One-pot synthesis of cyclic triamides with a triangular cavity from trans-stilbene and diphenylacetylene monomers

Article abstract of DOI:10.1021/ol801083r

(Chemical Equation Presented) Base-promoted self-condensation reactions of trans-stilbene and diphenylacetylene monomers bearing 4-alkylamino and 4′-methoxycarbonyl groups were investigated. Reactions of N-propyl monomers under pseudohigh-dilution conditions (a THF solution of monomer was added dropwise to a THF solution of LiHMDS) afforded the corresponding cyclic triamides in good yields. X-ray crystallographic analysis showed that these cyclic triamides possessed an almost equilateral triangle structure with a cavity surrounded by tilted benzene rings.

Full text of DOI:10.1021/ol801083r

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3207-3210
One-Pot Synthesis of Cyclic Triamides
with a Triangular Cavity from
trans-Stilbene and Diphenylacetylene
Monomers
Akihiro Yokoyama,*,† Takurou Maruyama,† Kei Tagami,† Hyuma Masu,‡
Kosuke Katagiri,‡ Isao Azumaya,*,‡ and Tsutomu Yokozawa*,†
Department of Material and Life Chemistry, Kanagawa UniVersity, 3-27-1
Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan, and Faculty of
Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity, 1314-1
Shido, Sanuki-city, Kagawa 769-2193, Japan
yokozt01@kanagawa-u.ac.jp
Received May 12, 2008
ABSTRACT
Base-promoted self-condensation reactions of trans-stilbene and diphenylacetylene monomers bearing 4-alkylamino and 4′-methoxycarbonyl
groups were investigated. Reactions of N-propyl monomers under pseudohigh-dilution conditions (a THF solution of monomer was added
dropwise to a THF solution of LiHMDS) afforded the corresponding cyclic triamides in good yields. X-ray crystallographic analysis showed
that these cyclic triamides possessed an almost equilateral triangle structure with a cavity surrounded by tilted benzene rings.
Cyclic molecules composed of a rigid backbone and a
noncollapsible nanometer lumen are classified as shape-
persistent macrocycles1 and have attracted increasing atten-
tion due to their potential use as scaffolds and building blocks
of supramolecules. These compounds are frequently con-
structed of arylene units connected by unsaturated linkages,
such as ethynylene. When the arylene units are directed
vertical to the macrocycle plane, the molecule possesses a
belt-shaped structure, with an intriguing cavity surrounded
by the arylene wall.2 Herges and co-workers synthesized such
belt-shaped molecules via metathesis reaction with tetrade-
hydrodianthracene,3 and Kawase, Oda, and co-workers
reported the synthesis and complex formation of [6]- and
[8]paraphenylacetylenes with fullerenes.4
The amide linkage has been often used as a building
block of macrocycles, and its hydrogen-bonding ability
(2) For a review, see: Kawase, T.; Kurata, H. Chem. ReV. 2006, 106,
5250.
† Kanagawa University.
(3) (a) Kammermeier, S.; Jones, P. G.; Herges, R. Angew. Chem., Int.
Ed. Engl. 1996, 356, 2669. (b) Kammermeier, S.; Jones, P. G.; Herges, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2200.
‡ Tokushima Bunri University.
(1) For reviews, see: (a) Moore, J. S. Acc. Chem. Res. 1997, 30, 402.
(b) Bunz, U. H. F.; Rubin, Y.; Tobe, Y. Chem. Soc. ReV. 1999, 28, 107. (c)
Ho¨ger, S. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 2685. (d)
Diederich, F. Chem. Commun. 2001, 219. (e) Grave, C.; Schlu¨ter, A. D.
Eur. J. Org. Chem. 2002, 3075. (f) Zhao, D.; Moore, J. S. Chem. Commun.
2003, 807. (g) Yamaguchi, Y.; Yoshida, Z.-I. Chem.-Eur. J. 2003, 9, 5430.
(h) Höger, S. Chem.-Eur. J. 2004, 10, 1320. (i) Moore, J. S. Angew. Chem.,
Int. Ed. 2006, 45, 4416.
(4) (a) Kawase, T.; Darabi, H. R.; Oda, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2664. (b) Kawase, T.; Ueda, N.; Tanaka, K.; Seirai, Y.; Oda, M.
Tetrahedron Lett. 2001, 41, 5509. (c) Kawase, T.; Seirai, Y.; Darabi, H. R.;
Oda, M.; Sarakai, Y.; Tashiro, K. Angew. Chem., Int. Ed. 2003, 42, 1621.
(d) Kawase, T.; Tanaka, K.; Fujiwara, N.; Darabi, H. R.; Oda, M. Angew.
Chem., Int. Ed. 2003, 42, 1624. (e) Kawase, T.; Tanaka, K.; Shiono, N.;
Seirai, Y.; Oda, M. Angew. Chem., Int. Ed. 2004, 43, 1722.
10.1021/ol801083r CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society

plays a crucial role in the function and structure of the
macrocycles. For instance, organic nanotubes were con-
structed by taking advantage of intermolecular hydrogen
bonding of cyclic oligopeptides,5 and folded conformation
assisted by intramolecular hydrogen bonding led to easy
formation of aromatic oligoamide macrocycles.6,7 On the
other hand, the N-alkylated aromatic amide linkage prefer-
entially takes a cis conformation,8 and its intrinsic curved
structure has been utilized to achieve one-pot synthesis of
aromatic oligoamide macrocycles.9,10 Furthermore, the N-
alkylated cyclic triamides of 4-(alkylamino)benzoic acids
adopt a beltlike triangle structure, because steric repulsions
between the aromatic rings connected with N-alkylated cis-
amide linkages cause the aromatic rings to take conforma-
tions almost vertical to the amide plane.11,12 However, the
cyclic triamides do not have a cavity large enough to
incorporate another molecule. In the course of our study of
controlled synthesis of N-alkylated aromatic polyamides,13
we found that polycondensation of trans-stilbene and diphe-
nylacetylene monomers bearing both 4-alkylamino and 4′-
alkoxycarbonyl groups afforded the corresponding polya-
mides, accompanied with cyclic oligoamides.14 These cyclic
oligoamides are expected to have larger cavities, although
they were byproducts in the polycondensation. Here, we
report a selective and convenient synthesis of cyclic triamides
containing trans-stilbene or diphenylacetylene units by base-
promoted condensation reaction of the corresponding ami-
noester monomers. X-ray analysis of the crystal structures
of the obtained macrocycles revealed that the macrocycles
possess a beltlike triangular structure with a larger cavity
than that of the cyclic trimer of 4-(alkylamino)benzoic acid.
We first examined the oligomerization of the N-methyl
trans-stilbene monomer 1a (Scheme 1), expecting that the
reaction conditions for the polymerization of a trans-
stilbene monomer with other N-alkyl groups,14 lithium
1,1,1,3,3,3-hexamethyldisilazide (LiHMDS) was used as
a base to deprotonate the monomer amino group. As in
the case of cyclic trimerization of 4-(alkylamino)benzoic
acid dimer esters,10 the reaction was carried out under
pseudohigh-dilution conditions; i.e., a solution of the
monomer 1a was added dropwise to a THF solution of
LiHMDS (5 equiv to the monomer) over 4 h. Because of
the low solubility of 1a, we used a mixture of THF and
HMPA as a solvent for the monomer. When the oligo-
merization was carried out at -30 °C, the monomer 1a
was not fully consumed even after 65 h. On the other hand,
dropwise addition of the monomer at -30 °C, followed
by stirring at -10 °C for 60 h, resulted in higher
conversion of 1a. The elution curve obtained by size
exclusion chromatography (SEC) analysis of the crude
product showed a sharp peak in the oligomeric-molecular-
weight region and a broad peak in the higher-molecular-
weight region (Figure 1a). MALDI-TOF mass spectra of
Figure 1. SEC profiles of the crude product obtained by the
oligomerization of (a) 1a at -10 °C for 60 h, (b) 1b at rt for 1 h,
and (c) 1c at rt for 45 min.
Scheme 1. Condensation of trans-Stilbene Monomer 1
the product obtained after precipitation in diethyl ether
showed the formation of 2a accompanied by the cyclic
tetramer and hexamer.15 However, the products showed
poor solubility, and it was difficult to separate them.
(7) Yuan, L.; Feng, W.; Yamamoto, K.; Sanford, A.; Xu, D.; Guo, H.;
Gong, B. J. Am. Chem. Soc. 2004, 126, 11120.
(8) (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177. (b) Azumaya, I.; Kagechika,
H.; Yamaguchi, K.; Shudo, K. Tetrahedron 1995, 51, 5277.
(9) (a) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
Tetrahedron 2003, 59, 2325. (b) Azumaya, I.; Okamoto, T.; Imabeppu, F.;
Takayanagi, H. Heterocycles 2003, 60, 1419.
cyclic triamide 2a would show high crystallinity to afford
a single crystal suitable for X-ray analysis. Following the
(10) Yokoyama, A.; Shimizu, Y.; Yokozawa, T. Chem. Lett. 2005, 34,
1128.
(5) For a review, see: (a) Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri,
M. R. Angew. Chem., Int. Ed. 2001, 40, 988. (b) Ghadiri, M. R.; Granja,
J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N. Nature 1993, 366,
324. (c) Ghadiri, M. R.; Granja, J. R.; Buehler, L. K. Nature 1994, 369,
301. (d) Fernandez-Lopez, S.; Kim, H.-S.; Choi, E. C.; Delgado, M.; Granja,
J. R.; Khasanov, A.; Kraehenbuehl, K.; Long, G.; Weinberger, D. A.;
Wilcoxen, K. M.; Ghadiri, M. R. Nature 2001, 412, 452.
(11) Azumaya, I.; Okamoto, T.; Takayanagi, H. Anal. Sci. 2001, 17,
1363.
(12) Campbell, F.; Plante, J.; Carruthers, C.; Hardie, M. J.; Prior, T. J.;
Wilson, A. J. Chem. Commun. 2007, 2240.
(13) For a review, see: Yokoyama, A.; Yokozawa, T. Macromolecules
2007, 40, 4093.
(14) Yokoyama, A.; Shimizu, Y.; Saito, J.; Yokozawa, T. Chem. Lett.
2008, 37, 8.
(6) Jiang, H.; Le´ger, J.-M.; Guionneau, P.; Huc, I. Org. Lett. 2004, 6,
2985
.
(15) See Supporting Information for details.
3208
Org. Lett., Vol. 10, No. 15, 2008

To increase the solubility of the reaction product, the
N-alkyl group of the monomer was replaced with an ethyl
group. Oligomerization of the N-ethyl monomer 1b was
carried out at -30 °C under the same conditions, and the
SEC profile suggested that the conversion of 1b was lower
than that of 1a. We thought that the nucleophilicity of
the deprotonated 1b might have been lowered due to the
introduction of the bulkier N-ethyl group, and therefore
the oligomerization of 1b was examined at higher tem-
perature than that of 1a. Reaction of 1b at room temper-
ature proceeded smoothly, and the SEC profile of the
product obtained after 1 h showed a sharp peak, like that
in the case of the reaction of 1a at -10 °C (Figure 1b).
The crude product exhibited good solubility in common
organic solvent, and the product corresponding to the sharp
peak in the SEC elution curve was isolated by silica gel
Figure 2. Two independent molecules in an asymmetric unit of
1
column chromatography. The H NMR spectrum showed
the crystal structure of 2c shown in a space-filling representation.
Hydrogen atoms are omitted for clarity, and the carbon atoms of
each molecule are represented in different colors so that the
molecules can be easily distinguished.
only one series of signals assignable to a repeating unit,
without any signals assignable to the terminal units of
linear oligomers, and the lower field shift of the N-CH2
signal to 3.99 ppm suggested amide bond formation.
These results indicated that the isolated product was the
cyclic amide (41% yield). However, MALDI-TOF MS
analysis of the product showed a signal corresponding to
the cyclic triamide 2b as a major peak, accompanied by
signals of the cyclic tetramer and hexamer as minor
peaks.15
2, are directed toward the cavity of neighboring molecules.
The N-propyl groups of the other independent macrocycle
shown in light gray in Figure 2 fill the space between the
molecules.
When oligomerization of the N-propyl monomer 1c at
room temperature was conducted using a mixture of THF
and HMPA, the SEC analysis of the crude product showed
an elution profile similar to that of the N-ethyl monomer
1b, and separation with silica gel column chromatography
gave a mixture of cyclic tri- and tetraamides. In contrast to
the N-methyl and N-ethyl monomers, the N-propyl monomer
1c showed higher solubility in THF, and homogeneous
reaction could be carried out in the absence of HMPA.
Oligomerization of 1c in THF at room temperature resulted
in complete consumption of the monomer, and the SEC
elution curve showed only a sharp signal in the oligomer-
molecular-weight region, indicating selective cyclic oligoa-
mide formation (Figure 1c). The crude product was separated
by means of preparative HPLC, and MALDI-TOF MS
analysis revealed the product to be the pure cyclic triamide
2c (61% yield).
Scheme 2. Condensation of Diphenylacetylene Monomer 3
We next carried out the oligomerization of N-propyl
diphenylacetylene monomer 3 (Scheme 2). On the basis
A single crystal of 2c was obtained by recrystallization
from CH3CN-CH2Cl2 and analyzed by X-ray crystal-
lography (Figure 2). The asymmetric unit contained two
independent molecules, both of which showed an almost
equilateral triangle structure with a cavity. The aromatic
rings were inclined from the perpendicular plane to the
triangle but acted as walls of the cavity, as expected. The
side length of the triangles is approximately 13 Å,
indicating that the cavity would be able to accommodate
a sphere with a diameter of 7.5 Å. This estimation is
consistent with the fact that the distances between the
carbon atoms of the neighboring vinylene units are 7-8
Å. In the crystal, N-alkyl amide moieties of one indepen-
dent molecule, whose carbon atoms are dark gray in Figure
Figure 3
. Space-filling representation of 4 with the solvent molecule
(toluene). Hydrogen atoms are omitted for clarity.
Org. Lett., Vol. 10, No. 15, 2008
3209

of the optimized conditions for the oligomerization of 1c,
a THF solution of 3 was added dropwise over 4 h to a
THF solution of 5 equiv of LiHMDS at room temperature,
and the mixture was stirred at that temperature. The
monomer was consumed completely 0.5 h after the
addition, and separation with silica gel column chroma-
tography afforded the cyclic triamide 4 in 62% yield.
Reaction at 0 °C also proceeded smoothly, but the yield
of 4 was reduced to 32% due to increased formation of
higher-molecular-weight products, as judged from the SEC
profile of the crude product.
Recrystallization of 4 from toluene gave a single crystal,
which was analyzed by X-ray crystallography (Figure 3).
The crystal structure of 4 was similar to that of 2c: the
shape was an equilateral triangle whose side length was
approximately 13 Å, and the benzene rings were tilted.
However, unlike 2c, the crystal contained four molecules
of the recrystallization solvent, toluene, in an asymmetric
unit, and the cavity of 4 was filled with a toluene molecule
(Figure 3). Furthermore, the packing of 4 occurred in
layers along the a and c axes of the unit cell (Figure 4a).
The toluene molecules filled the space between the
molecules of 4. The layers stacked along the b axis and
formed channels filled with solvent molecules (Figure 4b
and 4c).
In conclusion, we have demonstrated that cyclic tria-
mides can be obtained from the N-propyl trans-stilbene
and diphenylacetylene monomers 1c and 3, respectively,
in good yield by one-pot condensation reaction. X-ray
crystallographic analysis revealed that the cycles 2c and
4 possess triangular cavities surrounded by tilted benzene
rings. This one-pot trimeric cyclization approach has
potential for the synthesis of macrocycles possessing larger
cavities and functional units in the backbone and side
chain. Studies along this line are in progress.
Supporting Information Available: Synthesis and con-
densation reaction of the monomers 1a-c and 3, MALDI-
TOF mass spectra of the products obtained by the reaction
of 1a and 1b, NMR spectra and X-ray crystallographic
data for 2c and 4, and CIFs. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 4. Packing structure of 4. (a) Layer form of 4 and toluene
molecules. The magenta-colored line is the layer above. (b) Channel
structure of 4. Toluene molecules are omitted for clarity. (c) Side
view of the channel structure. Toluene molecules are cyan-colored.
OL801083R
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Org. Lett., Vol. 10, No. 15, 2008