Bambusurils Bearing Nitro Groups and Their Further Modifications

Article abstract of DOI:10.1002/ejoc.201701329

Bambusurils are recently developed neutral anion receptors that show a high affinity towards many inorganic anions, not only in organic solvents but also in water. However, the number of water-soluble bambusurils and also those bearing functional groups is very limited. In this paper we report the synthesis of four- and six-membered bambusurils containing eight and twelve nitro groups. All the nitro groups on the bambusuril portals could be transformed into amino functions, which provided the macrocycles with water solubility and allowed their further modification. For example, we have demonstrated the conversion of amino groups on the bambusurils into the corresponding urea-functionalized bambusuril derivatives. We also report the first example of a bambusuril bearing only two functional groups, which was prepared by the condensation of two different glycolurils.

Full text of DOI:10.1002/ejoc.201701329

DOI: 10.1002/ejoc.201701329
Full Paper
Synthesis of Macrocycles
Bambusurils Bearing Nitro Groups and Their Further
Modifications
Mirza Arfan Yawer,[ Kristina Sleziakova,[a,b] Lukas Pavlovec,[a,c] and Vladimir Sindelar*[a,b]
a,b]
Abstract: Bambusurils are recently developed neutral anion which provided the macrocycles with water solubility and al-
receptors that show a high affinity towards many inorganic lowed their further modification. For example, we have demon-
anions, not only in organic solvents but also in water. However, strated the conversion of amino groups on the bambusurils into
the number of water-soluble bambusurils and also those bear- the corresponding urea-functionalized bambusuril derivatives.
ing functional groups is very limited. In this paper we report We also report the first example of a bambusuril bearing only
the synthesis of four- and six-membered bambusurils contain- two functional groups, which was prepared by the condensa-
ing eight and twelve nitro groups. All the nitro groups on the tion of two different glycolurils.
bambusuril portals could be transformed into amino functions,
Introduction
form, whereas the macrocycle BU[6]f containing carboxybenzyl
[
2]
groups is soluble in neutral and basic water. Besides our
group, other research teams have explored the chemistry of
bambusurils. Heck and co-workers decorated BU[n]s with allyl
Bambus[n]urils (BU[n]s) are a family of macrocyclic anion recep-
tors that have been developed by our group and others since
[
1]
2
010. These macrocycles are composed of n glycoluril units
[
14]
substituents to obtain BU[4]c and BU[6]c (Figure 1).
They
[
2]
connected by n methylene bridges. The name of these macro-
cycles originated from the similarity of their shape to the hollow
part of bamboo stems. BU[n]s are prepared by the acid-
catalyzed condensation of 2,4-disubstituted glycolurils and
paraformaldehyde. Only BU[n]s with four (n = 4) and six (n = 6)
glycoluril units have been synthesized up to now. BU[4] is the
thermodynamic product of the macrocyclization reaction. The
BU[4] cavity is too small for the inclusion of any anion. On the
other hand, BU[6] is able to encapsulate inorganic anions of
different sizes to form BU[6] anion complexes. That is why inor-
ganic anions are used as templates to favor the formation of
BU[6] over BU[4]. In other words, six glycoluril units assemble
around a template as a result of 12 stabilizing C–H···anion
hydrogen bonds, giving rise to the six-membered macrocycle
also explored the possibility of linking neighboring allyl groups
by cross metathesis. Another approach came with Reany and
co-workers, who modified the BU[n] core by replacing half of
[
4,5]
the carbonyl groups by thiocarbonyl
and, subsequently, the
[
6]
thiocarbonyl by imine moieties.
[
2,3]
BU[6].
BU[n] derivatives differing in the substituents attached to the
nitrogen atoms on their portals have been prepared. The type
of substituent significantly influences the solubility of the
macrocycle. For example, bambusurils bearing benzyl groups,
[
3]
BU[4]d and BU[6]d (Figure 1), show good solubility in chloro-
Figure 1. Bambus[4]urils and bambus[6]urils bearing different substituents.
[
a] Department of Chemistry, Faculty of Science, Masaryk University,
Kamenice 5, 62500 Brno, Czech Republic
E-mail: sindelar@chemi.muni.cz
http://ustavchemie.sci.muni.cz/
b] RECETOX, Faculty of Science, Masaryk University,
Kamenice 5, 62500 Brno, Czech Republic
http://www.recetox.muni.cz/
c] Institute of Macromolecular Chemistry, Academy of Sciences of the Czech
Republic,
Recent findings have encouraged us to explore the prepara-
tion of other BU[n] derivatives. We were particularly interested
in BU[n] derivatives bearing functional groups with good solu-
bility in water. Receptors with good selectivity as well as an
affinity towards anions functioning in water are rare. We re-
[
[
cently demonstrated that BU[n]s are able to bind various anions
[2,7]
in water very efficiently.
The water solubility of these BU[n]s
was achieved by decorating their portals with substituents
bearing carboxylate functions. Such substitutions make bam-
busuril portals negatively charged, which complicates the en-
Heyrovsky Sq. 2, 16206 Prague 6, Czech Republic
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701329.
Eur. J. Org. Chem. 2018, 41–47
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trance of anions. Therefore, it is of interest to investigate the yield after purification by column chromatography. The struc-
synthesis of water-soluble BU[n]s that are decorated by neutral ture of 5a was also confirmed by X-ray diffraction (Figure 2).
of positively charged substituents. Here, we report the synthesis
of BU[n]s bearing 2- and 4-nitrobenzyl groups (6a,b, 7a,b) and
their reduction to the corresponding amine derivatives, which
are soluble in water after protonation of the amino groups. The
amino groups on BU[n] were subsequently converted into urea
functions, thereby yielding derivative 9.
Figure 2. Crystal structure of glycoluril 5a.
Results and Discussion
Synthesis of 4b from 1b followed similar synthetic protocols
Synthesis of Glycoluril Building Blocks
as described for 4a. Contrary to the synthesis of 5a, the conver-
sion of 4b into 5b was straightforward, employing slightly mod-
ified conditions to those already reported for the preparation
Bambusurils are formed by the condensation of 2,4-disubsti-
[
8]
tuted glycolurils with formaldehyde. Therefore, we first syn-
thesized glycolurils 5a and 5b (Scheme 1). The essential build-
ing block 5a was synthesized starting from the commercially
available 4-nitrobenzyl alcohol (1a). First, 1a was converted by
[
3]
of 2,4-diisopropylglycoluril. Hydantoin 11b was also obtained
as a minor product.
[
9]
using a Vilsmeier–Haack reagent into 4-nitrobenzyl chloride,
Synthesis of Bambus[4]urils 6a,b
which was transformed into 4-nitrobenzyl azide (2a). Staud-
inger reduction of 2a using triphenylphosphine in a mixture of
THF and water led to the formation of amine 3a. After work-
Acid-catalyzed condensation reactions of glycolurils 5a and 5b
with paraformaldehyde (PFA) were carried out without a tem-
plating anion, which in both cases promoted the formation of
the thermodynamically stable four-membered macrocycle
over the kinetic product, the six-membered macrocycle
[
10]
up,
crystalline 4-nitrobenzylammonium chloride (3a) was
subjected to N,N′-carbonyldiimidazole in basic anhydrous tolu-
ene to obtain pure N,N′-bis(4-nitrobenzyl)urea (4a) in 64 %
yield. Another reagent, diphenyl carbonate, was also used in-
stead of the expensive and moisture-sensitive N,N′-carbonyldi-
[
3]
(
Scheme 2). However, the macrocyclization was always in
equilibrium with the formation of acyclic linear oligomers.
When glycoluril 5a was used, the solid material isolated after
the reaction contained bambusuril 6a together with acyclic oli-
gomers. The byproducts were removed by simply washing with
acetone to give 6a in 55 % yield.
[
11,12]
imidazole to give 4a in a similar yield.
Scheme 1. Synthesis of glycolurils 5a–b. Reagents and conditions: i. SOCl
DCM, reflux, 12 h; ii. NaN , NH Cl, H O, 70 °C, 48 h; iii. PPh , THF/H O, reflux,
h; iv. conc. HCl, reflux, 3 h; v. Et N, dry CH Ph, N,N-carbonyldiimidazole
0.5 equiv.), 80 °C, 4 h, then 20 °C, 12 h; vi. H O/MeOH, HCl, reflux, 18 h.
2
,
3
4
2
3
2
6
(
3
3
2
Scheme 2. Synthesis of nitrobenzylbambus[n]urils 6a,b and 7a,b: Reagents
3 3
and conditions: i. PFA (1 equiv.), PTSA (1 equiv.), CHCl , reflux, 20 h; ii. CH Ph,
–
–
–
Attempts to convert 4a into 5a were complicated by the
formation of the undesired N,N′-bis(4-nitrobenzyl)hydantoin
11a, Scheme 1). Therefore, we screened various mixtures of
PFA (1 equiv.), PTSA (1 equiv.) TBAX (0.16 equiv. X = Cl , Br , or I ).
(
Single crystals of 6a were grown from a concentrated solu-
organic solvents and aqueous HCl and also different concentra- tion of the macrocycle in DMSO upon standing at room temper-
tions of aqueous HCl (see the Supporting Information for more ature for a few hours (Figure 3). The structure of 6a is in good
details). Finally, the reaction between 4a and 4,5-dihydroxy- agreement with previously published bambusuril crystal struc-
[
1,3]
imidazolidin-2-one in a 1:6 molar ratio was performed in a mix- tures.
The glycoluril units adopt an alternate conformation
ture of THF/H O in the presence of HCl, which gave 5a in 65 % with the methine hydrogen atoms, which are directed towards
2
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the center of the cavity. As expected, the cavity of 6a was too sulfonic acid present in the reaction mixture serving as the re-
small to incorporate even a single molecule of solvent.
quired catalyst for this reaction. Compound 6d was confirmed
to be a dimer of glycoluril 5a. Isolation of higher oligomers was
unsuccessful due to their poor solubility.
Bambusuril 6b was synthesized analogously to 6a. Because
2
-nitrobenzyl groups are known to be photolabile when ex-
posed to UV light in the range 300–365 nm, we tried to remove
them to prepare bambusuril with unprotected nitrogen atoms
available for further reactions. However, all the attempts (de-
scribed in the Supporting Information) failed to provide unpro-
tected bambusuril 6b.
Synthesis of Bambus[6]urils 7a,b
Figure 3. Side and top views of the crystal structure of 6a. Hydrogen atoms
and solvent molecules have been omitted for a better view of the structure.
Because macrocycles 6a,b are not capable of forming com-
plexes with anions, we next focused our efforts on the prepara-
tion of six-membered bambusurils 7a,b (Scheme 2), which
could potentially be used as anion receptors. The size of the BU
After isolation of 6a, the mixture containing the byproducts
was subjected to column chromatography. From this mixture,
glycoluril derivatives 6c and 6d were isolated in pure form. The
structures of both glycoluril derivatives 6c and 6d were eluci-
dated on the basis of NMR spectroscopy, and finally confirmed
by X-ray diffraction (Figure 4). It was found that compound 6c
resembles glycoluril 5a, but differs by the presence of methoxy-
methyl groups attached to the two unprotected nitrogen atoms
of the glycoluril. We anticipate that these groups were formed
by the reaction of the corresponding hydroxymethyl groups
upon exposure to methanol during work-up, the p-toluene-
[
7]
cavity can be controlled by the presence of a template. More
specifically, BU[6] emerges mainly due to the presence of ani-
ons that are recognized by the six glycoluril subunits through
directional CH···anion hydrogen bonds. It was found that the
strength of these interactions depends on several criteria, such
as the type of solvent, solvation, or size and shape of the anion.
For example, among spherical halide anions, BU[6]d (see Fig-
ure 1 for structure) has the strongest affinity towards iodide
9
–1
(
8
Ka = 3.8 × 10 M ) and the weakest towards fluoride (K =
a
.6 × 10 M
–1) in CHCl3.[8] We assumed that the stronger the
5
stabilization of the anion, the better its role as template. There-
fore, we first utilized iodide as a template [in the form of the
tetrabutylammonium (TBA) salt] to shift the reaction equilib-
rium towards the six-membered macrocycle over the four-
membered one. Moreover, iodide could eventually be removed
from the cavity of bambusuril by its oxidation to obtain anion-
[
3,13]
free receptors 7a,b.
Therefore, we followed the previously
[
3,13]
reported macrocyclization conditions
and prepared 7a as a
complex with iodide in 40 % yield (Scheme 2). When we used
–
Cl (as its TBA salt) as a template, 7a was limited to only 7 %,
–
whereas its yield was 35 % in the presence of Br . These experi-
ments confirmed our expectations that the yield of the six-
membered bambusurils increases when an anion with a high
affinity towards the resulting macrocycle is used as a template
during its synthesis.
Bambus[6]uril 7b was synthesized according to the same
[
3]
synthetic protocol as 7a; bambus[6]uril 7b was achieved in
only 23 % yield when iodide was used as a template after care-
ful optimization. Finally, we performed the reaction in a micro-
[
14]
wave reactor, as reported previously for different BU[n]s,
which shortened the reaction time from 16 to 4 h and doubled
–
the amount of 7b·I (46 %).
At this stage we decided to investigate synthetic routes for
the conversion of all the nitro groups on the prepared bam-
busuril derivatives into amino functionalities. The presence of
amino groups would allow further substitution of the bam-
busurils, for example, their diazotization or direct transforma-
tion into urea moieties. Moreover, the protonation of the amino
groups would result in water-soluble bambusurils. Thus, we in-
Figure 4. Chemical formula and X-ray structures of (A) 6c and (B) 6d.
Eur. J. Org. Chem. 2018, 41–47
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vestigated the reduction of the four-membered bambusurils tion of various polymer structures. Thus, we decided to investi-
6
7
a,b, which were isolated in higher yields than macrocycles gate the preparation of nonsymmetrical bambus[4]uril 10
a,b (Scheme 3). After testing several reaction conditions (see (Scheme 5).
Table S1 in the Supporting Information for more details)
hydrogenation using palladium or platinum on activated char-
coal in DMF was successfully applied to facilitate the complete
reduction of 6a into 8a in 69 % yield. The reduction of 6b was
performed in THF using hydrogen or hydrazine as the proton
source and 10 % Pd on carbon supported with a dry matrix to
prepare 8b in 64 % yield.
Scheme 5. Synthesis of partially functionalized bambus[4]uril 10.
Scheme 3. Preparation of bambusurils 8a,b bearing amino groups.
The synthesis of macrocycles with chemically diverse sub-
units often requires multistep manipulations with low yields
and difficult separations. However, the macrocyclization reac-
tion of 10 took place in a single step without the presence of
any template and with a relatively good separation profile. The
condensation reaction between 2,4-bis(4-nitrobenzyl)glycoluril
We further explored the reactivity of 8a with reagents pro-
moting the formation of urea moieties. Amino groups can read-
ily undergo reactions with electron-deficient centers that are
present within cyanates and aldehydes among others. Thus, we
investigated the reaction between 8a and KOCN, which led to
the corresponding urea derivative 9 in 89 % yield (Scheme 4).
It should be noted that reactions with hexyl isocyanate, phenyl
isocyanate, and benzyl isocyanate did not provide the corre-
sponding urea derivatives, probably due to steric hindrances.
(5a), 2,4-dibenzylglycoluril (12), and paraformaldehyde in chlo-
roform with a catalytic amount of p-toluenesulfonic acid gave
rise to the desired partially functionalized bambusuril 10. The
crucial parameter here was the appropriate ratio of glycolurils
5a and 12 to suppress the formation of undesired bambusuril
BU[4]d (see Figure 1 for structure). We optimized this process
by mixing 1 equivalent of 5a with 3 equivalents of 12. However,
despite the optimization, BU[4]d was always present as the ma-
jor component in the reaction mixture, and the partially func-
tionalized bambusuril 10 was isolated in only 7 % yield after
purification by column chromatography. The conversion of
bambusuril 10 into its amino analogue and its use in the prepa-
ration of polyimide membranes is currently being investigated
in our laboratory.
Scheme 4. Synthesis of bambusuril 9 bearing urea moieties.
Conclusions
We have expanded the family of bambusurils through the syn-
thesis of several new derivatives. Four- and six-membered bam-
Synthesis of Partially Functionalized Bambus[4]uril 10
The synthesis of bambusurils that are composed of several busurils bearing eight and twelve nitro groups, respectively,
types of glycoluril building blocks has not been explored so far. have been isolated and their conversion into the corresponding
With glycoluril 5a in hand, we decided to test its reaction with amino analogues was studied; peraminobambus[4]urils were
the previously used dibenzylglycoluril 12 to explore the prepa- prepared and successfully transformed into their urea ana-
[
3]
ration of partially functionalized bambusurils. Special atten- logues. We have also shown that the yields of the six-mem-
tion was paid to the preparation of bambusurils containing just bered macrocycles depend on the type of template used. Fur-
one unit of glycoluril 5a within the macrocycle. This would yield thermore, the first partially functionalized bambusuril consist-
bambusurils bearing two functional groups, which could be ing of two different glycoluril building blocks was prepared and
subsequently used, for example, as monomers for the prepara- isolated from the reaction mixture. This partially functionalized
Eur. J. Org. Chem. 2018, 41–47
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bambus[4]uril will be used in the future for the development (2-Nitrophenyl)methanaminium Chloride (3b): 1-(Azidomethyl)-
2
-nitrobenzene (2b; 26.51 g, 149 mmol) was dissolved in a mixture
of polyimide membranes.
of THF (260 mL) and H O (48 mL). The mixture was cooled (0 °C)
2
and Ph P (78.62 g, 298 mmol) was added in small portions (within
3
Experimental Section
15 min) with vigorous stirring, which resulted in the rapid evolution
of bubbles of N . When the evolution of N attenuated, the reaction
mixture was heated at reflux for 6 h. After that, a concentrated 35 %
HCl solution (96 mL) was carefully added and the mixture heated
at reflux for another 3 h. The THF was then removed under reduced
pressure, and the resulting mixture was extracted with EtOAc (4 ×
2
2
General Methods: All reagents were of commercial grade and were
used as received. Reactants and catalysts were purchased from
commercial suppliers. Microwave irradiations were performed by
using a CEM Discover reactor. TLC was performed on aluminium
plates coated with silica gel (60 Å pore diameter, 200 μm layer
thickness, 8.0–12.0 μm particle size) with fluorescent indicator
60 mL). The water phase was then evaporated, and the solid mate-
rial was washed with EtOAc and dried under vacuum to afford a
(254 nm). As a stationary phase for column chromatography, Acros
yellowish powder (18.24 g, 63 %). The characterization data match
Organics silica gel was used (60 Å pore diameter, 40–60 μm particle
1
those reported in the literature. H NMR (300 MHz, [D ]DMSO): δ =
6
1
13
size). H and C NMR spectra were recorded with a Bruker Avance
8
.44 (br. s, 3 H, NH ), 8.20 (d, J = 8.1 Hz, 1 H, CH), 7.89–7.84 (m, 1
3
3
00 or 500 spectrometer equipped with a BBFO probe (30 °C), and
H, CH), 7.76–7.68 (m, 2 H, CH), 4.35 (s, 2 H, CH ) ppm.
2
[
15]
the shifts are referenced to solvent residual peaks.
MALDI-TOF
General Procedure for the Conversion of the Ammonium Salts
mass spectra were recorded with a MALDI-TOF MS UltrafleXtreme
spectrometer (Bruker Daltonics), and the samples were ionized by
using a Nd-YAG laser (355 nm) and 2,5-dihydroxybenzoic acid (DHB)
or α-cyano-4-hydroxycinnamic acid (HCCA) matrices. HRMS were
obtained with an Agilent 6224 Accurate-Mass TOF spectrometer,
and samples were ionized by electrospray ionization (ESI) or atmos-
pheric-pressure chemical ionization (APCI).
into the Corresponding Amines: A 2
(
(
M
NaOH solution in water
100 mL) was added to the nitrobenzylammonium chloride
97 mmol) until pH > 10 was reached. The resulting oil was ex-
tracted with diethyl ether (3 × 40 mL). The combined organic ex-
tracts were dried with Na SO . After filtration, diethyl ether was
2
4
evaporated, and the product was dried overnight at reduced pres-
sure.
1
-(Azidomethyl)-4-nitrobenzene (2a): 1-(Chloromethyl)-4-nitro-
benzene (33.60 g, 196 mmol) was added to a solution of NaN3
25.75 g, 396 mmol) and NH Cl (26.22 g, 490 mmol) in distilled
General Procedure for the Synthesis of Urea 4a,b
(
4
Method 1: 1,3-Carbonyldiimidazole (58 mmol) was suspended in
freshly prepared dry toluene (150 mL) in a predried 250 mL Schlenk
water (105 mL). The suspension was allowed to react at 70 °C for
d. After that, the reaction mixture was extracted with CH Cl or
2
2
2
flask equipped with a stirrer. The flask was flushed with N by seal-
2
CHCl (3 × 30 mL). The combined organic phases were washed with
3
ing with a septum and fitting a balloon containing N . Then a solu-
2
brine (2 × 60 mL) and dried with Na SO . After filtration, the solvent
2
4
tion of nitrobenzylamine (97 mmol) in dry toluene (20 mL) was
injected into the suspension in the Schlenk flask. The reaction was
carried out for 3.5 h at 80 °C. After that, another portion of 1,3-
carbonyldiimidazole (10 mmol) was added, allowed to react for an-
other 0.5 h at 80 °C, and then stirred overnight at ambient tempera-
ture. The obtained white precipitate was filtered, washed with acet-
one, and dried in vacuo.
was evaporated under reduced pressure. The residue was dried un-
der vacuum overnight to give a yellowish oil (34.80 g, 99 %). 1
NMR (300 MHz, CDCl ): δ = 8.20 (d, J = 8.7 Hz, 2 H, CH), 7.50 (d, J =
H
3
9
.0 Hz, 2 H, CH), 4.50 (s, 2 H, CH ) ppm.
2
1
-(Azidomethyl)-2-nitrobenzene (2b): 1-(Chloromethyl)-2-nitro-
benzene (26.60 g, 155 mmol) was added to a solution of NaN3
20.15 g, 310 mmol) and NH Cl (20.73 g, 387.5 mmol) in distilled
(
4
Method 2: An alternative, moisture-insensitive route was also per-
formed. A solution of nitrobenzylamine (155 mmol) and diphenyl
carbonate (76 mmol) in triethylamine (388 mmol) was heated at
water (85 mL). The suspension was allowed to react at 70 °C for 2 d.
After that, the reaction mixture was extracted with CH Cl or CHCl
2
2
3
(
(
3 × 30 mL). The combined organic phases were washed with brine
2 × 60 mL) and dried with Na SO . After filtration, the solvent was
80 °C for 8 h. The resulting suspension was filtered, washed with
2
4
acetone (3 × 50 mL), and dried at room temp. under vacuum.
evaporated under reduced pressure. The residue was dried under
vacuum overnight to give a dark-brown oil (26.51 g, 96 %). The
1
,3-Bis(4-nitrobenzyl)urea (4a): This compound was prepared, fol-
lowing method 1, from (4-nitrophenyl)methanaminium chloride
3a; 13.71 g, 91 mmol) to afford a white powder (9.55 g, 64 %).
characterization data match those reported in the literature. 1
H
(
NMR (300 MHz, CDCl ): δ = 8.12 (d, J = 7.8 Hz, 1 H, CH), 7.79–7.62
3
Method 2 gave similar results, starting from (4-nitrophenyl)meth-
(m, 2 H, CH), 7.54–7.48 (m, 1 H, CH), 4.86 (s, 2 H,CH ) ppm.
2
anaminium chloride (3a; 13.71 g, 91 mmol) to afford a white pow-
(
4-Nitrophenyl)methanaminium Chloride (3a): 1-(Azidomethyl)-
-nitrobenzene (2a; 27.10 g, 152 mmol) was dissolved in a mixture
of THF (266 mL) and H O (49 mL). The mixture was cooled (0 °C)
1
der (9.1 g, 62 %). H NMR (500 MHz, [D ]DMSO): δ = 8.20 (d, J =
6
4
8
.4 Hz, 4 H, CH), 7.51 (d, J = 8.3 Hz, 4 H, CH), 6.79 (t, J = 6.2 Hz, 2
13
2
H, NH), 4.36 (d, J = 6.1 Hz, 4 H, CH ) ppm. C NMR (125 MHz,
2
and Ph P (79.74 g, 304 mmol) was added in small portions (within
3
[D ]DMSO): δ = 159.2, 149.9, 146.7, 128.3, 123.8, 42.8 ppm.
6
1
5 min) with vigorous stirring, which resulted in the rapid evolution
1,3-Bis(2-nitrobenzyl)urea (4b): This compound was prepared, fol-
of bubbles of N . When the evolution of N attenuated, the reaction
2
2
lowing method 1, from 2-nitrobenzylamine (14.71 g, 97 mmol) to
mixture was heated at reflux for 6 h. After that, a concentrated 35 %
HCl solution (98 mL) was carefully added and the mixture heated
at reflux for another 3 h. The THF was then removed under reduced
pressure, and the resulting mixture was extracted with EtOAc (4 ×
1
afford a white powder (15.96 g, 65 %). H NMR (500 MHz,
[
D ]DMSO): δ = 8.02 (d, J = 8.1 Hz, 2 H, CH), 7.76–7.68 (m, 2 H, CH),
6
7
6
1
3
.59–7.46 (m, 4 H, CH), 6.75 (t, J = 6.1 Hz, 2 H, NH), 4.49 (d, J =
13
.1 Hz, 4 H, CH ) ppm. C NMR (125 MHz, [D ]DMSO): δ = 157.84,
2
6
60 mL). The aqueous phase was then concentrated, and the solid
47.87, 135.74, 133.62, 129.57, 128.01, 124.40, 40.33, 40.08, 39.80,
9.52, 39.24, 38.96, 38.68 ppm.
material was washed with EtOAc and dried under vacuum to give
a yellowish powder (28.69 g, 64 %). The characterization data match
1
those reported in the literature. H NMR (300 MHz, D O): δ = 8.37– 2,4-Bis(4-nitrobenzyl)glycoluril (5a): A suspension of urea 4a
2
8
.40 (d, J = 9.0 Hz, 2 H, CH), 7.74–7.77 (d, J = 9.0 Hz, 2 H, CH), 4.41
(2.0 g, 6.1 mmol) and 4.5-dihydroxyimidazolidin-2-one (4.3 g,
(
s, 2 H, CH ) ppm.
36 mmol) was stirred in H O (120 mL), THF (300 mL), and 35 % HCl
2
2
Eur. J. Org. Chem. 2018, 41–47
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45
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(
2
39 mL) at reflux for 18 h (suspension turned yellow solution during
h). The reaction mixture was then concentrated and purified by
silica gel column chromatography [EtOAc/CH Cl /acetone (1:1:0.2)
49.53, 45.14 ppm. HRMS (ESI+): calcd. for [C H N O + H]+
1697.4598; found 1697.4592.
76 64 24 24
2
2
2,4-Bis(4-nitrobenzyl)-6,8-bis(methoxymethyl)glycoluril
(6c):
1
as eluent] to afford 5a as a white powder (2.50 g, 65 %). H NMR
500 MHz, [D ]DMSO): δ = 8.23 (d, J = 8.8 Hz, 4 H, CH), 7.59 (s, 2 H,
This compound was obtained as a byproduct during the purifica-
tion of 6a as a minor fraction (70 mg, 5 %). Crystals suitable for
(
6
NH), 7.56 (d, J = 8.8 Hz, 4 H, CH), 5.21 (s, 2 H, CH), 4.49 (dd, J = 16.4,
1
X-ray analysis were prepared from the collected fractions by slow
1
3
05.4 Hz, 4 H, CH ) ppm. C NMR (125 MHz, [D ]DMSO): δ = 159.21,
2
6
1
evaporation of the solvent. H NMR (500 MHz, [D ]DMSO): δ = 8.25
6
1
59.18, 147.26, 146.72, 128.65, 124.22, 71.81, 46.63, 30.67 ppm.
(
d, J = 8.7 Hz, 4 H, CH), 7.53 (d, J = 8.7 Hz, 4 H, CH), 5.34 (s, 2 H,
HRMS (APCI ): calcd. for [C H N O + H]+ 413.1204; found
+
1
8
16
6
6
13
CH), 4.66 (m, 8 H, CH ), 3.12 (s, 6 H, CH ) ppm. C NMR (125 MHz,
2
3
4
13.1202.
[
D ]DMSO): δ = 158.5, 147.3, 145.9, 130.0, 124.2, 75.5, 68.8, 55.5,
6
–
–
2
(
,4-Bis(2-nitrobenzyl)glycoluril (5b): A suspension of urea 4b
5.96 g, 18 mmol) and 4.5-dihydroxyimidazolidin-2-one (12.74 g,
45.6 ppm. HRMS (APCI ): calcd. for [C22
found 499.1535.
H N O – H] 499.1582;
24 4 6
1
08 mmol) was stirred in H O (360 mL), MeOH (900 mL), and 35 %
2
Dimer of 2,4-Bis(4-nitrobenzyl)-6,8-bis(methoxymethyl)glycol-
uril (6d): This compound was obtained as a byproduct during the
purification of 6a as a minor fraction (40 mg, 3 %). Crystals suitable
HCl (120 mL) at reflux for 18 h (suspension turned yellow solution
during 2 h). The reaction mixture was cooled and MeOH was evapo-
rated. After evaporation, cooling to 10 °C initiated the formation of
a precipitate that was filtered and thoroughly washed with water
for X-ray analysis were prepared from the collected fractions by
1
slow evaporation of the solvent. H NMR (500 MHz, [D ]DMSO): δ =
6
1
to give 5b as a white powder (4.69 g, 63 % yield). H NMR (500 MHz,
8
6
6
1
4
.18–8.23 (m, 8 H, CH), 7.49–7.52 (m, 8 H, CH), 5.26 (dd, J = 8.5,
[D ]DMSO): δ = 8.09 (d, J = 8.5 Hz, 2 H, CH), 7.79 (t, J = 7.5 Hz, 2 H,
6
3 Hz, 4 H, CH), 4.48–4.83 (m, 12 H, CH ), 4.34 (s, 2 H, CH ), 3.09 (s,
2
2
CH), 7.58 (t, J = 7.1 Hz, 4 H, CH), 7.46 (s, 2 H, NH), 5.33 (s, 2 H, CH),
4
DMSO): δ = 160.35, 157.97, 147.93, 133.86, 132.97, 128.71, 128.36,
13
H, CH ) ppm. C NMR (125 MHz, [D ]DMSO): δ = 160.0, 158.9,
3
6
1
3
.83 (dd, J = 17.6, 180.5 Hz, 4 H, CH ) ppm. C NMR (125 MHz,
2
47.3, 147.0, 145.7, 128.1, 128.3, 124.1, 124.0, 75.8, 69.6, 68.6, 55.6,
9.1, 47.1, 45.6 ppm.
+
+
1
4
24.83, 66.28, 42.09 ppm. HRMS (ESI ): calcd. for [C H N O + H]
13.1204; found 413.1202.
18 16 6 6
Dodecakis(4-nitrobenzyl)bambus[6]uril·TBAI (7a): A suspension
of 2,4-bis(4-nitrobenzyl)glycoluril (5a; 4.0 g, 9.7 mmol), paraform-
aldehyde (0.450 g, 14.6 mmol), TBAI (0.596 g, 1.35 mmol), and
Octakis(4-nitrobenzyl)bambus[4]uril (6a): Glycoluril 5a (1.236 g,
mmol), paraformaldehyde (0.090 g, 3 mmol), and p-toluene-
3
PTSA·H O (0.921 g, 4.85 mmol) in toluene (180 mL) was heated at
2
sulfonic acid (0.573 g, 3 mmol) were suspended in CHCl (50 mL).
3
reflux for 16 h. The reaction mixture was cooled to room temp., and
the yellowish suspension was concentrated in a rotary evaporator.
Sonication in MeOH (200 mL) was performed for 10 min to give a
yellow powder that was filtered and washed with MeOH (2 × 50 mL)
and then with acetone (2 × 100 mL) to give pure macrocycle 7a
The suspension was stirred overnight under reflux. The solvent was
then evaporated in a rotary evaporator and the crude product was
sonicated in MeOH (50 mL) for 10 min. The precipitated material
was collected by filtration and washed with MeOH (2 × 50 mL) and
CH Cl2 (2 × 50 mL) to isolate bambusuril 6a as a white solid
1
2
(1.9 g, 40 %). H NMR (500 MHz, [D ]DMSO): δ = 8.18 (d, J = 8.4 Hz,
6
(0.700 g, 55 %). The remaining filtrate was concentrated and sub-
24 H, CH), 7.52 (d, J = 8.4 Hz, 24 H, CH), 5.69 (s, 12 H, CH), 4.84 (dd,
jected to column chromatography with CH Cl /EtOAc (4:1) as eluent
to isolate crystalline glycoluril 5c and dimer 5d. Data for 6a:
NMR (500 MHz, [D ]DMSO): δ = 8.12 (d, J = 8.7 Hz, 16 H, CH), 7.46
2
2
J = 17.4, 78.6 Hz, 24 H), 3.96 (s, 12 H, CH ), 3.15 (m, 8 H, CH ), 1.58
2
2
1
H
13
(
m, 8 H, CH ), 1.32 (m, 8 H, CH ), 0.93 (m, 12 H, CH ) ppm. C NMR
2 2 3
6
(125 MHz, [D ]DMSO): δ = 159.5, 158.5, 146.9, 146.4, 127.4, 123.6,
6
(d, J = 8.7 Hz, 16 H, CH), 5.69 (s, 8 H, CH), 4.49 (dd, J = 17.5, 99.9 Hz,
6
9.6, 57.5, 47.2, 46.9, 23.1, 19.2, 13.4 ppm. MS (MALDI-TOF, –ve
1
3
16 H, CH ), 3.29 (s, 8 H, CH ) ppm. C NMR (125 MHz, [D ]DMSO):
–
2
2
6
mode, DHB): calcd. for [C114H96N O + I] 2671.587; found
36 36
δ = 159.2, 158.6, 147.2, 146.1, 128.5, 124.0, 71.7, 50.2, 46.7 ppm.
2671.603.
HRMS (APCI ): calcd. for [C H N O + H]+ 1697.4598; found
+
7
6 64 24 24
Dodecakis(2-nitrobenzyl)bambus[6]uril·TBAI (7b)
1
697.4580.
Method 1: A suspension of glycoluril 5b (825 mg, 2.0 mmol), para-
formaldehyde (90 mg, 3.0 mmol), TBAI (126 mg, 0.34 mmol), and
Octakis(2-nitrobenzyl)bambus[4]uril (6b): A suspension of glycol-
uril 5b (3.40 g, 8.25 mmol), paraformaldehyde (0.248 g, 8.25 mmol),
and PTSA·H O (1.569 g, 8.25 mmol) in CHCl (150 mL) was heated
PTSA·H O (190 mg, 1 mmol) in toluene (40 mL) was heated at reflux
2
2
3
for 21 h. The yellowish suspension was subsequently concentrated.
Sonication with MeOH (5 mL) afforded a white powder that was
filtered, washed with MeOH (2 × 5 mL), and air-dried. Purification
by silica gel chromatography (CH Cl /MeOH, 1:0.05) gave 7b as an
at reflux for 20 h. The yellowish suspension was subsequently con-
centrated. Addition of MeOH (10 mL) initiated the precipitation of
a white powder, which was washed with MeOH (2 × 10 mL), filtered,
and further purified by column chromatography over silica gel with
CH Cl /EtOAc (4:1) as eluent. The collected fractions were checked
2
2
off-white powder (233 mg, 24 %).
2
2
by TLC and UV light. Impurities remained at the starting point on a
Method 2: A suspension of glycoluril 5b (413 mg, 1.0 mmol), para-
TLC plate, and bambusuril 6b eluted as a single spot with R = 0.89.
formaldehyde (41 mg, 1.37 mmol), TBAI (63 mg, 0.17 mmol), and
f
Unfortunately, the TLC method appeared to be poorly indicative for
PTSA·H O (95 mg, 0.5 mmol) in toluene (15 mL) was subjected to
2
column chromatography. Bambusuril 6b overlapped in the column
microwave irradiation in a pressurized reactor at 200 W and 110 °C
set-up during elution, with some of the fractions containing unde- with magnetic stirring for 4 h. The resulting yellowish suspension
sired byproducts. Therefore, the collected 10 mL fractions were al-
lowed to slowly concentrate and afforded an additional 44 % of
was concentrated. Sonication with MeOH (5 mL) offered a white
powder that was filtered, washed with MeOH (2 × 5 mL), and air-
dried. Purification by silica gel chromatography (CH Cl /MeOH,
bambusuril 6b. In combination with the first fractions, bambusuril
2
2
1
1
6
b was isolated as a white powder (1.89 g, 54 %). H NMR (500 MHz,
1:0.05) gave 7b as an off-white powder (222 mg, 46 %). H NMR
[
D ]DMSO): δ = 8.10 (d, J = 7.4 Hz, 8 H, CH), 7.54 (m, 16 H, CH), 7.34
(500 MHz, [D ]DMSO): δ = 8.05 (d, J = 7.9 Hz, 12 H, CH), 7.51 (dt,
6
6
(
1
d, J = 6.9 Hz, 8 H, CH), 5.75 (s, 8 H, CH), 4.83 (dd, J = 18.2, 149.2 Hz,
J = 7.3, 23.7 Hz, 24 H, CH), 7.37 (d, J = 7.6 Hz, 12 H, CH), 5.82 (s, 12
H, CH), 4.87 (dd, J = 17.8, 45.6 Hz, 24 H, CH ), 4.14 (s, 12 H, CH ),
1
3
6 H, CH ), 3.64 (s, 8 H, CH ) ppm. C NMR (125 MHz, DMSO): δ =
2 2
2
2
1
59.12, 158.36, 147.10, 133.90, 132.58, 128.71, 127.98, 125.03, 71.82, 3.16 (t, J = 8.2 Hz, 8 H, CH ), 1.57 (quint;, J = 7.4 Hz, 8 H, CH ), 1.31
2
2
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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
sext., J = 7.3 Hz, 8 H, CH ), 0.93 (t, J = 7.3 Hz, 12 H, CH ) ppm. 13C
[D ]DMSO): δ = 8.19 (d, J = 8.7 Hz, 4 H, PhNO ), 7.45 (d, J = 8.7 Hz,
2
3
6
2
NMR (125 MHz, [D ]DMSO): δ = 158.25, 147.21, 133.84, 133.62,
4 H, PhNO ), 7.34–7.05 (m, 30 H, CH), 5.64–5.53 (m, 8 H, CH), 4.83–
6
2
1
1
28.25, 128.05, 124.92, 68.87, 57.51, 45.13, 38.68, 23.01, 19.15,
4.56 (m, 8 H, CH ), 4.36–4.11 (m, 8 H, CH ), 3.80–3.60 (m, 8 H,
2
2
13
3.40 ppm. MS (MALDI-TOF, –ve mode, DHB): calcd. for
CH ) ppm. C NMR (125 MHz, [D ]DMSO): δ = 159.5, 3 × 159.4, 3 ×
2
6
+
[C114H N O + H] 2646.587; found 2646.683.
158.5, 146.7, 145.8, 137.9, 3 × 137.7, 2 × 128.5, 128.2, 128.0, 2 ×
96
36 36
1
27.3, 2 × 126.9, 126.8, 123.7, 2 × 71.3, 2 × 71.2, 49.6, 49.4, 2 × 46.8,
Octakis(4-aminobenzyl)bambus[4]uril (8a): A suspension of bam-
busuril 6a (0.169 g, 0.118 mmol) and 10 % Pd/C (0.010 g) in DMF
+
+
46.5 ppm. HRMS (APCI ): calcd. for [C H N O + H] 1427.5493;
76 70 18 12
found 1427.5469.
(
5 mL) was stirred overnight under H in an autoclave (p = 3 bars).
2
The reaction mixture was filtered through a short Celite pad and X-ray Crystallography
concentrated under vacuum. Water was added to the residual con-
Details of data collection and refinement are given in the Support-
ing Information.
centrate to give 8a as a white solid (0.100 g, 69 %). 1H NMR
(
500 MHz, [D ]DMSO): δ = 6.88 (d, J = 8.0 Hz, 16 H, CH), 6.53 (d, J =
6
CCDC 1571626 (for 5a), 1571627 (for 6a), 1571628 (for 6c), and
1571629 (for 6d) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
8
1
.0 Hz, 16 H, CH), 5.43 (s, 8 H, CH), 5.04 (s, 16 H, NH ), 4.21 (dd, J =
2
1
3
5.5, 58.0 Hz, 16 H), 3.96 (s, 8 H, CH ) ppm. C NMR (125 MHz,
2
[D ]DMSO): δ = 159.2, 159.1, 148.1, 128.7, 125.1, 114.5, 71.4, 50.5,
6
+
4
6.7 ppm. MS (MALDI-TOF, HCCA): calcd. for [C H N O + Na]
76 80 24 8
1
479.648; found 1479.646.
Octakis(2-aminobenzyl)bambus[4]uril (8b): A mixture of bam- Acknowledgments
busuril 6b (200 mg, 0.118 mmol) and 10 % Pd/C (10 mg, dry sup-
This work was supported by the Czech Science Foundation (13-
port) in THF (200 mL) was stirred overnight under H . The mixture
was filtered through a short Celite pad and concentrated under
2
1
5576S) and MEYS CR (projects LO1214 and LM2015051). The
CIISB Research Infrastructure Project (LM2015043) funded by
NaOH was added MEYS CR is gratefully acknowledged for the financial support
vacuum. The resulting white powder was suspended in 1
25 mL). The suspension was centrifuged and 2
M HCl
(
M
to the collected supernatant to pH = 10 to give compound 8b as a of the measurements at the CF X-ray Diffraction and Bio-SAXS
1
white powder (110 mg, 64 %). H NMR (500 MHz, [D ]DMSO): δ = and CF Proteomics.
6
6
8
9
[
1
.94 (m, 16 H, CH), 6.60 (d, J = 7.7 Hz, 8 H, CH), 6.46 (t, J = 7.4 Hz,
H, CH), 5.65 (s, 8 H, CH), 5.07 (s, 16 H, NH ), 4.24 (dd, J = 16.2,
0.8 Hz, 16 H), 4.08 (s, 8 H, CH ) ppm. C NMR (125 MHz,
D ]DMSO): δ = 159.35, 159.08, 146.04, 128.62, 128.25, 119.64,
15.92, 114.91, 71.76, 50.04, 44.13 ppm. HRMS (ESI ): calcd. for
C H N O + Na] 1479.6483; found 1479.6479.
2
1
3
Keywords: Macrocycles · Bambusurils · Template
synthesis · Receptors · Glycolurils
2
6
+
+
[
76 80 24 8
[
[
[
[
[
1] J. Svec, M. Necas, V. Sindelar, Angew. Chem. Int. Ed. 2010, 49, 2378–2381;
Angew. Chem. 2010, 122, 2428.
2] M. A. Yawer, V. Havel, V. Sindelar, Angew. Chem. Int. Ed. 2015, 54, 276–
Octakis[4-(carbamoylamino)benzyl]bambus[4]uril (9): Bam-
busuril 8a (0.035 g, 0.02 mmol) was dissolved in 15 % acetic acid
10 mL) and then KOCN in 15 % acetic acid (2 mL) was added. The
reaction mixture was stirred at room temp. for 12 h. The white
precipitates obtained were filtered and dried under vacuum to yield
(0.032 g, 89 %). H NMR (500 MHz, [D ]DMSO): δ = 8.53 (s, 8 H,
NH), 7.34 (d, J = 8.1 Hz, 16 H, CH), 7.06 (d, J = 8.1 Hz, 16 H, CH),
.88 (s, 16 H, NH ), 5.47 (s, 8 H, CH), 4.28 (m, 16 H, CH ), 3.95 (m, 8
H, CH ) ppm. C NMR (125 MHz, [D ]DMSO): δ = 159.2, 158.8, 156.6,
40.0, 130.7, 128.2, 118.2, 71.3, 50.6, 46.5 ppm. MS (MALDI-TOF,
2
79; Angew. Chem. 2015, 127, 278.
(
3] V. Havel, J. Svec, M. Wimmerova, M. Dusek, M. Pojarova, V. Sindelar, Org.
Lett. 2011, 13, 4000–4003.
4] M. Singh, G. Parvari, M. Botoshansky, E. Keinan, O. Reany, Eur. J. Org.
Chem. 2014, 2014, 933–940.
1
9
6
5] M. Singh, E. Solel, E. Keinan, O. Reany, Chem. Eur. J. 2015, 21, 536–540.
5
[6] M. Singh, E. Solel, E. Keinan, O. Reany, Chem. Eur. J. 2016, 22, 8848–8854.
[7] V. Havel, M. Babiak, V. Sindelar, Chem. Eur. J. 2017, 23, 8963–8968.
[8] See ref.[
2
2
13
2
6
1]
1
+
[9] D. Xiang, Y. Yang, R. Zhang, Y. Liang, W. Pan, J. Huang, D. Dong, J. Org.
Chem. 2007, 72, 8593–8596.
HCCA): calcd. for [C H N O + Na] 1823.792; found 1823.665.
84 88 32 16
Bis(4-nitrobenzyl)hexabenzylbambus[4]uril (10): A suspension
of glycoluril 5a (0.412 g, 1.0 mmol), 2,4-dibenzylglycoluril (12;
[
10] Y. G. Gololobov, I. N. Zhmurova, L. F. Kasukhin, Tetrahedron 1981, 37,
437–472.
0
.967 g, 3.0 mmol), paraformaldehyde (0.120 g, 4 mmol), and PTSA
[11] N. Yamazaki, T. Iguchi, F. Higashi, J. Polym. Sci. Polym. Chem. Ed. 1979,
17, 835–841.
(0.760 g, 4 mmol) was heated at reflux for 48 h in CHCl (55 mL).
3
[
12] X. Zhang, J. Rodrigues, L. Evans, B. Hinkle, L. Ballantyne, M. Peña, J. Org.
Chem. 1997, 62, 6420–6423.
Then the reaction mixture was extracted with sat. aq. NaHCO (3 ×
3
1
00 mL) and brine (3 × 50 mL). The collected organic layers were
[
13] J. Svec, M. Dusek, K. Fejfarova, P. Stacko, P. Klán, A. E. Kaifer, W. Li, E.
Hudeckova, V. Sindelar, Chem. Eur. J. 2011, 17, 5605–5612.
14] J. Rivollier, P. Thuéry, M.-P. Heck, Org. Lett. 2013, 15, 480–483.
15] G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman,
B. M. Stoltz, J. E. Bercaw, K. I. Goldberg, Organometallics 2010, 29, 2176–
2179.
dried with anhydrous Na SO , filtered, and the solvents were evapo-
rated. The resulting yellowish crude product was heated at reflux
in MeOH (30 mL) and then hot-filtered. The resulting white powder
was purified by column chromatography on silica gel with CH Cl /
acetone (4:1) as the eluent. Bambusuril 10 was eluted as a single
2
4
[
[
2
2
spot with R = 0.57. Concentration of the collected fractions gave
f
1
bambusuril 10 as a white powder (94 mg, 7 %). H NMR (500 MHz,
Received: September 23, 2017
Eur. J. Org. Chem. 2018, 41–47
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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim