Dynamic assembly of a zinc-templated bifunctional organocatalyst in the presence of water for the asymmetric aldol reaction

Article abstract of DOI:10.1039/c5cc07847d

A bifunctional organocatalytic system consisting of simple pyridine ligands containing separate catalytic functionalities was assembled using ZnCl₂. This novel metal-templated catalyst furnished high yields and stereoselectivities towards the a

Full text of DOI:10.1039/c5cc07847d

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DOI: 10.1039/C5CC07847D
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Dynamic assembly of a zinc-templated bifunctional organocatalyst
in the presence of water for the asymmetric aldol reaction.
Received 00th January 20xx,
Accepted 00th January 20xx
Anna Serra-Pont, Ignacio Alfonso, Ciril Jimeno* and Jordi Solà*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A bifunctional organocatalytic system consisting of simple pyridine
ligands containing the separate catalytic functionalities was
assembled using ZnCl2. This novel metal-templated catalyst
furnished high yields and stereoselectivities towards the aldol
reaction. The addition of controlled amounts of water turned out
crucial to dissolve the system and achieve optimal results.
Among the growing types of supramolecular catalysts and
strategies for their preparation,1-3 metal-templating has
emerged as a powerful tool for the design of new asymmetric
organocatalysts.4, 5 In these entities, the catalytic function is
carried out solely by the cooperative action of the ligands, and
the metal center participates as assembly point, providing the
correct geometry for catalysis. The vast majority of metal- Scheme 1. Zn-templated formation of thiourea-prolinamide
templated organocatalysts consist of octahedral complexes bifunctional organocatalysts.
where chirality at the metal is often encountered, thus leading
to diastereomeric complexes that must be isolated and tested three components (two ligands and a zinc salt) in a one-pot
separately. A remarkable example of an iridium-templated reaction, thus facilitating the screening. Zinc was chosen as
enantioselective
-amination of aldehydes through an templating agent because it binds pyridines strongly and
enamine/H-bonding bifunctional catalyst has been described generates tetrahedral complexes17 that would ensure a close
recently. The octahedral geometry of the metal center was the contact between the ligands around it and avoid the formation
exclusive source of chirality.6 Simpler yet still efficient systems of configurational isomers. Of course, several complexes can
are known, but they might not be considered true arise from these dynamic mixtures of ligands and metals. At
organocatalysts: the now classical Zn-prolinate system7-11 and least an statistical 1:2:1 mixture of MA2:MAB:MB2 complexes
recent Cu-pyridinylamine complexes12 are proposed to work could be expected, if no higher coordination numbers appear,
under dual Lewis acid-Lewis base catalysis.
together with free ligands. Still, we were aware that whenever
In this Communication we present as proof-of-concept a a catalytically active species was formed in sufficient amount
method in which simple monodentate pyridine ligands from such a complex dynamic system, isolation of the putative
containing separate thiourea and prolinamide functionalities catalysts would not be necessary and catalysis (and
assemble on Zn salts generating a highly stereoselective stereoselectivity) would be easily recorded.18
organocatalyst from a dynamic mixture (Scheme 1).13-16 The
Our initial experiments were aimed at determining the
simplicity of these ligands made their preparation trivial (See optimal ligands structure, zinc salt, and reaction conditions for
ESI), and therefore libraries of ligands could be generated very catalysis to take place. The asymmetric aldol reaction of
fast. Catalysts were generated and tested just by mixing the
cyclohexanone and p-nitrobenzaldehyde was used as test
reaction. After synthesizing a library of pyridines, quinolines
and isoquinolines with different substitution patterns bonded
Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Department of
Biological Chemistry and Molecular Modelling, c/Jordi Girona 18-26, E08034
Barcelona (Spain).
Email: ciril.jimeno@iqac.csic.es, Jordi.sola@iqac.csic.es.
Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/x0xx00000x
either to
a
prolinamide or
a
3,5-bis(trifluoromethyl)
phenylthiourea moieties, we concluded that simple pyridine
ligands were unsurpassed by the other nitrogen ligands and
that ZnCl2 was the metal source of choice (see ESI for the full
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screening of ligands, zinc salts and other metal sources). The
effect of the zinc counterion in zinc-prolinate catalysts had
been found to be indeed remarkable, being chloride and
acetate the most convenient salts.19 Further experimentation
led to the observation that the ZnCl2 - pyridine ligands
mixtures were not fully soluble in organic solvents.
Nevertheless, the addition of a small amount of water to THF
produced a fast dissolution of the system and an enhancement
of the catalytic activity and specially stereoselectivity (Table 1,
entries 1-2 and 5-7). Other solvents were tested as well, but
poorer results were always obtained (See ESI).
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DOI: 10.1039/C5CC07847D
80
70
60
50
40
30
20
10
0
0
2
4
6
8
10
equiv. water
Figure 1. Effect of the amount of water in the benchmark aldol
reaction catalyzed by 20 mol% ZnCl2, P3 and T3 in THF at rt.
Under these conditions (THF plus 3 equivalents of water
respect to p-nitrobenzaldehyde),
a deep effect of the
substitution pattern in the pyridine ligands was observed,
showing that best results were achieved when both 1,3-
substituted prolinamide and thiourea ligands were used (Table
1, entries 5 and 6). When the temperature was decreased to -
20 °C, the d.r. could be increased to 95/5 and the ee up to 92%
and still keeping a high level of conversion (Entry 6, Table 1). It
is worth highlighting how the combination of these two
ligands, P3 and T3, led to such a high level of reactivity and
stereoselectivity compared to the other possible combinations
of ligands. A strong cooperative effect and bifunctional
catalysis was thus suggested.
Several zinc-prolinate complexes that catalyze aldol
20-23
reactions have been shown to be water-compatible.7-11,
Table 1. Effect of the isomeric substitution at the pyridine
ligands and the addition of water in the benchmark aldol
reaction.
However, in our zinc-pyridine ligands example presented
herein, water is necessary to achieve higher stereoselectivity
(Entries 5 and 7, Table 1). Furthermore, the amount of water
must be carefully controlled to achieve optimal results. In
Figure 1, the dramatic effect on enantioselectivity of the
amount of water for the aldol addition of cyclohexanone to p-
nitrobenzaldehyde is shown, being 3 equivalents of water
(respect to p-nitrobenzaldehyde) ideal for this reaction.
Therefore, we suggest that the role of water is more complex
than just dissolving the catalytic system, and likely actively
participates in the mechanistic scenario.24
While addressing the structural features of the putative
catalyst, no single crystals suitable for X-rays diffraction could
be obtained, but solution NMR of the ZnCl2:P3:T3 mixture at
variable temperature showed several species in fast exchange
in the pyridine region. This result was confirmed by NMR
titration of the ZnCl2:P3:T3 mixture with P3 ligand. Moreover,
MS (MALDI-TOF) allowed us to identify ZnCl2(P3)2H+ and
ZnCl(H2O)(P3)(T3)+ complexes in the catalytic mixture. Finally,
UV-Vis spectroscopy showed small changes in the ZnCl2:P3:T3
absorption spectrum that did not correspond to a full
overlapping of the independent species spectra, suggesting the
formation of a new complex (See ESI for details). Altogether,
the presence of a dynamic mixture of zinc complexes with
exchange of pyridine ligands was suggested, in accordance to
our working hypothesis.
Then, a series of control experiments were carried out to
clarify the nature of the catalytic species present in the
reaction medium (Table 2). Ligand P3 alone showed little
catalytic activity and poor d.r. and ee (Entry 3, Table 2). The
addition of ligand T3 enhanced the reactivity but kept the
same poor stereoselectivity, likely due to an activating effect
of the thiourea on the aldehyde (Entry 4, Table 2). Still, ZnCl2
and ligands P3 and T3 (Entries 1 and 2, Table 2) is the
combination that clearly led to higher conversion and
Entry
1
P
T
Conv.[%]a d.r. anti/syna ee [%]b
P2 T2
P2 T2
P2 T3
P3 T2
P3 T3
P3 T3
P3 T3
P4 T2
P4 T3
52
33
24
99
99
81
97
0
69/31
76/24
77/23
91/9
87/13
95/5
84/16
-
76
56
74
48
79
92
14
-
2c
3
4
5
6d
7c
8
9
10
90/10
nd
a
b
Determined by 1H NMR. ee of the anti diastereomer.
c
Determined by HPLC on a chiral statiorary phase. Reaction
run without added water in anhydrous THF. d Reaction run at -
20 °C.
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stereoselectivity. The mixture of ZnCl2 and ligand P3 (Entries 7
and 9, Table 2), potentially leading to Lewis acid-Lewis base
catalysis, proved to be very active as well at rt, but clearly
providing lower ee’s. Nevertheless, at -20 °C, a mixture of
ZnCl2:P3 led to lower conversion (36%) and ee (77% ee) than
View Article Online
DOI: 10.1039/C5CC07847D
100
80
60
40
20
0
the active ZnCl2:P3:T3 mixture (entry 8, Table 2). Finally, the
presence of protonated catalytic species arising from
adventitious acid due to the hydrolysis of ZnCl2 was discarded
by adding controlled amounts of HCl to the mixture of ligands
P3 and T3 (entries 5 and 6, Table 2). Very low conversion and
poor ee’s were found, but even more importantly,
diastereoselectivities were the opposite and the syn
diastereomer predominated.
ZnCl2:P3:T3
ZnCl2:P3
0
5
10
time [h]
15
20
25
Figure 2. Conversion vs. time profiles in the aldol reaction of
cyclohexanone with p-nitrobenzaldehyde for the ZnCl2:P3
(diamonds) and ZnCl2:P3 (squares) mixtures.
:T3
In Figure 2, a conversion vs. time plot for the ZnCl2:P3:T3
and ZnCl2:P3 mixture is shown, demonstrating the rate
enhancement achieved when T3 is present. Therefore it can be
concluded that several species with potential catalytic activity
might be present in the dynamic mixture of ZnCl2 and ligands,
ranging from free ligands to ZnCl2:P3 complexes, but
predominant catalysis and stereoselectivity must arise from a
bifunctional zinc complex coordinated by P3 and T3 ligands.
From these data, a simple model for catalysis can be
tentatively inferred (Scheme 2): Ligands P3 and T3 would bind
to a zinc complex in a tetrahedral fashion, and once the
enamine is formed, the aldehyde would bind the thiourea and
dispose in such a way that steric crowding from the inner
coordination shell (the zinc-pyridines region) would be
minimized. The stereochemistry of the major aldol can be
predicted correctly from this model.
Finally, with the optimized conditions in hand (20 mol%
catalyst loading, THF and 3 equiv. water at -20 °C), a small set
of substrates were tested in the asymmetric aldol reaction to
determine the scope of the catalyst (Table 3). Although
Scheme 2. Model of a ZnCl2:P3:T3 complex leading to the
observed major stereoselectivity.
Table 2. Blank aldol reactions indicating the formation of a
1:1:1 Zn:P3:T3 catalytic complex.
stereoselectivity (d.r. and ee) was high in the reaction of
cyclohexanone with benzaldehyde (Table 3, entry 2), yield was
low, and other aldehydes with electron donating groups were
not tested.25 However, aromatic aldehydes with electron
withdrawing groups furnished the desired aldol adducts of
cyclohexanone with good yields and excellent ee’s (ranging
from 88 to 97% ee) and d.r. (Table 3, entries 1 and 3-6).
Cyclopentanone aldol derivatives could also be isolated in
good yields but reversed d.r. (the syn diastereomer
predominated), although the ee was modest. (Table 3, entry
7). Finally, the adduct of acetone and p-nitrobenzaldehyde was
also prepared using our catalyst with excellent yield but
modest ee (Table, 3, entry 8).
Entry ZnCl2 P3 T3 Conv. d.r.
ee
[%]
20
20
0
0
0
[%] [%] [%]a
20 20 99
20 20 81
anti/syna [%]b
1
87/13
95/5
79
92
50
50
5
47
63
77
54
2e
3
20
20 20 77
20 20
20 20 17
0
21
69/31
71/28
30/70
14/86
85/15
94/6
In conclusion, we have developed
a
bifunctional
4
5c
6d
7
9
ZnCl2:P3 T3 catalyst suitable for the asymmetric aldol reaction
:
with separate catalytic functions (prolinamide and thiourea) in
each ligand from a dynamic mixture, using very simple,
monodentate 3-aminopyridine ligand derivatives. The catalyst
was formed in situ, and experimental evidence suggested that
ZnCl2 templates the assembly of the pyridine ligands towards
the catalytically active species, among other species that
present lower catalytic activity and stereoselectivity. The
0
20
20
20
20
20
40
0
0
98
36
98
8e
9
0
83/17
a
1
b
Determined by H NMR. Determined by HPLC on a chiral
statiorary phase. c 20 mol% of HCl (4 M in dioxane) added. d 40
mol% of HCl (4 M in dioxane) added. e Reaction run at -20 °C.
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Table 3. Substrate scope of the ZnCl2:P3
asymmetric aldol reaction at -20 °C for 24 h.
:
T3 catalyst in the
Notes and references
View Article Online
DOI: 10.1039/C5CC07847D
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75
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93
3d
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88
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,
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Financial support from Mineco (CTQ2012-38594-C02-02
Adv., 2015,
5
, 62331-62335.
and CTQ2012-38543-C03-03), Generalitat de Catalunya (2014
SGR 231) and EU (FP7-PEOPLE-2012-CIG-321659) is gratefully
acknowledged. CJ and JS are Ramón y Cajal fellows (RYC-2010-
06750 and RYC-2011-08925). ASP thanks Mineco for a FPI
predoctoral fellowship (BES-2013-067087).
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