A copper-templated, bifunctional organocatalyst: A strongly cooperative dynamic system for the aldol reaction

Article abstract of DOI:10.1039/c7ob01370a

The study of novel metal-templated dynamic organocatalytic systems has led to the identification of CuSO₄ as the most efficient template to assemble monofunctional prolinamide- and thiourea-modified pyridine ligands. The structural and electron

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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A copper-templated, bifunctional organocatalyst: a strongly
cooperative dynamic system for the aldol reaction.
Received 00th January 20xx,
Accepted 00th January 20xx
Anna Serra-Pont, Ignacio Alfonso, Jordi Solà* and Ciril Jimeno*
The study of novel metal-templated dynamic organocatalytic systems has led to the identification of CuSO4 as the most
efficient template to assemble monofunctional prolinamide- and thiourea-modified pyridine ligands. The structural and
electronic requirements to assemble an efficient catalyst have been disclosed: both pyridine ligands must bear a 1,3-
substitution pattern, and the thiourea ligand serves as reducing agent to copper(I) as well. Eventually, the cooperative
effects achieved with such a simple system deliver high reaction rates and stereoselectivities at room temperature in the
asymmetric aldol reaction, requiring only 1 mol% of copper salt.
DOI: 10.1039/x0xx00000x
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Introduction
Within the broad field of self-assembled organocatalysis,1-4
metal-templated organocatalysis has emerged as a powerful
way of assembling the catalytic functions around a metal
center that solely provides the correct geometry for catalysis.
Such supramolecular catalysts have been known for some
time, although their use is not widespread yet maybe because
their preparation, isolation and characterization are not trivial.
Chiral ligands but also chirality at metal exclusively have been
exploited to achieve highly stereoselective reactions.5-6
Nevertheless several exciting examples that make use of
octahedral geometries are known in the literature: cobalt7-12
and iridium13-18 have been successfully used to generate
octahedral complexes able to perform asymmetric
organocatalytic reactions through their coordination sphere.
Remarkable examples include those of Gong, Meggers and co-
workers, who have disclosed a series of iridium-templated
catalysts with exclusive chirality at the metal center that were
able to carry out Michael additions and conjugate reductions,
aza-Henry reactions, α-amination and Friedel-Craft alkylations
in high yields and stereoselectivities.13-18 Catalysis took place
through hydrogen bonding interactions from the ligands
without any participation of the metal center. In turn, previous
work by Belokon and co-workers had made use of Co(III)
complexes comprising both chirality at metal and chiral hemi-
salen ligands to achieve high ee’s in the alkylation of enolates
under phase transfer conditions or the epoxidation of
enones.7-10 Chiral Co(III) complexes with octahedral geometry
Scheme 1 The original dynamic catalytic mixture of ZnCl2, P3 and T3, and
reaction conditions for the asymmetric direct aldol reaction.
that combine chirality at the metal center and chiral ligands
have been used by Gladysz et al. for asymmetric Michael
additions as well.11-12
The following recent example also shows the potential of
metal-bound organocatalytic ligands: Mirkin et al. have
demonstrated how Pt complexes bearing amino-squaramide
P,S-ligands can be allosterically regulated by HCl in the non-
asymmetric Michael addition of nitroethane to nitrostyrene.19
In the context of our program aimed at understanding and
developing water-tolerant organocatalysts20-24 and dynamic
systems able to recognize organic molecules in aqueous
environment,25-26 we have recently developed
a metal-
templated, dynamic approach wherein ligands and metal salts
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Table 1 Effect of the metal salt in the asymmetric aldol reaction.
were simply mixed together to generate efficient
organocatalytic asymmetric systems. Catalysis was carried out
solely through the ligands, which upon binding to the metal
center generate a new bifunctional, efficient catalyst in the
asymmetric aldol reaction (Scheme 1).27
This approach avoids the tedious preparative steps, and
libraries of ligands and metal salts can be thus easily
constructed and screened. In particular, we found that
pyridine-based prolinamide and thiourea ligands assembled on
zinc chloride to generate a highly active catalytic species,
among other catalytic entities of lower activity. Such
monodentate ligands required a 1,3-substitution pattern and
were termed P3 and T3 respectively (Scheme 1). Notably, the
addition of controlled amounts of water (3 equiv.) was crucial
to ensure the full solubility of the catalytic system and achieve
Entry
1
Metal salt
Conv.
[%][a]
89
d.r.
ee [%][b]
(anti/syn)[a]
Zn(OAc)2·
2H2O
71/29
67
2
3
Zn(OTf)2
Zn(ClO4)2·
6H2O
45
60
68/32
72/28
73
79
4
5
ZnI2
89
100
99
52
38
3
83/17
85/15
87/13
76/24
75/25
76/24
70/30
95/5
62
59
ZnBr2
high yields and stereoselectivities. We proposed that
a
6
7[c]
ZnCl2
79
ZnSO4·7H2O
CdCl2
72
tetrahedral geometry achieved by a ZnCl2·P3·T3 complex was
8
61
responsible for the enhanced catalytic activity towards the
asymmetric aldol reaction of cyclohexanone with aromatic
aldehydes at -20 °C (Scheme 1).27
It is noteworthy that complexes of the Zn(II)-prolinate28-32 and
Cu(II)-pyridinylamine33-34 type have been proposed to work as
single catalysts through a Lewis acid/Lewis base mechanism.
Other Lewis acids have been successfully used in combination
with organocatalysts too.35-36 Nevertheless, the high reaction
9
NiCl2·6H2O
CaCl2·2H2O
CuCl2·2H2O
n. d.
68
10
11
59
17
98
[a] Determined by 1H NMR on crude mixtures. [b] Deter-mined by HPLC on a
chiral stationary phase. [c] No water added. N. d., not determined.
in a new, copper-based catalytic system despite its initial low
conversion.
acceleration achieved by our ZnCl2·P3·T3 system in
We therefore turned our attention to copper and undertook
an screening of Cu(I) and Cu(II) salts using several solvents and
variable amounts of water at rt (1-3 equiv. water with respect
to p-nitrobenzaldehyde, Table 2). It must be noted that copper
salts and ligands were mixed together for 1 hour prior to the
addition of the rest of the reactants to ensure a good solubility
and the formation of the putative catalysts.
combination with careful control experiments clearly indicated
the presence of a metal-templated assembly delivering a
remarkable cooperative catalysis. Hence, the only role of the
metal center was to provide the assembly point for the
organocatalytic ligands.27
In this article we want to give a full account of our subsequent
research that has led to the identification of an improved Cu-
templated catalyst containing P3 and T3 ligands. An even
stronger cooperative effect between P3 and T3 has been
discovered in the presence of CuSO4, rendering an extremely
efficient catalytic system under milder reaction conditions. We
also provide evidence on the nature of the catalytic species,
which shows that a Cu(I) sulfate complex is responsible for the
observed catalytic activity.
First, Cu(I) salts were studied (Entries 1-6, Table 2). In THF,
conversion increased when moving from CuCl and CuBr to CuI
(67% conversion) but diastereo- and enanti-oselectivity
decreased: from 92% ee for CuCl to 85% ee for CuBr and 78%
ee for CuI (Entries 2, 5 and 6, Table 2). The addition of a small
amount of water to CuCl did not lead to any significant
improvement (Entry 1), and neither the use of DMF or
acetonitrile as solvents (Entries 3 and 4, Table 2). High ee’s and
d.r. were already achieved, although conversion was still
modest.
Results and discussion
Then, we performed an screening of Cu(II) salts (Entries 7-18,
Table 2). Copper(II) chloride (Entry 7) rendered high
stereoselectivity but low conversion, similarly to CuCl (Entry 7).
These results were not surpassed by copper(II) bromide (Entry
8). Basic copper(II) carbonate and copper(II) perchlorate
performed poorly in all aspects (Entries 9 and 10). However,
copper(II) sulfate turned out to make the catalytic system very
active and stereoselective, furnishing the aldol product in
>96% conversion and up to 95% ee. The presence of water in
THF was moderately important (20 mol% CuSO4·5H2O already
supplies the system with 1 equiv. of water) and best conditions
were achieved when 2-3 equiv. of total water were present
(Entries 11-14, Table 2). Other solvents were tested as well,
After the optimization of the ZnCl2-templated dynamic
organocatalytic system, we turned our attention back to the
role of the metal center, which must be a key parameter in
defining the structure of the self-assembled catalyst. The
screening of zinc and other metal salts at room temperature
suggested a new direction to further improve the dynamic
catalytic system (Table 1). Most Zn(II) salts in the presence of
prolinamide P3 and thiourea T3 provided high conversion and
reasonable ee for the aldol reaction of cyclohexanone and p-
nitrobenzaldehyde at room temperature (Entries 1-7, Table 1).
Other metal salts tested were deceiving (Entries 8-10, Table 1).
The very high stereoselectivity obtained with CuCl2, though,
(d.r. 95/5 and 98% ee, Entry 11) encouraged us to work further
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Table 2 Effect of copper salts in the asymmetric aldol reaction of cyclohexanone and p-
Table 3 Effect of the amount of CuSO4 and ligands in the asymmetric aldol reaction of
cyclohexanone and p-nitrobenzaldehyde.
nitrobenzaldehyde.
CuSO4
[mol%]
1[d] [e]
1[d] [e]
1[d] [e]
1[c]
P3 , T3
Conv.
[%][a]
9
d.r.
(anti/syn)[a]
80/20
86/14
88/12
92/8
ee
[%][b]
78
Copper salt
Solvent
Conv.
[%][a]
14
43
10
17
32
67
17
7
d.r. (anti/
syn)[a]
96/4
ee
[%][b]
[mol%]
1
2
3
4
5
6
2
1
2
CuCl
CuCl
THF[c]
THF
92
5
40
86
90/10
82/18
79/21
86/14
77/23
95/5
92
10
10
20
20
79
91
3
CuCl
CH3CN
DMF
93
91
93
4
CuCl
86
1[e]
100
99
92/8
94
5
CuBr
THF
85
5[d] [e]
93/7
95
6
CuI
THF
THF[c]
78
7
CuCl2·2H2O
CuBr2
98
[a]Determined by 1H NMR on crude mixtures. [b]Determined by HPLC on a chiral
[c]
[d]
8
THF
90/10
75/25
50/50
91/9
93
stationary phase. After 4 hours premixing CuSO4 and ligands.
CuSO4 was
partially soluble. [e] After 1 hour pre-mixing CuSO4 and ligands.
9
CuCO3·Cu(OH)2
Cu(ClO4)2·6H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
THF
30
4
76
10
11
12
13
14
15
16
17
18
THF
n. d.
93
THF
96
98
98
96
12
95
35
45
A deeper analysis of this system (1 mol% CuSO4 plus 20 mol%
P3 and 20 mol% T3) was embraced to ascertain the nature of
the catalytic species and the origin of activity and
stereoselectivity. Several control reactions were sampled to
construct conversion vs. time plots (Figure 1).
THF[e]
THF[d]
THF[c]
MeOH
Dioxane[c]
DMF
93/7
95
93/7
95
91/9
95
88/12
93/7
90
95
Free ligand P3 (20 mol%) showed poor catalytic activity,
reaching ca. 40% conversion after 21 hours at rt. The
combination of P3 and T3 (both at 20 mol% loading) led to a
slight enhancement, likely due to hydrogen bonding activation
of the aldehyde. We had previously observed this effect too.7
In contrast, the addition of 1 mol% of CuSO4 to P3 produced a
small decrease of the catalytic activity compared to the free
P3. This negative result is important because it demonstrates
that there is no Lewis acid enhancement at all for this system.
91/9
n. d.
99
DMF[d]
94/6
[a] Determined by 1H NMR on crude mixtures. [b] Determined by HPLC on a
chiral stationary phase. [c] In the presence of 3 equiv. of added water. [d] In the
presence of 2 equiv. of added water. [e] In the presence of 1 equiv. of added
water. N. d., not determined.
but except dioxane, which furnished similar results to THF,
MeOH and DMF were clearly inferior (Entries 15-18, Table 2).
After this screening, we moved on to further understand the
copper sulfate-based catalytic system. First, the amount of
copper was studied because its dissolution into the system had
proven difficult: solubility depended on the amount of copper
and its ratio with respect to P3 and T3 ligands. For example,
CuSO4 was still not fully soluble at 5 mol% loading and 20
mol% P3 and T3, and no difference in catalytic output was
observed with respect to the original 20 mol% loading
(Compare Entry 6 in Table 3 with Entry 13 in Table 2). Using 1
mol% CuSO4 and decreasing amounts of ligands P3 and T3
from 20 down to 2 mol% led to a concomitant decrease in
conversion, diastereo- and enantioselectivity (Entries 5 and 3-
1, Table 3). This decrease in efficiency can be associated to a
decrease in the solubility of CuSO4 in the system as well.
Finally, the CuSO4·P3
·T3 system (1 mol% Cu and 20 mol% P3
and T3) was analyzed. A very important rate enhancement was
100
80
60
40
20
0
94% ee
83% ee
80% ee
72% ee
71% ee
Optimal results were thus set for a 1:20:20 CuSO4:P3:T3 molar
ratio, wherein all CuSO4 was dissolved within one hour. It must
be noted that under these conditions a clear pale yellow
solution was obtained after 1 hour of pre-mixing with the
ligands. Additionally, a 10 mol% of P3 and T3 ligands can be
used provided that the system is left 4 hours pre-mixing before
adding the reactants (Entry 4, Table 3). These results show the
role of the ligands in solubilizing copper sulfate, which
saturates the reacting solution at ca. 1 mol%.
0
6
12
18
24
time / h
1 Conversion vs. time plots for the asymmetric aldol reaction of
cyclohexanone and p-nitrobenzaldehyde using 1 mol% of CuSO4 and 20 mol% of
ligands, in THF plus 2 equiv. of water at rt. CuSO4·P3 T3, circles; P3 T3, triangles;
Figure
·
U3, stars and dotted line.
·
P3, diamonds; CuSO4·P3, squares; CuSO4·P3
·
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observed, and full conversion was reached after ca. 10-12
hours (Figure 1).
The importance of the thiourea ligand T3 in this reaction was
made evident by running an analogous reaction using the urea
derivative (1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyridin-3-yl)
urea, U3): a clearly lower rate was recorded (Figure 1).
Regarding enantioselectivity, the new copper-templated
catalytic system exhibited an important enhancement as well:
the aldol product was obtained in 94% ee, whereas free P3
only reached 72% ee. No improvement was ob-served upon
addition of hydrated CuSO4 to P3 (71% ee) and only a small
improvement up to 80% ee was detected in the P3 plus T3
mixture. The use of the urea ligand (U3) led to significantly
poorer result as well (83% ee). Altogether, a clear cooperative
94% ee
89% ee
72% ee
100
80
60
40
20
0
85% ee
effect emerges from the CuSO4·P3
·T3 system that clearly
surpasses simple organocatalysis and Lewis acid or hydrogen
bonding enhancements.
suggested (Figure 1).
A Cu-templated system is thus
0
6
12
18
24
time / h
At this point, it is also worth highlighting that the absolute
configuration of the major aldol product corresponds in all
Figure 2 Conversion vs. time plots for the asymmetric aldol reaction of cyclohexanone
and p-nitrobenzaldehyde using 1 mol% of CuSO4 and 20 mol% of ligands, in THF plus 2
equiv. of water at rt. CuSO4·P3·T3, circles; CuSO4·P4·T3, squares; CuSO4·P2·T3,
diamonds; CuSO4·P3·T, stars and dotted line.
cases
to
(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)
cyclohexanone, as determined by its specific optical rotation
and the elution order in the chiral HPLC traces (See SI). This is
valid for the free prolinamide ligands and our previous Zn(II)-
based catalytic system as well. Therefore the chiral
prolinamide ligand determines the absolute configuration of
the aldol product.
Coordination of P3 to Cu(II) was observed through the signal
shift and the generation of a fine structure in the EPR
spectrum. However, upon addition of T3, all paramagnetic
species disappeared in less than 10 minutes (Figure 3).
The reduction of CuSO4 and other copper salts by thiourea
(H2NCSNH2) is indeed well known in the literature.37-40 We
must notice that each thiourea group can reduce one Cu(II)
atom.41 Moreover, ureas (like U3) do not participate of this
reactivity, and therefore its poor performance observed in
Figure 1 makes full sense.
To assess the regiochemical pattern in the pyridine ligands,
new conversion vs. time plots were constructed using 1,2- and
1,4-substitued pyridine-prolinamide ligands, which we termed
P2 and P4, respectively (Figure 2). In the presence of 1 mol%
CuSO4, the P3·T3 combination was clearly superior to the
P2·T3 mixture, and still more efficient than the P4·T3 system.
Differences were even more striking in terms of ee: The slower
P2·T3 combination reached a moderate 85% ee of the aldol
product, whereas the faster reacting P4·T3 system only
reached 72% ee. In contrast, the matched P3·T3 system not
only was the fastest, but also the most enantioselective
catalytic system for the aldol reaction studied (94% ee, Figure
2).
Finally, it must be added that all the experiments carried out in
this piece of work were actually carried out under fully
reducing conditions to Cu(I) and an excess of P3 and T3
ligands.
An additional experiment was carried out with a combination
of CuSO4, P3 and a thiourea analog
instead of the 3-pyridinyl moiety (Figure 2). The observed
reaction rate falls compared to the optimum CuSO4·P3 T3
T containing a phenyl ring
·
system, eventually obtaining a lower ee as well (89% vs. 94%
ee). The need of a pyridine-type ligand for copper is thus
evident. These results also show the importance of generating
a particular geometry in the assembled catalytic system to
achieve cooperativity. This will ultimately lead to the highest
conversion and stereoselectivity.
The fast color change of the CuSO4·P3·T3 system from bright
blue to pale yellow upon dissolution and the similarity
between CuCl and CuCl2 in terms of catalytic output (Table 2,
entries 1 and 7) prompted us to examine the oxidation state of
copper. In fact, after EPR analysis of several samples we
concluded that a fast reduction of paramagnetic Cu(II) to
Figure 3 Superimposed EPR spectra of CuSO4 with the P3 and T3 ligands. [CuSO4] = 2
mM, [P3] = [T3] = 40 mM in THF/ water mixtures.
diamagnetic Cu(I) was taking place in the presence of T3
.
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In turn, MALDI provided evidence for the formation of Cu(I)
complexes containing the catalytically active ligands. In
positive mode, [CuSO4(H2O)3(P3H)(P3)+Na]+ (m/z = 619.1) and
[CuSO4(H2O)3(P3H)(T3)+Na]+ (m/z = 793.0) were detected,
whereas in negative mode [CuSO4(H2O)3(P3)(T3)+Na-H]- (m/z =
791.0) and [CuSO4(H2O)2(THF)(P3)(T3)]- (m/z = 823.0) were
identified. In all cases, intense and easily identifiable peaks
were observed. The isotopic distribution patterns observed
fitted the proposed structures as well (See SI).
Further characterization of the CuSO4·P3·T3 organocatalytic
1
system was then carried out by H NMR. A mixture of P3 and
T3 in THF-d8 (16 mM each) was titrated with CuSO4 ensuring a
constant concentration of ligands (Figure 5). Signal broadening
and shifting was observed for most peaks. Since no
paramagnetic species are present in solution, this is indicative
of a dynamic system in fast exchange at room temperature. No
new signals appeared either. In Figure 5 the spectral region
corresponding to the aromatic and NH signals (7-11 ppm) has
Figure 4 UV-Vis spectra of CuSO4·P3·T3 (black line), CuSO4·5H2O (blue line), T3 (orange
line) and P3 (red line). [CuSO4] = 84 mM. [P3] = [T3] = 840 mM.
UV-Vis spectrophotometry also showed that the absorp-tion
band of an aqueous solution of CuSO4 centered at 805 nm was
not present in the CuSO4·P3·T3 system (which in this case
1
been expanded. The full H NMR spectra with the assignment
contains a ten-fold amount of ligands compared to copper). In
this latter case, the strong absorption at < 500 nm is a
contribution of the absorption of both P3 and T3, but no trace
of the spectral characteristics of aqueous CuSO4 is maintained
(Figure 4). This result also suggests a full reaction of the copper
salt to furnish new Cu(I) complexes. Detailed UV-Vis spectra
of the ligand peaks can be found in the SI. It is also noteworthy
that under realistic reaction conditions (Ligands to copper ratio
of ca. 20/1) signal broadening and shifting are already evident
(Figure 5, spectrum (d)).
All the spectroscopic evidence showed above leads to the
conclusion that a dynamic Cu(I)·P3·T3 system is responsible for
for P3
can also be appreciated that the spectrum of CuSO4·P3
corresponds roughly to the sum of P3 and T3
,
T3, and CuSO4·P3
·
T3 can be found in the SI, where it
the catalysis.
·
T3
.
Figure 5 1H NMR titration of P3 and T3 with CuSO4 (From bottom to top). Expansion of the pyridine signals region (6.90-10.40 ppm). Performed in THF-d8 at 25 °C at
400 MHz.
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Accordingly, it is very difficult to propose a specific catalyst in practice identical to those obtained with CuSO4 (Scheme 2).
structure due to the very dynamic nature of the system itself. A sulfate ion bridging two Cu(I) atoms is plausible, but again
It is even possible that several catalytic species do coexist. the large excess of T3 and P3 ligands makes this scenario
Several additional details are important to help streamline this unlikely.
catalytic system in the absence of crystallographic information: Sixth, In view of these results, the experiment in Figure 1 with
First, a related NMR experiment consisting of the titration of P3 and an urea ligand (U3) should be carried out now using a
P3 with paramagnetic Cu(II) shows a significantly higher peak Cu(I)-sulfate metal template. Accordingly, the above
broadening for the signals of the pyridine region compared to CuCl/Ag2SO4 system was used. The asymmetric aldol reaction
the pyrrolidine region (see SI). A preferable coordination of the proceeded in moderate yield (63%) and ee (78% ee). This is in
pyridine vs. pyrrolidine moieties in P3 is thus suggested agreement with the higher hydrogen-bonding donor ability of
(Solomon equation), at least for Cu(II).42
thioureas vs. ureas. The full conversion vs. time plots can be
Second, Cu(I) complexes have d10 electronic configuration, the found in the SI.
same as Zn(II) from our previous catalytic system.27 Therefore Seventh, the absence on non-linear effects (NLE) suggests the
a tetrahedral geometry is likely for the catalytically active presence of one P3 ligand in the catalytic complex as well (See
complex.
SI).
Third, the existence of other geometries cannot be discarded, Eight, it could be even argued that a protonated pyridine-
though, as the detection by MS of six-coordinated Cu(I) aqua prolinamide arising from acid coming from the oxidation of the
complexes might suggest.
Fourth, it could be argued that T3 could bind to copper example working under different reaction conditions is known
through the sulfur atom, as it is actually well stablished with wherein a 1,2-substituted pyridine is required, though.45
thiourea ligand could be the responsible for catalysis. An
A
thiourea ligands. However, in the case of pyridine-thiourea heterogeneous system comprising dodecylsulfonic acid and
ligands, only the 1,2-substituted pyridines (like T2) are known pyridine-prolinamide proved to be catalytically efficient.46
to bind in a bidentate fashion leading to discrete Cu(I) However that micellar system in water is far different from our
complexes.43-44 1,3- and 1,4-pyridine-thiourea ligands yield homogeneous system in organic medium as well. Furthermore,
coordination networks with Cu(I) instead.44 In this respect we control experiments with pyridine-prolinamide ligands and
have shown in Figure 2 how both the pyridine and thiourea acid in our previous communication discarded that
moieties of T3 ligand (1,3 substitution) are necessary and possibility.27
clearly superior to a pyridine-free analogue, which highlights Altogether, in combination with the conversion vs. time plots
the requirement of the pyridine moiety. The bidentate chelate of the catalytic system and other control experiments (Figures
of this T3 ligand is nevertheless unlikely due to geometric 1 and 2) it is strongly suggested that cooperative catalysis in
reasons, and the large excess of ligands P3 and T3 compared this dynamic system must arise from
a Cu(I) complex
to Cu(I) would prevent the formation of coordination containing both P3 and T3. A tentative model that can predict
networks. Therefore a discrete, pyridine-bound coordination the observed stereoselectivity is shown in Scheme 3. The
complex is suggested.
aldehyde binds in such a way that steric repulsion from the
Fifth, the requirement of a sulfate counter ion for an efficient inner coordination shell is minimized.
catalysis is clear. In this respect, the importance of the sulfate At this point it is also worth mentioning that although 20 mol%
ion in accelerating the reaction is evident with the following of ligands P3 and T3 is used, the catalytically active species
experiment: When CuCl (which renders a poor conversion, see cannot represent more than 1 mol% (the amount of CuSO4).
Table 2, entries 1 and 2) is treated with Ag2SO4, it becomes This fact tells in favor of the high performance of the self-
catalytically active and furnishes full conversion and high assembled, catalytically active species. We attribute the
stereoselectivity in the aldol reaction. Indeed, these results are comparatively high amount of P3 and T3 ligands required to
the dynamic nature of the catalytic system and the low
O
O
OH
solubility of CuSO4.
1 mol% CuCl
0.5 mol% Ag2SO4
CHO
Finally, we proceeded to test the performance of the Cu·P3·T3
+
system with a variety of substrates. The aldol reaction of
cyclohexanone with aromatic aldehydes took place from good
P3
T3
and
20 mol%
O2N
NO2
THF, 2 equiv. water
rt, 24 h
99% conversion
anti/syn 88/12
92% ee
to
excellent
yields,
high
diastereo-
and
high
enantioselectivities in the range of 90-94% ee (Table 4, entries
1-6). Aldehydes with electron-withdrawing groups afforded
Scheme 2 Effect of sulfate ion in the asymmetric aldol reaction catalyzed by
Cu(I)·P3 T3
·
.
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24 hours, which represents faster and more practical
conditions than the previous ZnCl2-based system at -20 °C.
H
O
O
O
OH
N
H
H
N
CF3
Conclusions
N
N
N
H
N
Metal-templated bifunctional organocatalytic systems provide
a fast platform for the development of asymmetric reactions.
Within the complexity of the dynamic mixture of metal salt,
ligands and solvents, the generation of a self-assembled
species leading to the emergence of strong cooperative
catalysis will overcome all other side reactions. These
XnCu
S
CF3
2-
X = H2O, THF, SO4
Scheme 3. Predictive model for the CuSO4·P3
·
T3 catalytic system.
Table 4. The asymmetric aldol reaction catalyzed by CuSO4 and P3 and T3.
secondary
reactions
might
include
single
ligand
organocatalysis and Lewis acid catalysis combined with
organocatalysis. However, once a metal-templated species is
able to deliver cooperative catalysis, this will become the
predominant reaction mechanism.
We have found that inexpensive CuSO4·5H2O renders the most
active metal-templated organocatalytic system to date,
surpassing our previously described ZnCl2-based system. Cross
aldol reactions can now be performed at room temperature in
15-24 hours instead of -20 °C in 24-48 h with excellent yields
Product
Yield
d.r.
ee
[%][a] (anti/syn)[b] [%][c]
1
95
23[d]
83
92/8
87/13
93/7
94
90
92
and stereoselectivities. Furthermore, only
1 mol% of
CuSO4·5H2O is necessary, which means that the real copper-
templated catalyst is indeed at very low concentration.
Further research aimed at extending the use of metal-
templated organocatalytic systems to other reactions is
underway in our laboratory.
2
3
Conflicts of interest
4
The authors declare no conflicts of interest.
45
93/7
93
Acknowledgments
5
6
7
Financial support from MINECO/FEDER (Grant CTQ2015-
70117-R) and Generalitat de Catalunya (Grant 2014SGR231)
and EU (FP7-PEOPLE-2012-CIG-321659) is gratefully
acknowledged. ASP thanks MINECO for a FPI predoctoral
fellowship (BES-2013-067087).
82
68
98/2
93/7
94
94
References and notes
90
95
24/76
61[e]
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TOC Graphic:
A copper-templated bifunctional organocatalyst
delivers aldol adducts in high yields and
stereoselectivities
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