Polymer-supported 1,5,7-triazabicyclo [4.4.0] dec-5-ene as polyvalent ligands in the copper-catalyzed Huisgen 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/adsc.200900680

Abstract: New supported catalysts for the Huisgen's [3.+ 2]azide-alkyne cycloaddition have been prepared by immobilization of copper species on commercially available polymeric matrixes incorporating the 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) template

Full text of DOI:10.1002/adsc.200900680

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DOI: 10.1002/adsc.200900680
Polymer-Supported 1,5,7-Triazabicyclo[4.4.0]dec-5-ene as
G
Polyvalent Ligands in the Copper-Catalyzed Huisgen
1,3-Dipolar Cycloaddition
Alberto Coelho,a,* Paula Diz,a Olga CaamaÇo,b and Eddy Soteloa,b,*
a
Institute of Industrial Pharmacy (IFI), Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de
Compostela, Spain
Fax : (+34)-981-528-093; phone: (+34)-981-563-100 ext. 15222; e-mail: albertojose.coelho@usc.es or eddy.sotelo@usc.es
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de
b
Compostela, Spain
Received: September 30, 2009; Revised: March 4, 2010; Published online: April 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900680.
Abstract: New supported catalysts for the Huisgenꢀs egies. The new catalytic systems enabled the devel-
[3+2]azide-alkyne cycloaddition have been pre- opment of regioselective, efficient, modular, mild
pared by immobilization of copper species on com- and eco-friendly multicomponent syntheses of di-
mercially available polymeric matrixes incorporating versely decorated 1,2,3-triazoles, contributing to
the 1,5,7-triazabicycloACTHUNTGRNEUNG[4.4.0]dec-5-ene (TBD) tem- expand the scope and versatility of the Cu-catalyzed
plate. The synergic exploitation of the exceptional Huisgen 1,3-dipolar cycloaddition.
copper chelating ability and basicity profile of the
TBD framework, in addition to ensuring effective
immobilization and stabilization of copper species, Keywords: catalysis; copper; cycloaddition; multi-
allows the implementation of three-component strat- component reaction; supported catalysts
Introduction
the reaction, the inherent thermodynamic instability
of Cu(I) species generally imposes strict experimental
The recent advances in metal-catalyzed [Cu(I)[1,2] or conditions, which usually require the use of ligands
Ru(II)[3]] alkyne-azide cycloadditions have led to the that accelerate the reaction,[5] thus minimizing the for-
evolution of the classical Huisgen reaction[4] into a mation of undesired by-products [probably due to
highly efficient transformation that is able to deliver shielding of the Cu(I) species from interactions that
libraries of either 1,4- or 1,5-disubstituted 1,2,3-tri- lead to degradation]. Most of these shortcomings
ACHTUNGTRENNUNGazoles under mild conditions. In particular, the Cu(I)- have been elegantly surmounted by the in situ genera-
catalyzed alkyne-azide cycloaddition (CuAAC)[5] tion of the Cu(I) species,[5] either by comproportiona-
(Figure 1) – by virtue of its regiospecificity, experi- tion of Cu(0) and Cu(II) or reduction of copper(II)
mental simplicity, reliability and excellent functional salts [for example, copper(II) sulfate pentahydrate] by
selectivity – has emerged as the flagship of click using a sacrificial reducing agent, typically sodium as-
chemistry,[6] a new synthetic paradigm of remarkable corbate. Although alkyne-azide cycloaddition is effec-
practical and ecological significance that has found tively catalyzed under “ligand-free” conditions,[5] in
extensive applications in diverse research areas.[7] which solvent molecules or bases serve as ligands to
Whereas Cu(I) catalysis guarantees regiospecificity, the metal, the wide-ranging applications of CuAAC
wide substrate scope and tremendous acceleration of have stimulated the development of a plethora of new
Cu(I)-stabilizing ligands[5,8] as well as catalytic sys-
tems[5,9] that can preserve the reliability of the trans-
formation during the assembly of diverse molecules.
The synthetic and environmental connotations
make the development of new heterogeneous catalyt-
Figure 1. Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition.
ic systems for CuAAC a topic of major conceptual
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Figure 2. Representative polymeric matrixes employed in CuAAC.
and practical interest.[10] In particular, the use of new Results and Discussion
catalysts that consist of a copper salt bound to a func-
tionalized polymeric matrix through chelation has re- A preliminary analysis of a range of commercially
cently been described.[11–14] The pioneering reports de- available polymer-supported bases showed the poten-
scribed the use of an Amberlyst resin (I, Figure 2) tial advantages of the use of those incorporating the
and these provided proof of concept.[11] However, the 1,5,7-triazabicyclo
ACTHNUTRGNEU[GN 4.4.0]dec-5-ene (TBD) scaffold
relatively weak coordination of copper to the support (Figure 2). This choice relied on the well-documented
resulted in facile leaching of the metal and its oxida- availability of TBD to act as an effective ligand for
tion. This problem required a subsequent copper-scav- copper species by chelation.[16] This template, in addi-
enging step[12] and reduced the overall activity and se- tion to stabilizing catalytically active copper species
lectivity of the catalyst. In an effort to overcome by shielding them from interactions that lead to deg-
these drawbacks, Fokin[14] recently described the four- radation (and so minimizing the formation of side-
step immobilization of tris[(1-benzyl-1H-1,2,3-triazol- products), would guarantee exceptional efficacy as
4-yl)methyl]amine (TBTA), a highly effective ligand copper scavengers. This would in turn prevent signifi-
for CuAAC,[15] onto a TentaGel resin (II, Figure 2) cant leaching of the metal from the polymeric matrix
and its successful application to the synthesis of 1,2,3- to the reaction media. Another two issues were con-
triazoles.
sidered when making this choice: (i) the basic profile
The unique profile exhibited by CuAAC led us to (pKa ꢀ24)[17] exhibited by these reagents could be ex-
exploit this reliable transformation in several library ploited in the implementation of three-component re-
generation programs. In the course of these studies it actions and (ii) the commercial availability of TBD-
was envisioned that the use of a commercially avail- supported reagents from different suppliers[18] and
able polymer-supported guanidine superbase [for ex- their availability on two different polymeric matrixes
ample, PS-TBD (III) or Si-TBD (IV), Figure 2] for (polystyrene and silica) would facilitate the optimiza-
this transformation could, in addition to offering the tion of experimental protocols under diverse condi-
excellent chelating profile required to immobilize and tions (i.e., in organic or aqueous media). At the
stabilize catalytically active copper species, also facili- outset of the project the new catalytic systems
tate the implementation of three-component strat- (Figure 3) were obtained by fixation of the metal on
egies.
the selected supported bases. The immobilization ex-
We describe here the development of efficient and periments were carried out at room temperature
operationally simple transformations that allow the using 1.0 g of the corresponding resin (III or IV
rapid assembly of diverse libraries of 1,2,3-triazoles Figure 2) and variable amounts of copper(I) iodide as
from simple and readily available starting materials. the metal source in 30 mL of either DMF or CH3CN
The processes, which exemplify the synergic exploita- (see Experimental Section). After 24 h of orbital stir-
tion of successful concepts of modern organic synthe- ring the green resin was filtered off, washed and dried
sis (e.g., click chemistry, supported reagents and mul- under vacuum.[19] These experiments afforded hetero-
ticomponent reactions), are noteworthy for a number geneous catalytic systems (Figure 3) that incorporated
of reasons: they are regioselective, efficient, mild, variable copper loadings (0.12%, 0.21% and 0.28%
eco-friendly and, at the same time, address the availa- for PS-TBD and 0.17% and 0.30% for Si-TBD) as
bility of structurally diverse azides while avoiding quantified by wavelength dispersive X-ray fluores-
their manipulation. As a result, this approach contrib- cence spectrometry (WD-XRF).[20] It is noteworthy
utes to expanding the scope and versatility of the that similar immobilization experiments with either
Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition.
DMF or acetonitrile did not reveal significant differ-
ences (X-ray fluorescence) in the copper loadings of
the heterogeneous catalytic systems obtained, despite
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Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Figure 3. Photomicrographs of the starting polymer-supported bases and the new copper heterogeneous catalyst systems.
the different coordination abilities of the solvents em- tained in independent syntheses. It can be seen from
ployed.
the results (Table 1) that the new heterogeneous poly-
Once the polymer-supported copper reagents were mer-supported reagents give rise to highly effective
available, their effectiveness as catalysts in Huisgenꢀs catalytic activity in the Huisgen 1,3-dipolar cycloaddi-
1,3-dipolar cycloaddition was evaluated with two tion of the tested substrates. In all cases the transfor-
model substrates (Scheme 1) utilizing the organic mation provided regiospecifically the 1,4-substituted
azides 1a, b and terminal acetylenes 2a, b (Table 1). 1,2,3-triazoles (3–6) in satisfactory to excellent yields
In these studies equimolar amounts of the reactants under aerobic conditions. The transformation was suc-
were treated with the heterogeneous catalysts at dif- cessful regardless of the differences in the loading
ferent copper loadings. The reactions were subjected levels and polymeric matrix present in the supported
to orbital stirring at 408C for the required time (8– catalysts. The results obtained using two representa-
24 h) and the effect of a range of solvents [CH2Cl2, tive catalytic systems that incorporate similar loading
CH3CN and DMF for PS-TBD/Cu and DMF and t- levels but a different polymeric matrix (e.g., polystyr-
BuOH-H2O for Si-TBD/Cu] on the reaction outcome ene or silica) are shown in Table 1.
was also investigated.
A comparison of these preliminary experiments re-
A summary of the most salient results of these ex- veals that the differences between the supported cata-
periments is given in Table 1, with the reported yields lytic systems employed (i.e., polymeric matrix or
being the mean of at least two experiments in which loading levels) were not clearly reflected in the reac-
freshly prepared catalysts were used that were ob- tion outcome (yields or reaction times). In particular,
the claimed intrinsic advantages of silicas over poly-
styrene resins (i.e., no swelling or solvent compatibili-
ty)[21] were not observed, most probably due to the
fact that the latter can swell sufficiently in the sol-
vents tested. Two equivalents of the supported cata-
lytic system (ca. 3 mol% Cu) are able to produce
complete transformation of the reactants under mild
conditions in reasonable reaction times. Reduced
Scheme 1. Copper-mediated Huisgenꢀs 1,3-dipolar cycloaddi-
tion employing the new heterogeneous catalytic systems.
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Table 1. Representative 1,2,3-triazoles obtained during method optimization.
Compound
Azide (1)
Alkyne (2)
Product
Yield [%]
Si-TBD[b]
PS-TBD[a]
À
À
À ꢁ
3
4
5
N3 CH2 Ph (1a)
Ph C CH (2a)
3a=83/3b=90
4a=78/4b=84
5a=72/5b=85
6a=53/6b=78
3a=81/3b=84
4a=77/4b=80
5a=67/5b=83
6a=55/6b=72
À
À
À ꢁ
Ph C CH (2a)
N3 CH2 COOEt (1b)
À
À
À ꢁ
N3 CH2 Ph (1a)
HOCH2 C CH (2b)
À
À
À ꢁ
6
N3 CH2 COOEt (1b)
HOCH2 C CH (2b)
[a]
Yield obtained using 2 equivalents of PS-TBD/Cu 0.28% [ca. 3 mol% of Cu] in either (a) CH2Cl2 or (b) DMF.
Yield obtained using 2 equivalents of Si-TBD/Cu 0.30% [ca. 3 mol% of Cu] in either (a) t-BuOH-H2O or (b) DMF.
[b]
loading of the catalyst (i.e., 1.5 mol% Cu) was accept- issue to be considered during the development of het-
able to obtain complete conversion, albeit with a erogeneous catalytic systems for CuAAC. To chal-
longer time, for example, 8–12 h with 3 mol% Cu lenge our supported reagents in this regard, and in
versus 36 h with 1.5 mol% for >99% conversion at order to obtain evidence as to whether this is a true
408C in DMF. In a similar way, the effect of the sol- heterogeneous catalyst or if the migration from the
vent does not appear to be particularly critical. Two polymeric matrix produces active homogeneous
protocols (with CH2Cl2 and DMF as solvents) with copper species, a three-phase test[23] was designed
PS-TBD/Cu were optimized for library production (Scheme 2). In such an experiment the immobilized
purposes.
catalyst is exposed to soluble reagents and reagents
A comparison of the effectiveness of the preformed bound to a solid support, if an active catalyst leaches
heterogeneous polymer-supported Cu catalysts with from the immobilized media it will result in conver-
respect to the simultaneous addition of copper(I) sion of the resin-bound reagent. With this aim the
iodide and PS-TBD or Si-TBD to the model reactions supported benzyl azide 8 was prepared (Scheme 2).
revealed that the use of the preloaded catalysts guar- The polystyrene-bound 4-benzyloxybenzyl alcohol
anteed quantitative consumption of reactants in short- (1.25 mmolg,À1 Wang resin) was chosen as the alter-
er reaction times (ca. 10 h). These results, in conjunc- native support due to its rapid and efficient cleavage
tion with the easier implementation of parallel auto- protocol. Firstly, 4-(chloromethyl)benzoyl chloride
mated synthetic protocols, highlight the advantage was tethered to Wang resin under basic conditions
and potential for the use of preformed catalytic sys- and subsequently incubated with trimethylsilyl azide
tems. The recyclability of the supported catalytic sys- and TBAF (Scheme 2) generating the polymer-bound
tems was also examined for the model reactions in di- reactive 1,3-dipolar compound 8. The immobilized
chloromethane (Scheme 1) at two different levels. azide (8) was then subjected to 1,3-dipolar cycloaddi-
Firstly, it was verified that, once washed and dried tion (Scheme 2) utilizing phenylacetylene (2a) as di-
under vacuum, the heterogeneous catalytic systems polarophile and one of the herein described catalysts
recovered from a reaction can be reused at least five (PS-TBD/Cu, copper loading: 0.12%). In a parallel
times in new cycloaddition experiments without dra- experiment, the supported azide 8 and 2a were react-
matic yield loss (the average yield for the targeted ed in the presence of DIPEA and copper(I) iodide
structures being as follow: 3: 81%, 4: 75%, 5: 70%, 6: (Scheme 2). After 24 h at room temperature complete
56%) and generate products with purities similar to conversion of 8 is observed, both experiments afford-
those obtained in the first run. Secondly, the possibili- ing (after appropriate work-up and cleavage) the 4-
ty of completely regenerating the reactivity profile [(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]benzoic acid
and appearance of the original supported bases (III (9). These findings correlate with the results obtained
or IV) was also experimentally confirmed by remov- during the determination of copper in two representa-
ing the metallic species by incubating the recovered tive 1,2,3-triazoles of the series (compounds 3 and 6).
heterogeneous catalytic system with a highly efficient Inductively coupled plasma mass spectroscopy (ICP-
copper chelatant such as tetramethylethylenediamine MS) analysis confirmed the presence of copper traces
(TMEDA, 15% in CH2Cl2).[22]
in the 1,2,3-triazoles 3 and 6 (15.0863Æ0.2538 ppb
In addition to its catalytic efficacy and recyclability, and 12.7517Æ0.1183 ppb, respectively). These findings
the leaching of metal to the reaction media is a key unequivocally confirm that soluble copper species are
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Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Scheme 2. Three-phase test to evaluate the copper leaching with PS-TBD/Cu.
Scheme 3. Synthesis of representative 1,2,3-triazoles employing PS-TBD/Cu.
involved in the catalytic cycle of the Huisgen 1,3-di- tained is depicted in Figure 4. It can be seen that the
polar cycloaddition when employing PS-TBD-Cu, reaction allows the preparation of not only 1,4-substi-
while the observed negligible release of copper to the tuted 1,2,3-triazoles (3–6 and 10–15) but also 4-substi-
reaction media is most probably a consequence of the tuted 1H-1,2,3-triazoles (16–20) when trimethylsilyl
excellent chelating properties of the TBD framework azide (1c) is employed as the azide partner. The
(which confers an exceptionally efficient scavenging purity of the crude isolated adducts was generally
ability to the support). These attributes make the new greater than 95%, as judged by LC-MS analysis, and
catalyst reported here useful in reactions aimed at the compounds that did not reach this level were purified
preparation of pharmaceutical agents, where the fate by simple preparative chromatography. The complete
of the metal catalyst and ancillary ligands is of partic- analytical and spectroscopic data for all compounds
ular interest.
described are included in the Supporting Information.
Encouraged by the results described above we initi-
Having established the feasibility of the proposed
method for the model systems, and also having identi- ated a program to develop multicomponent transfor-
fied a set of optimal experimental conditions to per- mations to enable the rapid assembly of complex and
form the Huisgen 1,3-dipolar cycloaddition with the diverse structures incorporating the 1,2,3-triazole
prepared catalysts, the robustness and scope of the backbone. The designed sequences (Scheme 4,
developed methodology was briefly assessed by em- Scheme 5, Scheme 6, and Scheme 7) exploit the ad-
ploying
a
set of assorted reactive precursors vantages derived from the dual role (base and cata-
(Scheme 3). We were pleased to observe that simply lyst) of these heterogeneous polymer-supported cata-
mixing a range of commercially available organic lysts. A serious limitation for the extensive applica-
azides (1a–c) and acetylenes (2a–e) with PS-TBD/Cu tion of the copper-mediated Huisgen cycloaddition in
under the conditions described in Scheme 3 led to drug discovery programs arises from the relatively
smooth cycloaddition to afford the desired 1,2,3-tri- low abundance of structurally diverse collections of
ACHTUNGTRENNUNGazoles. A representative selection of compounds ob- commercially available organic azides. Several au-
Adv. Synth. Catal. 2010, 352, 1179 – 1192
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Figure 4. Representative 1,2,3-triazoles obtained employing optimized conditions.
thors have overcome this drawback by developing cient catalysis of the Huisgen reaction had been deter-
three-component transformations.[24,25] In these ap- mined (Table 1), it was evident that the more de-
proaches the dipolarophile is captured by an organic manding requirements of the heterogeneous catalysts
azide that is generated in situ from the appropriate in the three-component reaction were a consequence
halide or epoxide and sodium azide. This strategy has of the need to achieve sufficient base to address both
been elegantly combined with the use of non-conven- the nucleophilic displacement of the halide and the
tional heating modes (e.g., microwave energy).[25] copper-catalyzed Huisgen cycloaddition. Such a hy-
Based on previous findings it was anticipated that the pothesis was investigated experimentally by simulta-
exploitation of the dual role (catalyst and base) exhib- neously employing two equivalents of heterogeneous
ited by the heterogeneous catalytic systems described copper catalyst (ca. 3.0 mol% of copper) and one
here would facilitate the development of a general, equivalent of PS-TBD. Nonetheless, in order to facili-
simple and mild three-component procedure to pre- tate the implementation of synthetic methodologies
pare libraries of 1,2,3-triazoles.
amenable to parallel approaches it was decided to
Preliminary exploration of the feasibility of the employ three base equivalents of the heterogeneous
three-component reaction revealed that only slight copper catalyst (ca. 4.5 mol% of copper).
modifications of the previously optimized experimen-
Having optimized the performance of the catalytic
tal protocol (Scheme 3) were required to verify that, system and established the other experimental condi-
in the presence of PS-TBD/Cu, phenylacetylene (2a), tions, the scope of the three-component reaction on a
sodium azide and benzyl bromide (21c) are smoothly number of assorted substrates was examined
converted to 1-benzyl-4-phenyl-1,2,3-triazole (3) in (Scheme 4). It can be seen from the results in Table 2
satisfactory yield. Investigation of the reaction condi- that the reaction is broadly successful to both variable
tions showed that the optimal alkyne/halide/sodium components (i.e., alkynes and halides) and is not in-
azide ratio was 1.0:1.0:1.1 and that the use of DMF as fluenced by the electronic and steric variations of the
the reaction medium is critical for the success of the reacting substrates. Significant structural variation is
three-component reaction. It should be noted that, in well tolerated in the halide, as exemplified by a range
a clear contrast with the results obtained for the of alkyl, benzyl and heteroaryl halides, including the
alkyne-azide 1,3-dipolar cycloaddition (which re- sterically hindered 2-iodobenzyl bromide (21d,
quired the use of 3 mol% of copper), a higher level of Table 2, compounds 23, 28, 33 and 40). With respect
supported TBD/catalyst (ca. 4.5 mol% Cu) was re- to the dipolarophile, reactions of aliphatic acetylenes
quired to achieve complete conversion in the three- were slightly slower compared to those of aryl acety-
component version of the Huisgen reaction while lenes, although the corresponding 1,2,3-triazoles were
maintaining the mild experimental conditions (408C) still isolated in satisfactory yields.
and reasonable reaction times (8–16 h). Since the op-
An additional attractive feature of this transforma-
timal amount of copper and base required for the effi- tion is that allows the direct use of protonated halides
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Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Scheme 4. Three-component synthesis of 1,2,3-triazoles employing PS-TBD/Cu.
Table 2. Representative 1,2,3-triazoles obtained employing optimized conditions.
Compound
Alkyne (2a–d)
Alkylating agent (21a–g)
Product (3–6, 10, 15, 22–43)
Yield [%]
75
À ꢁ
Ph C CH
À
I Et
22
À ꢁ
À
À
4
3
Ph C CH
Br CH2 COOEt
83
86
À ꢁ
Ph C CH
À ꢁ
23
24
25
Ph C CH
78
82
86
À ꢁ
Ph C CH
À ꢁ
Ph C CH
À ꢁ
26
27
6
Ph C CH
71
41
47
À ꢁ
À
HOCH2 C CH
I Et
À ꢁ
À
À
HOCH2 C CH
Br CH2 COOEt
À ꢁ
5
HOCH2 C CH
71
64
À ꢁ
HOCH2 C CH
28
À ꢁ
29
30
31
HOCH2 C CH
69
80
87
À ꢁ
HOCH2 C CH
À ꢁ
HOCH2 C CH
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Table 2. (Continued)
Compound
Alkyne (2a–d)
Alkylating agent (21a–g)
Product (3–6, 10, 15, 22–43)
Yield [%]
90
À ꢁ
4-MeC6H4 C CH
À
I Et
32
À ꢁ
À
À
15
10
4-MeC6H4 C CH
Br CH2 COOEt
83
80
À ꢁ
4-MeC6H4 C CH
À ꢁ
33
34
35
4-MeC6H4 C CH
79
81
74
À ꢁ
4-MeC6H4 C CH
À ꢁ
4-MeC6H4 C CH
À ꢁ
36
37
38
4-MeC6H4 C CH
70
35
29
À
À ꢁ
À
HO
U
I Et
À
À ꢁ
À
À
HO
U
Br CH2 COOEt
À
À ꢁ
39
40
41
HO
G
74
62
81
À
À ꢁ
HO ACHTUGNTRENNNUG
(CH2)4 C CH
À
À ꢁ
HO ACHTUGNTRENNNUG
(CH2)4 C CH
À
À ꢁ
42
43
HO
G
88
86
À
À ꢁ
HO ACHTUGNTRENNNUG
(CH2)4 C CH
(e.g., compound 21g, Table 2, compounds 26, 31, 36 nating the need to isolate organic azides and employ
and 43), although for this substrate the use of an addi- equipment not yet available in all research laborato-
tional equivalent of base was required. As previously ries (e.g. microwave reactors).
demonstrated, the heterogeneous catalyst is recycla-
Despite the advantages of the three component re-
ble and its activity is retained after five reaction action described above, one inherent shortcoming of
cycles. The information contained in Table 2 enables the Huisgen 1,3-dipolar cycloaddition is that it pro-
the scope of this mild and highly efficient procedure vides 1,2,3-triazoles that incorporate only two diversi-
to be evaluated, exemplifying its contribution in ty points. An attempt was made to further demon-
terms of rapid access to hitherto unexplored diversity strate the potential of the supported catalytic systems
spaces. This simple method preserves the versatility of documented here to improve the versatility of the
the previous multicomponent approaches while elimi- Huisgen 1,3-dipolar cycloaddition by assembling more
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Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Scheme 5. Three-component synthesis of functionalized 1,2,3-triazoles.
complex structures (Scheme 5). The structure and re- perimental conditions is shown in Scheme 5 and these
activity profile of the reagents obtained [which consist employ 2.1 equivalents of the acetylenic compound,
of a catalytically active copper species immobilized 1.1 equivalents of the iodobenzyl halide, 1.2 equiva-
on a highly effective chelating/stabilizing basic residue lents of sodium azide, 3 equivalents of PS-TBD/Cu
(TBD) attached to a polymeric matrix (polystyrene or (ca. 4.5 mol% of Cu), 3 mol% of PdACHTNUGTRNEG(UN PPh3)2Cl2, and
silica)] suggest a wide range of potential applications 2 equivalents of PS-TBD at 408C. Under these condi-
for these catalytic systems in diverse copper-catalyzed tions the sequence proceeded smoothly and complete
transformations,[26] some of which are currently being conversion was achieved to afford, after the appropri-
explored in our group. As part of these studies it was ate work-up and chromatographic purification, 2-
planned to carry out the simple assembly of highly (benzyl-2’-phenylethynyl)-4-phenyl-1,2,3-triazole (44).
functionalized 1,2,3-triazoles (44–58) by combining
The satisfactory results obtained for the model
the Huisgen cycloaddition with another reaction that compound led us to evaluate the general applicability
requires Cu(I) catalysis (e.g., a Sonogashira cross-cou- of the transformation for a range of representative
pling reaction).[27]
acetylenes (2) and (2-, 3- or 4-) iodobenzyl bromides
The success achieved on employing 2-iodobenzyl (21d, h, i) (Figure 5). It was found (Figure 5) that
bromide in the three-component Huisgen cycloaddi- compounds 44–58 were generally isolated in satisfac-
tion (Table 2, compounds 23, 28, 33 and 40) suggested tory yields and with complete regioselectivity, a
the possibility of further increasing the complexity of highly remarkable result on considering that during
the target molecule by exploiting the reactivity of the the assembly of these polyfunctional molecules 4 new
iodo-substituent present in the benzylic residue of the bonds are formed in an operationally simple and
heterocycle. As proof of concept of this strategy the highly convergent one-pot process. A unique feature
development of a new transformation to combine a of this simple transformation is that it expands the
copper-mediated Huisgen 1,3-dipolar cycloaddition scaffold diversity. As can be seen in Figure 5, this
and a Sonogashira reaction was evaluated (Scheme 5). transformation allows the acetylenic partner (2) to be
Such a sequence would require the inclusion of a pal- incorporated at position 4 or on the benzylic moiety
ladium catalyst in the reaction medium, while the het- of the heterocyclic backbone, generating two different
erogeneous supported reagent (PS-TBD/Cu) would structural residues with distinct functional diversities
2
2
À
À
provide the catalytically active copper species as well (R or R C<=3>) depending on the reaction in-
as the basic conditions required for both transforma- volved in the scaffold assembly (Huisgen or Sonoga-
tions.
The feasibility of the planned transformation was
shira, Scheme 5).
The availability of a pure sample of 1-(3-iodoben-
evaluated with different experimental conditions, re- zyl)-4-phenyl-1,2,3-triazole (59) enabled unequivocal
actants and base ratios for the reaction of phenylace- evidence to be obtained regarding the preferential
tylene (2a), sodium azide and the sterically hindered synthetic pathway operating during the sequence. Evi-
2-iodobenzyl bromide (21d) with a homogeneous pal- dence of the intermediacy of this compound during
ladium complex [PdACHTUNGTRENUNG(PPh3)2Cl2]. A set of optimal ex- the reaction of phenylacetylene, sodium azide and 3-
Adv. Synth. Catal. 2010, 352, 1179 – 1192
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Alberto Coelho et al.
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Figure 5. Representative 1,2,3-triazoles obtained by the three-component reaction.
iodobenzyl bromide was obtained by TLC and observed when the reactions were carried out with
HPLC-MS analysis of the reaction mixture, as well as 3 mol% of the palladium catalyst [Pd(PPh3)2Cl2] and
AHCTUNGTRENNUNG
by quenching and work-up of the transformation after 3 equivalents of PS-TBD in absence of copper, even
4 h, which led to the isolation of 1,2,3-triazole 59 on prolongated heating. In contrast, successful forma-
(45%) as compared with an authentic sample pre- tion of the derivatives 49 and 50 was observed on per-
pared as described in Scheme 3. This result confirmed forming the same transformations with the new heter-
a sequence that involves the initial azidation of the ogeneous catalytic system (PS-TBD/Cu).
starting iodobenzyl bromide, its capture by the dipo-
larophile and then the alkynylation of the reactive 1,3-dipolar
iodo-substituent on the benzylic moiety through a So- (Scheme 5), and in order to challenge the versatility
nogashira cross-coupling reaction. of the supported catalysts (PS-TBD/Cu), we won-
The key role played by the supported copper spe- dered if it would be possible to replace the homoge-
cies during the last step of the sequence (i.e., the So- neous catalyst [Pd(PPh3)2Cl2] employed in the three-
Having confirmed the feasibility of the Huisgen
cycloaddition/Sonogashira sequence
AHCTUNGTRENNUNG
nogashira alkynylation process) was validated, there- component transformation described above with
fore ruling out a thermal process, by submitting 1-(3- other palladium sources (e.g., a heterogeneous cata-
iodobenzyl)-4-phenyl-1,2,3-triazole (59) to the Sono- lyst). Pearlmanꢀs catalyst [Pd(OH)2/C],[28] (a heteroge-
gashira cross-coupling reaction with phenylacetylene neous palladium catalyst that has proven its ability to
or 4-tolylacetylene (Scheme 6). Conversion was not generate active palladium homogeneous species
1188
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Adv. Synth. Catal. 2010, 352, 1179 – 1192

Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Scheme 6.
during cross-coupling reactions)[28] was selected to test exploiting the advantages derived from the use of two
the viability of the transformation.
different catalytic systems. This approach is currently
As shown in Scheme 7, the viability of the transfor- being explored in our group for the development of
mation was examined in the reaction of some alkynes new synthetic strategies.
(2), sodium azide and the three regioisomeric (2-, 3-,
or 4-) iodobenzylbromides (21d, h, i) using the previ-
ously optimized experimental conditions (e.g., reagent Conclusions
ratios and solvent). During these studies the catalyst
loading (5–20 mol%) and the temperature of the reac- In summary, we have documented the use of structur-
tion (40–1008C) were the main variables assessed. As ally simple, robust and recyclable heterogeneous
usual when working with Pd(OH)2/C,[28] it was veri- copper catalysts that contribute to expanding the reli-
fied that relatively high temperatures were required ability and scope of the Huisgen 1,3-dipolar cycload-
for the alkynylation process to advance – otherwise dition. The use of these catalysts facilitates the imple-
the corresponding 4-phenyl-1-(iodobenzyl)-1,2,3-tri- mentation of high-throughput synthetic methodolo-
ACHTUNGTRENNUNGazoles would be isolated. Gratifyingly, it was found gies while the exceptional efficacy of the TBD frame-
that a catalyst loading of 20 mol% and a temperature work as copper scavenger guarantees negligible
of 708C led to smooth and regioselective reaction to copper leaching. The exploitation of the dual role of
give the desired alkynyl 1,2,3-triazoles in satisfactory the new catalytic systems enabled the development of
yields (Scheme 7). These findings not only validate regioselective, convergent, operationally simple and
the feasibility of the designed sequence using a more efficient three-component transformations that allow
economical palladium source, but also document the the rapid assembly of complex 1,2,3-triazoles. Further
efficient and rapid assembly of complex structures by work is in progress in our laboratories to develop new
Scheme 7. Synthesis of functionalized 1,2,3-triazoles using Pearlmanꢀs catalyst
Adv. Synth. Catal. 2010, 352, 1179 – 1192
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Alberto Coelho et al.
FULL PAPERS
was vigorously stirred under orbital stirring at room temper-
ature for 24 h. The resulting green supported base was fil-
tered through a fritted syringe and washed (H2O and
MeOH) and dried under vacuum for 8 h at room tempera-
ture.
multicomponent transformations based on the reactiv-
ity profile of PS-TBD/Cu.
Experimental Section
Representative Procedure for the Azide-Alkyne
Cycloaddition
Commercially available starting materials and reagents were
purchased and used without further purification from freshly
opened containers. Polymer supported 1,5,7-triazabicyclo-
To a Kimble vial containing a mixture of the alkyne
(0.172 mmol) and the organic azide (0.189 mmol) in DMF
(3 mL) or t-BuOH/H2O (3 mL) was added the correspond-
ing supported catalyst [PS-TBD/Cu (0.344 mmol) or Si-
TBD/Cu (0.344 mmol)]. The reaction mixture was submitted
to orbital stirring, at 408C, until reactions reached comple-
tion (8–12 h), the polymer supported catalyst was filtered
off and successively washed (5 mL) with CH2Cl2, THF,
AcOEt and MeOH. Evaporation of the solvents afforded an
oily residue that upon precipitation from ether afforded the
corresponding substituted 1,2,3-triazole. Purification of the
obtained molecules was accomplished either by recrystalliza-
tion or preparative chromatography.
ACHTUNGTRENNUNG[4.4.0]dec-5-ene (TBD) was purchased from different com-
mercial sources. Polystyrene supported TBD (PS-TBD) was
purchased from Fluka (2.6 mmolgÀ1), Aldrich (2.6 mmolgÀ1)
and Merck (2.9 mmolgÀ1), while Si-TBD was purchased
from Aldrich (0.7 mmolgÀ1). All solvents were purified and
dried by standard methods. Organic extracts were dried with
anhydrous Na2SO4. The reactions were monitored by TLC
with 2.5 mm Merck silica gel GF 254 strips, purified com-
pounds each showed a single spot. Unless stated otherwise,
UV light and/or iodine vapour were used for detection of
compounds. The synthesis, isolation and purification of all
compounds were accomplished using the equipment routine-
ly available in laboratories for parallel synthesis. A PLS (6ꢂ
4) Organic Synthesiser or sealed tubes were used for com-
pound preparation. Isolation of precipitated/triturated prod-
ucts was performed in a 12-channel vacuum manifold from
Aldrich. Chromatographic purification was carried out on
preparative TLC. Compounds synthesized were character-
ized by spectroscopic and analytical data. Melting points
were determined on a Gallenkamp melting point apparatus
and are uncorrected. The NMR spectra were recorded on
Bruker AM300 MHz (1H) and 75 MHz (13C) and XM500
spectrometers. Chemical shifts are given as d values against
tetramethylsilane as internal standard and J values are given
in Hz. Unless otherwise quoted, NMR spectra were record-
ed in CDCl3. Mass spectra were obtained on a Varian MAT-
711 instrument. High-resolution mass spectra (HR-MS)
were obtained on an Autospec Micromass spectrometer.
Fluorescence analysis was performed on a X-ray fluores-
cence spectrometer with molybdenum anode. Elemental
analyses were performed on a Perkin–Elmer 240B appara-
tus. Inductively coupled plasma mass spectroscopy (ICP-
MS) analysis of compounds 3 and 6 was performed on a
Varian 820-MS spectrometer (after microwave-assisted di-
gestion of the samples).
Representative Procedure for the Three-Component
Reactions that Involve Alkylation+Cycloaddition
Reactions
To a Kimble vial containing a mixture of the alkyne
(0.172 mmol), sodium azide (0.189 mmol), and the corre-
sponding alkyl halide (0.172 mmol), in DMF (3 mL) was
added the PS-TBD/Cu (0.344 mmol). The reaction mixture
was submitted to orbital stirring, at 408C, until reactions
reached completion (8–16 h), the polymer-supported catalyst
was filtered off and successively washed (5 mL) with
CH2Cl2, THF, AcOEt and MeOH. Evaporation of the sol-
vents afforded an oily residue that upon precipitation from
ether afforded the corresponding substituted 1,2,3-triazole.
Purification of the obtained molecules was accomplished
either by recrystallization or preparative chromatography.
Representative Procedure for the Three-Component
Reaction that Involves Alkylation+Cycloadition+
Sonogashira Cross-Coupling (Method A)
To a Kimble vial containing a mixture of the alkyne
(0.517 mmol), sodium azide (0.189 mmol), the corresponding
alkyl halide (0.172 mmol) and PdCl2ACHTNUTRGNEG(UN PPh3)2 (0.006 mmol) in
Representative Procedure for the Immobilization of
Copper Species on Polystyrene-Supported TBD (PS-
TBD)
DMF (3 mL) was added PS-TBD/Cu (0.517 mmol) and PS-
TBD (0.344 mmol). The reaction mixture was submitted to
orbital stirring, at 408C, until reactions reached completion
(12–24 h), the polymer-supported catalyst was filtered off
and successively washed (5 mL) with CH2Cl2, THF, AcOEt
and MeOH. Evaporation of the solvents afforded an oily
residue that upon precipitation from ether afforded the cor-
responding substituted 1,2,3-triazole. Purification of the ob-
tained molecules was accomplished either by recrystalliza-
tion or preparative chromatography.
To a solution of CuI (5 mg, 9 mg or 18 mg) in 35 mL of
MeCN was added 1.0 g of PS-TBD (2.6 mmolgÀ1 loading)
and the suspension was vigorously stirred under orbital stir-
ring at room temperature for 24 h. The resulting green sup-
ported base was filtered through a fritted syringe and
washed (MeCN, DMF, CH2Cl2) and dried under vacuum for
8 h at room temperature.
Representative Procedure for the Immobilization of
Copper Species on Silica-Supported TBD (Si-TBD)
To a solution of 18 mg of CuI in 35 mL of MeCN was added
1.0 g of Si-TBD (loading 0.7 mmolgÀ1) and the suspension
1190
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Adv. Synth. Catal. 2010, 352, 1179 – 1192

Polymer-Supported 1,5,7-TriazabicycloACTHNUTRGNEUGN[4.4.0]dec-5-ene as Polyvalent Ligands
Representative Procedure for the Three-Component
Reaction that Involves Alkylation+Cycloadition+
Sonogashira Cross-Coupling (Method B)
Supporting Information
Detailed experimental procedures and spectroscopic infor-
mation for all compounds described are available in the
Supporting Information.
To a Kimble vial containing a mixture of the alkyne
(0.517 mmol), sodium azide (0.189 mmol), the corresponding
alkyl halide (0.172 mmol) and Pd(OH)2/C (12 mg, 20%
mmol of Pd) in DMF (3 mL) was added PS-TBD/Cu
(0.517 mmol). The reaction mixture was submitted to orbital
stirring, at 708C, until reactions reached completion (12–
24 h), the heterogeneous catalysts were filtered off and suc-
cessively washed (5 mL) with CH2Cl2, THF, AcOEt and
MeOH. Evaporation of the solvents afforded an oily residue
that upon precipitation from ether afforded the correspond-
ing substituted 1,2,3-triazole. Purification of the obtained
molecules was accomplished either by recrystallization or
preparative chromatography.
Acknowledgements
Part of this work was financially supported by the Fondo Eu-
ropeo de Desarrollo Social (FEDER) and the Galician Gov-
ernment (project: PGIDIT06PXIB203299PR). E. Sotelo is
the recipient of a Consolidation Group Research Grant from
the Conselleria de Educaciꢀn (Xunta de Galicia). E. Sotelo
and A. Coelho are research fellows of the Isidro Parga
Pondal program (Xunta de Galicia, Spain).
Representative Procedure for the Synthesis of
Polymer-Supported Benzyl Azide 8
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Adv. Synth. Catal. 2010, 352, 1179 – 1192