This is the peer reviewed version of the following article Chem.	
  Commun.	
  2016,	
  52,	
  1997-­‐2010, which has been
published in final form http://pubs.rsc.org/en/content/articlelanding/2016/cc/c5cc08961a#!divAbstract

Synthesis and Catalytic Applications of C3-Symmetric Tris(triazolyl)methanol
Ligands and Derivatives
Pablo Etayo,a Carles Ayatsa and Miquel A. Pericàsa,b*
Recently introduced tris(1,2,3-triazol-4-yl)methanols and derivatives (TTM ligands) have become a valuable subclass of
C3-symmetric tripodal ligands for transition metal-mediated reactions. TTM-based ligand architectures are modularly
constructed through regioselective, one-pot triple [3+2] cycloaddition of azides and alkynes. Applications of homogeneous
systems of this type and of heterogenized (polystyrene- and magnetic nanoparticle-supported) TTM ligands in synthesis
and catalysis are compiled in this Feature Article.

1. Introduction and general remarks
The 1H-1,2,3-triazole scaffold is absent from natural structures; however, this heterocyclic unit finds ubiquitous presence in myriad
synthetic compounds. In the early 60's of the last century, the discovery by Huisgen of the 1,3-dipolar thermal cycloaddition of azides
and alkynes1 triggered the first synthetic approaches towards triazole heterocycles. Nonetheless, it was not until the early 2000s, when
the ground-breaking reports by the groups of Meldal,2 and Fokin and Sharpless3 on the copper-catalysed azide−alkyne cycloaddition
(CuAAC) reactions for the highly efficient, regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles (Fig. 1) provided a definitive
impulse to this area.2,3 Extensive research on [3+2] cycloadditions of azides and alkynes prompted the discovery of the rutheniumcatalysed variant (RuAAC)4 of the reaction, enabling synthetic access to 1,5-disubstituted 1,2,3-triazole regioisomers in a selective
manner. Nowadays, the synthesis of 1,4-disubstituted 1,2,3-triazoles via CuAAC reactions5 is considered as the paradigmatic example of
click chemistry.6 Thus, the process (Fig. 1) delivers in a predictable manner the target nitrogen-containing heterocycles (C) from their
precursors (A and B) under mild conditions and with practically no limitations with respect to the functional groups on the reactants.
H
1

N
2N

5

H

[Cu(I)]
N

4

N3

CuAAC

C
1,4-disubstituted
1H-1,2,3-triazole

A

N

+
N
B

Fig. 1 Retrosynthetic approach to 1,4-disubstituted 1,2,3-triazoles via CuAAC.

Since its discovery, the CuAAC reaction has become a very commonly employed ligation tool. Given its reliability, specificity and
biocompatibility, the CuAAC reaction has propelled the development of countless applications for triazole chemistry in diverse
disciplines from pharmaceutical to materials science. Accordingly, 1,4-disubstituted 1,2,3-triazoles have emerged as valuable, yet readily
available building blocks in the preparation of functional materials displaying an enormous wealth of unique properties.7
Regarding biomedical and biological applications, the profound impact of click reactions and triazole products in the vast field of
medicinal chemistry has been extensively reviewed.8 The triazole chemical inertness together with its inherent structural features
converts this heterocycle into an excellent amide-bond surrogate (bioisosteric replacement). Consistently, triazole rings have been
inserted into peptide sequences for the development of peptidomimetics that mimic the secondary structure of proteins, a topic of high
relevance in chemical biology.9 Another closely related important application of the CuAAC reaction arises from its bioorthogonality
(i.e., non-interacting with biological components while proceeding under physiological conditions, namely in aqueous medium under
ambient temperature). This last feature has enabled the conjugation of several biomacromolecules −encompassing proteins, nucleic acids,
lipids and glycans− with biophysical probes delivering biocompatible systems for both in vitro and in vivo studies.10
Concerning the preparation of triazole-based molecular architectures, CuAAC reactions have exerted a tremendous influence in the
materials chemistry arena. Thus, the reaction has provided access to well-defined, complex polymeric materials (linear polymers,
surfaces, star-shaped polymers),11 functional polymers (stimuli-responsive hydrogels)12 and also dendrimers.13 Supramolecular chemistry
has also benefitted from the diverse supramolecular interactions involving 1,2,3-triazoles.14 In this context, click-derived triazoles have
led to a wide range of supramolecular functional systems,14,15 applications as chemical sensors or receptors for the molecular recognition
of metal ions being noteworthy.16

Threefold rotational symmetry, structural modularity and other key aspects of ligand design have played a crucial role in the
development of new types of chelating tripodal ligands.17 Due to the beneficial influence of molecular symmetry in catalytic reactions,
the design and preparation of C3-symmetric ligands and of their metal complexes has found numerous successful applications in
homogeneous catalysis.18 C3-Symmetric tripodal ligands typically coordinate to metal atoms in a tridentate fashion. This topology of
ligation is found, for instance, in tris(pyrazolyl)borates19 (I, Fig. 2), the most common example of scorpionate multidentate ligands.20
Monoanionic tris(pyrazolyl)borates are amongst the most versatile tridentate ligands for transition-metal coordination and their
complexes have been extensively applied in diverse catalytic transformations.19 The analogous tris(pyrazolyl)alkanes21 (II, Fig. 2),
bearing a carbon atom as the central bridging apex, have received much less attention likely because of their limited synthetic
accessibility. Tris(2-pyridyl)methanes22 (III, Fig. 2) and tris(oxazolinyl)ethanes23 (IV, Fig. 2) represent other related ligand platforms of
the same class. Chiral tris(oxazolinyl) ligands, in particular, have been successfully applied in asymmetric catalysis.23
R'

R'

H
N

B

N

R''

R'

N
NN
N

N
R'

H

Me
O

C
N
N

R
R

R
R
III
tris(2-pyridyl)methane

N

R N

N

N

N

R'

*

C
N

O

O
N
*
N
R
*
R

IV
tris(oxazolinyl)ethane

O

R

N N

N N

R''

N
NN
N

R'
II
tris(pyrazolyl)alkane

R
I
tris(pyrazolyl)borate

N

C

N

R

R

R''

R

N R

V
tris(1,2,3-triazolyl-4-methyl)amine

N

N R

P

R N
N

N

N
N R

N
N
VI
tris(1,2,3-triazol-4-yl)phosphine oxide

Fig. 2 Representative structures of selected C3-symmetric tripodal ligand architectures.

Given the broad applicability of the CuAAC reaction,5 it is not surprising that different C3-symmetric tripodal ligands containing three
equivalent 1,2,3-triazole rings and constructed through this methodology have been reported. Tris(1,2,3-triazolyl-4-methyl)amines (V,
Fig. 2), and more precisely tris(benzyltriazolylmethyl)amine (TBTA)24 and its derivatives25 have shown to be versatile ligands for
transition metal complexation. In particular, the derived copper(I) complexes26 depict impressive rate-accelerating ligand effects in a
wide range of CuAAC reactions.5,24,25
Click-derived phospha-scorpionates constitute a much less studied family of symmetrical tripodal ligand architectures.27 In spite of the
rich coordination chemistry of the air stable tris(1,2,3-triazolyl)phosphine oxide27a,c,d,f scorpionates (VI, Fig. 2) and of the air-sensitive
tris(1,2,3-triazolyl)phosphine27a,b,e ligands, no examples of catalytic applications of these species have been reported in the literature.
Starting from the consideration of the coordination possibilities offered by 1,2,3-triazoles,28 and bearing in mind the convenience of a
simple and versatile approach to tripodal ligands based on this structure, we realised some years ago the potential offered by the
tris(triazolyl)methanol (TTM) structure (VII) in coordination and catalysis.29 As shown in Fig. 3, the TTM ligands should be readily
accessible from simple precursors through a modular approach that also creates the tertiary alcohol as an innate feature. Modulation of
the TTM ligands should be possible by simple modification of R groups derived from azido precursors, while the alcohol moiety should
allow derivatisation and immobilisation onto solid supports.
Suitable for derivatisation
and immobilisation
OH

N

N R

C

R N

N

N

N

N

N
N R

VII
High modularity

1) triple
acetylide
attack
2) triple
CuAAC
reaction

O
Cl

OEt

Fig. 3 Retrosynthetic analysis of the generic TTM-based ligand structure.

The present Feature Article is intended to provide an overview of the chemistry and catalytic applications of TTM ligands and
derivatives. The discussion has been organised to discuss first the synthetic approaches leading to the preparation of TTM ligand
derivatives. The role of TTM ligands in homogeneous catalysis is next discussed, followed by a summary of the synthetic applications
of the CuCl complex of the originally developed TTM ligand and by a final section dealing with recently reported applications of
immobilised (polystyrene- and magnetic nanoparticle-supported) TTM ligands in heterogeneous catalysis.

2. Preparation of TTM ligand derivatives
Tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol (6), the originally developed TTM ligand, was reported in 2009.29 The original preparation
of 6 (Scheme 1) started with the one-pot synthesis of tris[(trimethylsilyl)ethynyl]methanol (3) in 72% yield from trimethylsilylacetylene
(1a) and ethyl chloroformate (2). The protodesilylation of 3 with methanol under basic conditions led to tris(ethynyl)methanol (4), which
was not isolated. Subsequent triple CuAAC reaction of tris(alkyne) 4 with benzyl azide (5a) under classical conditions (method A,
Scheme 1) furnished the target TTM ligand 6 in 55% overall yield (from 2). Treatment of 6 with a stoichiometric amount of CuCl in 1,4dioxane at 60 ºC rendered the neutral copper(I) complex 6·CuCl30 in almost quantitative yield (Scheme 1). Interestingly, 6·CuCl turned
out to be stable in open air, and this fact was attributed to efficient chelation by the TTM ligand. Complex 6·CuCl was also used in the
absence of any additive or base to catalyse the triple CuAAC reaction of 4 with 5a in water31 at rt (method B, Scheme 1). Gratifyingly, a
very reduced catalyst loading of 6·CuCl (0.5 mol%) was sufficient to promote the triple cycloaddition, affording the TTM ligand 6 in a
highly improved 86% overall yield.
OH

1) nBuLi, THF, 0 ºC
TMS

2) ClCO2Et (2),
!78 ºC to !30 ºC

C

TMS
3 (72% yield)

Method A: BnN3 (5a), CuSO4!5H2O (5 mol%),
NaAsc (15 mol%), MeOH, rt

H

C

MeOH, rt

TMS

1a
OH

K2CO3

TMS

Method B: BnN3 (5a), 6!CuCl (0.5 mol%),
H2O, rt

H
H
4

OH

OH
Bn

C

N
N

N Bn

N

N
N

N

N
N Bn

Bn

CuCl

N Bn

N
N

1,4-dioxane
60 ºC

N

N

N

N

N
N Bn

Cu

6 (Method A: 55% yield)
(Method B: 86% yield)

Cl
6!CuCl (95% yield)

Scheme 1 Original preparation of the TTM ligand 6 and 6·CuCl.

An alternative approach to tris(triazolyl)methanol 6 was later reported by Génisson and Chauvin and co-workers,32 involving a three-step
sequence for the preparation of 3 and a triple tandem desilylation−CuAAC process.33
Pericàs and co-workers34 recently developed a safe and practical, one-stage procedure for the large-scale (50−100 mmol) preparation of 6
(Scheme 2). The optimised one-pot protocol avoided the use of potentially hazardous reagents and solvents, did not require any
chromatographic purification and proceeded without the isolation of any reaction intermediate. As a salient feature, the triple CuAAC
reactions were conducted in three-component mode,35 avoiding the use of benzyl azide.36
OLi

1) nBuLi, THF, 0 ºC
TMS

2) ClCO2Et (2),
T ! 15 ºC

C

MeOH

TMS

0 ºC

TMS
TMS

1a

Li+ 3!
OH
H

C
H
H

BnBr (7a), NaN3 (8),
6!CuCl (0.5 mol%)
H2O/DMSO (30:1)
50 ºC

4

Scheme 2 Optimised one-pot procedure for large-scale preparation of TTM ligand 6.

OH
Bn

N

N Bn

C

N
N

N
N

N

N
N Bn

6 (64% yield; 30 g scale)

As already mentioned, the free hydroxyl group present in 6 offers opportunity for further derivatisation of TTM ligands. Taking
advantage of this structural feature, the TTM ligand 6 was transformed in high yields (77−82%) into the tris(triazolyl)methyl ethers 9a−c
by Williamson-type etherification reactions (Scheme 3).34,37
OH
Bn

N

N Bn 1) NaH, DMF, 0 ºC Bn

C

N

N

N

N

R

O

N

N
N Bn

2) RX (7), 0 ºC to rt
[ X = Br, I ]

6

N

N Bn

C

N

N

N

N

N

N
N Bn

R = Me: 9a (79% yield)
R = Bn: 9b (77% yield)
R = CH2C CH: 9c (82% yield)

Scheme 3 Derivatisation of TTM ligand 6 into tris(triazolyl)methyl ethers 9a−c.

A versatile approach to tris(triazolyl)methyl derivatives 9−13 was alternatively reported32 by exploiting the generation and trapping of
the tris(1-benzyl-1,2,3-triazol-4-yl)carbenium cation, a heterocyclic analogue of the well-studied trityl cation. Thus, treatment of 6 with
trifluoroacetic anhydride (TFAA) led to the intermediate carbocation, which could be trapped with a wide array of oxygen, nitrogen,
sulfur and carbon nucleophiles (Scheme 4).
OH
Bn

N
N

N Bn

C
N

N

N

N

N
N Bn

Nu

1) TFAA
DCM, 0 ºC

Bn

2) Nu!E, 0 ºC

N
N

N Bn

C
N

N

N

[ E = H, K, ZnEt ]

N

N
N Bn

Nu = OMe: 9a (77% yield)
Nu = OEt: 9d (68% yield)
Nu = OiPr: 9e (74% yield)
Nu = OtBu: 9f (63% yield)
Nu = HNtBu: 10a (54% yield)
Nu = (R)-NHCH(Me)Ph: 10b (75% yield)
Nu = NEt2: 10c (75% yield)
Nu = SC(S)OEt: 11 (75% yield)
Nu = 4-MeO-C6H4: 12 (86% yield)
Nu = Et: 13 (48% yield)

6

Scheme 4 Preparation of TTM derivatives 9−13 by trapping of the tris(1-benzyl-1,2,3-triazol-4-yl)carbenium cation.
OH
C

H2N

TMS

TMS

R

R = H: 14a
R = CF3: 14b
R = OMe: 14c

TMS
3

1) NaNO2, HCl
H2O, 0 ºC
2) NaHCO3, NaN3 (8)
H2O, 0 ºC to rt

K2CO3
MeOH, rt

OH
N3

H

C
H

R

R = H: 5b
R = CF3: 5c
R = OMe: 5d

H
4

6!CuCl (1.0 mol%)
DMSO (1% v/v), rt
OH

R
N
N

R

C
N

N
N
N

N
N

N

R

R = H: 15a (57% yield)
R = CF3: 15b (81% yield)
R = OMe: 15c (89% yield)

Scheme 5 Syntheses of tris(aryltriazolyl)methanol ligands 15a−c.

The high structural modularity of the C3-symmetric TTM ligands also facilitates the introduction of different sets of substituents at the

N1 atoms in the three equivalent triazole rings. Aryl groups, for instance, can be introduced by simply using aryl azides as reactive
partners in the triple CuAAC reaction of the key intermediate 4. Pericàs and co-workers34 prepared in this way the tris(1-aryl-1H-1,2,3triazol-4-yl)methanol ligands 15a−c bearing neutral (15a), electron-withdrawing (15b) or electron-donating (15c) para-substituents with
the purpose of modulating the catalytic behaviour of their metal complexes through fine-tuning of electronic properties (Scheme 5).
Parallel linear sequences were telescoped simultaneously towards the synthesis of tris(aryltriazolyl)methanols 15a−c, which could be
isolated in fair to excellent yields (57−89%) after a single recrystallization.

3. Applications of TTM ligands in homogeneous catalysis
The accelerating effect of the TTM ligand 6 in CuAAC reactions performed in aqueous media31 has already been shown above (see
Schemes 1, 2 and 5). The presence of the free OH group in the ligand template confers some hydrophilic character to 6·CuCl, while the
tight chelate structure efficiently protects the metal centre against undesired oxidation or disproportionation leading to inactive Cu(II)
species. Probably for these reasons, such a well-defined copper(I) complex38 is finding increasing application within the vast territory of
click chemistry.
The catalytic performance of 6·CuCl was initially scrutinised by conducting a variety of CuAAC reactions in water or under neat
conditions29 (Scheme 6). By using a very low catalyst loading (0.5 mol%) under ambient conditions (inert atmosphere not required) a
palette of 15 different 1,4-disubstituted-1,2,3-triazoles (16−19) was readily obtained. Notably, 6·CuCl exhibited high functional group
tolerance as substrates containing functional groups (primary amines) with high binding ability for copper gave rise to the corresponding
triazole products (19h).
6!CuCl (0.5 mol%)
R1

N3

+

R2

5

16!19

Ph

N

Bn

N

CO2Et

N

N

R1 = Bn: 17a (96% yield)
R1 = nOct: 17b (99% yield)
R1 N
N

R2

N
N

R1 = Bn: 16a (99% yield)
R1 = nOct: 16b (99% yield)
R1 = Ph: 16c (99% yield)
R1 N

N

N

H2O or neat, rt
1

R1 N

R2

R1 N

N

R2 = 2-pyridyl: 19a (99% yield)
R2 = BnCH2: 19b (99% yield)
a R2 = nBu: 19c (98% yield)
a R2 = nHex: 19d (98% yield)
a R2 = 4-chlorobutyl: 19e (64% yield)
R2 = 4-HOCH2C6H4: 19f (92% yield)
R2 = CH2OH: 19g (84% yield)
b R2 = CH NH : 19h (47% yield)
2
2

b

NMe2

(a 0.25 mol% cat. at 40 ºC;
1.0 mol% cat. in 2:1 nBuOH/H2O)

N

R1 = Bn: 18a (97% yield)
R1 = Ph: 18b (95% yield)

Scheme 6 Catalytic performance of 6·CuCl in cycloaddition reactions of azides (5) and terminal alkynes (1) on water or under neat conditions.

The three-component tandem version of the CuAAC reaction35 catalysed by complex 6·CuCl (1.0 mol%) was also explored.29 By
following this safe and convenient synthetic approach, a total of 11 triazoles were efficiently prepared in good to excellent yields
(Scheme 7) via in situ formation of n-octyl or benzyl azides from the corresponding bromides (7) and sodium azide (8). Two different
click methods were used involving either smooth heating in water31 at 40 ºC or microwave (MW) activation39 at 100 ºC in MeCN/H2O
(1:1), the latter protocol involving much shorter reaction times.
6!CuCl (1.0 mol%)
R1

Br
7

+

NaN3 + R2
8

aH

1

2O,

40 ºC, 8 h
or
b MeCN/H O (1:1),
2
MW 100 ºC, 40 min

R2

R1 N
N

N

11 examples
(70!99% yield)

Scheme 7 Three-component azide-alkyne cycloaddition reactions catalysed by 6·CuCl.

Tris(triazolyl)methyl ethers 9a and 9b (see Scheme 3) and tris(aryltriazolyl)methanols 15a−c (see Scheme 5) have also been used as
accelerating ligands for CuAAC reactions.34 A comparative study of the catalytic efficiency exhibited by neutral copper(I) complexes of
TTM derivatives in different solvents (water, n-hexane, toluene, DCM, THF, MeCN) was performed using the cycloaddition between
benzyl azide (5a) and phenylacetylene (1b) as the model reaction. The catalyst loading of TTM·CuCl was fixed at 2.0 mol% in all the

organic media whereas it was reduced down to 0.5 mol% in water. A detailed analysis of the whole set of results (Table 1; conversions
higher than 90% marked in bold) confirmed the excellent catalytic performance of 6·CuCl in water. Very remarkably, phenyl- (15a) and
p-trifluoromethyl-substituted (15b) ligands behaved notoriously well in almost every tested reaction solvent. Taking into account the
solubility characteristics of 1,2,3-triazoles, the Cu(I) complexes of 15a and 15b could be of particular importance for cascade sequences
requiring triazole products to be kept in solution.
Table 1 Comparative outcome and solvent effect in the model cycloaddition reaction of benzyl azide (5a) with phenylacetylene (1b) catalysed by
TTM·CuCl complexes.
TTM!CuCl (2.0 mol%)
N3

Bn

+

Ph

Bn

1b
waterb
(4 h)

TTMa

N

N

solvent, rt

5a

Ph

N
16a

n-hexane
(6 h)

toluene
(6 h)

DCM
(6 h)

THF
(16 h)

MeCN
(16 h)

6

98

5

75

25

90

21

9a

56

27

69

99

60

89

9b

99

43

26

98

92

96

15a

99

99

98

95

78

86

15b

82

99

99

99

80

50

15c

99

14

2

22

3

10

a

Results given as % conversion. b 0.5 mol% catalyst loading.

Given the excellent catalytic performance of 15b·CuCl for CuAAC reactions in toluene, the use of this catalyst/solvent combination was
further investigated.34 By using the reaction conditions shown in Scheme 8, a total of 17 different 1,4-disubstituted-1,2,3-triazoles
(16−20) were readily prepared in good to excellent yields (74−99%). Not only benchmark organic azides (5) and terminal alkynes (1) but
also other more challenging substrates bearing functional groups such as esters, amines, alcohols or carbamates were all compatible with
this methodology. The synthetic usefulness of 15b·CuCl was demonstrated with the successful preparation of triazole-linked, chiral
organocatalysts precursors such as pyrrolidine derivative 17d40 and proline derivatives 16e and 17e41 (Scheme 8). Another remarkable
application of 15b·CuCl in toluene enabled the synthesis of C3-symmetric tris(triazole)-containing structures 20a and 20b (Scheme 8).
Functionalised compounds 20a and 20b constitute valuable building blocks for the assembly of supramolecular polymers based on
hexasubstituted benzene scaffolds.42
15b!CuCl (2.0 mol%)
R1

N3

+

R2

5

N

toluene, rt or 40 ºC
1

Bn

N

nOct

N

N

N

CO2Et

17d (95% yield)
R2

N

Et
N Et

N

N

N
R2

N
N

N

R2 = Ph: 16d (99% yield)
R2 = CO2Et: 17c (93% yield)

N
Boc

N

R2

N

Bn

R2
N

N

R2 = Ph: 16b (99% yield)
R2 = CO2Et: 17b (99% yield)

(a In 1:1 tBuOH/H2O;
b 1.0 mol% cat.)

R2

R2

N

N

R2 = Ph: 16a (99% yield)
R2 = CO2Et: 17a (85% yield)
a,b R2 = CH NMe : 18a (99% yield)
2
2
R2 = 4-HOCH2C6H4: 19f (80% yield)
a R2 = C(Me) OH: 19i (95% yield)
2
R2 = CH(Ph)OH: 19j (95% yield)
2 = 4-H NC H : 19k (74% yield)
R
2
6 4
a R2 = CH O CMe: 19l (99% yield)
2 2

Et

N

16!20

R2

N

R2

R1 N

N
N

N

R2 = CO2Et: 20a (99% yield)
R2 = C(Me)2OH: 20b (80% yield)

N

N

CO2tBu
N
Boc
R2 = Ph: 16e (99% yield)
R2 = CO2Et: 17e (99% yield)

Scheme 8 Substrate scope of the best performing TTM-based catalytic system for CuAAC in toluene (15b·CuCl).

The suitability of 15b·CuCl as the catalyst in three-component CuAAC reactions,35 involving in situ formation of organic azides from
suitable bromide precursors and sodium azide, could also be demonstrated.34 These tandem, one-pot processes were conducted in a
MeCN/H2O (1:1) solvent mixture under MW-accelerated conditions39 and afforded triazole products in moderate to excellent yields.
Besides the applications of TTM ligands in CuAAC reactions, it is worth mentioning a very recently reported contribution by Taran et
al.43 where the TTM ligand 6 was applied in the Cu-catalysed sydnone−alkyne cycloaddition (CuSAC).44

4. Synthetic applications of 6·CuCl
The use of CuAAC reactions for the covalent immobilisation of chiral ligands and catalysts onto solid supports has found widespread
applications in asymmetric catalysis.45,46 In addition to the wide applicability of this immobilisation strategy, the resulting triazole tether
is thermally stable under standard reactions conditions and chemically inert towards most solvents and reactants, thus minimising
potential leaching issues.45 Another advantage of this strategy relies on the large dipole moment of the 1,2,3-triazolyl moiety that plays a
pivotal role in the overall hydrophilic character of the catalyst system and confers an enhanced compatibility with polar solvents.46b
Pericàs and co-workers, who reported for the first time a click-based approach for the immobilisation of a chiral organocatalytic
system,47 have further developed this field by introducing a variety of immobilised, triazole-linked chiral organocatalysts as highly
recyclable and enantioselective mediators. In these studies, formation of the triazole unit through CuAAC reaction has been mostly
accomplished by using 6·CuCl as the catalyst for its high functional group tolerance and high activity at low loadings under mild
reaction conditions.
O
PS

N3

+
N
Boc

5e

1c
or

1) 6!CuCl (1!2 mol%)
THF/DMF (1:1)
MW 80 ºC
2) TFA, DCM, rt

N3
PS

O

CO 2tBu +

N
Boc
5f

PS

CO 2tBu

N

N

1d

N
PS

N

O

O

N
N

or
N
H
21a

CO 2H

N
H

CO 2H

21b

Scheme 9 Synthesis of PS-supported triazole-linked chiral proline derivatives 23a and 23b by using 6·CuCl.

Proline derivative 21a has been prepared from 4-propargyloxyproline derivative 1c and azidomethylpolystyrene 5e through MWpromoted CuAAC reaction catalysed by 6·CuCl followed by deprotection (Scheme 9).48 The PS-supported derivative 21a has been used
in the highly enantioselective α-aminoxylation of aliphatic aldehydes under continuous flow conditions.48 The same organocatalytic
system was previously applied to the asymmetric α-aminoxylation of aldehydes and ketones under bath conditions,49 for the direct
enantioselective aldol reactions in batch41,47 and for highly enantioselective, syn-diastereoselective Mannich reactions in batch and
flow.50 Another immobilised chiral proline derivative (21b), which contains a longer spacer between the triazole ring and the polymer
backbone, was designed for higher catalytic activity and allowed the development of the first practical flow version of highly
enantioselective aldol reactions.51 The PS-supported organocatalyst 21b was efficiently prepared by click reaction between 4azidoproline derivative 5f and PS-functionalised alkyne 1d catalysed by 6·CuCl under MW irradiation, and subsequent acidic cleavage
of protecting groups (Scheme 9). The applicability of 21b in packed-bed reactors for the sequential preparation in flow of a series of
aldol adducts with very high diastereo- and enantioselectivities was shown.51
A series of PS-supported triazole-linked chiral diarylprolinol derivatives 23a−g was efficiently prepared by click reaction between
azidomethylpolystyrene 5e and 4-propargyloxydiarylprolinol derivatives 22a−g by using 6·CuCl under MW irradiation (Scheme 10).
Compound 23a proved to be a recyclable organocatalyst with enzyme-like selectivity in the asymmetric Michael additions of linear
aldehydes to β-nitrostyrenes.52 Different Michael additions were explored in depth by using the trimethylsilyl ether 23a as well as the
methyl ether 23b, with the best performing organocatalytic system 23a being also applied in enantioselective Michael-type additions of
malonates or nitromethane to α,β-unsaturated aldehydes.53 The catalytic performance of phenyl- and 3,5-bis(trifluoromethyl)phenylsubstituted diarylprolinol derivatives 23a and 23c, respectively, was compared in the enantioselective Michael−Knoevenagel domino

reaction of dimethyl 3-oxoglutarate and α,β-unsaturated aldehydes.54 Immobilised diphenylprolinol silyl ethers 23d−f (Scheme 10) were
developed to prevent deactivation by silyl ether hydrolysis as previously observed with 23a52,53 and were successfully applied in the
asymmetric α-amination of linear aldehydes with dibenzyl azodicarboxylate.55 The optimal system 23f showed very good recyclability
under batch conditions and allowed long-standing continuous flow operation.
On the other hand, PS-supported chiral diphenylprolinol derivative 23g (Scheme 10) was tested as a chiral organocatalyst in the
enantioselective cross-aldol reaction of acetaldehyde and 4-nitrobenzaldehyde mediated by a dual catalytic system operating under site
isolation conditions.56
N

PS

N

N

R2

R2
PS

O

N
H

O

N 3 (5e)

O

R2
6!CuCl (1!10 mol%)
R2
THF/DMF (1:1)
MW 80 ºC

N
H

a: R1 = TMS, R 2 = H
b: R1 = Me, R 2 = H
c: R1 = TMS, R 2 = CF3
d: R1 = TES, R 2 = H
e: R1 = TIPS, R 2 = H
f: R1 = TBDMS, R 2 = H
g: R1 = H, R 2 = H

R1
R2

22a!g

R2
R2
O

R1
R2

23a!g

Scheme 10 Synthesis of PS-supported triazole-linked chiral diarylprolinol derivatives 23a−g by using 6·CuCl.

Catalyst 6·CuCl was also used for the preparation of PS-supported (24a) and monomeric (24b) triazole-linked chiral 3-aminopyrrolidine
derivatives by MW-accelerated click reaction between 4-propargyloxypyrrolidine derivative 1e and azidomethylpolystyrene (5e) or
benzyl azide (5a), respectively, followed by TFA-mediated N-Boc deprotection (Scheme 11). Pyrrolidine derivatives 24a and 24b were
introduced as extremely active organocatalysts for asymmetric anti-selective Mannich reactions, and the supported one (24a) allowed the
implementation of a robust continuous flow process suitable for the sequential preparation of small libraries of anti-selective Mannich
products and for the large-scale production of single Mannich adducts.57
Ph

N3
5a
or

PS

+

N

1) 6!CuCl (1.0 mol%)
THF/DMF (1:1)
MW 80 ºC
2) TFA, DCM, rt

N
Boc
1e

N3
5e

PS

NHTf

O

N

N

Ph

NHTf

O

or

N

N

N

NHTf

O

N
H

N
H

24a

24b

Scheme 11 Synthesis of PS-supported (24a) and monomeric (24b) triazole-linked chiral 3-aminopyrrolidine derivatives by using 6·CuCl.

Catalyst 6·CuCl also allowed the immobilisation of squaramide organocatalysts onto polystyrene. Thus, the PS-supported chiral
squaramide 25 was accessible in two steps through an initial MW-promoted CuAAC reaction between the alkyne-functionalised
precursor 1f and azidomethylpolystyrene 5e, followed by reaction with a suitable enantiopure trans-1,2-diaminocyclohexane derivative
(Scheme 12). The resulting squaramide 25 was used as a highly recyclable organocatalyst for enantioselective Michael additions of 1,3dicarbonyl compounds to β-nitrostyrenes in batch58 and flow.59

1)
O

CF3

6!CuCl (3.0 mol%)
THF/DMF (1:1)
MW 80 ºC

O

O

N
H

OMe

O

1f

N 3 (5e)

PS

2)

H 2N
N
DCM, rt

O

CF3

O

O

N
H

N
H

O
N
N N

PS

N

25

Scheme 12 Synthesis of PS-supported triazole-linked chiral squaramide 25 by using 6·CuCl.

Following a closely related synthetic strategy, the PS-supported chiral thiourea 26 was prepared through a three-step sequence involving
6·CuCl-catalysed CuAAC reaction of 5e with terminal alkyne 1g, isothiocyanate formation and final integration of an enantiopure trans1,2-diaminocyclohexane derivative (Scheme 13). Thiourea 26 has shown very high activity and enantioselectivity in the α-amination of
cyclic 1,3-dicarbonyl compounds with azodicarboxylates under batch and continuous flow modes.60
CF3

O

1) 6!CuCl (8.0 mol%)
THF/DMF (1:1)
MW 80 ºC

O
N3 +

PS

NH 2
5e

1g

2) CSCl 2, NEt 3, DCM
H 2N

3)

N
THF, rt
O

CF3

O

S
N
H

N
N N

PS

N
H

N

26

Scheme 13 Synthesis of PS-supported triazole-linked chiral thiourea derivative 26 by using 6·CuCl.

Apart from the development of triazole-linked chiral organocatalytic systems, catalyst 6·CuCl has also been successfully applied to the
preparation of triazole-containing ligands for homogeneous metal catalysis. The click reaction between benzyl azide (5a) and bis(alkyne)
1h catalysed by 6·CuCl afforded the C2-symmetric bis(triazolecarboxamido) derivative 27 in 81% yield (Scheme 14). Compound 27 was
used as a tetradentate chiral ligand for molybdenum-catalysed asymmetric allylic alkylation reactions, with very high regio- and
enantioselectivities being recorded under thermal or MW-promoted conditions.61
Ph
O

O
NH

HN

N 3 (5a)
O

6!CuCl (3.0 mol%)

N
1h

O
NH

H 2O, rt

Ph

N

HN
N

N

N
27 (81% yield)

N
Ph

Scheme 14 Synthesis of C2-symmetric bis(triazolecarboxamido) ligand 27.

Catalyst 6·CuCl has also found use in the preparation of materials for non-catalytic purposes. An interesting application in the area of
biochemistry was developed by Bortvin and Greenberg et al.62 The click reaction between fluorescein azide (5f) and alkynefunctionalised 5-ethynyl-2’-deoxycytidine (EdC)-containing DNA 1i mediated by 6·CuCl under physiological conditions enabled the
fluorescence labelling of DNA fragments63 (Scheme 15). The so obtained fluorophore-conjugated DNA 28 constitutes a valuable
visualisation tool for exploring the chemical mechanism of DNA demethylation.

O

HO

NH 2

OH

N
+

O

O

6!CuCl (100 mol%)
O

N

H 2O, 37 ºC

O
O

N3

O

5f
(fluorescein azide)

1i
(EdC-containing DNA)

OH

N N

O

NH 2

N

N
O

HO

O

O

N

O

O
O
28

Scheme 15 Fluorescence labelling of EdC-containing DNA (1i) via CuAAC by using 6·CuCl.

Pericàs, Ros and co-workers envisioned applications of 6·CuCl for the preparation of liquid crystalline materials.64 These authors
prepared a library of symmetrical and non-symmetrical oligomers (29) by CuAAC reaction between suitable azide- and alkyne-ended
building blocks catalysed by 6·CuCl. Compounds 29 (Fig. 4) are bent-shaped structures featuring 1,2,3-triazole rings as the central core.
Such bent-core assemblies exhibited liquid crystalline properties ranging from lamellar to columnar or B4-like supramolecular
organisations.
N
( ) N
n

N
X
y

O
m

O
O

O
O

O
O

R2

R1

m, n, y, z = 0, 1
R1 = H, Cl
R 2 = OC14H 29, O(CH 2CH 2O) 4CH3
X = CH 2OC(O)

O
z

OC14H 29

29

Fig. 4 Bent-core triazole-based liquid crystalline materials (29) prepared by CuAAC using 6·CuCl as the catalyst.

The group of Lyle Isaacs has extensively used catalyst 6·CuCl as a tool for the preparation of triazole-functionalised cucurbituril65 (CB)
derivatives (30−32; Fig. 5), readily accessible through building block-based click approaches. Cucurbit[n]uril (n = 5−10) chemistry
delivers exceptional recognition properties of these pumpkin-shaped supramolecular macrocycles towards organic and inorganic guests.66
Cucurbit[6]uril derivative 30 features a CB[6] sized cavity covalently bound to an isobutylammonium tail through a 1,2,3-triazole linker.
Self-assembly of CB[6] 30 in water as a cyclic [c2] daisy chain showed responses to chemical stimuli in the form of competing guests
and hosts.67 Similarly, CB[7] derivative 31a, which bears a triazole-linked primary alkyl ammonium chloride group, underwent a selfassembly process into a cyclic tetramer and showed outstanding host-guest recognition properties.68 Closely related hydrophobic CB[7]
derivatives 31b and 31c, bearing triazole-linked secondary alkyl ammonium bromide residues, formed self-inclusion complexes leading
to vesicle-type supramolecular assemblies by addition of guests.69 Finally, two monofunctionalised propargyloxy-CB[6] and CB[7]azide derivatives were converted into CB[6]-CB[7] heterodimer 32 by click chemistry using 6·CuCl as the catalyst. Self-sorting
assembly of heterodimer 32 delivered hydrophobic or amphiphilic block copolymers giving rise to supramolecular networks and
micelles.70

O
N

N

OO

OO

N

N
N
N
N

N

N N
N

O

O

NN

N

N N

NN

Me

N
N

N

O

NH 2
N

O O

O

N

N

Cl
30

O
N

NN

O

O
N
N

N

N

N

N
N

NN

NN

NN

NN

OO

Me

O

O O

NN

N

NN

NN

N

O O
N

O

N
N

N N

OO

H2
N

N

N

OO

N

R

X

O

R = H, X = Cl: 31a
R = (CH 2) 9CH3, X = Br: 31b
R = (CH 2)11 CH3, X = Br: 31c
O
N
N
NN

N

NN

OO

O

O

N

N
N

N

O

O

N

NN

NN

N

N

OO

N

N

N

N
N
N
N

N
O

N N
N

O

O

N

NN
NN
O O

N
N

N N
N N
32

O

OO

OO

O

N
N

N

OO

O

O

N

O
NN

N

N

NN

N
O

N
N

N
N
O

Fig. 5 Triazole-functionalised supramolecular structures of CB[6] (30) and CB[7] (31a−c) derivatives as well as CB[6]−CB[7] heterodimer (32) prepared
by CuAAC using 6·CuCl.

5. Immobilised TTM ligands in heterogeneous catalysis
Immobilisation of catalysts and ligands onto solid supports can lead to important sustainability improvement whenever the activity of the
homogeneous system is retained and the supported system admits multiple recycling.45,46 As an additional bonus, heterogenised systems
can be separated by simple filtration, with suppression of wasteful work-up treatments.
In this context, Pericàs and co-workers37 reported on the grafting of monomeric tris(triazolyl)methanol 6 and tris(triazolyl)methyl
propargyl ether 9c onto polystyrene derivatives through two complementary strategies (Scheme 16). In both cases the innate OH group
present in the TTM ligands is used as the immobilisation point. This leaves the tris(triazolyl)methyl scaffold unperturbed by the polymer
backbone, thus favouring the preservation of catalytic activity. A click-based approach was initially followed to support the propargyl
ether 9c onto azidomethylpolystyrene 5e. Alternatively, etherification of the free hydroxy group in 6 with Merrifield resin 33a was
performed via SN2 reaction. These strategies yielded PS-supported tris(triazolyl)methyl ethers 9g and 9h featuring triazole and ether
linkages, respectively. Neutral copper(I) complexes of 9g and 9h were formed by treatment of the immobilised ligands with a
stoichiometric amount of CuCl in THF, and the resulting complexes (9g·CuCl and 9h·CuCl) were successfully used as catalysts in
CuAAC reactions.37

PS

N
O
Bn

N

N

N

6!CuCl (5.0 mol%)
THF/DMF (1:1) Bn

N Bn

C

N

N

N

O

N
N Bn

PS

N

9c

N

N

40 ºC

N

N Bn

C

N

N 3 (5e)

N

N

N
N Bn

N

9g

PS
OH
Bn

C

N

N

N

N

N

N

N
N Bn

O

1) NaH, DMF
0 ºC

N Bn
2)

PS

Bn

N

Cl (33a)

N

N

50 ºC

6

N Bn

C

N

N

N
N Bn

N

9h

Scheme 16 Immobilisation strategies leading to PS-supported tris(triazolyl)methyl ether ligands 9g and 9h.

When testing a model CuAAC reaction, the simple, ether-linked supported system 9h·CuCl exhibited superior catalytic performance and
recyclability in comparison to the triazole-linked system 9g·CuCl.37 Indeed, complex 9h·CuCl proved to be very active at low catalyst
loading (1.0 mol%) and low concentration (down to 0.125 M) in both aqueous and organic media. The best results were obtained in a
MeOH/H2O (1:1) solvent mixture, which enabled efficient recycling and reuse of the catalytic system for five consecutive cycles.
Additionally, the useful life of resin 9h could be unlimitedly extended by simply reloading it with CuCl every five reaction cycles.
The applicability of the heterogenized system 9h·CuCl for the CuAAC reaction between different azides and various alkynes under
optimised reaction conditions (Scheme 17) was subsequently studied. A representative set of 15 different 1,4-disubstituted 1,2,3-triazoles
featuring many different functionalities (alcohols, amines, esters, carboxylic acids, nitro groups, silyl ethers) was prepared in very high
yields (92−99% yield) and short reaction times at low catalyst loading (1.0 mol%). In all cases the product isolation was readily
accomplished by simple filtration (with full recovery of 9h·CuCl). The low catalyst loading and high recyclability of 9h·CuCl boded a
very reduced leaching of copper into the aqueous/alcohol reaction media, as confirmed by UV-Vis spectroscopy analyses of several
batches of triazole 16a.
9h!CuCl (1.0 mol%)
N3

R1

+

R2

5

R2

R1 N
N

MeOH/H 2O (1:1), 40 ºC

N

15 examples
(92!99% yield)

1

Scheme 17 CuAAC reactions mediated by PS-supported 9h·CuCl.

Very recently, Díaz-Requejo, Pérez and Pericàs et al.71 reported on the preparation of a fully recyclable heterogenized cationic copper(I)
complex 34 and its catalytic performance in carbene transfer reactions72 both in batch and continuous flow modes. The reaction of PSsupported tris(triazolyl)methyl ether ligand 9h with [Cu(MeCN)4][PF6] led to the formation of the immobilised complex 34 bearing a
labile acetonitrile ancillary ligand (Scheme 18). The authors postulated that cationic complex 34 would be much more robust than the
neutral counterpart 9h·CuCl, so that metal leaching during the reactions catalysed by this species could be minimised.
PS

PS

O
Bn

C

N
N

O
N

N

N
9h

N

N Bn [Cu(NCMe) 4][PF6]
N
N Bn

DCM, rt
(! 3 MeCN)

Bn

N Bn

N
N

N

N

N

N

N
N Bn

Cu
N
Me
[(9h)Cu(NCMe)] + [PF 6]! : 34

Scheme 18 Preparation of cationic copper(I) complex 34 derived from PS-supported TTM ligand 9h.

[ PF 6 ]

N2

34 (5.2 mol%)

+
H
35

CO 2Et
40

O

N2
H

36

CO 2Et
40
N2

H

37

CO 2Et

N2
H

EtO

CO 2Et

neat, rt

43 (99% yield)

H
N

34 (5.2 mol%)

+
14a

CO 2Et

42 (82% yield)

40

NH 2

O

neat, rt

34 (5.2 mol%)

+

EtOH

41 (98% yield)

34 (5.2 mol%)

+

CO 2Et

neat, rt

CO 2Et

CO 2Et

DCM, rt

40

44 (97% yield)
CO 2Et

N2

34 (5.2 mol%)

+
H
38

CO 2Et

34 (5.2 mol%)

Ph +
H
39

45 (88% yield)
CO 2Et

N2
Me

neat, rt

40

CO 2Et

DCM, rt

40

Me

Ph

46 (93% yield)

Scheme 19 Carbene transfer reactions catalysed by heterogenized cationic copper(I) complex 34.

The heterogenized system 34 (5.2 mol%) efficiently catalysed a diverse variety of carbene transfer reactions, under neat conditions or in
DCM as solvent at rt, by using inexpensive ethyl diazoacetate (40) as the carbene source (Scheme 19).71 Insertion reactions of the
carbene unit into C−H bonds of cyclohexane (35) and tetrahydrofuran (36), the O−H bond of ethanol (37) and the N−H bond of aniline
(14a), as well as addition reactions to benzene (38; Büchner reaction) and 1-phenyl-1-propyne (39; cyclopropenation) were all
successfully performed giving rise to an array of products (41−46) in very high yields (82-99% yield). After each carbene transfer
reaction, the catalyst was readily separated by simple filtration and reused for next cycle. Importantly, each reaction was repeated five
times without significant loss of catalytic activity in each run by using the same sample of supported catalyst. Moreover, twelve
consecutive experiments (six different substrates and each experiment run by duplicate) were performed with the same sample of catalyst
34 obtaining comparable yields to those recorded individually.
Parameters
to Ar line

34 (300 mg, f = 0.39 mmol!g-1, 0.117 mmol)
Flow rate: 0.5 mL!min -1
Residence time: 1 min

DCM
supply
CO 2Et
EtO

to Ar line

43

48 h operation time
12.6 g (95.8 mmol)
TON = 820

Switchable
Pumps
N 2=CHCO 2Et (40) / EtOH (37)
in DCM

Fig. 6 Experimental setup for continuous flow production of 43 catalysed by 34.

The application of continuous flow processes73,74 has recently increased in both industry and academia fields due to their intrinsic

advantages respect to conventional batch processes. The adaptation of covalently heterogenised catalysts to continuous flow
processing73,74 is a relatively new field but it offers several specific advantages: (a) no ligand losses occur during operation as the
heterogeneous catalyst is placed in packed-bed reactors, (b) mechanical degradation of the catalyst is suppressed because neither stirring
nor shaking is required, and (c) deactivation of the catalyst derived from oxidation and/or hydrolysis of labile catalytic species can be
avoided by simply using dry, deoxygenated solvents.
To exploit these advantages, the use in flow of immobilised catalyst 34 for carbene transfer reactions from ethyl diazoacetate (40) was
implemented.71 To challenge the catalyst' useful life in flow, the insertion of the carbene derived from 40 into the O−H bond of ethanol
(37) was studied by using the affordable experimental setup depicted in Fig. 6. After some modification with respect to the batch process,
operation of this device at very low catalyst loading led to work with a flow rate as high as 0.5 mL·min-1 (equivalent to 1 min residence
time). This very stable continuous flow process led to full conversion even after 48 h operation, when the experiment was stopped. When
conversion decreased, reconditioning of the catalyst by circulating DCM into the column produced a re-swelling of the polymeric matrix
allowing the complete reactivation of the system. In this manner, the process yielded 12.6 g (95.8 mmol, TON = 820) of pure product 43
without any kind of purification. Gratifyingly, copper content analyses showed negligible contamination of the collected samples
(0.8−1.6 ppm), indicating the high stability of catalyst 34 under these conditions.
As a further illustration of the potential of 34, a sequential preparation of five different products (41−44 and 46) involving four different
types of carbene transfers (O−H, N−H and C−H insertions, and cyclopropenation) was successfully carried out taking the advantage of
flow processing. Each starting material (35−37, 14a and 39) was circulated for 2 h through the column. Very high productivities, ranging
from 2.3 (for 46) to 17.5 (for 43) mmolproduct·mmolCu-1·h-1, were achieved in all cases. The robustness of catalyst 34 was further
demonstrated in this experiment, since the same catalyst sample was used to optimise the flow conditions for each substrate and for the
synthesis of the whole family of carbene transfer products (Fig. 7).
Operation time: 2 h per substrate
1)

2)

3)

O

CO 2Et

CO 2Et

4)

CO 2Et
Me
41

46

2.53 mmol (10.8)

0.94 mmol (4.0)

0.54 mmol (2.3)

Productivities in mmolproduct!mmol Cu

CO 2Et
COOEt

Ph

42

5)

H
N

OEt

44

!1

!h !1

43

3.91 mmol (16.7)

4.10 mmol (17.5)

are shown in parentheses

Fig. 7 Sequential production in flow of a small library of compounds resulting from carbene transfer reactions catalysed by 34.

Magnetic nanoparticles (MNPs) have recently arisen as a valuable alternative for the supporting of catalytic species in view of
recycling.75 MNPs can be readily separated from the reaction medium by magnetic decantation. In this way, MNP-supported catalysts are
easily recoverable for reuse.
Astruc and co-workers76 have recently immobilised the tris(triazolyl)methanol 629,34 onto silica-coated iron oxide-based magnetic
nanoparticles (γ-Fe2O3@SiO2). These core-shell nanoparticles77 constitute a class of multifunctional nanostructured materials containing
iron oxide nanoparticles as the core and covalently grafted silica as the shell.78 The anchoring strategy followed by Astruc et al. (Scheme
20) relied on the formation of an ether linkage by SN2-type alkylation reaction of alcohol 6 with 3-chloropropyltris(oxy)silanefunctionalised MNPs 33b, previously prepared through immobilisation of 3-chloropropyltriethoxysilane on the surface of robust γFe2O3@SiO2. The resulting MNP-supported tris(triazolyl)methyl ether ligand 9i was further used as a stable chelating framework for
Cu(I) salts. The corresponding heterogenized copper complexes (9i·CuCl and 9i·CuBr) proved to be highly active and magnetically
recoverable TTM-based catalytic systems for CuAAC reactions.76 The catalytic performance of both MNP-supported systems was
evaluated in the model reaction between benzyl azide (5a) and phenylacetylene (1b) conducted in water79 at rt under inert atmosphere.
Catalyst 9i·CuBr showed a superior catalytic activity and could be reused up to six times without significant loss of its catalytic activity
under these conditions. Analysis of copper leaching after the first cycle confirmed the amount of metal content into the triazole product
(16a) was negligible (approx. 1.5 pm). In contrast to 6·CuCl and 9h·CuCl, however, 9i·CuBr became readily deactivated in air,
probably due to aerobic oxidation into inactive Cu(II) species.

OH
Bn

N
N

SiO2
N

N

O

N Bn

C
N

N

+

N
N Bn

!-Fe 2O3

O Si

Cl

O
SiO2

6

33b

SiO2

1) 6, NaH, DMF
0 ºC to rt

O
!-Fe 2O3
SiO2

2) 33b
0 ºC to 80 ºC

O Si
O
Bn

O

N

N Bn

C

N

N

N

N

N

N
N Bn

9i

Scheme 20 Anchoring strategy relied on an ether linkage leading to silica-coated iron oxide-based MNP-supported tris(triazolyl)methyl ether ligand 9i.

The authors applied this methodology to prepare 17 different 1,4-disubstituted 1,2,3-triazoles in very high yields (81−99% yield)
repeating each reaction for three times using the same sample of MNP-supported catalyst 9i·CuBr (Scheme 21).76 Only a slight decrease
in the yield was observed from the first run to the third one. The catalytic performance of 9i·CuBr tolerated remarkably well a wide
range of substrates bearing diverse organic functionalities and all reactions were conducted in water79 under mild reaction conditions (0.5
mol%, rt). Additionally, applications of complex 9i·CuBr in three-component processes,35 involving in situ generation of organic azides
from benzyl bromides and sodium azide, were also tackled and efficiently delivered triazole products in good to excellent yields.76
9i!CuBr (0.5 mol%)
R1

N3
5

+

R2

H 2O, rt
1

R1 N

R2

N N
17 examples
(81!99% yield)

Scheme 21 CuAAC reactions mediated by MNP-supported 9i·CuBr.

The same authors76 used 9i·CuBr for the preparation of 27-branch dendrimers featuring 1→3 connectivity.80 Dendritic assemblies
containing 9 triazole units13 and 27 allyl (47a) or 27 triethylene glycol (47b) termini (Fig. 8) were quantitatively synthesised from a
common dendritic nona-azide precursor and two propargyl ether dendrons by using only 8 mol% of 9i·CuBr per branch (or per CuAAC
reaction). The amphiphilic dendrimer 47b featured by intradendritic triazole rings showcased an impressive accelerating effect in
CuAAC reactions acting as a recyclable catalytic nanoreactor at the part-per-million (ppm) level.81 Interestingly, this water-soluble
dendritic nanoreactor (47b) was used in turn for its own autocatalysed synthesis.81
Most recently,82 the same laboratory has reported (Scheme 22) the immobilisation of tris(triazolyl)methyl propargyl ether 9c37 onto
azido-functionalised,83 silica-coated iron oxide-based magnetic nanoparticles (γ-Fe2O3@SiO2).77,78 The resulting MNP-supported
tris(triazolyl)methyl ether ligand 9j was further used as a stable chelating framework for Pd species. Complexation reaction of 9j with
Pd(OAc)2 in toluene at 45 ºC led to a immobilised palladium(II) complex [9j·Pd(OAc)2], which was used to catalyse the oxidation of
benzyl alcohols by air at atmospheric pressure.82 Analysis of palladium leaching confirmed the amount of metal content into the
oxidation product was negligible after four reaction cycles.

RO
N

RO

N
N

N

N

N

N

Me
Si Me
Si

Me
RO

RO

N

Me

OR

Me

Me

N

N

N

Si

Si

N

N

Me

N
N

Me

Me

Si
Me

Me
N
RO

Si

N N

Me
Me

Si

Me
N

Me

N

N
Si
Me
N

Me

N

Me

Si
N

N

OR

N
N

OR

OR
O

R=

or

R=

O
O

O
O

O

O Me
O

O

O Me

O

47a

O Me

47b

allyl-ended 27-branch dendrimer

TEG-ended 27-branch dendrimer

Fig. 8 Dendritic structures containing 9 triazole units and 27 allyl (47a) or 27 triethylene glycol (47b) termini prepared by CuAAC using 9i·CuBr.
O
Bn

N
N

SiO2
N Bn

C
N

N

N

N

N
N Bn

O
+

!-Fe 2O3

THF/DMF (1:1)
rt

N3

O
SiO2

9c
CuI (7.5 mol%)
DIPEA

O Si

5g

SiO2
O
!-Fe 2O3

O Si

N

N
N

O
SiO2

O
Bn

N Bn

C

N
N

N

N
N

N

N
N Bn

9j

Scheme 22 Anchoring strategy relied on a triazole linkage leading to silica-coated iron oxide-based MNP-supported tris(triazolyl)methyl ether ligand 9j.

The authors investigated the substrate scope (11 examples) of the oxidation of primary and secondary alcohols 48 towards the
corresponding aldehydes and ketones 49 catalysed by MNP-supported complex 9j·Pd(OAc)2 under the reaction conditions shown in
Scheme 23.82 This transformation proceeded efficiently regardless of the substitution pattern of alcohols 48 and gave good results with
both electron-donating and electron-withdrawing substituents. In all cases selectivity towards desired oxidation products 49 was very
high, ranging from 86 to 94%.
OH

48

9j!Pd(OAc) 2 (1.9 mol%)

R2

R1

air, toluene, 85!90 ºC
K 2CO3

Scheme 23 Oxidations of benzyl alcohols catalysed by 9j·Pd(OAc)2.

6. Summary and conclusions

R1

O
R2

49
11 examples
(41!100% conversion)
(86!94% selectivity)

The ready synthetic access to C3-symmetric tripodal TTM ligands, its favourable geometry for efficient Cu(I) complexation and the
derivatisation opportunities offered by the innate OH group present in their structures have favoured the use of these ligands by different
laboratories working in very different areas.
Most of the applications developed so far have been in the field of CuAAC reactions and involve the use of a neutral copper(I) complex
derived from the benzyl-substituted TTM ligand 6 (6·CuCl). It has been found, however, that copper complexes of aryl-substituted TTM
ligands (15a·CuCl and 15b·CuCl) are also versatile catalysts suitable for work in a wide variety of solvents. In all these cases, the threepoint binding ability provided by these tridentate chelating ligands efficiently stabilises Cu(I) against undesired oxidation and avoids the
deactivating complexation of Cu(I) with amino, alcohol or thioether groups present in either reactants or products. This behaviour not
only extends catalyst life through favourable self-repair mechanism, but also allows the use of reduced catalyst loadings under mild
conditions.
Another group of interesting applications arises from the ready immobilisation of the TTM ligands onto solid supports (PS or MNPs) via
SN2 or CuAAC reactions. The corresponding CuX complexes (9h·CuCl and 9i·CuBr) show very high catalytic activity in CuAAC
reactions, while the Pd(II) complex [9j·Pd(OAc)2] behaves as an active catalyst in Pd-mediated oxidation reactions. In this area, the
development of the PS-heterogenized cationic Cu(I) complex (34) behaving as a highly active, general catalyst for carbene transfer
reactions in batch and flow is remarkable. Catalyst 34 operates with almost complete absence of copper leaching and can be used for
prolonged periods of time in processes involving multiple recycling in batch or sequential operation in continuous flow.
The modular design of TTM ligands allows the structural modification of the triazole moieties by simple selection of the organic azide
used to build the molecules. These modifications offer potential still to be developed for the modulation of the catalytic performance of
the corresponding metal complexes through the modification of steric and electronic properties of the ligand. We anticipate that progress
along these lines will lead to the development of efficient, TTM-based catalysts for a variety of metal-mediated processes.

Acknowledgements
This work was funded by MINECO (Grant CTQ2012-38594-C02-01), the Generalitat de Catalunya (Grant 2014SGR827) and the ICIQ
Foundation. We also thank MINECO for support through the Severo Ochoa Excellence Accreditation 2014−2018 (SEV-2013-0319).
C.A. thanks the CELLEX Foundation for financial support.

Notes and references
a

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Avgda. Països Catalans 16, E-43007
Tarragona, Spain. E-mail: mapericas@iciq.es; Fax: +34 977920244; Tel: +34 977920243
b
Departament de Química Orgànica, Universitat de Barcelona, 08028 Barcelona, Spain
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

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