Synthesis and estimation of gelation ability of C3-symmetry tris-urea compounds

Article abstract of DOI:10.1016/j.tet.2008.10.036

C₃-Symmetry tris-urea low molecular weight gelator (LMWG) (1), which shows chemical stimuli responsible for a sol-gel phase transition, was divided into five regions. Based on the division, 22 derivatives were synthesized. The gelation ability

Full text of DOI:10.1016/j.tet.2008.10.036

Tetrahedron 64 (2008) 11558–11567
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Tetrahedron
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Synthesis and estimation of gelation ability of C3-symmetry tris-urea compounds
*
Masamichi Yamanaka , Tomoe Nakagawa, Ryohei Aoyama, Tomohiko Nakamura
Department of Chemistry, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
C3-Symmetry tris-urea low molecular weight gelator (LMWG) (1), which shows chemical stimuli
responsible for a sol–gel phase transition, was divided into five regions. Based on the division, 22 de-
rivatives were synthesized. The gelation ability of these derivatives was tested in nine organic solvents
with a wide range of values for relative static permittivity (3r¼47.2–1.89). Some derivatives showed
a better performance as LMWGs than the original tris-urea LMWG (1). For example, the critical gelation
concentration (CGC) in acetone was improved from 1.5 wt % to 0.5 wt % by changing the core substituent
(18). Highly versatile LMWG for a variety of solvents was obtained by changing the linker moiety (23).
Structural information to design tris-urea LMWGs is important to create rationally a functional supra-
molecular gel.
Received 24 September 2008
Received in revised form 11 October 2008
Accepted 14 October 2008
Available online 18 October 2008
Keywords:
Gels
Hydrogen bonds
Self-assembly
Ureas
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a functional supramolecular gel. In this paper, we would like to
report the synthesis of 22 examples of novel tris-urea derivatives,
Research on low molecular weight gelators (LMWGs) has
attracted much attention for several decades.1 Hydrogen-bonding,2
and their gelation ability for nine types of organic solvents with
a wide range of values for relative static permittivity (3r¼47.2–1.89).
p–p
interaction,3 dipole–dipole interaction,4 and van der Waals
interaction5 are major driving forces for the self-assembly of
LMWGs. To design an LMWG, it is known empirically that low-
symmetry structures and the introduction of long alkyl chains are
generally effective. Therefore, a large number of cholesterol-based
LMWGs and/or LMWGs with long alkyl chains appended have been
developed. As examples of highly symmetric structures of LMWGs,
Meijer,6 van Esch and Feringa,7 and others4c,8 have reported
C3-symmetry LMWGs; however, many of them have long alkyl
chains appended. One of the great advantages of LMWGs are
stimuli-responsive reversible sol–gel phase transitions such as
photo,5a,9 redox,10 ultrasound,11 and chemical stimuli12 produced
by the rational design of the gelator. Previously, we reported C3-
symmetry tris-urea LMWG (1), which can gelate a variety of organic
solvents such as acetone, methanol, etc., following brief sonication.
The acetone gel of 1 was changed into a homogeneous solution by
adding anions (e.g., tetrabutylammonium fluoride), and the solu-
tion was re-gelated by adding a Lewis acid (e.g., ZnBr2) and irra-
diating with ultrasound.13 Because of the structural features of
tris-urea LMWG (1), a variety of derivatives can be synthesized due
to the polyfunctional and highly symmetric structure of 1. Sys-
tematic preparation of derivatives and evaluation of their gelation
properties would provide valuable information about the design of
2. Results and discussion
2.1. Structural division of tris-urea LMWG (1)
Tris-urea LMWG (1) was divided into five regions, which are (1)
the hydrogen-bonding part, (2) positional isomers of the urea
moiety, (3) substituent on the outer urea nitrogen, (4) substituent
on the central aromatic ring, and (5) linker moiety fastened to the
outer aromatic ring (Fig. 1). In the previous communication, we
reported the necessity of the urea moiety for gelation. Amide
derivative and N-methyl urea derivative showed no gelation abili-
ties.13 Therefore, the urea moiety was fixed as the hydrogen-
bonding part. The urea moieties are combined at the meta-position
with aromatic linkers of the original tris-urea LMWG (1). ortho- and
para-derivatives (2 and 3) were planned for synthesis and to apply
gelation tests. The substituent effect of the outer urea nitrogen was
evaluated using a variety of substituted tris-urea derivatives (4–17),
which were synthesized from the corresponding isocyanates. The
ethyl groups of 1 were replaced by different substituents (18–21).
Methyleneoxy linkers were replaced by inflexible ethynyl groups
and nonpolar ethylene groups (22 and 23).
2.2. Synthesis of tris-urea compounds
Tris-urea LMWG (1) was synthesized in three steps from 1,3,5-
tris(bromomethyl)-2,4,6-triethylbenzene (24).13 Reaction of 24 and
* Corresponding author. Tel.: þ81 54 238 4936; fax: þ81 54 237 3384.
E-mail address: smyaman@ipc.shizuoka.ac.jp (M. Yamanaka).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.036

M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
11559
Ph
O
R1
HN
HN
HN
Substituent effect of the
core aromatic ring (R2)
HN
O
Et
O
NH
NH
Ph
R2
Y
Y
NH
NH
R1
O
O
O
Et
Et
R2
R2
Y
Effect of the linker (Y)
O
O
R1
O
Effect of positional the isomer
N
H
N
H
Ph
N
H
N
H
Substituent effect of the urea nitrogen (R1)
Tris-urea LMWG (1)
R1
R2
R1
R2
Compoud position
Compoud position
Y
Y
meta
ortho
para
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
meta
meta
meta
meta
meta
meta
meta
meta
meta
meta
meta
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
1
2
Ph
Et
Et
Et
Et
13
14
15
16
17
18
19
20
21
22
23
4-CH3C6H4
4-C2H5C6H4
Et
Et
Ph
3
Ph
4-(CH3)2CHC6H4 Et
meta
meta
meta
meta
meta
meta
meta
meta
meta
4
n-octyl
4-C8H17C6H4
1-naphthyl
Et
5
n-dodecyl Et
Et
6
benzyl
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
H
7
2-FC6H4
3-FC6H4
4-FC6H4
Me
OMe
i-pentyl
H
8
9
C
C
10
11
12
4-ClC6H4 Et
4-BrC6H4 Et
CH2CH2
H
4-IC6H4
Et
Figure 1. Structural division of LMWG (1) and structure of 22 tris-urea compounds.
3-nitrophenol gave the tris-nitrophenoxylated product (25). Re-
duction of the nitro groups of 25 proceeded in the presence of
tin(II) chloride dihydrate in 1,4-dioxane solvent, and afforded tris-
amine (26). The tris-urea LMWG (1) was obtained by the reaction of
26 with phenyl isocyanate. A similar procedure afforded ortho and
para positional isomers (Scheme 1). Reaction of 24 and 2-nitro-
phenol or 4-nitrophenol gave tris-nitrophenoxylated products (27
and 29) in 88 and 82% yields, respectively. Reduction of the nitro
groups of 27 or 29 in the presence of tin(II) chloride dihydrate in
1,4-dioxane solvent afforded tris-amines (28 and 30). Tris-ureas (2
and 3) were obtained as a result of the reaction of 28 or 30 and
phenyl isocyanate in 67 and 80% yields, respectively. Synthesis of
a variety of substituted tris-urea derivatives was achieved by
reactions of tris-amine (26) and various isocyanates, and afforded
tris-ureas (4–17) in 62–90% yields (Scheme 2). Reaction of 1,3,5-
tris(bromomethyl)benzene (31) with 3-nitrophenol gave tris-
nitrophenoxylated product (32) in 90% yield. Tris-amine (33) was
obtained by reduction of the nitro groups of 32 in the presence of
tin(II) chloride dihydrate in 1,4-dioxane solvent in 91% yield. The
amino groups of 33 were converted into phenyl urea groups by
a condensation reaction with phenyl isocyanate, and the proposed
tris-urea (18) was obtained in 95% yield. Other tris-ureas (19–21)
were also prepared from 1,3,5-tris(halomethyl)-2,4,6-trisubstituted
benzenes (34, 37, and 40)14 via similar three-step reactions
(Scheme 3). Tris-ureas with modified methyleneoxy linkers (22 and
23) were synthesized from a common intermediate (45) (Scheme
4). The tris-amine (45) was prepared from the known 1,3,5-tri-
ethynylbenzene (43).15 A Sonogashira cross-coupling reaction of 43
and 3 equiv of 3-bromonitrobenzene afforded the trinitrophenyl-
substituted product (44) in 70% yield. Reduction of the nitro groups
of 44 in the presence of tin(II) chloride dihydrate in 1,4-dioxane
solvent gave tris-amine (45) in 78% yield. A tris-urea with an
inflexible ethynyl linker (22) was obtained from the reaction of 45
and phenyl isocyanate in 83% yield. Hydrogenation of the ethynyl
groups of 45 in the presence of palladium–carbon catalyst afforded
the tris-amine 46. Tris-urea with a flexible ethyl linker (23) was
Ph
HN
HN
O
X
Et
Br
Et
Et
O
Et
O
NH
NH
Ph
X
nitrophenol
K2CO3
Acetone
Br
O
O
O
PhNCO
DCE
Et
Et
Et
Et
Et
Br
O
O
24
O
Ph
N
H
N
H
X
X = NO2 25:meta (86%)
27:ortho (88%)
1:meta (89%)
2:ortho (67%)
3:para (80%)
SnCl2
29:para (82%)
1,4-dioxane
26:meta (97%)
28:ortho (85%)
30:para (63%)
X = NH2
Scheme 1. Synthetic scheme for generation of positional isomers of the urea moiety.

11560
M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
induced gel formation.9,16 In our case, dispersion and solvation of
R1
O
HN
HN
solid tris-urea caused by ultrasound should be the principle for
gelation. As support for this idea, vigorous stirring of a mixture of 1
and acetone using a vortex mixer (3200 rpm) for 10 min then
standing at ambient temperature for several hours afforded an
opaque gel; however, the firmness of the gel was much less than
the ultrasound-induced gel of 1 and acetone. Tris-urea 1 showed
gelation ability for relatively polar solvents, namely, MeOH
(CGC¼2.0 wt %), acetone (CGC¼1.5 wt %), diethyl phthalate
(CGC¼2.0 wt %), and THF (CGC¼5.0 wt %). Once formed, those gels
were stable at ambient temperature for months. A homogeneous
solution was obtained from a mixture of 1 and the very polar
DMSO. Insoluble suspensions appeared from mixtures of 1 and less
polar solvents, namely, EtOAc, CH2Cl2, toluene, and n-hexane. A
scanning electron microscope (SEM) image of a xerogel prepared by
freeze-drying an acetone gel of 1 showed intertwining nanofibers
(Fig. 2a). Tris-urea 2, which has ortho-substituted phenyl urea
groups, formed a gel upon mixing with THF, though the gel was soft
enough to flow slowly upon inversion of the test tube. Mixtures of 2
and the other solvents did not give gels, and afforded an insoluble
suspension, except for soluble DMSO. Tris-urea 3 with para-
substituted phenyl urea groups showed gelation abilities for MeOH
(CGC¼3.0 wt %), diethyl phthalate (CGC¼4.0 wt %), EtOAc
(CGC¼1.5 wt %), and THF (CGC¼5.0 wt %). Thus, four of the nine
solvents gave gels; in general, higher concentrations of gelator (3)
were needed for gelation than were needed for 1. Comparison of
the gelation abilities of three positional isomers (1–3) indicated the
meta-substituted tris-urea derivative (1) is favorable as an LMWG,
although the para-substituted 3 was better for gelation of EtOAc.
Then we focused on the gelation abilities of derivatives with various
substituents on the outer urea nitrogen (4–17). Full gelation of
octyl-substituted tris-urea (4) was found only by mixing with THF
(CGC¼1.5 wt %), although soft gel formation was observed in ace-
tone, diethyl phthalate, CH2Cl2, and toluene. The xerogel of toluene
soft gel of 4 showed plate-shaped aggregates (Fig. 2b). Their lengths
are shorter than the fibrous aggregates observed in the xerogel of
the acetone gel of 1. Longer dodecyl-substituted tris-urea (5) shows
limited gelation ability and formed a gel only in THF (CGC¼2.0 wt
%). Benzyl-substituted tris-urea (6) gelated five of the nine solvents.
Introduction of a long alkyl substituent is generally advantageous
for the design of an LMWG; however, the gelation ability is not
increased by introduction of a long alkyl substituent in regard to the
tris-urea LMWG. Tris-urea with aryl substitution (1 and 6) showed
Et
O
NH
NH
R1
R1NCO
O
O
26
CH2Cl2
or
Et
Et
DCE
O
O
R1
N
H
N
H
4:R1 = n-octyl (77%)
11:R1 = 4-BrC6H4 (77%)
13:R1 = 4-CH3C6H4 (76%)
5:R1 = n-dodecyl (65%) 12:R1 = 4-IC6H4 (87%)
6:R1 = benzyl (64%)
7:R1 = 2-FC6H4 (88%) 14:R1 = 4-C2H5C6H4 (90%)
8:R1 = 3-FC6H4 (78%) 15:R1 = 4-(CH3)2CHC6H4 (75%)
9:R1 = 4-FC6H4 (74%) 16:R1 = 4-C8H17C6H4 (62%)
10:R1 = 4-ClC6H4 (68%) 17:R1 = 1-naphthyl (82%)
Scheme 2. Synthetic scheme for generation of variety substituents on the outer urea
nitrogen.
obtained from the reaction of 46 and phenyl isocyanate in 76%
yield.
2.3. Gelation experiments of tris-urea compounds
Tris-urea LMWG (1) and 22 newly synthesized tris-urea de-
rivatives (2–23) were used in gelation experiments (Table 1). Gel
formation was tested with nine organic solvents having a wide
range of values for relative static permittivity (3r¼47.2–1.89);
namely, DMSO, MeOH, acetone, diethyl phthalate (DEP), EtOAc,
THF, CH2Cl2, toluene, and n-hexane. The following procedure was
used as a standard condition for gelation. Tris-urea and solvent
were mixed in an appropriate test tube then irradiated with
ultrasound (0.39 W cmꢀ2, 42 kHz) at ambient temperature for
15 min. Gel formation was confirmed by the inverted test tube
method. A stable sample upon inversion of the test tube was
defined as a gel. A homogeneous solid sample that flows slowly
upon inversion of the test tube was described as a soft gel. We
previously reported that ultrasound irradiation is necessary for
gelation of 1 and ordinary thermal dissolution and cooling did not
produce a gel.13 Some research has been reported on ultrasound-
Ph
HN
HN
O
O
X
R2
Y
R2
R2
O
X
O
NH
NH
Ph
3-nitrophenol
K2CO3
Acetone
Y
O
O
PhNCO
R2
R2
R2
O
R2
R2
R2
DCE
or
THF
Y
O
O
31:R2 = H; Y = Br
34:R2 = Me; Y = Br
37:R2 = OMe; Y = Br
40:R2 = i-pentyl; Y = Cl
Ph
N
H
N
H
X
32:R2 = H (90%)
X = NO2
18:R2 = H (95%)
19:R2 = Me (84%)
20:R2 = OMe (54%)
35:R2 = Me (86%)
SnCl2
1,4-dioxane
38:R2 = OMe (82%)
41:R2 = i-pentyl (91%)
21:R2 = i-pentyl (80%)
33:R2 = H (91%)
X = NH2
36:R2 = Me (70%)
39:R2 = OMe (92%)
42:R2 = i-pentyl (84%)
Scheme 3. Synthetic scheme for generation of variety substituents on the central benzene ring.

M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
11561
Ph
X
HN
HN
H
O
H
X
H
H
H
NH
NH
Ph
PdCl2(PPh3)2
H
X
H
O
CuI
PhNCO
DCE
43
H
H
Et3N
+
Br
O
O2N
Ph
SnCl2
1,4-dioxane
X = NO2
X = NH2
44 (70%)
45 (78%)
N
H
N
H
22 (83%)
Ph
HN
HN
O
NH2
H
NH
H
NH2
O
NH
Ph
H2
Pd/C
EtOAc
PhNCO
DCE
45
H
O
H
H
H
Ph
N
H
N
H2N
46 (96%)
H
23 (76%)
Scheme 4. Synthetic scheme for generation of tris-ureas with modified linkers.
better gelation ability than those with alkyl substitution (4 and 5).
The effect of adding substituents to the aryl groups of the urea
moieties was tested. Tris-urea with ortho-fluorophenyl groups (7)
formed a gel only in MeOH (CGC¼1.5 wt %) in testing the nine or-
ganic solvents. Tris-urea with meta-fluorophenyl groups (8) affor-
ded gels by mixing with MeOH (CGC¼2.0 wt %), acetone
(CGC¼3.0 wt %), diethyl phthalate (CGC¼2.0 wt %), and EtOAc
(CGC¼3.0 wt %). Tris-urea with para-fluorophenyl groups (9)
formed a gel upon mixing with five of the nine solvents, namely,
MeOH (CGC¼2.5 wt %), acetone (CGC¼2.0 wt %), diethyl phthalate
(CGC¼1.5 wt %), EtOAc (CGC¼3.0 wt %), and THF (CGC¼3.5 wt %).
Substituents on the para (or meta) position seem conducive to
maintaining gelation ability, so subsequent experiments were
focused on para-substituted aryl ureas. Intertwining fibrous ag-
gregates were found in the xerogels of these meta or para-fluo-
rophenyl-substituted tris-ureas, and an SEM image of a xerogel
prepared from the MeOH gel of 8 is shown in Figure 2c. Tris-urea
with para-chlorophenyl groups (10) gelated only MeOH
(CGC¼5.0 wt %) of the nine solvents. para-Bromophenyl-
substituted 11 showed gelation ability for MeOH (CGC¼3.5 wt %),
Table 1
Gelation ability of tris-urea compounds (1–23)a
Compound
DMSO
MeOH
Acetone
DEP
EtOAc
THF
CH2Cl2
Toluene
n-Hexane
1
2
3
4
5
6
7
8
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
G (2.0)
I
G (3.0)
I
G (1.5)
I
I
SG
I
G (3.0)
I
G (3.0)
G (2.0)
I
G (1.5)
G (1.5)
G (2.0)
G (3.0)
I
G (2.5)
G (2.0)
G (0.5)
G (1.5)
G (4.5)
G (2.5)
G (2.0)
G (2.5)
G (2.0)
I
G (4.0)
SG
I
I
G (5.0)
SG
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
G (1.5)
I
I
G (2.5)
I
G (3.0)
G (3.0)
G (5.0)
G (1.5)
G (2.0)
G (3.5)
S
SG
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
SG
I
I
I
I
I
I
SG
I
I
I
I
I
G (4.0)
G (1.5)
G (2.0)
G (2.5)
G (5.0)
G (3.5)
G (2.5)
G (2.5)
I
G (1.5)
I
G (2.0)
G (1.5)
I
I
I
I
I
I
I
I
G (1.5)
I
G (2.5)
G (1.5)
I
S
9
G (3.5)
S
G (5.0)
G (3.0)
G (2.5)
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
I
G (4.0)
G (4.0)
I
I
I
I
S
S
I
SG
SG
I
SG
I
I
I
I
SG
SG
SG
G (2.5)
G (1.0)
G (4.0)
G (3.5)
G (1.0)
I
G (1.0)
G (1.5)
I
I
I
G (3.5)
G (5.0)
I
G (2.0)
G (4.0)
G (2.5)
I
G (4.0)
I
SG
G (2.0)
G (2.0)
G (2.0)
G (2.5)
a
Tris-urea¼up to 5 wt %; G¼gel and CGCs (wt %) were shown in parentheses, SG¼soft gel, S¼solution, I¼insoluble.

11562
M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
Figure 2. SEM images of xerogel prepared from (a) acetone gel of 1, (b) toluene soft gel of 4, (c) MeOH gel of 8, (d) acetone gel of 18, (e) MeOH gel of 21, (f) toluene soft gel of 21, (g)
THF gel of 23, and (h) CH2Cl2 soft gel of 23.

M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
11563
acetone (CGC¼1.5 wt %), EtOAc (CGC¼4.0 wt %), and THF
(CGC¼5.0 wt %), and formed a soft gel in toluene. para-Iodophenyl-
substituted 12 gelated MeOH (CGC¼2.5 wt %), acetone (CGC¼1.5 wt
%), EtOAc (CGC¼4.0 wt %), and THF (CGC¼3.0 wt %). The gelation
ability of para-chlorophenyl-substituted tris-urea (10) is markedly
lower than that of the other halogen-substituted tris-ureas.
A possible reason is that larger (halogen) atoms interfere with
however, their CGCs were moderate. A nonpolar linker has poten-
tial to construct a versatile gelator for a variety of organic solvents.
3. Conclusion
In conclusion, we divided the structure of LMWG (1) into five
areas and synthesized 22 different derivatives. Indispensable
structural characteristics were determined by testing their gelation
abilities with a variety of organic solvents. The following guidelines
for the design of tris-urea LMWGs were suggested by these in-
vestigations (1) The urea functional group is essential for the
structure of these LMWGs.13 (2) meta-Substitution of the urea
moiety is effective for gelation. ortho-Substitution is disadvanta-
geous for forming a gel. (3) Aryl substitution of the peripheral urea
nitrogen is effective in achieving high gelation ability. A bulky
substituent on the aryl group prevents gelation. (4) A small sub-
stituent group on the core aryl cycle is important to improve the
gelation ability. A solvophilic alkyl substituent is effective in gel-
ating nonpolar solvents. (5) Flexibility of the linker region is effi-
cacious in maintaining the gelation ability. These derivatives of
LMWG 1 produced improvements in the gelation ability. For ex-
ample, the CGC for acetone became 0.5 wt % by changing the sub-
stituent of the core aryl ring and highly general LMWGs for a variety
of solvent were obtained by modification of the linker region.
Furthermore, these results enabled us to design novel functional
LMWGs logically. The design and synthesis of low molecular weight
hydrogelator and chiral LMWGs based on this knowledge are pro-
gressing in our laboratory.
aggregation; however, bromine and iodine show halogen–
p in-
teractions or CH–halogen interactions as a secondary driving force
for assembly.17 para-Tolyl-substituted tris-urea (13) formed gels in
MeOH (CGC¼2.5 wt %), acetone (CGC¼2.0 wt %), and THF
(CGC¼2.5 wt %). Tris-urea with para-ethylphenyl groups (14) gave
a gel only on mixing with acetone (CGC¼3.0 wt %) of the nine
solvents. Tris-urea with para-isopropylphenyl groups (15) did not
form a gel in the tested solvents. para-Octylphenyl-substituted tris-
urea (16) formed a gel in acetone (CGC¼2.5 wt %), and a soft gel in
MeOH, EtOAc, and toluene. These results also support the sugges-
tion that a bulky substituent on the aryl group of the peripheral
urea prevents formation of a gel. Tris-urea with 1-naphthyl groups
(17) gave a gel on mixing with MeOH (CGC¼2.5 wt %), acetone
(CGC¼2.0 wt %), and THF (CGC¼1.0 wt %). Considering the
substituent effect on the gelation ability of the peripheral urea, aryl
groups are better than alkyl groups. A bulky substituent on the aryl
group reduces the gelation ability. Next, we focused on the sub-
stituent effect of the core aryl cycle of tris-urea (1 and 18–21).
A remarkably enhancement of gelation ability was observed by
replacing the core ethyl groups with hydrogen (18). Tris-urea 18
gelated MeOH (CGC¼1.0 wt %), acetone (CGC¼0.5 wt %), diethyl
phthalate (CGC¼1.5 wt %), EtOAc (CGC¼3.5 wt %), and THF
(CGC¼1.5 wt %). The xerogel prepared from the acetone gel of 18
showed intertwining nanofibers upon SEM observation (Fig. 2d).
Tris-urea with methyl substituents (19) gelated MeOH (CGC¼4.0 wt
%), acetone (CGC¼1.5 wt %), and EtOAc (CGC¼5.0 wt %); however,
the gelation ability is lower than that of both 1 and 18. Polar
methoxy groups on the core aromatic ring are not effective for
gelation, and 20 formed a gel on mixing with MeOH (CGC¼3.5 wt
%), acetone (CGC¼4.5 wt %), and diethyl phthalate (CGC¼2.5 wt %).
Tris-urea with isopentyl substituents (21) gave a gel with MeOH
(CGC¼1.0 wt %), acetone (CGC¼2.5 wt %), diethyl phthalate
(CGC¼1.5 wt %), EtOAc (CGC¼2.0 wt %), and CH2Cl2 (CGC¼4.0 wt %),
and formed a soft gel in toluene. It is noteworthy that isopentyl-
substituted 21 gelated not only polar solvents such as MeOH, but
also nonpolar CH2Cl2 and toluene. Nano-size fibers were found
upon SEM observation of the MeOH gel of 21; however, a fibrous
aggregate was not discovered upon SEM observation of the toluene
soft gel of 21 (Fig. 2e and f). The substituent on the core aromatic
ring of tris-urea plays an important role in its gelation ability. Hy-
drogen-substituted tris-urea (18) is effective as a gelator possibly
because the small substituent makes 18 easy to assemble by
stacking. On the other hand, a longer alkyl substituent such as
isopentyl is effective in gelating nonpolar solvents. A moderate
solvophilic nature of alkyl chains towards nonpolar solvents may
promote its aggregation. The linker region connecting the core aro-
matic ring and outer aromatic ring was modified. Tris-urea with an
inflexible ethynyl linker (22) gelated acetone (CGC¼2.0 wt %),
EtOAc (CGC¼4.0 wt %), and THF (CGC¼2.0 wt %), and formed a soft
gel with toluene. Comparing the gelation ability of 18 with 22, the
flexibility of the linker region seemed important. Ethylene-linked
tris-urea (23) formed a gel with MeOH (CGC¼2.0 wt %), acetone
(CGC¼2.5 wt %), diethyl phthalate (CGC¼2.5 wt %), EtOAc
(CGC¼2.5 wt %), and THF (CGC¼2.0 wt %), and a soft gel with CH2Cl2
and toluene. Xerogel prepared from a firmly gelated mixture of 23
and THF showed intertwining nanofibers (Fig. 2g). In contrast, the
xerogel prepared from a loosely gelated mixture of 23 and CH2Cl2
showed short fibers and their interaction seemed poor (Fig. 2h).
Seven of the nine solvents were gelated, including soft gel, by 23;
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a JEOL JNM-AL400
spectrometer or a JEOL JNM-ECA600 spectrometer. Mass spectra
were measured on a JEOL JMS-T100LC AccTOF spectrometer. Ul-
trasound irradiation was performed using a BRANSON B2510J ul-
trasonic cleaner. SEM studies were carried out on a JEOL JSM-6300
spectrometer.
4.1.1. 1,3,5-Tris(3-nitrophenoxymethyl)-2,4,6-triethylbenzene (25)
To a mixture of 3-nitrophenol (9.4 g, 67 mmol) and K2CO3 (9.3 g,
67 mmol) in acetone (130 mL) was added 1,3,5-tris(bromomethyl)-
2,4,6-triethylbenzene18 (24, 9.9 g, 22 mmol) under argon atmosphere
at 0 ꢁC. The reaction mixture was stirred at room temperature for
17 h. Then the reaction mixture was diluted with chloroform, and the
precipitate was removed by filtration. The solvent was removed
under reduced pressure, and the crude product was purified by
reprecipitation from dichloromethane and hexane to give 25 as a pale
yellow solid (12 g, 86%). Mp 212–214 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.27 (t, J¼7.6 Hz, 9H), 2.84 (q, J¼7.6 Hz, 6H), 5.18 (s, 6H), 7.34 (dd,
J¼8.2, 2.3 Hz, 3H), 7.49 (t, J¼8.5 Hz, 3H), 7.89–7.91 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d 16.5, 23.1, 64.8, 108.4, 116.3, 122.0, 130.2, 130.4,
146.7, 149.3, 159.2; HRMS (ESI, MþNaþ) calcd for C33H33N3NaO9:
638.2115, found: 638.2140.
4.1.2. 1,3,5-Tris(3-aminophenoxymethyl)-2,4,6-triethylbenzene (26)
A mixture of 25 (1.0 g, 1.6 mmol) and tin(II) chloride dihydrate
(5.5 g, 24 mmol) in 1,4-dioxane (10 mL) was stirred at room tem-
perature for 1 h. Then the mixture was kept at 50 ꢁC for 2 h. Then
the reaction mixture was poured into ice-cooled water, and neu-
tralized with saturated sodium hydrogen carbonate solution. The
precipitate was removed by filtration through Celite, and remaining
solid on the Celite was washed with ethyl acetate. Organic layer and
aqueous layer were separated and the aqueous layer was extracted
with ethyl acetate. The combined organic layer was washed with

11564
M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
brine, and dried over Na2SO4. The solvent was removed under re-
duced pressure, and the crude product was purified by column
chromatography (SiO2, hexane/ethyl acetate 1:1 to 0:1). The desired
product (26) was obtained as a white solid (830 mg, 97%). Mp 180–
3.4 mmol) in dichloromethane (2.5 mL) under argon atmosphere at
0 ꢁC. The mixture was stirred at room temperature for 1 day, and
then refluxed for 1 h. The mixture was diluted with hexane, and the
precipitate was filtered off. The crude product was purified by
reprecipitation from acetone and hexane to give 4 as a white solid
(726 mg, 77%). Mp 191–195 ꢁC; 1H NMR (600 MHz, DMSO-d6)
182 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d
1.16 (t, J¼7.5 Hz, 9H), 2.71
(q, J¼7.5 Hz, 6H), 4.95 (s, 6H), 5.06 (s, 6H), 6.19 (d, J¼7.8 Hz, 3H),
6.22 (d, J¼7.8 Hz, 3H), 6.25 (s, 3H), 6.93 (t, J¼7.8 Hz, 3H); 13C NMR
d
0.84 (t, J¼6.5 Hz, 9H), 1.16 (t, J¼6.9 Hz, 9H), 1.25 (m, 30H), 1.38–
(100 MHz, DMSO-d6)
d
16.3, 22.4, 63.5, 99.9,101.9,107.1,129.7,131.0,
1.41 (m, 6H), 2.73 (q, J¼6.9 Hz, 6H), 3.05 (q, J¼6.9 Hz, 6H), 5.01 (s,
6H), 6.09 (t, J¼5.5 Hz, 3H), 6.63 (d, J¼8.3 Hz, 3H), 6.93 (d, J¼6.9 Hz,
3H), 7.14 (t, J¼8.2 Hz, 3H), 7.20 (s, 3H), 8.41 (s, 3H); 13C NMR
145.1, 150.1, 159.7; HRMS (ESI, MþNaþ) calcd for C33H39N3NaO3:
548.2889, found: 548.2877.
(150 MHz, DMSO-d6)
d 13.9, 16.2, 22.1, 22.4, 26.4, 28.7, 28.8, 29.7,
4.1.3. 1,3,5-Tris[3-(phenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (1)
31.2, 63.8, 103.8, 106.9, 110.3, 129.5, 130.9, 141.9, 145.4, 155.1, 159.0;
HRMS (ESI, MþNaþ) calcd for C60H90N6NaO6: 1013.6820, found:
1013.6791.
To a solution of 26 (200 mg, 0.38 mmol) in 1,2-dichloroethane
(10 mL) was added phenyl isocyanate (0.14 mL, 1.3 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 4 days. Then the mixture was refluxed for 3 h. During
this time, a precipitate formed in the reaction flask. Then the
mixture was diluted with hexane, and the precipitate was filtered
off. The crude product was purified by reprecipitation from acetone
and hexane to give 1 as a white solid (300 mg, 89%). Mp 230–240 ꢁC
4.1.7. 1,3,5-Tris[3-(dodecylureido)phenoxymethyl]-2,4,6-
triethylbenzene (5)
To a solution of 26 (100 mg, 0.19 mmol) in dichloromethane
(3.0 mL) was added n-dodecyl isocyanate (133 mg, 0.63 mmol)
under argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 4 days, and then refluxed for 3 h. During this time,
a precipitate formed in the reaction flask. Then the mixture was
diluted with hexane, and the precipitate was filtered off. The crude
product was purified by reprecipitation from acetone and hexane to
give 5 as a white solid (143 mg, 65%). Mp 198 ꢁC; 1H NMR
(decomp.); 1H NMR (400 MHz, DMSO-d6)
d
1.19 (t, J¼7.3 Hz, 9H),
2.76 (q, J¼7.3 Hz, 6H), 5.06 (s, 6H), 6.73 (d, J¼8.1 Hz, 3H), 6.95 (t,
J¼6.8 Hz, 3H), 7.03 (d, J¼8.3 Hz, 3H), 7.22–7.28 (m, 12H), 7.43 (d,
J¼8.3 Hz, 6H), 8.70 (s, 3H), 8.74 (s, 3H); 13C NMR (100 MHz, DMSO-
d6)
d
16.2, 22.4, 63.9, 104.5, 107.7, 110.9, 118.2, 121.8, 128.8, 129.7,
(600 MHz, DMSO-d6)
d
0.83 (t, J¼6.9 Hz, 9H), 1.16 (t, J¼7.6 Hz, 9H),
130.9, 139.6, 141.0, 145.4, 152.5, 159.1; HRMS (ESI, MþNaþ) calcd for
1.22 (m, 54H), 1.38–1.40 (m, 6H), 2.73 (q, J¼7.6 Hz, 6H), 3.04 (q,
J¼6.9 Hz, 6H), 5.01 (s, 6H), 6.09 (t, J¼5.5 Hz, 3H), 6.62 (d, J¼8.3 Hz,
3H), 6.91 (d, J¼8.2 Hz, 3H), 7.13 (t, J¼8.3 Hz, 3H), 7.20 (s, 3H), 8.40 (s,
C54H54N6NaO6: 905.4003, found: 905.4006.
4.1.4. 1,3,5-Tris[2-(phenylureido)phenoxymethyl]-2,4,6-
3H); 13C NMR (150 MHz, DMSO-d6)
d 13.9,16.2, 22.1, 22.4, 26.4, 28.7,
triethylbenzene (2)
28.8, 29.0, 29.1, 29.7, 31.3, 63.8, 103.9, 106.9, 110.3, 129.5, 130.9,
141.9, 145.4, 155.1, 159.0; HRMS (ESI, MþNaþ) calcd for
C72H114N6NaO6: 1181.8698, found: 1181.8705.
To a solution of 28 (128 mg, 0.24 mmol) in 1,2-dichloroethane
(6.4 mL) was added phenyl isocyanate (0.09 mL, 0.83 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 21 h. Then the mixture was diluted with hexane, and
the precipitate was filtered off. The crude product was purified by
reprecipitation from acetone and hexane to give the desired prod-
uct as a white solid (145 mg, 67%). Mp 198–199 ꢁC; 1H NMR
4.1.8. 1,3,5-Tris[3-(benzylureido)phenoxymethyl]-2,4,6-
triethylbenzene (6)
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(5.0 mL) was added benzyl isocyanate (0.077 mL, 0.63 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 19 h, and then refluxed for 8 h. Then the mixture was
diluted with hexane, and the precipitate was filtered off. The crude
product was purified by reprecipitation from acetone and hexane to
give 6 as a white solid (112 mg, 64%). Mp 221–230 ꢁC; 1H NMR
(400 MHz, DMSO-d6)
d
1.20 (t, J¼7.3 Hz, 9H), 2.82 (q, J¼7.3 Hz, 6H),
5.15 (s, 6H), 6.91 (d, J¼7.8 Hz, 3H), 6.95 (t, J¼7.8 Hz, 3H), 7.04 (t,
J¼7.8 Hz, 3H), 7.19 (t, J¼7.8 Hz, 6H), 7.34 (t, J¼7.8 Hz, 6H), 7.36 (d,
J¼6.8 Hz, 3H), 7.74 (s, 3H), 7.95 (d, J¼7.8 Hz, 3H), 9.29 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) d 16.4, 22.9, 65.0,112.2,118.1,118.3,120.9,
121.9,123.0,128.2,128.9,130.9,139.8,146.8,148.4,152.7; HRMS (ESI,
(600 MHz, DMSO-d6)
d
1.16 (t, J¼7.6 Hz, 9H), 2.73 (q, J¼7.6 Hz, 6H),
MþNaþ) calcd for C54H54N6NaO6: 905.4003, found: 905.4027.
4.29 (d, J¼6.2 Hz, 6H), 5.02 (s, 6H), 6.61 (t, J¼6.2 Hz, 3H), 6.65 (d,
J¼7.6 Hz, 3H), 6.97 (d, J¼7.6 Hz, 3H), 7.16 (t, J¼8.2 Hz, 3H), 7.22 (s,
3H), 7.24 (s, 3H), 7.28–7.33 (m, 12H), 8.60 (s, 3H); 13C NMR
4.1.5. 1,3,5-Tris[4-(phenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (3)
(150 MHz, DMSO-d6) d 16.2, 22.4, 42.7, 63.8, 104.0, 107.1, 110.5,
To a solution of 30 (160 mg, 0.30 mmol) in 1,2-dichloroethane
(8.0 mL) was added phenyl isocyanate (0.11 mL, 1.0 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 28 h. Then the mixture was diluted with hexane, and
the precipitate was filtered off. The crude product was purified by
reprecipitation from acetone and hexane to give 3 as a white solid
(215 mg, 80%). Mp 252–253 ꢁC (decomp.); 1H NMR (400 MHz,
126.7, 127.1, 128.3, 129.6, 130.9, 140.3, 141.8, 145.4, 155.2, 159.0;
HRMS (ESI, MþNaþ) calcd for C57H60N6NaO6: 947.4472, found:
947.4473.
4.1.9. 1,3,5-Tris[3-(2-fluorophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (7)
To a solution of 26 (200 mg, 0.38 mmol) in 1,2-dichloroethane
(10 mL) was added 2-fluorophenyl isocyanate (0.14 mL, 1.3 mmol)
under argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 4 days. Then the mixture was diluted with hexane,
and the precipitate was filtered off. The crude product was purified
by reprecipitation from acetone and hexane to give 7 as a white
solid (300 mg, 88%). Mp 159–167 ꢁC; 1H NMR (600 MHz, DMSO-d6)
DMSO-d6)
d
1.18 (t, J¼7.6 Hz, 9H), 2.75 (q, J¼7.6 Hz, 6H), 5.04 (s, 6H),
6.94 (t, J¼7.6 Hz, 3H), 7.02 (d, J¼8.9 Hz, 6H), 7.25 (t, J¼7.6 Hz, 6H),
7.38 (d, J¼8.9 Hz, 6H), 7.43 (d, J¼7.6 Hz, 6H), 8.50 (s, 3H), 8.59 (s,
3H); 13C NMR (100 MHz, DMSO-d6)
d 16.3, 22.4, 64.3, 114.6, 118.1,
120.2, 121.6, 128.7, 131.0, 133.0, 139.9, 145.3, 152.7, 153.9; HRMS (ESI,
MþNaþ) calcd for C54H54N6NaO6: 905.4003, found: 905.4028.
d
1.19 (t, J¼7.2 Hz, 9H), 2.76 (q, J¼7.2 Hz, 6H), 5.07 (s, 6H), 6.76 (d,
4.1.6. 1,3,5-Tris[3-(octylureido)phenoxymethyl]-2,4,6-
triethylbenzene (4)
To a solution of 26 (500 mg, 0.95 mmol) in dichloromethane
(10 mL) was transferred a solution of n-octyl isocyanate (0.60 mL,
J¼7.6 Hz, 3H), 6.99–7.02 (m, 6H), 7.12 (t, J¼7.9 Hz, 3H), 7.20–7.26 (m,
9H), 8.13 (t, J¼8.3 Hz, 3H), 8.53 (s, 3H), 9.10 (s, 3H); 13C NMR
(150 MHz, DMSO-d6) d 16.4, 22.6, 64.1, 104.7, 108.2, 111.1, 115.1 (d,
JC–F¼18.9 Hz), 120.9, 122.8 (d, JC–F¼8.2 Hz), 124.7, 127.5 (d,

M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
11565
JC–F¼10.7 Hz), 130.1, 131.0, 140.9, 145.7, 152.2 (d, JC–F¼240 Hz), 152.4,
159.3; HRMS (ESI, MþNaþ) calcd for C54H51F3N6NaO6: 959.3720,
found: 959.3719.
as a white solid (164 mg, 77%). Mp >250 ꢁC; 1H NMR (600 MHz,
DMSO-d6)
d
1.18 (t, J¼6.9 Hz, 9H), 2.75 (q, J¼6.9 Hz, 6H), 5.06 (s, 6H),
6.74 (d, J¼8.3 Hz, 3H), 7.02 (d, J¼8.2 Hz, 3H), 7.22 (t, J¼8.2 Hz, 3H),
7.24 (s, 3H), 7.33–7.62 (m, 12H), 8.73 (s, 3H), 8.81 (s, 3H); 13C NMR
4.1.10. 1,3,5-Tris[3-(3-fluorophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (8)
(150 MHz, DMSO-d6) d 16.2, 22.4, 64.0, 104.7, 107.9, 111.1, 113.2,
120.1, 129.7, 130.9, 131.5, 139.1, 140.8, 145.5, 152.3, 159.1; HRMS (ESI,
To a solution of 26 (250 mg, 0.48 mmol) in 1,2-dichloroethane
(13 mL) was added 3-fluorophenyl isocyanate (0.18 mL, 1.6 mmol)
under argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 2 days. Then the mixture was diluted with hexane,
and the precipitate was filtered off. The crude product was purified
by reprecipitation from acetone and hexane to give 8 as a white
solid (335 mg, 78%). Mp 202–204 ꢁC; 1H NMR (600 MHz, DMSO-d6)
MþNaþ) calcd for C54H51Br3N6NaO6: 1143.1277, found: 1143.1316.
4.1.14. 1,3,5-Tris[3-(4-iodophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (12)
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(5.0 mL) was added 4-iodophenyl isocyanate (154 mg, 0.63 mmol)
under argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 3 days, and then refluxed for 1 h. Then the mixture
was diluted with hexane, and the precipitate was filtered off. The
crude product was purified by reprecipitation from acetone and
hexane to give 12 as a white solid (209 mg, 87%). Mp >250 ꢁC; 1H
d
1.19 (t, J¼6.9 Hz, 9H), 2.76 (q, J¼6.9 Hz, 6H), 5.07 (s, 6H), 6.77 (m,
6H), 7.04 (d, J¼7.6 Hz, 3H), 7.10 (d, J¼7.6 Hz, 3H), 7.23–7.28 (m, 9H),
7.47 (d, J¼8.2 Hz, 3H), 8.76 (s, 3H), 8.90 (s, 3H); 13C NMR (150 MHz,
DMSO-d6)
d
16.3, 22.5, 64.0, 104.7, 104.9 (d, JC–F¼25.9 Hz), 108.0,
108.2 (d, JC–F¼21.5 Hz), 111.1, 114.0, 129.8, 130.3 (d, JC–F¼10.1 Hz),
NMR (600 MHz, DMSO-d6)
d
1.18 (t, J¼6.9 Hz, 9H), 2.75 (q, J¼6.9 Hz,
130.9, 140.7, 141.5 (d, JC–F¼11.5 Hz), 145.5, 152.3, 159.1, 162.4 (d, JC–
6H), 5.06 (s, 6H), 6.74 (d, J¼8.3 Hz, 3H), 7.02 (d, J¼8.2 Hz, 3H), 7.22
(t, J¼8.3 Hz, 3H), 7.24 (s, 3H), 7.29 (d, J¼8.2 Hz, 6H), 7.58 (d,
J¼8.3 Hz, 6H), 8.73 (s, 3H), 8.81 (s, 3H); 13C NMR (150 MHz, DMSO-
¼238 Hz); HRMS (ESI, MþNaþ) calcd for C54H51F3N6NaO6:
F
959.3720, found: 959.3718.
d6)
d 16.3, 22.5, 64.0, 84.7, 104.7, 107.9, 111.0, 120.5, 129.8, 130.9,
4.1.11. 1,3,5-Tris[3-(4-fluorophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (9)
137.3, 139.6, 140.8, 145.5, 152.3, 159.1; HRMS (ESI, MþNaþ) calcd for
C54H51I3N6NaO6: 1283.0902, found: 1283.0860.
To a solution of 26 (100 mg, 0.38 mmol) in 1,2-dichloroethane
(5.0 mL) was added 4-fluorophenyl isocyanate (0.071 mL,
0.63 mmol) under argon atmosphere at 0 ꢁC. The mixture was
stirred at room temperature for 2 days. Then the mixture was di-
luted with hexane, and the precipitate was filtered off. The crude
product was purified by reprecipitation from acetone and hexane to
give 9 as a white solid (126 mg, 74%). Mp >250 ꢁC; 1H NMR
4.1.15. 1,3,5-Tris[3-(4-methylphenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (13)
To a solution of 26 (200 mg, 0.38 mmol) in 1,2-dichloroethane
(10 mL) was added p-tolyl isocyanate (0.16 mL, 1.3 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 3 days. Then the mixture was diluted with hexane, and
the precipitate was filtered off. The crude product was purified by
reprecipitation from acetone and hexane to give 13 as a white solid
(600 MHz, DMSO-d6)
d
1.18 (t, J¼7.6 Hz, 9H), 2.76 (q, J¼7.6 Hz, 6H),
5.06 (s, 6H), 6.73 (d, J¼6.2 Hz, 3H), 7.02 (d, J¼8.2 Hz, 3H), 7.10 (t,
J¼8.6 Hz, 6H), 7.22 (t, J¼8.2 Hz, 3H), 7.24 (s, 3H), 7.43–7.45 (m, 6H),
(265 mg, 76%). Mp >250 ꢁC; 1H NMR (600 MHz, DMSO-d6)
d 1.19 (t,
8.68 (s, 6H); 13C NMR (150 MHz, DMSO-d6)
d
16.3, 22.5, 63.9, 104.6,
J¼6.9 Hz, 9H), 2.22 (s, 9H), 2.76 (q, J¼6.9 Hz, 6H), 5.06 (s, 6H), 6.73
(d, J¼8.3 Hz, 3H), 7.02 (d, J¼8.3 Hz, 3H), 7.07 (d, J¼8.2 Hz, 6H), 7.22
(t, J¼8.3 Hz, 3H), 7.25 (s, 3H), 7.32 (d, J¼8.2 Hz, 6H), 8.55 (s, 3H),
107.8, 111.0, 115.3 (d, JC–F¼23.0 Hz), 120.0 (d, JC–F¼7.2 Hz), 129.7,
130.9, 135.9, 141.0, 145.4, 152.6, 157.3 (d, JC–F¼237 Hz), 159.1; HRMS
(ESI, MþNaþ) calcd for C54H51F3N6NaO6: 959.3720, found:
959.3736.
8.65 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 16.3, 20.3, 22.5, 63.9,
104.5, 107.6, 110.9, 118.3, 129.2, 129.7, 130.7, 130.9, 137.1, 141.1, 145.5,
152.5, 159.1; HRMS (ESI, MþNaþ) calcd for C57H60N6NaO6:
947.4472, found: 947.4477.
4.1.12. 1,3,5-Tris[3-(4-chlorophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (10)
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(3.0 mL) was transferred a solution of 4-chlorophenyl isocyanate
(96 mg, 0.63 mmol) in 1,2-dichloroethane (2.0 mL) under argon
atmosphere at 0 ꢁC. The mixture was stirred at room temperature
for 18 h. Then the mixture was diluted with hexane, and the pre-
cipitate was filtered off. The crude product was purified by repre-
cipitation from acetone and hexane to give the desired product as
a white solid (129 mg, 68%). Mp >250 ꢁC; 1H NMR (600 MHz,
4.1.16. 1,3,5-Tris[3-(4-ethylphenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (14)
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(5.0 mL) was added 4-ethylphenyl isocyanate (0.090 mL,
0.63 mmol) under argon atmosphere at 0 ꢁC. The mixture was
stirred at room temperature for 1 day, and then refluxed for 3 h.
Then the mixture was diluted with hexane, and the precipitate was
filtered off. The crude product was purified by reprecipitation from
acetone and hexane to give 14 as a white solid (165 mg, 90%). Mp
DMSO-d6)
d
1.18 (t, J¼6.9 Hz, 9H), 2.75 (q, J¼6.9 Hz, 6H), 5.06 (s, 6H),
6.74 (d, J¼8.3 Hz, 3H), 7.01 (d, J¼8.2 Hz, 3H), 7.22 (t, J¼8.2 Hz, 3H),
7.24 (s, 3H), 7.31 (d, J¼8.3 Hz, 6H), 7.46 (d, J¼8.2 Hz, 6H), 8.73 (s,
>250 ꢁC; 1H NMR (600 MHz, DMSO-d6)
d
1.14 (t, J¼7.6 Hz, 9H), 1.19
(t, J¼6.9 Hz, 9H), 2.52 (q, J¼7.6 Hz, 6H), 2.76 (q, J¼6.9 Hz, 6H), 5.06
(s, 6H), 6.72 (d, J¼8.3 Hz, 3H), 7.02 (d, J¼8.9 Hz, 3H), 7.10 (d,
J¼8.2 Hz, 6H), 7.21 (t, J¼8.3 Hz, 3H), 7.23 (s, 3H), 7.33 (d, J¼8.2 Hz,
3H), 8.81 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 16.3, 22.4, 64.0,
104.7, 107.9, 111.1, 119.7, 125.4, 128.6, 129.7, 130.9, 138.6, 140.8, 145.5,
152.4, 159.1; HRMS (ESI, MþNaþ) calcd for C54H51Cl3N6NaO6:
1009.2804, found: 1009.2788.
6H), 8.55 (s, 3H), 8.64 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 15.8,
16.3, 22.4, 27.5, 63.9, 104.5, 107.6, 110.9, 118.4, 128.0, 129.7, 130.9,
137.2, 141.1, 145.4, 152.5, 159.1; HRMS (ESI, MþNaþ) calcd for
C60H66N6NaO6: 989.4942, found: 989.4965.
4.1.13. 1,3,5-Tris[3-(4-bromophenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (11)
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(5.0 mL) was added 4-bromophenyl isocyanate (125 mg,
0.63 mmol) under argon atmosphere at 0 ꢁC. The mixture was
stirred at room temperature for 1 day. Then the mixture was diluted
with hexane, and the precipitate was filtered off. The crude product
was purified by reprecipitation from acetone and hexane to give 11
4.1.17. 1,3,5-Tris[3-(4-isopropylphenylureido)phenoxymethyl]-
2,4,6-triethylbenzene (15)
To a solution of 26 (79 mg, 0.15 mmol) in 1,2-dichloroethane
(4.0 mL) was added 4-isopropylphenyl isocyanate (0.079 mL,
0.50 mmol) under argon atmosphere at 0 ꢁC. The mixture was
stirred at room temperature for 2 days, and then refluxed for 3 h.

11566
M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
Then the mixture was diluted with hexane, and the precipitate was
filtered off. The crude product was purified by reprecipitation
from acetone and hexane to give 15 as a white solid (114 mg,
4.1.21. 1,3,5-Tris[3-(phenylureido)phenoxymethyl]-2,4,6-
trimethylbenzene (19)
To a solution of 36 (300 mg, 0.62 mmol) in 1,2-dichloroethane
(15 mL) was added phenyl isocyanate (0.23 mL, 2.1 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 1 day. Then phenyl isocyanate (0.15 mL, 1.4 mmol) was
added and the mixture was refluxed for 1 day. Then the mixture
was diluted with hexane, and the precipitate was filtered off. The
crude product was purified by reprecipitation from acetone and
hexane to give 19 as a white solid (473 mg, 84%). Mp >250 ꢁC; 1H
75%). Mp >250 ꢁC; 1H NMR (600 MHz, DMSO-d6)
d 1.10 (d,
J¼6.9 Hz, 18H), 1.13 (t, J¼6.9 Hz, 9H), 2.70 (q, J¼6.9 Hz, 6H), 2.75
(sep, J¼6.9 Hz, 3H), 5.00 (s, 6H), 6.66 (d, J¼8.3 Hz, 3H), 6.96 (d,
J¼8.2 Hz, 3H), 7.07 (d, J¼8.2 Hz, 6H), 7.15 (t, J¼8.3 Hz, 3H), 7.18 (s,
3H), 7.28 (d, J¼8.2 Hz, 6H), 8.47 (s, 3H), 8.57 (s, 3H); 13C NMR
(150 MHz, DMSO-d6)
d 16.2, 22.4, 24.0, 32.7, 63.9, 104.5, 107.6,
110.9, 118.4, 126.4, 129.7, 130.9, 137.3, 141.1, 141.9, 145.4, 152.5,
159.0; HRMS (ESI, MþNaþ) calcd for C63H72N6NaO6: 1031.5411,
found: 1031.5381.
NMR (600 MHz, DMSO-d6)
d 2.39 (s, 9H), 5.10 (s, 6H), 6.72 (d,
J¼8.2 Hz, 3H), 6.96 (t, J¼6.9 Hz, 3H), 7.00 (d, J¼8.2 Hz, 3H), 7.22 (t,
J¼8.2 Hz, 3H), 7.26 (s, 3H), 7.28 (t, J¼6.9 Hz, 6H), 7.45 (d, J¼6.9 Hz,
4.1.18. 1,3,5-Tris[3-(4-octylphenylureido)phenoxymethyl]-2,4,6-
triethylbenzene (16)
6H), 8.66 (s, 3H), 8.68 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 15.5,
64.7, 104.7, 107.9, 110.9, 118.2, 121.8, 128.8, 129.6, 131.5, 138.7, 139.6,
141.0, 152.4, 159.3; HRMS (ESI, MþNaþ) calcd for C51H48N6NaO6:
863.3533, found: 863.3514.
To a solution of 26 (100 mg, 0.19 mmol) in 1,2-dichloroethane
(2.0 mL) was transferred a solution of 4-octylphenyl isocyanate
(146 mg, 0.63 mmol) in 1,2-dichloroethane (3.0 mL) under argon
atmosphere at 0 ꢁC. The mixture was stirred at room temperature
for 2 days, and then refluxed for 9 h. Then the mixture was diluted
with hexane, and the precipitate was filtered off. The crude product
was purified by reprecipitation from acetone and hexane to give 16
as a white solid (143 mg, 62%). Mp 220–222 ꢁC; 1H NMR (600 MHz,
4.1.22. 1,3,5-Tris[3-(phenylureido)phenoxymethyl]-2,4,6-
trimetoxybenzene (20)
To a solution of 39 (200 mg, 0.38 mmol) in 1,2-dichloroethane
(10 mL) was added phenyl isocyanate (0.14 mL, 1.3 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 4 days, and then refluxed for 3 h. The mixture was
diluted with hexane, and the precipitate was filtered off. The crude
product (233 mg) was reacted with phenyl isocyanate (0.10 mL,
0.92 mmol) in 1,2-dichloroethane (10 mL) again at reflux temper-
ature for 16 h. The mixture was diluted with hexane, and the pre-
cipitate was filtered off. The crude product was purified by
reprecipitation from acetone and hexane to give 20 as a white solid
DMSO-d6)
d
0.83 (t, J¼6.9 Hz, 9H), 1.18 (t, J¼6.9 Hz, 9H), 1.22–1.25
(m, 30H), 1.50–1.52 (m, 6H), 2.48 (t, J¼7.2 Hz, 6H), 2.75 (q, J¼6.9 Hz,
6H), 5.06 (s, 6H), 6.72 (d, J¼8.2 Hz, 3H), 7.01 (d, J¼8.2 Hz, 3H), 7.06
(d, J¼8.2 Hz, 6H), 7.21 (t, J¼8.3 Hz, 3H), 7.24 (s, 3H), 7.32 (d,
J¼8.2 Hz, 6H), 8.54 (s, 3H), 8.64 (s, 3H); 13C NMR (150 MHz, DMSO-
d6) d 13.9, 16.3, 22.1, 22.4, 28.6, 28.7, 28.8, 31.1, 31.3, 34.5, 63.9, 104.5,
107.6, 110.9, 118.4, 128.5, 129.7, 130.9, 135.8, 137.2, 141.1, 145.4, 152.5,
159.1; HRMS (ESI, MþNaþ) calcd for C78H102N6NaO6: 1241.7759,
found: 1241.7732.
(182 mg, 54%). Mp 162–163 ꢁC; 1H NMR (600 MHz, DMSO-d6)
d 3.88
(s, 9H), 5.01 (s, 6H), 6.74 (dd, J¼8.2, 2.1 Hz, 3H), 7.00 (t, J¼7.6 Hz,
3H), 7.04 (dd, J¼8.2, 2.1 Hz, 3H), 7.22 (t, J¼8.2 Hz, 3H), 7.26–7.33 (m,
9H), 7.44 (d, J¼7.6 Hz, 6H), 8.70 (s, 3H), 8.72 (s, 3H); 13C NMR
4.1.19. 1,3,5-Tris[3-(1-naphthylureido)phenoxymethyl]-2,4,6-
triethylbenzene (17)
(150 MHz, DMSO-d6)
d 59.9, 64.0, 104.6, 107.8, 110.9, 118.2, 120.6,
To a solution of 26 (200 mg, 0.38 mmol) in 1,2-dichloroethane
(10 mL) was added 1-naphthyl isocyanate (0.18 mL, 1.3 mmol) un-
der argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 3 days. Then the mixture was diluted with hexane,
and the precipitate was filtered off. The crude product was purified
by reprecipitation from acetone and hexane to give 17 as a white
solid (322 mg, 82%). Mp >250 ꢁC; 1H NMR (400 MHz, DMSO-d6)
121.8, 128.8, 129.7, 139.6, 141.0, 152.5, 158.9, 161.2; HRMS (ESI,
MþNaþ) calcd for C51H48N6NaO9: 911.3381, found: 911.3354.
4.1.23. 1,3,5-Tris[3-(phenylureido)phenoxymethyl]-2,4,6-
triisopentylbenzene (21)
To a solution of 42 (120 mg, 0.18 mmol) in 1,2-dichloroethane
(6.0 mL) was added phenyl isocyanate (0.080 mL, 0.73 mmol) un-
der argon atmosphere at 0 ꢁC. The mixture was stirred at room
temperature for 17 h. Then the mixture was diluted with hexane,
and the precipitate was filtered off. The crude product was purified
by reprecipitation from acetone and hexane to give 21 as a white
solid (150 mg, 80%). Mp 200 ꢁC; 1H NMR (600 MHz, DMSO-d6)
d
1.21 (t, J¼7.7 Hz, 9H), 2.79 (q, J¼7.7 Hz, 6H), 5.10 (s, 6H), 6.77 (d,
J¼8.3 Hz, 3H), 7.81 (d, J¼7.1 Hz, 3H), 7.26 (t, J¼8.1 Hz, 3H), 7.32 (s,
3H), 7.47 (t, J¼7.8 Hz, 3H), 7.54 (t, J¼7.3 Hz, 3H), 7.59 (t, J¼6.8 Hz,
3H), 7.64 (d, J¼8.3 Hz, 3H), 7.93 (d, J¼7.8 Hz, 3H), 8.00 (d, J¼7.8 Hz,
3H), 8.12 (d, J¼7.8 Hz, 3H), 8.78 (s, 3H), 9.12 (s, 3H); 13C NMR
(150 MHz, DMSO-d6)
d
16.3, 22.5, 64.0, 104.5, 107.9, 110.9, 117.6,
d
0.77 (d, J¼6.2 Hz, 18H), 1.46–1.52 (m, 9H), 2.69–2.72 (m, 6H), 5.01
121.3, 123.0, 125.7, 125.9, 125.9, 126.0, 128.4, 129.8, 130.9, 133.7,
134.2, 141.1, 145.5, 152.9, 159.2; HRMS (ESI, MþNaþ) calcd for
C66H60N6NaO6: 1055.4472, found: 1055.4493.
(s, 6H), 6.72 (dd, J¼8.2, 2.1 Hz, 3H), 6.96 (t, J¼7.6 Hz, 3H), 7.01 (d,
J¼8.2 Hz, 3H), 7.22 (t, J¼8.2 Hz, 3H), 7.26 (d, J¼7.6 Hz, 6H), 7.28 (s,
3H), 7.44 (d, J¼7.6 Hz, 6H), 8.66 (s, 3H), 8.68 (s, 3H); 13C NMR
(150 MHz, DMSO-d6) d 22.1, 27.2, 28.2, 40.7, 64.1, 104.5, 107.5, 110.6,
4.1.20. 1,3,5-Tris[3-(phenylureido)phenoxymethylbenzene (18)
To a solution of 33 (360 mg, 0.82 mmol) in THF (5.0 mL) was
added phenyl isocyanate (0.30 mL, 2.8 mmol) under argon atmo-
sphere at 0 ꢁC. The mixture was stirred at room temperature for 2
days, and then refluxed for 6 h. Then the mixture was diluted with
hexane, and the precipitate was filtered off. The crude product was
purified by reprecipitation from acetone and hexane to give 18 as
a white solid (620 mg, 95%). Mp 247–250 ꢁC (decomp.); 1H NMR
118.2, 121.8, 128.8, 129.7, 131.0, 139.6, 141.0, 144.3, 152.4, 159.1;
HRMS (ESI, MþNaþ) calcd for C63H72N6NaO6: 1031.5411, found:
1031.5374.
4.1.24. 1,3,5-Tris[3-(phenylureido)phenylethynyl]benzene (22)
To a solution of 45 (200 mg, 0.47 mmol) in 1,2-dichloroethane
(10 mL) was added phenyl isocyanate (0.17 mL, 1.5 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 3 day. The reaction mixture was diluted with hexane,
and the precipitate was filtered off. The crude product was purified
by reprecipitation from acetone and hexane to give 22 as a white
solid (306 mg, 83%). Mp >250 ꢁC; 1H NMR (600 MHz, DMSO-d6)
(400 MHz, DMSO-d6)
d
5.12 (s, 6H), 6.65 (d, J¼8.3 Hz, 3H), 6.93–6.97
(m, 6H), 7.17 (t, J¼8.1 Hz, 3H), 7.24–7.28 (m, 9H), 7.44 (d, J¼8.8 Hz,
6H), 7.53 (s, 3H), 8.65 (s, 3H), 8.66 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) d 68.9, 104.9, 108.0, 110.8, 118.2, 121.8, 126.3, 128.8, 129.6,
137.6, 139.6, 140.9, 152.4, 158.8; HRMS (ESI, MþNaþ) calcd for
d
6.97 (t, J¼8.2 Hz, 3H), 7.21 (d, J¼7.6 Hz, 3H), 7.28 (t, J¼8.2 Hz, 6H),
C48H42N6NaO6: 821.3064, found: 821.3081.
7.36 (t, J¼7.6 Hz, 3H), 7.42 (dd, J¼7.6, 2.1 Hz, 3H), 7.46 (d, J¼8.2 Hz,

M. Yamanaka et al. / Tetrahedron 64 (2008) 11558–11567
11567
6H), 7.80 (s, 3H), 7.81 (d, J¼2.1 Hz, 3H), 8.75 (s, 3H), 8.83 (s, 3H); 13
C
Park, S. Y. J. Am. Chem. Soc. 2004, 126, 10232–10233; (c) Messmore, B. W.;
Hulvat, J. F.; Sone, E. D.; Stupp, S. I. J. Am. Chem. Soc. 2004, 126, 14452–14458; (d)
Yang, X.; Lu, R.; Xu, T.; Xue, P.; Liu, X.; Zhao, Y. Chem. Commun. 2008, 453–455.
4. (a) Mamiya, J.; Kanie, K.; Hiyama, T.; Ikeda, T.; Kato, T. Chem. Commun. 2002,
1870–1871; (b) Wu¨rthner, F.; Yao, S.; Beginn, U. Angew. Chem., Int. Ed. 2003, 42,
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NMR (150 MHz, DMSO-d6)
d 87.1, 91.0, 118.3, 119.2, 120.7, 122.0,
122.1, 123.7, 125.1, 128.8, 129.3, 133.8,139.5, 140.0, 152.5; HRMS (ESI,
MþNaþ) calcd for C51H36N6NaO3: 803.2747, found: 803.2783.
4.1.25. 1,3,5-Tris[3-(phenylureido)phenylethyl]benzene (23)
5. (a) Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto,
To a solution of 46 (197 mg, 0.45 mmol) in 1,2-dichloroethane
(10 mL) was added phenyl isocyanate (0.17 mL, 1.5 mmol) under
argon atmosphere at 0 ꢁC. The mixture was stirred at room tem-
perature for 4 days and then refluxed for 3 h. During this time,
a precipitate formed in the reaction flask. Then the mixture was
diluted with hexane, and the precipitate was filtered off. The crude
product was purified by reprecipitation from acetone and hexane to
give 23 as a white solid (273 mg, 76%). Mp >250 ꢁC; 1H NMR
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(600 MHz, DMSO-d6)
d
2.80 (s-like, 12H), 6.84 (d, J¼6.9 Hz, 3H),
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6.94 (m, 6H), 7.16 (t, J¼7.6 Hz, 3H), 7.25 (m, 9H), 7.37 (s, 3H), 7.43 (d,
J¼7.6 Hz, 6H), 8.58 (s, 3H), 8.63 (s, 3H); 13C NMR (150 MHz, DMSO-
d6)
d 37.3, 37.4, 115.9, 118.2, 121.8, 122.1, 126.1, 128.7, 128.8, 139.6,
´
9. (a) Eastoe, J.; Sanchez-Dominguez, M.; Wyatt, P.; Heenan, R. K. Chem. Commun.
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C51H48N6NaO3: 815.3686, found: 815.3663.
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Acknowledgements
This work was partly supported by Tokuyama Science Founda-
tion and Kurata Grant.
Supplementary data
Experimental details and spectroscopic data can be found in the
PDF format. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.10.036.
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