Inherently Chiral Upper-Rim-Bridged Calix[4]arenes Possessing a Seven Membered Ring

Article abstract of DOI:10.1021/acs.orglett.7b01170

The mercuration of calix[4]arene immobilized in the cone conformation allowed the introduction of an amino group at the meta position of the basic skeleton. Acylation and subsequent intramolecular Bischler-Napieralski-type cyclization led to a novel type of bridged calixarene containing a seven-membered ring. These compounds with an enlarged and rigidified cavity represent a unique and inherently chiral system that may potentially be applicable for the design of chiral receptors. The absolute configuration of one enantiomer, obtained by resolution of the racemate using chiral HPLC, was assigned by single-crystal structure determination.

Full text of DOI:10.1021/acs.orglett.7b01170

Letter
pubs.acs.org/OrgLett
Inherently Chiral Upper-Rim-Bridged Calix[4]arenes Possessing a
Seven Membered Ring
Martin Tlusty,† Petr Slavík,† Michal Kohout,† Vaclav Eigner,‡ and Pavel Lhotak*,†
́
́
́
†Department of Organic Chemistry, University of Chemistry and Technology, Prague (UCTP), Technicka
Republic
‡Solid State Department, UCTP, 166 28 Prague 6, Czech Republic
́
5, 166 28 Prague 6, Czech
S
* Supporting Information
ABSTRACT: The mercuration of calix[4]arene immobilized in
the cone conformation allowed the introduction of an amino group
at the meta position of the basic skeleton. Acylation and
subsequent intramolecular Bischler−Napieralski-type cyclization
led to a novel type of bridged calixarene containing a seven-
membered ring. These compounds with an enlarged and rigidified
cavity represent a unique and inherently chiral system that may potentially be applicable for the design of chiral receptors. The
absolute configuration of one enantiomer, obtained by resolution of the racemate using chiral HPLC, was assigned by single-
crystal structure determination.
alix[n]arenes,1 and more recently thiacalix[n]arenes,2 are
Cmacrocyclic families frequently used as building blocks in
supramolecular chemistry. As one can simply select not only
the size of their cavity (from four to eight phenolic moieties)
but also their three-dimensional shape (in the case of
calix[4]arene), they have become popular starting points in
the design and synthesis of various receptors and/or supra-
molecular functional systems.3
The chemistry of calix[4]arenes is currently well-established,
offering many general derivatization methods for the basic
macrocyclic skeleton.1 Nevertheless, electrophilic aromatic
substitution commonly used for derivatization of the aromatic
region of the molecule (usually called the “upper rim”) suffers
from some limitations in terms of regioselectivity. Indeed, when
using common direct or ipso substitutions (halogenation,
nitration, sulfonation, Friedel−Crafts reactions, chloromethyla-
tion, etc.) only the para positions of the phenolic moieties
(with respect to the phenolic oxygen) are accessible.1
rim connecting two neighboring aromatic subunits. These
compounds, which possess a seven-membered ring within their
macrocyclic structure, represent inherently chiral systems9 with
an as yet unknown substitution pattern in calixarene chemistry
that may potentially be applicable for the design of chiral
receptors.
The starting tetrapropoxycalix[4]arene 1, immobilized in the
cone conformation, was transformed into meta-substituted
chloromercurio derivative 2 in 65% yield (on a multigram
scale) using a recently described procedure4 (Scheme 1). The
corresponding nitroso derivative 3 was obtained in 91% yield
Scheme 1. Preparation of the Upper-Rim-Bridged
Calix[4]arenes
We recently discovered4 direct mercuration in the calix[4]-
arene series with unprecedented regioselectivity. Thus, the
meta-substituted chloromercurio derivative 2 can be obtained
selectively in high yield by simple reaction of the starting
calix[4]arene 1 with mercury(II) trifluoroacetate (Hg(TFA)2)
and subsequent reaction with NaCl. Although organomercury
derivatives tend to be avoided because of their toxicity (all
organomercury derivatives are considered potentially hazardous
and require special consideration), in this case, meta-mercuration
represents an irreplaceable tool for the derivatization5 of
calix[4]arenes in this rarely accessible position.6 The synthetic
usefulness of this approach was demonstrated inter alia by the
formation of highly rigidified systems bearing single-bond7 or
carbonyl bridges8 within the calix[4]arene skeleton.
In this paper we report on the very straightforward synthesis
of calix[4]arenes rigidified by an additional bridge on the upper
Received: April 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01170
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Organic Letters
Letter
via reaction with nitrosyl chloride generated in situ from
isoamyl nitrite and aqueous HCl at 0 °C.10 Reduction of the
nitroso group was accomplished using Raney nickel and
hydrazine hydrate in refluxing EtOH to provide the key
intermediate, meta-amine 4, in 89% yield. The corresponding
acylation was carried out using various carboxylic acid
derivatives. Thus, compound 5a was smoothly prepared in
91% yield by reaction with acetic anhydride in THF in the
presence of triethylamine (TEA) as a base (Scheme 1). A
similar reaction with benzoyl chloride led to 5b in 53% yield.
To obtain intermediates possessing a reactive functional group
that is potentially capable of further derivatization, compounds
5c and 5d were prepared using BrCH2COBr and ClCH2COCl
in 42% and 39% yield, respectively.
oxidation of the free OH group to the ketone moiety, resulting
in the formation of 6e in 19% yield.
The structures of the products were confirmed by a
combination of NMR and MS techniques. The HRMS ESI+
analysis of 6a showed signals at m/z = 632.37399 and
654.35502, which were in good agreement with the [M +
H]+ (632.37344) and [M + Na]+ (654.35538) cations
1
predicted for the bridged product. The H NMR spectrum of
6a (CDCl3) revealed the presence of four doublets at 2.79,
3.19, 3.24, and 3.28 ppm with appropriate geminal coupling
constants (J ≈ 12.1−12.5 Hz), consistent with the equatorial
C−H bonds from the methylene bridges. Similarly, four
doublets corresponding to axial C−H bonds could be found
between 4.41 and 4.60 ppm. This clearly supported the absence
of any symmetry elements in the product (inherent chirality).
The racemic compound 6a was subsequently separated into
enantiomers 6a_1 and 6a_2 on a chiral polysaccharide column.
The method was developed on an analytical scale (see Figure
1a), allowing for efficient preparative enantioseparation (see the
(S)-O-Acetylmandelic acid was reacted with amine 4 using
standard DCC coupling conditions to provide amide 5e in 41%
yield. The same product 5e was obtained in slightly higher yield
(57%) using the chloride of the above-mentioned acid. Amide
5e combines the inherent chirality of the meta-substituted
skeleton with the stereogenic center of the mandelic acid
moiety, thus leading to a mixture of diastereomeric products.
Unfortunately, all of our attempts to separate this mixture were
unsuccessful.
The Bischler−Napieralski reaction11 is a well-known method
to access 3,4-dihydroisoquinolines from the β-ethylamides.
Initially we used the traditional condensation agent, POCl3 in
refluxing MeCN. The reaction of amide 5a led to a mixture of
two main products: the expected bridged compound 6a isolated
in 30% yield and the byproduct 7 with an additional
acetylimino group in 10% yield (Scheme 2). The latter is
Scheme 2. Unusual Course of the Bischler−Napieralski
Reaction
probably formed by initial direct acylation of 5a with MeCN
under the reaction conditions and subsequent bridging of the
intermediate. The structure of 7 was supported by the presence
Figure 1. (a) Chromatographic resolution of racemic compound 6a on
a chiral column (Chiral Art Amylose-SA; mobile phase: heptane/
propan-2-ol (95/5 v/v); flow rate: 1 mL/min; rt). (b) ECD spectra of
the separated enantiomers of 6a in MeOH: the first-eluting
enantiomer 6a_1, solid blue line; the second-eluting enantiomer
6a_2, dashed red line.
1
of two methyl singlets in the H NMR spectrum (CDCl3) at
2.83 and 2.91 ppm, together with a singlet from the aromatic
region of the molecule (7.73 ppm). The HRMS ESI+ analysis of
7 revealed signals at m/z = 673.40042 and 695.38144, which
were in agreement with the predicted values for the [M + H]+
(673.39998) and [M + Na]+ (695.38193) cations.
As benzoyl amide 5b under identical reaction conditions
yielded no cyclization product, we used higher-boiling toluene
instead of MeCN. Under these conditions, the corresponding
cyclic products 6a and 6b were isolated in 39% and 49% yield,
respectively, after purification of the crude reaction mixture by
preparative TLC on silica gel. Similar cyclization of 5d gave the
chloromethyl-substituted derivative 6d in 41% yield. Interest-
ingly, the same chloromethyl derivative 6d was obtained in
even higher yield (50%) by the reaction of bromoacetylamide
5c, showing the lower stability of the bromine atom in the
presence of POCl3. The cyclization of a diastereomeric mixture
of 5e led to deprotection of the acetyl group and subsequent
Supporting Information (SI)). The enantiomeric character of
the separated substances 6a_1 and 6a_2 was verified with
electronic CD (ECD) spectroscopy, which showed the typical
mirror images (Figure 1b). The optical purities of both
enantiomers were found to be >99.5% ee (see the SI).
Final unambiguous proof of the structure of the upper-rim-
bridged derivatives was obtained by single-crystal X-ray
structure determination12 of enantiomer 6a_1 (the first-eluting
isomer from the above-described racemate resolution) obtained
by slow evaporation from an EtOH/CH2Cl2 mixture. This
revealed that the enantiomer 6a_1 crystal belonged to the
monoclinic system, space group P21. As follows from the X-ray
B
DOI: 10.1021/acs.orglett.7b01170
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structure (Figure 2), the absolute configuration of inherently
chiral 6a_1 could be assigned as cS (or M).9 The asymmetric
Figure 3. (a) 1H NMR CIS values (+, upfield shift; −, downfield shift)
for compound 8 induced by the addition of 1 equiv of 6a_1 (400
Figure 2. Single crystal X-ray structures of the two pinched cone
conformations PC1 and PC2 of enantiomer 6a_1: (a) PC1 side view;
(b) PC1 top view; (c) PC2 side view; (d) PC2 top view.
1
MHz, CDCl3, c = 3 × 10−3 mol·dm−3, 298 K). (b) H NMR titration
curve for 6a_1 with 8 (400 MHz, CDCl3, c = 3 × 10−3 mol·dm−3, 298
K).
unit consists of two independent molecules showing two
different pinched cone conformations PC1 and PC2. If we define
the main plane of the molecule by the four C atoms of the CH2
bridges, the corresponding interplanar angles Φ with aromatic
subunits are 97.96°, 117.82°, 90.09°, and 137.83° for PC1
starting from the moiety bearing the nitrogen atom and
continuing clockwise from the top view (see Figure 2a,b). The
same angles for PC2 were Φ = 113.44°, 101.87°, 135.75°, and
101.02°. The existence of two different conformations PC1 and
PC2 was rather unexpected as it indicated that the two-atom
bridge is still long enough that it cannot stop the
interconversion between the two pinched cone conformers.
Our preliminary binding experiments with (rac)-6a indicated
that this bridged compound can interact with neutral molecules
bearing an acidic CH3 group. Thus, 1H NMR titration
experiments (CDCl3) carried out with MeCN and MeNO2
this part of the pyridinium moiety into the aromatic cavity of
the receptor using a combination of CH−π, π−π, and/or
cation−π interactions15 with surrounding aromatic subunits.
Methyl group A was obviously shielded by the magnetic
anisotropy of the aromatic cavity (CIS = −101), while the N-
methyl group B on the pyrrolidine part of the molecule showed
a small downfield shift (CIS = +5.6 Hz) at the same time.
Together with the very small shift for position 7 (CIS = −6.5
Hz), this confirmed that the pyrrolidine part of nicotine was
localized outside the cavity of the receptor.
As shown in Figure 3b, the addition of 8 to the solution of
6a_1 in CDCl3 also led to distinct upfield shifts of the aromatic
signals on the receptor that could be easily used for the
construction of the corresponding titration curve. The resulting
complexation constant for receptor 6a_1 was 81 2 M−1. The
same titration experiments with enantiomer 6a_2 led to a
yielded the corresponding complexation constants 5.5
and 20
1.2
12 M−1, respectively. The complexation constants
were determined by analyzing the binding isotherms (obtained
from NMR data) using the application Bindfit,12 which is
designed to work with classical supramolecular titration data
obtained from NMR, UV, fluorescence, and other methods.13
On the basis of these results, we attempted the enantioselective
resolution of the chiral guest molecule. Natural (S)-nicotine
was reacted with methyl iodide in AcOH to achieve
methylation of the pyridinium moiety,14 and the resulting N-
methylnicotinium salt 8 was used for the titration experiments.
As shown in Figure 3a, the addition of 1 equiv of receptor 6a_1
to a solution of 8 in CDCl3 led to the complexation-induced
shift (CIS) of the singlet of methyl group A (from the
pyridinium moiety) toward higher magnetic field (CIS = −101
Hz). Similar shielding effects were demonstrated for the
neighboring hydrogen atom at position 2 (CIS = −60 Hz),
especially that at position 6 (CIS = −143 Hz), and also that at
position 5 (CIS = −56 Hz). This indicated the immersion of
higher value (94
5 M−1), indicating only modest
enantioresolution ability of the receptors in this particular
case, probably as a consequence of the relatively large distance
between the chiral center and the point of immersion into the
cavity. Further research on chiral recognition is currently in a
progress.
In conclusion, mercuration of calix[4]arene immobilized in
the cone conformation allowed the introduction of an amino
group at the meta position of the basic skeleton. Acylation and
subsequent intramolecular Bischler−Napieralski-type cycliza-
tion led to a novel class of bridged calixarenes containing a
seven-membered ring. These compounds with an enlarged and
rigidified cavity represent a unique inherently chiral system that
may potentially be applicable for the design of receptors. This
can be documented by the complexation of neutral compounds
bearing an acidic CH3 group (MeCN, MeNO2) or by the
inclusion of N-methylpyridinium derivatives into the cavity
C
DOI: 10.1021/acs.orglett.7b01170
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Organic Letters
Letter
(7) (a) Flídrova,
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k
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́
, P.
through the combination of CH−π and/or cation−π
interactions. The absolute configuration of one enantiomer,
obtained by resolution of the racemate using chiral HPLC, was
assigned by single-crystal structure determination.
̌
k
́
ova,
́
H.; Eigner,
́
́
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01170.
(10) Vrzal, L.; Flídrova,
Chem. Commun. 2014, 50, 7590.
(11) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
́ ̌ ́ ́ ́
K.; Tobrman, T.; Dvorakova, H.; Lhotak, P.
(12) The binding constants were calculated using the Bindfit
application (freely available at http://supramolecular.org). The
complexation curves gave the best fits using 1:1 stoichiometry.
(13) For the determination of association constants and the
stoichiometry of the complexes from titration experiments in
supramolecular chemistry, see: (a) Thordarson, P. Chem. Soc. Rev.
2011, 40, 1305. (b) Ulatowski, F.; Dąbrowa, K.; Bałakier, T.; Jurczak, J.
J. Org. Chem. 2016, 81, 1746. (c) Hibbert, D. B.; Thordarson, P. Chem.
Commun. 2016, 52, 12792.
Experimental procedures, full characterization of com-
pounds 3, 4, 5a−e, 6a−d, 7, and 8, and results of the
complexation study (PDF)
X-ray crystallographic data for 6a_1 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
* E-mail: lhotakp@vscht.cz
ORCID
(14) (a) Seeman, J. I.; Whidby, J. F. J. Org. Chem. 1976, 41, 3824.
(b) Heckel, T.; Winkel, A.; Wilhelm, R. Tetrahedron: Asymmetry 2013,
24, 1127.
(15) For selected reviews of cation−π complexes of calixarenes, see:
(a) Abraham, W. J. Inclusion Phenom. Mol. Recognit. Chem. 2002, 43,
159. (b) Lhotak, P.; Shinkai, S. J. Phys. Org. Chem. 1997, 10, 273.
Pavel Lhotak: 0000-0003-3617-6596
Notes
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Czech Science Foundation
(Grant 16-13869S). Financial support from specific university
research (MSMT 20/2017) is also acknowledged.
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DOI: 10.1021/acs.orglett.7b01170
Org. Lett. XXXX, XXX, XXX−XXX