Toward reactant encapsulation for substrate-selectivity

Article abstract of DOI:10.1016/j.tetlet.2011.11.078

A synthetic tris-(bis-(aminomethyl)pyridine) receptor was prepared in excellent yields via reversible imine condensation strategy. Catalytic activity in Henry reactions of the corresponding copper(II) complex was studied. Capitalizing on previous works by

Full text of DOI:10.1016/j.tetlet.2011.11.078

Tetrahedron Letters 53 (2012) 462–466
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Tetrahedron Letters
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Toward reactant encapsulation for substrate-selectivity
⇑
Nicolas De Rycke, François Couty, Olivier R. P. David
Institut Lavoisier, Versailles, Université de Versailles St. Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic tris-(bis-(aminomethyl)pyridine) receptor was prepared in excellent yields via reversible
imine condensation strategy. Catalytic activity in Henry reactions of the corresponding copper(II) com-
plex was studied. Capitalizing on previous works by Anslyn with related receptors, the dramatic increase
in basicity induced by this type of complex on diketo-derivatives was used to perform a nucleophilic
addition of a deprotonated substrate onto an electrophile within the cavity. Hence, a Lewis acid stabilized
nitronate was reacted with various aldehydes. A notable preference for small reactants easily accommo-
dated in the cavity over encumbered ones was observed, thus representing an example of substrate-
selectivity.
Received 20 October 2011
Revised 7 November 2011
Accepted 15 November 2011
Available online 22 November 2011
Keywords:
Cage compounds
Cryptands
Enzyme models
N Ligands
Ó 2011 Elsevier Ltd. All rights reserved.
Schiff bases
Since their discovery, the fascinating reactivity of enzymes has
been idealized as perfect models for chemists aiming to promote or-
ganic reactions with high levels of selectivity. These natural cata-
lysts are able to selectively encapsulate substrates through
molecular recognition and to considerably modify their reactivity.1
This temporary enzyme–substrate association matches the perfect
conditions to catalyze an impressive number of reactions leading
to a wide variety of structural patterns with high efficiency and
selectivity.2 In this context,3 inspired by enzymes’ reactivity,
Diederich first reported an example of organocatalysis within a
macrocyclic host.4 The macrocyclic compound behaved as a pseu-
do-enzymatic catalyst allowing the efficient conversion of an
aldehyde substrate, followed by the release of the benzoin product.
Later, the groups of Fujita,5 Raymond6, and Rebek7 designed macro-
polycyclic compounds with a tridimensional internal cavity able to
promote transformations of encapsulated substrates.8 In this
context, Rebek first described the synthesis and evaluation of a
purely organic cage containing an acid functionality directed inside
the cavity which was shown to promote the ring closure of an
epoxyalcohol with very high levels of regioselectively. In this field,
Anslyn9,10 introduced aza-cryptand 1a and copper(II) complexes
1b,c and demonstrated their ability to increase the acidity of
carbon-acids complexed within their cavity. Hexa-amide receptor
1a could induce a pKa lowering of nearly three units uniquely
relying on H-bonding with the diketo-substrate. More strikingly,
aza-cryptand 1b-Cu(OTf)2 induced a lowering of the pKa value of
2-acetylcyclopentanone of not less than 12 units upon complexa-
tion in acetonitrile (Fig. 1). This dramatic effect was explained as
the result of an electrostatic/coordination interactions between
the copper(II) center and the anionic system of the diketo-system.
If the cage is able to tolerate an additional electrophile, one can thus
p
expect to promote a reaction between two complexed reactants,
2 TfO-
O
N
O
N
O
N
H
N
H
H
NH
N
O
O
HN
HN
HN
N
N
Cu2+
HN
NH
O
N
H
N
N
O
O
H
H
N
N
O
O
1a
1b-Cu(OTf)2
O
4 Cl-
N
N
N
H
H
H
N
N
N
NH
H
N
Cu2+
HN
N
N
N
NH
N
HN
Cu2+
N
NH
N
O
H
H
N
N
N
H
1c-2(CuCl2)
2
⇑
Corresponding author. Tel.: +33 139 254 36; fax: +33 139 254 452.
E-mail address: odavid@chimie.uvsq.fr (Olivier R. P. David).
Figure 1. Synthetic receptors 1 and 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.078

N. De Rycke et al. / Tetrahedron Letters 53 (2012) 462–466
463
N
N
OH
N
Cl
N
DiBAL
N
H
SOCl2
O
O
O
O
THF
- 40 °C
75%
O
O
O
O
N
N
DMF
Reflux
85%
N
toluene
reflux
84%
N
N
N
N
N
OH
OH
Cl
Cl
O
O
5
3
4
5
Scheme 3. Direct reduction to dialdehyde 3.
Scheme 1. Preparation of diamide 5.
investigated to achieve this delicate twofold selective reduction
and, after some experimentation following reported amide-alde-
hyde interconversion methodologies,20 optimal conditions were
spotted with DIBAL.
and this work aims to explore such possibility. However, a simple
synthetic access to similar aza-cryptands is first needed since non
C3-symmetrical 1b,c require multistep sequences for their prepara-
tion. Therefore, we took the advantage of the recently described effi-
cient preparations of C3-symmetrical aza-cyclophanes11 described
by Roelens,12 Delgado,13 Ghosh,14 and our group.15
These syntheses rely on thermodynamically driven imine con-
densation allowing nearly quantitative formation of polyamine of
type 2 after reduction of the imine functions. Therefore, our investi-
gation began with the synthesis of a new aza-cryptand 2 containing
three 2,6-bis-(aminomethyl)pyridine moieties able to bind cop-
per(II) salts (Fig. 1). Use of the corresponding copper(II) complex
for copper(II)-catalyzed Henry (nitroaldol) reaction16–18 was next
considered. Indeed, due to the modest size of the involved nucleo-
philic nitronate that can therefore easily enter within aza-cryptand’s
cavity, we hoped to demonstrate that such catalyst could display
some selectivity as regard to the size of the reacting aldehyde
partner.
Preparation of aza-cryptand 2 began with the synthesis of dial-
dehyde 3 which contains the 4-pyrrolidino-pyridine pattern. We
chose to include this electron-rich pyridine moiety in the structure
of cage 2 aiming to maximize the copper(II) chelation by the tri-
dentate 2,6-bis-(aminomethyl)pyridine moiety. Intermediate dia-
mide 5 was prepared from the commercially available chelidamic
acid by chlorination to give 4, followed by reaction with pyrroli-
dine leading to diamide 5 in good yields (Scheme 1).
A first approach to the targeted dialdehyde was explored fol-
lowing previously described route reported for the 4-dimethyl-
amino analog.19 Diamide 5 was thus hydrolyzed by a solution of
sodium hydroxide in ethanol and was then bis-esterified with
methanol in acidic medium, leading to diester 6 in 59% over two
steps. Reduction of the ester with LiAlH4 gave crude diol 7, which
was then oxidized using Swern conditions to give dialdehyde 3 in
moderate yield over two steps. This sequence allowed the prepara-
tion of small amounts of dialdehyde 3 in four steps in a global yield
of 22%, Scheme 2.
The double reduction was thus best effected in THF, at À40 °C,
using a DIBAL solution with a fourfold excess. This allowed the
preparation of dialdehyde 3 in a yield of 75% in only one step
(Scheme 3). Remarkably this protocol was repeated with the Wein-
reb diamide but did not allow us to produce any quantity of dial-
dehyde 3. As shown in the previous studies,15 this compound is a
good candidate for imine condensation reactions with an aromatic
triamine to elaborate hexa-azacryptands. Dialdehyde 3 was there-
fore reacted with triamine 8 in a mixture of DCM/MeOH to furnish
hexa-imine cage 9, containing a C3-symmetry axis, in quantitative
yield. The six imine moieties of macrocycle 9 were easily reduced
with an excess of NaBH4 to give hexa-amine cage 2, in a 92% yield,
without need for any purification (Scheme 4). This aza-cryptand
constitutes an electron-rich version of the cage prepared and stud-
ied by the group of Delgado.13
For comparative experiments, we also prepared the simple li-
gand 10 by reaction of aldehyde 3 with benzylamine and subse-
quent reduction, see Scheme 5.
Once the synthesis of cage 2 had been secured, we explored its
use, as a copper(II) complex, for its potential catalytic activity in ni-
tro-aldol reactions with aldehydes. Anslyn and co-workers exam-
ined the binding stoichiometry of receptors 1b and 1c with
copper(II) salts in acetonitrile, an aprotic solvent. These two recep-
tors are fitted with, respectively, one and two diaminopyridine
moieties, it was hence shown that cage 1b formed a 1:1 complex
with copper(II), while cage 1c formed the 1:2 complex. Titration
studies indicated high association constants.9 Due to the virtually
insoluble nature of cage 2 in acetonitrile, we could not perform a
comparable study. The group of Delgado recently undertook the
careful study of the complexing properties of a similar C3-symmet-
rical cage in an aqueous medium (H2O/MeOH: 1/1) taking into ac-
count the different protonated forms of the receptor. This study
demonstrated that cage 2, fitted with three complexing units,
was able to accommodate three copper(II) ions. For our catalysis
experiments only one copper(II) center is necessary inside the
reaction cavity, we thus assumed that upon addition of slightly less
than one equivalent of copper(II) salt, the predominant species in
organic solution would be the 1:1 complex.
The first set of experiment was devised in order to demonstrate
the feasibility of a Henry reaction within cage 2. We chose 4-nitro-
benzaldehyde as the test substrate for its good electrophilicity and
nitromethane as the nucleophile. We also adopted copper(II) ace-
tate as the copper source as being the most commonly employed
in the literature. Different solvents and mixtures of solvents were
tested. As mentioned above, cage-ligand 2 is poorly soluble in polar
solvents such as acetone, acetonitrile, DMF, DMSO or dioxane and
is totally insoluble in protic solvents like methanol, ethanol.
Although freely dissolved by THF, ethyl acetate or toluene, the best
results were obtained with a DCM/MeOH 1:1 mixture. All further
experiments were thus performed in this mixture. The successful
Henry condensation was observed using the protocol as follows
This lengthy preparation could be optimized through a direct
reduction of diamide 5 into dialdehyde 3. Various conditions were
N
1) NaOH
N
EtOH 95% reflux
O
O
2) H2SO4
MeOH reflux
59% two steps
N
MeO
OMe
N
N
N
O
O
O
O
5
6
N
N
(COCl)2, DMSO
LiAlH4, THF
reflux
Et3N, DCM
37% two steps
N
N
3
OH
OH
7
Scheme 2. First preparation of dialdehyde 3.

464
N. De Rycke et al. / Tetrahedron Letters 53 (2012) 462–466
N
O
N
N
N
N
N
N
N
3
N
N
DCM
O
N
N
+
MeOH
quant.
NH2
NH2
N
N
9
H2N
8
N
N
H
N
N
NH
NH
NaBH4
92%
HN
HN
N
N
H
N
N
2
Scheme 4. Preparation of azacryptand 2.
O
NO2
NO2
Ph
NO2
15
N
N
14
NH
NH
3
MeOH
O
N
N
+
NO2
NO2
OH
12
Scheme 7. Henry condensations with various nitroalcanes.
Ph
NO2
then NaBH4
95%
H2N
OH
OH
10
O2N
O2N
O2N
Scheme 5. Preparation of ‘open’-ligand 10.
11
13
with a catalyst loading of 10% in a 1:1 complex. The latter was pre-
formed by mixing 12% of ligand 2 with 10% of copper acetate for
12 h, resulting in a deep-blue clear solution (kmax = 500 nm). Reac-
tants were thus added and progression of the reaction was moni-
tored by TLC and proton NMR. At ambient temperature, 72 h
were necessary to observe the complete disappearance of the start-
ing aldehyde. After this period of time, nitroaldol derivative 11 was
isolated in quantitative yield (Scheme 6). Interestingly, the reac-
tion using the same conditions with pyridine derivative 10 as the
ligand gave 11 after only one night of reaction, showing the shield-
ing effect exerted by the cage around the reactive center.
Under similar conditions, hexa-imine cage 9 displayed much
lower catalytic activity, since after 6 days, aldehyde conversion into
nitroaldol was limited to 29%. This result can unveil a critical role of
the secondary amines inside the cryptand, may be acting as Brönsted
bases to deprotonate the complexed nitromethane. We then
checked the role of each constituent of the catalytic system by per-
forming blank experiments. Thus, Cu(OAc)2 or ligand 2 or ligand
10 alone was not able to promote the Henry reaction. Hence, the
occurrence of a background reaction promoted by remaining free
copper(II) ions can be ruled out. In the same way, the native bis-
(aminomethyl)pyridine moiety is not catalytically active either. This
proves that the only active species is indeed the liganded copper
center. Additionally, it should be noted that complexes prepared
by mixing cage 2 with either two or three equivalents of copper salt
were not effective in promoting the Henry reaction, suggesting that
only the mononuclear complex is active.
In the following set of experiments, various nitro-containing
substrates were engaged in the test reaction. Using open ligand
10, the Henry reaction was performed separately with nitrobutane
and phenylnitromethane21 to give both nitroaldol products as mix-
tures of diastereomers (syn/anti), see Scheme 7. We then ran com-
petition experiments in order to evaluate the different ligands
toward a potential substrate-selectivity, see Table 1. ‘Open’ ligand
10 was used in order to determine the relative chemical reactivity
of nitromethane/nitrobutane and nitromethane/phenylnitrome-
thane mixtures.
From this, we conclude to the intrinsic superior reactivity of
nitromethane over other nitro compounds. Nitrobutane seems to
inhibit cage-catalyst 2 since its introduction stops any Henry
reaction. We can hypothesize that nitronate derived from nitrobu-
tane is strongly bounded within the cage but is unreactive toward
the aldehyde. With nitromethane/phenylnitromethane mixtures
Table 1
Competition experiments with nitro-compoundsa
Ligand
MeNO2/nBuNO2
MeNO2/BnNO2
O
OH
ligand-Cu(OAc)2 10%
11/12:85/15 (95%,b 6 d)
nrc
11/13:80/20 (85%,b 5 d)
11/13:100/0 (65%,d 14 d)
NO2
10
Cage 2
H
MeNO2
MeOH/DCM
100%
11
O2N
O2N
a
Reactions and conditions: DCM/MeOH 9:1, Cu(OAc)2 10%, ligand 12%, MeNO2/
RNO2/ArCHO, 40/40/1. Time in days for disappearance of the aldehydic proton in
NMR. Product ratios according to proton NMR integrations.
ligand = cage 2:
72h
b
Based on mass-recovery after filtration over silica.
No reaction after 15 days.
Isolated yield.
ligand = pyridine 10: 12h
c
d
Scheme 6. Henry reaction.

N. De Rycke et al. / Tetrahedron Letters 53 (2012) 462–466
CHO
465
CHO
CHO
H
H
N
N
N
N
N
O
O
O
16
O
O
N
R
N Cu
X
N Cu
X
R
N
N
N
N
O
CHO
H
H
TS 19
TS 20
17
18
Figure 3. Two plausible transition states for the Henry reaction. (Substituents are
omitted for clarity reasons, X = OAc).
Figure 2. Various aldehydes tested in the Henry condensation.
cage-ligand 2 succeeds in discriminating the smaller nitroalkane
since only nitroaldol 11 is observed in the crude reaction mixture.
Different aldehyde partners with contrasted steric hindrance
around the carbonyl group were then tested as substrates. We first
tested separately: benzaldehyde, 1-naphthaldehyde 16 and two
aldehydes with much contrasted environments anthracene-9-
carbaldehyde 17 and anthracene-2-carbaldehyde 18 following
the disappearance of the aldehydic protons in NMR on aliquots,
see Figure 2. The experiments were done employing either the
open ligand 10 or cage 2. We determined the time necessary to
reach 50% and 90% conversion; the results are gathered in Table 2.
From this, we conclude that benzaldehyde and 16 behave in very
similar ways with the complex of 10 or with the cage 2 complex, the
latter showing no sign of discrimination between these substrates.
In contrast, upon examination results with aldehydes 17 and 18
with very dissimilar environment we can observe a partial discrim-
ination exerted by the cage ligand. Interestingly, with the open
ligand 10 the more encumbered aldehyde 17 is still the most reac-
tive, this can be explained by a more electrophilic 9-aldehyde func-
tion compared to the 2-substituted isomer 18. Then switching to
cage catalyst the observed reactivity is reversed. Henry reaction is
faster with the less hindered isomer 18 than with 17. Thus, these
two substrates are partially discriminated by the encapsulated
catalytic center, although reaction rates are only moderately differ-
entiated. In fact, if we examine the plausible mechanism22 of this
Henry reaction in the cage cavity, one is to wonder if reactants are
truly entering the empty space of cage 2. As reported by Anslyn with
an open-ligand complexing copper(II) triflate, X-ray diffraction
analysis shows that metallic center is adopting a pseudo-octahedral
geometry. We can thus infer that Henry reaction transition state
with this catalyst also possesses a copper ion with a nearly octahe-
dral environment, see Figure 3. With this hypothesis three arrange-
ments are possible according to the respective placement of the
three oxygenated ligands: nitronate, aldehyde, and acetate counter-
ion. If the acetate is coordinating in the plan defined by the three
nitrogen atoms, nitronate, and aldehyde partners are in trans dispo-
sition and cannot thus react. There is only two reactive coordination
isomers; either the nitronate is in the trisamine plan and thus inside
the cavity, the aldehyde occupying the cis-position ‘at the door’ of
the cavity, see TS 19. Alternatively, it is the aldehyde coordinated
inside and the nitronate that occupies the lateral position, just at
the entrance of the cavity, see TS 20.
In any cases, one of the reactant is not formally captured within
the cavity in order to reach the reactive center and is not in fact
fully subjected to the cage discriminating features. Therefore, in
order to insure more efficient substrate selection, larger cavities
are desirable mimicking an enzymatic pocket that could accommo-
date both reactants and let them interact with an inwardly direc-
ted active functionality playing the role of an active site.
We prepared in good yields hexa-amine cage compound 2,
using a reversible imine-condensation strategy with readily pre-
pared building blocks. This architecture displays three electron-
rich tris-dentate moieties able to coordinate a copper(II) ion center
which then shows catalytic activity in Henry reactions between
nitro alkanes and aldehydes. Premises of substrate selectivity were
observed by partial discrimination of small substrates. Relevant
selectivities are probably hampered by intrinsic inability of cage
2 to encapsulate both reacting partners. We are currently prepar-
ing larger cage-compounds with more spacious cavities that would
hopefully accommodate a truly incarcerated bimolecular reaction
triggered by an inwardly directed functional group.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.078.
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Table 2
Time for conversion of various aldehydes
Aldehyde
PhCHO
50% Conv
90% Conv
6 h with 10
24 h with 2
8 h with 10
26 h with 2
6 h with 10
72 h with 2
9 h with 10
48 h with 2
18 h with 10
72 h with 2
24 h with 10
72 h with 2
24 h with 10
360 h with 2
30 h with 10
168 h with 2
1-Naph-CHO 16
9-Anthr-CHO 17
2-Anthr-CHO 18
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