'Two-point'-bound supramolecular complexes from semi-rigidified dipyridine receptors and zinc porphyrins

Article abstract of DOI:10.1016/j.tet.2006.04.082

Two linear compounds 1 and 2 have been designed and synthesized as new receptors for zinc porphyrins. Both compounds consist of two folded aromatic amide moieties, which are connected with an acetylene linker in 1 or directly in 2. The rigid conformations

Full text of DOI:10.1016/j.tet.2006.04.082

Tetrahedron 62 (2006) 6973–6980
‘Two-point’-bound supramolecular complexes from
semi-rigidified dipyridine receptors and zinc porphyrins
Chang-Zhi Li,a Jiang Zhu,b Zong-Quan Wu,b Jun-Li Hou,b Chuang Li,b Xue-Bin Shao,b
a
a,
Xi-Kui Jiang,b Zhan-Ting Li,b, Xiang Gao and Quan-Rui Wang
*
*
aDepartment of Chemistry, Fudan University, Shanghai 200433, China
bState Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 20 March 2006; revised 20 April 2006; accepted 21 April 2006
Available online 19 May 2006
Abstract—Two linear compounds 1 and 2 have been designed and synthesized as new receptors for zinc porphyrins. Both compounds consist
of two folded aromatic amide moieties, which are connected with an acetylene linker in 1 or directly in 2. The rigid conformations of their
folded moieties are stabilized by intramolecular tri-centered hydrogen bonding, while the whole molecule adopts a ‘S’- or ‘C’-styled
conformation depending on the relative orientation of the two rigid moieties. Two pyridine units are introduced at the ends of 1 and 2 for
the complexation of zinc porphyrin guests. Although the 1H NMR investigation indicated that both compounds can bind two zinc porphyrin
guests at high concentrations (ꢀ5 mM) in chloroform, the UV–vis studies revealed that, at low concentration of 1 and 2 (4 mM), both
compounds complex one zinc porphyrin guest to form structurally unique ‘two-point’-bound 1:1 complexes. The association constants of
the 1:1 complexes have been determined with the UV–vis titration experiments.
Ó 2006 Elsevier Ltd. All rights reserved.
Me
O
Me
O
1. Introduction
2H
H1
The coordination between zinc porphyrin–nitrogen ligand is
one of the most used recognition motifs for supramolecular
self-assembly.1,2 Since metal-free and zinc porphyrins have
strong absorption bands in the visible light region, their
remarkable photoelectronic properties have been utilized
to build various supramolecular molecular devices. The co-
ordination bond between zinc porphyrin and nitrogen ligand
exchanges rapidly and most supramolecular complexes as-
sembled based on this coordination motif are also dynamic.
It is well known that porphyrin zinc is pentacoordinated and
therefore can bind only one nitrogen ligand.3 Theoretically,
for a symmetric zinc porphyrin, a nitrogen ligand can
equally approach it from both sides of its skeleton macro-
cycle. However, the feature of pentacoordination implies
that the central metal cannot simultaneously bind with two
ligands. As a result, there always exists a dynamic equilib-
rium between the two processes.
N
N
O(CH2CH2O)2Me
Me(OCH2CH2)2O
6
4
O
O
O
5
3
N
N
O
Me(OCH2CH2)2O
Me(OCH2CH2)2O
N
O
N
O
O(CH2CH2OH)2Me
H
H
H
1
Me
Me
Me
Me
O
O
H
N
N
O(CH2CH2O)2Me
O
O
O
N
N
Considering the great usefulness of the zinc porphyrin–
nitrogen ligand binding motif in molecular recognition and
O
Me2(OCH2CH2)2O
N
O
N
O
O(CH2CH2O)2Me
H
H
2
Me
Me
Keywords: Porphyrin;Coordination; Hydrogenbonding; ‘Two-point’binding;
Molecular recognition.
* Corresponding authors. Tel.: +86 21 5492 5122; fax: +86 21 6416 6128;
e-mail addresses: ztli@mail.sioc.ac.cn; qrwang@fudan.edu.cn
supramolecular self-assembly, it would be of importance
to develop suitable models to investigate this equilibrium.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.082

6974
C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
Me
Me
NO2
We recently reported the self-assembly of a new series of
foldamers,4 the folded or helical artificial secondary structures
by making use of intramolecular hydrogen bonding as driving
force.5 The shape-persistent folded structures have been used
as new generation of scaffolds for the construction of nonring
synthetic receptors, which can efficiently recognize saccha-
rides,6 aliphatic ammonium,7 and fullerenes.8 In order to fur-
ther explore the application of folded structures in molecular
recognition, we had designed two hydrogen bonded semi-
rigidified receptors 1 and 2. In this paper, we report their syn-
thesis and enhanced complexing properties to zinc porphyrins
through an unique dynamic ‘two-point’ binding motif.
Me
HNO3-H2SO4
aq. H2O2 (30%)
N
N
100 °C, 2 h
AcOH, r.t., 24 h
90%
O
N
O
50%
3
4
5
Cl
Cl
Me
CO2H
HCl (g), PCl3
KMnO4
CHCl3, r.t.
0.5 h, 96%
H2O, 80-90 °C
8 h, 36%
N
6
N
7
O(CH2CH2O)2Me
HO2C
Na, HO(CH2CH2O)2Me
90 °C, 3 h, 61%
8
N
MeO
OMe
MeO
H2N
OMe
2. Results and discussion
H2N
NH2
9
NH O(CH2CH2O)2Me
Thesyntheticrouteofcompound1is shown in Scheme1.Thus,
compound 7 was first prepared according to reported methods
and then converted into 8 in 61% yield. The latter was coupled
with 9 in dichloromethane in the presence of benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP) to give 10 in 83% yield. Then, compound 12 was pre-
pared byalkylation of11 andfollowed by treatment with iodine
in methanol to afford 13 in 89% yield. The Pd-catalyzed cou-
pling reaction of 13 with acetylene in hot piperidine produced
14 in 83% yield. This diester was hydrolyzed to 15 and then
coupled with 10 to give compound 1 in 88% yield.
BOP, NEt3, CH2Cl2
r.t., 8 h, 83%
O
10
N
O(CH2CH2O)2Me
CO2Me
CO2Me
OH
I2, Ag2SO4
Ts(OCH2CH2)2OMe
K2CO3, CH3CN
reflux, 7 h, 79%
MeOH, r.t.
0.5 h, 89%
12
11
O(CH2CH2O)2Me
MeO2C
O(CH2CH2O)2Me
CO2Me
C2H2 (gas), Pd(PPh3)4
For the synthesis of compound 2 (Scheme 2), compound 16
was first obtained in 71% yield from the Ullman’s coupling
reaction of 13 and then hydrolyzed with sodium hydroxide
to afford diacid 17 in 98% yield. The latter was coupled
with 10 in chloroform in the presence of BOP to produce 2
in 85% yield.
CuI, piperidine, 80 °C
20 min, 83%
13
I
14
MeO2C
O(CH2CH2O)2Me
O(CH2CH2O)2Me
HO2C
The three-centered intramolecular hydrogen bonding motif in
compounds 1 and 2 has been established by the X-ray analysis
and the H NMR and IR spectroscopy.5b,8a,9 The H NMR
spectrum of 1 in chloroform-d is shown in Figure 1a. The aro-
matic signals of 1 have been assigned with the 2D NOESYand
COSY techniques. Itcan befoundthatthe two NH protons dis-
play two singlets (9.95 and 9.64 ppm, Fig. 1a) in the downfield
area. The NH protons of 2 also appear in the downfield area
(10.13 and 9.71 ppm, Fig. 1g). These results support that intra-
molecular hydrogen bonds are also present in both com-
pounds. Due to the rotation of the acetylene unit in 1 and the
biphenyl C–C bond in 2, both compounds can in principle
adopt a S- and C-styled conformations in solution. The fact
that only one set of signals is observed in the 1H NMR spectra
suggests that the two conformations are in rapid exchange.
1
1
10, BOP, NEt3
CHCl3, r.t., 8 h
NaOH, MeOH, H2O
reflux, 3 h, 96%
1
88%
15
HO2C
O(CH2CH2O)2Me
O(CH2CH2O)2Me
Scheme 1.
MeO2C
MeO2C
copper (act.)
NaOH, MeOH, H2O
reflux, 3 h, 98%
13
210 °C, 4.5 h
71%
16
R
R
O(CH2CH2O)2Me
O(CH2CH2O)2Me
HO2C
R
R
R
R
N
N
N
N
10, BOP, NEt3
Zn
2
CHCl3, r.t., 8 h
85%
17
HO2C
O(CH2CH2O)2Me
18: R = t-Bu
19: R = H
R
R
Scheme 2.

C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
6975
NH-2
H-3 H-6 H-5
NH-1
H-4
(a)
(b)
2.0
2.0
1.6
1.2
0.8
0.4
1.6
1.2
0.8
0.4
0
500
1000
1500
6
2000
2500
(c)
(d)
(e)
[1] (M, x 10 )
0.0
400
450
500
Wavelength
550
600
Figure 2. The change of the absorption spectra of 18 (4.0ꢃ10ꢁ6 M) with the
addition of 1 (0–600 equiv) in chloroform at 25 ꢄC (inset: plot of the absorp-
tion of 18 at 422 [-] and 431 [C] nm vs [1]).
(f)
2.5
2.4
2.0
(g)
(h)
2.0
1.6
1.2
1.5
0.8
0.4
1.0
0
100 200 300 400 500 600
6
[1] (M, x 10 )
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5 PPM
0.5
1
Figure 1. Partial H NMR spectrum (400 MHz, 5 mM) of (a) 1, (b) 1+18
(0.1 equiv), (c) 1+18 (1 equiv), (d) 1+18 (2 equiv), (e) 1+18 (4 equiv), (f)
18, (g) 2, and (h) 21 in chloroform-d at 25 ꢄC.
0.0
400
450
500
Wavelength (nM)
550
600
Adding zinc porphyrin 18 to the solution of 1 in chloroform-
d caused remarkable upfield shifting of the signals of several
aromatic protons of 1 (Fig. 1b–e). For example, upon addi-
tion of 1 equiv of 18, the NH-1 signal moved from 9.64 to
9.27 ppm, and the H-4 signal shifted from 6.93 to
6.28 ppm. In addition, obviously due to the complexation-
induced shielding effect of 18, the signals of H-3 and H-5
of 1 disappeared in the presence of 18 (Fig. 1c–e).
Pronounced upfield shifting was also displayed for the pyr-
role protons (ꢁ0.12 ppm) of 18 as a result of complexation
with 1 (Fig. 1c,f). With the addition of more amount of 18,
the above signals of 1 further shifted upfield (Fig. 1d,e).
This result may reflect continual approach to complexation
saturation or the possibility that both pyridine units of 1
were bound to 18 to form a 1:2 complex. Similar results
were also observed for the system of 2 and 18 in chloro-
form-d.
Figure 3. The change of the absorption spectra of 19 (4.0ꢃ10ꢁ6 M) with the
addition of 1 (0–520 equiv) in chloroform at 25 ꢄC (inset: plot of the absorp-
tion of 19 at 422 [-] and 431 [C] nm vs [1]).
based on the UV–vis experiments as shown in Figure 4
with the 1:18 system as an example, revealed maximum
change in absorbance at [1]/([1]+[18])z0.5, supporting
a 1:1 stoichiometry.10 In addition, all the UV–vis titration
spectra display a clear isobestic point for the Soret band
and the Q-band, also suggesting a 1:1 binding mode.3a It is
obviously unreasonable to assume that only one pyridine
unit of 1 or 2 was coordinated with the zinc porphyrin.
Therefore, a ‘two-point’ binding motif should be formed
for the complexes of such kind of shape-persistent two-
pyridine derivatives with zinc porphyrin receptors. Figure 5
shows such kind of binding mode, with 1 as example of the
two-pyridine molecules.
The complexation behavior of 1 and 2 with zinc porphyrin
18 and 19 in chloroform was then investigated by the UV–
vis spectroscopy. As examples, the plots of the change of
the UV–vis absorbance of 18 and 19 with the incremental
addition of 1 are provided in Figures 2 and 3. Remarkable
bathochromic effect was exhibited by both porphyrins, indi-
cating strong intermolecular coordination. The Job’s plot,
The association constant (Ka) of complexes 1$18, 1$19,
2$18, and 2$19 was then evaluated by fitting their UV–vis
titration data, obtained in chloroform, to a 1:1 binding
mode,8,11 which gave a value of 9.8 (ꢂ0.4)ꢃ102, 5.3
(ꢂ0.2)ꢃ103, 3.5 (ꢂ0.2)ꢃ102, and 2.8 (ꢂ0.1)ꢃ103 Mꢁ1, re-
spectively. Although in principle the coordinating ability of

6976
C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
0.020
0.016
0.012
0.008
0.004
0.000
O(CH2CH2O)2Me
MeO2C
KOH, MeOH, H2O
14
reflux, 5 h, 52%
20
HO2C
O(CH2CH2O)2Me
Me
O
Me
O
H
N
H
Me(OCH2CH2)2O
N
O(CH2CH2O)2Me
O
O
0.0
0.2
0.4
0.6
0.8
1.0
N
[1]/([1]+[18])
10, BOP, NEt3
Figure 4. Job’s plot of 1 versus 18, revealing a maximum change of absor-
bance at 418 nm at 1:18¼0.5 ([1]+[18]¼5ꢃ10ꢁ6 M in chloroform at 25 ꢄC).
CHCl3, r.t., 8 h
85%
21
MeO
O
O(H2CH2CO)2Me
Me
O
Me
O
Scheme 3.
H
H
RO
N
N
OR
N
Because the UV–vis experiments were performed at very
low concentration of porphyrin receptors, the 1:1 binding
mode revealed by the UV–vis investigations is not in conflict
with the above 1H NMR observation that both pyridine units
of 1 and 2 may bind a zinc porphyrin to form a 1:2 complex.
The concentration of the samples for the 1H NMR ex-
periments is obviously higher than that necessary for the
UV–vis experiments. Therefore, a three-component com-
plex maybe produced. At enough lowered concentration,
the percentage of such three-component complexes maybe
reduced to be ignorable and, as a result, only the formation
of 1:1 complexes can be detected.
O
O
Ar
Ar
N
N
N
Zn
N
Ar
Ar
N
O
O
RO
N
O
N
O
OR
H
H
Me
Me
Figure 5. Proposed ‘two-point’ binding mode for the complex of 1 with
a zinc porphyrin receptor.
Because zinc porphyrin is of pentacoordination, the two-
pyridine nitrogen atoms of 1 and 2 cannot bind with the
porphyrin moiety simultaneously. Therefore, a dynamic
equilibrium should exist for the ‘two-point’-bonded 1:1
complexes as shown in Figure 6. Reducing the temperature
of the 1:1 solution of 1 or 2 with 18 or 19 in chloroform-d
to 0 ꢄC caused important shifting of several aromatic signals
of both components, but no splitting of the signals was
observed. This result indicates that, within the studied tem-
perature range, the exchange process shown in Figure 6 is
octa-tert-butylated zinc porphyrin 18 is greater than 19 due
to the electron-donating ability of the alkyl groups, the Ka of
the complexes of 18 is pronouncedly smaller than the corre-
sponding complexes of 19. This result maybe rationalized by
considering the increased steric hindrance of 18 relative to
19, which reduces its binding affinity.
1
quick on the H NMR time scale. Further experiments at
In order to detect whether this ‘two-point’ binding mode in-
creases the stability of the corresponding complexes, com-
pound 21 also was prepared (Scheme 3). Thus, compound
14 was first hydrolyzed with potassium hydroxide to give
20 in 52% yield. The acid was then reacted with 10 in chlo-
roform with BOP as a coupling reagent to afford 21 in 85%
lowered temperature could not be performed due to the
reduced solubility of 1 and 2, therefore at the present stage
we cannot determine the activation energy for this dynamic
process.
1
yield. As expected, the H NMR spectrum in chloroform-d
showed two peaks for the NH protons in the downfield
area (Fig. 1h), supporting the existence of intramolecular
hydrogen bonding in 21. On the basis of the UV–vis titration
experiments, the Ka of complexes 18$21 and 19$21 in
chloroform was determined to be 4.6 (ꢂ0.1)ꢃ102 and 1.2
(ꢂ0.1)ꢃ103 Mꢁ1. These values are pronouncedly smaller
than those of the corresponding complexes 1$18 and 1$19.
These results indicate that the existence of the second pyri-
dine unit in 1 promotes the stability of the complexes.
N
N
N
Zn
N
N
N
Zn
N
N
N
N
Figure 6. Dynamic process for the proposed ‘two-point’ binding mode for
the complexes of 1 and 2 with zinc porphyrin guest.

C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
6977
3. Conclusion
was washed with 10% aqueous Na2CO3 (30 mLꢃ2), water
(30 mL), brine (30 mL), and dried over sodium sulfate.
Upon removal of the solvent in vacuo, the crude product
was purified by column chromatography (CH2Cl2/MeOH
50:1) to afford compound 10 as a black powder (0.80 g,
In summary, we have reported the synthesis of a new series
of semi-rigidified bipyridine receptors and their binding
behavior toward zinc porphyrins. At high concentration,
the new receptors can complex with two zinc porphyrin
molecules to form 1:2 complexes, while at sufficiently
lowered concentration, only 1:1 complexes are formed.
Quantitative UV–vis experiments reveal that, for the 1:1
complexes, the existence of the second pyridine increases
the stability of the complexes, which leads to the formation
of an unique ‘two-point’ binding mode. Further work will
focus on the design of more rigidified bipyridine receptors
to quantitatively investigate the dynamic binding process
of the ‘two-point’-bound complexes.
1
83%). H NMR (CDCl3): 3.31 (s, 3H), 3.46–3.49 (m, 2H),
3.66–3.69 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.02
(t, J¼4.5 Hz, 2H), 4.48 (t, J¼4.5 Hz, 2H), 6.51 (s, 1H),
7.01 (d, J¼6.0 Hz, 1H), 8.04 (s, 1H), 8.59 (d, J¼6.0 Hz,
1H), 9.32 (s, 1H), 9.77 (s, 1H). 13C NMR (CDCl3): 56.05,
56.96, 59.00, 68.60, 68.87, 70.83, 71.91, 97.23, 107.56,
109.16, 118.38, 121.55, 129.78, 141.85, 143.62, 153.57,
154.11, 161.20, 162.30. IR (film): 3359, 2925, 1657, 1583,
1538, 1506, 1486, 1456, 1331, 1264, 1199, 1108,
1033 cmꢁ1. MS (EI): m/z 391 [M]+. Anal. Calcd for
C19H25N3O6: C, 58.30; H, 6.44; N, 10.74. Found: C,
58.42; H, 6.51; N, 10.51.
4. Experimental
4.1. General methods
4.1.3. Methyl 2-(2-(2-methoxyethoxy)ethoxy)benzoate
(12). A suspension of compound 11 (4.85 g, 30.0 mmol),
anhydrous K2CO3 (4.97 g, 36.0 mmol), and 2-(2-methoxy-
ethoxy)ethyl tosylate3 (8.22 g, 30.0 mmol) in acetonitrile
(100 mL) was stirred under reflux for 7 h and then cooled
to room temperature. The solid was filtered off and the
filtrate was concentrated under reduced pressure. The result-
ing residue was triturated with ethyl acetate (100 mL) and
the solution was washed with hydrochloric acid (1 N,
30 mLꢃ2), aqueous Na2CO3 solution (10%, 30 mLꢃ2),
brine (30 mL), and dried over sodium sulfate. Upon removal
of the solvent in vacuo, the crude product was purified by
column chromatography (petroleum ether/EtOAc 3:1) to
afford compound 12 as colorless oil (6.00 g, 79%). 1H
NMR (CDCl3): 3.39 (s, 3H), 3.55–3.59 (m, 2H), 3.76–3.80
(m, 2H), 4.37–4.41 (m, 5H), 4.22 (t, J¼4.8 Hz, 2H), 6.96–
7.02 (m, 2H), 7.42–7.45 (m, 1H), 7.79 (d, J¼7.8 Hz, 1H).
MS (EI): m/z 254 [M]+. Anal. Calcd for C13H18O5: C,
61.40; H, 7.14. Found C, 61.34; H, 7.08.
1
The H NMR spectra were recorded on 400 or 300 MHz
spectrometer in the indicated solvents. Chemical shifts are
expressed in parts per million using residual solvent protons
as internal standards. Chloroform (7.27 ppm) was used as an
internal standard for chloroform-d. Elemental analysis was
carried out at the SIOC Analytical Center. Unless otherwise
indicated, all commercially available materials were used as
received. All solvents were dried before use by following
standard procedures. All reactions were carried out under
an atmosphere of nitrogen. Silica gel (1–4 m) was used for
column chromatography. Compounds 4,12 5,13 6,14 7,15
9,16 18,17 and 1918 were prepared according to reported
methods. The methods for the determination of association
constants have been reported in previous papers.8
4.1.1. 4-(2-(2-Methoxyethoxy)ethoxy)nicotinic acid (8). A
suspension of sodium (0.84 g, 36.0 mmol) in 2-(2-methoxy-
ethoxy)ethanol (10 mL) was stirred at 90 ꢄC until a clear
solution was formed. Compound 7 (1.40 g, 9.00 mmol)
was then added in one portion. The reaction mixture was
stirred at 90 ꢄC for 3 h and then poured into ice water
(50 mL). The solution was extracted with dichloromethane
(20 mLꢃ3). The aqueous phase was then concentrated under
reduced pressure to about 10 mL and the resulting mixture
was acidified with hydrochloric acid (5 N) to pH¼3. The
precipitate formed was filtered, washed with cold water,
ether, dried in vacuo, and then recrystallized from ethanol
4.1.4. Methyl 5-iodo-2-(2-(2-methoxyethoxy)ethoxy)-
benzoate (13). A suspension of compound 12 (5.90 g,
23.0 mmol), iodine (6.32 g, 25.0 mmol), and silver sulfate
(6.98 g, 27.0 mmol) in dry methanol (100 mL) was stirred
at room temperature for 0.5 h. After the solid was filtered
off, the filtrate was evaporated in vacuo. The resulting resi-
due was dissolved in dichloromethane (100 mL) and the
solution was washed with saturated aqueous sodium bicar-
bonate solution (30 mLꢃ2), water (30 mL), brine (30 mL),
and dried over sodium sulfate. Upon removal of the solvent
in vacuo, the crude product was purified by column chroma-
tography (petroleum ether/EtOAc 3:1) to afford compound
1
to give compound 8 as a white solid (1.32 g, 61%). H
NMR (DMSO-d6): 3.20 (s, 3H), 3.40–3.43 (m, 2H), 3.58–
3.61 (m, 2H), 3.79 (t, J¼4.8 Hz, 2H), 4.45 (t, J¼4.8 Hz,
2H), 7.62 (d, J¼6.0 Hz, 1H), 8.78 (d, J¼6.0 Hz, 1H), 8.92
(s, 1H). 13C NMR (DMSO): 57.99, 68.08, 69.86, 70.72,
71.19, 111.68, 119.65, 144.10, 145.60, 162.88, 168.51. MS
(ESI): m/z 242 [M+H]+. Anal. Calcd for C11H15NO5: C,
54.77; H, 6.27; N, 5.81. Found: C, 54.35; H, 6.14; N, 5.88.
1
13 as colorless oil (7.78 g, 89%). H NMR (CDCl3): 3.39
(s, 3H), 3.54–3.58 (m, 2H), 3.73–3.76 (m, 2H), 3.87–3.91
(m, 5H), 4.18 (t, J¼4.8 Hz, 2H), 6.77 (d, J¼9.0 Hz, 1H),
7.65 (dd, J1¼9.0 Hz, J2¼2.1 Hz, 1H), 8.05 (d, J¼2.1 Hz,
1H). 13C NMR (CDCl3): 51.96, 58.86, 69.00, 69.31, 70.76,
71.82, 82.07, 115.96, 122.68, 139.79, 141.72, 158.07,
164.97. IR (film): 2953, 2923, 1728, 1607, 1487, 1434,
1281, 1225, 1081, 1063, 809, 783 cmꢁ1. MS (EI): m/z 380
[M]+. Anal. Calcd for C13H17IO5: C, 41.07; H, 4.51.
Found: C, 41.57; H, 4.79.
4.1.2. N-(5-Amino-2,4-dimethoxyphenyl)-4-(2-(2-
methoxyethoxy)ethoxy)nicotinamide (10). To a solution of
compound 8 (0.60 g, 2.48 mmol) and 9 (0.82 g, 4.48 mmol)
in dichloromethane (50 mL) were added BOP (1.32 g,
2.98 mmol), DMAP (20 mg), and triethylamine (1 mL).
The reaction mixture was stirred at room temperature for
8 h and diluted with dichloromethane (50 mL). The solution
4.1.5. Dimethyl 5,50-(ethyne-1,2-diyl)bis(2-(2-(2-meth-
oxyethoxy)ethoxy)benzoate) (14). A suspension of 13

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C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
(1.14 g, 3 mmol), Pd(PPh)3 (0.17 g, 0.15 mmol), and CuI
(57 mg, 0.30 mmol) in dry piperidine (50 mL) was stirred
at 35 ꢄC. When the reaction mixture turned to orange from
green, acetylene gas was introduced with a rubber balloon.
The mixture was stirred under acetylene atmosphere at
80 ꢄC for 0.2 h. The precipitate was filtered off and the fil-
trate was evaporated in vacuo. The resulting residue was trit-
urated in ethyl acetate (50 mL) and the solution was washed
with hydrochloric acid (1 N, 20 mLꢃ2), water (30 mL),
brine (30 mL), and dried over sodium sulfate. Upon removal
of the solvent under reduced pressure, the crude product
was purified by column chromatography (petroleum ether/
13C NMR (CDCl3): 56.30, 59.03, 68.58, 68.91, 69.18,
70.76, 70.84, 71.96, 88.12, 95.67, 107.61, 113.26, 116.92,
120.45, 120.90, 122.94, 135.66, 135.98, 146.57, 146.83,
153.30, 154.23, 156.28, 161.17, 162.01, 162.43. MS
(MALDI-TOF): m/z 1250 [M]+, 1272 [M+NaꢁH]+.
HRMS (MALDI-TOF) Calcd for C64H77N6O20 [MꢁH]+:
1249.5171. Found: 1249.5187.
4.1.8. Dimethyl 4,40-bis(2-(2-methoxyethoxy)ethoxy)-
biphenyl-3,30-dicarboxylate (16). An intimate mixture of
13 (1.76 g, 4.60 mmol) and activated copper bronze4
(3.50 g, 55.0 mmol) was covered with a thin layer of copper
bronze and heated at 210–220 ꢄC (internal temperature) for
4.5 h and then cooled to room temperature. The mixture was
triturated with hot ethyl acetate (50 mL) and the organic
phase was worked up. Upon removal of the solvent in vacuo,
the crude product was purified by column chromatography
(ethyl acetate) to afford 16 as colorless oil (0.83 g, 71%).
1H NMR (CDCl3): 3.40 (s, 6H), 3.57–3.60 (m, 4H), 3.77–
3.80 (m, 4H), 3.91–3.95 (m, 10H), 4.26 (t, J¼4.8 Hz, 4H),
7.05 (d, J¼9.0 Hz, 2H), 7.64 (dd, J1¼9.0 Hz, J2¼2.1 Hz,
2H), 7.99 (d, J¼2.1 Hz, 2H). 13C NMR (CDCl3): 51.93,
58.95, 69.12, 69.54, 70.86, 71.94, 114.27, 121.01, 129.66,
131.30, 132.20, 157.59, 166.57. IR (film): 2925, 2878,
1725, 1610, 1490, 1437, 1285, 1238, 1085, 1066, 1029,
924, 814, 786 cmꢁ1. MS (ESI): m/z 507 [M+H]+. Anal.
Calcd for C26H34O10: C, 61.65; H, 6.77. Found: C, 61.64;
H, 7.02.
1
EtOAc 2:1) to afford 14 as yellow oil (0.66 g, 83%). H
NMR (CDCl3): 3.39 (s, 6H), 3.58–3.54 (m, 4H), 3.79–3.74
(m, 4H), 3.92–3.87 (m, 10H), 4.18 (t, J¼4.8 Hz, 4H), 6.77
(d, J¼9.0 Hz, 2H), 7.65 (dd, J1¼9.0 Hz, J2¼2.1 Hz, 2H),
8.05 (d, J¼2.1 Hz, 2H). 13C NMR (CDCl3): 51.93, 58.92,
68.95, 69.41, 70.87, 71.92, 87.61, 113.64, 115.45, 120.77,
128.36, 128.46, 131.86, 131.95, 132.03, 134.86, 136.15,
158.08, 165.75. IR (film): 2926, 2878, 1732, 1610, 1504,
1451, 1437, 1277, 1244, 1145, 1110, 1081, 1053,
820 cmꢁ1. MS (EI): m/z 531 [M]+. Anal. Calcd for
C28H34O10: C, 63.39; H, 6.46. Found: C, 63.43; H, 6.21.
4.1.6. 5,50-(Ethyne-1,2-diyl)bis(2-(2-(2-methoxyethoxy)-
ethoxy)benzoic acid) (15). To a solution of 14 (0.60 g,
1.10 mmol) in methanol (15 mL) and water (5 mL) was
added sodium hydroxide (0.40 g, 10.0 mmol). The mixture
was stirred under reflux for 4 h and then concentrated to
about 5 mL. The residue was acidified with hydrochloric
acid to pH¼3 and the resulting precipitate was filtered,
washed with cold water, ether, and dried in vacuo. The crude
product was then recrystallized from ethanol to give com-
pound 15 as a white solid (0.54 g, 97%). 1H NMR
(DMSO-d6): 3.22 (s, 6H), 3.44–3.40 (m, 4H), 3.63–3.59
(m, 4H), 3.74 (t, J¼4.8 Hz, 4H), 4.18 (t, J¼4.8 Hz, 4H),
7.16 (d, J¼9.0 Hz, 2H), 7.63 (dd, J1¼9.0 Hz, J2¼2.1 Hz,
2H), 7.74 (d, J¼2.1 Hz, 2H). 13C NMR (DMSO-d6):
58.00, 68.59, 68.64, 69.83, 71.26, 87.58, 114.15, 122.25,
133.33, 135.48, 157.16, 166.36. MS (ESI): m/z 503
[M+H]+. Anal. Calcd for C26H30O10: C, 62.14; H, 6.02.
Found: C, 62.38; H, 6.03.
4.1.9. 4,40-Bis(2-(2-methoxyethoxy)ethoxy)biphenyl-3,30-
dicarboxylic acid (17). To a solution of 16 (0.70 g,
1.40 mmol) in methanol (20 mL) and water (5 ml) was
added sodium hydroxide (0.40 g, 10 mmol). The mixture
was stirred under reflux for 4 h and then concentrated to
about 5 mL. The resulting residue was acidified with hydro-
chloric acid to pH¼3 and then filtered. The solid was washed
with cold water, ether, dried in vacuo, and then recrystallized
1
from ethanol to give 17 as a white solid (0.66 g, 98%). H
NMR (DMSO-d6): 3.22 (s, 6H), 3.33–3.44 (m, 4H), 3.59–
3.75 (m, 4H), 3.75 (t, J¼4.8 Hz, 4H), 4.18 (t, J¼4.8 Hz,
4H), 7.16 (d, J¼9.0 Hz, 2H), 7.63 (dd, J1¼9.0 Hz,
J2¼2.1 Hz, 2H), 7.74 (d, J¼2.1 Hz, 2H). 13C NMR
(DMSO-d6): 58.00, 68.64, 68.73, 69.82, 71.26, 114.49,
122.19, 128.03, 130.43, 131.05, 156.51, 167.08. MS
(MALDI-TOF): m/z 478 [M]+. Anal. Calcd for C24H30O10:
C, 60.24; H, 6.32. Found: C, 60.12; H, 6.43.
4.1.7. N-(5-(5-((3-(2,4-Dimethoxy-5-(4-(2-(2-methoxy-
ethoxy)ethoxy)nicotinamido)phenylcarbamoyl)-4-(2-(2-
methoxyethoxy)ethoxy)phenyl)ethynyl)-2-(2-(2-meth-
oxyethoxy)ethoxy)benzamido)-2,4-dimethoxyphenyl)-
N-(2-(2-methoxyethoxy)ethoxy)nicotinamide (1). To a
solution of 10 (212 mg, 0.54 mmol) and 15 (134 mg,
0.27 mmol) in dichloromethane (30 mL) were added BOP
(0.26 g, 0.59 mmol), DMAP (20 mg), and triethylamine
(0.1 mL). The mixture was stirred at room temperature for
6 h and then diluted with dichloromethane (50 mL). The
solution was then washed with aqueous Na2CO3 solution
(10%, 30 mLꢃ2), water (30 mL), brine (30 mL), and dried
over sodium sulfate. Upon removal of the solvent in vacuo,
the crude product was purified by column chromatography
(CH2Cl2/MeOH 30:1, then 10:1) to afford compound 1 as
3
3
0
4.1.10. N ,N -Bis(2,4-dimethoxy-5-(4-(2-(2-methoxy-
ethoxy)ethoxy)nicotinamido)phenyl)-4,40-bis(2-(2-meth-
oxyethoxy)ethoxy)biphenyl-3,30-dicarboxamide (2). To a
solution of 10 (0.20 g, 0.51 mmol) and 17 (0.12 g,
0.25 mmol) in dichloromethane (30 mL) were added BOP
(0.25 g, 0.55 mmol), DMAP (20 mg), and triethylamine
(0.1 mL). The reaction mixture was stirred at room temper-
ature for 6 h and then diluted with dichloromethane (50 mL).
The solution was washed with aqueous Na2CO3 solution
(10%, 30 mLꢃ2), water (30 mL), brine (30 mL), and dried
over sodium sulfate. Upon removal of the solvent in vacuo,
the crude product was purified by column chromatography
(CH2Cl2/MeOH 30:1, then 10:1) to afford 2 as pale yellow
1
a pale yellow solid (0.29 g, 86%). H NMR (CDCl3): 3.29
(s, 12H), 3.43–3.47 (m, 8H), 3.67–3.71 (m, 8H), 3.94 (s,
12H), 4.00–4.03 (m, 8H), 4.41–4.50 (m, 8H), 6.53 (s, 2H),
7.00–7.02 (m, 4H), 7.58 (d, J¼9.0 Hz, 2H), 8.47–8.50
(m, 4H), 9.32–9.37 (m, 4H), 9.64 (s, 2H), 9.95 (s, 2H).
1
solid (0.26 g, 85%). H NMR (CDCl3): 3.28 (s, 6H), 3.30
(s, 6H), 3.46–3.52 (m, 8H), 3.69–3.73 (m, 8H), 3.96 (s,
6H), 3.99 (s, 6H), 4.02–4.07 (m, 8H), 4.46–4.53 (m, 8H),

C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
6979
6.58 (s, 2H), 7.03 (d, J¼6.0 Hz, 2H), 7.13 (d, J¼8.6 Hz, 2H),
7.80 (dd, J1¼8.6 Hz, J2¼2.4 Hz, 2H), 8.57 (d, J¼6.0 Hz,
2H), 8.62 (d, J¼2.4 Hz, 2H), 9.37 (s, 2H), 9.48 (s, 2H),
9.67 (s, 2H), 10.13 (s, 2H). 13C NMR (CDCl3): 56.33,
56.35, 59.04, 68.53, 68.91, 69.27, 70.74, 70.84, 71.95,
71.97, 95.79, 107.53, 109.01, 113.74, 116.71, 118.42,
120.56, 121.31, 122.93, 130.58, 130.96, 133.29, 141.64,
146.34, 146.70, 153.43, 154.42, 155.87, 161.20, 162.35,
162.75, 164.21. IR (film): 3358, 2885, 1661, 1615, 1583,
1549, 1484, 1470, 1424, 1337, 1308, 1277, 1243, 1222,
1202, 1109, 1030, 921, 813. MS (MALDI-TOF): m/z 1225
[M+H]+, 1247 [M+Na]+. HRMS (MALDI-TOF) Calcd for
C62H77N6O20 [M+H]+: 1225.5165. Found: 1225.5187.
(MALDI-TOF): m/z 912 [M+Na]+. HRMS (MALDI-TOF)
Calcd for C46H55N3O15Na [M+Na]+: 912.3553. Found:
912.3525.
Acknowledgements
We thank the National Natural Science Foundation of China
(20321202, 20372080, 20332040, 20425208, 20572126) for
financial support.
References and notes
4.1.11. 5-((3-(Methoxycarbonyl)-4-(2-(2-methoxyethoxy)-
ethoxy)phenyl)ethynyl)-2-(2-(2-methoxyethoxy)ethoxy)-
benzoic acid (20). To a solution of 14 (0.40 g, 0.76 mmol) in
methanol (20 mL) was added potassium hydroxide (52 mg,
0.76 mmol). The reaction mixture was stirred at reflux for
6 h. After normal work up, the crude product was purified
by column chromatography (CH2Cl2/MeOH 30:1) to afford
20 as colorless oil (0.22 g, 56%). 1H NMR (CDCl3): 3.31 (s,
3H), 3.32 (s, 3H), 3.49–3.53 (m, 4H), 3.64–3.71 (m, 4H),
3.82 (s, 3H), 3.82–3.87 (m, 4H), 4.17 (t, J¼4.8 Hz, 2H),
4.33 (t, J¼4.8 Hz, 2H), 6.89–6.96 (m, 2H), 7.49–7.59 (m,
2H), 7.89 (s, 1H), 8.23 (s, 1H). 13C NMR (CDCl3): 52.10,
59.07, 59.12, 68.63, 69.01, 69.33, 69.50, 70.78, 70.97,
71.88, 72.00, 87.06, 88.59, 113.64, 113.69, 115.18,
117.86, 120.79, 136.08, 136.39, 136.82, 137.32, 156.94,
158.35. IR (film): 2926, 2880, 1732, 1610, 1503, 1453,
1416, 1275, 1244, 1109, 1083, 1047, 917, 821. MS (ESI):
m/z 517 [M+H]+. Anal. Calcd for C27H32O10: C, 62.78; H,
6.24. Found: C, 62.64; H, 6.02.
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4.1.12. Methyl 5-((3-(2,4-dimethoxy-5-(4-(2-(2-methoxy-
ethoxy)ethoxy)nicotinamido)phenylcarbamoyl)-4-(2-(2-
methoxyethoxy)ethoxy)phenyl)ethynyl)-2-(2-(2-methoxy-
ethoxy)ethoxy)benzoate (21). To a solution of 10 (74 mg,
0.19 mmol) and 20 (0.10 g, 0.19 mmol) in dichloromethane
(30 mL) were added BOP (0.10 g, 0.23 mmol), DMAP
(20 mg), and triethylamine (0.1 mL). The reaction mixture
was stirred at room temperature for 6 h and then diluted
with dichloromethane (50 mL). The solution was washed
with aqueous Na2CO3 solution (10%, 30 mLꢃ2), water
(30 mL), brine (30 mL), and dried over sodium sulfate.
Upon removal of the solvent in vacuo, the crude product
was purified by column chromatography (CH2Cl2/MeOH
1
30:1) to afford 21 as pale yellow solid (136 mg, 80%). H
NMR (CDCl3): 3.27 (s, 6H), 3.37 (s, 3H), 3.42–3.47 (m,
4H), 3.54–3.57 (m, 2H), 3.63–3.68 (m, 4H), 3.73–3.76 (m,
2H), 3.87–3.92 (m, 8H), 3.94–4.00 (m, 4H), 4.22 (t, J¼
4.8 Hz, 2H), 4.35–4.42 (m, 4H), 6.44 (s, 1H), 6.88 (d,
J¼6.0 Hz, 2H), 6.94–6.98 (m, 2H), 7.51 (dd, J1¼8.6 Hz,
J2¼2.4 Hz, 1H), 7.57 (dd, J1¼8.6 Hz, J2¼2.4 Hz, 2H),
7.95 (d, J¼2.4 Hz, 1H), 8.43–8.54 (m, 2H), 9.33 (br, 1H),
9.42 (s, 1H), 9.64 (s, 1H), 9.92 (s, 1H). 13C NMR
(CDCl3): 52.03, 56.30, 59.03, 68.68, 68.88, 69.02, 69.15,
69.50, 70.75, 70.82, 70.96, 71.93, 72.01, 87.80, 88.02,
95.65, 113.17, 113.72, 115.69, 116.82, 116.94, 120.43,
120.77, 122.94, 134.98, 135.44, 136.16, 136.37, 146.55,
146.88, 156.29, 158.14, 161.03, 162.00, 165.84. IR (film):
3359, 2884, 1732, 1666, 1614, 1584, 1544, 1503, 1468,
1272, 1242, 1202, 1108, 1086, 1030, 918, 821 cmꢁ1. MS

6980
C.-Z. Li et al. / Tetrahedron 62 (2006) 6973–6980
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