HRESIMS calcd for C13H12ClN3NaO3 (M+) 316.0459, found
316.0471.
(1-((5-Chlorothiophen-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-
(phenyl)methanone, 5n: White solid; mp 115−116 °C; Method B,
yield 68% (38 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.43−8.39
(m, 2H), 8.24 (s, 1H), 7.61−7.58 (m, 1H), 7.54−7.48 (m, 2H), 6.96
(d, J = 3.9 Hz, 1H), 6.85 (d, J = 3.9 Hz, 1H), 5.68 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ (ppm) 185.4, 148.2, 136.2, 133.6, 133.3, 132.2,
130.4, 128.3, 128.2, 127.9, 126.3, 48.7; HRESIMS calcd for
C14H10ClN3NaOS (M+) 326.0125, found 326.0133.
1
5c: Yellow solid; mp 80−82 °C; Method A, yield 83% (36 mg); H
NMR (CDCl3, 300 MHz) δ (ppm) 8.11 (s, 1H), 7.43−7.41 (m, 2H),
7.37−7.33 (m, 5H), 7.37−7.31 (m, 2H), 5.59 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ (ppm) 186.9, 147.6, 145.0, 137.1, 133.4, 131.8,
130.3, 130.1, 129.2, 129.1, 128.3, 127.4, 126.4, 54.4; HRESIMS calcd
for C16H12ClN3NaO (M+) 320.0561, found 320.0561.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2,6-dichlorophenyl)-
methanone, 5d: White solid; mp 208−210 °C; Method A, yield 87%
1
(35 mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.10 (s, 1H), 7.43−
7.39 (m, 3H), 7.37−7.31 (m, 5H), 5.59 (s, 2H); 13C NMR (CDCl3, 75
MHz) δ (ppm) 185.6, 146.9, 137.2, 133.1, 131.6, 130.9, 129.3, 129.2,
128.4, 127.9, 126.9, 54.5; HRESIMS calcd for C16H11Cl2N3NaO (M+)
354.0171, found 354.0163.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2,4-dichlorophenyl)-
methanone, 5e: White solid; mp 163−164 °C; Method B, yield 85%
(35 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.11 (s, 1H), 7.61 (d,
J = 8.2 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.50−7.38 (m, 2H), 7.37−
7.31 (m, 4H), 5.59 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ (ppm)
185.9, 157.9, 138.9, 135.9, 133.3, 133.2, 131.3, 130.4, 129.4, 129.3,
128.4, 127.5, 126.9, 54.5; HRESIMS calcd for C16H11Cl2N3NaO (M+)
354.0171 found 354.0179.
(1-((5-Chlorothiophen-2-yl)methyl)-1H-1,2,3-triazol-4-yl)
(2,4-dichlorophenyl) methanone, 5o: Yellow solid; mp 115−116
(1-Benzyl-1H-1,2,3-triazol-4-yl)(4-fluorophenyl)methanone,
1
5f: White solid; mp 145−146 °C (lit. 145−146 °C);23 Method A, yield
°C; Method B, yield 69% (30 mg); H NMR (CDCl3, 300 MHz) δ
1
(ppm) 8.20 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J =
8.2 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.67 (s,
2H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 185.7, 147.6, 137.6, 135.3,
133.2, 133.1, 132.6, 131.3, 130.4, 128.4, 127.1, 126.9, 126.5, 48.9;
HRESIMS calcd for C14H8Cl3N3NaOS (M+) 393.9346, found
393.9351.
(2,4-Dichlorophenyl)(1-((pyridin-4-yl)methyl)-1H-1,2,3-tria-
zol-4-yl)metha-none, 5p: Yellow solid; mp 125−126 °C; Method B,
yield 78% (32 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.66 (d, J =
5.9 Hz, 2H), 8.22 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 1.9 Hz,
1H), 7.38 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 5.9 Hz, 2H), 5.63 (s, 2H);
13C NMR (CDCl3, 75 MHz) δ (ppm) 185.6, 150.7, 147.7, 142.2,
137.6, 135.1, 133.0, 131.2, 130.4, 127.8, 126.9, 122.1, 53.0; HRESIMS
calcd for C15H11Cl2N4O (M + H) 333.0304, found 333.0310.
Ethyl 2-[4-(2,4-difluorobenzoyl)-1H-1,2,3-triazol-1-yl]-
acetate, 5q: Yellow solid; mp 170−171 °C; Method B, yield 61%
(26 mg); 1H NMR (CDCl3, 300 MHz) δ (ppm) 8.36 (s, 1H), 7.61 (d,
J = 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 1.3 Hz, 1H),
5.22 (s, 2H), 1.30 (q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ (ppm) 185.6, 165.4, 147.6, 137.6, 135.4,
133.1, 131.3, 130.4, 129.1, 126.9, 62,8, 51.0, 14.0; HRESIMS calcd for
C13H11F2N3NaO3 (M+) 318.0661, found 318.0660.
88% (41 mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.53 (m, 2H),
8.16 (s, 1H), 7.42−7.40 (m, 3H), 7.35−7.32 (m, 2H), 7.18 (d, J = 8.7
Hz, 2H), 5.57 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 183.7,
165.8, 148.19, 133.59, 133.3, 132.6, 129.2, 129.0, 128.3, 128.28, 115.4,
54.3; HRESIMS calcd for C16H12FN3NaO (M+) 304.0857, found
304.0861.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2-fluorophenyl)methanone
5g: White solid; mp 101−102 °C; Method A, yield 92% (42 mg); 1H
NMR (CDCl3, 300 MHz) δ (ppm) 8.10 (s, 1H), 7.85−7.80 (m, 1H),
7.56−7.49 (m, 1H), 7.41−7.38 (m, 3H), 7.33−7.28 (m, 2H), 7.23−
7.13 (m, 2H), 5.59 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ (ppm)
184.7, 159.4, 148.0, 133.8, 133.5, 131.2, 129.3, 129.2, 128.3, 127.3,
126.1, 124.0, 116.5, 54.5; HRESIMS calcd for C16H12FN3NaO (M+)
304.0857, found 304.0855.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(3,4,5-trimethoxyphenyl)-
methanone, 5h: Yellow solid; mp 104−106 °C; Method A, yield
1
85% (33 mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.14 (s, 1H),
7.84 (s, 2H), 7.39−7.37 (m, 3H), 7.33−7.30 (m, 2H), 5.57 (s, 2H),
3.92 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 183.8, 162.4,
152.8, 148.6, 142.8, 133.6, 131.3, 129.1, 128.7, 128.3, 108.0, 60.9, 56.2,
54.4; HRESIMS calcd for C19H19N3NaO4 (M+) 376.1268, found
376.1268.
Ethyl-2-[4-(2,4-dichlorobenzoyl-1H-1,2,3-triazol-1-yl]-
(1-Benzyl-1H-1,2,3-triazol-4-yl)(naphthalen-2-yl)methanone,
1
acetate, 5r: Yellow solid; mp 164−166 °C; Method B, yield 41% (16
5i: White solid; mp 158−160 °C; Method A, yield 80% (34 mg); H
1
mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.35 (s, 1H), 7.99−7.93
NMR (CDCl3, 300 MHz) δ (ppm) 8.88 (s, 1H), 8.34−8.21 (m, 2H),
8.05−7.87 (m, 4H), 7.61−7.54 (m, 2H), 7.43−7.34 (m, 4H), 5.63 (s,
2H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 185.3, 148.2, 135.7, 133.7,
133.4, 132.5, 130.1, 129.4, 129.2, 128.6, 128.4, 128.3, 128.1, 127.7,
126.6, 125.5, 54.5; HRESIMS calcd for C20H16N3O (M + H)
314.1288, found 314.1285.
(m, 1H), 6.99−6.96 (m, 1H), 6.93−6.88 (m, 1H), 5.22 (s, 2H), 4.29
(q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ (ppm) 183.5, 165.4, 133.3, 131.3, 130.4, 129.0, 126.9, 111.4,
105.2, 104.9, 62.8, 50.9, 14.0; HRESIMS calcd for C13H11Cl2NaN3O3
(M+) 350.0070, found 350.0069.
H
dx.doi.org/10.1021/jo400800j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2,4-difluorophenyl)-
methanone, 5s: White solid; mp 118−120 °C; Method B, yield 65%
Chem., Int. Ed. 2013, 52, 381. (h) Budin, I.; Devaraj, N. K. J. Am. Chem.
Soc. 2012, 134, 751.
(4) Tornøe, C. W.; Christensen, C.; Medal, M. J. Org. Chem. 2002,
1
(28 mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.09 (s, 1H), 7.96−
7.90 (m, 1H), 7.40−7.36 (m, 3H), 7.31−7.23 (m, 2H), 6.99−6.94 (m,
1H), 6.91−6.86 (m, 1H), 5.57 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ
(ppm) 183.3, 166.6, 147.9, 133.4, 133.3, 133.1, 129.3, 129.2, 128.3,
128.0, 122.6, 111.6, 105.1, 54.5; HRESIMS calcd for C16H11F2N3NaO
(M+) 322.0762, found 322.0765.
67, 3057.
(5) Rostovtset, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(6) For representative examples, see: (a) Chan, T. R.; Hilgraf, R.;
Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853. (b) Rodionov,
V. O.; Presolski, S. I.; Diaz, D. D.; Fokin, V. V.; Finn, M. G. J. Am.
Chem. Soc. 2007, 129, 12705. (c) Tanaka, K.; Kageyama, C.; Fukase, K.
Tetrahedron Lett. 2007, 48, 6475. (d) Xu, W. M.; Huang, X.; Tang, E. J.
Comb. Chem. 2005, 7, 726. (e) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J.
Am. Chem. Soc. 2004, 126, 1638. (f) Reck, F.; Zhou, F.; Girardot, M.;
Kern, G.; Eyermann, C. J.; Hales, N. J.; Ramsay, R. R.; Gravestock, M.
B. J. Med. Chem. 2005, 48, 499. (g) Rodionov, V. O.; Presolski, S. I.;
Gardinier, S.; Lim, Y. H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129,
12696.
(1-Benzyl-1H-1,2,3-triazol-4-yl)(2,6-difluorophenyl)-
methanone, 5t: Yellow solid; mp 92−94 °C; Method B, yield 70%
1
(31 mg); H NMR (CDCl3, 300 MHz) δ (ppm) 8.15 (s, 1H), 7.50−
7.40 (m, 4H), 7.33−7.30 (m, 2H), 7.02−6.96 (t, J = 8.0 Hz, 2H), 5.59
(s, 2H); 13C NMR (CDCl3, 75 MHz) δ (ppm) 188.1, 133.3, 132.6,
132.5, 132.4, 129.4, 129.3, 128.4, 126.7, 112.0, 111.8, 54.6; HRESIMS
calcd for C16H11F2N3NaO (M+) 322.0762, found 322.0765.
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)butan-1-one, 5u: White
solid; mp 72−74 °C; Method B, yield 78% (6 mg); 1H NMR
(CDCl3, 300 MHz) δ (ppm) 7.77 (s, 1H), 7.23−7.19 (m, 3H), 7.14−
7.09 (m, 2H), 5.38 (s, 2H), 2.91 (t, J = 7.4 Hz, 2H), 1.63−1.54 (m,
2H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ (ppm)
195.2, 148.1, 133.5, 129.1, 129.0, 128.2, 125.1, 54.3, 41.2 17.2, 13.6;
HRESIMS calcd for C13H15N3NaO (M+) 252.1107, found 252.1114.
1-(4-Iodobenzyl)-1H-1,2,3-triazole-4-carbaldehyde, 5v:
́
(7) (a) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689. (b) Smith, C. D.; Baxendale, I.
R.; Lanners, S.; Hayward, J. J.; Smith, S. C.; Ley, S. V. Org. Biomol.
Chem. 2007, 5, 1559. (c) Sirion, U.; Bae, Y. J.; Lee, B. S.; Chi, D. Y.
Synlett 2008, 2326. (d) Chan, T. R.; Fokin, V. V. QSAR Comb. Sci.
̈
2007, 26, 1274. (e) Ozkal, E.; Ozcu
A. Catal. Sci. Technol. 2012, 2, 195.
̀
̧ bukcu̧ , S.; Jimeno, C.; Pericas, M.
1
White solid; mp 120−121 °C; Method B, yield 86% (11 mg); H
NMR (CDCl3, 300 MHz) δ (ppm) 10.10 (s, 1H), 8.01 (s, 1H), 7.72
(d, J = 6.6 Hz, 2H), 7.03 (d, J = 6.6 Hz, 2H), 5.52 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ (ppm) 184.8, 148.1, 138.5, 133.0, 130.0, 125.0,
95.1, 53.9; HRESIMS calcd for C10H8N3NaIO (M+) 335.9604, found
335.9614.
(8) (a) Caliendo, G.; Fiorino, F.; Perissutti, E.; Severino, B.; Scolaro,
D.; Gessi, S.; Cattabriga, E.; Borea, P. A.; Santagada, V. Eur. J. Pharm.
Sci. 2002, 16, 15. (b) Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.;
Mantuano, E.; Martelli, A.; Nardi, A. Eur. J. Med. Chem. 2005, 40, 521.
(c) Blass, B. E.; Coburn, K.; Lee, W.; Fairweather, N.; Fluxe, A.; Wu,
S.; Janusz, J. M.; Murawsky, M.; Fadayel, G. M.; Fang, B.; Hare, M.;
Ridgeway, J.; White, R.; Jackson, C.; Djandjighian, L.; Hedges, R.;
Wireko, F. C.; Ritter, A. L. Bioorg. Med. Chem. Lett. 2006, 16, 4629.
(d) Pardin, C.; Roy, I.; Lubell, W. D.; Keillor, J. W. Chem. Biol. Drug
Des. 2008, 72, 189.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of (1H and 13C) NMR spectra and HRMS for all
compounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
(9) Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981,
103, 7620.
AUTHOR INFORMATION
(10) (a) Flynn, D. L.; Devraj, R. V.; Parlow, J. J. Polymer-Assisted
Solution-Phase Methods for Chemical Library Synthesis. In Solid-
Phase Organic Synthesis; Burgess, K., Ed.; John Wiley: New York, 2000;
pp 149−194. (b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P.
S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.;
Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815.
(11) For representative examples, see: (a) Chassaing, S.; Kumarraja,
M.; Souna-Sido, A. S.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 883.
(b) Miao, T.; Wang, L. Synthesis 2008, 363. (c) Park, I. S.; Kwon, M.
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■
Corresponding Author
*E.S.: Tel., +34881815732; Fax, +34-881-815704; E-mail, e.
sotelo@usc.es. A.C.: Tel., +34881815732; Fax, +34-881-
815704; E-mail, albertojose.coelho@usc.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Part of this work was financially supported by the European
Regional Development Fund (ERDF) and the Galician
Government (Project: PGIDIT06PXIB203299PR). E.S. is the
recipient of a Consolidation Group Research Grant from
(12) Angell, Y.; Burgess, K. Angew Chem., Int. Ed. 2007, 46, 3649.
Conselleria de Educacion
́
(Xunta de Galicia).
(13) Coelho, A.; Diz, P.; Caamano, O.; Sotelo, E. Adv. Synth. Catal.
̃
2010, 352, 1179.
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