Hydrogen-bonding-induced planar, rigid, and zigzag oligoanthranilamides. Synthesis, characterization, and self-assembly of a metallocyclophane

Article abstract of DOI:10.1021/jo0490705

Four oligoanthranilamides 1-4, which are incorporated with three, five, seven, or nine benzene units, respectively, have been synthesized and characterized. X-ray analysis, 1D and 2D ¹H NMR, and IR experiments reveal that all the new oligoamide

Full text of DOI:10.1021/jo0490705

Hyd r ogen -Bon d in g-In d u ced P la n a r , Rigid , a n d Zigza g
Oligoa n th r a n ila m id es. Syn th esis, Ch a r a cter iza tion , a n d
Self-Assem bly of a Meta llocyclop h a n e
J iang Zhu,† Xiao-Zhong Wang,‡ Ying-Qi Chen,‡ Xi-Kui J iang,† Xin-Zhi Chen,‡ and
Zhan-Ting Li*,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China, and Department of Chemical Engineering, Zhejiang University,
Yuquan Campus, Hangzhou, Zhejiang 310027, China
ztli@mail.sioc.ac.cn
Received J une 3, 2004
Four oligoanthranilamides 1-4, which are incorporated with three, five, seven, or nine benzene
1
units, respectively, have been synthesized and characterized. X-ray analysis, 1D and 2D H NMR,
and IR experiments reveal that all the new oligoamides adopt rigid, planar and zigzagged
conformations in both solution and solid state, which are stabilized by intramolecular three-center
hydrogen bonding. A 5-mer oligomer 22, which is incorporated with two acetylene groups at the
ends, has also been synthesized and utilized for the self-assembly of a rigid hydrogen-bonded
metallocyclophane. The new rigid oligoanthranilamides represent useful building blocks for the
construction of supramolecular architectures.
In tr od u ction
be useful for the formation of other kinds of unfolding
conformations. Nevertheless, examples of such kinds of
controllable artificial secondary structures are very
limited.7-9
We recently initiated a project to develop simple
components that could be connected iteratively to produce
stable unfolding secondary structures. The long-term goal
of the work is to create a new generation of functionalized
Development of efficient methods to control the con-
formation or shape of complicated organic molecules is
of importance both theoretically and for practical pur-
pose. In particular, foldamers, the synthetic oligomers
that are induced by noncovalent forces to fold into well-
defined secondary structures, have received considerable
interest in the past decade.1 Among other noncovalent
interactions such as metal-ligand coordination,2 donor-
acceptor interaction,3 and solvophobic interaction,4 hy-
drogen bonding has proven itself to be highly efficient
for the formation of folding architectures. For example,
Hamilton and Gong have utilized the three-center hy-
drogen-bonding motif to construct a number of structur-
ally elegant aromatic oligoamide foldamers.5,6 In prin-
ciple, such efficient noncovalent approaches should also
(5) (a) Hamuro, Y.; Geib, S. J .; Hamilton, A. D. J . Am. Chem. Soc.
1997, 119, 10587. (b) Ernst, J . T.; Becerril, J .; Park, H. S.; Yin, H.;
Hamilton, A. D. Angew. Chem., Int. Ed. 2003, 42, 535. (c) Gong, B.
Chem.sEur. J . 2001, 7, 4337. (d) Parra, R. D.; Zeng, H.; Zhu, J .; Zheng,
C.; Zeng, X. C.; Gong, B. Chem.sEur. J . 2001, 7, 4352. (e) Gong, B.;
Zeng, H.; Zhu, J .; Yuan, L.; Han, Y.; Cheng, S.; Furukawa, M.; Parra,
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Acad. Sci. U.S.A. 2002, 99, 11583.
(6) For recent examples of other intramolecular H-bond-stabilized
oligoamide strands, see: (a) Armand, P.; Kirshenbaum, K.; Goldsmith,
R. A.; Farr-J ones, S.; Barron, A. E.; Truong, K. T.; Dill, K. A.; Mierke,
D. F.; Cohen, F. E.; Zuckermann, R. N.; Bradley, E. K. Proc. Natl. Acad.
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J . S.; Lee, H. S.; Lai, J . R.; Kim, B. M.; Gellman, S. H. J . Am. Chem.
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Li, W.; Qu, J .; Luo, S.-W.; Wu, Y.-D. J . Am. Chem. Soc. 2003, 125,
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J . Am. Chem. Soc. 2003, 125, 14518. (j) van Gorp, J . J .; Vekemans, J .
A. J . M.; Meijer, E. W. Chem. Commun. 2004, 60.
† Chinese Academy of Sciences.
‡ Zhejiang University.
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10.1021/jo0490705 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004
J . Org. Chem. 2004, 69, 6221-6227
6221

Zhu et al.
CHART 1
SCHEME 1
molecular and supramolecular scaffolds with new recog-
nition or assembling properties. Previously, we have
shown that readily available anthranilamide derivatives
can be combined to form oligomers with linear, rigid, and
planar secondary structures, which are stabilized by
repeated three-center hydrogen bonding.9,10 In this paper,
we describe (1) a further development of this hydrogen-
bonding approach for the formation of a new series of
zigzagged oligoanthranilamide secondary structures and
(2) the application of a rigid zigzagged anthranilamide
diacetylene for the self-assembly of a new hydrogen-
bonded metallocyclophane.11,12
Resu lts a n d Discu ssion
Compounds 1-4, which possess three, five, seven, or
nine aromatic units, respectively, have been designed and
synthesized (Chart 1). A previous study by Gong et al.
had revealed that 2-methoxy-N-(2-methoxyphenyl)ben-
zamide, the subunit for the present oligomers, takes up
a rigid and planar structure due to the presence of two
intramolecular hydrogen bonds.5d It was envisioned that
the longer oligomers 1-4 should also adopt similar
conformations with repeated zigzagged secondary struc-
tures.
The synthetic routes for 3-mer 1 and 5-mer 2 are
presented in Scheme 1. Treatment of 1 equiv of diamine
5 with 2 equiv of acyl chloride 6 in dichloromethane with
triethylamine as base afforded 1 in 85% yield. For the
(10) For three-center hydrogen bonding in folding oligoamides, see:
(a) Dolain, C.; Maurizot, V.; Huc, I. Angew. Chem., Int. Ed. 2003, 42,
2738. (b) Kolomiets, E.; Berl, V.; Odriozola, I.; Stadler, A.-M.; Kyrit-
sakas, N.; Lehn, J .-M. Chem. Commun. 2003, 2868. (c) Maurizot, V.;
Linti, G.; Huc, I. Chem. Commun. 2004, 924. (d) Recker, J .; Tomcik,
D.; Parquette, J . R. J . Am. Chem. Soc. 2000, 122, 10298. (e) Huang,
B.; Parquette, J . R. J . Am. Chem. Soc. 2001, 123, 2689. (f) Huang, B.;
Prantil, M. A.; Gustafson, T. L.; Parquette, J . R. J . Am. Chem. Soc.
2003, 125, 14518.
(11) Zigzagged o-phenylene ethynylene oligomers have been de-
scribed; see: (a) J ones, T. V.; Blatchly, R. A.; Tew, G. N. Org. Lett.
2003, 5, 3297.
(12) For examples of duality between linear and folding tapes and
rosettes, see: (a) Odriozola, I.; Kyritsakas, N.; Lehn, J .-M. Chem.
Commun. 2004, 62. (b) Zerkowski, J . A.; Whitesides, G. M. J . Am.
Chem. Soc. 1994, 116, 4298.
synthesis of 2, compound 7 was first oxidized to diacid 8
with potassium permanganate in hot potassium hydrox-
ide solution. The latter was then converted into 9 by
dimethylation, followed by a monohydrolysis reaction.
Compound 5 was then coupled with 2 equiv of 8 in
dichloromethane in the presence of DCC to produce
trimer 10 in 70% yield. The reaction of diamine 10 with
1 equiv of 6 in dichloromethane and triethylamine
afforded pentamer 2 and 11 in 40% and 20% yields,
6222 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of a Metallocyclophane
SCHEME 2
F IGURE 1. Crystal structures of 3-mer 1 (a) and 5-mer 2 (b).
Both molecules adopt preorganized conformations due to the
strong three-center hydrogen bonding.
respectively. Under similar conditions, treatment of 10
with 2.2 equiv of 6 produced 2 in 85% yield.
For the synthesis of 7-mer 3, compound 12 was first
produced in 70% yield from the reaction of 5 and 6 in
dichloromethane (Scheme 2). Under similar conditions,
compound 12 reacted with 13 to afford 14 in 75% yield.
The latter was then hydrolyzed with lithium hydroxide
in hot THF and methanol to afford acid 15 quantitatively.
Compound 15 was coupled with 11 in dichloromethane
in the presence of DCC to produce 7-mer 3 in 30% yield.
Under similar reaction conditions, 9-mer 4 was produced
in 40% yield from the reaction of 9 and 11. Similarly,
treatment of diamine 5 with 2.2 equiv of 15 afforded 3
in 16% yield.
Single crystals of 3-mer 1 were grown by slow evapora-
tion of the ethyl acetate solution at room temperature.
Figure 1a shows the crystal structure of 1. As expected,
the NH bonds are involved in both five-membered (N-
H‚‚‚O distance ) 2.23 Å) and six-membered (N-H‚‚‚O
distance ) 1.83 Å) ring hydrogen bond, leading to a
planar conformation. Evidence for the planar and zig-
zagged conformation of the oligoamides is provided by
the X-ray structure of 5-mer 2. The crystals of 2 were
grown by slow evaporation of the chloroform solution at
room temperature. As shown in Figure 1b, compound 2
possesses three sets of three-center hydrogen bonds. The
N-H‚‚‚O distances of the peripheral and central six-
membered ring hydrogen bonds are 1.82 and 1.83 Å,
respectively, while the N-H‚‚‚O distances of the corre-
sponding two five-membered ring hydrogen bonds are
2.22 and 2.24 Å, respectively. These values are very close
to that revealed in the solid state of 1, suggesting a
similarity in the backbone of the compounds. In addition,
all five benzene units and the amide groups in compound
2 also share one plane due to the presence of the strong
intramolecular three-center hydrogen bonds. The back-
F IGURE 2. CPK model of 9-mer 4, produced with AccuModel
2.1.
bone formed by the five benzene units also clearly
displays a rigid zigzagged secondary structure. Since the
longer 7-mer 3 and 9-mer 4 possess the identical struc-
tural subunit, it is reasonable to consider that these
oligomers or even longer polymers of the same skeleton
should also adopt similar planar and zigzagged confor-
mations. A space filling model of planar 9-mer 4, with a
length of 4.60 nm, is shown in Figure 2, which reveals
that the long oligomer takes up a slightly curved confor-
mation due to the presence of the intramolecular hydro-
gen bonding. This result is consistent with the solid-state
structure of 5-mer 2, as shown in Figure 1b.
The solution conformations of the oligoamides were
1
investigated by H NMR in chloroform-d. The selected
chemical shifts of oligomers 1-4 and intermediates 10
and 14 are collected in Table 1. The signals have been
assigned based on the NOESY experiments. The 1H NMR
results show several features to support the rigid planar
structures. In particular, large downfield shifts (∆δ 2.03-
2.66 ppm) of the NH resonances were displayed for all
the compounds, compared to that of 4-methoxy-N-(4-
methoxyphenyl)benzamide (7.64 ppm).5d The H-2 reso-
nances (PhHa and PhHc in Table 1) of the isophthalamide
units of all the oligomers were also greatly downfield
shifted due to the strong shielding effect of the two
adjacent carbonyl groups, which are well consistent with
the rigid planar conformation.5e,6b Adding 20% DMSO-
d6 to the solution of 1 in chloroform-d caused only a
J . Org. Chem, Vol. 69, No. 19, 2004 6223

Zhu et al.
TABLE 1. Selected 1H NMR Reson a n ces of
The successful construction of the new class of rigid
zigzagged secondary structures from readily available
anthranilamide derivatives boded well for the develop-
ment of new generation of rigid building blocks for
supramolecular assemblies or recognition. To explore this
possibility, compound 22 was prepared as the precursor
for the preparation of a new rigid metallocyclophane.15
The two acetylene groups in 22 were expected to be
orientated on one side of the rigid backbone due to the
presence of the intramolecular hydrogen bonding as
established for 5-mer 2, which would greatly facilitate
the formation of the corresponding metallocyclophane.
The syntheses of diacetylene 22 and metallocyclophane
23 are shown in Scheme 3. In brief, compound 16 was
first reacted with iodine in methanol in the presence of
silver sulfate to afford iodide 17 in 96% yield. The latter
was then coupled with compound 18 in hot pyrrolidine
with Pd(0) as catalyst to give compound 19 in 72% yield.
Treatment of 19 with potassium hydroxide in hot metha-
nol and then in hot benzene produced 21, which was then
coupled with diamine 10 in dichloromethane in the
presence of DCC to afford 22 in 63% yield. Finally, 22
reacted with trans-Pt(PEt3)2Cl2 in the presence of cupric
chloride in dichloromethane to afford 23 in 18% yield.16
Both 22 and 23 are soluble in common organic solvents
such as chloroform and dichloromethane.
Oligoa n th r a n ila m id es (5.0 m M) in CDCl3 a t 25 °C
compda NHa
NHb NHc NHd PhH PhHb PhHc PhHd
1
10.23
10.26
10.30
10.31
10.30
9.91
9.59 6.53
9.57 6.56
9.56 6.54
9.52 6.58
1b
2
9.74
9.81 9.67
3
4
10
14
9.54
9.55
6.58
6.53
9.78 9.74 9.67 9.52 6.56
8.04 6.54
10.29 10.11
9.58 6.58
a
b
The numbering is provided in the text. In CDCl3 with 20%
of DMSO-d6 (v/v).
relatively small chemical shift of the NH signal (<0.12
ppm), also indicating that the NH proton was involved
in stable intramolecular hydrogen bonding.5e,9 Further
evidence for the role of the intramolecular hydrogen
bonding in stabilizing the rigid zigzagged conformation
of the oligomers comes from the temperature dependence
of the NH resonance of 1 in chloroform-d, which reveals
a small variation with temperature (1.8 × 10-3 ppm/K-1
from 0 to 55 °C), which is expected for intramolecularly
hydrogen-bonded amide NH.13 1H NMR NOESY experi-
ments in chloroform-d revealed NOE connections be-
tween the NH protons and the neighboring methyl
protons for all the oligomers investigated, which are also
consistent with the proposed rigid conformation. 1H NMR
dilution experiments in chloroform-d revealed very small
concentration dependence (<0.01 ppm in the range of
20-0.3 mM) for the NH and aromatic proton signals of
1 and 2, showing that these rigid planar oligoamides have
small aggregating tendency in chloroform. However, the
existence of the three-centered hydrogen bonding in the
molecules does not mean that the population of the
hydrogen-bonded conformers is as high as 100% in the
solution.
1H NMR in chloroform-d revealed typical hydrogen-
bonded NH resonances (22: 10.02 and 9.71 ppm; 23: 9.99
and 9.72 ppm, respectively). Their NH and aromatic
proton signals displayed very small concentration de-
pendence (<0.01 ppm from 20 mM to 0.5 mM) and
temperature dependence (2.5 × 10-3 and 2.6 × 10-3
1
ppm/K within the region of 0-55 °C). 2D-NOESY H
NMR studies revealed moderate strength of NOE con-
nections between the NH and the neighboring OCH3 and
OCH2 signals. All of these observations show that both
the precursor and the metallocyclophane takes up a rigid
and planar conformation as established for oligomers 1-4
as a result of the stable intramolecular hydrogen bonding.
Compared to the signal of the periphery NH protons,
the signals of the central NH protons of oligomers 2-4
move upfield significantly (∆δmax ) -0.64 ppm for 3). The
result indicates that two NH units sharing the hydrogen
bond donor (OMe) at the central area notably reduces
the strength of the corresponding hydrogen bonding.
Con clu sion
In summary, we have reported a general efficient
approach to constructing highly stable rigid, planar, and
zigzagged secondary structures from anthranilamide
derivatives by making use of intramolecular three-center
hydrogen bonding. The work, to some extent, represents
a conceptual derivation or extension from the very active
foldamer chemistry to control the well-defined secondary
structures of large synthetic molecules. Successful self-
assembly of metallocyclophane 23 from rigid anthranil-
amide precursor 22 demonstrates the potential of the new
rigid hydrogen bonded oligomers as building blocks for
supramolecular self-assembly. Further work will focus
on the modification of the skeleton to introduce additional
Infrared spectroscopy also supports the formation of
intramolecular hydrogen bonding in stabilizing the rigid
zigzagged conformation of the oligomers. The IR spec-
trum of 1-4 in chloroform displays N-H stretch peak
at 3324, 3335, 3340, and 3336 cm-1, respectively. Com-
pound 14 shows two N-H stretching peaks at 3328 and
3298 cm-1, respectively. All the stretching frequencies
are those of typical hydrogen bonded N-H groups.14 No
peaks were displayed in the free N-H stretching region
(3400-3500 cm-1).14 The NH stretching frequencies
obtained in chloroform were also independent of the
concentration changes within the concentration range of
25-2.0 mM, further indicating that these compounds
adopt intramolecularly hydrogen-bonded rigid conforma-
tions.
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6224 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of a Metallocyclophane
SCHEME 3
of the solvent under reduced pressure, the resulting residue
was recrystallized from dichloromethane/petroleum ether (1:
2) to afford compound 1 as colorless needles (0.38 g, 85%).
functional groups for assembling new giant supramo-
lecular architectures, which will be reported in due
course.
1
Mp: 206-208 °C. H NMR (CDCl3): δ 3.94 (s, 6 H), 4.05 (s, 6
H), 6.57 (s, 1 H), 7.01 (d, J ) 7.8 Hz, 2 H), 7.12 (t, J ) 7.8 Hz,
2 H), 7.40 (m, 2 H), 8.36 (m, 2 H), 9.58 (s, 1 H), 10.25 (s, 2 H).
13C NMR (CDCl3): δ 56.0, 56.5, 95.6, 111.3, 115.1, 121.4, 121.5,
122.4, 132.6, 132.7, 145.6, 157.3, 162.4. IR (CHCl3): ν 3324,
1653, 1618, 1600, 1553, 1535, 1484, 1467, 1430, 1342, 1295,
1234, 1201, 1097, 1037, 921, 748 cm-1. MS (EI): m/z 436 [M]+.
Anal. Calcd for C24H24N2O6: C, 66.04; H, 5.54; N, 6.42.
Found: C, 66.19; H, 5.57; N, 6.43.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Melting points are uncorrected.
All reactions were performed under an atmosphere of dry
nitrogen. The 1H NMR spectra were recorded on a 400 MHz
spectrometer, and chemical shifts are expressed in parts per
million relative to the residual solvent protons as internal
standards in an indicated solvent. Chloroform (δ ) 7.26 ppm)
or TMS (δ ) 0 ppm) is used as an internal standard,
respectively. Elemental analysis was carried out at the SIOC
analytic center. Unless otherwise indicated, all starting ma-
terials were obtained from commercial suppliers and were used
without further purifications. Solvents were purified according
to standard procedures before use. Silica gel (10-40 µm) was
used for all column chromatography.
N,N′-m -(4,6-Dim eth oxy)p h en ylen ebis(2-m eth oxy)ben -
za m id e (1). To a stirred solution of compound 517 (0.17 g, 1.00
mmol) and triethylamine (0.5 mL) in dichloromethane (20 mL)
was added a solution of 618 (0.30 g, 2.00 mmol) in dichlo-
romethane (10 mL) dropwise in 0.5 h at room temperature.
The mixture was stirred for 10 h at room temperature, washed
with hydrochloric acid (1 N, 2 × 20 mL), water (20 mL), and
brine (20 mL), and dried over sodium sulfate. After evaporation
2-Meth oxyisop h th a lic Acid (8). A suspension of com-
pound 7 (7.00 g, 50.0 mmol), potassium permanganate (52.0
g, 0.33 mol), and potassium hydroxide (9.00 g, 0.16 mol) in
water (250 mL) was stirred at 80 °C for 3 h and then cooled to
room temperature. The solid was filtered off, and the filtrate
was acidified with concentrated hydrochloric acid to pH ) 7.
The resulting precipitate was filtered, washed with water, and
dried in vacuo. After recrystallization from ethanol, the desired
product was obtained as a white solid (7.30 g, 75%). M.p. 220-
1
221 °C (219-221 °C19). H NMR (DMSO-d6): δ 3.80 (s, 3 H),
7.26 (t, J ) 7.5 Hz, 1 H), 7.80 (d, J ) 7.5 Hz, 2 H), 13.12 (s, 2
H). 13C NMR (CDCl3): δ 52.7, 64.5, 123.5, 124.7, 125.0, 137.0,
137.1, 159.4, 165.2, 165.6. MS (EI): m/z 197 [M + H]+.
2-Meth oxyisop h th a lic Acid Mon om eth yl Ester (9). To
a stirred suspension of compound 8 (2.00 g, 10.0 mmol) and
potassium carbonate (4.10 g, 30.0 mmol) in DMF (50 mL) was
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J . Org. Chem, Vol. 69, No. 19, 2004 6225

Zhu et al.
added methyl iodide (2.00 mL, 30.0 mmol) at room tempera-
ture. The mixture was stirred at 80 °C overnight and then
concentrated in vacuo. The resulting residue was triturated
with dichloromethane (150 mL), and the organic phase was
washed with water (50 mL) and brine (50 mL) and dried over
sodium sulfate. After removal of the solvent, a yellow oily
residue was obtained (2.24 g) that was dissolved in methanol
(30 mL). To the solution was added potassium hydroxide (0.56
g, 10.0 mmol), and the mixture was heated under reflux for
3.5 h and then concentrated under reduced pressure. The
resulting oily residue was dissolved in water (40 mL) and then
acidified with concentrated hydrochloric acid to pH ) ca. 3.
The solution was then extracted with dichloromethane (3 ×
50 mL). The combined organic phase was washed with water
and brine and dried over sodium sulfate. After the solvent was
removed under reduced pressure, the crude product was
recrystallized from ethyl acetate to give 9 as a white solid (1.64
romethane was stirred at 0 °C for 3 h. After workup, the crude
product was purified by column chromatography (dichlo-
romethane) to give 12 as a white solid (0.21 g, 70%). H NMR
1
(CDCl3): δ 3.61 (s, 2 H), 3.85 (s, 3 H), 3.90 (s, 3 H), 4.06 (s, 3
H), 6.53 (s, 1 H), 7.01 (d, d, J 1 ) 0.9 Hz, J 2 ) 8.1 Hz, 1 H),
7.12 (d, t, J 1 ) 0.9 Hz, J 2 ) 8.1 Hz, 1 H), 7.45-7.51 (m, 1 H),
8.16 (s, 1 H), 8.29 (d, d, J 1 ) 2.1 Hz, J 2 ) 8.1 Hz, 1 H), 10.43
(s, 1 H). MS (ESI): m/z 303 [M + H]+. 13C NMR (CDCl3): δ
56.0, 56.1, 57.3, 97.4, 108.6, 111.4, 121.4, 122.3, 122.4, 130.0,
132.3, 132.8, 141.6, 143.1, 157.3, 162.5. IR (CHCl3): ν 3443,
3319, 1643, 1551 cm-1. Anal. Calcd for C16H18N2O4 : C, 63.56;
H, 6.00; N, 9.27. Found: C, 63.56; H, 6.02; N, 9.19.
N-[2,4-Dim eth oxy-5-(2-m eth oxyben zoyla m in o)p h en yl]-
2-m eth oxyisop h th a la m ic Acid Meth yl Ester (14). This
compound was prepared from 12 (0.91 g, 3.00 mmol) and 1320
(0.68 g, 3.00 mol) on the basis of the method described above
for 1. After workup, the crude product was purified by column
chromatography (EtOAc/CH2Cl2 1:1) to afford 14 (1.11 g) in
1
g, 78%). Mp: 154-156 °C. H NMR (CDCl3): δ 3.98 (s, 3 H),
1
4.06 (s, 3 H), 7.34 (m, 1 H), 8.10 (m, 1 H), 8.34 (m, 1 H). MS
75% yield as a pale yellow solid. H NMR (CDCl3): δ 3.94 (s,
(EI): m/z 210 [M]+.
3 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 4.01 (s, 3 H), 4.06 (s, 3 H),
6.58 (s, 1 H), 7.02 (d, J ) 8.4 Hz, 1 H), 7.12 (t, J ) 7.8 Hz, 1
H), 7.32 (t, J ) 7.8 Hz, 1 H), 7.44-7.47 (m, 1 H), 7.94-7.97
(m, 1 H), 8.35-8.38 (m, 1 H), 8.43-8.46 (m, 1 H), 9.58 (s, 1
H), 10.11 (s, 1 H), 10.30 (s, 1 H). 13C NMR (CDCl3): δ 52.4,
56.0, 56.2, 56.5, 63.8, 95.4, 111.4, 115.2, 120.7, 121.5, 122.3,
124.5, 125.1, 128.6, 132.7, 134.6, 136.5, 145.8, 145.9, 157.3,
159.0, 161.7, 162.5, 166.0. IR (CHCl3): ν 3328, 3298, 1722,
1673, 1659, 1551 cm-1. MS (ESI): m/z 495 [M + H]+. Anal.
Calcd for C26H126N2O8: C, 63.15; H, 5.30; N, 5.67. Found: C,
62.77; H, 5.31; N, 5.56.
N,N′-Bis(5-a m in o-2,4-d im et h oxyp h en yl)-2-m et h oxy-
isop h th a la m id e (10). To a stirred solution of compounds 5
(0.70 g, 4.20 mmol) and 8 (0.41 g, 2.10 mmol) in tetrahydro-
furan (100 mL) were added DCC (0.95 g, 4.60 mmol) and HOBt
(0.62 g, 4.60 mmol) at room temperature. The solution was
stirred for 12 h, and then the solid was filtered off. After
workup, the crude product was purified by column chroma-
tography (CH2Cl2/MeOH 100:1) to afford compound 10 as a
1
yellow solid (0.73 g, 70%). H NMR (CDCl3): δ 3.65 (s, 4 H),
3.88 (s, 6 H), 3.92 (s, 6 H), 4.00 (s, 3 H), 6.55 (s, 2 H), 7.41 (t,
J ) 7.5 Hz, 1 H), 8.09 (s, 2 H), 8.25 (d, J ) 7.5 Hz, 2 H), 9.92
(s, 2 H). 13C NMR (CDCl3): δ 56.1, 56.9, 64.0, 97.1, 108.6, 121.5,
125.4, 128.2, 129.9, 134.9, 141.7, 143.6, 155.8, 162.1. MS
(ESI): m/z 497 [M + H]+. Anal. Calcd for C25H28N4O7: C, 60.48;
H, 5.68; N, 11.28. Found: C, 60.47; H, 5.77; N, 11.09.
N-[2,4-Dim eth oxy-5-(2-m eth oxyben zoyla m in o)p h en yl]-
2-m eth oxyisop h th a la m ic Acid (15). A suspension of 14
(0.20 g, 0.40 mmol) and lithium hydroxide hydrate (82 mg,
2.00 mmol) in a mixture of tetrahydrofuran (10 mL) and
methanol (10 mL) was stirred at 50 °C for 3 h and then cooled
to room temperature. Water (60 mL) and hydrochloric acid
(10%) were added to pH ) 6. The resulting precipitate was
filtered, washed thoroughly with water, and dried to give 15
N,N′-Bis[2,4-d im et h oxy-5-(2-m et h oxyb en zoyla m in o)-
p h en yl]-2-m eth oxyisop h th a la m id e (2) a n d N-(5-Am in o-
2,4-d im et h oxyp h en yl)-N′-[2,4-d im et h oxy-5-(2-m et h oxy-
ben zoyla m in o)p h en yl]-2-m eth oxyisop h th a la m id e (11). A
solution of 6 (0.24 g, 1.40 mmol) in dichloromethane (20 mL)
was added to a solution of 10 (0.70 g, 1.40 mmol) and
triethylamine (1 mL) in dichloromethane (20 mL) at 0 °C. The
mixture was stirred at room temperature overnight and then
concentrated in vacuo. After workup, the crude product was
purified by column chromatography (EtOAc/CH2Cl2 1:1) to
afford compounds 2 as a pale yellow solid (0.43 g, 40%) and
compound 11 as a pale yellow solid (0.18 g, 20%). Compound
1
as a pale yellow solid (0.19 g, 98%). H NMR (CDCl3): δ 3.95
(s, 3 H), 3.97 (s, 3 H), 4.07 (s, 3 H), 4.09 (s, 3 H), 6.60 (s, 1 H),
7.03 (d, J ) 8.4 Hz, 1 H), 7.13 (t, J ) 7.5 Hz, 1 H), 7.41 (t, J
) 8.1 Hz, 1 H), 7.43-7.51 (m, 1 H), 8.21-8.24 (m, 1 H), 8.35-
8.39 (m, 2 H), 9.47 (s, 1 H), 9.56 (s, 1 H), 10.34 (s, 1 H). 13C
NMR (DMSO-d6): δ 56.4, 56.5, 56.7, 63.3, 96.8, 112.6, 114.8,
119.3, 120.5, 121.2, 121.3, 124.4, 128.7, 131.2, 133.1, 133.4,
145.9, 146.8, 155.3, 157.1, 161.6, 162.6. IR (CHCl3): ν 3310,
1714, 1663, 1553 cm-1. MS (ESI): m/z 481 [M + H]+.
1
N,N′-(4,6-Dim eth oxy-m-ph en ylen e)bis[2-m eth oxy-3-[2,4-
d im e t h o x y -5-(2-m e t h o x y b e n zo y la m in o )p h e n y l]a m i-
n oca r b on yl]b en za m id e (3). A solution of compounds 15
(0.13 g, 0.28 mmol), 11 (0.18 g, 0.28 mmol), DCC (70 mg, 0.34
mmol), and HOBt (46 mg, 0.34 mmol) in dichloromethane (40
mL) was stirred at room temperature for 12 h. The solid was
filtered off, and the filtrate was concentrated under reduce
pressure. The resulting residue was subjected to column
chromatography (CH2Cl2/MeOH 1:100-1:20) to afford the
desired product as a white solid (90 mg, 30%). Mp: >250 °C.
1H NMR (CDCl3): δ 3.95 (s, 6 H), 3.97 (s, 6 H), 3.98 (s, 6 H),
4.05 (s, 6 H), 4.07 (s, 6 H), 6.57 (s, 1 H), 6.58 (s, 2 H), 7.02 (d,
J ) 7.8 Hz, 2 H), 7.13 (t, J ) 7.8 Hz, 2 H), 7.40-7.48 (m, 4 H),
8.31-8.38 (m, 6 H), 9.53 (s, 1 H), 9.55 (s, 2 H), 9.67 (s, 2 H),
9.81 (s, 2 H), 10.32 (s, 2 H). IR (CHCl3): ν 3340, 1673, 1542,
1338, 1236, 1198, 1028, 753 cm-1. HRMS (MALDI-tof): m/z
1093 [M + H]+. HRMS (MALDI-tof): calcd for C58H57N6O16
1093.3825 [M + H]+, found 1093.3837.
2. Mp: >250 °C. H NMR (CDCl3): δ 3.90 (s, 6 H), 3.95 (s, 6
H), 4.00 (s, 3 H), 4.04 (s, 6 H), 6.49 (s, 2 H), 6.99 (d, J ) 8.2
Hz, 2 H), 7.12 (t, J ) 7.3 Hz, 2 H), 7.40-7.49 (m, 3 H), 8.33-
8.38 (m, 4 H), 9.59 (s, 2 H), 9.75 (s, 2 H), 10.33 (s, 2 H). 13C
NMR (CDCl3): δ 56.1, 56.3, 56.5, 64.2, 95.5, 111.4, 115.4, 120.6,
121.5, 121.6, 122.2, 125.4, 128.2, 132.7, 132.8, 135.3, 146.0,
146.1, 155.9, 157.3, 162.2, 162.6. IR (CHCl3): ν 3335, 1615,
1599, 1542, 1459, 1233, 1199, 909, 753 cm-1. MS (ESI): m/z
765 [M + H]+. Anal. Calcd for C41H40N4O11‚H2O: C, 62.94; H,
5.42; N, 7.16. Found: C, 62.78; H, 4.93; N, 6.91. Compound
11: 1H NMR (CDCl3): δ 3.65 (s, 2 H), 3.88 (s, 3 H), 3.93 (s, 3
H), 3.96 (s, 3 H), 3.97 (s, 3 H), 4.03 (s, 3 H), 4.07 (s, 3 H), 6.55
(s, 1 H), 6.61 (s, 1 H), 7.03 (d, J ) 7.8 Hz, 2 H), 7.10 (t, J ) 7.8
Hz, 2 H), 7.41-7.51 (m, 2 H), 8.10 (s, 1 H), 8.25-8.39 (m, 3
H), 9.55 (s, 1 H), 9.68 (s, 1 H), 9.96 (s, 1 H), 10.32 (s, 1 H). 13C
NMR (CDCl3): δ 56.0, 56.1, 56.2, 56.5, 56.9, 64.1, 95.5, 97.1,
108.7, 111.4, 115.4, 120.5, 121.4, 121.5, 121.7, 122.3, 125.4,
128.0, 128.4,129.8, 132.6, 132.8, 134.8, 135.3, 141.8, 143.6,
145.9, 146.1, 155.8,157.3, 162.0, 162.1, 162.6. IR (CHCl3): ν
3321, 1734, 1669, 1553 cm-1. MS (ESI): m/z 630 [M + H]+.
Anal. Calcd for C33H34N4O9: C, 62.85; H, 5.43; N, 8.88.
Found: C, 62.16; H, 5.74; N, 8.15.
N,N′-Bis[2,4-dim eth oxy-5-[2-m eth oxy-3-[2,4-dim eth oxy-
5-(2-m et h oxyb en zoyla m in o)b en zoyla m in o]]p h en yl]-2-
m eth oxyisop h th a la m id e (4). This compound was prepared
from 9 (50 mg, 0.25 mmol) and 11 (0.32 g, 0.5 mmol) on the
N-(5-Am in o-2,4-d im et h oxyp h en yl)-2-m et h oxyb en za -
m id e (12). A solution of compounds 5 (1.68 g, 10.0 mmol), 6
(1.70 g, 10.0 mmol), and triethylamine (2 mL) in dichlo-
(20) Naito, T.; Kuroda, E.; Miyata, O.; Ninomiya, I. Chem. Pharm.
Bull. 1991, 39, 2216.
6226 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of a Metallocyclophane
basis of the method described for 3. After workup, the crude
product was purified by column chromatography (CHCl3/
MeOH 1:35) to afford 4 as a white solid (142 mg, 40%). Mp:
5-Eth yn yl-2-(n -octyloxy)ben zoic Acid (21). To a solution
of compound 20 in benzene (80 mL) was added potassium
hydroxide (0.56 g, 10.0 mmol). The mixture was refluxed for 3
h. After workup, the crude product was subjected to column
chromatography (CH2Cl2) to afford compound 21 as a pale
1
>250 °C. H NMR (CDCl3): δ 3.94 (s, 6 H), 3.97 (s, 6 H), 3.98
(s, 12 H), 4.05 (s, 9 H), 4.08 (s, 6 H), 6.54 (s, 2 H), 6.56 (s, 2 H),
7.01 (d, J ) 8.4 Hz, 2 H), 7.12 (t, J ) 7.8 Hz, 2 H), 7.39-7.47
(m, 5 H), 8.30-8.37 (m, 8 H), 9.52 (s, 2 H), 9.55 (s, 2 H), 9.67
(s, 2 H), 9.75 (s, 2 H), 9.81 (s, 2 H), 10.32 (s, 2 H). MS (MALDI-
tof): m/z 1443 [M + Na]+. IR (CHCl3): ν 3336, 1672, 1617,
1543, 1467, 1342, 1239, 1201, 1110, 1034 cm-1. Anal. Calcd
for C75H72N8O21: C, 63.37; H, 5.11; N, 7.88. Found: C, 63.28;
H, 5.56; N, 7.38.
1
yellow solid (1.50 g, 78%). Mp: 63-64 °C. H NMR (CDCl3):
δ 0.86-0.90 (m, 3 H), 1.25-1.48 (m, 10 H), 1.89-1.94 (m, 2
H), 3.06 (s, 1H), 4.26 (t, J ) 6.5 Hz, 2 H), 6.99 (d, J ) 6.6 Hz,
1 H), 7.64 (d, d, J 1 ) 6.5 Hz, J 2 ) 2.2 Hz, 1 H), 8.32 (d, J ) 2.2
Hz, 1 H), 10.84 (br, 1 H). 13C NMR (CDCl3): δ 14.2, 22.7, 26.5,
29.7, 29.9, 32.0, 68.4, 79.7, 82.1, 113.4, 113.6, 114.1, 129.8,
158.0, 169.4. MS (EI): m/z 274 [M]+. Anal. Calcd for
C
17H22O3: C, 74.42; H, 8.08. Found: C, 72.30; H, 8.17.
Meth yl 5-Iod o-2-(n -octyloxy)ben zoa te (17). A mixture
of compound 1621 (14.0 g, 53.0 mmol), iodine (14.0 g, 55.0
mmol), and silver sulfate (17.0 g, 55.0 mmol) in methanol (200
mL) was stirred at room temperature for 0.5 h and then
concentrated in vacuo. The resulting residue was triturated
with ethyl acetate (300 mL). The organic phase was washed
with water (80 mL × 2) and brine (80 mL) and dried over
sodium sulfate. After the solvent was distilled under reduced
pressure, the resulting residue was subjected to flash chro-
matography (dichloromethane/petroleum ether 10:1) to give
compound 17 as a pale yellow oil (19.9 g, 96%). 1H NMR
(CDCl3): δ 0.85-0.90 (m, 3 H), 1.25-1.48 (m, 10 H), 1.76-
1.83 (m, 2 H), 3.87 (s, 3 H), 3.98 (t, J ) 6.4 Hz, 2 H), 6.72 (d,
J ) 6.6 Hz, 1 H), 7.68 (d, d, J 1 ) 6.6 Hz, J 2 ) 2.2 Hz, 1 H),
8.04 (d, J ) 2.2 Hz, 1 H). 13C NMR (CDCl3): δ 14.2, 22.5, 26.0,
29.5, 29.6, 31.8, 51.8, 69.4, 85.8, 115.4, 115.6, 137.9, 141.6,
N 1,N 3-Bis(5-(5-e t h yn yl-2-(oct yloxy)b e n za m id o)-2,4-
d im eth oxyp h en yl)-2-m eth oxyisop h th a la m id e (22). To a
stirred solution of compound 21 (0.20 g, 0.40 mmol), DCC (0.21
g, 1.00 mmol), and HOBt (0.16 g, 1.00 mmol) in dichlo-
romethane (20 mL) was added a solution of compound 10 (0.25
g, 0.90 mmol) in dichloromethane (5 mL) at room temperature.
Stirring was continued for 12 h at room temperature, and the
insoluble materials were filtered off. The filtrate was concen-
trated under reduced pressure, and the resulting residue was
subjected to column chromatography (CH2Cl2/MeOH 20:1) to
afford the desired product as a pale yellow solid (0.29 g, 73%).
Mp: 176-178 °C. 1H NMR (CDCl3): δ 0.84-0.88 (m, 6 H),
1.22-1.49 (m, 20 H), 1.92-2.01 (m, 4 H), 3.03 (s, 2 H), 3.88 (s,
6 H), 3.96 (s, 6 H), 4.00 (s, 3 H), 4.18 (t, J ) 7.2 Hz, 4 H), 6.49
(s, 2 H), 6.92 (d, J ) 7.4 Hz, 2 H), 7.40 (t, J ) 7.5 Hz, 1 H),
7.53 (d, d, J 1 ) 6.6 Hz, J 2 ) 2.1 Hz, 2 H), 8.32 (d, J ) 7.8 Hz,
2 H), 8.51 (d, J ) 2.1 Hz, 2 H), 9.54 (s, 2 H), 9.71 (s, 2 H),
10.02 (s, 2 H). 13C NMR (CDCl3): δ 14.2, 22.7, 32.0, 29.2, 29.5,
25.9, 29.6, 68.2, 114.2, 155.2, 118.2, 135.9, 114.5, 132.5, 164.7,
82.2, 79.4, 55.8, 55.9, 100.9, 149.8, 149.9, 116.8, 116.9, 115.8,
164.7, 118.4, 158.4, 131.6, 122.0, 56.2. IR (CHCl3): ν 3328,
1670, 1547 cm-1. MS (MALDI-tof): m/z 1009 [M + H]+, 1031
[M + Na]+, 1047 [M + K]+. Anal. Calcd for C59H68N4O11: C,
70.22; H, 6.79; N, 5.55. Found: C, 70.07; H, 6.98; N, 5.34.
156.7, 167.0. MS (EI): m/z 390 [M]+. Anal. Calcd for C16H23
-
IO3: C, 49.24; H, 5.94. Found: C, 49.11; H, 6.21.
Meth yl 5-(3-Hyd r oxy-3-m eth ylbu t-1-yn yl)-2-(octyloxy)-
ben zoa te (19). A suspension of compounds 17 (4.00 g, 10.3
mmol), 18 (1.30 g, 15.0 mmol), Pd(PPh3)4 (0.38 g, 0.50 mmol,
5%), and cupric iodide (0.10 g, 0.50 mmol) in pyrrolidine (30
mL) was stirred at 60 °C for 2 h and then concentrated under
reduced pressure. The resulting residue was triturated with
ethyl acetate (150 mL), and the organic phase was washed with
dilute hydrochloric acid (0.5 N, 50 mL), water (50 mL × 2),
and brine (50 mL) and dried over sodium sulfate. After the
solvent was distilled under reduced pressure, the crude product
was subjected to flash chromatography (dichloromethane) to
give compound 19 (2.58 g, 72%) as a yellow oil. 1H NMR
(CDCl3): δ 0.86-0.90 (m, 3 H), 1.28-1.50 (m, 10 H), 1.60 (s,
6 H), 1.77-1.84 (m, 2 H), 3.87 (s, 3 H), 4.02 (t, J ) 6.6 Hz, 2
H), 6.88 (d, J ) 6.5 Hz, 1 H), 7.47 (d, d, J 1 ) 6.5 Hz, J 2 ) 2.2
Hz, 1 H), 7.85 (d, J ) 2.2 Hz, 1 H). 13C NMR (CDCl3): δ 14.1,
22.9, 26.0, 29.1, 29.3, 29.8, 32.0, 32.3, 51.9, 65.2, 69.0, 80.6,
92.9, 113.6, 113.7, 114.1, 133.8, 137.6, 157.4, 166.2. MS (EI):
m/z 346 [M]+. Anal. Calcd for C21H30O4: C, 72.80; H, 8.73.
Found: C, 72.67; H, 8.88.
5-(3-Hyd r oxy-3-m et h ylbu t -1-yn yl)-2-(oct yloxy)b en zo-
ic Acid (20). Compound 19 (2.00 g, 5.80 mmol) and potassium
hydroxide (0.56 g, 10.0 mmol) were added to a mixture of
methanol (50 mL) and water (20 mL). The mixture was stirred
under reflux for 2 h and concentrated to about 20 mL. The
solution was neutralized with dilute hydrochloric acid to pH
) 6 and then extracted with dichloromethane (80 mL × 2).
The combined organic phase was washed with water and brine
and dried over sodium sulfate. Upon removal of the solvent
under reduced pressure, the resulting brown residue was
subjected to flash chromatography (CH2Cl2/EtOAc 10:1) to give
the desired acid as a yellow oil (1.75 g, 91%). 1H NMR
(CDCl3): δ 0.85-0.90 (m, 3 H), 1.25-1.49 (m, 10 H), 1.60 (s,
6 H), 1.88-1.93 (m, 2 H), 4.22-4.26 (t, J ) 6.6 Hz, 2 H), 6.96
(d, J ) 6.4 Hz, 1 H), 7.56 (d, d, J 1 ) 6.4 Hz, J 2 ) 2.3 Hz, 1H),
8.22 (d, J ) 2.3 Hz, 1 H). 13C NMR (CDCl3): δ 14.2, 22.9, 26.2,
29.2, 29.7, 31.6, 32.0, 65.1, 67.3, 80.2, 93.6, 113.7, 114.0, 114.2,
134.1, 138.4, 158.0, 169.2. MS (EI): m/z 332 [M]+. Anal. Calcd
for C20H28O4: C, 72.26; H, 8.49. Found: C, 72.27; H, 8.64.
Meta llocyclop h a n e 23. A suspension of compound 22 (0.20
g, 0.20 mmol), trans-PtCl2(PEt3)2 (0.10 g, 0.20 mmol), cupric
acid (10 mg), and diethylamine (1.0 mL) in dichloromethane
(200 mL) was stirred at room temperature for 12 h. The
insoluble materials were filtered off, and the solution was
washed with water (50 mL × 2) and brine (50 mL) and dried
over sodium sulfate. After removal of solvent in vacuo, the
crude product was purified with column chromatography (CH2-
Cl2/MeOH 40:1) to afford compound 23 as a light yellow solid
(52 mg, 18%). Mp: >250 °C. 1HNMR (CDCl3): δ 0.85-0.88 (m,
12 H), 1.19-1.47 (m, 80 H), 1.91-1.96 (m, 8 H), 2.20-2.26
(m, 24 H), 3.90 (s, 12 H), 3.96 (s, 12 H), 4.04 (s, 6 H), 4.14 (t,
J ) 7.2 Hz, 8 H), 6.56 (s, 4 H), 6.85 (d, J ) 7.8 Hz, 4 H), 7.35
(d, J ) 7.4 Hz, 4 H), 7.41 (t, J ) 6.6 Hz, 2 H), 8.27 (s, 4 H),
8.34 (d, J ) 7.5 Hz, 4 H); 9.60 (s, 4 H), 9.78 (s, 4 H), 10.14 (s,
4 H). 13C NMR (CDCl3): δ 9.6, 15.2, 17.8, 17.9, 18.2, 24.0, 27.6,
30.1, 30.6, 30.9, 33.2, 55.1, 55.8, 56.5, 70.3, 96.2, 101.9, 113.7,
116.8, 118.2, 121.0, 122.9, 123.5, 131.7, 135.4, 137.9, 146.0,
149.7, 155.9, 158.2, 163.8, 164.3. MS (MALDI-tof): m/z 2877
[M + H]+. Anal. Calcd for C142H192N8O22P4Pt2: C, 59.28; H,
6.73; N, 3.89. Found: C, 58.78; H, 6.41; N, 3.48.
Ack n ow led gm en t. We are grateful to the Ministry
of Science and Technology (G2000078101), the National
Natural Science Foundation (20321202, 20332040,
20372080), the State Laboratory of Bioorganic and
Natural Products Chemistry of China, and the Chinese
Academy of Sciences for financial support.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for compounds 1 and 2 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Zeng, H.; Miller, R. S.; Flowers, R. A.; Gong, B. J . Am. Chem.
Soc. 2000, 122, 2635.
J O0490705
J . Org. Chem, Vol. 69, No. 19, 2004 6227