Fine-tunable tris(triazolyl)methane ligands for copper(I)-catalyzed azide-alkyne cycloaddition reactions

Article abstract of DOI:10.1002/adsc.201300887

The preparation of a small library of modular tris(triazolyl)methane ligands for copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions is reported. The synthesis of the first generation ligand, tris(1-benzyl-1H-1,2,3- triazol-4-yl)methanol (1a), s

Full text of DOI:10.1002/adsc.201300887

UPDATES
DOI: 10.1002/adsc.201300887
Fine-Tunable Tris(triazolyl)methane Ligands for Copper(I)-
Catalyzed Azide–Alkyne Cycloaddition Reactions
Erhan Ozkal,a Patricia Llanes,a Fernando Bravo,b Alessandro Ferrali,b
and Miquel A. Pericꢀsa,c,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢁsos Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-97-792-0244; e-mail: mapericas@iciq.es
Catalyst Selection and Optimization Laboratory (CSOL), ICIQ, Av. Paꢁsos Catalans 16, 43007 Tarragona, Spain
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona, 08028 Barcelona, Spain
b
c
Received: October 2, 2013; Revised: December 10, 2013; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300887.
Abstract: The preparation of a small library of
modular tris(triazolyl)methane ligands for copper-
catalyzed azide–alkyne cycloaddition (CuAAC) re-
actions is reported. The synthesis of the first gener-
ation ligand, tris(1-benzyl-1H-1,2,3-triazol-4-yl)me-
thanol (1a), suitable for work in aqueous systems, is
reported at the 50–100 mmol scale through a one-
stage, environmentally benign procedure. One-stage
procedures for the synthesis of tris(aryltriazolyl)me-
thanol structures (1b, phenyl; 1c, para-trifluorome-
thylphenyl; 1d, para-methoxyphenyl) designed for
electronic fine-tuning of catalytic properties, and of
1a-derived ethers 2c (OBn) and 2d (OMe), de-
signed for CuAAC reactions in organic solvents, are
also reported. The complete set of ligands (1a–d,
2c–d) has been tested in the reaction of phenylace-
tylene with benzyl azide in six different solvents
(water, hexane, toluene, dichloromethane, tetrahy-
drofuran, and acetonitrile), and this has allowed the
identification of 1b, 1c and 2c as the ligands depict-
ing the highest tolerance to changes in solvent po-
larity within the considered family. The comparative
performance of ligands 1b–d and 2c in the cycload-
dition of a small family of alkynes with benzyl azide
in two very different reaction media (1:1 t-BuOH/
H2O and toluene) has been studied as a guide for
catalyst selection in specific applications. The ap-
plicability of 1c in CuAAC reactions involving func-
tional substrates in toluene has been explored
under thermal and microwave-accelerated (tandem
azide formation plus CuAAC reaction) reaction
conditions.
Introduction
In the short period of time following its discovery,[1,2]
the copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction has evolved into one of the most
employed connective strategies in organic chemistry[3]
and has found application in many different fields.[4]
Initial reaction conditions for CuAAC reactions in-
volved the in situ reduction of a Cu(II) salt such as
CuSO4, used at rather high loading, with ascorbic acid
to generate in the reaction media the catalytically
active Cu(I) species.[2] However, it was later realized
that polydentate nitrogen ligands were able to stabi-
lize Cu(I) intermediates[5] and could also accelerate
the catalytic process,[6] and this allowed the direct use
of Cu(I) salts as catalysts in CuAAC reactions at
highly reduced loadings. Tris(triazolylmethyl)amines
I,[5a,6a,c,7] tetraamino ligands II,[8] N-heterocyclic car-
benes III[9] (Figure 1), as well as various copper-coor-
dinating species[10] have been found to be excellent li-
gands for this chemistry.
In this context, we have recently introduced tris-
AHCTUNGTREGUN(NN triazolyl)methanol 1a (Figure 2) as an effective
ligand for CuCl, and have shown that the correspond-
ing neutral complex (1a·CuCl) is a very efficient cata-
lyst for the azide–alkyne [3+2]cycloaddition reaction
Keywords: alkynes; azides; click chemistry; copper;
cycloaddition reactions
Figure 1. Cu(I) ligands for CuAAC reactions.
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
857

UPDATES
Erhan Ozkal et al.
Scheme 1. Retrosynthetic analysis of TTM ligands 1 and 2.
ing to Scheme 1 and involving safe and scalable pro-
cedures. Derivatives 1b–d are tris(aryltriazolyl)metha-
nols designed to modulate electron density at a com-
plexed Cu atom and to study the effect of this modu-
lation on catalytic activity. Derivatives 2c, 2d are
tris(aryltriazolyl)methanol ethers designed to expand
the range of solvents where the corresponding CuCl
Figure 2. Homogeneous (1a·CuCl) and heterogenized
(2a·CuCl and 2b·CuCl) catalysts for CuAAC with the tris-
ACHTUNGTRENNUNG(triazolyl)methanol (TTM) structure.
in aqueous systems.[11] We have subsequently immobi- complexes can be used in catalysis.
lized 1a onto polystyrene resins by using different li-
gation methods, and have shown that the CuCl com-
plexes of the functional resins 2a, 2b behave as highly Results and Discussion
active and recyclable catalysts for azide–alkyne cyclo-
additions in a variety of solvents.[12]
Implementation of a Scalable Procedure for the
The structural characteristics of catalysts 1a·CuCl, Preparation of 1a
2a·CuCl,[12] and 2b·CuCl[12] confer interesting proper-
ties to these materials. Thus, the three-point binding The initially reported procedure for the preparation
provided by the triazole units notably increases the of 1a[11] involved several chromatographic purifica-
stability of the CuCl complexes and allows their cata- tions and made use of the relatively expensive and
lytic use at very low loadings even with substrates potentially hazardous benzyl azide. In view of the in-
with high affinity for Cu, such as thioethers and pri- terest in this ligand, whose activity and performance
mary and secondary amines.[11–13]
compare very favorably with those of highly priced,
Tris(triazolyl)methanol (TTM) derivatives such as commercially available analogs, we aimed at develop-
1 and 2 are modularly constructed from a simple, ing an optimized procedure for the preparation of this
readily available trisACHTNUTGRNEUNG
(alkynyl)methanol derivative 3.[11] material fulfilling the following requirements: (i)
If the development of a general purpose catalyst li- avoiding the isolation or purification of intermediates,
brary for CuAAC reactions based on this structure is (ii) using available reagents and environmentally con-
considered, it can be readily envisioned that parame- venient solvents, (iii) avoiding the use of benzyl azide,
ters such as solubility in aqueous or organic solvents and (iv) avoiding the use of chromatography for the
can be controlled by simple etherification of the hy- final purification of 1a.
droxy group in 1 leading to 2, while the use of di-
After extensive experimentation, the process repre-
versely substituted aryl azides in the synthesis of the sented in Scheme 2 was developed. In the optimized
TTM structure can allow the modulation of electron procedure, trimethylsilylacetylene (ca. 330 mmol) in
density at the triazole unit and, consequently, at the anhydrous THF is converted to its Li salt by treat-
copper atom in the corresponding CuCl complexes.[14] ment with a solution of n-butyllithium in hexanes
To make this useful ligand fully available, we wish with strict temperature control (ꢀ158C), and the gen-
to report here a large-scale (50–100 mmol) prepara- erated acetylide is reacted with ethyl chloroformate
tion of 1a through a one-stage process optimized to (4, ca. 90 mmol; limiting reagent) in anhydrous THF,
avoid potentially hazardous solvents or reagents, and again with strict temperature control. The intermedi-
not requiring any chromatographic separation. We ate lithium salt arising from the double addition–elim-
also report the preparation of a small library of tris- ination plus addition sequence (3-Li), obtained in
ACHTUNGTRENNUNG(triazolyl)methanol derivatives (1b–d, 2c, 2d) accord- THF solution does not need to be isolated for the
858
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
with 5 (or with its partially cycloadded derivatives) as
it forms, and accumulation in the reaction media of
this potentially hazardous reagent is avoided. Crude
1a, which precipitates as the reaction proceeds, can be
purified to a white powder by recrystallization from
acetonitrile-ethyl acetate-cyclohexane (1:1:2). In this
manner, 30 g of 1a (64% yield) are obtained in
a single batch, the whole process not involving
a single purification by column chromatography. At
this scale, the preparation of 1a can be performed in
a 1-L flask and involves the use of environmentally
benign solvents and conventional reaction conditions.
As we will see later in this update, the process can
also be adapted for the one-pot preparation of aryl-
substituted TTM ligands without isolation of the in-
volved aryl azides.
Synthesis of Modular Tris(triazolyl)methane
Derivatives
Scheme 2. Optimized procedure for the large-scale produc-
tion of 1a.
As we have already mentioned, the immobilization of
preparation of 1a. If desired, however, the stable tris- 1a on polystyrene matrices, using its hydroxy group as
ACHTUNGTRENNUNG(trimethylsilylethynyl)carbinol 3 can be easily isolated the anchoring point, allowed the preparation of com-
from this solution after neutralization and used as plexes 2a·CuCl and 2b·CuCl, which performed as effi-
a convenient, advanced precursor for the synthesis of cient and highly recyclable catalysts for CuAAC reac-
different TTM ligands.
tions in a variety of organic solvents. In view of this
Addition of excess MeOH to the THF solution of behavior, we decided to prepare simple monomeric
3-Li (ꢀ158C) followed by 2 h stirring at ca. 58C pro- ethers of 1a in order to expand the use of their
vokes complete protodesilylation of 3 and generates copper complexes to organic solvents covering
a light brown solution of 5. Evaporation under a broad range of polarity. This can be of particular
vacuum to a final volume of 50 mL, followed by importance when the product triazoles need to be
water addition (300 mL), evaporation of residual kept in solution as, for example, in processes involving
THF, and addition of a small volume of DMSO multiple consecutive reactions.
(10 mL) delivers a solution of 5 suitable for the triple
The benzyl ether (2c) and the methyl ether (2d)
CuAAC reaction leading to 1a. This is performed by were selected for this purpose and were readily pre-
addition to the solution of 5 of benzyl bromide pared in high yield by simple etherification
(310 mmol), sodium azide (330 mmol) and 1a·CuCl (Scheme 3).
(ca. 0.50 mmol). In this manner, benzyl azide reacts
Scheme 3. Etherification of 1a leading to 2c, 2d.
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
859

UPDATES
Erhan Ozkal et al.
Performance of the CuCl Complexes of Modular
Tris(triazolyl)methane Derivatives 1a–d and 2c, 2d in
CuAAC Reactions
With the aim of determining the applicability of the
prepared TTM ligands in CuAAC reactions, the cy-
cloaddition between phenylacetylene and benzyl
azide was first performed in different solvents in the
presence of 1a–d and 2c, 2d. The same amount of cat-
alyst (2 mol%) was used in all cases and, for each par-
ticular solvent, the same reaction time was used with
the whole set of ligands to facilitate comparison. The
outcome of this study has been summarized in
Table 1, where results for the optimal ligand/solvent
combinations are and highlighted in boldface.
Several trends observed in this study deserve a com-
ment. First, with the exception of 2d, all the members
of the considered family of catalysts perform very
well in water (column 1), the reactions taking place in
a short time with only 0.5 mol% catalyst loading.
Second, and according to our expectations, ligands 2c
and 2d, resulting from the etherification of the hy-
droxy group in 1a, behave well in aprotic solvents of
medium polarity (CH2Cl2, THF, CH3CN). Third,
among the tris(aryltriazolyl)methanols 1b–d, both 1b
(R=H) and the electron-poor 1c (R=CF3) give high
conversions in all the studied solvents at the specified
reaction times; by contrast, ligand 1d bearing the
electron-rich 4-methoxyphenyl substituents originates
Scheme 4. One-stage preparation of 1b–d.
The preparation of analogs of 1a bearing aryl sub- a very poor catalyst in all solvents but in water.
stituents at the triazole rings was also undertaken. In Next, to determine if the catalytic behavior of the
this manner, the electronic characteristics exerted by different ligands was correlated to the nature of the
substituents at the aryl groups could be transmitted to reactants, we decided to compare the performance of
the copper atom upon complexation, thus modulating ligands 1b–d and 2c in four cycloadditions involving
the catalytic behavior of the complexes. As shown in
Scheme 4, derivatives 1b (R=H), 1c (R=CF3), and
1d (R=OCH3) were prepared for this purpose. The
synthetic procedures for the preparation of 1b–d were
optimized in view of potential scale-up, and involved
the use of benign solvents and reaction conditions,
while avoiding manipulation and storage of aryl
azides.
Table 1. Comparative performance[a] of catalysts 1a–d and
2c, 2d in the reaction of phenylacetylene with benzyl azide
leading to 8a in different solvents.
TrisACHTUNGTRENNUNG(ethynyl)carbinol 5 was readily prepared in
L
H2O[b] C6H14 PhCH3 CH2Cl2 THF CH3CN
methanol solution from the stable and readily avail-
able alcohol 3 (see above) by protodesilylation with
methanol in the presence of K2CO3 followed by filtra-
tion to remove solid materials. Aryl azides 7a–c, in
turn, were prepared in aqueous solution from the cor-
responding amines 6a–c by treatment with HNO2,
neutralization, and reaction with sodium azide. Then,
combination of the two solutions in the presence of
1a·CuCl (0.5 mol%) and a small amount of DMSO
(1% v/v) at room temperature led to the target TTM
derivatives 1b–d in 57–89% yield. Noteworthy, the
preparation of these materials does not involve any
chromatographic purification, and only a final recrys-
tallization may be required.
4 h
6 h
6 h
6 h
16 h
16 h
1a 98
1b 99
1c
1d 99
2c 99
5
75
98
99[d]
2
26
69
25
95
99
22
98
99
90
78
80
3
92
60
21
86
50
10
96
89
99
99[c]
14
43
27
82
2d 56
[a]
Conversion in [%].
0.5 mol% catalyst was used in this solvent.
Conversion was 99% after 3 h and 73% after 1 h. With
1 mol% catalyst, conversion was 99% in 4 h. With
0.5 mol% catalyst, conversion was 73% after 4 h.
Conversion was 95% after 3 h.
[b]
[c]
[d]
860
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
Table 2. Comparative performance[a] of ligands 1b, 1c, 1d,
and 2c in the CuAAC reactions[b] of benzyl azide with repre-
sentative alkynes.
As we have already mentioned, 2c·CuCl exhibits
optimal catalytic conditions in organic solvents of
medium polarity (see Table 1). To more properly
assess the merits of this catalyst for the preparation of
adducts 8a–d in non-aqueous media, the reactions in
column 8 of Table 2 were repeated in CH2Cl2 under
otherwise identical conditions. Very gratifyingly, uni-
form yields (in parentheses) were obtained under
these conditions for all four studied substrates. Thus,
in preparative experiments a simple extension of reac-
tion time will ensure very high yields of the corre-
sponding adducts irrespective of the nature of the in-
volved alkyne.
In view of the good performance exhibited by
1c·CuCl for reactions in toluene leading to 8a–d
(mean yield: 85%), some additional experiments in-
cluding especially challenging substrates, like primary
amines, or problematic adducts, like those exhibiting
good chelating characteristics for copper were per-
formed in this solvent (Table 3). It is important to
point out that CuAAC reactions involving these sub-
strates usually fail when copper salts are used as
metal sources, and this can be attributed to the forma-
tion of catalytically inactive Cu complexes involving
either the reactants or the cycloadducts. According to
the observed behavior of 1a·CuCl in aqueous media,
we reasoned that the efficient three-point metal bind-
ing in 1c·CuCl would preserve its catalytic activity in
toluene.
1b
A
1c
A
1d
A
2c
A
Product
O
O
O
4
O[g]
90 99 99
99 88 76
99 63 99
99
64
80 21 (68)
85
84
88 79 90 82 (75)
79 69 88 99 (82)
99 63 95[f] 72[f] 66 59 73 67 (70)
[a]
Isolated yields in [%].
[b]
Aqueous conditions (A): (1:1) t-BuOH/H2O, 4 h, room
temperature; organic conditions (O): toluene, 4 h, room
temperature.
Reactions in conditions O performed with 2 mol% cata-
lyst for 6 h.
Reactions leading to this adduct performed with 2 mol%
catalyst for 16 h.
Reactions leading to this adduct in conditions O per-
formed under argon.
[c]
[d]
[e]
As it can be seen, 1c·CuCl behaves as a very gener-
al and active catalyst for CuAAC reactions in this
media. Proline derivatives depicting azido groups in
different positions (entries 1–3) were efficiently con-
verted into triazoles 8e–g, which are advanced inter-
mediates for organocatalytic prolines and pyrroli-
dines.[15] As already mentioned, functional group tol-
erance in the alkyne component is also very broad
(entries 4–7) and alcohols, primary amines and esters
[f]
2 mol% catalyst was used.
Yields in parentheses correspond to reactions in di-
chloromethane.
[g]
in all cases benzyl azide and representative alkynes lead to the corresponding adducts in high yield. In the
bearing different functionalities. The reactions were same way, alkyl azides (entries 8–11) afford the corre-
performed with 1 mol% catalyst loading, in two dif- sponding cycloadducts in essentially quantitative
ferent solvent systems covering a wide range in polar- yield. Very gratifyingly, 1,3,5-tris(azidomethyl)-2,4,6-
ity: 1:1 tert-butyl alcohol:water and toluene. Results triethylbenzene, an important precursor for supra-
of this study are summarized in Table 2, where results molecular systems,[16] readily underwent triple
for optimal ligands and reaction conditions are high- CuAAC reactions mediated by 1c·CuCl in toluene to
lighted in boldface.
afford the corresponding adducts 8p and 8q in very
To compare these results, it should be first kept in high yields (entries 12 and 13).
mind that one of the employed alkynes (i.e., 2-
Finally, the use of 1c·CuCl in tandem processes in-
methyl-3-butyn-2-ol) is much less reactive with benzyl volving azide generation from an organyl bromide
azide than the other three. When reactions in aqueous and sodium azide and subsequent CuAAC reaction is
media are performed, 1b·CuCl appears as the catalyst illustrated by the examples in Table 4. The reactions
of choice. Thus, all four adducts are obtained in excel- were performed in acetonitrile/water, at 1008C under
lent yields with this catalyst and reaction conditions microwave irradiation in a remarkably short 40 min
(column 1). For reactions in toluene, very good results period.
are achieved with 1c·CuCl (column 4), especially
when the low reactivity of 2-methyl-3-butyn-2-ol is
considered.
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
861

UPDATES
Erhan Ozkal et al.
Table 3. CuAAC reactions mediated by 1c·CuCl in toluene.
Table 3. (Continued)
Product
Time
[h]
Yield
[%][a]
Product
Time
[h]
Yield
[%][a]
13[d]
24
80
1
2
2
95
99
[a]
Isolated yields as mean value of two experiments.
At room temperature.
In t.BuOH-H2O (1:1) at 408C.
[b]
[c]
[d]
22
2 mol% catalyst per CuAAC reaction.
3
3
99
Table 4. One-pot azide formation plus CuAAC reactions
mediated by 1c·CuCl.
4[b]
9
95
74
Entry
1
Product
Yield [%][a]
55
5
13
6
7
80
99
99
93
99
99
7[c]
10
22
2
2
3
98
8
99
53
9
10
11
20
2
4[b]
[a]
Isolated yield as mean value of two experiments.
Reaction time was 80 min.
[b]
Conclusions
12[d]
6
99
The results presented in this study clearly show that
modular tris(triazolyl)methanols (TTM) are among
most useful ligands for copper-catalyzed azide–alkyne
cycloaddition reactions. The three-point binding pro-
vided by these ligands efficiently stabilizes Cu(I)
against oxidation or complexation with amino, hy-
droxy, and/or thioether groups present in either reac-
tants or reaction products, likewise through favorable
862
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
4.79 for proton and carbon, respectively]. The following ab-
breviations are used for the multiplicity: s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet; br-s, broad signal.
Melting points are all uncorrected. IR spectra were recorded
on a FT-IR spectrometer operating in ATR mode.
self-repair of the catalytic complex. This behavior not
only extends catalyst life and allows very reduced cat-
alyst loadings; it also allows its use with substrates
(primary and secondary amines) where most catalysts
for CuAAC reactions completely fail.
The first generation catalyst in this family, 1a·CuCl,
tolerates a wide range of functional groups on either
the alkyne or the azide reactant, being particularly
suitable for work in aqueous media. We believe that,
with the fully optimized preparation of 1a reported
here, our catalyst constitutes a cost-efficient alterna-
tive to other Cu catalysts for similar purposes.[17]
The modification of the first generation catalyst, by
simple etherification of the tertiary hydroxy group,
provides catalytic species (2c·CuCl and 2d·CuCl) suit-
able for work in organic solvents that behave particu-
larly well in solvents of medium polarity.
The modular design of the TTM ligands has been
exploited for the preparation of a small library of tris-
ACHTUNGTRENNUNG(aryltriazolyl)methanol derivatives 1b–d. While the
system involving a para-methoxy substituent in the
aryl groups (1d) has proved to be a mediocre ligand,
the parent tris(phenyltriazolyl) derivative (1b) and
the one involving a para-trifluoromethyl substituent
(1c) behave as very active ligands in a full range of
solvents. In particular, 1c tolerates a wide variety of
Large-Scale Procedure for the Preparation of Tris(1-
benzyl-1H-1,2,3-triazol-4-yl)methanol (1a)[11]
In a flame-dried, 1-L, three-neck, round-bottom flask, pro-
vided with magnetic stirrer, addition funnel and thermome-
ter,
a
solution of trimethylsilylacetylene (47.0 mL,
332.6 mmol) in anhydrous THF (100 mL) is prepared. The
solution is cooled with an ice-water bath, and stirred until
the internal temperature is ca. 58C. Then, a solution of BuLi
2.5M in hexanes (122.0 mL, 305.0 mmol) is slowly added to
the solution from the addition funnel (exotherm!), control-
ling the addition rate in order to keep the internal tempera-
ture ꢀ158C. In this way, the addition is completed in ca.
1 h. The addition funnel is rinsed with fresh anhydrous THF
(20 mL), which is also added to the reaction mixture. The
solution is stirred in the ice-water bath (the internal temper-
ature decreases to ca. 58C) for 1 h. Then, a solution of ethyl
chloroformate (10.0 g, 92.2 mmol) in anhydrous THF
(60 mL) is slowly added (exotherm!) through the addition
funnel, controlling the addition rate so that the internal tem-
perature is kept below 158C. In this way, the addition is
completed in ca. 30 min. Afterwards, the addition funnel is
functional groups on either the alkyne or the azide re- rinsed with anhydrous THF (20 mL), which is also added to
the reaction mixture. The reaction mixture is then allowed
to warm slowly to room temperature (ca. 238C), and is
stirred overnight. The solution takes a light brown color as
the reaction proceeds. After 14 h at room temperature, TLC
analysis of the light brown solution indicates the formation
of tris(trimethylsilylethynyl)carbinol (eluent: cyclohexane/
ethyl acetate 9:1; Rf: 0.37; stain: phosphomolybdic acid).
Next, the reaction mixture is cooled with an ice-water bath
until the internal temperature reaches ca. 58C, and then
MeOH (100 mL) is slowly added through the addition
funnel (exotherm!), controlling the addition rate in order to
keep the internal temperature below 158C. This addition is
completed in ca. 20 min. The reaction mixture is further
stirred while cooling with the external ice-water bath (inter-
nal temperature stabilizes at ca. 58C) for 2 h. At this point,
the reaction mixture has the aspect of a light brown solu-
tion. TLC analysis of this solution indicates formation of
actants, and appears as a convenient alternative to 1a
when work in non-aqueous solvents is mandatory.
Experimental Section
General Considerations
All reagents and solvents were used as received. For reac-
tions requiring exclusion of oxygen and moisture, SPS quali-
ty THF and DMF were used. Unless otherwise stated, reac-
tions were performed in oven-dried round-bottom flasks
fitted with rubber septa and stirring bars, and reactions were
conducted under a positive pressure of argon. Syringes or
cannulae were used to transfer air- and moisture-sensitive
liquids. All copper catalyzed azide–alkyne cycloaddition
(CuAAC) reactions were performed in glass vials fitted with
stirring bars without any precaution to exclude air and mois-
ture. All flash chromatography purifications were carried
out using 60 mesh silica gel and dry-packed columns. For
thin layer chromatography (TLC) analysis, pre-coated TLC
plates (silica gel 60 GF254, 0.25 mm) were used, with UV
light and/or phosphomolybdic acid (PMA) or basic aqueous
potassium permanganate (KMnO4) as developing agents.
Solutions were concentrated under reduced pressure on ro-
tatory evaporators at 308C. Nuclear magnetic resonance
(NMR) spectra were recorded at 400 MHz or 500 MHz for
1H and at 100 MHz or 126 MHz for 13C at room tempera-
ture. Chemical shifts (d) are reported in parts per million
(ppm) with respect to tetramethylsilane as internal standard,
or to the corresponding solvent residual peak [CDCl3: 7.28,
77.16; (CD3)2SO: 2.50, 39.52; CD3OD: 3.31, 49.00; D2O:
trisACHTNUTRGNEUNG(ethynyl)carbinol (eluent: cyclohexane/ethyl acetate 9:1;
Rf: 0.02; stain: phosphomolybdic acid). The mixture is con-
centrated under vacuum to a final volume of 50 mL, keeping
the bath temperature at 30–358C. Water (300 mL) is then
added, the solution is concentrated again under vacuum
until only water distills, and the distillation is continued for
15–30 more minutes to ensure the removal of rests of organ-
ic solvent (bath temperature: 30–358C). Finally, enough
water is added to adjust the volume of the solution to
300 mL. DMSO (10 mL) is then added, followed by benzyl
bromide (37.0 mL, 312.0 mmol), sodium azide (21.5 g,
330.7 mmol) and 1a·CuCl (0.277 g, 0.460 mmol, 0.5 mol%).
The resulting mixture is warmed to 508C and stirred vigo-
rously overnight at this temperature [CAUTION: benzyl
azide is formed under these conditions; benzyl azide may be
explosive. Differential scanning calorimetry (DSC) of pure
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
863

UPDATES
Erhan Ozkal et al.
benzyl azide shows an exothermic event starting at about
1608C, providing a sufficient safety margin]. After 14 h re-
action, a brownish solid is abundantly formed, that tends to
stick to the walls of the reactor. At this point, the progress
of the reaction can be easily monitored by TLC, by taking
a sample of the aqueous solution and extracting it with
CH2Cl2. The absence of the spot corresponding to the start-
129.9, 128.6, 121.4, 120.1, 68.0; FT-IR (neat): n=3304, 3138,
1597, 1548, 1466, 1235, 1042, 991, 889, 811, 750, 666 cmÀ1
;
HR-MS (ESI-TOF): m/z=484.1610 [M+Na]+, calcd. for
C25H19N9ONa: 484.1614; elemental analysis: found (calcd.
for C25H19N9O): C 65.06 (65.07), H 4.27 (4.15), N 26.87
(27.32).
ing trisACHTUNGTRENNUNG(ethynyl)carbinol is indicative of reaction completion.
Tris(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-
The aqueous mother liquors are filtered, and all solids re-
maining in the reactor and in the filter are washed with
water (2ꢄ100 mL, then 1ꢄ200 mL) [CAUTION: the aque-
ous phase should be disposed of with basic aqueous resi-
dues; addition of acid may generate hazardous and poison-
ous hydrazoic acid (HN3) as a gas]. The brownish solid re-
covered is partially dried on the filter by passing air through
it and, while still wet, it is suspended in a mixture of aceto-
nitrile (80 mL) and ethyl acetate (160 mL), warmed to
reflux (internal temperature ca. 808C) and stirred at that
temperature for 1 h. During this process, the solid almost
completely dissolves. Cyclohexane (220 mL) is added slowly
over 1 h while keeping the mixture under reflux, and then
the mixture is cooled to room temperature (ca. 238C) over
3 h. The resulting slurry is aged overnight at room tempera-
ture. The white solid obtained is separated by filtration,
then washed 3 times with a 1:1 mixture of ethyl acetate and
cyclohexane (3ꢄ50 mL). The solid recovered is dried in an
oven under vacuum overnight at 658C to afford 1a as
a white solid; yield: 29.8 g (64%). 1H NMR (500 MHz,
CDCl3): d=7.76 (s, 3H), 7.32–7.18 (m, 15H), 5.76 (br-s,
1H), 5.39 (s, 3H); 13C NMR [126 MHz, (CD3)2SO]: d=
151.4, 135.2, 127.9, 127.3, 127.2, 122.2, 67.1, 52.4.
yl)methanol (1c)
Following the above procedure for 1b and starting from 4-
(trifluoromethyl)aniline (967 mg, 6.00 mmol), 1c was ob-
tained as a pale-yellow solid; yield: 808 mg (81%); mp 240–
2418C. 1H NMR [500 MHz, (CD3)2SO]: d=8.96 (s, 3H),
8.25 (d, 6H, J=8.5 Hz), 7.99 (d, 6H, J=8.5 Hz), 7.32 (s,
1H); 13C NMR [126 MHz, (CD3)2SO]: d=152.7, 139.4, 128.6
(q, J=32.42 Hz), 127.2 (q, J=3.40 Hz), 124.3 (q, J=
274.05 Hz), 122.7, 121.9, 120.5, 67.4; 19F NMR [376 MHz,
(CD3)2SO]:
d
À61.06; FT-IR (neat): n=3258, 1650,
1524,1323, 1161, 1126, 1069, 1044, 895, 840, 594 cmÀ1; HR-
MS (ESI-TOF): m/z=688.1212 [M+Na]+, calcd. for
C28H16F9N9ONa: 688.1232.
Tris(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-
methanol (1d)
Following the above procedure for 1b and starting from 4-
(methoxy)aniline (741 mg, 6.00 mmol), 1d was obtained as
a pale-yellow solid; yield: 736 mg (89%); mp 128–1308C.
1H NMR (400 MHz, CDCl3): d=8.20 (s, 3H), 7.66 (d, 6H,
J=9.0 Hz), 7.02 (d, 6H, J=9.0 Hz), 4.98 (s, 1H), 3.88 (s,
9H); 13C NMR (100 MHz, CDCl3): d=159.9, 151.7, 130.4,
122.3, 120.9, 114.7, 68.1, 55.6; FT-IR (neat): n=3141, 2955,
2834, 1514, 1303, 1251, 1108, 1027, 888, 829, 796, 635,
530 cmÀ1; HR-MS (ESI-TOF): m/z=574.1927 [M+Na]+,
calcd. for C28H25N9O4Na: 574.1927.
Tris(1-phenyl-1H-1,2,3-triazol-4-yl)methanol (1b)
Concentrated aqueous hydrochloric acid solution [37%
ACHTUNGTRENNUNG(v/v), 1.5 mL, 18 mmol] was added dropwise to a suspension
of aniline (559 mg, 6.00 mmol) in water at 08C. After
15 min, a solution of sodium nitrite (621 mg, 9 mmol) in
water (1 mL) was added via syringe. After 15 min, solid
sodium bicarbonate was added until pH~7, followed by ad-
dition of a solution of sodium azide (702 mg, 10.8 mmol) in
water (1.7 mL). The reaction mixture was allowed to warm
to room temperature and stirred for 1 h. In a simultaneous
manner and in a separate flask, solid potassium carbonate
(2.01 g, 14.5 mmol) was added to a solution of tris(trimethyl-
silylethynyl)methanol (3) (481 mg, 1.5 mmol) in methanol
(5 mL) and the mixture was stirred at room temperature for
30 min. The solids were separated by filtration, and the solu-
tion was concentrated under reduced pressure to a final
volume of ca. 3 mL. This solution was added to the mixture
containing phenyl azide, followed by the addition of DMSO
(0.15 mL) and 1a·CuCl (9 mg, 0.015 mmol, 1 mol%), and the
reaction mixture was stirred overnight at room temperature.
After 14 h, a brown precipitate of 1b was formed; it was
separated by filtration and washed with cold diethyl ether
(10 mL) to provide essentially pure 1b. This material can be
purified to analytical level by recrystallization from acetoni-
trile-water (1:2 mixture, 15 mL) to afford 1b as a pale-
4,4’,4’’-[(Benzyloxy)methanetriyl]tris(1-benzyl-1H-
1,2,3-triazole) (2c)
A solution of 1a (503 mg, 1.0 mmol) in anhydrous DMF
(2 mL) was added dropwise via cannula, under a positive
pressure of argon, to a stirred suspension of sodium hydride
(80 mg, 60% in oil, 2.0 mmol) in anhydrous DMF (2 mL) at
08C, and the reaction mixture was allowed to warm to room
temperature (238C). After 2 h, the suspension became
a clear solution, which was cooled to 08C and benzyl bro-
mide (0.238 mL, 2.0 mmol) was added dropwise via syringe.
The reaction mixture was allowed to warm to 238C and was
stirred overnight. After 14 h, water (10 mL) was added
dropwise and the mixture was extracted with dichlorome-
thane (3ꢄ10 mL). The organic layer was dried over anhy-
drous MgSO4, filtered, and concentrated under reduced
pressure. Residual DMF can be removed by dissolving the
crude product in ethyl acetate-hexane (4:1, 50 mL) and
washing with water (3ꢄ20 mL). Drying (anhydrous MgSO4)
and evaporation under reduced pressure affords crude 2c,
which is further purified by flash column chromatography
(silica gel, ethyl acetate). The product was obtained as
a white foam; yield: 0.456 g (77%). 1H NMR (500 MHz,
CDCl3): d=7.84 (s, 3H), 7.32–7.28 (m, 9H), 7.24–7.19 (m,
6H), 7.19–7.11 (m, 5H), 5.44 (s, 6H), 4.41 (s, 2H); 13C NMR
(126 MHz, CDCl3): d=149.0 138.1, 134.3, 128.9, 128.5, 127.9,
1
yellow solid; yield: 394 mg (57%); mp 211–2128C. H NMR
[500 MHz, (CD3)2SO]: d=8.76 (s, 3H), 7.96 (d, 6H, J=
8.3 Hz), 7.60 (t, 6H, J=7.9 Hz), 7.49 (t, 3H, J=8.0 Hz), 7.16
(s, 1H); 13C NMR [126 MHz, (CD3)2SO]: d=152.6, 136.7,
864
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
127.7, 127.1, 124.4, 72.7, 66.5, 54.0; FT-IR (neat): n=3144,
3064, 2934, 2871, 1496, 1453, 1226, 1130, 1040, 910, 889, 807,
734 cmÀ1; HR-MS (ESI-TOF): m/z=616.2546 [M+Na]+,
calcd. for C35H31N9ONa: 616.2549.
complex as a green powder; yield: 0.330 g (86%). 13C NMR
(126 MHz, CD3CN): d=133.5, 131.1 (d, J=31.5 Hz), 128.6,
126.6 (d, J=52.9 Hz), 124.5 (d, J=49.0 Hz), 122.4; FT-IR
(ATR, neat): n=3085, 1617, 1523, 1323, 1168, 1112, 1069,
1057, 843, 594, 469 cmÀ1
; HR-MS (ESI-TOF): m/z=
728.0617 [MÀCl]+, calcd. for C28H16F9N9OCu: 728.0625.
4,4’,4’’-(Methoxymethanetriyl)tris(1-benzyl-1H-1,2,3-
triazole) (2d)
Tris[1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-
Following the above procedure for 2c and using methyl
iodide (0.124 mL, 2.0 mmol), 2d was obtained as a white
foam; yield: 0.408 g (79%); mp 127–1298C. 1H NMR
(500 MHz, CDCl3): d=7.80 (s, 3H), 7.35–7.33 (m, 9H),
7.26–7.25 (m, 6H), 5.49 (s, 6H), 3.14 (s, 3H); 13C NMR
(126 MHz, CDCl3): d=148.8, 134.3, 129.1, 128.7, 128.1,
124.4, 72.8, 54.2, 52.1; FT-IR (neat): n=3141, 2943, 1605,
1526, 1497, 1232, 1120, 1080, 856, 776 cmÀ1; HR-MS (ESI-
TOF): m/z=540.2229 [M+Na]+, calcd. for C29H27N9ONa:
540.2236; elemental analysis: found (calcd. for C29H27N9O):
C 66.87 (67.30), H 5.18 (5.26), N 24.01 (24.36).
methanol·CuCl (1d·CuCl)
Prepared according to the general procedure for complex
formation using 1d (0.276 g, 0.50 mmol) to afford the de-
sired complex as a light green powder; yield: 0.257 g (79%).
13C NMR (100 MHz, CD3CN): d=161.4, 134.7, 133.2, 131.6,
126.1, 123.8, 116.2, 56.8; FT-IR (ATR, neat): n=3353, 3081,
2936, 2837, 1515, 1306, 1254, 1112, 1028, 830, 799, 613 cmÀ1
;
HR-MS (ESI-TOF): m/z=614.1309 [MÀCl]+, calcd. for
C28H25N9O4Cu: 614.1320.
4,4’,4’’-[(Benzyloxy)methanetriyl]tris(1-benzyl-1H-
1,2,3-triazole)·CuCl (2c·CuCl)
General Procedure for the Preparation of the
Copper(I) Complexes of 1a–d and 2c, 2d
Prepared according to the general procedure for complex
formation using 2c (0.297 g, 0.50 mmol) to afford the desired
complex as a light green powder; yield: 0.300 g (87%). FT-
IR (ATR, neat): n=3448, 3115, 3031, 2946, 2870, 1496, 1453,
1227, 1132, 1046, 980, 898, 807, 716 cmÀ1; HR-MS (ESI-
TOF): m/z=656.1928 [MÀCl]+, calcd. for C35H31N9OCu:
656.1942.
The ligand L (x mmol) (L=1a–d, 2c, 2d) and copper(I)
chloride (1.05x mmol) in dioxane (10 mLmmolÀ1 L) were
stirred at 608C for 6 h. The solvent was then removed under
reduced pressure, the green solid residue being redissolved
in the minimal amount of dichloromethane (1–2 mL) and
precipitated into hexane (20 mL) via dropwise addition of
the dichloromethane solution. The solid material was col-
lected by filtration and dried in a vacuum oven at 408C for
14 h to afford L·CuCl.
4,4’,4’’-(Methoxymethanetriyl)tris(1-benzyl-1H-1,2,3-
triazole)·CuCl (2d·CuCl)
Prepared according to the general procedure for complex
formation using 2d (0.259 g, 0.50 mmol) to afford the de-
sired complex as a light green powder; yield: 0.278 g (91%).
FT-IR (ATR, neat): n=3135, 2935, 1542, 1497, 1226, 1132,
Tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol·CuCl
(1a·CuCl)
Prepared according to the general procedure for complex
formation using 1a (0.504 g, 1.00 mmol) to afford the desired
complex as a light green powder; yield: 0.588 g (98%).
1H NMR (500 MHz, CD3OD): d=7.41–7.07 (m, 18H), 5.92
(s, 6H); 13C NMR (126 MHz, CD3CN): d=131.6, 131.2,
130.7, 129.9, 129.5, 101.0, 84.0; FT-IR (ATR, neat): n=3380,
3111, 3062, 2949, 1718, 1584, 1432, 1142, 1077 cmÀ1;: HR-MS
1077, 893, 783, 717 cmÀ1
; HR-MS (ESI-TOF): m/z=
580.1629 [MÀCl]+, calcd. for C29H27N9OCu: 580.1629.
General Procedure for CuAAC Reactions
In a 3-mL vial, the specified amount of L·CuCl (L=1a–d,
2c, 2d) was added to a mixture of the reacting alkyne
(1.05 mmol) and the corresponding azide (1.00 mmol) in the
specified solvent (1 mL), and the mixture was stirred at
408C for the indicated times or until complete reaction. In
reactions with complete conversion providing insoluble com-
pounds, simple filtration afforded the desired CuAAC prod-
ucts with analytical purity. Otherwise, the reaction mixture
was diluted with ethyl acetate (10 mL), and the resulting so-
lution was washed with water (5 mL) and brine (10 mL),
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. When required, the product was
purified by flash column chromatography.
(ESI-TOF):
C28H25N9OCu: 566.1473.
m/z=566.1473
[MÀCl]+,
calcd.
for
Tris(1-phenyl-1H-1,2,3-triazol-4-yl)methanol·CuCl
(1b·CuCl)
Prepared according to the general procedure for complex
formation using 1b (0.232 g, 0.50 mmol) to afford the de-
sired complex as a light green powder; yield: 0.233 g (83%).
13C NMR (126 MHz, CD3CN): d=135.1, 131.0, 130.6, 129.9,
129.5, 126.8, 121.9; FT-IR (ATR, neat): n=3324, 3136, 1597,
1552, 1465, 1237, 1039, 999, 892, 811, 752, 686 cmÀ1; HR-MS
(ESI-TOF):
C25H19N9OCu: 524.1003.
m/z=524.0997
[MÀCl]+,
calcd.
for
General Procedure for the Tandem Azide Formation
and CuAAC Reactions under Microwave Irradiation
Tris{1-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-
yl}methanol·CuCl (1c·CuCl)
In
a sealed microwave tube, sodium azide (91 mg,
1.40 mmol) was dissolved in water (1 mL). Acetonitrile
(1 mL) was added as co-solvent, followed by the corre-
sponding alkyl or benzyl bromide (1.20 mmol), the alkyne
Prepared according to the general procedure for complex
formation using 1c (0.333 g, 0.50 mmol) to afford the desired
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
865

UPDATES
Erhan Ozkal et al.
(1.0 mmol), and 1 mol% of catalyst L·CuCl (L=1a–d, 2c,
2d). The mixture was heated in the microwave reactor at
1008C for 40 min (constant temperature mode, 5 min heat-
ing ramp, maximum power=300 W, power max mode kept
on; maximum allowed pressure=300 PSI with stirring on).
After cooling to room temperature, the reaction mixture
was diluted with ethyl acetate. The solution was washed
with water and brine, dried over MgSO4, filtered, and vola-
tiles removed under reduced pressure. If required, the tria-
zole product was purified by flash chromatography on
a short silicagel column, or by recrystallization.
(*minor rotamer); elemental analysis: found (calcd. for
C15H24N4O4): C 54.88 (55.54), H 7.07 (7.46), N 16.93 (17.27).
AHCTUNGTREG(NNUN 2S,4R)-1,2-Di-tert-butyl 4-(4-Phenyl-1H-1,2,3-triazol-
1-yl)pyrrolidine-1,2-dicarboxylate (8f)
Prepared according to the general procedure for CuAAC re-
actions using ethynylbenzene (0.107 g, 1.05 mmol) and
(2S,4R)-di-tert-butyl
4-azidopyrrolidine-1,2-dicarboxylate
(0.312 g, 1 mmol) to afford the desired product as a white
solid; yield: 0.410 g (0.99 mmol, 99%); mp 148–1508C.
1H NMR (400 MHz, CDCl3): d=7.83–7.81 (m, 2H), 7.76 (s,
1H), 7.45–7.41 (m, 2H), 7.36–7.33 (m, 1H), 5.32–5.28 (m,
1H), 4.49–4.43 (m, 1H), 4.41–4.08 (m, 1H), 3.97–3.85 (m,
1H), 2.96–2.80 (m, 1H), 2.54–2.52 (m, 1H), 1.51 (s, 9H),
1.46 (s, 9H); 13C NMR (126 MHz, CDCl3): d=171.3, 153.5,
148.1, 130.3, 128.9, 128.3, 125.7, 118.2*, 118.0, 82.1*, 81.9,
80.9, 58.6*, 58.3, 57.8, 51.9*, 51.7, 36.7*, 35.7, 28.3*, 28.0
(*minor rotamer); FT-IR (ATR, neat): n=2978.1, 1725.4,
1691.1, 1401.3, 1367.1, 1257.7, 1130.4, 1040.7, 1006.4, 912.2,
767.7, 694.1, 512.9 cmÀ1; HR-MS (ESI-TOF): m/z=437.2151
[M+Na]+, calcd. for C22H30N4O4Na: 437.2165; elemental
analysis: found (calcd. for C22H30N4O4): C 63.55 (63.75), H
7.00 (7.30), N 13.66 (13.52); [a]2D5: À24.9 (c 0.1 in CHCl3).
1-Benzyl-4-phenyl-1H-1,2,3-triazole (8a)[18]
Prepared according to the general procedure for CuAAC re-
1
actions as indicated in Table 2. H NMR (400 MHz, CDCl3):
d=7.80–7.79 (m, 2H), 7.65 (s, 1H), 7.41–7.31 (m, 8H), 5.57
(s, 2H); 13C NMR (126 MHz, CDCl3): d=148.2, 134.7, 130.5,
129.1, 128.8, 128.14, 128.04, 125.7, 119.4, 54.2.
Ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (8b)[19]
Prepared according to the general procedure for CuAAC re-
actions as indicated in Table 2. 1H NMR (400 MHZ,
CDCl3): d=7.97 (s, 1H), 7.40–7.28 (m, 5H), 5.58 (s, 2H),
4.43–4.37 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); 13C NMR
(126 MHz, CDCl3): d=160.7, 140.6, 133.7, 129.3, 129.1,
128.2, 127.2, 61.3, 54.4, 14.3.
AHCTUNGTREG(NNNU 2S,4R)-1,2-Di-tert-butyl 4-(4-Ethoxycarbonyl-1H-
1,2,3-triazol-1-yl)pyrrolidine-1,2-dicarboxylate (8g)
Prepared according to the general procedure for CuAAC re-
actions using ethyl propiolate (0.103 g, 1.05 mmol) and
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-N,N-dimethyl-
(2S,4R)-di-tert-butyl
4-azidopyrrolidine-1,2-dicarboxylate
methanamine (8c)[11]
(0.312 g, 1.0 mmol) to afford the desired product as a yellow
1
oil; yield: 0.406 g (99%). H NMR (400 MHz, CDCl3): d=
Prepared according to the general procedure for CuAAC re-
8.10 (s, 1H), 5.36–5.25 (m, 1H), 4.39–4.38 (m, 3H), 4.11–
4.06 (m, 1H), 3.93–3.80 (m, 1H), 2.90–2.73 (m, 1H), 2.54–
2.53 (m, 1H), 1.50–1.46 (m, 18H), 1.41 (t, J=7.1 Hz, 3H);
13C NMR (126 MHz, CDCl3): d=171.1, 160.5, 153.7*, 153.4,
140.6, 126.1, 125.9*, 82.2*, 82.1, 81.0, 61.4, 58.3, 58.1*, 51.8*,
51.6, 36.6*, 35.6, 28.2*, 28.0, 14.3 (*minor rotamer); FT-IR
(neat): n=2976.9, 1698.6, 1476.8, 1453.3, 1206.2, 1147.1,
1
actions as indicated in Table 2. H NMR (500 MHz, CDCl3):
d=7.40 (s, 1H), 7.37–7.36 (m, 3H), 7.27–7.25 (m, 2H), 5.51
(s, 2H), 3.58 (s, 2H), 2.25 (s, 6H); 13C NMR (126 MHz,
CDCl3): d=145.7, 134.7, 129.1, 128.7, 128.1, 122.3 54.4, 54.1,
45.1.
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-ol (8d)[20]
1042.4, 844.9, 754.7 cmÀ1
;
HR-MS (ESI-TOF): m/z=
433.2063 [M+Na]+, calcd. for C19H30N4O6Na: 433.2058;
[a]2D5: À20.6 (c 0.1 in CHCl3).
Prepared according to the general procedure for CuAAC re-
1
actions as indicated in Table 2. H NMR (400 MHz, CDCl3):
d=7.38–7.26 (m, 6H), 5.50 (s, 2H), 2.50 (s, 1H), 1.62 (s,
6H); 13C NMR (126 MHz, CDCl3): d=134.6, 129.1, 128.7,
128.1, 68.3, 54.2, 30.5 ppm.
(1-Benzyl-1H-1,2,3-triazol-4-yl)ACTHNUTRGNE(NUG phenyl)methanol
(8h)[22]
Prepared according to the general procedure for CuAAC re-
actions using 1-phenylprop-2-yn-1-ol (0.139 g, 1.05 mmol)
and benzyl azide (0.133 g, 1.0 mmol) to afford the desired
product as a white solid; yield: 0.252 g (95%). 1H NMR
[500 MHz, (CD3)2SO]: d=7.94 (s, 1H), 7.42–7.22 (m, 10H),
5.99 (d, J=4.6 Hz, 1H), 5.83 (d, J=4.6 Hz, 1H), 5.55 (s,
2H); 13C NMR [126 MHz, (CD3)2SO]: d=151.8, 144.0,
136.1, 128.7, 128.1, 128.0, 128.0, 127.0, 126.3, 122.1, 68.0,
52.7.
(S)-Ethyl 1-[(1-tert-Butoxycarbonyl)pyrrolidin-2-yl]-
methyl-1H-1,2,3-triazole-4-carboxylate (8e)[21]
Prepared according to the general procedure for CuAAC re-
actions using ethyl propiolate (0.103 g, 1.05 mmol) and (S)-
tert-butyl 2-(azidomethyl)pyrrolidine-1-carboxylate (0.226 g,
1 mmol) to afford the crude product that was further puri-
fied by flash column chromatography [silica gel, hexanes-
ethyl acetate (3:1)] to give desired product as white solid;
1
yield: 0.308 g (95%). H NMR (400 MHz, CDCl3): d=8.05
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)aniline (8i)[23]
(br s+s, 1H), 4.75–4.45 (m, 2H), 4.44–4.39 (m, 2H), 4.13
(br s, 1H), 3.43–3.09 (m, 2H), 1.97–1.73 (m, 3H), 1.50 (s,
9H), 1.41 (t, J=7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d=160.6, 154.8, 140.3, 128.3,127.8*, 99.9, 80.5*, 80.1, 61.2,
57.0, 52.9*, 51.7, 47.0, 46.8*, 28.4, 28.2*, 23.3, 22.6*, 14.2
Prepared according to the general procedure for CuAAC re-
actions as indicated in Table 3 using 4-ethynylaniline
(0.123 g, 1.05 mmol) and benzyl azide (0.133 g, 1.0 mmol) to
afford the desired product as a white solid; yield: 0.185 g
866
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
4-Octyl-1-phenyl-1H-1,2,3-triazole (8n)[26]
(74%). It was also prepared according to the general proce-
dure for tandem azide formation and CuAAC reaction
under microwave irradiation, as indicated in Table 4 using
sodium azide (0.091 g, 1.4 mmol), benzyl bromide (0.205 g,
1.2 mmol) and 4-ethynylaniline (0.117 g, 1.0 mmol) to afford
the desired product as a white solid; yield: 0.127 g (55%).
1H NMR (400 MHz, CDCl3): d=7.60 (d, J=8.5 Hz, 2H),
7.52 (s, 1H), 7.36–7.29 (m, 5H), 6.62 (d, J=8.6 Hz, 2H),
5.58 (s, 2H), 3.76 (br-s, 2H); 13C NMR (126 MHz, CDCl3):
d=134.9, 129.1, 128.7, 128.0, 126.9, 121.1, 118.2, 115.2, 54.1.
Prepared according to the general procedure for CuAAC re-
actions using ethynylbenzene (0.107 g, 1.05 mmol) and octyl
azide (0.155 g, 1.0 mmol) to afford the desired product as
a white solid; yield: 0.255 g (99%). 1H NMR (500 MHz,
CDCl3): d=7.84–7.83 (m, 2H), 7.74 (s, 1H), 7.42 (t, J=
7.6 Hz, 2H), 7.33 (t, J=7.4 Hz, 1H), 4.39 (t, J=7.3 Hz, 2H),
2.01–1.90 (m, 2H), 1.35–1.26 (m, 10H), 0.87 (t, J=7.0 Hz,
3H); 13C NMR (126 MHz, CDCl3): d=147.7, 130.7, 128.8,
128.0, 125.7, 119.3, 50.4, 31.7, 30.4, 29.0, 29.0, 26.5, 22.6, 14.0.
[4-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl]methanol
Ethyl 1-Octyl-1H-1,2,3-triazole-4-carboxylate (8o)[11]
(8j)[24]
Prepared according to the general procedure for CuAAC re-
actions using ethyl propiolate (0.103 g, 1.05 mmol) and octyl
azide (0.155 g, 1.0 mmol) to afford the desired product as
a white solid; yield: 0.251 g (99%). 1H NMR (500 MHz,
CDCl3): d=8.07 (s, 1H), 4.45–4.39 (m, 4H), 1.94–1.90 (m,
2H), 1.42 (t, J=7.1, 3H), 1.31–1.28 (m, 10H), 0.88 (t, J=
7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=160.9, 140.5,
127.2, 61.3, 50.7, 31.6, 30.1, 29.0, 28.8, 28.8, 26.3, 22.5, 14.3,
14.0.
Prepared according to the general procedure for CuAAC re-
actions
using
(4-ethynylphenyl)methanol
(0.139 g,
1.05 mmol) and benzyl azide (0.133 g, 1.0 mmol) to afford
the desired product as a white solid; yield: 0.212 g (80%).
1H NMR (400 MHz, CDCl3): d=7.78 (d, J=8.5 Hz, 2H),
7.65 (s, 1H), 7.40–7.31 (m, 7H), 5.57 (s, 2H), 4.70 (s, 2H),
1.90 (t, J=4.7 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
148.0, 140.9, 134.6, 129.8, 129.2, 128.8, 128.1, 127.4, 125.8,
119.4, 65.0, 54.2.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl Acetate (8k)[25]
Triethyl 1,1’,1’’-[(2,4,6-Triethylbenzene-1,3,5-triyl)-
tris(methylene)]tris(1H-1,2,3-triazole-4-carboxylate)
(8p)
Prepared according to the general procedure for CuAAC re-
actions using prop-2-yn-1-yl acetate (0.102 g, 1.05 mmol)
and benzyl azide (0.133 g, 1.0 mmol) to afford the desired
product as a colorless oil; yield: 0.229 g (99%). 1H NMR
(400 MHz, CDCl3): d=7.51 (s, 1H), 7.39–7.27 (m, 5H), 5.52
(s, 2H), 5.18 (s, 2H), 2.05 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=170.5, 142.9, 134.2, 128.8, 128.5, 127.9, 123.4,
57.3, 53.9, 20.6.
Prepared according to the general procedure for CuAAC re-
actions using ethyl propiolate (0.309 g, 3.15 mmol) and 1,3,5-
tris(azidomethyl)-2,4,6-triethyl-benzene (0.327 g, 1.0 mmol)
to afford the desired product as a thick oil; yield: 0.615 g
1
(99%). H NMR (300 MHz, CDCl3): d=7.85 (s, 3H), 5.73 (s,
6H), 4.40 (q, J=7.1 Hz, 6H), 2.77 (q, J=7.5 Hz, 6H), 1.39
(t, J=7.1 Hz, 9H), 0.99 (t, J=7.5 Hz, 9H); 13C NMR
(126 MHz, CDCl3): d=160.5, 146.8, 140.4, 129.9, 129.7, 61.4,
48.1, 23.6, 15.3, 14.2; FT-IR (neat): n=3127, 2978, 1720,
1539, 1449, 1375, 1337, 1197, 1036, 840, 772 cmÀ1; HR-MS
1-Phenethyl-4-phenyl-1H-1,2,3-triazole (8l)[20]
Prepared according to the general procedure for CuAAC re-
actions using ethynylbenzene (0.107 g, 1.05 mmol) and (2-
azidoethyl)benzene (0.147 g, 1.0 mmol) to afford the desired
product as a white solid; yield: 0.247 g (99%). 1H NMR
(400 MHz, CDCl3): d=7.76 (d, J=8.5 Hz, 2H), 7.46 (s, 1H),
7.42–7.27 (m, 6H), 7.14–7.13 (m, 2H), 4.63 (t, J=4.7 Hz,
2H), 3.25 (t, J=4.6 Hz, 2H); 13C NMR (126 MHz, CDCl3):
d=147.5, 137.1, 128.8, 128.7, 128.7, 128.1, 127.1, 125.7, 119.9,
51.7, 36.8.
(ESI-TOF):
m/z=644.2919
[M+Na]+,
calcd.
for
C30H39N9O6Na: 644.2916.
2,2’,2’’-{1,1’,1’’-[(2,4,6-Triethylbenzene-1,3,5-triyl)-
tris(methylene)]tris(1H-1,2,3-triazole-4,1-diyl)}tris-
(propan-2-ol) (8q)
Prepared according to the general procedure for CuAAC re-
actions using 2-methylbut-3-yn-2-ol (0.267 g, 3.15 mmol) and
1,3,5-tris(azidomethyl)-2,4,6-triethyl-benzene
(0.327 g,
Ethyl 1-Phenethyl-1H-1,2,3-triazole-4-carboxylate
1.0 mmol) to afford the desired product as a white solid;
yield: 0.463 g (80%); mp 208–2098C. 1H NMR [400 MHz,
(CD3)2SO]: d=7.66 (s, 3H), 5.60 (s, 6H), 5.09 (s, 6H), 2.84
(q, J=7.4 Hz, 6H), 1.41 (s, 18H), 0.76 (t, J=7.4 Hz, 9H);
13C NMR [126 MHz, (CD3)2SO]: d=156.0, 145.5, 130.1,
120.1, 67.2, 47.3, 30.7, 22.9, 14.8; FT-IR (ATR, neat): n=
3328, 2973, 1456, 1370, 1166, 1041, 957 cmÀ1; HR-MS (ESI-
TOF): m/z=602.3554 [M+Na]+, calcd. for C30H45N9O3Na:
602.3538.
(8m)
Prepared according to the general procedure for CuAAC re-
actions using ethyl propiolate (0.103 g, 1.05 mmol) and (2-
azidoethyl)benzene (0.147 g, 1.0 mmol) to afford the desired
product as a white solid; yield: 0.228 g (93%); mp 64–668C
1H NMR (300 MHz, CDCl3): d=7.78 (s, 1H), 7.32–7.18 (m,
3H), 7.09–7.08 (m, 2H), 4.64 (t, J=7.2 Hz, 2H), 4.40 (q, J=
6.0 Hz, 2H), 3.23 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H);
13C NMR (126 MHz, CDCl3): d=160.6, 139.9, 136.3, 128.8,
128.5, 127.6, 127.2, 61.1, 51.9, 36.4, 26.8, 14.2; FT-IR (ATR,
1-(4-Nitrobenzyl)-4-phenyl-1H-1,2,3-triazole (8r)[19]
neat): n=3084, 2973, 1724, 1526, 1201, 1050, 1027, 695 cmÀ1
;
HR-MS (ESI-TOF): m/z=246.1238 [M]+, calcd. for
C13H16N3O2: 246.1237; elemental analysis: found (calcd. for
C13H15N3O2): C 63.71 (63.66), H 6.15 (6.16), N 17.19 (17.12).
Prepared according to the general procedure for tandem
azide formation and CuAAC reaction under microwave irra-
diation, as indicated in Table 4, using sodium azide (0.091 g,
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
867

UPDATES
Erhan Ozkal et al.
1.4 mmol),
1-(bromomethyl)-4-nitrobenzene
(0.258 g,
1231–1232; b) C. O. Kappe, E. Van der Eycken, Chem.
Soc. Rev. 2010, 39, 1280–1290; c) C. Chu, R. Liu, Chem.
Soc. Rev. 2011, 40, 2177–2188; d) E. Lallana, R. Ri-
guera, E. Fernandez-Megia, Angew. Chem. 2011, 123,
8956–8966; Angew. Chem. Int. Ed. 2011, 50, 8794–8804;
e) Y. H. Lau, P. J. Rutledge, M. Watkinson, M. H. Todd,
Chem. Soc. Rev. 2011, 40, 2848–2866; f) T. Muller, S.
Brꢅse, Angew. Chem. 2011, 123, 12046–12047; Angew.
Chem. Int. Ed. 2011, 50, 11844–11845; g) E. M. Sletten,
C. R. Bertozzi, Acc. Chem. Res. 2011, 44, 666–676; h) S.
Yigit, R. Sanyal, A. Sanyal, Chem. Asian J. 2011, 6,
2648–2659; i) L. Liang, D. Astruc, Coord. Chem. Rev.
2011, 255, 2933–2945; j) D. M. Beal, L. H. Jones,
Angew. Chem. 2012, 124, 6426–6432; Angew. Chem.
Int. Ed. 2012, 51, 6320–6326; k) H. Durmaz, A. Sanyal,
G. Hizal, U. Tunca, Polym. Chem. 2012, 3, 825–835;
l) D. Astruc, L. Liang, A. Rapakousiou, J. Ruiz, Acc.
Chem. Res. 2012, 45, 630–640.
1.2 mmol) and ethynylbenzene (0.102 g, 1.0 mmol) to afford
the desired product as a white solid; yield: 0.277 g (98%).
1H NMR (400 MHz, CDCl3): d=8.24 (d, J=8.6 Hz, 2H),
7.81 (d, J=7.2 Hz, 2H), 7.74 (s, 1H), 7.47–7.32 (m, 4H),
7.34 (t, J=7.4 Hz, 1H), 5.71 (s, 2H); 13C NMR (126 MHz,
CDCl3): d=148.7, 148.0, 141.7, 130.1, 128.9, 128.5, 128.4,
125.7, 124.3, 119.7, 53.2.
{4-[1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl]phenyl}-
methanol (8s)[11]
Prepared according to the general procedure for tandem
azide formation and CuAAC reaction under microwave irra-
diation, as indicated in Table 4, using sodium azide (0.091 g,
1.4 mmol),
1.2 mmol)
1-(bromomethyl)-4-nitrobenzene
and (4-ethynylphenyl)methanol
(0.258 g,
(0.132 g,
1.0 mmol) to afford the desired product as a white solid;
yielçd: 0.307 g (99%). H NMR (400 MHZ, CD3OD): d=
1
[5] a) T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin,
Org. Lett. 2004, 6, 2853–2855; b) W. G. Lewis, F. G.
Magallon, V. V. Fokin, M. G. Finn, J. Am. Chem. Soc.
2004, 126, 9152–9153.
8.39 (s, 1H), 8.25 (d, J=8.6 Hz, 2H), 7.79 (d, J=8 Hz, 2H),
7.55 (d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 5.80 (s, 2H),
4.63 (s, 2H), 4.56 (s, 1H); 13C NMR (126 MHz, CD3OD):
d=149.4, 144.1,143.3, 130.6, 130.1, 128.6, 126.8, 125.2, 124.9,
122.7, 64.9, 54.1.
[6] a) V. O. Rodionov, S. I. Presolski, D. Dꢂaz Dꢂaz, V. V.
Fokin, M. G. Finn, J. Am. Chem. Soc. 2007, 129, 12705–
12712; b) V. O. Rodionov, S. I. Presolski, S. Gardinier,
Y.-H. Lim, M. G. Finn, J. Am. Chem. Soc. 2007, 129,
12696–12704; c) S. I. Presolski, V. Hong, S.-H. Cho,
M. G. Finn, J. Am. Chem. Soc. 2010, 132, 14570–14576.
[7] P. S. Donnelly, S. D. Zanatta, S. C. Zammit, J. M. White,
S. J. Williams, Chem. Commun. 2008, 2459–2461.
[8] a) L. Liang, J. Ruiz, D. Astruc, Adv. Synth. Catal. 2011,
353, 3434–3450. For a preliminary account, see: b) N.
Candelon, D. Lastecoueres, A. K. Diallo, J. Ruiz Aran-
zaes, D. Astruc, J.-M. Vincent, Chem. Commun. 2008,
741–743.
[9] a) S. Dꢂez-Gonzꢆlez, A. Correa, L. Cavallo, S. P. Nolan,
Chem. Eur. J. 2006, 12, 7558–7564; b) S. Dꢂez-Gonzꢆlez,
S. P. Nolan, Angew. Chem. 2008, 120, 9013–9016;
Angew. Chem. Int. Ed. 2008, 47, 8881–8884; c) T. Naka-
mura, T. Terashima, K. Ogata, S.-i. Fukuzawa, Org.
Lett. 2011, 13, 620–623; d) for a novel mechanistic
work, see: B. T. Worrell, J. A. Malik, V. V. Fokin, Sci-
ence 2013, 340, 457–460.
1-Octyl-4-[(phenylthio)methyl]-1H-1,2,3-triazole
(8t)[11]
Prepared according to the general procedure for tandem
azide formation and CuAAC reaction under microwave irra-
diation, as indicated in Table 4, using sodium azide (0.091 g,
1.4 mmol), octyl bromide (0.230 g, 1.2 mmol) and phenyl-
ACHTUNGTRENNUNG(prop-2-yn-1-yl)sulfane (0.148 g, 1.0 mmol) to afford the de-
sired product as
a white solid; yield: 0.164 g (53%).
1H NMR (400 MHz, CDCl3): d=7.34–7.25 (m, 5H), 7.20–
7.17 (m, 1H), 4.28–4.24 (m, 4H), 1.84–1.81 (m, 2H), 1.25
(m, 10H), 0.88 (t, J=7.02 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d=144.9, 135.5, 129.5, 128.9, 126.4, 121.2, 99.9, 50.3,
31.7, 30.2, 29.0, 28.9, 28.9, 26.4, 22.6, 14.0.
Acknowledgements
[10] a) L. S. Campbell-Verduyn, L. Mirfeizi, R. A. Dierckx,
P. H. Elsinga, B. L. Feringa, Chem. Commun. 2009, 0,
2139–2141; b) S. Diez-Gonzalez, Catal. Sci. Technol.
2011, 1, 166–178; c) R. Thorwirth, A. Stolle, B. On-
druschka, A. Wild, U. S. Schubert, Chem. Commun.
2011, 47, 4370–4372; d) M. Liu, O. Reiser, Org. Lett.
2011, 13, 1102–1105.
We thank MINECO (grants CTQ2008-00947/BQU and
CTQ2012-38594-C02-01), DEC (grant 2009SGR623), and
ICIQ Foundation for financial support. E. O. thanks
MECYD for an FPU fellowship.
[11] S. ꢇzc¸ubukc¸u, E. Ozkal, C. Jimeno, M. A. Pericaꢈs,
References
Org. Lett. 2009, 11, 4680–4683.
[12] E. Ozkal, S. Ozcubukcu, C. Jimeno, M. A. Pericꢀs,
Catal. Sci. Technol. 2012, 2, 195–200.
[1] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057–3064.
[13] For some applications, see: a) E. Alza, M. A. Pericꢀs,
Adv. Synth. Catal. 2009, 351, 3051–3056; b) E. Alza, C.
Rodrꢂguez-Escrich, S. Sayalero, A. Bastero, M. A. Peri-
cꢀs, Chem. Eur. J. 2009, 15, 10167–10172; c) E. Alza, S.
Sayalero, X. Cambeiro C, R. Martꢂn-Rapffln, P. Miranda
O, M. Pericꢀs A, Synlett 2011, 2011, 464–468; d) E.
Alza, S. Sayalero, P. Kasaplar, D. Almas¸i, M. A. Peri-
cꢀs, Chem. Eur. J. 2011, 17, 11585–11595; e) X. C. Cam-
[2] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharp-
less, Angew. Chem. 2002, 114, 2708–2711; Angew.
Chem. Int. Ed. 2002, 41, 2596–2599.
[3] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem.
2001, 113, 2056–2075; Angew. Chem. Int. Ed. 2001, 40,
2004–2021.
[4] For some recent reviews on click chemistry, see:
a) M. G. Finn, V. V. Fokin, Chem. Soc. Rev. 2010, 39,
868
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 857 – 869

UPDATES
Fine-Tunable Tris(triazolyl)methane Ligands
beiro, R. Martꢂn-Rapffln, P. O. Miranda, S. Sayalero, E.
Alza, P. Llanes, M. A. Pericꢀs, Beilstein J. Org. Chem.
A. Bastero, C. Jimeno, M. A. Pericꢀs, Org. Lett. 2008,
10, 337–340.
2011, 7, 1486–1493; f) C. Ayats, A. H. Henseler, M. A.
Pericꢀs, ChemSusChem 2012, 5, 320–325; g) L. Cao, L.
Isaacs, Org. Lett. 2012, 14, 3072–3075; h) N. Gimeno,
R. Martin-Rapun, S. Rodriguez-Conde, J. L. Serrano,
C. L. Folcia, M. A. Pericꢀs, M. B. Ros, J. Mater. Chem.
2012, 22, 16791–16800; i) P. Kasaplar, P. Riente, C.
Hartmann, M. A. Pericꢀs, Adv. Synth. Catal. 2012, 354,
2905–2910; j) M. Oukessou, Y. Genisson, D. El Ar-
faoui, A. Ben-Tama, E. El Hadrami, R. Chauvin, Tetra-
hedron Lett. 2013, 54, 4362–4364.
[16] A. Ustinov, H. Weissman, E. Shirman, I. Pinkas, X.
Zuo, B. Rybtchinski, J. Am. Chem. Soc. 2011, 133,
16201–16211.
[17] Samples of 1a are available on request.
[18] H. Sharghi, R. Khalifeh, M. M. Doroodmand, Adv.
Synth. Catal. 2009, 351, 207–218.
[19] S. T. Abu-Orabi, M. A. Atfah, I. Jibril, F. M. Mari’i,
A. A.-S. Ali, J. Heterocycl. Chem. 1989, 26, 1461–1468.
[20] P. Appukkuttan, W. Dehaen, V. V. Fokin, E. Van der
Eycken, Org. Lett. 2004, 6, 4223–4225.
[21] A. Paul, H. Bittermann, P. Gmeiner, Tetrahedron 2006,
62, 8919–8927.
[14] It is to be noted, however, that the proposed structure
for the L·Cu complexes in this manuscript is only tenta-
tive. While it is similar to the structures proposed for
similar complexes,[7,8] and is in agreement with the sym-
metry predicted by 13C NMR spectroscopy and with the
molecular mass determined by HR-MS, no X-ray struc-
ture has been determined for these complexes.
[22] S. Chassaing, A. S. S. Sido, A. Alix, M. Kumarraja, P.
Pale, J. Sommer, Chem. Eur. J. 2008, 14, 6713–6721.
˝
[23] K. Lorincz, P. Kele, Z. Novꢆk, Synthesis 2009, 3527–
3532.
[24] Q. Zhang, J. M. Tacaks, Org. Lett. 2008, 10, 545–548.
[25] Z. Gonda, Z. Novꢆk, Dalton Trans. 2010, 39, 726–729.
[26] K. Kacprzak, Synlett 2005, 943–946.
[15] a) E. Alza, X. C. Cambeiro, C. Jimeno, M. A. Pericꢀs,
Org. Lett. 2007, 9, 3717–3720; b) D. Font, S. Sayalero,
Adv. Synth. Catal. 2014, 356, 857 – 869
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
869