1,6-Dibenzylglycoluril for synthesis of deprotected glycoluril dimer

Article abstract of DOI:10.1016/j.tet.2011.08.097

1,6-Dibenzylglycoluril is not accessible via classical condensation reaction between substituted urea and glyoxal. In this paper 1,6-dibenzylglycoluril was successfully prepared by alkylation of 1,6-diacetylglycoluril with benzylbromide for the first time. 1,6-Dibenzylglycoluril reacted with formaldehyde to give tetrabenzylglycoluril dimer. Deprotection of this dimer and the previously reported o-xylyleneglycoluril dimer was achieved by dissolving metal reduction, whereas propyleneglycoluril dimer was deprotected by action of potassium persulfate.

Full text of DOI:10.1016/j.tet.2011.08.097

Tetrahedron 67 (2011) 8937e8941
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,6-Dibenzylglycoluril for synthesis of deprotected glycoluril dimer
,b,
Marek Stancl a, Muhammad S.A. Khan a, Vladimir Sindelar a
*
a Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
b Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 3, 625 00 Brno, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2011
Received in revised form 11 August 2011
Accepted 31 August 2011
Available online 7 September 2011
1,6-Dibenzylglycoluril is not accessible via classical condensation reaction between substituted urea and
glyoxal. In this paper 1,6-dibenzylglycoluril was successfully prepared by alkylation of 1,6-diacetylgly-
coluril with benzylbromide for the first time. 1,6-Dibenzylglycoluril reacted with formaldehyde to give
tetrabenzylglycoluril dimer. Deprotection of this dimer and the previously reported o-xylyleneglycoluril
dimer was achieved by dissolving metal reduction, whereas propyleneglycoluril dimer was deprotected
by action of potassium persulfate.
Keywords:
Glycoluril
Ó 2011 Elsevier Ltd. All rights reserved.
Glycoluril dimer
Alkylation
Protecting group
Deprotection
1. Introduction
Therefore, suitable protecting groups should be found, which could
be selectively introduced to the positions 1 and 6 on the glycoluril
Glycoluril1 is a simple heterobicyclic compound, which was
prepared for the first time in the 19th century. Since then, glycoluril
and its derivatives have found applications in many fields of
chemistry. Among others, glycoluril is used as a building block of
supramolecular host molecules, molecular clips, and cucurbiturils.2
The latter family of macrocyclic compounds is known to bind or-
ganic and inorganic cations with high affinity and selectivity. These
properties made cucurbiturils one of the most promising supra-
molecular hosts. However, the low solubility and difficult modifi-
cation represent the main drawbacks for the use of cucurbiturils.
Recent approaches for the preparation of new cucurbiturils with
improved properties lie in the gradual connecting of glycoluril units
into acyclic structures, glycoluril oligomers, and their subsequent
transformation into macrocycles.3 Glycoluril oligomers are pre-
pared by the acid catalyzed condensation of glycoluril and form-
aldehyde, which yields a statistical mixture of products with
different number of glycoluril units.4 Recently, we and others
demonstrated that glycoluril dimers, trimers, and tetramers can be
prepared selectively using 1,6-protected glycoluril for the termi-
nation of glycoluril oligomer.5 However, it is important that the
selectively prepared oligomers framed by the 1,6-protected glyco-
luril can be later deprotected, which would allow the use of the
oligomers for the synthesis of macrocycles or higher oligomers.
skeleton and also methods should be developed, which would
enable its easy and high yielding deprotection (Fig. 1).
O
2
3
1
NH
HN
6a
HN
3a
NH
4
6
5
O
Fig. 1. Glycoluril.
A literature search gave us some inspiration,6 for instance, Rebek
and co-workers used p-methoxybenzyl (PMB) and tert-butox-
ycarbonyl (Boc) protecting groups in the synthesis of capsule pre-
cursors.7 In biotin synthesis, a urea moiety was protected using
benzyl substituent; deprotection was achieved by hydrobromic
acid8a or by the dissolving metal reduction.8b Unfortunately, (de)
protections methods were illustrated only on glycolurils bearing
additional substitution in position 3a and 6a. In our work, we focus
on glycoluril bearing hydrogen atoms in the central positions be-
cause of their potential use in the cucurbituril synthesis. To the best
of our knowledge, the deprotection of these glycolurils has not been
described in the literature until now.
* Corresponding author. Fax: þ420 549 49 2443; e-mail address: sindelar@
chemi.muni.cz (V. Sindelar).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.097

8938
M. Stancl et al. / Tetrahedron 67 (2011) 8937e8941
Herein we present the several methods of the preparation of 1,6-
The listed values demonstrate that the acetyl groups bound in the
positions N1 and N4 are more twisted compared to those in posi-
tions N3 and N2, which can rationalize their higher reactivity with
nucleophiles.13
dibenzylglycoluril including the selective synthesis of this glyco-
luril isomer. We further demonstrate that the dimer prepared by
the condensation of 1,6-dibenzylglycoluril with formaldehyde can
be deprotected with high efficiency. The deprotection of the pre-
viously prepared glycoluril dimers is also discussed.
We envisioned that when bifunctional instead of monofunc-
tional nucleophiles will be used, they could react with acetyl groups
on one face of 1 yielding 1,6-diacetylglycoluril 2b. Therefore, we
tested 1 in the reactions with several bifunctional nucleophiles
(Table 1). The bifunctional reagents with the nucleophilic groups
directly attached to aromatic ring did not satisfy our expectation as
only undesired isomer 2a was formed. In these reagents the rigid
arrangement and lower reactivity of nucleophilic groups, caused by
their direct attachment to the aromatic system, probably hinder
reaction of both nucleophilic groups with acetyl groups on one face
of 1. On the other hand, primary diamines with more flexible
structure and higher nucleophilicity furnished 1,6-diacetylglycoluril
2b in acceptable yields.
2. Results and discussion
The preparation of dibenzylglycouril was previously described;9
nevertheless the position of substituents on the resulting product
was not specified. We repeated the published procedure, which
was based on the reaction between N-benzylurea and glyoxal and
obtained a mixture in which 1,4-dibenzylglycoluril, 1-benzyl-
hydantoin, and 3-benzylhydantoin were the main products. Only
traces of desired 1,6-dibenzylglycoluril 4 were detected. This result
is in agreement with the observation that an increase in the bulk-
iness of the substituent results in a decrease in the yield of 1,6-
disubstituted glycoluril.10 Therefore, we looked for a different
preparative method. Alkylation of 1-benzylglycoluril with benzyl-
chloride in the presence of NaH and KI resulted in the complex
mixture of alkylated glycolurils. Nevertheless, we were able to
isolate 1,6-dibenzylglycoluril 4 using column chromatography in an
unsatisfactory yield.
Table 1
Reaction of bifunctional nucleophiles with 1 at room temperature
Nucleophile
2a/2bc
a
Pyrocatechol, K2CO3
100:0
100:0
55:45
59:41
o-Phenylenediamineb
m-Xylylenediamineb
Ethylenediamineb
The other approach we tested for the preparation of 1,6-
dibenzylglycoluril 4 was based on the 1,3,4,6-tetraacetylglyco-
a
In CH3CN.
In CH2Cl2.
Product ratio based on NMR.
b
luril.11 1. This compound was previously prepared by Kuhling and
€
c
it was used by him11 and others12 as a mild acylating reagent.
€
Kuhling shown that the reaction between 1 and 2 equiv of mono-
functional nucleophiles results in the formation of the acetylated
nucleophiles and 1,4-diacetylglycoluril 2a. However, our aim was to
prepare 1,6-diacetylglycoluril 2b isomer, which can later serve for
the preparation of 4. Clearly, the selective formation 2a is caused by
the different reactivity of acetyl groups of 1 with nucleophiles. To
understand different reactivity of acetyl groups of 1, we prepared
1,3,4,6-tetraacetylglycoluril and obtained its monocrystals suitable
for the X-ray measurement.
The crystal structure of 1 revealed that acetyl groups are at-
tached to glycoluril unit with the different degree of twisting rel-
ative to the planes of the corresponding ureido moieties (Fig. 2).
This is illustrated by different values of dihedral angles comprising
acetyl groups: 141.35ꢀ (O3eC5eN1eC1), ꢁ167.86ꢀ (O4eC7eN2e
C1), ꢁ172.33ꢀ (O5eC9eN3eC2), and 157.39ꢀ (O6eC11eN4eC2).
Separation of 2b from 1,4-diacetylderivative 2a was achieved by
the fractional crystallization from glacial acetic acid (Scheme 1).
This simple separation procedure allows the preparation of desired
product on a multigram scale.
O
O
O
O
O
O
O
N
N
N
N
HN
N
N
HN
HN
N
N
Nucleophile
CH2Cl2
+
NH
O
O
O
O
O
O
O
1
2a
2b
Scheme 1. Reaction of 1 with nucleophilic reagent.
Glycoluril 2b was used for the synthesis of 1,6-dibenzylglycoluril
4. First, it was alkylated with benzylbromide in the presence of
K2CO3 in DMSO (Scheme 2). Resulting acetylglycoluril 3 was sub-
sequently hydrolyzed without the isolation to furnish 1,6-
dibenzylglycoluril 4. Note that the use of stronger base (t-BuOK)
in the alkylation step resulted in the rearrangement and 1,4-
dibenzylglycoluril was formed as a side-product.
O
O
O
O
O
O
O
HN
HN
N
N
N
N
N
N
N
N
NH
NH
BnBr, K2CO3
DMSO
NaOH
Ph
Ph
Ph
Ph
MeOH, H2O
O
O
O
2b
3
4
21 %
Fig. 2. ORTEP representation of the crystal structures of 1.14
Scheme 2. Synthesis of 1,6-dibenzylglycoluril 4.

M. Stancl et al. / Tetrahedron 67 (2011) 8937e8941
8939
Since we had a relatively high yielding method for the prepa-
ration of 1,6-dibenzylglycoluril 4, we prepared the smallest glyco-
luril oligomer, the dimer, reaction between glycoluril 4 and
paraformaldehyde in concd HCl resulted in the formation of dimer
5a in 81% yield (Scheme 3).
Nevertheless, the direct preparation of higher deprotected glyco-
luril oligomers is very difficult compared to the easy preparation of
the protected analogs e.g., o-xylyleneglycoluril trimer.5c Therefore,
the demonstrated deprotection should be understood as a proof of
the concept for future applications.
O
O
O
3. Conclusions
N
N
NH
NH
N
N
N
N
N
N
N
N
(CH2O)n
Ph
Ph
Ph
Ph
Ph
Ph
In conclusion, we have developed method for the preparation of
1,6-diacetylglycoluril. This glycoluril derivative was used for the
selective preparation of 1,6-dibenzylglycoluril. New methods for
the deprotection of glycoluril dimers have been also demonstrated.
HCl, H2O
O
O
O
4
5a
81 %
Scheme 3. Preparation of protected glycoluril dimer 5a.
4. Experimental section
4.1. General
Deprotecting of the dimer 5a was achieved by the dissolving
metal reduction using sodium in liquid ammonia (Scheme 4). This
methodology is commonly used for the deprotection of benzyla-
mides.6 Deprotected dimer4b,5e 6 was isolated in 92% yield. The
same deprotecting protocol could be used also in the case of o-
xylyleneglycoluril dimer 5b. Dimer 5b was originally suggested as
an easily accessible protected dimer,5b and deprotected dimer 6
was obtained in 67% yield.
All reagents were purchased from commercial sources and were
used without further purification. Melting points were determined
using Kofler block. 1H and 13C NMR spectra were recorded with
Bruker Avance 300 spectrometer. Chemical shifts were measured
using the
d scale with TMS or residual solvent signal as a standard.
LC-HRMS measurements were performed with Waters Micromass
Q-TOF micro spectrometer. IR spectra were recorded using Mattson
ATI Genesis FT-IR spectrometer. X-ray diffraction datawerecollected
on a KUMA KM-4 k-axis CCD diffractometer with Mo Ka radiation
ꢀ
(l
¼0.71073 A). The temperature during data collectionwas 120(2) K.
The structure was solved by direct methods and refined by full-
matrix least-squares methods using ShelXTL software. The ther-
mal ellipsoids in figure were drawn at the 50% probability level.
O
O
O
O
O
O
O
O
R
R
R
R
N
N
N
N
HN
HN
N
N
N
N
N
N
N
N
NH
NH
cond.
4.1.1. 1,3,4,6-Tetraacetylglycoluril (1). HClO4 (70% aqueous solution;
3.5 mL) was added dropwise tothe suspension of glycoluril1c (50.0 g;
0.35 mol) in Ac2O (331 mL; 357.3 g; 3.5 mol; 10 equiv) under cooling
with water bath. The temperature did not exceed 40 ꢀC, and the
solids gradually dissolved to form yellow solution. Reaction mixture
was stirred at room temperature, under a calcium chloride stopper
overnight. Separated solid material was filtered off and washed
three times with 100 mL of water, affording of a 64.6 g white crys-
talline solid. A second crop was obtained by concentration of the
mother liquor to approx. 2/3 of the volume followed by overnight
crystallizationprovidingan additional 22.6 g. Totalyield 80%. Mp dec
5a, b, c
6
R =
5a
5b
5c
conditions:
5a, b: Na / NH3 liq. 5c: K2S2O8 / H2O
Yield 92 % and 67 % Yield 22 %
Scheme 4. Deprotection of protected dimers.
above 180 ꢀC (lit.11a 234e238 ꢀC).1H NMR (300 MHz, CDCl3):
(s, 2H, CH), 2.54 (s,12H, CH3).13C NMR (75 MHz, CDCl3):
¼169.6 (C]
O acetyl), 150.7 (C]O glycoluril), 61.9 (CH), 24.9 (CH3). IR (Nujol):
d¼6.55
d
n
¼2973, 2879, 2839, 1805, 1753, 1733, 1702, 1436, 1361, 1297, 1266,
During our previous work on the synthesis of glycoluril dimers,
we prepared propyleneglycoluril dimer 5c.5b Simple alkyl groups
are not generally considered as protecting groups. Nevertheless,
few examples could be found in literature.15 It is also known that
simple alkylamides are dealkylated by the action of potassium
persulfate (K2S2O8).16 We have found, that K2S2O8 could be also
used for deprotecting of 5c. Deprotected dimer 6 was easily isolated
by filtration from water soluble side-products. Unfortunately, the
yield is rather low. Based on HPLCeHRMS studies we determined
that those water soluble side-products corresponds to propylene-
glycoluril dimers substituted in positions 3a and 6a with hydroxyl
groups. Major product was tetrahydroxylated and trihydroxylated
propyleneglycoluril dimer. Minor product was dihydroxylated di-
mer, while monohydroxylated dimer was present only in traces.
Formation of these side-products was not surprising as similar
reaction conditions were used by Kim and co-workers for the
preparation of hydroxylated cucurbiturils.17
1216,1189,1097,1035, 987, 921, 779 cmꢁ1. HRMS (ESIþ) m/z calcd for
[C12H14N4O6þH]þ 311.0992, found 311.0967.
4.1.2. 1,4-Diacetylglycoluril (2a). 1,3,4,6-Tetraacetylglycoluril
1
(22.6 g; 72.8 mmol) was dissolved in dichloromethane (400 mL).
A solution of ethylenediamine (5.42 mL; 4.87 g; 81.0 mmol;
1.1 equiv) in dichloromethane (30 mL) was added dropwise over
15 min, and the resulting mixture was stirred at room temper-
ature for 3 days. The resulting solid was filtered off, washed
three times with 80 mL of water and once with 40 mL of ace-
tone to remove acetylated ethylenediamine. The dried solid
(13.4 g) was recrystallized from 200 mL of glacial acetic acid,
filtered off and washed with Et2O, affording a white crystalline
solid 5.03 g (30%). Analytical sample was recrystallized from
glacial acetic acid. Mp >300 ꢀC (lit.11a 328e330 ꢀC). 1H NMR
(300 MHz, DMSO-d6):
(s, 6H, CH3). 13C NMR (75 MHz, DMSO-d6):
tyl), 153.8 (C]O glycoluril), 61.8 (CH), 23.1 (CH3). IR (Nujol):
¼3269, 2965, 2944, 2886, 2869, 2844, 1760, 1667, 1445, 1380,
d
¼8.85 (s, 2H, NH), 5.66 (s, 2H, CH), 2.35
d
¼169.6 (C]O ace-
Please note that the deprotected dimer 6 can be easily obtained
by the condensation of glycoluril and formaldehyde.4b,5e
n

8940
M. Stancl et al. / Tetrahedron 67 (2011) 8937e8941
1346, 1320, 1239, 1163, 1071, 974, 872, 770, 724 cmꢁ1. HRMS
benzyl), 4.27 (d, J¼14.7, 2H, NCH2N), 4.07 (d, J¼16.2, 4H, CH2 ben-
zyl) ppm. 13C NMR (75 MHz, DMSO-d6):
arom.), 128.5 (CH arom.), 127.3 (CH arom.), 127.2 (CH arom.), 70.8
(CH), 67.9 (CH), 52.6 (NCH2N), 46.1 (CH2 benzyl) ppm. IR (Nujol):
(ESIþ) m/z calcd for [C8H10N4O4þH]þ 227.0780, found 227.0773.
d¼156.9 (C]O), 136.9 (C
4.1.3. 1,6-Diacetylglycoluril (2b). The acetic acid mother liquor
from the previous reaction (2a) was evaporated to dryness
(Caution, foaming!). The resulting solid (8.45 g) was recrystal-
lized from glacial acetic acid (100 mL), filtered off, washed with
Et2O and recrystallized from glacial acetic acid, affording a white
crystalline solid 3.40 g (21%). Attempts to isolate more of the 1,6-
derivative from mother liquor by repeated crystallization failed.
n
¼2953, 2925, 2854, 1710, 1474, 1451, 1382, 1320, 1220, 1130, 955,
807, 793, 737 cmꢁ1. HRMS (ESIþ) m/z calcd for [C38H36N8O4þH]þ:
669.2938, found: 669.2952.
4.1.6. Glycoluril dimer (6). Method A: Glycoluril dimer 5a or 5b5b
(0.39 mmol) was added to liquid ammonia (20 mL) and the
resulting mixture was cooled to ꢁ40 to ꢁ45 ꢀC. Sodium metal
(0.28 g, 12.48 mmol, 32 equiv) was added portionwise over 5 min.
The resulting dark blue mixture was stirred with a glass coated
magnetic stirring bar at ꢁ45 to ꢁ40 ꢀC for additional time
(30 mine1 h), before solid NH4Cl (0.66 g) was slowly added. (The
temperature did not exceed ꢁ35 ꢀC during addition of NH4Cl.) The
reaction mixture was left to reach room temperature, the resulting
white solid was mixed with water, filtered off, washed with water,
acetone, and Et2O. Yield 92% and 67%, respectively.
Mp dec above 210 ꢀC 1H NMR (300 MHz, DMSO-d6):
2H, NH), 6.44 (d, J¼7.2, 1H, CH), 5.25 (d, J¼7.2, 1H, CH), 2.31 (s,
6H, CH3) ppm. 13C NMR (75 MHz, DMSO-d6):
¼168.9 (C]O
acetyl), 154.7 (C]O glycoluril), 65.9 (CH), 59.0 (CH), 24.1 (CH3)
ppm. IR (Nujol):
d
¼8.69 (s,
d
n
¼3268, 3218, 2976, 2923, 2881, 2835, 1776,
1754, 1694, 1462, 1381, 1328, 1235, 1152, 1076, 978, 865, 782,
737 cmꢁ1. HRMS (ESIþ) m/z calcd for [C8H10N4O4þH]þ 227.0780,
found 227.0781.
4.1.4. 1,6-Dibenzylglycoluril (4). Method A: 1-Benzylglycoluril18
(2.50 g, 10.7 mmol) was dissolved in dry DMF (110 mL). NaH
(60% dispersion in mineral oil, 0.40 g, 10.7 mmol, 1 equiv) was
added, and the resulting mixture was stirred at room temperature
until the evolution of gas ceased. Benzylchloride (1.35 mL, 1.50 g,
11.8 mmol, 1.1 equiv) was added followed by KI (1.78 g, 10.7 mmol,
1 equiv), and the reaction mixture was heated to 80e90 ꢀC for
12 h. DMF was evaporated and residue was separated by column
chromatography (silica, CH2Cl2/MeOH 10:1) affording 0.25 g of
a yellowish crystalline solid (7%), which was recrystallized from
MeOH.
Method B: 1,6-Diacetylglycoluril 2b (0.50 g, 2.21 mmol) was
dissolved in dry DMSO (5 mL). Benzylbromide (0.55 mL, 0.79 g,
4.64 mmol, 2.1 equiv) was added, followed by K2CO3 (0.64 g,
4.64 mmol, 2.1 equiv). The reaction mixture was heated to 80 ꢀC
under an argon atmosphere for 17 h, diluted with EtOAc (50 mL)
and washed three times with water (50 mL) and once with brine
(50 mL). The organic phase was dried over Na2SO4 and evaporated
to give 0.62 g of yellow oil, which was redissolved in methanol
(20 mL). A solution of NaOH (0.30 g, 7.5 mmol) in water (20 mL) was
added, and the resulting mixture was heated to reflux for 2.5 h.
Methanol was evaporated and the resulting crystalline material
was filtered off and washed with water. White to yellow crystals
Method B: Propyleneglycoluril dimer5b 5c (0.2 g; 0.515 mmol)
was mixed with a solution of K2S2O8 (0.69 g; 2.57 mmol;
5 equiv) in 25 mL of water. A slow stream of nitrogen was passed
through the resulting mixture for 1 h. Then, the mixture was
heated to 80 ꢀC for 16 h under nitrogen, the resulting solid was
filtered off and washed with water and acetone. 35 mg Beige
solid (22%). Mp >300 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.60
(s, 4H, NH); 5.60 (d, J¼14.5, 2H, CH2), 5.35 (d, J¼8.5, 2H, CH), 5.23
(d, J¼8.5, 2H, CH), 4.03 (d, J¼14.5, 2H, CH2) ppm. 13C NMR
(75 MHz, DMSO-d6):
(CH2) ppm. IR (Nujol):
1760, 1704, 1491, 1404, 1329, 1293, 1243, 1189, 1108, 959, 884,
800, 724 cmꢁ1. HRMS (ESIþ) m/z calcd for [C10H12N8O4þH]þ
309.1060, found 309.1055.
d
¼157.8 (C]O), 74.1 (CH), 60.1 (CH), 51.2
n
¼3599, 3534, 3214, 3079, 2921, 2825,
Acknowledgements
Support for this work was provided by the Czech Science
Foundation (P207/10/0695) and the project CETOCOEN (no.
CZ.1.05/2.1.00/01.0001) from the European Regional Development
ꢁ
Fund. The authors acknowledge J. Frantisek for HRMS measure-
ꢁ
ments and M. Necas for measuring X-ray structure.
(0.15 g, 21%). Mp 197e200 ꢀC 1H NMR (300 MHz, DMSO-d6):
d¼7.64
Supplementary data
(s, 2H, NH), 7.33e7.08 (m, 10H, CH arom.), 5.26 (d, J¼8.5, 1H, CH),
4.98 (d, J¼8.5, 1H, CH), 4.48 (d, J¼16.1, 2H, CH2), 3.98 (d, J¼16.1, 2H,
1H and 13C NMR spectra of compounds 1, 2a, 2b, 4, 5a, 6 and cif
of 1. Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2011.08.097.
CH2) ppm. 13C NMR (75 MHz, DMSO-d6):
arom.), 128.5 (CH arom.), 127.2 (CH arom.), 127.1 (CH arom.), 70.7
(CH), 60.4 (CH), 45.1 (CH2) ppm. IR (Nujol):
2880, 2838, 1719, 1694, 1455, 1375, 1351, 1239, 1127, 1072, 960, 885,
720, 700 cmꢁ1. HRMS (ESIþ) m/z calcd for [C18H18N4O2þH]þ
323.1508, found 323.1507.
d
¼159.7 (C]O), 137.5 (C
n
¼2970, 2923, 2907,
References and notes
1. (a) Rheineck, H. Liebigs Ann. Chem. 1865, 134, 219e228; (b) Schiff, H. Liebigs Ann.
Chem. 1877, 189, 157e161; (c) Slezak, F. B.; Hirsch, A.; Rosen, I. J. Org. Chem. 1960,
Note: In the case of larger charges, the final product may contain
1-benzylglycoluril as an impurity. This impurity could be easily
removed by trituration with boiling water.
€
25, 660e661; (d) Jansen, K.; Wego, A.; Buschmann, H.-J.; Schollmeyer, E.; Dopp,
D. Des. Monomers Polym. 2003, 6, 43e55.
2. (a) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew. Chem., Int. Ed.
2005, 44, 4844e4870; (b) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.;
Kim, J. Chem. Soc. Rev. 2007, 36, 267e279.
4.1.5. Tetrabenzylglycoluril dimer (5a). Concentrated hydrochloric
acid (4 mL) was added to the mixture of 1,6-dibenzylglycoluril 4
(0.36 g, 1.11 mmol) and paraformaldehyde (33.5 mg, 1.11 mmol).
The resulting mixture was heated to 80 ꢀC (bath temperature) with
stirring for 1.5 h (After approx. 20 min yellow gummy material
formed.) The mixture was then evaporated and residue was tritu-
rated with toluene (60 mL). The resulting solid was filtered off,
washed with toluene and Et2O, to give 0.30 g of an off-white solid
(81%). Mp 288e289 ꢀC (dec). 1H NMR (300 MHz, DMSO-d6):
3. (a) Flinn, A.; Hough, G. C.; Stoddart, J. F.; Williams, D. J. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1475e1477; (b) Zhao, J.; Kim, H.-J.; Oh, J.; Kim, S.-Y.; Lee, J. W.;
Sakamoto, S.; Yamaguchi, K.; Kim, K. Angew. Chem., Int. Ed. 2001, 40,
4233e4235; (c) Isobe, H.; Sato, S.; Nakamura, E. Org. Lett. 2002, 4, 1287e1289;
(d) Day, A. I.; Arnold, A. P.; Blanch, R. J. Molecules 2003, 8, 74e84; (e) Yu, D.-H.;
Ni, X.-L.; Tian, Z.-C.; Zhang, Y.-Q.; Xue, S.-F.; Tao, Z.; Zhu, Q.-J. J. Mol. Struct. 2008,
891, 247e253; (f) Lagona, J.; Fettinger, J. C.; Isaacs, L. J. Org. Chem. 2005, 70,
10381e10392.
4. (a) Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. Angew. Chem., Int. Ed. 2007, 46,
7425e7427; (b) Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2008, 130,
8446e8454; (c) Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. Org. Lett. 2009, 11,
3918e3921.
d¼7.35e7.11 (m, 20H, CH arom.), 5.80 (d, J¼14.7, 2H, NCH2N), 5.46
5. (a) Wu, A.; Chakraborty, A.; Witt, D.; Lagona, J.; Damkaci, F.; Ofori, M. A.; Chiles, J. K.;
Fettinger, J. C.; Isaacs, L. J. Org. Chem. 2002, 67, 5817e5830; (b) Stancl, M.; Necas, M.;
(d, J¼8.7, 2H, CH), 5.05 (d, J¼8.7, 2H, CH), 4.46 (d, J¼16.2, 4H, CH2

M. Stancl et al. / Tetrahedron 67 (2011) 8937e8941
8941
Taraba, J.; Sindelar, V. J. Org. Chem. 2008, 73, 4671e4675; (c) Stancl, M.; Hodan, M.;
Sindelar, V. Org. Lett. 2009, 11, 4184e4187; (d) Ma, D.; Zavalij, P. Y.; Isaacs, L. J. Org.
Chem. 2010, 75, 4786e4795; (e) Zhao, Y.; Xue, S.; Zhu, Q.; Tao, Z.; Zhang, J.; Wei, Z.;
Long, L.; Hu, M.; Xiao, H.; Day, A. I. Chin. Sci. Bull. 2004, 49, 1111e1116.
6. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; Wiley: New Jersey, 2007, pp 894e916.
12. (a) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 2106e2108; (b) Kalisiak, J.;
Trauger, S. A.; Kalisiak, E.; Morita, H.; Fokin, V. V.; Adams, M. W. W.; Sharpless,
K. B.; Siuzdak, G. J. Am. Chem. Soc. 2009, 131, 378e386.
13. Matta, C. F.; Cow, C. C.; Sun, S.; Britten, J. F.; Harrison, P. H. M. J. Mol. Struct. 2000,
523, 241e255.
14. Crystallographic data for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC-816004. Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.Uk).
7. Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. 1997, 36, 846e848.
ꢁ
8. (a) Baggiolini, E. G.; Lee, H. L.; Pizzolato, G.; Uskokovic, M. R. J. Am. Chem.
Soc. 1982, 104, 6460e6462; (b) Field, G. F. J. Org. Chem. 1978, 43,
1084e1085.
9. Slezak, F. B.; Bluestone, H.; Magee, T. A.; Wotiz, J. H. J. Org. Chem. 1962, 27,
2181e2183.
15. Beyersbergen van Henegouwen, W. G.; Fieseler, R. M.; Rutjes, F. P. J. T.; Hiem-
stra, H. J. Org. Chem. 2000, 65, 8317e8325.
10. Kravchenko, A. N.; Sigachev, A. S.; Maksareva, E. Y.; Gazieva, G. A.; Trunova, N.
S.; Lozhkin, B. V.; Pivina, T. S.; Il’in, M. M.; Lyssenko, K. A.; Nelyubina, Y. V.;
Davankov, V. A.; Lebedev, O. V.; Makhova, N. N.; Tartakovsky, V. A. Russ. Chem.
Bull., Int. Ed. 2005, 54, 691e704.
11. (a) Kuhling, D. Liebigs Ann. Chem. 1973, 263e277; (b) Hase, C.; Kuhling, D. Lie-
bigs Ann. Chem. 1975, 95e102.
16. (a) Needles, H. L.; Whitfield, R. E. J. Org. Chem. 1964, 29, 3632e3634; (b) Nee-
dles, H. L.; Whitfield, R. E. J. Org. Chem. 1966, 31, 341e342.
17. Jon, S. Y.; Selvapalam, N.; Oh, D. H.; Kang, J.-K.; Kim, S.-Y.; Jeon, Y. J.; Lee, J. W.;
Kim, K. J. Am. Chem. Soc. 2003, 125, 10186e10187.
€
€
18. (a) F. B. Slezak, H. Bluestone, US3187004 1965; (b) Grillon, E.; Gallo, R.; Pierrot,
M.; Boileau, J.; Wimmer, E. Tetrahedron Lett. 1988, 29, 1015e1016.