The fluxional amine gold(III) complex as an excellent catalyst and precursor of biologically active acyclic carbenes

Article abstract of DOI:10.1039/c5dt00703h

A new amine gold(III) complex [Au(C₆F₅)₂(DPA)]ClO₄ with the di-(2-picolyl)amine (DPA) ligand has been synthesised. In the solid state the complex has a chiral amine nitrogen because the ligand coordinates to the gold centre through one nitrogen atom from a pyridine and through the NH moiety, whereas in solution it shows a fluxional behaviour with a rapid exchange between the pyridine sites. This complex can be used as an excellent synton to prepare new gold(III) carbene complexes by the reaction with isocyanide CNR. The resulting gold(III) derivatives have unprecedented bidentate C∧N acyclic carbene ligands. All the complexes have been spectroscopically and structurally characterized. Taking advantage of the fluxional behaviour of the amine complex, its catalytic properties have been tested in several reactions with the formation of C-C and C-N bonds. The complex showed excellent activity with total conversion, without the presence of a co-catalyst, and with a catalyst loading as low as 0.1%. These complexes also present biological properties, and cytotoxicity studies have been performed in vitro against three tumour human cell lines, Jurkat (T-cell leukaemia), MiaPaca2 (pancreatic carcinoma) and A549 (lung carcinoma). Some of them showed excellent cytotoxic activity compared with the reference cisplatin.

Full text of DOI:10.1039/c5dt00703h

View Article Online
View Journal
Dalton
Transactions
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. C. Gimeno, S.
Montanel-Pérez, R. P. Herrera, A. Laguna and M. D. Villacampa, Dalton Trans., 2015, DOI:
10.1039/C5DT00703H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/dalton

Page 1 of 12
Dalton Transactions
View Article Online
DOI: 10.1039/C5DT00703H
Journal Name
RSCPublishing
ARTICLE
Fluxional Amine Gold(III) Complex as Excellent
Catalyst and Precursor of Biologically Active
Acyclic Carbenes
Cite this: DOI: 10.1039/x0xx00000x
Sara Montanel-Pérez,a Raquel P. Herrera,b Antonio Laguna,a M. Dolores
Villacampaa,* and M. Concepción Gimenoa,*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A new amine gold(III) complex [Au(C6F5)2(DPA)]ClO4 with the di-(2-picolyl)amine (DPA) ligand has been
synthesised. In the solid state the complex has a chiral amine nitrogen because the ligand coordinates
to the gold centre through one nitrogen atom from a pyridine and through the NH moiety, whereas in
solution shows a fluxional behaviour with a rapid exchange between the pyridine sites. This complex can
be used as excellent symptom to prepare new gold(III) carbene complexes by the reaction with
isocyanide CNR. The resulting gold(III) derivatives have unprecedented bidentate C^N acyclic carbene
ligands. All the complexes have been spectroscopically and structurally characterized. Taking advantage
of the fluxional behaviour of the amine complex, its catalytic properties have been tested in several
reactions with formation of C-C and C-N bonds. The complex showed excellent activity with total
conversion, without the presence of a co-catalyst, and with a catalyst loading as low as 0.1 %. These
complexes also present biological properties and cytotoxicity studies have been performed in vitro
against three tumour human cell lines, Jurkat (T-cell leukaemia), MiaPaca2 (pancreatic carcinoma) and
A549 (lung carcinoma). Some of them showed excellent cytotoxic activity compared with the reference
cisplatin.
www.rsc.org/
group.33ꢀ36 However, we believe that these gold(III) acyclic
carbenes may exhibit a wide range of unexplored possibilities
Introduction
Gold(III) derivatives are attracting much interest mainly
because of their potential applications in diverse fields such as
medicine as antitumor or antiviral agents,1ꢀ7 in material
chemistry for their optical properties, with products with
interesting luminescence8ꢀ10 or in catalysis, where the gold(III)
complexes are active in several organic transformations, some
of them of industrial interest.11ꢀ15
The discovery of the extraordinary properties of gold(I), and
to a lesser extend gold(III), Nꢀheterocyclic carbene compounds,
especially in catalysis,16,17 medicine18 and luminescence19
prompts the research in gold acyclic carbene derivatives.
Nowadays, several gold(I) acyclic carbene complexes with
outstanding catalytically activity have been reported,20ꢀ25 some
of them with a very low catalyst loading and excellent turnover
numbers,26 or with interesting luminescence properties.27ꢀ30
However, gold(III) acyclic carbene derivatives are very scarce
and only a few have been described thus far, including the
pioneering work of Bonati et al31,32 and those reported in our
for this type of applications.
With this idea in mind, we proposed the preparation of new
and novel gold(III) acyclic carbene complexes. Usually, metal
acyclic carbenes are obtained by nucleophilic attack of an
amine to a metal isocyanide complex. This procedure does not
work easily for all the amines, and in some cases with aryl or
less activated amines the reaction does not occur. We
considered the possibility of using functionalised amine
derivatives that upon coordination to the gold(III) centre could
favour the reaction with isocyanide and formation of the
carbene.36 Consequently, the use of
a wide range of
funcionalised amines could open the entry to a great variety of
unprecedented bidentate carbene ligands. Furthermore, these
gold(III) synthons in which hemilabile bidentate amine ligands
are coordinated to the metallic centre could be excellent
catalysts in many organic processes. Not many gold(III)
complexes have been successfully used in catalysis, apart from
the widely used AuCl3, AuBr3 or Na[AuCl4] salts.37,38 Hashmi
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

Dalton Transactions
Page 2 of 12
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5DT00703H
et al reported the use of pyridineꢀbased ligands for stabilising pyridine and methyl signals are observed at room temperature,
the gold(III) ion,39 a few examples of chiral gold(III) Schiff at least two structures are possible in solution. One with both
base complexes were reported by Corma et al 40
and also some pyridine nitrogen atoms coordinated to the gold(III) (Scheme 2,
,
NHC,41ꢀ45 cyclometallated,46ꢀ48 salen,49 pentafluorophenyl50 or a), other with the amine nitrogen bonded to the gold(III) and the
iminophosphorane derivatives51 have been used as catalysts. In pyridine nitrogen atoms in a dynamic exchange process that
most of the cases the complex is a preꢀcatalyst and activation make them equivalent (Scheme 2, b).
with silver salts or acids is necessary.
Herein we report the design and synthesis of stable
unprecedented gold(III) species with bidentate acyclic carbene
ligands. For this purpose we have developed a pioneering
procedure consisting in the preparation of gold(III) derivatives
with functionalised amines. The latter compounds could be
excellent synthons for the preparation of novel gold(III) species
with bidentate acyclic carbenes through activation of
isocyanides. Furthermore, this wellꢀdefined gold(III)
compounds with hemilabile amines could be unique catalytic
systems in several organic transformations, including
Scheme 2 a) non-fluxional behaviour, b) fluxional behaviour in solution
multicomponent reactions for the synthesis of biological active
species. Additionally, the antitumor properties of these
In order to obtain more information, the 1H variable
complexes have been tested in vitro against three tumour
human cell lines, such as Jurkat (Tꢀcell leukaemia), MiaPaca2
(pancreatic carcinoma) and A549 (lung carcinoma).
temperature spectra of
1 in (CD3)2CO were carried out. As
shown in Fig. 1, the signals began to broaden near ꢀ35 ºC,
reached decoalescence point near ꢀ55 ºC and at ꢀ73 ºC each
pyridine peaks was split into two broad peaks with a 1:1 ratio.
The diastereotopic methylene protons CHaHb were observed as
two “AB” multiplets. At 200 K the structure with two different
–CH2py groups was confirmed (Fig. 1, D). This dynamic
behaviour has also been observed in other gold(III)
derivatives.52,53
Results and discussion
Synthesis and characterisation
The
utilisation
of
the
gold(III)
precursor
cisꢀ
[Au(C6F5)2(OEt2)2]ClO4, which has two labile diethyl ether
molecules, allows coordination of practically any ligand, and
thus we have chosen functionalised amine diꢀ(2ꢀpicolyl)amine
py
CH2
to prepare the starting compound. Then, complex
1 has been
obtained by the reaction at room temperature of cis
ꢀ
A
[Au(C6F5)2(OEt2)2]ClO4, prepared in situ, with an
equimolecular amount of diꢀ(2ꢀpicolyl)amine (Scheme 1). It has
been characterised by means of IR, elemental analysis, NMR
9.0
8.0
7.0
6.0
5.0
ppm (t1)
1
spectroscopy, and mass spectrometry. Assignments of the H
B
NMR and 13C NMR signals were made on the basis of 2D
COSY and HSQC spectra. In the ESI+ mass spectra the
fragment [M – ClO4]+ appears at m/z = 730 (100 %).
9.0
8.0
7.0
6.0
5.0
ppm (t1)
C
9.0
8.0
7.0
6.0
5.0
ppm (t1)
py
py
CH2 CH2
D
9.0
8.0
7.0
6.0
5.0
ppm (t1)
Figure 1 1H NMR (CD3)2CO spectra of complex
1. A: 298 K. B: 238 K. C: 218 K. D:
200 K.
Scheme 1 Synthesis of complex 1.
The 19F NMR spectrum at room temperature presents two
multiplets for the ortho and meta and a triplet for the para
fluorine indicating that pentafluorophenyl groups become
1
The H NMR spectrum of complex
1 (Fig. 1 A) shows
resonances assigned to the protons of the diꢀ(2ꢀpicolyl)amine
(protons named H and H’ in Scheme 1). Since only one type of
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 12
Journal Name
Dalton Transactions
View Article Online
ARTICLE
DOI: 10.1039/C5DT00703H
equivalents in solution and there is no hindered rotation for
1
is that the amine nitrogen of picolylamine group becomes
them. Variable temperature 19F NMR spectra have been chiral after its coordination to the gold(III) atom.
measured (Fig. 2), showing that the signals decoalesced near ꢀ
15 ºC. At ꢀ73 ºC appeared four multiplets for the ortho and
meta fluorines, which are partially overlapped, and two pseudoꢀ
triplets for the para fluorines. This spectrum corresponds to two
different pentafluorophenyl groups that do not rotate at this
temperature.
A
-125.0
-130.0
-135.0
-140.0
-145.0
-150.0
-155.0
-160.0
ppm (t1)
B
Figure 3 Diagram of the cation of complex
Hydrogen atoms (except NH) are omitted for clarity. Selected bond lengths [Å]
and angles [deg] for complex : Au(1)-C(11) 2.006(4); Au(1)-C(1) 2.018(4) ;
1 with 50% probability ellipsoids.
1
-130
-140
-150
-160
ppm (t1)
Au(1)-N(1) 2.073(4); Au(1)-N(2) 2.115(4); C(11)-Au(1)-C(1) 86.47(1); C(11)-Au(1)-
N(1) 95.53(15); C(1)-Au(1)-N(2) 97.94(15); N(1)-Au(1)-N(2) 80.11(14).
C
-130
-140
-150
-160
ppm (t1)
The reaction of [Au(C6F5)2(DPA)]ClO4
equimolecular amount of the corresponding isocyanide CNR (R
= 2ꢀnaphthyl, cyclohexyl, 2,6ꢀdimethylphenyl) gives complexes
(1) with an
D
2−4, respectively, in which the nucleophilic attack of the amine
-130
-140
-150
-160
coordinated to the gold(III) centre to the isocyanide produces
the formation of unprecedented bidentate N^C acyclic carbenes
(Scheme 3). They have been characterized by means of IR,
elemental analysis, NMR spectroscopy, and mass spectrometry.
ppm (t1)
Figure 2 19F NMR (CD3)2CO spectra of complex
1. A: 298 K, B: 258 K, C: 238 K, D:
200 K.
1
Assignments of the H NMR and 13C NMR signals were made
2
1
on the basis of D COSY and HSQC spectra. The H NMR
spectra of complexes show the resonances assigned to the
protons of the diꢀ(2ꢀpicolyl)amine ligands (protons named H
and H’ in Scheme 3) and the signals characteristic of the
isocyanide group (H’’). Two different diastereotopic methylene
The structure of complex
1 in solid state was solved by Xꢀ
ray diffraction spectroscopy showing that the amine nitrogen
atom and one pyridine nitrogen atom are coordinated to the
gold(III) centre, in a slightly distorted squareꢀplanar geometry
(Fig. 3). Complex
1 crystallizes in the monoclinic P2(1)/c space
protons were observed as two “AB” quartets (in
2 and 3) or
group. Mean deviation from the plane formed by the four
donor atoms of the gold centre is 0.0381 Å (N1, N2, C1, C11).
The distance between the other pyridine nitrogen and the gold
atom is 2.888 Å, too long to be considered a bond but enough
short to explain the fluxional behaviour observed in solution.
This distance, shorter than the sum of the van der Waals radii of
gold and nitrogen atoms (3.21 Å), suggests some secondary
bonding interaction. As can be seen in Fig. 3, the nitrogen atom
of the nonꢀcoordinated pyridine (N3) seems to be located in
direction of the gold atom, ready for bonding. This might
explain the fluxional behaviour observed in solution.
multiplets (in ). In these spectra is possible to observe that the
4
complexes do not show any fluxional behaviour in solution,
probably because the coordination of the Nꢀacyclic ligand with
a delocalised NCN unit makes the rotation more hindered. The
19F NMR spectra of
2, 3 and 4 show two different para
fluorines accordingly with two different C6F5 groups, and for
each one two different ortho and meta fluorines (in a 1:1 ratio).
This indicates that the pentafluorophenyl rings cannot rotate at
room temperature. In the ESI+ mass spectra the fragments [M –
ClO4]+ of
861 (100), respectively.
2, 3 and 4 appear at m/z (%) = 883 (100), 839 (100),
Considering the second nitrogen atom
a
pseudoꢀfiveꢀ
coordinated geometry is observed around the gold centre.
Although not many examples of pseudoꢀfiveꢀcoordinate
gold(III) complexes are known,54 some of them have been
recently published.55,56 An interesting feature of solid complex
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

Dalton Transactions
Page 4 of 12
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C5DT00703H
complex
1
and in other complexes with pentafluorophenyl rings
5
4
trans to Nꢀligands.57
ClO4
ClO4
6
3
2
R
Au
R
N
N
R
R
N
C
C
N
R'
Au
N
H
DCM/Acet
H
HN
R'
2'
N
3'
4'
N
R = C6F5
6'
5'
2''
7''
3''
6''
1''
1''
3''
H3C
CH3
2''
3''
4''
5''
2''
1''
R' =
2''
3'' 4''
2''
8''
3''
4''
2
3
4
Scheme 3 Synthesis of complexes 2ꢀ4.
Figure 5 Diagram of the cation of 3 with 50% probability ellipsoids. Hydrogen
atoms (except NH) are omitted for clarity. Selected bond lengths [A] and angles
[deg] for complex : Au(1)-C(11) 2.017(3); Au(1)-C(1) 2.067(3); Au(1)-C(37)
The crystal structures of complexes
2
, 3 and 4 have been
3
2.084(3); Au(1)-N(3) 2.091(2); N(1)-C(37) 1.339(3); N(2)-C(37) 1.323(3); C(11)-
Au(1)-C(1) 86.85(10); C(11)-Au(1)-C(37) 93.06(10); C(1)-Au(1)-N(3) 94.91(10);
C(37)-Au(1)-N(3) 84.99(10); N(2)-C(37)-N(1) 120.5(2); N(2)-C(37)-Au(1)
124.59(19); N(1)-C(37)-Au(1) 114.89(18).
determined by Xꢀray diffraction studies. All of them
crystallised in the triclinic space group Pꢀ1 with one molecule
in the asymmetric unit (Fig. 4, 5 and 6). The gold atoms in
these
complexes
show
a
distorted
squareꢀplanar
AuCcarbeneNpyC2pentafluorophenyl coordination. Mean deviations
from the planes formed by the four donor atoms of the gold
The sixꢀmembered AuC3N2 chelate ring adopts in all of them a
boat conformation as can be seen in Fig. 6 for the complex 4,
centres are 0.0525 Å (C37, N1, C1, C11) (
2
), 0.0512 Å (C37,
).
with the Au atom and the methylene carbon lying to the same
side of the plane of the other four atoms, C2N2, which are
almost coplanar.
N3, C1, C11) ( ), and 0.0684 Å (C49, N1, C1, C11) (
3
4
Figure 6 Diagram of the cation of complex
Hydrogen atoms (except NH) are omitted for clarity. Selected bond lengths [A]
and angles [deg] for complex : Au(1)-C(11) 2.012(3); Au(1)-C(1) 2.066(4); Au(1)-
4 with 50% probability ellipsoids.
Figure 4 Diagram of the cation of
atoms (except NH) are omitted for clarity. Selected bond lengths [A] and angles
[deg] for complex Au(1)-C(1) 2.030(7); Au(1)-C(11) 2.059(8); Au(1)-C(37)
2 with 50% probability ellipsoids. Hydrogen
4
2:
C(49) 2.070(3); Au(1)-N(1) 2.094(3); N(2)-C(49) 1.333(4); N(3)-C(49) 1.323(4);
C(11)-Au(1)-C(1) 88.64(13); C(11)-Au(1)-C(49) 92.13(13); C(1)-Au(1)-N(1)
93.59(12); C(49)-Au(1)-N(1) 85.27(12); N(3)-C(49)-N(2) 120.5(3); N(3)-C(49)-
Au(1) 125.5(3); N(2)-C(49)-Au(1) 114.4(2). Boat conformation of the metallacycle
2.066(7); Au(1)-N(1) 2.094(6); N(2)-C(37) 1.324(9); C(37)-N(4) 1.332(9); C(1)-
Au(1)-C(11) 88.9(3); C(1)-Au(1)-C(37) 91.5(3); C(11)-Au(1)-N(1) 92.5(3); C(37)-
Au(1)-N(1) 87.1(3); N(2)-C(37)-N(4) 119.5(7); N(2)-C(37)-Au(1) 116.3(5); N(4)-
C(37)-Au(1) 124.1(5).
in complex 4.
The angles around the gold(III) atoms range from 84.99(10)º to
94.91(10)º. The smallest one in each compound corresponds to
the CcarbeneꢀAuꢀNpy angle. The Au(III)ꢀCpentaflourophenyl bond
distances range from 2.012(3) to 2.067(3) Å and the AuꢀN bond
distances from 2.091(2) to 2.094(3) Å. In each complex, the
longest AuꢀCpentafluorophenyl bond length corresponds to the
distance trans to the Au(III)ꢀCcarbene bond, in agreement with
the high trans influence of the carbene group compared with Nꢀ
ligands. The other AuꢀCpentafluorophenyl is similar to that found in
Cytotoxic activity
In the last years a number of gold(III) compounds that are
highly cytotoxic towards cancer cells have been discovered.1ꢀ7
Among the families of gold(III) complexes that are stable under
physiologicalꢀlike
antiproliferative properties in vitro, are gold dithiocarbamates,6
gold porphyrins,4,58 gold bypridines59 and
variety of
conditions
and
have
significant
a
organogold compounds mainly derived from cyclometallated
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 12
Journal Name
Dalton Transactions
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5DT00703H
derivatives.60,61 These compounds are not only strongly complex
1
is the less active of these complexes. However, the
cytotoxic, but they are also able to overcome cisplatin compounds with the Nꢀacyclic carbenes exhibit good
resistance and they exert their antiproliferative activity through antiproliferative activities, with IC50 values ranging from 1.52
a broader scope of targets than the latter. Studies suggested that to 20.45
ꢀ
M in A549 cells, 0.79 to 4.55
ꢀM in Jurkat cells, and
heterogeneous molecular mechanisms are involved including 1.74 to 25
ꢀ
M in MiaPaca2. These values are very low if we
inhibition
of
cyclinꢀdependent
kinases
or
histone take into account that they are measured at 24 h and that very
deacetylases.62
tough cell lines (MiaPaca2 and A549) have been used. It is
Since our complexes are organogold amineꢀpyridine species remarkable that these values are much lower than the
or with bidentate chelate C^N ligands, which can be considered corresponding to cisplatin.
analogous to cyclometallated ligands, we envisaged the great
potential of these compounds for having antiproliferative these cell lines, but the examples reported by Messori et al for
activity. Consequently, the cytotoxic activity of complexes cyclometallated compounds in A549 cell lines gave values
was tested against three different human tumour cell lines: around 50 M after 72 h exposure to the drugs, or bypirine
There is not much data of the activity of gold(III) species in
1ꢀ4
ꢀ
Jurkat (Tꢀcell leukaemia), MiaPaca2 (pancreatic carcinoma) gold(III) derivatives studied also in A549 were negligible.
and A549 (lung carcinoma), compared to the results with These results show that our complexes present an outstanding
cisplatin.
Compounds
soluble in DMSO and in the DMSO/water mixtures used in the complex
activity in all the cell lines, but it is noteworthy that the values
1
ꢀ
4
are not soluble in water, but they are of 1.74
ꢀ
M for complex
2 in MiaPaca2 and 1.52 ꢀM for
4
in A549 are very promising in order to continue the
tests, which contain a small amount of DMSO. We did not evaluation and mechanism studies of these metalloꢀdrugs.
observe any precipitation of the complexes or metallic gold Several NMR experiments have been carried out in order to
while performing the tests. Moreover, no protonation of the understand how these complexes could behave in biological
pyridine unit is produced in these conditions, and only with media, and exert their cytotoxic activity. Addition of biological
addition of an excess of acetic acid, protonation takes place. molecules such as Lꢀcysteine or BSA (bovine serum albumin)
Their colourless D6ꢀDMSO solutions are very stable at room to complex
3 in a DMSOꢀd6/D2O mixture shows that
1
temperature, as shown in the H NMR spectra in which the interaction of these molecules with the gold(III) Nꢀacyclic
signals remain the same for weeks. Cells were exposed to carbenes occurs, probably by displacement of the pyridine
different concentrations of each compound for a total of 24 h. moiety by the sulfur atom of the cysteine fragment. This could
Using the colorimetric MTT viability assay,63 (MTT = 3ꢀ(4,5ꢀ indicate that the activity of these complexes could involve the
dimethylꢀthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyltetrazolium bromide), the interaction with relevant enzimes containing cysteine moieties.
IC50 values (final concentration < 0.5 % DMSO) were
Catalytic activity of complex 1
calculated from dose–response curves obtained by nonlinear
regression analysis. IC50 values are concentrations of a drug
required to inhibit tumour cell proliferation by 50%, compared
to the control cells treated with DMSO alone. The IC50 values
In this broad spectrum of properties and taking into account the
fluxional behaviour in solution observed for complex
1, we
envisioned the possibility of testing this structure as a
promising candidate for homogeneous catalysis. In this respect,
at least one of the four positions around gold atom would be
almost free and suitable to coordinate the substrates. It is
remarkable that the addition of an external coꢀcatalyst such as a
Ag salt is not necessary in this case. Over the last decade, gold
catalysis has undergone an impressive development and proof
of that is the increasing number of publications reported in this
area of reseach.64ꢀ70 Among the number of gold catalysed
reactions we decided to explore three different benchmark
reactions (Fig. 7).
for complexes 1ꢀ4 are collected in Table 1. Cytotoxicity values
of cisplatin (chemotherapeutic platinum clinically employed)
are tested too and used for comparison purposes.
Table 1. IC50 (ꢀM) (24 h) of complexes against Jurkat, MiaPaca2 and A549.
Compounds
Jurkat
MiaPaca2
A549
Cisplatina
10.8±1.2
9.09±1.2
0.79±0.7
4.55±0.9
1.26±0.6
114.2±9.1
>25
76.5±7.4
>25
(1)
(2)
(3)
(4)
1.74±0.8
9.11±1.0
25
17.51±1.7
20.45±1.8
1.52±0.8
a cisplatin was dissolved in H2O
As can be observed, all the complexes synthesised were
active against all the different tumour cell lines in low
concentrations (low micromolar range). The Jurkat cell line was
the most sensitive to our compounds, while A549 or MiaPaca2
showed more resistance to the complexes. The starting amine
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Dalton Transactions
Page 6 of 12
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5DT00703H
Scheme 5 Synthesis of propargylamines via three-component coupling reaction.
Interestingly, we were able to perform these reactions with only
1 mol% of catalyst
1 and it is also noteworthy that the
methodology was carried out in absence of solvent, an
interesting aspect from a sustainable point of view, without
inert atmosphere and in the presence of light, in contrast to
previous protocols.49 The reactions were controlled by 1H NMR
(CDCl3) and the crudes remained very clean without sideꢀ
products after 24 hours. The observed diastereoselection in 13
and 14 reveals that the chirality in the new formed sp3 carbon
centre depends on the αꢀsubstituents on the prolinol derivatives.
This process is a proof of fact of the versatility of our catalytic
complex.
Figure 7 Model reactions explored.
In order to explore the efficiency of our active candidate 1, we
firstly tested its activity in the appealing reaction for the phenol
synthesis from furan derivative showed in Scheme 4.
Catalytic activity of AuCl3 to produce a highly substituted
phenol without side products was first reported by Hashmi et
al 71ꢀ74 Our reaction was easily monitored by 1H NMR
5
6
.
spectroscopy in (CD3)2CO and in CDCl3 without special
conditions, being our catalyst tolerant to different reaction
media. Interestingly, no reduction to metallic gold was
observed during reaction and an almost complete conversion in
We also intended to explore the possibility of synthesizing
indolizines in a tandem reaction involving a multicomponent
approach (Scheme 6), in order to expand the spectrum of
reactivity and the potential of 1 78
.
Indolizines are a privileged
structural motif found in a variety of potent biological active
compounds and in variety of applications for drug
6
without sideꢀproducts has been observed after 24 or 72 h at
room temperature.
a
discovery.79 Goldꢀbased catalysts have been rare involved in
the synthesis of indolizines,80ꢀ83 and there is only one example
where the authors perform the synthesis following a tandem
multicomponent strategy.82 Due to the short background of this
reaction in gold catalysts together with the interesting
biological properties of indolizines, the development of new
efficient, general and ecoꢀfriendly protocols using benign
catalysts still remains a continuous demand. For such propose
we set out the exploration of the catalytic activity of our
Scheme 4 Synthesis of a phenol
6 from furan derivative 5.
Encouraged by this interesting result we examined another complex
appealing target reaction, such the formation of
propargylamines via A3ꢀcoupling reaction,75 in order to extend
our catalytic study. The core of these structures is present in
many nitrogenꢀcontaining natural products and drug molecules
and their synthesis are very interesting since they are versatile
synthetic intermediates. However, to the best of our knowledge
the use of catalytic amounts of goldꢀbased catalysts in this A3ꢀ
coupling procedure has been shortly developed.49,76 In addition,
multicomponent processes are of great interest from atom
1 in the model reaction depicted in Scheme 6.
Scheme 6 Synthesis of indolizines via three-component coupling reaction.
economy point of view allowing the generations of compound
libraries and their development have been focused of an
increasing interest over the years.77 For few representative
examples of this reaction we have synthesised the structures 12-
The reactions were conducted by heating
1 (0.05 mmol), 2ꢀ
pyridinaldehyde (0.50 mmol), amine 16 or 17 (0.55 mmol), and
phenylacetylene 11 (0.6 mmol) in absence of solvent, without
inert atmosphere at 60 °C for 3 h. We were pleased to find that
the catalyst also promoted this process with excellent results
14 illustrated in Scheme 5 using different amines 8-10
.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 12
Journal Name
Dalton Transactions
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5DT00703H
(>99). The final crudes were very clean and the final products available. Solvents were used as received without purification
are almost pure. With these results in hand and with the or drying.
continuous concern about sustainable chemistry we focused our Caution: perchlorate salts with organic cations might be
efforts in decreasing the amount of catalyst without impairing explosive.
the yield of the process (Scheme 7), since efforts are pushed in
decreasing the amount of gold catalysts.
Synthesis of the Complex 1. Diꢀ(2ꢀpicolyl)amine (0.0598 g,
0.3 mmol, ρ = 1.107 g/mL) was added to a freshly prepared
solution of [Au(C6F5)2(OEt2)2]ClO4 (0.2336 g, 0.3 mmol) in
diethyl ether (20 mL), and the mixture was stirring for 3h.
Complex
1 precipitated as beige solid and was filtered off.
Yield: 0.2399 g (96 %). Anal. Calcd for C24H13AuClF10N3O4
(829.78): C 34.74, H 1.58, N 5.06. Found: C 34.56, H 1.93, N
4.86. IR: (NH): 3150; (C6F5): 1508, 969; (cisꢀC6F5): 818, 807;
1
(ClO4): 1072, 622 cm−1. H NMR (400 MHz, (CD3)2CO): δ
3
8.53 (m, 2H, 6ꢀH, 6’ꢀH), 8.13 (td, JHH = 7.8 Hz, 4JHH = 1.5 Hz,
2H, 4ꢀH, 4’ꢀH), 7.85 (m, 1H, NH), 7.74 (m, 2H, 3ꢀH, 3’ꢀH),
2
7.56 (m, 2H, 5ꢀH, 5’ꢀH), 5.16, 5.10 (2d, AB system, 4H, JAB
=
Scheme 7 Study of the efficiency of catalyst 1.
1
17.2 Hz, CH2) ppm. H NMR (300 MHz, (CD3)2CO, 200K)
δ
:
8.57 (m, 2H, 6ꢀH, 6’ꢀH), 8.06 (m, 2H, 4ꢀH, 4’ꢀH), 7.78 (m, 2H,
3ꢀH, 3’ꢀH), 7.41 (m, 2H, 5ꢀH, 5’ꢀH), 5.59, 5.15 (2d, AB system,
Complex
since this is not observed in solution for the Nꢀacyclic carbene
complexes . However, they could also act as catalysts if
displacement of the pyridine group takes place. In normal
conditions, at r.t., reaction with nucleophiles such as PPh3 or
1 is the best candidate as catalyst for its hemilability,
2
2JAB = 14.5 Hz, 2H, CH2), 5.02, 4.61 (2d, AB system, JAB
=
2ꢀ4
16.9 Hz, 2H, CH2) ppm. 19F NMR (400 MHz, (CD3)2CO): δ ꢀ
123.3 (d, JoꢀF, mꢀF = 21.3 Hz, 4F, oꢀF), ꢀ156.4 (t, JpꢀF, mꢀF = 19.4
Hz, 2F, pꢀF), ꢀ162.0 (m, 4F, mꢀF) ppm. 19F NMR (300 MHz,
3
3
PhC≡CH does not occur, but complex
in the synthesis of indolizines at 60 ºC, although with lower
yield compared to complex
3 shows catalytic activity
(CD3)2CO, 200K) δ: ꢀ123.1 (m, 2F, oꢀF); ꢀ123.9 (m, 1F, oꢀF), ꢀ
125.1 (m, 1F, oꢀForto), ꢀ156.2 (“t”, 3JpꢀF,mꢀF = 17.7 Hz, 1F, pꢀF), ꢀ
1
.
3
156.5 (“t”, JpꢀF,mꢀF = 20.8 Hz, 1F, pꢀF), ꢀ160.8 (m, 1F, mꢀF), ꢀ
In spite of the great progress achieved in homogeneous gold
catalysis, in many cases the catalytic charge of gold is higher
than 1 mol% and normally the use of an additional Ag salt is
necessary. This necessity opens the possibility of developing
new more active structures. In our case, we explored the
reactivity with different catalytic charges and excellent results
were reached even at 0.1 mol% and at 0.05 mol% although with
longer reaction times. This also demonstrates the stability of
our catalyst since we do not appreciate decomposition in the
reaction crude and we are convinced that the reaction could
finish with longer reaction times.
161.6 (m, 2F, mꢀF), ꢀ162.1 (m, 1F, mꢀF) ppm. 13C{1H} NMR
(300 MHz, (CD3)2CO): δ 158.4 (s, 2C, 2ꢀC, 2’ꢀC), 148.4 (s, 2C,
6ꢀC, 6’ꢀC), 140.4 (s, 2C, 4ꢀC, 4’ꢀC), 124.8 (s, 2C, 5ꢀC, 5’ꢀC),
123.5 (s, 2C, 3ꢀC, 3’ꢀC), 58.5 (s, 2C, CH2) ppm. MS (ESI+):
m/z (%) 730 (100) [M – ClO4]+.
General Procedure of the Synthesis of the Complexes 2-4. A
mixture of CNꢀnaphthnaphthylyl (0.0306 g, 0.2 mmol), CNꢀ
cyclohexyl (0.0218 g, 0.2 mmol), or CNꢀxylyl (0.0262 g, 0.2
mmol) and complex
1 (0.1660 g, 0.2 mmol) in a mixture
dichloromethane/acetone (20 mL/5 mL), was stirred at room
temperature. After stirring during 24 h, the solution was filtered
over Celite. The volume was reduced to 5 mL, and addition of
nꢀhexane for
afforded as a brown solid,
pink solid, which were finally filtered.
2
and
3
) or nꢀhexane/diethyl ether (1:1) for
4
Experimental
2
3
as a beige solid or as a pale
4
General Measurements and Analysis Instrumentation
Complex 2. Yield: 0.0590 g (30 %). Anal. Calcd for
C35H20AuClF10N4O4 (982.96): C 42.77, H 2.05, N 5.70. Found:
C 42.98, H 1.76, N 5.64. IR: (NH): 3049; (C=N): 1592; (C6F5):
C, H, and N analysis were carried out with a PERKINꢀELMER
2400 microanalyzer. Mass spectra were recorded on a VG
1
Autospec, with the ESI technique. H, 13C{H} and 19F NMR,
1
2
1509, 967; (cisꢀC6F5): 812, 796; (ClO4): 1065, 622 cm−1. H
including D experiments, were recorded at room temperature
NMR (400 MHz, (CD3)2CO)): δ 9.12 (m, 1H, 6ꢀH), 8.64 (m,
on a BRUKER AVANCE 400 spectrometer (1H, 400 MHz, 13C,
100.6 MHz) or at low temperature on a BRUKER AVANCE II
300 spectrometer (1H, 300 MHz, 13C, 75.5 MHz), with
chemical shifts (δ, ppm) reported relative to the solvent peaks
of the deuterated solvents.84
3
4
1H, 6’ꢀH), 8.46 (td, JH−H = 7.7 Hz, JH−H = 1.5 Hz, 1H, 4ꢀH),
8.25 (m, 1H, 3ꢀH), 7.98 (m, 4H, 4’ꢀH, 5ꢀH, naphthyl), 7.85 (m,
2H, naphtyl), 7.77 (m, 1H, 3’ꢀH), 7.60 (m, 2H, naphthyl), 7.48
(m, 1H, 5’ꢀH), 7.15 (m, 1H, naphthyl), 5.70, 5.63 (2d, AB
2
system, JAB = 16.0 Hz, 2H, CH2), 5.45, 5.35 (2d, AB system,
Materials and Procedures
2JAB = 15.9 Hz, 2H, CH2) ppm. 19F NMR (300 MHz,
(CD3)2CO): δ ꢀ119.7 (m, 1F, oꢀF), ꢀ122.6 (d, 3JoꢀF, mꢀF = 25.6 Hz,
1F, oꢀF), ꢀ122.9 (m, 1F, oꢀF), ꢀ124.1 (m, 1F, oꢀF), ꢀ157.8 (t, 3Jpꢀ
The starting material [Au(C6F5)2(OEt2)2]ClO4 was prepared by
published procedure.85 All other reagents were commercially
3
F, mꢀF = 23.2, 1F, pꢀF), ꢀ158.3 (t, JpꢀF, mꢀF = 18.4 Hz, 1F, pꢀF), ꢀ
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

Dalton Transactions
Page 8 of 12
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5DT00703H
161.6 (m, 1F, mꢀF), ꢀ162.8 (m, 1F, mꢀF), ꢀ163.7 (m, 1F, mꢀF), ꢀ (m, 1C, CH2), 18.6 (m, 1C, CH3), 18.1 (m, 1C, CH3) ppm. MS
164.2 (m, 1F, mꢀF) ppm. 13C{1H} NMR (300 MHz, (ESI+): m/z (%) 861 (100) [M – ClO4]+.
(CD3)2CO): δ 155.1 (s, 1C, 2ꢀC), 153.6 (s, 1C, 2’ꢀC), 152.8 (m,
1C, 6ꢀC), 150.1 (s, 1C, 6’ꢀC), 144.6 (s, 1C, 4ꢀC), 139.1 (s, 1C), Cell culture
134.8 (s, 1C, naphthyl), 133.0 (s, 1C, naphthyl), 130.7 (s, 1C,
naphthyl), 128.9 (s, 1C), 128.6 (s, 1C), 128.2 (s, 1C), 127.4 (s, Jurkat (leukaemia) and MiaPaca2 (pancreatic carcinoma) cell
1C, naphthyl), 124.7 (s, 1C, 5’ꢀC), 124.5 (s, 1C, 3’ꢀC), 122.7 lines were maintained in RPMI 1640, while A549 (lung
(m, 1C, naphthyl), 122.4 (s, 1C, naphthyl), 61.9 (m, 1C, CH2), carcinoma) were grown in DMEM (Dulbecco´s Modified
59.1 (m, 1C, CH2) ppm. MS (ESI+): m/z (%) 883 (100) [M – Eagle´s Medium). Both media were supplemented with 5%
ClO4]+.
Complex 3. Yield: 0.1133 g (60 %). Anal. Calcd for streptomycin and 2 mM Lꢀglutamine. Medium for A549 cells
C31H24AuClF10N4O4 (938.95): C 39.65, H 2.58, N 5.97. Found: was also supplemented with 2.2 g/l Na2CO3, 100 g/ml
fetal bovine serum (FBS), 200 U/ml penicillin, 100 ꢀg/ml
ꢀ
C 39.61, H 2.82, N 5.75. IR: (NH): 3257; (C=N): 1591; (C6F5): piruvate and 5 ml nonꢀessential amino acids (Invitrogen).
1
1508, 961; (cisꢀC6F5): 813, 799; (ClO4): 1065, 621 cm−1. H Cultures were maintained in a humidified atmosphere of 95%
NMR (300 MHz, (CD3)2CO)): δ 9.40 (bs, 1H, NHcy), 8.83 (d, air/5% CO2 at 37 ºC.
3
3JHꢀH = 5.5 Hz, 1H, 6ꢀH), 8.31 (m, 2H, 4ꢀH, 6’ꢀH), 8.01 (d, JHH
= 7.5 Hz, 1H, 3ꢀH), 7.86 (m, 2H, 4’ꢀH, 5ꢀH), 7.63 (m, 1H, 3’ꢀ Cytotoxicity assay by MTT
2
H), 7.33 (m, 1H, 5’ꢀH), 5.71, 5.44 (2d, AB system, JAB = 15.8
2
Hz, 2H, CH2), 5.33, 5.09 (2d, AB system, JAB = 16.4 Hz, 2H, The MTT assay was used to determine cell viability as an
CH2), 3.75 (m, 1H, CHCy), 1.85ꢀ0.76 (m, 10H, Cy) ppm. 19F indicator for cells sensitivity to the complexes. Exponentially
NMR (300 MHz, (CD3)2CO): δ ꢀ121.4 (m, 1F, oꢀF), δ ꢀ123.3 growing cells were seeded at a density of approximately 1x105
(m, 2F, oꢀF), δ ꢀ124.9 (m, 1F, oꢀF), ꢀ156.5 (m, 1F, pꢀF), ꢀ158.2 cells/ml (A549, MiaPaca2) or 3x105 cells/ml (Jurkat), in a 96ꢀ
(m, 1F, pꢀF), ꢀ161.9 (m, 4F, mꢀF) ppm. 13C{1H} NMR (300 well flatꢀbottomed microplate and 24 h later they were
MHz, (CD3)2CO): δ 152.5 (s, 1C, Cꢀ6), 149.7, 144.4 (2s, 2C, Cꢀ incubated for 24 h with the compounds. The complexes were
4, Cꢀ6’), 138.7 (s, 1C), 128.5 (m, 2C), 124.5, 124.2 (2s, 2C, Cꢀ dissolved in DMSO and tested in concentrations ranging from
3’, Cꢀ5’), 61.7 (m, 1C, CH2), 60.8 (m, 1C, CHCy), 58.3 (s, 1C, 0.5 to 25
CH2), 34.8 (s, Cy), 33.2 (s, Cy), 25.7 (s, Cy), 25.4 (m, Cy) ppm. our compounds for 24 h at 37 ºC. 10
MS (ESI+): m/z (%) 839 (100) [M – ClO4]+.
added and plates were incubated for 1ꢀ3 h at 37 ºC. Finally, 100
ꢀ
M and in quadruplicate. Cells were incubated with
ꢀ
l of MTT (5 mg/ml) was
i
Complex 4. Yield: 0.1042 g (54 %). Anal. Calcd for µl/well PrOH (0.05 M HCl) was added. The optical density
C33H22AuClF10N4O4 (960.96): C 41.25, H 2.31, N 5.83. Found: was measured at 490 nm using a 96ꢀwell multiscanner
C 41.12, H 2.16, N 5.46. IR: (NH): 3050; (C=N): 1586; (C6F5): autoreader (ELISA). The IC50 was calculated by nonꢀlinear
1
1505, 954; (cisꢀC6F5): 810, 791; (ClO4): 1071, 622 cm−1. H regression analysis using Origin software (Origin Software,
3
NMR (300 MHz, (CD3)2CO)): δ 8.92 (d, JHH = 5.6 Hz, 1H, 6ꢀ Electronic Arts, Redwood City, California, USA).
3
H), 8.37 (m, 2H, 4ꢀH, 6’ꢀH), 8.08 (d, JHH = 7.5 Hz, 1H, 3ꢀH),
7.93 (m, 2H, 4’ꢀH, 5ꢀH), 7.74 (d, 3JHH = 7.8 Hz, 1H, 3’ꢀH), 7.38 Crystal Structure Determinations
(m, 1H, 5’ꢀH), 7.29 (m, 1H, 3’’ꢀH), 7.15 (m, 1H, 3’’ꢀH), 6.85
(m, 1H, 4’’ꢀH), 5.75 y 5.58 (2m, AB system, 2H, CH2), 5.58 Crystals were mounted in inert oil on glass fibers and
and 5.37 (2m, AB system, 2H, CH2), 2.46 (s, 3H, CH3), 1.82 transferred to the cold gas stream of an APEX SMART
(m, 3H, CH3) ppm. 19F NMR (400 MHz, (CD3)2CO): δ ꢀ120.1 diffractometer equipped with a lowꢀtemperature attachment.
(m, 1F, oꢀF), ꢀ124.4 (m, 2F, oꢀF), ꢀ125.6 (m, 1F, oꢀF), ꢀ158.6 Data were collected using monochromated Mo K
α radiation
(m, 1F, pꢀF), ꢀ159.1 (m, 1F, pꢀF), ꢀ162.6 (m, 1F, mꢀF), ꢀ 163.6 = 0.71073 Å). Scan type . Absorption correction based on
(
λ
ω
(m, 2F, mꢀF), ꢀ164.7 (m, 1F, mꢀF) ppm. 13C{1H} NMR (300 multiple scans were applied with the program SADABS. The
MHz, (CD3)2CO)): δ 151.9 (m, 1C, 6ꢀC), 149.9 (s, 1C, 6’ꢀC), structures were solved by direct methods and refined on F2
144.5 (s, 1C, 4ꢀC), 138.8 (s, 1C, 4’ꢀC), 130.9 (m, 2C, 3’’ꢀC), using the program SHELXLꢀ97.86 Hydrogen atoms were
129.1 (s, 1C, 5ꢀC), 128.8 (m, 1C, 3ꢀC), 128.4 (m, 1C, 4’’ꢀC), included using a riding model. Further details of the data
124.6 y 124.5 (2m, 2C, 3’ꢀC, 5’ꢀC), 59.4 (m, 1C, CH2), 58.3 collection and refinement are shown in Table 2. CCDC
1039443ꢀ1039446.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 12
Journal Name
Dalton Transactions
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5DT00703H
Table 2 Details of Data Collection and Structure Refinement for Complexes 1 – 4.
Compound
Chemical Formula
Cryst habit
Cryst size/ mm
Cryst system
Space group
a /Å
1
C24H13AuClF10N3O4
Colorless prism
0.24x 0.16 x 0.06
Monoclinic
P21/c
2·(CH3)2CO
C38H26AuClF10N4O5
Colorless prism
0.24 x 0.10 x 0.08
Triclinic
Pꢀ1
3·(CH3)2CO
C34H30AuClF10N4O5
Colorless rhomboid prism
0.16 x 0.16x 0.16
Triclinic
Pꢀ1
4·(CH3)2CO
C36H28AuClF10N4O5
Colorless tablet
0.16 x 0.08 x 0.08
Triclinic
Pꢀ1
15.629(2)
9.8536(15)
16.354(2)
ꢀ
8.1961(16)
11.368(2)
20.475(4)
97.15(3)
101.31(3)
101.21(3)
1808.6(6)
2
10.010(2)
13.750(3)
13.960(3)
84.66(3)
70.66(3)
79.31(3)
1780.5(7)
2
10.500(2)
13.507(3)
13.812(3)
80.76(3)
69.01(3)
77.33(3)
1777.1(6)
2
b /Å
c /Å
α
/deg
β
γ
/ deg
101.680(2)
ꢀ
/deg
3
U /Å
2466.4(6)
4
Z
-3
D /Mg m
2.235
1.912
1.860
1.904
c
M
829.79
1041.04
1016
997.04
1019.04
996
F(000)
T /°C
1584
976
ꢀ100(2)
60
ꢀ100(2)
ꢀ100(2)
ꢀ100(2)
60
2θ
/ °
60
60
max
-1
ꢀ(Mo-Kα)/mm
6.190
4.245
4.307
4.318
Transmission
0.7077ꢀ0.3181
19320
0.7276ꢀ0.4290
12983
0.5457ꢀ0.5457
14758
0.7239ꢀ0.5450
10778
no. of reflns measd
no. of unique refns.
Rint
4838
6962
6936
5973
0.0339
0.0403
0.0153
0.0183
R (F>4
σ
(F))
0.0236
0.0515
0.0199
0.0224
Rw (F2, all refl.)
No. of reflns used
No. of params
No. of restraints
S
0.0560
0.1178
0.0500
0.0538
4838
6962
6936
5973
388
534
478
498
8
102
0
0
1.110
1.099
1.037
1.037
max./min ∆ρ / eÅꢀ3
0.826/ꢀ0.850
2.419/ꢀ3.532
1.364/ꢀ0.597
1.001/ꢀ0.524
General procedure for Au-catalyzed synthesis of phenol General procedure for Au-catalyzed three-component
derivative 6.
synthesis of indolizines 18 and 19 under solvent-free
conditions.
Gold complex
1 (0.83 mg, 0.001 mmol) and furan 5 (30.3 mg,
0.1 mmol) are solved in CDCl3 (0.5 ml) in a test tube. The A mixture of gold complex
1 (4.1 mg, 0.005 mmol), pyridineꢀ2ꢀ
resulting mixture was stirred at room temperature until the carboxaldehyde 15 (48 ꢁl, 0.5 mmol) and amine 16 or 17 (1.1
reaction was completed as monitored by thinꢀlayer mmol), phenylacetylene 11 (67 ꢁl, 1.2 mmol) was added
chromatography. The yield of the reaction is given by 1H NMR. successively at 60 ºC. The resulting mixture was stirred at 60 ºC
until the reaction was completed as monitored by thinꢀlayer
1
General procedure for Au-catalyzed three-component chromatography. The yield of the reaction is given by H NMR
synthesis of propargylamines 12-14.
using dimethylfumarate as internal standard.
A mixture of gold complex
1 (4.1 mg, 0.005 mmol),
benzaldehyde (51 ꢁl, 0.5 mmol), amine 8-10 (0.55 mmol),
7
Conclusions
phenylacetylene 11 (84 ꢁl, 0.75 mmol) was added under
solventꢀfree conditions. The resulting reaction mixture was
stirred at 40 ºC for 24 h. The d.r. and the yields of the reaction
are given by 1H NMR using dimethylfumarate as internal
standard.
A new fluxional amine gold(III) complex has been synthesised
and characterised. Interestingly, its dynamic behaviour in
solution has been studied and, in solid state, the molecule is
chiral with an asymmetric quaternary amine nitrogen
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

Dalton Transactions
Page 10 of 12
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5DT00703H
coordinated to gold(III). Reactions of this complex with
isocyanides led unprecedented bidentate C^N gold(III) acyclic
carbene derivatives. Antitumor properties of these complexes
have been tested in vitro against three tumour human cell lines,
Jurkat (Tꢀcell leukaemia), MiaPaca2 (pancreatic carcinoma)
and A549 (lung carcinoma), showing excellent cytotoxic
activity in very tough cell lines such as MiaPaca2 and A549,
compared with cisplatin and with other gold(III) derivatives.
Taking advantage of the fluxional behaviour of the amine
complex, its catalytic properties have been tested in several
model reactions with formation of CꢀC and CꢀN bonds. The
4
JꢀJ. Zhang, R. W.ꢀY. Sun and C.ꢀM. Che, Chem. Commun., 2012, 48
3388–3390.
,
5
6
B. Bertrand and A. Casini, Dalton Trans., 2014, 43, 4209ꢀ4219.
L. Ronconi, C. Marzano, P. Zanello, M. Corsini, G. Miolo, C. Macca,
A. Trevisan and D. Fregona, J. Med. Chem., 2006, 49, 1648ꢀ1657.
7
8
9
J.ꢀJ. Zhang, W. Lu, R. W.ꢀY. Sun and C.ꢀM. Che, Angew. Chem. Int.
Ed., 2012, 51, 4882ꢀ4886.
V. WꢀW. Yam and E. C.ꢀC. Cheng, Top. Curr. Chem., 2007, 281
,
,
269−309.
C. Bronner and O. S. Wenger, Dalton Trans., 2011, 40
12409−12420.
complex showed excellent activity with total conversions, 10 V. K.ꢀM. Au, K. M.ꢀC. Wong, N. Zhu and V. WꢀW. Yam, Chem. Eur.
without the presence of a coꢀcatalyst, and with a low catalyst ., 2011, 17, 130 – 142.
J
loading. These results can be seen as new examples of the 11 M. E. Hanham, Gold Bull., 2011, 44, 43 − 47.
versatile behaviour of wellꢀdefined functionalised amine 12 N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994–2009.
gold(III) complexes. We believe that with these three 13 K. J. Kilpin, B. P. Jarman, W. Henderson and B. K. Nicholson, Appl.
benchmark examples we have demonstrated the strong capacity
Organometal. Chem., 2011, 25, 810–814.
of our complex to act as an efficient catalyst in a variety of 14 J. Wimberg, S. Meyer, S. Dechert and F. Meyer, Organometallics
,
different reactions. Additional catalytic studies are actually
ongoing in our laboratory and will be reported in due course.
In summary, a new type of gold(III) species with functionalised
2012, 31, 5025ꢀ5033.
15 H.ꢀM. Ko, K. K.ꢀY. Kung, J.ꢀF. Cui and M.ꢀK. Wong, Chem.
Commun. 2013, 49, 8869ꢀ8871.
amines are proposed as excellent synthons for the preparation 16 S. DíezꢀGonzalez, N. Marion and S. P. Nolan, Chem. Rev. 2009, 109
of novel gold(III) complexes with bidentate acyclic carbenes, 3612ꢀ3676.
which show excellent cytotoxic activity, and also as 17 S. P. Nolan, Acc. Chem. Res., 2011, 44, 91ꢀ100.
outstanding wellꢀdefined catalysts for several organic 18 L. Oehninger, R. Rubbiani and I. Ott, Dalton Trans., 2013, 42, 3269ꢀ
,
transformations, including the synthesis of products of
biological interest.
3284.
19 R. Visbal and M. C. Gimeno, Chem. Soc. Rev., 2014, 43, 3551ꢀ3574.
20 C. Bartolomé, Z. Ramiro, P. PérezꢀGalán, C. Bour, M. Raducan, A.
Acknowledgements
M. Echavarren and P. Espinet, Inorg. Chem., 2008, 47
,
11391−11397.
Authors thank the Ministerio de Economía y Competitividad
(MINECO/FEDER CTQ2013ꢀ48635ꢀC2ꢀ1ꢀP) and DGAꢀFSE
(E77) for financial support. We also acknowledged Dr. Isabel
Marzo for her help in the cell viability tests.
21 A. S. K. Hashmi, T. Hengst, C. Lothschütz and F. Rominger, Adv.
Synth. Catal., 2010, 352, 1315−1337.
22 C. Bartolomé, Z. Ramiro, D. GarcíaꢀCuadrado, P. PérezꢀGalán, M.
Raducan, C. Bour, A. M. Echavarren and P. Espinet,
Organometallics, 2010, 29, 951−956.
Notes and references
a
23 C. Bartolomé, D. GarcíaꢀCuadrado, Z. Ramiro and P. Espinet, Inorg.
Chem., 2010, 49, 9758−9764.
Departamento de Química Inorgánica, Instituto de Síntesis Química y
Catálisis Homogénea (ISQCH), Universidad de ZaragozaꢀCSIC, Eꢀ50009
Zaragoza, Spain. Eꢀmail: gimeno@unizar.es; Fax: +34 976761187; Tel:
+34 976762291 and dvilla@unizar.es; Tel: +34 976761183.
24 Y. M. Wang, C. N. Kuzniewski, V. Rauniyar, C. Hoong and F. D.
Toste, J. Am. Chem. Soc., 2011, 133, 12972−12975.
b
Departamento de Química Orgánica, Instituto de Síntesis Química y
Catálisis Homogénea (ISQCH), Universidad de ZaragozaꢀCSIC, Eꢀ50009
Zaragoza, Spain.
25 L. G. M. Slaughter, ACS Catal., 2012, 2, 1802ꢀ1816.
26 M. C. Blanco Jaimes, C. R. N. Böhling, J. M. SerranoꢀBecerra and A.
S. K. Hashmi, Angew. Chem. Int. Ed., 2013, 52, 7963ꢀ7966.
27 R. L. WhiteꢀMorris, M. M. Olmstead, F. Jiang, D. S. Tinti and A. L
Balch, J. Am. Chem. Soc., 2002, 124, 2327−2336.
†
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
28 D. Rios, M. M. Olmstead and A. L. Balch, Dalton Trans., 2008,
4157−4164.
29 C. Bartolomé, M. CarrascoꢀRando, S. Coco, C. Cordovilla, J. M.
MartínꢀAlvarez and P. Espinet, Inorg. Chem., 2008, 47, 1616−1624.
30 D. Rios, M. M. Olmstead and A. L. Balch, Inorg. Chem., 2009, 48
,
1
2
W. Henderson, Adv. Organomet. Chem., 2006, 54, 207−265.
5279−5287.
A. Casini, Ch. Hartinger, Ch. Gabbiani, E. Mini, P. J. Dyson, B. K.
Keppler and L. Messori, J. Inorg. Biochem., 2008, 102, 564−575.
C. Gabbiani, G. Mastrobuoni, F. Sorrentino, B. Dani, M. P.
Rigobello, A. Bindoli, M. A. Cinellu, G. Pieraccini, L. Messori and
31 G. Minghetti and F. Bonati, J. Organomet. Chem., 1973, 54
,
C62−C63.
3
32 G. Minghetti, F. Bonati and G. Banditelli, Inorg. Chem., 1976, 15
,
1718−1720.
A. Casini, Med. Chem. Commun., 2011, 2, 50−54.
33 R. Usón, A. Laguna, J. Vicente, J. García, B. Bergareche and P.
Brun, Inorg. Chim. Acta, 1978, 28, 237−243.
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 11 of 12
Journal Name
Dalton Transactions
View ArticAle ROnTliInCeLE
DOI: 10.1039/C5DT00703H
34 R. Usón, A. Laguna and M. D. Villacampa, Inorg. Chim. Acta, 1984, 59 A. Casini, M. C. Diawara, R. Scopelliti, S. M. Zakeeruddin, M.
81, 25−31. Grätzel and P. J. Dyson, Dalton Trans. 2010, 39, 2239ꢀ2245.
35 R. Usón, A. Laguna, M. D. Villacampa, P. G. Jones and G. M. 60 L. Messori, G. Marcon, M. A. Cinellu, M. Coronnello, E. Mini, C.
Sheldrick, J. Chem. Soc., Dalton Trans., 1984, 2035−2038. Gabbiani and P. Orioli, Bioorg. Med. Chem., 2004, 12, 6039ꢀ6043.
36 O. Crespo, M. C. Gimeno, A. Laguna, S. MontanelꢀPérez and M. D 61 M. Coronnello, E. Mini, B. Caciagli, M. A. Cinellu, A. Bindoli, C.
Villacampa, Organometallics, 2012, 31, 5520ꢀ5526.
37 A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180ꢀ3211.
38 A. S. K. Hashmi and G. J. Hutchings, Angew. Chem. Int. Ed., 2006,
45, 7896ꢀ7936.
Gabbiani and L. Messori, J. Med. Chem., 2005, 48, 6761ꢀ6765.
62 A. Casini, G. Kelter, C. Gabbiani, M. A. Cinellu, G. Minguetti, D.
Fregona, H. H. Fiebig and L. Messori, J. Biol. Inorg. Chem., 2009,
14, 1139ꢀ1149.
39 A. S. K. Hashmi, J. P. Weyrauch, M. Rudolph and E. Kuperjovic, 63 M. C. Alley, D. A. Scudiero, A. Monks, M. L. Hursey, M. J.
Angew. Chem. Int. Ed. Eng., 2004, 43, 6545ꢀ6547.
40 C. GonzálezꢀArellano, A. Corma, M. Iglesias and F. Sánchez, Chem.
Commun., 2005, 1990ꢀ1992.
Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo, R. H. Shoemaker
and M. R. Boyd, Cancer Res., 1988, 48, 589ꢀ601.
64 D. Garayalde and C. Nevado, Beilstein J. Org. Chem., 2011, 7, 767–
41 M. Paz
̌
780.
Rominger, C. Ja
̈
65 D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev., 2008, 108
,
Organometallics, 2010, 29, 4448−4458.
42 N. P. Mankad and F. D. Toste, J. Am. Chem. Soc., 2010, 132
12859−12861.
3351–3378.
,
66 A. Arcadi, Chem. Rev., 2008, 108, 3266–3325.
67 A. Corma, A. LeyvaꢀPérez and M. J. Sabater, Chem. Rev., 2011, 111
,
43 M. K. Samantaray, C. Dash, M. M. Shaikh, K. Pang, R. J. Butcher
and P. Ghosh, Inorg. Chem., 2011, 50, 1840−1848.
1657–1712.
68 E. JiménezꢀNúñez and A. M. Echavarren, Chem. Rev., 2008, 108
,
44 E. TomásꢀMendivil, P. Y. Toullec, J. Díez, S. Conejero, V. Michelet
and V. Cadierno, Org. Lett., 2012, 14, 2520−2523.
3326–3350.
69 M. C. Blanco, Catalysis in Modern Supramolecular Gold Chemistry:
gold-Metal Interactions and Applications, Ed. A. Laguna, Wileyꢀ
VCH Verlag, Weinheim, 2008, 429ꢀ494.
45 M. Muuronen, J. E. PereaꢀBuceta, M. Nieger, M. Patzschke and J.
Helaja, Organometallics, 2012, 31, 4320−4330.
46 P. OñaꢀBurgos, I. Fernández, L. Roces, L. Torre Fernández, S. 70 A. S. K. Hashmi and D. F. Toste, D. F. (Eds), Modern Gold
GarcíaꢀGranda and F. LópezꢀOrtiz, Organometallics, 2009, 28, 1739ꢀ
1747.
Catalysed Synthesis WyleyꢀVCH Verlag, Weinheim, 2009.
71 A. S. K. Hashmi, T. M. Frost and J. W. Bats, J. Am. Chem. Soc.,
2000, 122, 11553ꢀ11554.
47 K. K. Y. Kung, G. L. Li, L. Zou, H. C. Chong, Y. C. Leung, K. H.
Wong, V. K. Y. Lo, C. M. Che and M. K. Wong, Org. Biomol.
Chem., 2012, 10, 925ꢀ930.
72 A. S. K. Hashmi, T. M. Frost, J. W. Bats, Org. Lett. 2001, 3, 3769ꢀ
3771.
48 K. K. Y. Kung, V. K. Y. Lo, H. M. Ko, G. L. Li, P. Y. Chan, K. C.
Leung, Z. Zhou, M. Z. Wang, C. M. Che and M. K. Wong, Adv.
Synth. Catal., 2013, 355, 2055ꢀ2070.
73 S. Carrettin, M. C. Blanco, A. Corma, A. S. K. Hashmi, Adv. Synth.
Catal. 2006, 348, 1283ꢀ1288.
74 A. S. K. Hashmi, M. Rudolph, H.ꢀU. Siehl, M. Tanaka, J. W. Bats, W.
Frey, Chem. Eur. J. 2008, 14, 3703ꢀ3708.
49 V. K. Y. Lo, Y. G. Liu, M.ꢀK. Wong and C. M. Che, Org. Lett.
,
2006, , 1529ꢀ1532.
8
75 V. A. Peshkov, O. P. Pereshivko and E. V. Van der Eycken, Chem.
Soc. Rev., 2012, 41, 3790ꢀ3807.
50 R. Casado, M. Contel, M. Laguna, P. Romero and S. Sanz, J. Am.
Chem. Soc., 2003, 125, 11925ꢀ11935.
76 C. Wei and C.ꢀJ. Li, J. Am. Chem. Soc., 2003, 125, 9584ꢀ9585.
51 D. Aguilar, M. Contel, R. Navarro and E. P. Urriolabeitia, 77 J. Zhu and H. Bienaymé, Eds. Multicomponent Reactions, Wileyꢀ
Organometallics, 2007, 26, 4604ꢀ4611. VCH: Weinheim, 2005.
52 L. Cao, M. C. Jennings and R. J. Pudddephatt, Inorg. Chem., 2007, 78 Y. Liu, Y. Arkivoc, 2014, (
i), 1ꢀ20.
46, 1361ꢀ1368.
79 For a recent review, see: G. S. Singh and E. E. Mmatli, Eur. J. Med.
Chem., 2011, 46, 5237ꢀ5257.
53 A. P. Shaw, M. K. Ghosh, K. W. Törnroos, D. S. Wragg, M. Tilset,
O. Swang, R. H. Heyn and S. Jakobsen, Organometallics, 2012, 31
,
80 I. V. Seregin and V. Gevorgyan, J. Am. Chem. Soc., 2006, 128,
7093ꢀ7100.
12050ꢀ12051.
54 W. T. Robinson and E. Sinn, J. Chem. Soc. Dalton Trans., 1975, 726ꢀ 81 T. Schwier, A. W. Sromek, D. M. L. Yap, D. Chernyak and V.
731. Gevorgyan, J. Am. Chem. Soc., 2007, 129, 9868ꢀ9878.
55 Z. D. Hudson, C. D. Sanghvi, M. A. Rhine, J. J. Ng, S. D. Bunge, K. 82 B. Yan and Y. Liu, Org. Lett., 2007, , 4323ꢀ4326.
I. Hardcastle, M. R. Saadein, C. E. MacBeth and J. F. Eichler, Dalton 83 I. V. Seregin, A. W. Schammel and V. Gevorgyan, Tetrahedron
Trans., 2009, 7473ꢀ7480. 2008, 64, 6876ꢀ6883.
56 C. Topf, C. Hirtenlehner, M. Zabel, M. List, M. Fleck and U. 84 G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A.
9
,
Monkowius, Organometallics, 2011, 30, 2755–2764.
57 O. Crespo, M. C. Gimeno, P. G. Jones, A. Laguna, M. Naranjo and
M. D. Villacampa, Eur. J. Inorg. Chem., 2008, 5408ꢀ5417.
58 R. W. Y. Sun and C. M. Che., Coord. Chem. Rev., 2009, 253, 1682ꢀ
1691.
Nudelman, B. M. Stoltz, J. E. Bercaw and K. I. Goldberg,
Organometallics, 2010, 29, 2176ꢀ2179.
85 R. Usón, A. Laguna and M. L. Arrese, Synth. React. Inorg. Met-Org.
Chem., 1984, 14, 557ꢀ567.
86 G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112−122.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 11

Dalton Transactions
Page 12 of 12
View Article Online
DOI: 10.1039/C5DT00703H
104x49mm (300 x 300 DPI)