Synthesis of water-soluble highly charged and methylene-bridged resorcin[4]arenes

Article abstract of DOI:10.1055/s-2008-1032192

Methylene-bridged resorcin[4]arenes featuring electrochemically active and hydrophilic viologen units, chemically attached to their 'rim' regions, and a variety of pendent groups ('feet') have been synthesized. These compounds were designed to act as electrochemically active cavitands and especially as guests in mycobacterial channel proteins (channel blockers). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032192

932
PAPER
Synthesis of Water-Soluble Highly Charged and Methylene-Bridged
Resorcin[4]arenes
M
ethylene-Bridge
i
dResor
a
cin[4]are
n
o
es xuan Leaym, Stefan Kraft, Stefan H. Bossmann*
Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, KS 66506-3701, USA
Fax +1(785)5326666; E-mail: cherrygr@ksu.edu; E-mail: skraft@ksu.edu; E-mail: sbossman@ksu.edu
Received 27 September 2007; revised 13 December 2007
dinium cavitands possessing larger than methyl groups
were found to aggregate in water. Similarly, cavitands
featuring an sp3-ammonium center were obtained by re-
acting hexamethylenetetraamine as (bulky) amine with
Abstract: Methylene-bridged resorcin[4]arenes featuring electro-
chemically active and hydrophilic viologen units, chemically at-
tached to their ‘rim’ regions, and a variety of pendent groups (‘feet’)
have been synthesized. These compounds were designed to act as
electrochemically active cavitands and especially as guests in the same precursor.17 Other examples comprise the use of
mycobacterial channel proteins (channel blockers).
amidinium groups on the upper rim of resorcin[4]arene
cavitands.19
Key words: hydrophilic methylene-bridged resorcin[4]arenes,
4,4¢-viologens, host/guest, supramolecular
Here, we describe the synthesis of methylene-bridged re-
sorcin[4]arenes featuring 4,4¢-bipyridinium and 3,3¢-di-
methyl-4,4¢-bipyridinium units, chemically linked to the
Resorcin[4]arenes1,2 as building elements of various su-
pramolecular assemblies, such as cavitands,3 hemicar-
cerands,4 and carcerands,5 have been synthesized since
Högberg published the basic procedures in 1980.6,7 This
class of compounds has undergone a considerable evolu-
tion and diversification along the way. Only a few high-
lights, which are important for the development of water-
soluble, highly cationic and methylene-bridged resor-
cin[4]arenes, can be covered here.
‘rim’ of the cavitand. tert-Butyldiphenylsilyl20 and acetyl
ester protection groups11 have been introduced and then
again removed to facilitate the synthesis of a ‘feet’-region
consisting of hydrophilic propanol groups.
As it is apparent from Figure 1, the charge-repulsion be-
tween the four bipyridinium units, which are connected to
methylene groups permitting them relatively unhindered
rotation, causes a flower-like opening of the resor-
cin[4]arene rim. Our objectives for synthesizing these
macrocycles were two-fold: A) The (3,3¢-dimethyl)-4,4¢-
bipyridinium units are very suitable electron-relays,
which can be reduced stepwise to viologen-monoradical
cations and then to the uncharged viologen diradicals. The
latter feature possesses a redox potential of approximately
–0.79 V (vs. SHE)21 allowing them to reduce and detoxify
chlorinated toxic hydrocarbons, such as carbon tetrachlo-
ride and tetrachloroethylene.22 It must be noted that the
doubly reduced viologens are hydrophobic in nature.
They can form supramolecular aggregates by hydropho-
bic interaction. For example, Willner and co-workers
have shown that they can be bound to the hydrophobic in-
terior of b-cyclodextrins.23,24 Therefore, we anticipate that
the doubly reduced bipyridinium-modified methylene-
bridged resorcin[4]arenes will form deep cavitands1 for
uncharged halogenated compounds. Furthermore, we ex-
pect that electron-transfer from the singly or doubly re-
duced viologens to the chlorinated compounds25 will take
place inside such a deep cavitand.
Methylene-bridged resorcin[4]arene cavitands have been
introduced because of their viability as precursors for the
syntheses of (hemi)carcerands, as well as for creating
greatly stabilized rigid cavities.8 Hydroxy-footed methyl-
ene-bridged resorcin[4]arenes possessing n-butanol as
pendant groups were introduced by Cram and co-work-
ers.9 Sherman and his team developed a more facile meth-
od for the synthesis of n-alcohols as pendant groups
(‘feet’).10,11 Based on the previous studies investigating
the influence of the chain lengths and especially the pres-
ence of functional groups of the cavitands on their water-
solubility, we decided to introduce propanol feet.12
Recently, pyridyl units have been attached to methylene-
bridged resorcin[4]arenes13 in order to create versatile su-
pramolecular building units and especially containers for
the purpose of drug delivery.14
A variety of positively15–17 or negatively18 charged meth-
ylene-bridged resorcin[4]arenes have been made, all for
the purpose of being hosts of polar and/or ionic com-
pounds in aqueous environments.1 Reinhoudt and co-
workers synthesized the first resorcin[4]arene cavitands
possessing an sp2-ammonium center via the nucleophilic
reaction of pyridine with bromomethyl cavitand precur-
sors.16 Due to the presence of pendant alkyl groups, pyri-
B) Recently, we were able to demonstrate that methylene-
bridged resorcin[4]arenes featuring 4,4¢-bipyridinium
units can be employed as channel blockers of mycobacte-
rial porins (model porin: MspA from mycobacterium
smegmatis).27 The binding of the resorcin[4]arene within
the porin was detected by monitoring the fluorescence oc-
curring from one coumarin fluorophore,28 which was
chemically linked to one of the propanol pendant groups.
The resorcinarene serves as a guest in this system, the
SYNTHESIS 2008, No. 6, pp 0932–0942
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032192; Art ID: M07007SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Methylene-Bridged Resorcin[4]arenes
933
Figure 1 Methylene-bridged resorcin[4]arene possessing four hy-
drophilic, redox-active 3,3¢-dimethyl-4,4¢-bipyridinium units, bonded
via methylene groups to its rim (calculated using PM326)
mycobacterial porin is the host! Due to the flexibility of
these systems, the macrocycle can act as a supramolecular
clamp, blocking the constriction zone (bottleneck) of the
porins. The blocking of the mycobacterial porin MspA is
schematically shown in Figure 2.
Figure 2 Binding of a methylene-bridged resorcin[4]arene posses-
sing four hydrophilic 4,4¢-bipyridinium units to MspA from M. smeg-
matis
sis of water-soluble highly positively charged and methyl-
ene-bridged resorcin[4]arenes.
We are assuming that the structures and especially bio-
physical properties of mycobacterial porins of the model
bacterium M. smegmatis and the culprit for several mil-
lion deaths per year, M. tuberculosis, are related to a cer-
tain extent.29 The constriction zone of MspA is
approximately 1 nm in diameter,29 however, a variety of
channel diameters must be expected if we would like to
block the porins in general. We are aiming at high charges
in the guest, since it can be expected that its binding with-
in the model porin MspA will be aided by the presence of
positive charges. MspA features a constriction zone con-
sisting of a double-ring of eight aspartates each, resulting
in a maximum of 16 negative charges in that particular re-
gion.30 On the other hand, if the paradigm that all porins
contain a high density of negative charges at their inner
pores’ walls turns out to be incorrect, a synthetic strategy
permitting high flexibility1 will be very welcome.
Optimization of the Synthesis of the Reactive
Cavitand
We have followed the strategy developed by Mezo and
Sherman11 for the synthesis of water-soluble cavitands
featuring four aromatic methyl substituents at their rims
that can be easily derivatized. The acid-catalyzed conden-
sation of 2-methylresorcinol and 2,3-dihydrofuran in
MeOH led to the C4v-symmetric product, 2-methyldode-
col 1 (Scheme 1).
In order to improve the overall yields of the (mostly) lin-
ear synthesis of highly charged cavitands, we have revis-
ited the second step of the original procedure described in
reference 11 (2-methyl cavitand, compound 3 in the orig-
inal procedure). By exchanging DMA against DMSO and
optimizing the reagent concentrations and heating inter-
Since hydrophilic nutrients and metabolic waste cannot
diffuse through the very hydrophobic mycobacterial outer
cell membranes, this can be achieved only through the
water-filled inner pores of the porins.29 Therefore, the
blocking of these channels will cause starvation and/or
metabolic poisoning of the mycobacteria, resulting in
their dormancy or death. The size (diameter) of the de-
sired organic channel blockers may range from approxi-
mately 0.5 to 2.5 nm, in order to block virtually all
mycobacterial porin channels. Here, we report the synthe-
HO
OH
HO
OH
HCl
4
MeOH
O
1
OH
Scheme 1 HCl-catalyzed cyclic condensation of 2-methylresorci-
nol and 2,3-dihydofuran to 2-methyldodecol 1
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

934
X. Leaym et al.
PAPER
O
O
HO
OH
O
O
O
O
TBDPSCl
BrClCH2
catalyst: imidazole
DMF
K2CO3
DMSO
4
4
4
4
2
1
2
5
OH
OH
OH
OTBDPS
Scheme 2 Four-fold bridging of 2-methyldodecol 1 to the 2-methyl
cavitand 2
NBS
CCl4
AIBN
O
O
O
O
Ac2O
Br
catalyst: pyridine
O
O
4
4
2
3
4
OH
OAc
6
OTBDPS
NBS
CCl4
Scheme 4 TBDPS-protection and benzylic monobromination of the
2-methyl cavitand 2
AIBN
Br
procedure, as reported in reference 11, was clearly superi-
or in the reaction purity and yield (Scheme 4).
O
O
As in the case of the acetylated cavitand, our variant of
Sorell’s bromination method using AIBN instead of ben-
zoyl peroxide, worked better than the literature
procedure11 (Scheme 4).
4
4
OAc
Scheme 3 Acetylation and benzylic monobromination of the
2-methyl cavitand 2
Synthesis of the 4,4¢-Bipyridinium Cavitands
After we had optimized the procedures for the bromo-
methylated cavitands possessing acetylated and TBDPS-
protected ‘feet’, our next step consisted in enlarging their
rim-region by exploiting a simple nucleophilic substitu-
tion reaction. 4,4¢-Bipyridine and 3,3¢-dimethyl-4,4¢-bi-
pyridine were connected to the rim by forming
monopyridinium cations. Because of the intended appli-
cations of our cavitands, we were aiming at the symmetri-
cal substitution of all four bromomethyl groups with the
bipyridine-building elements.
vals, we have achieved an increase of the yield of purified
2-methyl cavitand 2 from 42 to 80% (Scheme 2).
The next four reactions, as shown in Schemes 3 and 4, are
optimizations of the original procedures by Mezo and
Sherman.11 The introduction of acetyl- or TBDPS-protec-
tion groups was necessary due to the inferior solubility of
2 in nonpolar solvents and the high probability of unwant-
ed oxidation during the subsequent bromination reaction.
It is commonly known that the acetyl group is base-sensi-
tive.11 The acetylated 2-methyl cavitand 3 was then sub-
jected to a variant of Sorrell’s bromination method.31
AIBN instead of benzoyl peroxide was used as radical ini-
tiator and NBS provided the low levels of bromine neces-
sary for successful benzylic monobromination. The
change of the radical initiator was mainly due to safety
concerns due to the fact that AIBN reacts at lower temper-
atures than benzoyl peroxide and is regarded as much
safer.32
The second step consisted in the quaternization of the four
remaining sp2 nitrogen centers using iodomethane as
quaternization reagent. The reaction sequence 4, 7, 8 is
characterized by acceptable synthetic yields (Scheme 5).
However, 8 is less water-soluble than desirable for its ap-
plication as a channel blocker. An attempt to remove the
acetyl-protection groups from 8 by treating it with a basic
aqueous solution failed due to the occurrence of a mixture
of numerous reaction products; and ion-exchange, using
DOWEX-50, led to a high degree of irreversible adsorp-
tion. Therefore, we have hydrolyzed compound 7 and then
quaternized this hydroxy-footed cavitand using dimethyl
sulfate. This strategy led to the hydroxy-footed cavitand
10, which possesses eight positive charges and hydrogen-
sulfate counter-anions. The physical properties of 10 are
much more suitable for microbiological applications.
The use of the tert-butyldiphenylsilyl (TBDPS) group for
the protection of the hydroxy feet has the advantage of in-
troducing an acid-sensitive group20 that can be removed
under conditions that preserve the acetal bridges of the
cavitands.11 It is, therefore, complementary to the use of
acetyl protection groups. Our attempts to enhance the
yield of this protection reaction were futile. The original
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

PAPER
Methylene-Bridged Resorcin[4]arenes
935
I–
N
N
Br
Br
Br
N
N
O
O
O
O
O
O
4,4'-bpy
DMF
MeI
DMF
4
4
4
4
7
8
OAc
OAc
OAc
H2O NaOH
2–
N
SO4
N
HO
N
N
O
O
O
O
DMS
MeOH
4
4
9
10
OH
OH
Scheme 5 Synthesis of highly charged cavitands possessing 4,4¢-bipyridinium building elements attached to their rims; 4,4¢-bpy = 4,4¢-bi-
pyridine, DMS = dimethyl sulfate
N
N
Br
Br
Br
N
N
O
O
O
O
O
O
4,4'-bpy
DMF
HBr
H2O
4
4
4
6
11
9
OTBDPS
OTBDPS
OH
Scheme 6 Alternative pathway to cavitand 9 starting from the TBDPS-protected bromomethylated cavitand 4
Our attempts to synthesize the eight-fold charged 4,4¢-bi- anism involving either two coupled or consecutive (most
pyridinium cavitands via a TBDPS-protected route failed. likely) SN reactions is summarized in Scheme 8. SN reac-
As shown in Scheme 6, the SN2 reaction of the bromo- tions of silicon-bound halides (19F vs. 18F) were described
methylated cavitand 6 with 4,4¢-bipyridine led to the four- in the literature.34 These reactions proceed most likely via
fold charged cavitand 11. The yield of this reaction is pentavalent transition states or intermediates. It is note-
somewhat lower than for the analogous synthesis using worthy that the reaction of methyl iodide and the TBDPS-
the acetyl-protected cavitand 4 (82% instead of 85%). We protected alcohol 11 led to the formation of numerous re-
attribute these findings to the higher solubility of 11 in action products and, surprisingly, also methylviologen.
acetone compared to 7. 1H NMR indicated nearly quanti- From the 1H and 13C NMRs of the reaction mixture, we as-
tative yields after the completion of reaction.
sume that a competition between the methylation of the
bipyridine units, the pendant groups, and a substitution re-
action at the sp2 ammonium centers occurred (Scheme 7).
Since this reaction is of apparently no preparative value,
we did not pursue it any further.
We have also attempted to quaternize the remaining sp2
centers of the TBDPS-protected cavitand 11 without prior
removal of the protection group. To our surprise, we
found that a very similar reaction occurred then during the
TBDPS deprotection by using aqueous HBr11 or a fluoride Due to the inferior solubility of TBDPS-protected cav-
salt in (dipolar) aprotic solvents.33 This reaction led to the itands in water and aqueous buffers in comparison to 9
basic resorcin[4]arene system 12 featuring methylated and 10, the reaction displayed in Scheme 8 is of limited
pendant groups (Scheme 7). Our proposed reaction mech- value here. However, the opportunity to attach longer
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

936
X. Leaym et al.
PAPER
N
O
O
O
O
O
MeI
Br
DMF
Br
N
4
4
O
O
3,3'-dm-4,4'-bpy
DMF
O
O
5
12
Me
OTBDPS
4
4
Scheme 7 Unexpected reaction: formation of methyl ether-footed
cavitands by nucleophilic substitution
4
13
OAc
OAc
H2O NaOH
Me
I
I
Si
O R
+
+
I
Si
I
Me
O
R
N
N
2–
SO4
HO
N
N
Scheme 8 Proposed mechanism of the deprotection reaction of the
TBDPS group in the presence of iodide in DMF
O
O
O
O
DMS
MeOH
4
4
alkyl chains to the feet of a TBDPS-protected cavitands
may exist.
15
14
OH
OH
Synthesis of the (3,3¢-Dimethyl)-4,4¢-bipyridinium
Cavitands
Scheme 9 Synthesis of highly charged cavitands possessing 3,3¢-di-
methyl-4,4¢-bipyridinium building elements attached to their rims;
3,3¢-dm-4,4¢-bpy = 3,3¢-dimethyl-4,4¢-bipyridine
3,3¢-Dimethyl-4,4¢-bipyridine has been chosen as a build-
ing element of four- and eight-fold charged cavitands,
because it is a more hydrophobic building element. Fur-
thermore, its reduction potentials for the first and second
reduction waves are considerably lower, compared to
4,4¢-bipyridine.21 Based on our experience in synthesizing
the cavitands 7, 9, and 10, we haven chosen to follow the
same synthetic path that led to the hydroxy-footed cav-
itand 10 possessing four 4,4¢-bipyridinium units that are
rim-linked in a flexible manner. The attachment of 3,3¢-
dimethyl-4,4¢-bipyridine to the bromomethyl groups was
achieved using the acetyl-protected cavitand 4 as the start-
ing material. Basic hydrolysis led to the hydroxy-footed
cavitand 13. Finally, the quaternization of the four re-
maining sp2 nitrogen centers was achieved by employing
dimethyl sulfate. This synthetic route is summarized in
Scheme 9.
Coumarins possess unusually high quantum yields of
fluorescence and permit the detection of their binding to
biological targets via fluorescence depolarization and
fluorescence resonance energy transfer (FRET).37 7-Ami-
nocoumarin was synthesized according to a literature pro-
cedure,38 though we have optimized the conditions.
Because of solubility problems of the cavitands 10 and 16,
the esterification of the tethered coumarin to the hydroxy
function of the resorcin[4]arene was achieved at the stage
of the four-fold charged cavitands. Then the previously
optimized quaternization procedure using dimethyl sul-
fate in methanol was used again to methylate the remain-
ing sp2 nitrogen centers (Scheme 10).
We have synthesized methylene-bridged resorcin[4]ar-
enes featuring electrochemically active and hydrophilic
viologen units, chemically attached to their ‘rim’ regions,
and thus extending their cavities. Two parallel synthetic
pathways, featuring acetyl- or TBDPS-protection groups
have been followed to arrive at the final substituted mac-
rocycles possessing hydroxy ‘feet’, which make them
especially suited for aqueous environments. These com-
pounds were designed to act as electrochemically active
cavitands and especially as guests in mycobacterial chan-
nel proteins, acting as mycobacterial channel blockers.
For the latter use, 7-aminocoumarin has been attached via
a linker to one of the pendant groups.
Linking of One Coumarin Fluorophore to the 4,4¢-
Bipyridinium and (3,3¢-Dimethyl)-4,4-bipyridinium
Cavitands
7-Aminocoumarin was linked to one hydroxy-foot of the
4,4¢-bipyridinium and (3,3¢-dimethyl)-4,4¢-bipyridinium
cavitands via Mitsunobu reaction35 (Scheme 10). Because
of their suitable fluorescence properties, coumarins are
very good fluorescence markers.28,36 Note that the intend-
ed use of these resorcin[4]arenes is as mycobacterial
channel blockers. Furthermore, it should be noted that at-
taching only one coumarin label is breaking the symmetry
of the resorcin[4]arene.
Solvents (ACS grade) and inorganic chemicals were purchased
from Aldrich and Acros Organics. DMF was further purified by
azeotropic distillation of DMF–toluene/H2O (85:10:5). Anhydrous
and amine-free DMF was collected when the temperature reached
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

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Methylene-Bridged Resorcin[4]arenes
937
O
HO
R
R
O
N
N
R
N
HN
O
O
HO
N
HO
N
R
O
HO
R
N
17
R
O
O
O
O
O
TPP, DEAD
DMF
3
4
18 R = H
19 R = Me
9
R = H
O
OH
14 R = Me
OH
O
O
R
R
N
HN
O
O
N
2–
4 SO4
N
N
R
R
O
O
O
O
DMS
MeOH
3
20 R = H
21 R = Me
O
OH
O
O
HN
O
O
Scheme 10 A: Attaching succinyl-tethered 7-aminocoumarin to one hydroxy-foot of the four-fold charged cavitands 9 and 14 by means of a
Mitsunobu reaction. B: Final quaternization of the cavitands 18 and 19, which were linked via ester-formation to one succinyl-tethered 7-ami-
nocoumarin.
152 °C at the top of a 20 cm Vigreux column. All other chemicals
and chromatography materials were either purchased from Aldrich
or Acros Organics and used without further purification. H2O was
of bidistilled quality. All distillations under vacuum were per-
formed using a Büchi rotavap equipped with a solvent recovery sys-
tem and pressure control. All high-pressure reactions were
performed in a PARR reactor (V = 50 mL). Further instrumenta-
tion: 400 MHz NMR (Varian), FT-IR (Nicolet 870), MS: Bruker
Esquire 3000, Melting point apparatus (Fisher, all melting points
are uncorrected), Carlo Erba Strumentatione (CHN).
2-Methyl Cavitand 2
Anhyd K2CO3 (predried for 24 h at 100 °C, 46.0 g, 0.333 mol) was
added under N2 to a solution of 2-methyldodecol 1 (20.0 g, 0.0258
mol) in anhyd DMSO (800 mL). Bromochloromethane (7.5 mL,
0.0113 mol) was then added dropwise under N2. It is of great impor-
tance to stir the mixture rigorously during the addition. The mixture
was stirred overnight and then heated to 50 °C in 1 h and then kept
at that temperature for an additional 8 h. Then the mixture was re-
moved from the heating bath. Another portion of bromochlo-
romethane (1.0 mL, 0.0015 mol) was added after the mixture had
cooled to r.t. After stirring for an additional 5 h at r.t., the mixture
was poured into sat. aq NH4Cl (2.4 L) and the precipitate was col-
lected by filtration. The whitish solid obtained was washed with
H2O (3 × 200 mL) and then dried under normal pressure. The prod-
uct was further purified by descending column chromatography us-
ing silica gel as stationary phase. After the impurities have been
eluted with CHCl3–MeOH (12:1), the product was obtained using
CHCl3–MeOH (10:1). After removal of the solvent mixture at re-
duced pressure, the product was obtained as a white powder; yield:
17.0 g (80%); mp 227 °C (dec.).
2-Methyldodecol 1 was prepared by following a published proce-
dure;11 our yields ranged from 76–80% (published 78%). TBDPS-
protected 2-methyl cavitand 5 was prepared by following a pub-
lished procedure as well.11 Our maximum yield was 85% (published
87%). 3,3¢-Dimethyl-4,4¢-bipyridine was synthesized according to a
previously published procedure.34 Compounds 8–12 melted partial-
ly under decomposition at the temperature interval between 140–
150 °C. Compounds 14–20 underwent decomposition when heated
above 300 °C without melting.
The IR and NMR data of the compounds 1–15, 17–21 prepared are
collected in Table 1.
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

938
X. Leaym et al.
PAPER
Table 1 Characterization of the Optimized and the Newly Synthesized Compounds
Pro- FT-IR (KBr)
ducta cm–1
1H NMR (400 MHz, CDCl3)
d, J (Hz)
13C NMR (400 MHz, CDCl3)
d
1
3237, 2950, 2873, 1475, 1347, 1306, 1214, DMSO-d6: 8.62 (8 H, s), 7.27 (4 H, s), 4.19 DMSO-d6: 149.11, 124.82, 121.31, 111.61,
1107, 1066
(4 H, t, J = 7.8), 4.1 (4 H, s), 3.44 (8 H, t, 60.71, 34.02, 31.31, 30.69, 29.34, 10.05
J = 6.7), 2.24 (8 H, m), 1.94 (12 H, s), 1.35
(8 H, m)
2
3406, 2940, 1470, 1306, 1245, 973
DMSO-d6: 7.43 (4 H, s), 5.86 (4 H, d,
DMSO-d6: 152.50, 137.72, 123.65, 119.30,
J = 7.4), 4.59 (4 H, t, J = 6.1), 4.43 (4 H, t, 98.08, 60.51, 40.41, 36.63, 30.98, 25.57,
J = 5.1), 4.19 (4 H, d, J = 7.4), 3.48 (8 H, 10.01
m), 2.35 (8 H, m), 1.88 (12 H, s), 1.42 (8 H,
m)
3
4
5
2942, 1726, 1480, 1240, 973
CDCl3: 6.93 (4 H, s), 5.86 (4 H, d, J = 6.9), CDCl3: 171.29, 153.62, 137.63, 124.42,
4.82 (4 H, t, J = 9.1), 4.23 (4 H, d, J = 6.9), 117.14, 98.60, 64.32, 36.60, 27.12, 26.65,
4.15 (8 H, t, J = 6.5), 2.26 (8 H, m), 2.03
21.01, 10.48
(12 H, s), 1.95 (12 H, s), 1.69 (8 H, m)
2942, 1726, 1480, 1240, 973
CDCl3: 7.09 (4 H, s), 6.01 (4 H, d, J = 6.1), CDCl3: 185.25, 153.38, 138.10, 123.67,
4.82 (8 H, t, J = 8.1), 4.55 (4 H, d, J = 6.7), 118.81, 98.75, 63.03, 41.19, 37.20, 26.76,
4.39 (8 H, s), 4.15 (8 H, t, J = 6.5), 2.28 (8 21.79, 10.52
H, m), 2.05 (12 H, s), 1.67 (8 H, m)
2937, 2863, 1475, 1112, 973, 702, 513
CDCl3: 7.60 (16 H, m), 7.28 (24 H, m), 6.91 CDCl3: 153.50, 137.94, 135.72, 134.10,
(4 H, s), 5.85 (4 H, d, J = 6.9), 4.77 (4 H, t, 129.72, 127.82, 123.95, 117.61, 98.65,
J = 8.2), 4.23 (4 H, d, J = 6.9), 3.66 (8 H, t, 63.63, 36.58, 30.80, 27.11, 26.23, 19.43,
J = 6.4), 2.22 (8 H, m), 1.95 (12 H, s), 1.59 10.56
(8 H, m), 0.99 (36 H, s)
6
7
8
9
2935, 2858, 1475, 1434, 1265, 1117, 979, CDCl3: 7.59 (16 H, m), 7.30 (24 H, m), 7.06 CDCl3: 153.78, 138.00, 135.65, 133.88,
707, 507
(4 H, s), 6.00 (4 H, d, J = 6.2), 4.78 (4 H, t, 129.76, 127.82, 124.84, 120.96, 99.22, 63.38,
J = 7.9), 4.54 (4 H, d, J = 6.2), 4.39 (8 H, s), 36.37, 30.53, 27.08, 26.73, 26.19, 23.14,
3.65 (8 H, t, J = 6.3), 2.22 (8 H, m), 1.56 (8 19.38
H, m), 0.99 (36 H, s)
b
3053, 2945, 1736, 1644, 1465, 1250, 958, DMSO-d6: 9.16 (8 H, d, J = 6.4), 8.93 (8 H,
–
–
–
978, 815
d, J = 6.4), 8.62 (8 H, d, J = 6.4), 8.03 (8 H,
d, J = 6.4), 8.00 (4 H, s), 6.64 (4 H, d,
J = 5), 5.85 (8 H, d, J = 4), 4.52 (12 H, m),
4.05 (12 H, m), 1.93 (12 H, s), 1.54 (8 H, m)
b
3052, 2945, 2863, 1726, 1639, 1460, 1245, DMSO-d6: 9.25 (16 H, m), 8.73 (16 H, m),
979, 830
7.94 (4 H, s), 6.44 (4 H, d, J = 5), 5.87 (8 H,
s), 4.60 (12 H, m), 4.42 (12 H, s), 4.03 (12
H, m), 2.60 (8 H, m), 1.90 (12 H, s), 1.48 (8
H, m)
b
3272–3626 (br), 1639, 1250, 1153, 1020, DMSO-d6: 9.19 (8 H, d, J = 7.7), 8.88 (8 H,
989, 953, 553
d, J = 7.7), 8.65 (8 H, d, J = 7.7), 8.04 (8 H,
d, J = 7.7), 7.92 (4 H, s), 7.46 (4 H, m), 7.05
(4 H, m), 6.47 (4 H, d, J = 5), 5.90 (4 H, d,
5), 4.62 (8 H, m), 4.47 (4 H, m), 3.40 (4 H,
m), 1.38 (8 H, m)
b
b
10
11
3426, 1644, 1112, 620
DMSO-d6: 9.34 (16 H, m), 8.83 (16 H, m),
8.04 (4 H, s), 6.50 (4 H, d, J = 5), 6.00 (8 H,
d, J = 4), 4.63 (12 H, m), 4.47 (12 H, m),
1.37 (8 H, m)
–
–
2923, 2853, 1634, 1460, 1404, 1240, 1148, DMSO-d6: 9.14 (8 H, d, J = 7.7), 8.90 (8 H,
1102, 1020, 979, 953, 815, 702, 610, 502 d, J = 7.7), 8.76 (8 H, d, J = 7.7), 8.60 (8 H,
d, J = 7.7), 7.97 (12 H, m), 7.87 (4 H, d,
J = 7.4), 7.48 (16 H, m), 7.34 (16 H, m),
6.47 (4 H, d, J = 5), 5.83 (8 H, d, J = 4),
4.60 (12 H, m), 3.66 (8 H, m), 1.46 (4 H,
m), 0.80 (36 H, s)
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

PAPER
Methylene-Bridged Resorcin[4]arenes
939
Table 1 Characterization of the Optimized and the Newly Synthesized Compounds (continued)
Pro- FT-IR (KBr)
ducta cm–1
1H NMR (400 MHz, CDCl3)
d, J (Hz)
13C NMR (400 MHz, CDCl3)
d
12
2950, 2873, 1649, 1475, 1306, 1240, 1157, CDCl3: 6.90 (4 H, s), 5.87 (4 H, d, J = 5.7), CDCl3: 153.48, 137.93, 124.09, 120.76,
1096, 973, 671, 589, 502
4.76 (4 H, t, J = 4.6), 4.24 (4 H, d, J = 4.6), 98.65, 76.91, 72.62, 58.60, 36.79, 28.07,
3.47 (8 H, t, J = 6.2), 3.34 (12 H, s), 2.28 (8 26.81, 10.46
H, m), 1.96 (12 H, s), 1.63 (8 H, m)
b
13
2935, 1726, 1460, 1465, 1245, 958, 989
DMSO-d6: 9.15 (4 H, s), 8.90 (4 H, d,
J = 6.4), 8.64 (4 H, s), 8.56 (4 H, d, J = 8),
8.03 (8 H, m), 7.98 (4 H, s), 7.28 (4 H, d, J
= 8), 6.46 (4 H, d, J = 6), 5.75 (8 H, s), 4.61
(12 H, m), 4.03 (8 H, m), 3.43 (4 H, m),
2.46 (12 H, s), 2.45 (12 H, s), 2.14 (12 H, s),
1.46 (8 H, m)
–
b
14
15
3391, 2976, 2899, 2853, 1614, 1578, 1527, DMSO-d6: 9.28 (4 H, m), 8.97 (4 H, m),
1501, 1445, 1424, 1337, 1276, 1204, 1168, 8.67 (4 H, m), 8.58 (4 H, m), 8.04 (4 H, m),
–
–
1122, 1035, 1004, 979, 871, 804
7.95 (4 H, m), 7.33 (4 H, m), 6.45 (4 H, m),
5.81 (8 H, m), 4.64 (12 H, m), 3.49 (12 H,
m), 3.42 (12 H, m), 2.08 (12 H, m), 2.26 (12
H, m), 1.42 (8 H, m)
b
3406, 3104, 2981, 2909, 1695, 1537,
1419,1342, 1163, 1122, 1035, 994, 973,
881, 830, 717, 676, 605
DMSO-d6: 9.36 (4 H, s), 9.27 (4 H, d, J =
5.8), 9.07 (4 H, s), 8.92 (4 H, d, J = 5.8),
8.14 (8 H, m), 7.95 (4 H, s), 6.44 (4 H, d,
J = 5.8), 5.75 (8 H, d, J = 5.8), 4.68 (8 H,
m), 4.42 (12 H, s), 4.16 (16 H, m), 3.50 (12
H, s), 2.82 (12 H, s), 1.42 (8 H, m)
17
18
3493, 3421, 3308, 2930, 1742, 1711, 1670, DMSO-d6: 10.35 (1 H, s), 7.645 (2 H, m), DMSO-d6: 173.05, 170.23, 159.37, 153.04,
1624, 1583, 1537, 1398, 1363, 1229, 1178, 7.403 (1 H, d, J = 5.9), 6.18 (1 H, s), 2.49 (4 152.45, 141.89, 125.26, 114.27, 111.43,
871, 815, 717
H, m), 2.326 (3 H, s)
104.63, 30.53, 27.88, 17.29
b
3631–3308 (br),1745, 1710, 1639, 1460,
DMSO-d6: 9.17 (8 H, m), 8.89 (8 H, m),
–
1250, 1163, 1112, 984, 958, 820, 723, 538 8.04 (8 H, m), 7.90 (8 H, m), 7.79 (3 H, m),
7.38 (1 H, m), 6.46 (4 H, m), 5.88 (8 H, m),
4.64 (4 H, m), 4.08 (2 H, m), 3.62 (6 H, m),
2.40–2.45 (16 H, m), 2.30 (4 H, m), 1.4–
1.75 (11 H, m)
b
19
3401, 2991, 2899, 1608, 1537, 1501, 1429, DMSO-d6: 9.32 (4 H, m), 8.96 (4 H, m),
–
1347, 1286, 1204, 1173, 1127, 1030, 1000, 8.65 (4 H, m), 8.56 (4 H, m), 8.03 (8 H, m),
979, 886, 804
7.77 (1 H, m), 7.64 (1 H, m), 7.46 (1 H, m),
7.33 (4 H, m), 6.53 (4 H, m), 6.21 (1 H, m),
5.84 (8 H, m), 4.66 (8 H, m), 4.39 (4 H, m),
4.08 (4 H, m), 2.56 (4 H, m), 2.38 (3 H, m),
2.26 (8 H, m), 2.07 (24 H, m), 1.41 (8 H, m)
b
20
21
3442, 1639, 1189, 1122, 620
DMSO-d6: 9.26 (16 H, m), 8.72 (20 H, m),
8.20–7.62 (3 H, m), 6.42 (4 H, m), 5.86 (8
H, m), 4.60 (12 H, m), 4.42 (16 H, m), 3.73
(4 H, m), 3.31 (4 H, m), 2.45–2.48 (7 H, m),
1.44 (8 H, m)
–
b
3404, 3063, 2905, 1639, 1475, 1250, 1152, DMSO-d6: 9.28 (4 H, m), 9.19 (4 H, m),
–
1060, 1014, 989, 769, 620, 589
9.02 (4 H, m), 8.90 (4 H, m), 8.13 (8 H, m),
8.10 (4 H, m), 7.86 (4 H, m), 7.51 (3 H, m),
6.41 (4 H, m), 5.71 (8 H, m), 4.64 (8 H, m),
4.51 (4 H, m), 4.37 (12 H, m), 3.45 (4 H,
m), 2.73 (12 H, m), 2.46 (19 H, m), 2.20 (8
H, m), 2.12 (8 H, m), 1.99 (4 H, m)
a Satisfactory microanalyses obtained: C 0.04, H 0.03, N 0.05.
b Concentrations in DMSO-d6 and CDCl3 were too low to record the 13C NMR spectra within one day.
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

940
X. Leaym et al.
PAPER
Acetylated 2-Methyl Cavitand 3
added and the mixture was refluxed for 1 d. H2O (0.10 mL) was
added to the mixture and the solvent was removed at normal pres-
sure by purging with N2 and collecting in a liquid N2 cooled trap.
The residue was washed with H2O (3 × 5 mL) and recrystallized
from acetone (3 mL). The product was obtained as a light brown
powder after drying under vacuum; yield: 0.14 g (92%).
2-Methyl cavitand 2 (0.72 g, 0.87 mmol) was slowly dissolved in a
mixture of anhyd pyridine (1 mL) and Ac2O (16 mL). The mixture
was stirred for 5 h and then heated to 60 °C for an additional 12 h.
The solvent mixture was removed under high vacuum and the crude
product purified by descending column chromatography using sili-
ca gel as stationary phase and CHCl3–MeOH (96:4) as eluent; yield:
0.82 g (95%); mp 211 °C.
TBDPS-Protected 2-[4-(Pyridin-4-yl)-4-pyridinium]methyl
Cavitand 11
Acetylated 2-Bromomethyl Cavitand 4
TBDPS-protected 2-bromomethyl cavitand 6 (1.22 g, 0.58 mmol)
and 4,4¢-bipyridine (0.73 g, 4.67 mmol) was dissolved in DMF (10
mL) and heated to 60 °C under N2 for 5 d. The solvent was removed
at normal pressure by purging with N2 and collecting in a liquid N2
cooled trap. The residue was washed with (35 mL), then recrystal-
lized from acetone, and dried at reduced pressure. The product was
obtained as a red-brown powder; yield: 1.30 g (82%).
Acetylated 2-methyl cavitand 3 (0.74 g, 0.75 mmol), NBS (0.58 g,
3.3 mmol) and AIBN (20 mg) were dissolved in CCl4 (20 mL) and
then refluxed under argon for 24 h. The mixture was stirred for an-
other 12 h at r.t., cooled to 10 °C and filtered. The solvent was re-
moved under vacuum and the reddish-brown residue was subjected
to descending column chromatography using silica gel as stationary
phase and EtOAc–n-hexane (1:1) as eluent. After removing the sol-
vent under vacuum, the product was obtained as a slightly yellow
powder; yield: 1.0 g (88%); mp 186 °C (dec.).
Methoxylated 2-Methyl Cavitand 12
TBDPS-protected 2-methyl cavitand 5 (0.10 g, 0.055 mmol) and
MeI (19.5 mg, 0.138 mmol) was dissolved in DMF (5 mL) and heat-
ed to 50 °C under N2 for 2 d. The excess of MeI was quenched with
MeOH (2 mL). The solvent was removed at normal pressure by
purging with N2 and then collecting in a liquid N2 cooled trap. The
crude product was purified by column chromatography (10:1 hex-
anes–EtOAc) to afford cavitand 12 as a white solid; yield: 11.4 mg
(11%).
TBDPS-Protected 2-Bromomethyl Cavitand 6
TBDPS-protected 2-methyl cavitand 5 (6.83 g, 3.74 mmol), NBS
(2.93 g, 4.1 mmol) and AIBN (20 mg) were dissolved in CCl4 (20
mL) and then refluxed under argon for 24 h. The mixture was stirred
for another 12 h at r.t., cooled to 10 °C and filtered. The solvent was
removed under vacuum and the reddish-brown residue was purified
by descending column chromatography using silica gel as station-
ary phase and n-hexane–EtOAc (96:4) as eluent. After removing the
solvent under vacuum, the product was obtained as a slightly yellow
powder; yield: 3.30 g (74%); mp 134 °C (dec.).
Acetylated 2-[4-(3-Methylpyridin-4-yl)-4-(3-methylpyridini-
um)]methyl Cavitand 13
Acetylated 2-bromomethyl cavitand 4 (0.70 g, 0.535 mmol) and
3,3¢-dimethyl-4,4¢-bipyridine (0.80 g, 4.34 mmol) were dissolved in
DMF (6 mL) and kept at 60 °C for 4 d. The solvent was removed at
normal pressure by purging with N2 and collecting in a liquid N2
cooled trap. The residue was washed with acetone (3 × 5 mL), then
recrystallized from acetone, and dried at reduced pressure. The
product was obtained as a dark brown powder; yield: 0.75 g (68%);
mp 98 °C.
Acetylated 2-[4-(Pyridin-4-yl)-4-pyridinium]methyl Cavitand 7
Acetylated 2-bromomethyl cavitand 4 (0.40 g, 0.40 mmol) and 4,4¢-
bipyridine (0.376 g, 2.4 mmol) was dissolved in DMF (6 mL) and
kept at 60 °C for 3 d. The solvent was removed at normal pressure
by purging with N2 and collecting in a liquid N2 cooled trap. The
residue was washed with acetone (3 × 5 mL), then recrystallized
from acetone, and dried at reduced pressure. The product was ob-
tained as a yellow-brown powder; yield: 0.50 g (85%).
Hydroxylated 2-[4-(3-Methylpyridin-4-yl)-4-(3-methylpyridini-
um)]methyl Cavitand 14
Acetylated 2-[4-(4-Methylpyridinium)-4-pyridinium]methyl
Cavitand 8
Acetylated cavitand 13 (0.20 g, 0.098 mmol) was dissolved in aq
NaOH (pH 10, 10 mL) and then stirred at 25 °C for 5 h. The solution
was then neutralized (final pH 7.0) using aq 4 N HCl. The solvent
was removed at normal pressure by purging with N2 and the residue
was washed with acetone (35 mL) and dried under high vacuum. Fi-
nally, MeOH (5 mL) was added to the residue and the mixture was
stirred for 5 min and then filtered. The filtrate was collected and the
solvent was removed under reduced pressure. The product was ob-
tained as a light brown powder; yield: 0.15 g (98%).
Acetylated cavitand 7 (0.50 g, 0.26 mmol) was dissolved in DMF (6
mL), then MeI (0.13 mL, 2.08 mmol) was added to the solution. The
mixture was heated to 40 °C under N2 for 3 d and then treated with
H2O (0.10 mL). The solvent was removed at normal pressure by
purging with N2 and collecting in a liquid N2 cooled trap. The resi-
due was washed with H2O (3 × 5 mL) and recrystallized from ace-
tone (3 mL). The product was obtained as a dark brown powder
after drying under vacuum; yield: 0.61 g (95%).
Hydroxylated 2-{4-[4-Methyl(3-methylpyridinium)-4-(3-meth-
ylpyridinium)]}methyl Cavitand 15
Hydroxylated 2-[4-(Pyridin-4-yl)-4-pyridinium]methyl Cav-
itand 9
Cavitand 14 (0.10 g, 0.049 mmol) was dissolved in MeOH (10 mL).
Dimethyl sulfate (74.7 mg, 0.24 mmol) was then added and the mix-
ture was refluxed for 1 d. H2O (0.10 mL) was added to the mixture
and the solvent was removed at normal pressure by purging with N2
and collecting in a liquid N2 cooled trap. The residue was washed
with H2O (3 × 5 mL) and recrystallized from 3 mL of acetone. It was
then dried under vacuum. The product was obtained as a light brown
powder; yield: 0.103 g (~100%).
Acetylated cavitand 7 (0.30 g, 0.153 mmol) was dissolved in aq
NaOH (pH 10, 10 mL) and then stirred at 25 °C for 5 h. The solution
was then neutralized (final pH 7.0) using aq 4 N HCl. The solvent
was removed at normal pressure by purging with N2 and the residue
was washed with acetone (35 mL) and dried under high vacuum. Fi-
nally, MeOH (5 mL) was added to the residue and the mixture was
stirred for 5 min and then filtered. The filtrate was collected and the
solvent was removed under reduced pressure. The product was ob-
tained as a light brown powder; yield: 0.25 g (91%).
7-Amino-4-methyl-2H-chromen-2-one (16)
N-Acetylaminophenol: To a solution of m-aminophenol (5.0 g,
0.0459 mol) in anhyd THF (200 mL) was added Ac2O (4.4 mL,
0.0459 mol) And the mixture was stirred at r.t. for 2 h. The solvent
was then removed at reduced pressure and the residue was recrys-
Hydroxylated2-[4-(4-Methylpyridinium)-4-pyridinium]methyl
Cavitand 10
Hydroxylated cavitand 9 (0.10 g, 0.066 mmol) was dissolved in
MeOH (10 mL). Dimethyl sulfate (41.7 mg, 0.33 mmol) was then
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

PAPER
Methylene-Bridged Resorcin[4]arenes
941
tallized from toluene. N-Acetylaminophenol was obtained as white
needles; yield: 6.90 g (~100%).
× 3 mL), and dried under reduced pressure. A light brown powder
was obtained; yield: 0.075g (78%).
N-(4-Methyl-2-oxo-2H-chromen-7-yl)acetamide: N-Acetylamino-
phenol (3.63 g, 0.024 mol) and ethyl acetoacetate (3.74 g, 0.029
mol) were mixed with 70% H2SO4 (58 mL) and the mixture was
stirred at r.t. for 6 h. The mixture was then poured into ice water
(250 mL), allowed to remain at 4 °C overnight and filtered. The
white crystals recovered are the first fraction of the product N-(4-
methyl-2-oxo-2H-chromen-7-yl)acetamide. A second fraction was
obtained by extracting the mother liquor with Et2O (3 × 30 mL). The
Et2O layers were combined and the solvent removed under reduced
pressure. The white solid obtained was combined with the other
batch of product; yield: 2.42 g (46%).
Quaternization of 19 to 21 with Dimethyl Sulfate
Compound 19 (0.08 g, 0.04 mmol) and dimethyl sulfate (0.025 g,
0.20 mmol) was dissolved in DMF (4 mL) under N2 and heated to
50 °C for 1 d. The precipitate was collected, washed with acetone (3
× 3 mL), and dried under reduced pressure. A light brown powder
was obtained; yield: 0.071 g (75%).
Acknowledgment
Financial support from Kansas State University, Kansas NSF-
EPSCoR (First Award #4166) and the Terry C. Johnson Center for
Basic Cancer Research (Innovative Cancer Research Grant) is gra-
tefully acknowledged. The authors thank Prof. Dr. Ruth Welti and
Mary Roth, Kansas Lipidomics Research Center, for the use of the
Applied Biosystems API-4000 triple quadrupole mass spectrometer
with electrospray and APCI sources. The authors also thank Prof.
Dr. Dan Higgins for the use of a Fluoromax-2 fluorometer and an
Agilent UV/Vis-spectrometer.
7-Amino-4-methyl-2H-chromen-2-one (16): N-(4-Methyl-2-oxo-2H-
chromen-7-yl)acetamide (1.40 g, 6.45 mmol) was refluxed in 90%
H2SO4 (10 mL) for 5 h. The mixture was then poured into ice water
(250 mL) and allowed to remain at 4 °C overnight. The solution was
then carefully neutralized using aq 50% NaOH. The white precipi-
tate was filtered and washed with ice water (3 mL) and dried at nor-
mal pressure under N2; yield: 1.0 g (89%) of the hydrogen sulfate
salt of the protonated product! The latter was dissolved in as little
DMF as possible (usually 4 mL). Anhyd K2CO3 (0.90 g) was added,
which resulted in a suspension. After stirring for 2 h at r.t., the mix-
ture was cooled to 0 °C and then filtered. The solvent from the fil-
trate was removed at r.t. under high vacuum; yield: 0.35 g (98%).
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916.
Hydroxylated 2-{4-[(3-Methyl)pyridin-4-yl]-4-(3-methyl)pyri-
dinium}methyl Cavitand [3-(4-Methyl-2-oxo-2H-chromen-7-yl-
carbamoyl)propanoic Acid] Monoester 19
Hydroxylated cavitand 14 (0.18 g, 0.11 mmol), 3-(4-methyl-2-oxo-
2H-chromen-7-ylcarbamoyl)propanoic acid (17; 0.03 g, 0.11
mmol) and TPP (0.0058 g, 0.22 mmol) were dissolved in DMF (10
mL) under N2. DEAD (38 mL, 0.22 mmol) was added and the mix-
ture was kept at 60 °C for 12 h. The solvent was removed at normal
pressure by purging with N2 and collecting in a liquid N2 cooled
trap. The residue was washed with acetone (3 × 5 mL) and then re-
crystallized from acetone. A light brown powder was obtained;
yield: 0.164 g (81%).
Quaternization of 18 to 20 with Dimethyl Sulfate
(23) Mandler, D.; Willner, I. J. Am. Chem. Soc. 1987, 109, 7884.
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Compound 18 (0.080 g, 0.045 mmol) and dimethyl sulfate (0.028 g,
0.225 mmol) was dissolved in DMF (4 mL) under N2 and heated to
50 °C for 1 d. The precipitate was collected, washed with acetone (3
Synthesis 2008, No. 6, 932–942 © Thieme Stuttgart · New York

942
X. Leaym et al.
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