Cyclic-tri(N-methyl-meta-benzamide)s: Substituent effects on the bowl-shaped conformation in the crystal and solution states

Article abstract of DOI:10.1016/j.tet.2010.08.049

Cyclic trimers of 3-(N-alkylamino)benzoic acid (calix[3]amides) with various substituents at the meta position of the phenyl rings were synthesized and the effects of the substituents on the crystal structures and energy profiles in solution were examined. The calixamides existed in a syn conformation in the crystal state, and this was also the major conformation in solution, especially in polar solvents. The energy barrier between syn and anti conformers in the solution was not significantly affected by substituents (12.7-14.0 kcal/mol). The effect of the substituent on the temperature dependence of the syn/anti ratio are discussed.

Full text of DOI:10.1016/j.tet.2010.08.049

Tetrahedron 66 (2010) 8254e8260
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclic-tri(N-methyl-meta-benzamide)s: substituent effects on the bowl-shaped
conformation in the crystal and solution states
,
b
c
b
Hiroki Kakuta a, Isao Azumaya b , Hyuma Masu , Mio Matsumura , Kentaro Yamaguchi ,
*
Hiroyuki Kagechika d, Aya Tanatani c
,
*
a Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
c Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
d Graduate School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2010
Received in revised form 17 August 2010
Accepted 18 August 2010
Available online 24 August 2010
Cyclic trimers of 3-(N-alkylamino)benzoic acid (calix[3]amides) with various substituents at the meta
position of the phenyl rings were synthesized and the effects of the substituents on the crystal structures
and energy profiles in solution were examined. The calixamides existed in a syn conformation in the
crystal state, and this was also the major conformation in solution, especially in polar solvents. The
energy barrier between syn and anti conformers in the solution was not significantly affected by sub-
stituents (12.7e14.0 kcal/mol). The effect of the substituent on the temperature dependence of the syn/
anti ratio are discussed.
Keywords:
Calix[3]amide
Substituent effect
Aromatic-aromatic interactions
syneanti conformation
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
this reaction, the cis4 conformational preference of the N-methyl-
benzanilide moiety5 and the preorganization due to aroma-
Bowl-shaped macrocyclic molecules represented by calixar-
enes1 are used to the framework of the host compound, which trap
complementary guests within a cavity. The molecular recognition
event by the host compound can be applied to the chemical tools in
the fields of analytical chemistry and biological sciences.2 We have
previously reported that cyclic-tri(N-methyl-meta-benzamide)
(calix[3]amide, 1, Fig. 1) can be easily formed by the condensation
reaction of 3-(N-methylamino)benzoic acid in moderate yield.3 In
ticearomatic interactions6 in the intermediate species appears to
be important for cyclization.
The cyclic triamide 1 shows a bowl-shaped structure (syn con-
formation, Fig. 2) in the crystal,7 where the three N-phenyl groups
are directed to the same side. The syn conformation of 1 has a small
cavity and molecular chirality based on the direction of the amide
bond. Although the size of the cavity is rather small, compared with
those of cyclodextrins and calixarenes, it plays a significant role in
formation of dimers of the cyclic triamides 2 bearing 5-nitro groups
in the crystalline state.8 In the dimeric structure, the nitro group of
one molecule resides in the cavity of the other molecule. Thus, the
cyclic triamides, such as 1, represent macrocyclic molecules with
Figure 1. Cyclic triamides 1e8.
* Corresponding authors. Tel./fax: þ81 3 5978 2716 (A.T); tel.: þ81 87 894 5111;
fax: þ81 87 894 0181 (I.A.); e-mail addresses: azumayai@kph.bunri-u.ac.jp
(I. Azumaya), tanatani.aya@ocha.ac.jp (A. Tanatani).
Figure 2. Conformational equilibrium of 1 in solution.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.049

H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
8255
unique functions based on conformational preference. In solution,
cyclic triamide 1 exists in rapid equilibrium between the syn and
anti conformations, in which one phenyl group flips to an alternate
direction (Fig. 2). Therefore, understanding of the conformational
properties of cyclic triamides is important in the development of
functional molecules based on the bowl-shaped structure. In this
study, the substituent effects on the crystal structures and the
conformational equilibrium of cyclic triamide 1 are studied.
The conversion reactions of the bromo groups of 3 into other
substituents are shown in Scheme 2. The Heck reaction of 3 with
cyclohexene in the conditions using tetrabutylammonium chloride
as a phase transfer catalyst,9 followed by the catalytic hydrogena-
tion, gave tricyclohexyl compound 4 in 27% (two steps), and also
the di- (30%) and monocyclohexyl (20%) compounds, and 1 (13%).
Phenylation of 3 with phenylboronic acid in the presence of tri-
phenylphosphine and palladium on carbon afforded compound 5 in
35% yield.10 Introduction of the nitrogen atom was performed by
the Buchwald’s amination reactions of 3. Aromatic methylaniline
and aliphatic piperadine were reacted with 3 to give compounds 6
(70%) and 7 (39%), respectively.11 Finally, treatment of 3 with cop-
per(I) cyanide at 170 ꢀC afforded compound 8 in 45% yield.12
2. Result and discussion
2.1. Synthesis
To clarify the substituent effects on the structures of cyclic tri-
amides, compounds 3e8 with 5-substituents on the phenyl rings
were synthesized. Several types of the substituents, such as hydro-
phobic aliphatic, aromatic, electron-donating amino and electron-
withdrawing cyano groups were introduced by the replacement of
the bromo group of cyclic amide 3. The synthesis of the key com-
pound 3 is shown in Scheme 1. Bromination of methyl 3-nitro-
benzoate (9) in the presence of silver sulfate and sulfuric acid,
followed by the esterification of the partially formed benzoic acid
moiety, afforded methyl 3-bromo-5-nitrobenzoate (10) in 57% yield.
After conversion of the nitro groups of 10 into methylamino groups
in four steps, the condensation reaction of the compound 14 using
silane tetrachloride and pyridine afforded the cyclic trimer 3 (41%)
with the cyclic tetramer (7%) as a by-product.
2.2. Crystal structures
X-ray crystal analyses of 3e5 and 8 were successfully achieved.
The crystallographic data are shown in Table 1. All compounds
examined have the syn structure similar to compound 1 (Fig. 3).
The structural parameters of the cyclic triamides including those
of compound 1 and 2 are shown in Table 2. Small torsion angles of
the amide bonds (MeeNeCeO,
4 in Table 2) show that the amide
bonds of all compounds are held in plane. In the syn structure of 1,
the three phenyl rings are tilted back, forming a truncated cone-
shaped conformation with larger distances between the three C(5)
carbons (d1 in Table 2) and smaller distances between the three C
(2) carbons (d2 in Table 2). Other compounds 2e4 and 8 have
Scheme 1. Synthesis of cyclic triamide 3.
Scheme 2. Conversion reactions of the bromo groups of 3 into other substituents.

8256
H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
Table 1
Crystallographic data of cyclic triamides 3e5 and 8
3
4
5
8
Formula
C24H18N3O3Br3
C42H51N3O3$(O)a
C42H33N3O3$C6H6
C27H18N6O3
Recryst solvent
Crystal system
Space group
a (Å)
b (Å)
c (Å)
CH2Cl2/EtOH
Triclinic
P-1
CH3CN
Triclinic
P-1
Benzene/n-C6H14
Monoclinic
P21/n
15.61(2)
12.923(5)
19.90(2)
90
105.52(7)
90
3868(6)
4
CH2Cl2/MeOH
Monoclinic
P21/c
14.646(2)
11.369(2)
15.880(3)
90
111.750(2)
90
2455.9(7)
4
9.337(3)
10.848(3)
13.433(2)
105.32(2)
92.53(2)
113.27(2)
1188.5(6)
2
9.406(1)
11.259(1)
19.233(2)
94.96(1)
93.63(1)
110.48(1)
1891.3(4)
2
a
b
g
(deg)
(deg)
(deg)
V (Å3)
Z
Dcalcd (Mg mꢁ3
T (K)
)
1.778
296
1.162
296
1.212
288
1.283
299
GOF
1.004
1.047
1.175
0.864
R1 [I>2
wR2 (all data)
CCDC
s
(I)]
0.0587
0.1921
779185
0.0936
0.2252
779186
0.0903
0.2382
779187
0.0568
0.1622
779188
a
The positions of hydrogen atoms included in water molecules were not calculated.
Table 2
Structural parameters of the cyclic triamides
a
a
a
a
Comp.
d1
Å
d1ave
d2
Å
d2ave
q
deg
qave
4
deg
4ave
1b
5.35
5.89
5.11
5.45
3.43
3.65
3.68
3.59
98.8
121.4
119.6
113.3
110.5
112.6
107.2
100.0
109.0
4.3
7.8
11.5
7.9
2c
3
5.32
4.95
5.42
5.23
5.37
5.05
4.62
5.15
3.59
3.44
3.83
3.62
3.58
3.65
3.79
3.64
120.2
103.1
108.4
0.3
8.9
7.3
5.5
7.1
4.0
1.5
4.9
5.52
5.15
5.45
3.61
3.41
3.73
122.1
108.2
107.6
7.8
6.1
7.5
4
5.29
4.80
5.05
3.72
3.46
3.78
116.5
106.1
98.9
2.1
8.2
1.7
Figure 3. Thermal ellipsoid models of crystal structures of cyclic triamides 3 (a), 4 (b), 5
(c), and 8 (d). Ellipsoids are drawn at the 30% probability level while isotropic hydrogen
atoms are represented by spheres of arbitrary size. Solvent molecules are omitted.
5
4.59
4.83
4.43
3.78
3.82
3.78
93.5
105.4
101.1
3.6
1.0
0.1
8
5.29
5.49
4.67
3.75
3.72
3.44
99.0
122.8
105.4
8.5
5.6
0.5
similar structural parameters. However, the cyclic structure of 5 is
rather different from the structure of the other triamides. The dif-
ference of d1 and d2, and the dihedral angles of the phenyl rings
with a plane formed by the six carbon atoms connecting to amide
a
An average of three values for each compound.
Ref. 7.
Ref. 8.
b
c
linkers (q in Table 2) of 5 are significantly smaller than those of 1 or
the other cyclic triamides. This indicates that the three phenyl rings
of 5 are nearly perpendicular to the macrocyclic chain. These con-
formational characteristics of the cyclic triamides are explained by
the weak intramolecular interactions and the crystal packing effect.
Compound 3 formed the dimeric crystal structure similar to com-
pound 2 (Fig. 4a). Compound 8 also formed a dimeric structure
through the interdigitation of the cyano groups (Fig. 4d). These
structures give the molecules a truncated cone-shaped conforma-
tion and a cavity. Compound 4 does not form the dimeric structure,
but has a large d1 value due to steric hindrance of the bulky
cyclohexyl substituents (Fig. 4b). Conversely, the structure of 5 with
a smaller cavity in the macrocycles arises from the aroma-
ticearomatic interactions between the three phenyl substituents
(Fig. 4c). The dihedral angles of the three phenyl substituents are
52.6, 54.5, and 73.4ꢀ, and the distances between their centers are
4.75, 5.63, and 5.04 Å, which is similar to the values in the calcu-
lated stable benzene dimers with
a T-shaped conformation
(5.0 Å).13 Such interactions between the substituents may affect the
conformation of the syn structures of the cyclic triamides.
2.3. Conformational equilibrium in solution
The cyclic triamide 1 exists in rapid equilibrium between syn
and anti conformers in solution (Fig. 2). At room temperature the
1H NMR signals are broad and become two sets of sharp signals at
213 K. To clarify the substituent effects on the conformational

H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
8257
equilibrium, temperature-dependent 1H NMR spectra of com-
pounds 3e8 were acquired. All compounds examined showed
similar 1H NMR spectral features, in which broad signals were ob-
served at room temperature and two sets of peaks were observed at
213 K. The assignment of the conformers was essentially based on
the syn and anti conformers of 1. For the anti conformer, the aro-
matic proton signal was at higher field (6.0e6.5 ppm), corre-
sponding to the H-2 position. The ratio of the two conformers and
the coalescence points were determined using the signals arising
from the N-methyl groups. Thermodynamic parameters of syn/anti
equilibria are listed in Table 3.
In all compounds examined, the syn conformer is the major
species in CD2Cl2 (D
G0<0), and the ratio of syn/anti increased in
CD3OD. The preference for the syn conformation in a polar solvent
arises from the large dipole moment of the syn conformer with
three amide bonds in the same orientation. The energy barrier
between the two conformers was not affected by either the sub-
stituent or solvent properties. Thus, the DG
s value (13.8 kcal/mol)
of 5 is similar to those of other compounds (12.7e14.0 kcal/mol),
and therefore the total stabilizing energies derived from aromatice
aromatic interactions are not noticeably in the syn and anti confor-
mations, and the transition state.
The ratio of syn and anti conformers of each compound was
dependent on the temperature. The plot of the equilibrium con-
stant (ln K) against the temperature (1/T) afforded the enthalpy
(D D
H0) and entropy ( S0) differences (Fig. 5, Table 3). In most cases,
the ratio of the syn conformer increases as the temperature de-
creased, except compound 5 in CD2Cl2. The syn conformer is
enthalpically favored, especially in the polar methanol solution.
Interestingly, the entropy difference (D
S0) is positive and rather
large in compound 5. This means that the syn conformation with
three sets of aromaticearomatic contacts is more disordered than
the anti conformation with only one aromaticearomatic contact.
This also indicates that stabilization by one aromaticearomatic
interaction in the anti conformation would be larger than the sum
of the three aromaticearomatic interactions in the syn conforma-
tion. This phenomenon is seemingly contradictory in the case of our
previous report on the conformational behaviors of benzene-
tricarboxanilide analog 15 (Fig. 6).14 In the case of 15, the syn
conformation with aromaticearomatic interactions between three
phenyl groups is enthalpically favored. The different conforma-
tional behavior of 5 arises from the geometry of the cyclic amides
compared with the acyclic compound 15, and is due to the third
neighboring phenyl group inhibiting the relatively tight aroma-
ticearomatic interactions between two phenyl groups in the anti
Figure 4. Packing of the crystal structures of the cyclic triamides 3 (a), 4 (b), 5 (c), and 8 (d).
The hydrogen atoms for each molecule and the water molecules in the crystal of 4 are
omitted.
Table 3
Thermodynamic parameters of syn/anti equilibria of the cyclic triamides
Comp.
Solvent
Tc
D
Gsd
K (213 K)
D
G0
D
H0e
D
S0e
kcal/mol
([syn]/[anti])
kcal/mol
kcal/mol
cal/mol K
1
CD2Cl2
CD3OD
CD2Cl2
CD2Cl2
CD3OD
CD2Cl2
CD3OD
CD2Cl2
CD3OD
CD2Cl2
CD3OD
CD2Cl2
268ꢂ5
268ꢂ5
268ꢂ5
268ꢂ5
dc
13.7ꢂ0.3
13.7ꢂ0.3
13.1ꢂ0.3
13.8ꢂ0.3
dc
5.6
35
1.5
13
71
2.5
51
8.5
57
5.2
43
ꢁ0.7
ꢁ1.5
ꢁ0.2
ꢁ1.1
ꢁ1.8
ꢁ0.4
ꢁ1.7
ꢁ0.9
ꢁ1.7
ꢁ0.7
ꢁ1.6
ꢁ0.6
ꢁ0.8
ꢁ1.8
0.2
ꢁ1.1
ꢁ1.9
0.7
ꢁ0.9
ꢁ0.8
ꢁ1.5
ꢁ0.6
ꢁ1.5
ꢁ1.4
ꢁ0.7
ꢁ1.6
1.7
ꢁ0.3
ꢁ0.5
4.9
3.5
0.3
1.1
0.5
a
3
4
5
268ꢂ5
13.8ꢂ0.3
dc
dc
6b
7
278ꢂ5
dc
14.0ꢂ0.3
dc
268ꢂ5
13.6ꢂ0.3
dc
dc
0.5
ꢁ3.9
8a
258ꢂ5
12.7ꢂ0.3
4.0
a
Poor solubility in CD3OD.
b
c
1H NMR studies were performed for the compound bearing N-methyl-d3-N-phenylamino groups as the substituents.
Minor signals are too small to determine the coalescence point.
d
D
Gs was calculated by the following equation:
D
Gs¼19.14Tc{9.97þlog (Tc/Dn)} in which Tc is the coalescence point, and Dn is the chemical shift difference of the
N-methyl groups.
e
D
H
0 and
D
S
0 were calculated by the following equation: ln K¼ꢁ
D
H0/RTþ
D
S0/R.

8258
H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
analyses were carried out in the Microanalytical Laboratory, Faculty
a 3.0
b
4.5
4.0
3.5
3.0
4
of Pharmaceutical Sciences, The University of Tokyo, and were
within ꢂ0.3% of the theoretical values. The crystals for X-ray crys-
tallography were obtained by normal recrystallization by using the
mixed solvent with proper ratio. 1H NMR spectra were recorded on
a JEOL JNM-GX400, and chemical shifts are expressed in ppm rela-
tive to tetramethylsilane. Temperature dependent NMR was per-
formed by using 2e3 mg of compound in 0.5 mL of solvent at the
intervals of 10ꢀ from 273 to 213 K. The thermodynamic parameters
shown in Table 3 were calculated from the correlation line shown in
6
4
6
5
2.5
2.0
1
1
7
8
1.5
2.5
ln K
ln K
7
8
2.0
1.5
1.0
0.5
1.0
0.5
0
5
3
Fig. 5 by using the equation of ln K¼ꢁ
D
H0/RTþ
D
S0/R. Mass spectra
were measured on JEOL JMS-SZ 102A (EI) or on Brucker Daltonics
microTOF-2focus in the positive ion detection modes (ESIþ).
0.0036 0.0040 0.0044
0.0048
0.0036 0.0040 0.0044
0.0048
4.2. Synthesis
1/T
1/T
Figure 5. Temperature-dependent syn/anti equilibria in (a) CD2Cl2 and (b) CD3OD.
4.2.1. Synthesis of methyl 3-bromo-5-nitrobenzoate (10). A mixture
of methyl 3-nitrobenzoate (9, 50.0 g, 0.28 mol), silver sulfate
(48.1 g, 15 mmol), and 300 mL of sulfuric acid was stirred at 90 ꢀC.
Bromine (20 mL) was added dropwise to the mixture over 30 min
and the reaction mixture was stirred at 90 ꢀC for 1 h. After cooling,
the precipitated silver bromide was filtered off and the filtrate was
poured into iced water, and extracted with ethyl acetate. The or-
ganic layer was washed successively with water, satd sodium
hydrosulfite, water and brine, and dried over sodium sulfate. After
evaporation, the residue was dissolved in methanol (500 mL) and
sulfuric acid (10 mL), and the mixture was refluxed overnight. After
evaporation, the residue was poured into iced water, and extracted
with ethyl acetate. The organic layer was washed with water and
brine, dried over sodium sulfate, and evaporated. The residue was
recrystallized from methanol to give 10 (39.9 g, 57%). 10: colorless
needles (methanol); mp 70e71.5 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.79 (t, 1H, J¼1.8 Hz), 8.56 (t, 1H, J¼1.8 Hz), 8.49 (t, 1H, J¼1.8 Hz),
and 4.00 (s, 3H); IR (KBr) 1540 cmꢁ1. Anal. Calcd for C8H6BrNO4: C,
36.92; H, 2.31; N, 5.38. Found: C, 36.77; H, 2.01 N, 5.16.
4.2.2. Synthesis of methyl 3-amino-5-bromobenzoate (11). A mix-
ture of iron powder (56 g,1.0 mol), water (200 mL), and hydrochloric
acid (10 mL) was heated at reflux for 20 min. A solution of 10 (105 g,
0.408 mol) in ethanol (1.6 L) was added dropwise to the refluxing
mixture over 2 h, and the mixture was refluxed for 3 h. After cooling,
the mixture was filtered with Celite, and the filtrate was basified
with sodium carbonate. After filtration with Celite, the filtrate was
extracted with ethyl acetate. The organic layer was washed with
water and brine and dried over sodium sulfate. After evaporation,
the crude product (92.1 g, 99%) was recrystallized fromethylacetate/
n-hexane to give 11. Compound 11: pale yellow needles (ethyl ace-
Figure 6. The syn/anti equilibrium of 1,3,5-tris(N-methyl-N-phenylamino)benzene 15.
conformation of 5. This results in destabilizing the aroma-
ticearomatic interactions between the three sets of contacts of the
phenyl groups, and therefore the disordered appearance of these
rings in the syn conformation. This consideration is not inconsistent
with the feature seen in the energy profile of 5, which is different
from the other analogs.
3. Conclusion
tate/hexane);mp 93e94.5ꢀC; 1HNMR (400 MHz, CDCl3)
d 7.52 (t,1H,
The effects of substituents on the phenyl rings of cyclic triamide 1
were examined. The cyclic triamides with various substituents on the
phenyl rings were easily synthesized from the key compound 3. The
syn conformations were observed in the crystal structures of all
compounds examined, and were the major species in solution, es-
pecially in a polar solvent. Considering the synthetic convenience and
the preferential syn structure with a small chiral cavity that arrange
three substituents inthe sameorientation, thecyclictriamides should
be useful constructing macrocycles with unique molecular recogni-
tion capabilities, for example, switching a recognition mode by
altering the environment, such as solvent or temperature.
J¼1.8 Hz), 7.25 (t,1H, J¼1.8 Hz), 6.99 (t,1H, J¼1.8 Hz), 3.89 (s, 3H), and
3.84 (s, 2H); IR (KBr) 3400 cmꢁ1. Anal. Calcd for C8H8BrNO2: C, 41.74;
H, 3.48; N, 6.09. Found: C, 41.96; H, 3.37; N, 6.09.
4.2.3. Synthesis
of
methyl
3-acetamino-5-bromobenzoate
(12). Acetic anhydride (500 mL) and pyridine (5 mL) was added to
compound 11 (92.1 g, 0.40 mol) at 0 ꢀC and the mixture was stirred
at room temperature for 1 h. The mixture was poured into iced
water, and extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate, and
evaporated to give 12 (106.4 g, 98%). Compound 12: colorless
powder; mp 132e135 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.17 (s, 1H),
4. Experimental
4.1. General
7.89 (m, 2H), 7.25 (t, 1H, J¼1.8 Hz), 3.91 (s, 3H), and 2.21 (s, 3H); IR
(KBr) 3400e3200, 1720, 1670 cmꢁ1. Anal. Calcd for C10H10BrNO3: C,
44.10; H, 3.68; N, 5.15. Found: C, 43.98; H, 3.46; N, 5.18.
Melting points were determined by using a Yanagimoto hot-
stage melting point apparatus and are uncorrected. Elemental
4.2.4. Synthesis of methyl 3-bromo-5-(N-methylacetamino)benzoate
(13). Sodium hydride (9.6 g, 60% purity, 0.24 mol) was washed with

H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
8259
n-hexane, and suspended in DMF (100 mL). A solution of 12 (54.4 g,
0.20 mol) in DMF (180 mL) was dropwise added to the suspension
over 1 h. Methyl iodide (15 mL, 0.24 mol) was then added to the
mixture over 20 min. After 1 h, the solvent was removed under
vacuum, and the residue was poured into water and extracted with
ethyl acetate. The organic layer was washed with water and brine,
dried over sodium sulfate, and evaporated to give 13 (54.7 g, 96%).
Compound 13: colorless powder; mp 70e73 ꢀC; 1H NMR (400 MHz,
1.8e1.1 (m, 30H); IR (KBr) 1640, 1590 cmꢁ1; HRMS (ESIþ) calcd for
C42H52N3O3 (MþHþ): 646.4003. Found: 646.4024. Anal. Calcd for
C42H51N3O3$H2O: C, 75.98; H, 8.05; N, 6.33. Found: C, 75.75; H, 8.17;
N, 6.17.
4.2.8. Synthesis of cyclic triamide 5. A mixture of 3 (127 mg,
0.2 mmol), phenylboronic acid (88 mg, 0.72 mmol), 10% Pd/C
(28 mg), and triphenylphosphine (29 mg, 1.1 mmol) in dry DME
(1 mL) was stirred for 15 min. Sodium carbonate (2 M) was added to
the mixture and the reaction mixture was heated at 80 ꢀC over-
night. After cooling, the mixture was diluted with methylene
chloride, and filtered over Celite. The filtrate was washed with
water and brine, and dried over sodium sulfate. After evaporation,
the residue was purified by flash silica gel column chromatography
(ethyl acetate/methylene chloride 8:1) to give 5 (47 mg, 35%).
Compound 5: colorless prisms (ethyl acetate/methanol); mp
CDCl3)
d
8.14 (s, 1H), 7.82 (t, 1H, J¼1.8 Hz), 7.56 (s, 1H), 3.95 (s, 3H),
3.28 (s, 3H), and 1.92 (s, 3H); IR (KBr) 1720, 1650, 1600 cmꢁ1. Anal.
Calcd for C11H12BrNO3: C, 46.20; H, 4.20; N, 4.90. Found: C, 45.93; H,
4.12; N, 4.69.
4.2.5. Synthesis of 3-bromo-5-(N-Methylamino)benzoic acid (14). A
solution of 13 (54.7 g, 0.19 mol) in hydrochloric acid (200 mL) and
water (300 mL) was refluxed overnight. After cooling, the mixture
was extracted with ethyl acetate. Sodium hydroxide (4 M) was
added to the aqueous layer until pH¼4 and extracted with ethyl
acetate. The organic layer was washed with water and brine, and
dried over sodium sulfate. After evaporation, the crude product
(40.8 g, 92%) was recrystallized from ethyl acetate/hexane to give
14. Compound 14: brown prisms (ethyl acetate/hexane); mp
168e169 ꢀC; 1H NMR (400 MHz, CD2Cl2, 213 K)
d 7.72 (s, minor 3H),
7.58 (s, minor 3H), 7.5e7.3 (m, minor 15H), 7.25 (t, major 3H,
J¼8.1 Hz), 7.22 (s, major 3H, J¼1 Hz), 7.13 (s, major 3H), 7.11 (d,
major 6H, J¼8.1 Hz), 6.95 (s, major 3H), 6.93 (d, major 6H, J¼8.1 Hz),
6.48 (s, minor 3H), 3.37 (s, minor 9H), and 3.34 (s, major 9H); IR
(KBr) 1650, 1590 cmꢁ1; HRMS (EI) calcd for C42H33N3O3: 627.2522.
Found: 627.2524. Anal. Calcd for C42H33N3O3$1/3H2O: C, 79.60; H,
5.35; N, 6.63. Found: C, 79.61; H, 5.37; N, 6.50.
165e167 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d 7.15 (s,1H), 7.09 (s,1H),
6.87 (s, 1H), 6.23 (d, 1H, J¼5.1 Hz) and 3.29 (s, 3H); IR (KBr)
1700 cmꢁ1. Anal. Calcd for C8H8BrNO2: C, 41.74; H, 3.48; N, 6.09.
Found: C, 41.84; H, 3.46; N, 5.80.
4.2.9. Synthesis of cyclic triamide 6. A solution of N-methylaniline
(0.04 ml, 0.36 mmol) in dry toluene (1 mL) was added to a mixture
of 3 (64 mg, 0.1 mmol), Pd2(dba)3 (5.5 mg, 0.006 mmol), BINAP
(9 mg, 0.015 mmol), and sodium tert-butoxide (40 mg, 0.42 mmol)
under Ar atmosphere, and the mixture was heated at 80 ꢀC for 6 h.
After cooling, the mixture was diluted with ethyl acetate and fil-
tered over Celite. The filtrate was washed with water and brine, and
dried over sodium sulfate. After evaporation, the residue was pu-
rified by flash silica gel column chromatography (ethyl acetate/
hexane 4:1) to give 6 (50 mg, 70%). 6: pale brown prisms (metha-
4.2.6. Synthesis of cyclic triamide 3. Tetrachlorosilane (0.17 ml,
1.5 mmol) was added to a solution of 14 (0.33 mmol) in dry pyridine
(10 mL) at 0 ꢀC and the mixture was heated at 130 ꢀC for 2 days.
After removal of the solvent under vacuum, the residue was
extracted with methylene chloride. The organic layer was washed
successively with 2 M hydrochloric acid, water, 2 M sodium hy-
droxide, water and brine, and dried over sodium sulfate. After
evaporation, the crude product was purified by silica gel column
chromatography (ethyl acetate: methylene chloride 1: 2) to give 3
(88 mg, 41%) with cyclic tetraamide (16 mg, 7%) as a by-product. 3:
colorless prisms (methylene chloride/ethanol); mp>300 ꢀC; 1H
nol); mp 124 ꢀC; 1H NMR (400 MHz, CD2Cl2, 213 K)
d 7.28 (t, minor
6H, J¼8.1 Hz), 7.19 (t, major 6H, J¼8.1 Hz), 7.05 (t, minor 3H,
J¼8.1 Hz), 7.01 (t, major 3H, J¼8.1 Hz), 6.97 (t, minor 6H, J¼8.1 Hz),
6.72 (t, major 6H, J¼8.1 Hz), 6.70 (s, minor 3H), 6.53 (s, major 3H),
6.46 (s, major 3H), 6.45 (s, minor 3H), 6.43 (s, major 3H), 6.02 (s,
minor 3H), 3.25 (s, minor 9H), 3.24 (s, minor 9H), 3.18 (s, major 9H),
and 3.09 (s, major 9H); IR (KBr) 1640, 1590 cmꢁ1. Anal. Calcd for
C45H42N6O3: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.29; H, 6.04; N,
11.66.
NMR (400 MHz, CD2Cl2, 213 K)
d
7.72 (t, minor 3H, J¼1.8 Hz), 7.51 (t,
minor 3H, J¼1.8 Hz), 7.23 (t, major 3H, J¼1.8 Hz), 7.18 (t, major 3H,
J¼1.8 Hz), 6.96 (t, major 3H, J¼1.8 Hz), 6.36 (t, minor 3H, J¼1.8 Hz),
3.38 (s, minor 9H) and 3.34 (s, major 9H); IR (KBr) 1650, 1600 cmꢁ1
.
Anal. Calcd for C24H18Br3N3O3: C, 45.28; H, 2.83; N, 6.60. Found: C,
45.08; H, 2.72; N, 6.84.
4.2.7. Synthesis of cyclic triamide 4. Palladium acetate (33.6 mg,
0.15 mmol) was added to the mixture of sodium acetate (308 mg,
3.75 mmol), tetra(n-butyl)ammonium chloride (417 mg, 1.5 mmol),
cyclohexene, and DMF (5 mL) under Ar atmosphere in a sealed
tube. After the solution turned orange, compound 3 (318 mg,
0.5 mmol) was added to the mixture. The tube was heated at 85 ꢀC
in a sealed bottle with cyclohexane for 1 week. After cooling, the
mixture was diluted with methylene chloride and filtered over
Celite. The filtrate was washed successively with 2 M hydrochloric
acid, water and brine, and dried over sodium sulfate. After evapo-
ration, the crude mixture was dissolved in methanol (6 mL), and
was hydrogenated with 10% Pd/C (60 mg) under hydrogen atmo-
sphere for 2 h. After filtration and evaporation, the residue was
purified by silica gel column chromatography and preparative TLC
to give 4 (86 mg, 27%) with 1 (27 mg, 13%), monocyclohexyl (48 mg,
20%), dicyclohexyl compounds (83 mg, 30%) as by-products. Com-
pound 4: colorless prisms (ethanol/hexane); mp 278e279 ꢀC; 1H
4.2.10. Synthesis of cyclic triamide 7. A solution of piperidine
(0.07 ml, 0.72 mmol) in dry toluene (2 mL) was added to a mixture
of 3 (127 mg, 0.2 mmol), Pd2(dba)3 (11.0 mg, 0.01 mmol), BINAP
(19 mg, 0.03 mmol), and sodium tert-butoxide (81 mg, 0.84 mmol)
under Ar atmosphere, and the mixture was heated at 80 ꢀC for 8 h.
After cooling, the mixture was diluted with methylene chloride and
filtered over Celite. The filtrate was washed with water and brine,
and dried over sodium sulfate. After evaporation, the residue was
purified by flash silica gel column chromatography (ethyl acetate/n-
hexane 4:1) to give 7 (50 mg, 39%). 7: yellow prisms (methanol);
mp>300 ꢀC; 1H NMR (400 MHz, CD2Cl2, 213 K)
d 6.96 (s, minor 3H),
6.72 (s, minor 3H), 6.50 (s, major 3H), 6.48 (s, major 3H), 6.31 (s,
major 3H), 5.87 (s, minor 3H), 3.24 (s, minor 9H), 3.20 (s, major 9H),
3.00 (s, minor 3H), 2.89 (s, major 3H), and 1.8e1.45 (br, minor and
major 9H); IR (KBr) 1640, 1590 cmꢁ1. Anal. Calcd for C39H48N6O3: C,
72.19; H, 7.46; N, 12.95. Found: C, 71.90; H, 7.58; N, 12.80.
NMR (400 MHz, CD2Cl2, 213 K)
d
7.32 (s, minor 3H), 7.09 (s, minor
4.2.11. Synthesis of cyclic triamide 8. A mixture of 3 (127 mg,
0.2 mmol), copper(I) cyanide (65 mg, 0.72 mmol), and DMF (5 mL)
was heated at 170 ꢀC under Ar atmosphere for 7 h. A solution of iron
(III) chloride (0.8 g) in hydrochloric acid (0.2 mL) and water (2 mL)
3H), 6.87 (br s, major 3H), 6.76 (t, major 3H, J¼1.5 Hz), 6.75 (t, major
3H, J¼1.5 Hz), 6.21 (s, minor 3H), 3.36 (s, minor 9H), 3.22 (s, major
9H), 2.42 (t, minor 3H, J¼12.0 Hz), 2.26 (t, major 3H, J¼12.0 Hz), and

8260
H. Kakuta et al. / Tetrahedron 66 (2010) 8254e8260
was added to the mixture at room temperature. The mixture was
poured into water and extracted with methylene chloride. The or-
ganic layer was washed with water and brine, and dried over so-
dium sulfate. After evaporation, the residue was purified by flash
silica gel column chromatography (ethyl acetate/hexane 4:1) to
give 8 (37 mg, 45%). Compound 8: colorless prisms (methylene
chloride/methanol); mp>300 ꢀC; 1H NMR (400 MHz, CD2Cl2, 213 K)
References and notes
1. (a) Gutsche, C. D. Acc. Chem. Res. 1983, 16, 161e170; (b) Gutsche, C. D.; Rogers, J.
S.; Stewart, D.; See, K. A. Pure Appl. Chem. 1990, 62, 485e491; (c) Shinkai, S.
Tetrahedron 1993, 49, 8933e8968; (d) Coquiere, D.; Le Gac, S.; Darbost, U.;
Seneque, O.; Jabin, I.; Reinaud, O. Org. Biomol. Chem. 2009, 7, 2485e2500.
2. (a) Lehn, L. M. Supramolecular ChemistrydConcepts and Perspectives; VCH:
Veinheim, 1995; (b) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278e286; (c) Steed, J.
W.; Atwood, J. L. Supramolecular Chemistry; John Wiley: Chichester, 2000.
3. (a) Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron Lett. 1996,
37, 5003e5006; (b) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
Tetrahedron 2003, 59, 2325e2331.
4. In this letter, ‘cis’ and ‘trans’ are used to show the relative position of phenyl
groups connected to the amide group. The designation can be easily un-
derstood at a glance; though, ordinarily, ‘cis-amide’ and ‘trans-amide’ should be
named (E)- and (Z)-amide, respectively.
5. (a) Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron 1995, 51,
5277e5290; (b) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433e6442.
d
7.83 (s, minor 3H), 7.64 (s, minor 3H), 7.43 (s, major 3H), 7.42 (s,
major 3H), 7.18 (s, major 3H), 6.54 (s, minor 3H), 3.35 (s, minor 9H),
and 3.27 (s, major 9H); IR (KBr) 1650,1580 cmꢁ1; HRMS (ESIþ) calcd
for C27H18N6NaO3 (MþNaþ): 497.1333. Found: 497.1352. Anal. Calcd
for C27H18N6O3$1/3H2O: C, 67.49; H, 3.92; N, 17.49. Found: C, 67.76;
H, 4.07; N, 17.42.
6. (a) Desvergne, J. P.; Bitit, N.; Castellan, A.; Bouas-Laurent, H. J. Chem. Soc., Perkin
Trans. 2 1983, 109e114; (b) Burley, S. K.; Petsko, G. A. Science 1985, 229, 23e28;
(c) Muehldorf, A. V.; Van Engen, D.; Warner, J. C.; Hamilton, A. D. J. Am. Chem.
Soc. 1988, 110, 6561e6562; (d) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc.
4.3. X-ray crystallography
1990, 112, 5525e5534; (e) Nishio, M.; Hirota, M.; Umezawa, Y. The CH/
p
Single crystal X-ray diffraction data of the crystals were col-
lected on a four-circle diffractometer (for 3 and 4) with graphite
Interaction, Evidence Nature, and Consequences; Wiley-VCH: New York, NY, 1998.
7. Elhadi, F. E.; David Ollis, W.; Fraser Stoddart, J.; Williams, D. J.; Woode, K. A.
Tetrahedron Lett. 1980, 21, 4215e4218.
8. Imabeppu, F.; Katagiri, K.; Masu, H.; Kato, T.; Tominaga, M.; Therrien, B.;
Takayanagi, H.; Kaji, E.; Yamaguchi, K.; Kagechika, H.; Azumaya, I. Tetrahedron
Lett. 2006, 47, 413e416.
9. Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905e908.
10. Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett. 1994, 35, 3277e3280.
11. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805e818; (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131e209.
12. Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522e2524.
13. (a) Jorgensen, W. L.; Severance, D. L. J. Am. Chem. Soc. 1990, 112, 4768e4774; (b)
Hobza, P.; Selzle, H. L.; Schlag, E. W. J. Am. Chem. Soc. 1994, 116, 3500e3506; (c)
Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Am. Chem. Soc.
2001, 124, 104e112.
monochromated Cu K
diffractometer (for 5) or CCD diffractometer (for 8) with graphite
a
(
l
¼1.5418 Å) radiation or an imaging plate
monochromated Mo K
a
(
l
¼0.7107 Å). The crystal structure was
solved by direct methods SIR200415 or SHELXS-9716 and refined by
full-matrix least-squares. All non-hydrogen atoms were refined
anisotropically and hydrogen atoms were included at their calcu-
lated positions. Details of each crystal data are described in Table 1
and supplementary CIF files.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC,12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
14. Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.;
Shudo, K. J. Am. Chem. Soc. 1991, 113, 5474e5475.
15. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro,
L.; Giacovazzo, C.; Polidori, G.; Spagn, R. J. Appl. Crystallogr. 2005, 38, 381e388.
16. A short history of SHELX Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.