Calix[3]amides - Bowl-shaped cyclic trimers toward building block for molecular recognition: Self-complementary dimeric structure in the crystal

Article abstract of DOI:10.1016/j.tetlet.2005.11.082

Bowl-shaped cyclic trimers of aromatic amides were simply synthesized in high yield by condensation reaction of meta-substituted 3-(alkylamino)benzoic acid using dichlorotriphenylphosphorane. The cyclic amides exist in syn conformation, which has a small chiral cavity, and a pair of each enantiomeric conformer formed a dimeric structure in the crystal.

Full text of DOI:10.1016/j.tetlet.2005.11.082

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 413–416
Calix[3]amides—bowl-shaped cyclic trimers toward building
block for molecular recognition: self-complementary
dimeric structure in the crystal
Fumiaki Imabeppu,a Kosuke Katagiri,b Hyuma Masu,b Takako Kato,b
Masahide Tominaga,b Bruno Therrien,c, Hiroaki Takayanagi,d Eisuke Kaji,d
Kentaro Yamaguchi,b Hiroyuki Kagechikaa and Isao Azumayab,*
aSchool of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
bFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
cSchool of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
dSchool of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Received 24 October 2005; revised 15 November 2005; accepted 17 November 2005
Available online 5 December 2005
Abstract—Bowl-shaped cyclic trimers of aromatic amides were simply synthesized in high yield by condensation reaction of meta-
substituted 3-(alkylamino)benzoic acid using dichlorotriphenylphosphorane. The cyclic amides exist in syn conformation, which has
a small chiral cavity, and a pair of each enantiomeric conformer formed a dimeric structure in the crystal.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Macrocyclic structures with a cavity are often seen in
compounds that have molecular recognition abilities.1
Calixarenes2 and cyclodextrins3 are examples that have
been extensively studied. A feature of these classes of
compounds is a structure constructed by a repeated
monomer unit, which can be synthesized by a single step
reaction from an appropriate monomer. This multi-
component cyclization reaction is often successful when
the linkage places two monomer units in the same direc-
tion. In the course of our studies on the stereochemistry
of aromatic amides,4 we found that a cyclic structure
could easily be constructed using conformational alter-
nation by N-alkylation of aromatic amides from trans
to cis.5 Using this structural property, 3-(methyl-
amino)benzoic acid was coupled with itself by a one-step
reaction using tetrachlorosilane to give a mixture con-
sisting mainly of cyclized trimer 1 of the monomer.6
The trimer has a bowl shape with a small cavity, which
may be suitable to construct a molecular recognition site
(Fig. 1).
*
Corresponding author. Tel.: +81 87 894 5111x6308; fax: +81 87 894
0181; e-mail: azumayai@kph.bunri-u.ac.jp
´
ˆ
Figure 1. Structural formula and stereoview of the crystal structure6 in
a space filling model of 1.
Present address: Institut de Chimie, Universite de Neuchatel, Case
postale 2, CH-2007 Neuchaˆtel, Switzerland.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.082

414
F. Imabeppu et al. / Tetrahedron Letters 47 (2006) 413–416
The trimer 1 was originally synthesized by Ollis and
co-workers7 stepwise using a hydrolysis of an ester and
activation to acid chloride at the carboxylic acid termi-
nal. However, no functionalized derivative has been syn-
thesized. As we reported previously, while searching for
an effective condensation reagent to couple a carboxylic
acid with an N-alkylated aniline with low nucleophilic-
ity, we found that dichlorotriphenylphosphorane was
highly effective in the one-step cyclization reaction of
N-methylaminobenzoic acids.8 The yield of trimer is
the highest among the cyclized oligomers obtained in
relatively mild conditions, so this reagent is suitable
for the synthesis of various functionalized cyclic aro-
matic amides.
step reaction from 3-amino-5-nitrobenzoic acid in rela-
tively high yield without any difficulty for purification
of the reaction mixture. These N-substituted monomers
were cyclized by dichlorotriphenylphosphorane in 1,1,
2,2-tetrachloroethane at 120 ꢁC to give the correspond-
ing cyclic trimer as a major compound in high yield.
This is because the amino and carboxyl groups at the
end of chained trimer with two amide connections are
close together due to the cis conformational preference
of tertiary amide that holds two substituents of amide
at a direction of 60ꢁ. In these syntheses, it is notable that
the calix[3]amides 5c and 5d could be synthesized by
just two steps form the commercially available starting
material.
Here we report a simple, one-step synthesis of cyclic
trimers of 3-(alkylamino)-5-nitrobenzoic acid. We also
report the characteristic crystal structure of nitro and
amino derivatives obtained by the catalytic reduction
of the corresponding nitro derivative. These cyclic
aromatic amides would be classified as ÔcalixamideÕ
and are a suitable skeleton for producing a new class
of cyclic oligomers toward molecular recognition.
X-ray single crystal structure analysis was carried out
for crystals of the calix[3]amides 5a and 5b,10 which were
obtained by recrystallization from CH3OH–CHCl3. All
compounds have syn conformation in the crystal, where
the three N-phenyl groups are directed to the same side.
The cyclic compounds have a small cavity surrounded
by three substituted-benzene rings. The conformations
have a molecular chirality based on the direction of
the amide bonds in the syn conformation. The unit cell
has the same number of enantiomeric conformers, which
results in the crystals having no chiral property. Interest-
ingly, these enantiomeric conformers existed in dimeric,
complementary form in the crystal where the cavity of
one molecule was filled with the nitro group of another
enantiomeric conformer. The crystal structure and di-
meric feature of compound 5b is shown in Figure 2.
Two oxygen atoms with high electronegativity (red area)
of the nitro group in a cavity seemed to be directed to
the relatively electropositive (blue area) of the ring cen-
ter of the two aromatic rings of the cavity. The distance
between the two aromatic planes (distance A in Fig. 3) is
The calix[3]amides 5a–d with various alkyl groups on
the nitrogen atoms were synthesized by a one-step
cyclization of 3-(alkylamino)-5-nitrobenzoic acid as a
monomer using dichlorotriphenylphosphorane as a con-
densation reagent in a method that is very effective for
macrocyclic aromatic amide construction (Scheme 1).
In the case that alkyl groups on the nitrogen atoms
are methyl or ethyl groups, the N-alkylated monomer
was synthesized from commercially available 3-amino-
5-nitrobenzoic acid as a starting material by the usual
protection–deprotection steps including N-alkylation
(see Supplementary data). Contrarily, N-allylated or
N-decylated monomer was simply synthesized by a one-
˚
3.202 A and the horizontal distance between centers of
NO2
NO2
R = CH3 or CH2CH3
R
N
COOCH2CH3
R
H2N
COOH
2
O
CH3
CH3
3a
3b
R =
RX, HMPA
120 ˚C
CH2CH3
CH2CH=CH2
or C10H21
NO2
O
R
N
Ph3PCl2
(2.4 eq)
NO2
R
O
N
R
N
(CHCl2)2
120 ˚C
COOH
O2N
N
R
NO2
H
O
R
4a CH3 (86% y.)a
5a (61% y.)
4b CH2CH3 (73% y.)a
4c CH2CH=CH2 (66% y.)b
4d C10H21 (52% y.)b
5b (62% y.)
5c (65% y.)
5d (70% y.)
Scheme 1. (a) The yield was calculated through the reactions from 2
via 3a or 3b. (b) The yield was calculated for the direct alkylation from
2 based on the halide (RX).
Figure 2. Static potential map9 of compound 5b based on the crystal
structure and the dimeric feature.

F. Imabeppu et al. / Tetrahedron Letters 47 (2006) 413–416
415
B
X
A
X
Figure 3. Schematic representation of relative position of two benzene
rings, where each substituent (–X) is grabbed by a cavity of the other
molecule.
˚
two benzene rings (distance B) is 5.268 A. Compound
5a, which has an N-methyl group instead of the N-ethyl
group of compound 5b, shows intrinsically the same
crystal structure and packing features including the di-
meric assemble (see Supplementary data).
The calix[3]amide 5b was easily converted to the corre-
sponding amine 6 by catalytic reduction under a hydro-
gen atmosphere in a quantitative yield (Scheme 2).
Single X-ray crystallographic analysis was carried out
for the crystals obtained from CH3OH.11 The conformer
of cyclic trimer 6 also formed a dimeric structure con-
structed by enantiomeric conformers (Fig. 4).
Figure 4. Static potential map9 of compound 6 based on the crystal
structure and the dimeric feature.
these compounds cannot be observed in solution under
various conditions (solvent, temperature and concentra-
tion). Therefore, the formation of the dimeric assemble
in the crystals is caused by the crystal packing assisted
by aromatic–aromatic interactions (and hydrogen bon-
dings for 6), and is weakened by the dynamic feature,
the fast equilibrium between syn and anti conformations.
The crystal structure and dimeric feature of compound 6
is shown in Figure 4. Hydrogen atoms of an amino
group, which is grabbed in a cavity is interacted with
two out of three amino groups of the cavity through
hydrogen bondings, where the distances between the
˚
nitrogen atoms are 3.569 and 3.945 A. The distance
In conclusion, substituted cyclic trimers can be easily
synthesized in high yields in just a few steps from a com-
mercially available starting material. These macrocyclic
compounds have a small cavity, which grabs a substitu-
ent of another molecule and results in the dimeric com-
plementary assemble in the crystals. The macrocycle
with amino groups can be converted for various ana-
logues such as amide, urea, and carbamate. We believe
that these macrocyclic skeletons can be used as the scaf-
fold for various host molecules, especially anion recep-
tors because those functional groups will work as
binding sites.12 We are now exploring diversification
and recognition abilities of three-dimensionally triden-
tate anion receptors based on the cyclic triamide
skeletons.
between two aromatic planes (distance A in Fig. 3) is
3.282 A that is longer than that of 5b, and the horizontal
˚
distance between the centers of two benzene rings (dis-
˚
tance B) is 4.843 A, which is shorter than that of 5b,
which might be due to the hydrogen bondings between
the amino groups.
1H NMR measurements of 5a–d and 6 at ambient tem-
perature showed that the equilibrium between the syn
and anti conformations, which includes racemization
process, is fast as that of compound 1 reported before.6
1
Preliminary dynamic H NMR measurement in DMF-
d7 of 5a–d and 6 revealed that the energy barrier between
the syn and anti conformations is not significantly
affected by the substituents at the meta position (data
not shown). The self-complementary dimeric feature of
Supplementary data
NH2
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2005.11.082.
H2, 10% Pd/C
ethanol
1 atm, reflux
1 h
O
N
CH2CH3
O
N
CH3CH2
H2N
5b
quant.
References and notes
N
NH2
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1999, 32, 278–286.
O
CH2CH3
6
Scheme 2.

416
F. Imabeppu et al. / Tetrahedron Letters 47 (2006) 413–416
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structure for each compound was used as a starting point;
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10. Crystal data of 5a: C25H19Cl3N6O9, M = 653.81, triclinic,
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˚
P-1, a = 9.326(2), b = 11.689(3), c = 13.557(3) A, a =
100.258(4), b = 97.600(4), c = 92.500(4)ꢁ, V = 1438.0
(6) A , Z = 2, Dc = 1.510 Mg mÀ3, T = 173 K, crystal size
3
˚
0.50 · 0.30 · 0.10 mm3, R = 0.0510, wR2 = 0.139 [I >2r(I)],
GOF on F2 = 1.047, l = 0.382 mmÀ1
, Tmin = 0.8321,
Tmax = 0.9628. CCDC-280333. Crystal data of 5b: C27-
H24N6O9, M = 576.52, monoclinic, P21/n, a = 9.4900(4),
˚
b = 16.0952(7), c = 17.6257(8) A, a = 98.8950(10)ꢁ, V =
2659.8(2) A , Z = 4, Dc = 1.440 Mg mÀ3, T = 150 K, crys-
3
˚
tal size 0.15 · 0.15 · 0.10 mm3, R = 0.393, wR2 = 0.0544
[I >2r(I)], GOF on F2 = 1.706, l = 0.111 mmÀ1, Tmin
0.9836, Tmax = 0.9890. CCDC-280334.
=
11. Crystal data of 6: C27H30N6O3, M = 486.57, triclinic, P-1,
˚
a = 9.602(4), b = 10.329(2), c = 13.845(4) A, a = 74.489(20),
3
˚
b = 77.38(3), c = 72.99(2)ꢁ, V = 1250.4(7) A , Z = 2,
Dc = 1.292 Mg mÀ3, T = 296 K, crystal size 0.20 · 0.10 ·
0.10 mm3, R = 0.751 [I > 2r(I)], GOF on F2 = 1.000,
l = 0.070 mmÀ1. CCDC-280335.
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position of phenyl groups connected to the amide group.
The designation can be easily understood at a glance;
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named (E)- and (Z)-amide, respectively.
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´
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