Gold(I)-Mediated Thiourea Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis

Article abstract of DOI:10.1002/cctc.201601527

Several group 11 metal complexes with chiral thiourea organocatalysts have been prepared and tested as organocatalysts. The promising results on the influence of metal-assisted thiourea organocatalysts in the asymmetric Friedel–Crafts alkylation of indole

Full text of DOI:10.1002/cctc.201601527

Accepted Article
Title: Gold(I) mediated thiourea organocatalyst activation: A synergic
effect for asymmetric catalysis
Authors: M. Concepción Gimeno, Raquel P. Herrera, and Anabel Izaga
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ChemCatChem
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FULL PAPER
Gold(I) mediated thiourea organocatalyst activation: A synergic
effect for asymmetric catalysis
[
a]
[b]
[a]
Anabel Izaga, Raquel P. Herrera,* and M. Concepción Gimeno*
Abstract: Several group 11 metal complexes with chiral thiourea
organocatalysts have been prepared and tested as organocatalysts.
The promising results on the influence of metal assisted thiourea
organocatalysts in the asymmetric Friedel–Crafts alkylation of indole
with nitrostyrene are described. Better results with the metal
complexes have been achieved because of the cooperative effects
between the chiral thiourea and the metal. The synergic effect
between both species is higher than the effect promoted by each
one separately, especially for gold(I). These outcomes are attributed
to a pioneering gold(I) activation of the thiourea catalysts, affording a
more acidic and rigid catalytic complex than that provided by the
thiourea alone. Furthermore, the use of the gold-thiourea
organocatalyst allows reducing the catalyst loading to 1-3 mol%.
This contribution could become an important starting point for further
investigations opening a new line of research overlooked so far in
the literature.
complex systems have inspired many catalytic systems such as
[
4]
chiral bifunctional thioureas/ureas, among others, which keep
simultaneous activation of the nucleophile and the electrophile
involved in the process (Figure 1).
CF
3
S
X
chiral
scaffold
F3C
N
H
N
H
Activation of
the electrophile
base
Activation of
H the nucleophile
Nu
R
H
Figure 1. Bifunctional activation mode.
Other strategy to improve the reactivity of the
organocatalysts, which has received considerable attention in
the last years, has been the use of two different catalysts in a
cooperative way, a metal catalyst and an organocatalyst, called
Introduction
In the last decade, between the two main families of catalysts:
metal and enzymatic catalysis, a third complementary approach
has emerged, the Organocatalysis, which has become an
important tool able to provide efficient and environmentally
friendly access to enantiomerically pure compounds, including
[5]
dual catalysis (Figure 2). This idea has emerged as a
[
1]
promising strategy for developing new and more valuable
processes, and also takes advantage of simultaneous activation
of the electrophile as well as the nucleophile by two different, but
compatible and synergically acting catalysts.
[
2]
many drugs and bioactive natural products.
Although the organocatalysis has experimented great
progress in the field of homogeneous catalysis, the
organocatalysts still require more improvements in order to
emulate and to reach the achievements reported with metal or
enzyme catalysts. With this aim, many efforts have been directed
towards the synthesis of more efficient organocatalysts through
the use of several strategies. One of them has been the
R
[M]
R
N
N
N
O
[
M]
[M]
H
H
H
H
R
R
R
R
[
3]
development of bifunctional organocatalysts, following the
multifunctional catalytic mode exhibited by enzymes. These
Figure 2. Activation by dual catalysis: combination of enamine nucleophiles
and transition metal electrophiles.
[
[
a]
b]
A. Izaga, Prof. M. C. Gimeno
The enormous success of chiral ureas and thioureas as
hydrogen bond donor organocatalysts in asymmetric synthesis
has led to a continuous improvement of these organocatalysts
through the use of several modes of activation, trying to improve
parameters such as catalysts loading, reaction time and
substrate scope for a given reaction. All these efforts made in
the last years have materialized in several upgraded catalysts.
Among them, Seidel and coworkers have reported the use of an
internal Brønsted acid forming a protonated thiourea catalyst
Departamento de Química Inorgánica.
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH),
CSIC-Universidad de Zaragoza.
C/ Pedro Cerbuna, Nº12, E-50009 Zaragoza, Spain
E-mail: gimeno@unizar.es
Dr. R. P. Herrera
Departamento de Química Orgánica. Laboratorio de Organocatálisis
Asimétrica
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH),
CSIC-Universidad de Zaragoza.
C/ Pedro Cerbuna, Nº12, E-50009 Zaragoza, Spain.
E-mail: raquelph@unizar.es
[6]
(
Figure 3a), although it was not the most active catalyst in this
work. Later, Smith’s group developed new conformationally well-
defined but flexible thiourea catalysts, stabilized by
Supporting information for this article is given via a link at the end of
the document.
[
7,8]
intramolecular hydrogen bonds (Figure 3b).
More recently,
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ChemCatChem
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Herrera and coworkers have described the use of an external
Brønsted acid (Figure 3c), in order to improve the efficiency of
the corresponding chiral thiourea catalysts.
complexes. However, this work represents the first example
where coordination to chiral thioureas strongly activates them as
organocatalysts.
[
9]
[
14]
CF3
CF
CF
3
3
CF3
AH
M
H
S
S
S
O
vs
vs
*R
*R
*R
R2
N
H
N
H
CF3
N
N
H
CF3
N
N
H
CF
3
H
H
N
H
N
H
thiourea
I
thiourea-HA
II
thiourea-Metal
III
H
O
S
N
S
*R
R*
Figure 4. Challenging idea.
N
N
H
R1
N
H
N
H
H
a) Seidel 2008
b) Smith 2009
In the context of our research program focused on the
design and synthesis of more active organocatalysts, we report
here an unprecedented mode of activation of thiourea
organocatalysts through the use of metallic Lewis acids. A wide
range of group 11 metal-thiourea complexes have been
synthesized and used as single catalysts in asymmetric catalysis,
taking advantages of the best part of both species in a synergic
way.
CF3
L L
AH
B
S
O
*R
R
N
N
CF3
N
H
N
H
H
H
c) Herrera 2011
d) Mattson 2012
Figure 3. Activation of thiourea organocatalysts through an internal or an
external Brønsted acid.
Results and Discussion
In order to test our hypothesis, we started our study with the
synthesis of a variety of group 11 metal complexes with
thioureas as potential catalysts for the Friedel-Crafts alkylation
reaction as a model process.
Thioureas T1-3 were chosen as model catalytic structures
since they exhibit different electronic and steric properties
The use of an internal Brønsted acid produced significant
rate acceleration and only
a
slight improvement in
[
6]
enantioselectivity for the Friedel–Crafts reaction. In contrast,
the external Brønsted acid was able to assist thiourea catalysts
as very effective catalytic species for promoting the
(
Figure 5). Moreover, T3 was the best catalyst in our previously
[
9]
enantioselective addition of indoles to nitroalkenes.
The
[9,15]
developed works.
synergic effect between both species was demonstrated to be
higher than the effect promoted by each one separately and
better results in terms of enantioselectivity and reactivity were
F
CF
3
OH
S
OH
OH
[9]
S
S
reached compared with the corresponding thiourea alone.
Mattson and co-workers have also developed hybrid transition
metals which act as hydrogen bond donor catalysts such as
N
N
N
H
N
F
N
H
N
CF
3
H
H
H
H
T1
T2
T3
[
10]
urea palladacycles
ureas developed by the same research group (Figure 3).
However, in these examples the authors only use non-chiral
inspired at the same time in boronates
[
11]
Figure 5. Model thioureas used in this work.
[
12]
ureas.
In the search of new types of activation of thioureas as
organocatalysts, and taking into account this novel concept
together with our experience in the chemistry of group 11
The exploration was started with T1 presenting less steric
hindrance and without electronegative groups in the aromatic
ring. The straightforward preparation of the metal complexes 1a-
g is shown in Scheme 1. There are neutral or cationic Cu(I),
Ag(I), Au(I) or Au(III) species that have been perfectly identified
and characterized by NMR spectroscopy (see Supporting
Information).
[
13]
metals,
encouraged us to face the results described here;
where instead of an external Brønsted acid we will use a Lewis
acid metal atom (Figure 4, III). This will open a novel and
interesting line of research where the metal center will activate
the thiourea catalyst, and this activation could be fine-tuned by
carefully choosing the Lewis acid character of the metal, its
oxidation state and also its auxiliary ligands. Interestingly, the
metal will not participate in the activation of none of the reagents.
The coordination chemistry of gold to thiourea-based ligands
has been previously explored with other purposes, mainly
because of the interesting biological properties displayed by the
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ChemCatChem
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FULL PAPER
X
OTf
PPh
3
Ag
M
OH
OH
S
S
N
H
N
N
H
N
H
H
1
a
M = Cu (1b), Ag (1c), Au (1d)
i)
ii)
OH
S
N
H
N
H
T1
iv)
iii)
H
N
H
N
OTf
C6F5
S
C6F5
Au
C6F
5
S
M
S
OH
HN
OH
HN
HO
N
H
N
H
1g
M = Ag (1e), Au (1f)
3 3 2 3 3
Scheme 1. Catalytic complex structures 1a-g with Cu-T1, Ag-T1 and Au-T1. i) Ag(OTf); ii) [Cu(NO )(PPh ) ] or [Ag(OTf)(PPh )] or [Au(OTf)(PPh )]; iii) ½ Ag(OTf)
or ½ [Au(tht) ]OTf; iv) [Au(C (tht)].
2
6 5 3
F )
Subsequently, the efficiency of these species in the
benchmark reaction between indole 4 and nitrostyrene 5 was
analyzed and the results of these tests are reported in Table
1.
[
16]
a
Table 1. Screening of the reaction promoted by M-T1 (1a-g) complexes.
Ph
NO2
NO
2
M-T1
solvent, temperature
N
H
N
H
4
5
6
b
c
Entry
M-T1 (mol %)
1a (10%)
1a (10%)
1b (10%)
1c (10%)
1d (10%)
1e (10%)
1e (10%)
1e (10%)
1e (10%)
1f (10%)
1g (10%)
Solvent (mL)
T (ºC)
t (days)
yield (%)
22
ee (%)
20
14
6
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
(0.5)
(0.25)
(0.5)
(0.5)
(0.5)
(0.5)
(0.25)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
-17
r.t.
r.t.
r.t.
r.t.
3
3
5
4
3
3
6
3
3
3
4
83
60
38
18
42
20
32
8
22
60
60
Toluene (0.25)
CHCl (0.25)
75
3
53
20
30
5
1
1
0
1
CH
2
2
Cl
Cl
2
(0.5)
(0.5)
19
CH
2
23
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d
1
1
2
3
T1 (10%)
[Au(tht) ]OTf (5%)
CH
2
2
Cl
Cl
2
2
(0.5)
(0.5)
r.t.
r.t.
4
3
10
10
Rac.
2
CH
_
[
a]
[b]
[c]
Amount of reagents: indole 4 (0.15 mmol) and nitrostyrene 5 (0.1 mmol). Isolated yields after column chromatography. Determined by
[d]
chiral HPLC analysis (Chiralpak Daicel IA, 90:10 Hex:iPrOH, 1 mL/min). Racemic mixture.
Interestingly, with these results we confirmed our hypothesis
about the possibility of activation of a potential organocatalyst,
since according to these results better yields and
enantioselectivies are obtained in all the cases compared with
the almost lack of reactivity found with T1 (entry 12) or the metal
precursors alone (entry 13), as a proof of fact of the synergic
effect between both species. Moreover, probably the new more
hindered complexes make the TS of this reaction more rigid and
stable and consequently, able to induce enantioselectivity
contrasting the results obtained with thiourea T1 (entry 12).
Excellent reactivity values were found for the silver complexes
3 2
[Au(PPh )T1]OTf 1d (entry 5) and [Au(T1) ]OTf 1f (entry 10),
with ee values of 42 and 30%, respectively. We can conclude
that coordination of a Lewis acid to the thiourea organocatalyst
T1 produces a great increment of reactivity and selectivity,
taking into account the values obtained with this thiourea alone.
These initial promising results encouraged us to examine
other M-thiourea complexes varying the electronic properties of
the thiourea catalyst. Thiourea T2 was the center of the
subsequent study. Since better values were obtained in terms of
enantioselectivity with Au-T1 1d and 1f complexes and in terms
of reactivity the best value was obtained with Ag-T1 1a, in the
ensuing screening, different Ag-T2 and Au-T2 catalysts were
designed and tested (Scheme 2 and Table 2).
2
[Ag(OTf)T1] 1a (entry 2) and [Ag(T1) ]OTf 1e (entry 8) and
promising selectivities were achieved for the gold species
PPh
3
OTf
PPh
3
OTf
Au
F
Ag
F
OH
OH
S
S
N
H
N
H
F
N
H
N
F
H
2
a
2b
i)
OTf
ii)
OTf
H
H
N
F
N
H
N
H
N
F
S
Ag
S
F
S
OH
HO
OH
iii)
F
vi)
S
F
F
Au
OH
F
HO
N
N
F
S
H
H
T2
N
N
H
F
F
N
H
N
H
H
2
c
v)
iv)
2f
ClO
4
6 5
C F
NH
Au
F
F
OH
Au
NH
OH
C
6
F
5
S
S
F
F
N
H
C
6
F
5
N
F
S
H
HN
OH
F
HN
2
e
2d
Scheme 2. Catalytic complex structures 2a-f with Ag-T2 and Au-T2. i) [Au(OTf)(PPh
3
)]; ii) [Ag(OTf)(PPh
3
)]; iii)
½
Ag(OTf); iv) [Au(C
6
F
5
)(tht)]; v)
[
6 5 2 2 2 4 2
Au(C F ) (OEt ) ]ClO ; vi) ½ [Au(tht) ]OTf.
In this case, the better ee values were found with complexes
a and 2e (entries 1 and 5, respectively), although in terms of
reactivity complex 2e was the most active one (88%, entry 5),
followed by 2f (60%, entry 6). In summary, the silver(I) 2c, the
gold(I) 2a and 2f and the gold(III) 2e species bearing two
thiourea ligands showed better results, as previously observed
for T1 with complexes 1e and 1f (Table 1, entries 6-10). As
previously found for T1, T2 activated with a metal Lewis acid
2
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ChemCatChem
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affords better results compared with T2 alone (entry 7, Table 2),
which again supports the development of our main idea. It is
also remarkable the increase reaction rate observed using 10
mol% of complex 2e (entry 5) in comparison with 20 mol% of T2
alone (entry 7), probably due to a considerable decrease in the
pKa of thiourea T2. With the aim of improving the values of
reactivity and enantioselectivity of this process, we tested the
efficiency of T3 synthesizing the same promising metal
complexes 3a-d containing Ag or Au (Scheme 3).
a
Table 2. Screening of the reaction promoted by M-T2 (2a-f) complexes.
Ph
NO2
NO
2
M-T2
N
solvent, temperature
H
N
H
4
5
6
b
c
Entry
M-T2 (%)
Solvent (mL)
T (ºC)
r.t.
t (days)
yield (%)
ee (%)
54
1
2
3
4
5
6
7
2a (10%)
2b (10%)
2c (10%)
2d (10%)
2e (10%)
2f (10%)
T2 (20%)
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
3
3
3
3
3
4
45
37
41
19
88
60
22
r.t.
16
r.t.
28
r.t.
8
r.t.
50
r.t.
40
r.t.
4
20
[a]
[b]
[c]
Amount of reagents: indole 4 (0.15 mmol) and nitrostyrene 5 (0.1 mmol). Isolated yields after column chromatography. Determined
by chiral HPLC analysis (Chiralpak Daicel IA, 90:10 Hex:iPrOH, 1 mL/min).
OTf
OTf
CF3
PPh3
H
N
H
F3C
N
Ag
CF3
OH
S
Ag
S
S
HO
CF3
CF3
OH
N
H
N
H
3b
N
H
N
CF3
i)
H
ii)
3a
CF3
OH
S
N
H
N
CF3
H
OTf
T3
H
N
H
F3C
N
iii)
OTf
S
Au
S
iv)
HO
PPh3
CF3
CF3
OH
Au
CF3
OH
S
N
H
N
CF3
N
H
N
H
CF3
H
3d
3c
3 3 2
Scheme 3. Synthesis of the M-T3 complexes 3a-d. i) ½Ag(OTf); ii) [Ag(OTf)(PPh )]; iii) [Au(OTf)(PPh )]; iv) ½ [Au(tht) ]OTf.
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All these complexes were completely characterized and the
data are collected in the Supporting Information. Subsequently,
the efficiency of these species in the benchmark reaction
between indole and nitrostyrene was analyzed and the results
are reported in Table 3. As thiourea T3 reaches the best results
in this reaction, and because one of our concerns is the high
catalyst loading of thioureas as organocatalysts, we decided to
test the reaction with only 5 mol% compared with the reported
[
9,15]
20 mol% for T3.
a
Table 3. Screening of the reaction promoted by M-T3 (3a-d) complexes.
Ph
NO2
NO
2
M-T3
N
solvent, temperature
H
N
H
4
5
6
b
c
Entry
M-T3 (%)
Solvent (mL)
T (ºC)
r.t.
t (days)
yield (%)
>95
ee (%)
32
1
2
3a (5%)
3b (5%)
CHCl
CHCl
CHCl
3
3
3
(0.25)
(0.25)
2
5
r.t.
90
34
3
4
5
3c (5%)
3d (5%)
T3 (20%)
(0.25)
r.t.
r.t.
r.t.
2
79
48
CHCl
3
(0.25)
3
>95
51
56
CH
2
Cl
2
(0.5)
4
38
[a]
[b]
[c]
Amount of reagents: indole 4 (0.15 mmol) and nitrostyrene 5 (0.1 mmol). Isolated yields after column chromatography. Determined
by chiral HPLC analysis (Chiralpak Daicel IA, 90:10 Hex:iPrOH, 1 mL/min).
The results show that the gold(I) bis(thiourea) complex 3d
was found to be the most active, leading to the best results in
terms of reactivity and enantioselectivity (entry 4). It is
remarkable the use of only 5 mol% of catalyst loading of our
complexes in comparison with 20 mol% used in the former
afforded to changes in the values of enantioselectivity and
reactivity. However, at low temperature we discarded the use of
only 1 equivalent of indole because the rate of the reaction
would decrease more. An increase in the enantioselectivity was
observed by lowering the reaction temperature to –15 from
25 °C (Table 5, entries 5-9) although the reaction rate was lower.
Increasing the concentration of the reaction accelerates the rate
of the process and better yields are obtained. Unfortunately, the
large differences achieved at room temperature between the
reaction performed with the thiourea T3 alone or with 3d are not
maintained at low temperature, and this may be due to a
different mode of coordination between the thiourea catalyst and
the metal at different temperature. The solvent of choice was
[
9,15]
works with T3.
catalyst thiourea T3 alone, even using a lower catalyst loading
entry 5).
In order to finely tune the optimal reaction conditions with T3,
These data exceed those obtained with the
(
we carefully checked the variation of other parameters such as
solvent, temperature, and variation in the concentration of all
species (Table 4), since on the basis of our experience we
realized that small variations in all these parameters could play
an important role in governing the enantioselectivity and
reactivity of the process. Variations in the amount of indole
2 2
found to be CH Cl .
a
Table 4. Screening of the reaction promoted by 3d.
b
c
Entry
Cat. (%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
3d (5%)
Solvent (mL)
T (ºC)
r.t.
t (days)
yield (%)
72
ee (%)
60
d
1
CH
CH
2
Cl
Cl
2
(0.25)
(0.10)
5
5
3
3
3
5
5
4
4
3
d
2
2
2
r.t.
84
56
d
3
CHCl
CHCl
3
3
(0.25)
(0.25)
r.t.
83
53
e
4
r.t.
82
48
5
6
7
8
9
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
(0.50)
(0.25)
(0.10)
-15
-15
-15
-15
-15
-15
15
63
2
2
40
76
66
72
CHCl
CHCl
3
3
(0.25)
(0.10)
38
53
60
58
1
0
Toluene (0.25)
21
29
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ChemCatChem
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1
1
1
2
3d (5%)
3d (5%)
CH
3
CN (0.25)
-15
-15
3
5
38
29
33
ClCH
2
CH Cl (0.10)
2
74
[
a]
[b]
[c]
Amount of reagents: indole 4 (0.15 mmol) and nitrostyrene 5 (0.1 mmol). Isolated yields after column chromatography. Determined by
[d]
[e]
chiral HPLC analysis (Chiralpak Daicel IA, 90:10 Hex:iPrOH, 1 mL/min). Reaction performed with 1 equiv. of indole. Reaction performed
with 2 equiv. of indole.
With the optimal reaction conditions in hand, and giving that
one of our concerns in organocatalysis is the high catalyst
loading we decided to investigate the changes of reactivity and
selectivity between the thioureas T1-3 and the corresponding
gold complexes [Au(thiourea) ]OTf, depending on the catalysts
2
loading in the benchmark reaction (Table 5).
2
racemic mixture. However, the gold complex [Au(T1) ]OTf 1f in a
10% produces a 65% yield and an ee of 40% (entry 2), which
means a considerable increase in both reactivity and overall
selectivity. The decrease in the catalyst loading to 3 mol %
affords only slightly lower values of 51% and 32% ee (entry 3).
The same tendency is observed with thiourea T2, which values
are increased from 35% yield and 26% ee (entry 6) to 64% and
48% for the gold complex 2f (entry 7). Again, these values are
maintained to a lowering of the catalyst amount up to 3%. With
thiourea T3 which provided the best results in previous studies,
we have managed to lower the catalyst loading to 1 mol%
without a significant decreasing neither the reactivity nor the
enantioselectivity (entry 18). Figure 6 shows, for a better vision,
the comparative study between the thiourea T3 alone and the
Table 5. Comparison ofa activity of thioureas T1-3 versus
[
Au(thiourea)
2
]OTf (1f,2f,3d)
Cat. (%)
T1 (10%)
1f (10%)
1f (5%)
a
b
Entry
yield (%)
19
ee (%)
d
1
2
3
4
5
6
7
8
9
Rac.
65
40
32
32
12
26
48
44
40
25
34
30
22
8
54
2
gold complex [Au(T3) ]OTf 3d for a variation in the catalyst
loading.
1f (3%)
51
1f (1%)
29
T2 (10%)
2f (10%)
2f (5%)
37
64
60
2f (3%)
63
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
2f (10%)
T3 (10%)
T3 (5%)
T3 (3%)
T3 (1%)
3d (10%)
3d (5%)
3d (3%)
3d (1%)
56
57
25
24
21
94
60
56
54
50
93
95
Figure 6. Comparative study of reactivity and selectivity between T3 and
complex [Au(T3) ]OTf 3d.
83
2
[a]
Experimental conditions: To a mixture of catalyst (mol%) and
nitroalkene 5 (0.1 mmol) in CH Cl (0.25 mL), indole 4 (0.15 mmol)
was further added, in a test tube at room temperature. After the
2
2
The effect of the metal over the electronic properties of the
thiourea T3 is disclosed in the NMR-spectra of Figure 7. Under
the same concentration (0.005 mmol catalyst/500 μL CD Cl ) in
2 2
two NMR tubes both compounds, T3 and 3d, were analyzed at
[
b]
reaction time, product 6 was isolated by flash chromatography.
[c]
Isolated yields after column chromatography. Determined by chiral
[
d]
HPLC analysis (Chiralpak Daicel IA, 90:10 Hex:iPrOH, 1 mL/min).
Racemic.
room temperature.
As it can be observed T1 in a 10 mol% of catalyst loading
gives very poor values (entry 1), with a yield of only 19% and a
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CF3
OH
S
N
H
N
CF3
H
T3
OTf
H
N
H
F3C
N
S
Au
S
HO
CF3
CF3
OH
N
H
N
CF3
H
3d
1
2 2
Figure 7. H NMR experiments performed in CD Cl at room temperature (400 MHz).
Some of the most relevant resonances in the thiourea
catalysts T3 are downfield shifted because of coordination to the
Au center in the new catalytic complex 3d. A displacement of 0.9
ppm (signal from 8.01 ppm to 9.00 ppm) was observed for the
thiourea N-H hydrogen atom, and 0.27 ppm (signal from 6.98
ppm to 7.25 ppm) was observed for the aminoindanol N-H
hydrogen atom of T3. Additionally, a downfield shifting of the OH
group in the aminoindanol scaffold was observed of 0.56 ppm
Mechanistic study
Interestingly, the sense of the stereoselection in product 6 was
in all cases the same as that expected when (R,R)-aminoindanol
thioureas T2 and T3 were the sole catalysts. This fact shows
that chirality is preferentially governed by the thiourea catalyst
and this outcome prompted us to think that the metal is only
activating the thiourea moiety better than simply driving by itself
some of the reagents into the transition state. Moreover, it is
remarkable that the metal does not activate this process as
above mentioned. Based on our previous works (TSI and
(signal from 2.23 ppm to 2.79 ppm). These displacements would
be in agreement with our initial hypothesis and the better values
of yield found with complex 3d with a more acidic thiourea
skeleton. Both aliphatic CH-Het protons experience an upfield
shifting (Figure 8).
[
9,15]
TSII),
we proposed TSIII as the plausible mode of activation
in our reaction (Figure 9).
It can be assumed that the M-thiourea catalyst complex is
the most reactive species, due to the increased acidity of the NH
in the thiourea after a synergic coordination with the metal atom,
thereby increasing the reaction rate and favoring the activation
of the substrates. Furthermore, improvement in the
enantioselectivity could be attributed to the formation of a more
rigid assembly in the transition state TSIII as combination of both
structures. This mode of activation TSIII (Figure 9) would agree
with the fact that the observed enantiomer is given by the
enantioselectivity of the thiourea organocatalyst employed as
T3

  0.56 ppm
Au CF3
OH

  0.12 ppm
S
N
H
N
CF3
  0.9 ppm
  0.27 ppm
H


  0.05 ppm
[9,15]
obtained in the previous works.

Since the gold atom is joined to two thiourea ligands in the
best catalyst 3d, we cannot discard that the same process is
Figure 8. Chemical shifts experienced after coordination of T3 to gold(I).
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occurring by both thiourea organocatalysts, supporting the better
yields and enantioselectivities observed in this really congested
catalyst, in comparison with the thiourea T3 alone.
CF3
CF3
R
Au
AH
S
H
H
S
N
S
N
H
F3C
N
H
N
H
N
H
N
H
CF3
R
N
H
N
H
O H
H O
O H
H
N
H
N
H
N
O
O
O
O
O
O
N
R= H, F, CF3
T1-T3
R
Ph
Ph
TSI
TSII
TSIII
Figure 9. Proposed transition states for the Friedel-Crafts reaction.
Starting Materials. All reactions were performed under air atmosphere
and solvents were used as received without further purification or drying.
[
18]
[19]
[20]
The complexes [Ag(OTf)(PPh
3
)],
(OEt)
[Au(OTf)(PPh
with Ag(OTf) in dichloromethane. All other reagents were
[Au(tht)
2
]OTf,
were prepared following
)] was obtained from
6 5 3
[Au(C F ) (tht)],
Conclusions
[21]
[
22]
[
Au(C
published
3
AuCl(PPh) ]
6
F
5
)tht)],
6 5
[Au(C F )
2
2 4
]ClO
procedures.
3
The unprecedented activation of thiourea organocatalysts
through the coordination of a metallic Lewis acid has been
described. Coordination of the metal produces the consequent
acidification of the thiourea protons achieving a better activity in
terms of conversion and selectivity in the benchmark reaction of
addition of indole to nitrostyrene. Three thiourea organocatalysts
T1-3 with different electronic and steric requirements have been
used to prepare several group 11 metal complexes 1-3. All the
tested M-thiourea complexes provided better results than the
[20]
[
commercially available.
NMR spectra of all synthesized catalysts and the characterization of all
new compounds are reported in the Supporting Information.
General Procedure for the Catalyzed Friedel–Crafts Alkylation
Reaction: To
nitroalkene 5 (0.1 mmol) at the indicated temperature (r.t. or –15 °C) in a
test tube with CH Cl (0.25 mL), indole 4 (0.15 mmol) was further added.
After the appropriate reaction time (see Tables 1-5), the residue was
purified by column chromatography (SiO ; hexane/EtOAc, 8:2) to afford
a mixture of catalyst M-(T1-T3) (1-10 mol%), and
2
2
thioureas
Au(thiourea)
After achieving the best experimental conditions a comparison of
the activity of the thioureas versus the [Au(thiourea) ]OTf
themselves,
being
the
gold
complexes
[
2
]OTf the best in terms of reactivity and selectivity.
2
final adduct 6. Yields and enantioselectivities are reported in Tables 1-5.
Spectral and analytical data for compound 6 is in agreement with those
previously reported in the literature.
2
[15a]
complexes in different catalysts loading have been carried out.
As expected the higher values were achieved with thiourea T3
and [Au(T3)
]OTf 3d showing a great improvement in the Acknowledgements
2
reactivity and selectivity values of the metal thiourea complex
compared with the thiourea alone. It has been possible to
reduce the catalyst loading to 1 mol% without a significant
decrease of the activity, although optimum values are afforded
with a 3 mol% of catalyst loading. Thus, a new concept has
been proved, the cooperative effect between a metallic Lewis
acid and thioureas providing metal complexes acting as
organocatalysts.
Authors thank the Ministerio de Economía y Competitividad
MINECO/FEDER CTQ2016-75816-C2-1-P), the High Council of
(
Scientific Investigation (CSIC) (PIE-201580I010) and Gobierno
de Aragón-Fondo Social Europeo (E77 and E104) for financial
support of our research.
Keywords: thiourea • gold • asymmetric • organocatalysis •
synergy
Experimental Section
[
1]
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Weinheim, 2005; b) P. I. Dalko (Ed.) Enantioselective Organocatalysis;
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Instrumentation. Mass spectra were recorded on a BRUKER ESQUIRE
3
000 PLUS, with the electrospray (ESI) technique. The ATR-FTIR
spectra of solid samples were recorded on PerkinElmer FT-IR
a
1
spectrometer equipped with a universal ATR sampling accessory. H and
13
1
C{ H}-APT NMR, including 2D experiments, were recorded at room
1
[2]
temperature on a BRUKER AVANCE 400 spectrometer ( H, 400 MHz;
1
3
19
C, 100.6 MHz; F, 376.5 MHz) or on a BRUKER AVANCE II 300
1
13
19
spectrometer ( H, 300 MHz; C, 75.5 MHz; F, 282.3 MHz), with
chemical shifts (ppm) reported relative to the solvent peaks of the
deuterated solvent.
[17]
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Entry for the Table of Contents (Please choose one layout)
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[
a]
[b]
A pioneering gold(I) activation of
thiourea organocatalysts is described.
The synergic effect between both
species affords a more acidic and rigid
catalytic complex than that provided
by the thiourea alone. Considerably
better results in terms of reactivity and
selectivity are obtained with the use of
the gold-thiourea organocatalyst,
which has also allowed reducing the
catalyst loading to 1-3 mol%.
Anabel Izaga, Raquel P. Herrera,*
[
a]
and M. Concepción Gimeno*
Page No. – Page No.
Title
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