Development of helical aromatic amide foldamers with a diphenylacetylene backbone

Article abstract of DOI:10.1021/acs.joc.9b02758

We designed and synthesized aromatic polyamides with a diphenylacetylene backbone, α-DPA and β-DPA, bearing (S)-α-and (S)-β-methyl-substituted triethyleneglycol (TEG) side chains, respectively, and examined their conformations in solution. Both polymers exhibit strong, solvent polarity-dependent circular dichroism spectra, which indicated that they take helical conformations in low-polarity solvents. The spectra were mirror images, depending on the chiral position of the side chains. Thus, the polyamide α-DPA bearing (S)-α-methyl-substituted TEG groups takes a left-handed helical conformation, while the polyamide β-DPA with (S)-β-methyl-substituted TEG groups takes a right-handed helical conformation. The difference in the screw sense of α-DPA and β-DPA would be caused by the steric interaction between the main chain and the side chain, as observed in poly(p-benzamide) possessing (S)-β-methyl-substituted TEG side chains (β-PA) because the large cavity of the helical structure of DPA would disturb the solvophobically induced helical folding. Detailed conformational analyses of the oligoamides 6-12 with β-methyl-substituted TEG groups were conducted. Theoretical calculations indicated that the oligoamides with β-methyl-substituted TEG groups exist in a helical conformation with a cavity of 7 ? in diameter. The ¹H NMR spectra of the oligomers revealed interactions with small anions such as chloride and acetate anions and with pyridinium cations.

Full text of DOI:10.1021/acs.joc.9b02758

Subscriber access provided by Universite du Quebec a Montreal (UQAM)
Article
Development of Helical Aromatic Amide
Foldamers with a Diphenylacetylene Backbone
Ko Urushibara, Tatsunori Yamada, Akihiro Yokoyama, Hirotoshi Mori, Hyuma
Masu, Isao Azumaya, Hiroyuki Kagechika, Tsutomu Yokozawa, and Aya Tanatani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02758 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Development of Helical Aromatic Amide Foldamers with a
Diphenylacetylene Backbone
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
,3
1,†
Ko Urushibara, Tatsunori Yamada, Akihiro Yokoyama,* Hirotoshi Mori, Hyuma
4
5
6
,2
,1
Masu, Isao Azumaya, Hiroyuki Kagechika, Tsutomu Yokozawa,* Aya Tanatani*
1
Department of Chemistry and Biochemistry, Graduate School of Humanities and
Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
2
Department of Materials and Life Chemistry, Kanagawa University, Rokkakubashi,
Kanagawa-ku, Yokohama 221-8686, Japan
3
Department of Materials and Life Science, Faculty of Science and Technology, Seikei
University, 3-3-1 Kichijoji-Kitamachi, Musashino, Tokyo 180-8633, Japan
4
Center for Analytical Instrumentation, Chiba University, 1-33 Yayoi, Inage, Chiba
2
63-8522, Japan
5
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan
6
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University,
2
-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
†
Present address. Faculty of Science and Engineering, Chuo University, 1-13-27
Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
Corresponding author’s e-mail address:
Akihiro Yokoyama: ayokoyama@st.seikei.ac.jp
Tsutomu Yokozawa: yokozt01@kanagawa-u.ac.jp
Aya Tanatani:tanatani.aya@ocha.ac.jp
Table of Contents/Abstract Graphic
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Abstract
We designed and synthesized aromatic polyamides with a diphenylacetylene backbone,
-DPA and -DPA, bearing (S)-- and (S)--methyl-substituted triethyleneglycol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

(TEG) side chains, respectively, and examined their conformations in solution. Both
polymers exhibit strong, solvent-polarity-dependent CD spectra, which indicated that
they take helical conformations in low-polarity solvents. The spectra were mirror
images, depending on the chiral position of the side chains. Thus, the polyamide -DPA
bearing (S)--methyl-substituted TEG groups takes a left-handed helical conformation,
while the polyamide -DPA with (S)--methyl-substituted TEG groups takes a
right-handed helical conformation. The difference in the screw sense of -DPA and

-DPA would be caused by the steric interaction between the main chain and the side
chain, as observed in poly(p-benzamide) possessing (S)--methyl-substituted TEG side
chains (-PA), since the large cavity of the helical structure of DPA would disturb the
solvophobically induced helical folding. Detailed conformational analyses of the
oligoamides 6 – 12 with -methyl-substituted TEG groups were conducted. Theoretical
calculations indicated that the oligoamides with -methyl-substituted TEG groups exist
1
in a helical conformation with a cavity of 7 Å in diameter. The H NMR spectra of the
oligomers revealed interactions with small anions such as chloride and acetate anions,
and with pyridinium cation.
2
ACS Paragon Plus Environment

Page 3 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
INTRODUCTION
Biological macromolecules such as DNA and proteins adopt unique three-dimensional
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
structures, including helical and -sheet structures, and are regarded as natural
1
foldamers. Helical foldamers have attracted much attention in the past few decades,
both to investigate the relationship of structure to function for natural foldamers, and to
develop artificial foldamers that mimic natural foldamers or have unique feature not
2
found in nature. They are classified into two categories, peptidomimetic foldamers and
3
abiotic foldamers, from the viewpoint of design. The study of artificial foldamers
begun with aliphatic -amino acids.4,5 Then, many abiotic foldamers consisting of
aromatic units and torsionally flexible linkers have been reported. They utilize
6
noncovalent interactions such as hydrogen bonding, aromatic-aromatic interaction,
7
8
9
metal coordination, donor-acceptor interaction, solvophobic effect, salt-bridges, etc.,
to build helical structures.
m-Phenylene ethynylene (mPE) oligomers are well-known foldamers that utilize
solvophobic effects. mPE oligomers bearing triethyleneglycol (TEG) side chain take
random coil structure in nonpolar solvents such as chloroform, while they fold into
10
helical structures in polar solvents such as acetonitrile. The helical structure of mPE
oligomers is stabilized by aromatic stacking, and one helical turn consists of six
monomer units.11 mPE oligomers with alkyl side chains take helical structure in
heptane.12 However, they still exist as random coils in chloroform, and it remains
unclear whether van der Waals interaction or the solvophobic effect plays the
predominant role in helix formation.
The basic skeleton of mPE oligomers has been widely applied, with various
modifications of the main chain or side chains.13 As an example of main chain
modification, Yamaguchi introduced helicene into mPE oligomers and showed that the
1
4
products formed a double helix. On the other hand, Hecht inserted azo units to control
helical structure formation by photoirradiation.15 As for side chain modification,
Yashima developed mPE polymer bearing chiral TEG side chains via amide bonds and
reported that it adopted a stable helical conformation in chloroform via intramolecular
1
6
hydrogen bonding. They were able to observe the helical sense directly by means of
atomic force microscopy (AFM). Furthermore, it was reported by Zhao17 and
1
8
Yashima, respectively, that not only PE linked at the m-position, but also PE linked
alternately at the o- and p-positions adopts helical structure.
We previously reported that N-substituted aromatic amides show cis preference in the
19
crystalline state and in solution. The dihedral angle of tertiary cis-amide is about 60
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
degrees, and by utilizing this folded cis-amide moiety repeatedly, we can construct
helical
foldamers.20
Among
them,
poly(p-benzamide)
possessing
(S)--methyl-substituted TEG side chains (-PA, Figure 1) was shown by exciton
model analysis to adopt a dynamic helical conformation with three monomer units per
turn and a right-handed form.21 The conformation of -PA was independent of the
solvent. Poly(p-benzamide) with (S)--methyl-substituted TEG side chains (-PA) was
also synthesized in the expectation of a larger bias to one helical handedness, compared
with -PA. However, -PA adopted a right-handed helical conformation in polar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
solvents, such as water and methanol, and a random structure in chloroform. These
results indicate that the solvophobic effect plays a significant role in the helical folding
of -PA. An attempt to synthesize -PA by amide bond formation between the
monomer units using potassium hexamethyldisilazide (KHMDS) and 18-crown-6 was
unsuccessful, because of preferential formation of cyclic trimer. The synthesis was
finally achieved by the use of Et SiH, CsF and 18-crown-6. Formation of cyclic trimer
3
indicated that the high planarity of the amide linkages causes the two end groups of the
trimer to be located close to each other in a triangular conformation. If this is the case,
we anticipated that elongation of the monomer unit would increase the distance between
the two terminals of the trimer and thus should favor polymer formation rather than
cyclization.
In addition, - and -PA have small cavities, which are difficult to apply for guest
encapsulation. Our previous study showed that the cavity size of macrocycles with
folded cis-amide bonds could be controlled by using two aromatic molecules linked by
various bonds as the monomer unit.23 Recently, we have developed alternately
N-alkylated amide oligomers and succeeded in expanding the helical cavity.24
Here, we describe the synthesis and helical structure of polyamides -DPA and

-DPA (Figure 1), which have a diphenylacetylene backbone with (S)-- and
(S)--methyl-substituted TEG side chains, respectively, based on the idea that changing
the benzene moiety of PA to diphenylacetylene would afford -DPA and -DPA with a
larger helical cavity than - and -PA. In addition, we systematically synthesized a
series of oligomers and conducted detailed conformational analyses.
4
ACS Paragon Plus Environment

Page 5 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Structures of the polyamides.
RESULTS AND DISCUSSION
1. Syntheses of Polyamides -DPA and -DPA.
We initially tried to synthesize -DPA by polymerization of monomer 1 (Scheme 1),
which was derived from 1-bromo-4-iodobenzene in 5 steps (see Experimental Section).
The condensation polymerization of 1 using lithium hexamethyldisilazide (LiHMDS) as
a base and phenyl 4-methylbenzoate as an initiator did not proceed in a chain-growth
manner, but afforded the cyclic trimer as the major product. The reaction of 1 using
KHMDS and 18-crown-6 at 50 °C afforded the polymer (M = 9210, M /M = 6.18).
n
w
n
However, the purified polymer (M = 6230, M /M = 1.40) incorporated undesired
n
w
n
1
structures, as deduced from the H NMR spectrum. The polymerization using the
combination of Et SiH, CsF, and 18-crown-6 in the absence of initiator, as optimized
3
2
1
for the synthesis of -PA, afforded only oligoamides (7−9-mers). Therefore, -DPA
could not be obtained by the condensation of 1 using base.
Scheme 1. Condensation polymerization of 1.
Therefore, we examined the preparation of -DPA by repeated Sonogashira reaction
(Scheme 2a). Monomer 2 was prepared from 4-iodobenzoyl chloride in 2 steps (see
Experimental Section). Sonogashira reaction of 2 was performed without a copper
catalyst to prevent acetylene homocoupling,25 and afforded -DPA (M = 14900,
n
M /M = 1.58).
w
n
To investigate the influence of chiral position on the helical conformation, -DPA was
also synthesized in the same manner as -DPA. (S)--Methyl-substituted TEG was
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
6
prepared in 6 steps according to the reported method, and converted to monomer 3
see Experimental Section). The Sonogashira coupling condensation of 3 afforded
-DPA (M = 14200, M /M = 1.31) (Scheme 2b).
(
n
w
n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Polymerization of (a) 2 and (b) 3 by Sonogashira reaction.
. CD Spectra of Polymers.
2
The CD spectra of -DPA were measured in various solvents (Figure 2a). Split-type
signals, in which the negative Cotton effects appeared at 330–335 nm and the positive
Cotton effects appeared at 280–290 nm, were observed in low-polarity solvents such as
chloroform and THF, while the negative Cotton effect at 330–335 nm was not observed
in mixtures of THF with high-polarity solvents such as acetonitrile, methanol, and water.
The chiral monomeric unit 4 showed only a broad positive Cotton effect at around 290
nm (Figure 2b), which suggested that the negative Cotton effect of -DPA was derived
from secondary structures. Thus, chiral secondary structure appeared to be induced as
the solvent polarity was decreased.
Figure 2. CD spectra of (a) -DPA, (b) model compounds 4 and (c) 5 in various
6
ACS Paragon Plus Environment

Page 7 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
solvents at 0 °C (0.01 g/L). (d) Structures of compounds 4 and 5.
We next synthesized compound 5, which has only two diphenylacetylene units linked
by a cis-amide bond with a chiral side chain, and could not form helical structure, and
we measured its CD spectrum (Figure 2c). A strong positive Cotton effect was observed
at around 280 nm in all solvents examined. In contrast, the negative Cotton effect at
around 330 nm was not observed in chloroform or acetonitrile/THF (20:1), though it
was observed in THF, methanol/THF (4:1) or water/THF (1:1). These results indicated
that the positive Cotton effect at 280–290 nm of -DPA represents the sum of the
contributions of the local structure around the amide bond and the helical structure, and
that the strong negative Cotton effect at 330–335 nm of -DPA in chloroform arises
mainly from the helical structure. Therefore, -DPA takes the helical structure in less
polar solvents, such as chloroform.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Because
-[[4-(alkylamino)phenyl]ethynyl]benzoyl unit, the chromophore behaves as a typical
donor-acceptor diphenylacetylenes whose transition moment lies along the molecular
the
monomeric
chromophore
of
-DPA
is
4
2
7
axis, as in the case of 4-(alkylamino)benzoyl unit, a monomeric chromophore of -PA
2
1
(Figure 1). Therefore, the CD spectrum of -DPA can be interpreted in a similar
manner to those of -PA and -PA. Since the CD spectrum of -DPA was a
2
2
mirror-image of that of -PA, -DPA takes a left-handed helical structure, opposite to
that of -PA.
The difference of screw senses was probably due to the different driving forces to
induce the helical structure of -DPA and -PA. As described in the previous report,22
the helical folding of -PA needed solvophobic interactions. In contrast, as for -DPA,
the main chain and the side chain of -DPA were solvated similarly in chloroform and
THF, and the preference of left-handed helical conformation of -DPA would be
determined by the steric interaction between the main chain and the side chain, not by
solvophobic interactions. As we expected, the helical folding of -DPA without
solvophobic interactions would come about by the elongation of the monomer unit
compared to -PA. Since the helical cavity of -DPA will be larger than that of -PA,
it should be solvated. However, because polar solvents such as acetonitrile, methanol
and water could not solvate the hydrophobic cavity, -DPA could not adopt helical
structure in acetonitrile/THF (20:1), methanol/THF (4:1), and water/THF (1:1).
-DPA also showed a similar solvent-dependency of the CD spectra to -DPA (Figure
3
a). The split-type CD signal of -DPA was observed in low-polarity solvents such as
chloroform and THF, and the intensity was larger in chloroform than in THF. In
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
methanol/THF (4:1), the positive Cotton effect at 340–350 nm was not observed, and
the negative Cotton effect was blue-shifted. These results suggested that -DPA and
-DPA were folded into helical structure in low-polarity solvent independently of the
chiral position in the side chain. The absorption peaks of -DPA and -DPA were
observed in the range of 295–305 nm with shoulders at ca. 320 nm and ca. 330 nm,
respectively (Figure 3b). These results also support that the CD spectra of -DPA and
-DPA can be interpreted by the coupling of electric transition dipole moments of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
21
helically arranged chromophore units in a similar manner to -PA. The opposite sign
of the Cotton effect between -DPA and -DPA indicates that the helicity is also
opposite, and -DPA takes right-handed helical structure as in the case of -PA (Figure
3b). These results indicate that the screw sense of the polyamide was determined by the
steric interaction between the polymer main chain and the -substituted side chain. In
addition, the g value of -DPA was 2.8 times larger than that of -DPA in chloroform,
which indicates that the helical conformation of -DPA is more strongly biased to one
helical sense than that of -DPA. Because the -methyl group of the side chain
interacts sterically with the amide bond, the planarity of the amide linkage is higher in
the case of -DPA, which might interfere with helical folding.
Figure 3. (a) CD spectra of -DPA in various solvents at 0 °C and (b) comparison of
UV (lower) and CD (upper) spectra of - and -DPA in chloroform at 0 °C.
The effect of temperature on the helical conformation was next examined (Figure S1).
The CD signal intensities of - and -DPA decreased with increasing temperature.
These results reflect the thermodynamical nature of the helical folding process of these
polyamides.
3. Syntheses of Oligoamides.
8
ACS Paragon Plus Environment

Page 9 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In order to understand why -DPA has a stable helical structure with a stronger
handedness bias than -DPA, we synthesized a series of oligoamides 6c – 12c with
(S)--methyl-substituted TEG side chains (Figure 4). We also synthesized oligoamides
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
a – 7a with N-methyl groups and 6b – 12b with achiral TEG groups as N-substituents
for X-ray crystallographic analysis and for the chiral induction experiments,
respectively.
Figure 4. Structures of oligoamides 6 – 12.
Monomer 6a and dimer 7a were synthesized as shown in Scheme S6. However,
elongation of oligomers bearing chiral or achiral TEG side chains via this strategy
requires many steps, and the introduction of TEG side chains after the synthesis of the
main chain is difficult. Therefore, the oligomers 6b – 12b and 6c – 12c were
synthesized by means of sequential Sonogashira reactions (see Experimental Section).
4. X-ray Crystallographic Analysis.
Single crystals were obtained only for monomer 6a and for 13, the synthetic
intermediate of dimer 7a (Figures S4-S6, and Table S1). The tertiary amide bond exists
in cis form in both compounds. The dihedral angle of the two benzene units of
diphenylacetylene is 66.88° for 6a, and 88.08° and 87.86° for 13. Intermolecular CH-O
and CH- interactions were observed in the packing structure of 13 (Figure S6), which
may generate the zig-zag conformation of 13. These results suggested that cis-form
tertiary amide bonds are preferable to enable oligomers to form well-ordered folded
conformations.
5. UV and CD spectra of Oligomers.
The UV and CD spectra of oligoamides 6c – 12c bearing chiral (S)-methyl-substituted
TEG side chains were measured to investigate their conformations. The CD intensity of
the oligomers increased with elongation of the chain length (Figure 5). In addition, the
intensity showed temperature dependency (Figure S2). The shapes of the UV and CD
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
spectra were different between monomer 6c and oligoamides 7c – 12c. In the CD
spectra, monomer 6c showed a weak, broad negative Cotton effect at around 290 nm,
while oligoamides 7c – 12c gave sharp split-type spectra (a negative Cotton effect at
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
15 nm and a positive Cotton effect at 350 nm), like -DPA. In the UV spectra, the
absorption maximum of 6c was at 315 nm, whereas those of oligoamides 7c – 12c were
at 305 nm, with a shoulder at 330 nm as in the case of -DPA and -DPA.
Figure 5. UV and CD spectra of the oligomers 6c – 12c in chloroform at 20 °C.
Like the polymer -DPA, the oligomer 12c showed solvent-dependent CD spectra
(Figures 6 and S3). In low-polarity solvents such as THF, chloroform and
dichloromethane, the oligomer 12c showed bisignate CD spectra. In high-polarity
solvents such as methanol and acetonitrile, only a negative Cotton effect was observed
with a blue shift. Not only the shape, but also the intensity was correlated with solvent
polarity, especially dielectric constant, and the intensity was high in low-polarity
solvents. Similar tendencies were observed in the CD spectra of the dimer 7c, though
the intensity of the positive Cotton effect at 350 nm was very weak, even in
low-polarity solvent. These results indicated that oligomers bearing
(S)-methyl-substituted TEG side chains exist in helical conformation only in
low-polarity solvents, and adopt other structures in high-polarity solvents, probably
because the solvation of the helical cavity with polar solvents is difficult due to the
solvophobic nature of the cavity. These oligomers have a diphenylacetylene moiety as
the monomer unit, like mPE oligomers, but the solvent dependency of their properties is
quite different. The major difference is that our oligomers have cis-form tertiary amide
bonds, and this results in a difference in the direction of the benzene units with respect
to the helical axis. In the case of mPE, the benzene units are perpendicular to the axis,
and the helical structure is further stabilized by strong - stacking interactions.
Furthermore, our oligomers are linked at the para position, while mPE linkages are at
1
0
ACS Paragon Plus Environment

Page 11 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the meta position. This may lead to a difference of cavity size.
We examined the solution structures of oligomers 6c – 12c by means of NMR
1
spectroscopy. However, the H NMR spectra of the oligomers did not show any
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
significant dependence on oligomer length or solvent polarity, in contrast to the UV/CD
spectra (Figures S7-S8).
Figure 6. CD and UV spectra of oligomers 7c and 12c in various solvents at 20 °C. (12c
was insoluble in n-hexane.).
6. Theoretical Study of the Structural and Spectral Properties of
Oligomers.
To understand the relationship between the helical structure of oligomers and the
spectral features, we performed geometry optimization calculations on oligoamides 8a,
1
0a, and 12a at the RI-DFT-D B-LYP/def-SV(P) level after optimization by the PM3
method with Gaussian03, based on the crystal structure of monomer 6a. The optimized
conformations are helical and possess a cavity of approximately 7 Å (Figure 7).
Geometry optimization was also done at the RI-DFT B-LYP/def-SV(P) level. The result
also indicated helical conformation, but the aromatic rings along the helical axis are
divergent, suggesting that van der Waals interactions strongly influence the helical
1
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
conformation of these oligoamides.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 7. Optimized conformations of 8a, 10a, and 12a.
We also employed time-dependent DFT at the RI-B-LYP/def-SV(P) level to calculate
the UV and CD spectra of the optimized conformations of monomer 6a, and oligomers
8a and 10a (Figure S14). The calculated UV spectra show a similar tendency to the
experimental UV spectra as regards the blue shift from monomer 6 to oligomer 8. In
addition, the shape of the calculated CD spectra resembles that of the experimental
spectra. These results support the idea that the oligomers take helical conformation in
low-polarity solvents.
7. Guest Recognition Ability of Oligomers.
The binding interaction between oligomers 8a and various kinds of chiral molecules
was examined by computational study, and the chiral induction of oligomers 8b, 10b,
and 12b with achiral TEG side chains was investigated by means of CD and UV
measurements. However, addition of any chiral molecule to solutions of these oligomers
did not affect the spectra. Thus, any structural change induced by interaction with guest
molecules may be too modest to detect by means of CD and UV measurements.
Cyclic derivatives of diphenylacetylene linked by cis-amide bonds were reported to
–
–
28
show high binding affinity for Cl and I anions. Energy minimization calculation
using the MM2 force field revealed that the diameter of the macrocycle cavity is about
7.5 Å, and the driving force for anion binding can be attributed to weak C-H···Cl or
C-H···I hydrogen bonding.
Taking account of previous findings on cyclic derivatives, the anion recognition
abilities of oligomers 6b – 12b bearing achiral TEG side chains were evaluated by
means of NMR study. When tetrabutylammonium chloride (TBACl, 1 equiv) was added
1
2
ACS Paragon Plus Environment

Page 13 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
to a solution of oligomers 6b – 12b, no chemical shift change was observed up to trimer
8
b (Figures S9 and 8a). In tetramer 9b, the chemical shift and the signal shape were
slightly but significantly changed by addition of TBACl. The aromatic proton signal at
.20 ppm was shifted upfield by about 0.01 ppm, and the signals of TEG side chain
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
were also shifted. The addition of excess TBACl (3 and 5 equiv) did not induce further
changes in the chemical shifts (data not shown). TBACl also induced smaller changes in
the chemical shifts of pentamer 10b. The relationship between the oligomer length and
the chemical shift change () of the signal at 7.20 ppm is plotted in Figure 8b. The
biggest change was observed in tetramer 9b, which exhibits 1.5 helical turns, and the
change was diminished in longer oligomers. In the case of longer oligomers, it may be
difficult for an anion to approach the cavity, or the helical structure may be increasingly
stabilized, so that the effect of anion encapsulation on the NMR spectra would be small.
Furthermore, the signals of the TEG side chains were also shifted by addition of
TBACl, depending on the oligomer length. Alteration of the helical conformation
induced by anion encapsulation would induce a change in the conformation of the TEG
side chain.
1
Figure 8. (a) H NMR (600 MHz, CDCl ) spectral changes of 9b (1 mM) with 1 equiv
3
of TBACl in CDCl at 25 °C. (b) Chemical shifts of the aromatic proton signal at
3
around 7.20 ppm of 6b – 12b when complexed with 1 equiv of TBACl in CDCl at
3
2
5 °C.
Next, the solvent effect was examined with a mixture of tetramer 9b and 1 equiv of
TBACl (Figure S10). A similar tendency was observed in CD Cl , while there was no
2
2
change in CD OD and CD CN, in which the helical conformation of the oligomer was
3
3
not stable. In addition, VT-NMR spectra of 9b were measured in CD Cl in the
2
2
presence and absence of TBACl (Figure S11). The aromatic signals became broader at
low temperature in the absence of TBACl. In the presence of TBACl, they were broad
at 263 K, but became sharp at lower temperatures. These results suggest that the
–
complex between oligomer and Cl anion is stable, and the helical conformation is
fixed.
1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Anion selectivity was also examined with tetramer 9b in CDCl (Figure S12). The
3
chemical shift change upon addition of tetrabutylammonium bromide and acetate was
similar to that in the case of TBACl. However, there was no change in the case of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
–
tetrabutylammonium iodide. The ionic radii increase in the order of Cl (1.81 Å), AcO
–
–
29
(1.86 Å), Br (1.96 Å), and I (2.20 Å), suggesting that the selectivity is determined by
the ion size. Anion- interaction rather than CH-halogen interaction may cause these
changes, because they were observed with not only halogen anion, but also acetate
anion.
Since we expected that encapsulation could occur via cation- interaction, we
examined the effect of addition of some pyridinium cations to a solution of tetramer 9b
by means of NMR measurements (Figure S13). In the case of pyridinium
–
p-toluenesulfonate, the chemical shifts of 9b changed, similarly to the case of Cl anion.
Although the signals of sulfonate anion did not change, those of pyridinium cation were
slightly shifted (o-H: +0.047 ppm, m-H: −0.024 ppm, p-H: −0.017 ppm), suggesting that
the oligomer interacted with pyridinium cation.
CONCLUSIONS
We synthesized polyamides and oligoamides consisting of a diphenyl acetylene
backbone linked by cis-amide bonds, and found that they formed helical structures in
low-polarity solvents such as chloroform and THF. The solvent-dependent CD spectra
of the polyamides indicates that the screw sense of -DPA and -DPA would be
determined by the steric interaction between the main chain and the side chain, as in the
case of -PA, and that the solvophobic property is less significant in DPA with the
longer monomer unit and the large helical cavity, unlike the case of -PA. Theoretical
study of the oligoamides suggested these molecules take helical structures with a larger
cavity than that of PA. With respect to guest recognition, NMR study revealed that the
oligomers interact with anions and cations.
EXPERIMENTAL SECTION
General Information. All reagents were purchased from Sigma-Aldrich Chemical
Co., Wako Pure Chemical Industries, Tokyo Chemical Industry Co., and Kanto
Chemical Co., Inc. Silica Gel 60 N (spherical, neutral) and Kieselgel 60 (230–400
mesh) for column chromatography were purchased from Kanto Chemical Co., Inc. and
1
13
Merck, respectively. H and C NMR spectra were recorded on JEOL JNM-ECS400,
JNM-ECA500, and JNM-ECA600 spectrometers, and Bruker Avance 600 spectrometer
by using solvent molecules such as chloroform (7.26 ppm), methylene chloride (5.32
1
4
ACS Paragon Plus Environment

Page 15 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ppm), methanol (3.31 ppm) or DMSO (2.50 ppm) as the internal standard peak. Infrared
(
IR) spectra were recorded on a JASCO FT/IR-410. Mass spectral data were obtained
on a Shimadzu Biotech Axima CFRplus in the linear and reflectron modes using a laser
λ = 337 nm), a Bruker Daltonics micro TOF-2focus in the positive ion detection mode,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
and a Thermo Fisher Scientific Q Exactive Hybrid Quadrupole-Orbitrap Mass
Spectrometer. Gel permeation chromatography (GPC) profiles were obtained on a
Shodex GPC-101 equipped with Shodex UV-41 and RI-71S detectors, and two Shodex
KF-804L columns (bead size = 7 μm, pore size = 200 Å). Tetrahydrofuran (THF) was
used as the eluent (temperature = 40 °C, flow rate = 2 mL/min), and calibration was
carried out using polystyrene standards. Isolation of the oligomer and polymer was
carried out with a Japan Analytical Industry (JAI) LC-908 recycling preparative HPLC
(eluent: chloroform) using two TSK-gel columns (2 x G2000HHR) and a JAI LC-9201
recycling preparative HPLC (eluent: chloroform) using JAIGEL-1H and -2H columns.
Preparative thin layer chromatography (PTLC) was performed on silica gel 60 F254
plates (Merck, Germany). X-ray crystallographic data on compounds 6a and 13 were
collected on a Bruker SMART APEX II ULTRA diffractometer attached with a CCD
detector and graphite-monochromated Mokα (λ = 0.71073 Å) radiation. Data were
corrected for absorption by the multiscan semiemprical method implemented in
SADABS and their crystal structures were solved by intrinsic phasing method SHELXT
30
and refined by SHELXL. Full-matrix least-squares refinement was performed on F2
for all unique reflections with anisotropic displacement parameters for non-hydrogen
atoms. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were
included as their calculated positions. UV spectra were recorded with JASCO V-650
and Shimadzu UV-1800, and CD spectra were recorded with JASCO J-820
spectropolarimeter using 2 mm and 10 mm quartz cells. The concentration of each
solution of CD experiments was adjusted so that the absorbance of the oligomer was 1
at the maximum absorption wavelength in the examined solvents.
Synthesis of Monomer 1. The monomer 1 was synthesized as shown in Scheme
S1.
23
(
(4-Bromophenyl)ethynyl)triisopropylsilane (14). In a round bottom flask with a
three-way stopcock, 1-bromo-4-iodobenzene (604 mg, 2.14 mmol), Pd(PPh ) Cl (151
3
2
2
mg, 0.215 mmol), and CuI (38 mg, 0.20 mmol) were added, and the flask was degassed
under reduced pressure and filled with argon. A dry DMF (21 mL) was added, and the
atmosphere in the flask was replaced with argon again. Then distilled Et N (0.75 mL,
3
5.4 mmol) and (triisopropylsilyl)acetylene (0.50 mL, 2.2 mmol) were added via
syringes from the three-way stopcock with a stream of nitrogen. After stirred at room
1
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
temperature for 6 h, the mixture was diluted with AcOEt, washed with 1 M
hydrochloric acid and brine, and dried over anhydrous MgSO . Purification with silica
4
gel column chromatography (hexane) gave a colorless liquid (719 mg) which was a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture of 14 (yield: 92%), 1-bromo-4-iodobenzene (recovery: 1%),
1
(triisopropylsilyl)acetylene (recovery: 1%), and its dimer (yield: 3%); H NMR (500
MHz, CDCl ) δ 7.43 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 9.0 Hz, 2H), 1.13–1.12 (m, 21H);
3
1
3
1
C{ H} NMR (126 MHz, CDCl ) δ 133.4, 131.4, 122.5, 122.4, 105.8, 92.0, 18.6, 11.2;
3
IR (neat) 3081, 3054, 2891, 2864, 2158, 1585, 1485, 1384, 1071, 824 cm−1.
(S)-N-(1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)-4-((triisopropylsilyl)ethynyl)a
3
1
t
t
22
niline (16). Pd(P Bu ) (0.325 g, 0.636 mmol), BuONa (3.00 g, 31.2 mmol) and 15
3
2
(
3.70 g, 20.9 mmol) were placed in a round bottom flask with a three-way stopcock, and
the flask was degassed under reduced pressure and filled with argon. A degassed
solution of 14 containing small amount of 1-bromo-4-iodobenzene,
a
(triisopropylsilyl)acetylene, and its dimer (7.06 g, 14 = 18.6 mmol) in dry toluene (64
mL) was added to the flask via syringes from the three-way stopcock with a stream of
nitrogen. The flask was cooled to 0 °C, degassed under reduced pressure, and filled with
argon. Then, the mixture was stirred at 90 °C in an oil bath for 2 h, cooled to room
temperature, diluted with CH Cl , and filtered with Celite. The filtrate was washed with
2
2
1
M hydrochloric acid and water, and dried over anhydrous Na SO . The crude product
2 4
was purified with silica gel column chromatography (AcOEt/hexane = 1/2) to give 16 as
1
a light brown syrup (6.93 g, 86%); H NMR (500 MHz, CDCl ) δ 7.28 (d, J = 9.0 Hz,
3
2H), 6.51 (d, J = 9.0 Hz, 2H), 4.10 (br m, 1H), 3.68–3.59 (m, 7H), 3.55–3.47 (m, 4H),
13
1
3
.38 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.11–1.10 (m, 21H); C{ H} NMR (126 MHz,
CDCl ) δ 147.5, 133.3, 112.7, 111.4, 108.3, 87.0, 74.3, 71.9, 70.7, 70.6, 70.5, 59.0, 48.1,
3
1
8.7, 17.7, 11.4; IR (neat) 3360, 2941, 2865, 2361, 2145, 1608, 1518, 1365, 1104, 1017
−
1
cm .
S)-4-Ethynyl-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)aniline (17).32
(
A
1.0 M solution of tetrabutylammonium fluoride in THF (18 mL, 18 mmol) was added to
a solution of 16 (6.50 g, 15.0 mmol) in dry THF (14.8 mL) stirred at 0 °C, and the
mixture was stirred at 0 °C for 2.5 h. A saturated aqueous solution of ammonium
chloride and water was added successively, and the mixture was extracted with Et O.
2
The organic layer was washed with brine and dried over anhydrous Na SO .
2
4
Purification with silica gel column chromatography (AcOEt/hexane = 1/1) gave 17 as a
1
light brown syrup (3.96 g, 95%); H NMR (500 MHz, CDCl ) δ 7.29 (d, J = 9.0 Hz, 2H),
3
6
.52 (d, J = 9.0 Hz, 2H), 4.15 (br m, 1H), 3.69–3.61 (m, 7H), 3.55–3.47 (m, 4H), 3.38 (s,
1
6
ACS Paragon Plus Environment

Page 17 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
1
3H), 2.94 (s, 1H), 1.22 (d, J = 6.6 Hz, 3H); C{ H} NMR (126 MHz, CDCl ) δ 147.9,
3
1
33.4, 112.7, 109.6, 84.7, 74.5, 74.3, 71.9, 70.7, 70.53, 70.50, 59.0, 48.0, 17.7; IR (neat)
−
1
3490, 2873, 2097, 1351, 1328, 1259, 1199, 1174, 1028, 825 cm .
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phenyl 4-iodobenzoate (18). A mixture of 4-iodobenzoic acid (7.00 g, 28.2 mmol)
in thionyl chloride (17 mL, 23 mmol) was refluxed in an oil bath for 12 h under an
argon atmosphere, and then concentrated under reduced pressure. To the residue was
added dry CH Cl (96 mL), a solution of phenol (2.64 g, 28.1 mmol) in dry CH Cl (9
2
2
2
2
mL), and Et N (4.40 mL, 31.7 mmol), successively, and the mixture was stirred at room
3
temperature for 3 h. After addition of water, the mixture was extracted with CH Cl .
2
2
The organic layer was washed with 1 M hydrochloric acid, water, and a saturated
aqueous solution of NaHCO , and dried over anhydrous MgSO . Recrystallization of
3
4
the crude product from AcOEt-hexane gave 18 as colorless plates (7.46 g, 82%); mp
1
131.6−135.1 °C; H NMR (500 MHz, CDCl ) δ 7.91 (d, J = 8.5 Hz, 2H), 7.88 (d, J =
3
8
.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H);
−
1
IR (KBr) 1732, 1582, 1281, 1203, 1179, 1075, 1054, 1001, 750, 702, 510 cm .
Phenyl
(S)-4-((4-((1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)amino)phenyl)ethynyl)ben
33
zoate (1). In a round bottom flask equipped with a three-way stopcock, 18 (4.29 g,
13.2 mmol), Pd(PPh ) (0.705 g, 0.610 mmol), and CuI (0.232 g, 1.22 mmol) were
3
4
placed, and the flask was degassed under reduced pressure and filled with argon.
Distilled Et N (126 mL, 908 mmol) and a solution of 17 (3.49 g, 12.6 mmol, dried
3
azeotropically twice with toluene) in dry THF (126 mL) were added successively via
syringes from the three-way stopcock with a stream of nitrogen, and the atmosphere in
the flask was replaced with argon again. After stirred at room temperature for 2.5 h, a
saturated aqueous solution of ammonium chloride was added, and the mixture was
extracted with AcOEt. The organic layer was washed water and brine, and dried over
anhydrous Na SO . Purification with silica gel column chromatography (AcOEt/hexane
2
4
1
=
1/1) afforded 1 as a yellow syrup (5.58 g, 94%); H NMR (500 MHz, CDCl ) δ 8.15
3
(d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.37 (d, J = 8.6
Hz, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 6.58 (d, J = 8.6 Hz, 2H),
4.24 (d, J = 7.7 Hz, 1H), 3.74–3.61 (m, 7H), 3.57–3.51 (m, 4H), 3.39 (s, 3H), 1.25 (d, J
13
1
=
6.6 Hz, 3H); C{ H} NMR (126 MHz, CDCl ) δ 164.8, 150.9, 148.1, 133.2, 131.1,
3
130.0, 129.7, 129.5, 127.9, 125.9, 121.7, 112.8, 110.0, 94.7, 86.8, 74.3, 71.9, 70.7, 70.6,
0.5, 59.0, 48.1, 17.7; IR (neat) 2874, 2206, 1734, 1370, 1332, 1263, 1198, 1072, 824
7
−
1
cm .
Polymerization of 1.
1
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Polymerization with LiHMDS. All glass apparatus was dried prior to use. Addition
of reagents into the reaction flask was conducted via a syringe from the three-way
stopcock with a stream of nitrogen. A round bottom flask equipped with a three-way
stopcock was heated under reduced pressure and then cooled to room temperature under
an argon atmosphere. A 1 M solution of LiHMDS in THF (0.40 mL, 0.40 mmol) was
placed in the flask, and the atmosphere in the flask was replaced with argon. A solution
of the monomer 1 (187 mg, 0.396 mmol, dried at 50 °C under reduced pressure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
34
overnight prior to use) and phenyl 4-methylbenzoate (2.3 mg, 0.011 mmol) in dry
THF (0.5 mL) was added at room temperature, and the mixture was stirred at room
temperature for 8 days. An aqueous saturated solution of ammonium chloride was
added, and the mixture was extracted with CH Cl . The organic layer was washed with
2
2
water and brine, dried over anhydrous MgSO , and concentrated under reduced pressure
4
to give the crude product (111 mg) as a deep yellow syrup. Separation of the crude
1
product by preparative HPLC afforded the cyclic trimer; H NMR (500 MHz, CDCl ) δ
3
7.26–7.25 (m, 6H), 7.20 (d, J = 8.3 Hz, 6H), 7.14 (d, J = 8.3 Hz, 6H), 7.11–7.05 (br m,
6
H), 5.12 (sext, J = 7.2 Hz, 3H), 3.75-3.47 (m, 30H), 3.39 (s, 9H), 1.18 (d, J = 7.2 Hz,
+
9H); MALDI-TOF MS (dithranol) calcd for C H N O [M + Na] 1160.53, found
6
9
75
3
12
1
160.40.
Polymerization with KHMDS. All glass apparatus was dried prior to use. Addition
of reagents into the reaction flask was conducted via a syringe from the three-way
stopcock with a stream of nitrogen. A round bottom flask equipped with a three-way
stopcock was heated under reduced pressure and then cooled to room temperature under
an argon atmosphere. To a 0.5 M solution of KHMDS in toluene (0.80 mL, 0.40 mmol)
in the flask was added a solution of 18-crown-6 (520 mg, 1.97 mmol, dried at 50 °C
under reduced pressure overnight prior to use) in dry THF (0.25 mL), and the solution
was stirred at 50 °C in an oil bath. A solution of the monomer 1 (191 mg, 0.402 mmol,
dried azeotropically twice with toluene prior to use) and phenyl 4-methylbenzoate (2.7
mg, 0.013 mmol) in dry THF (0.25 mL) was added, and the mixture was stirred at 50 °C
in an oil bath for 26 h. After the mixture was cooled to room temperature, an aqueous
saturated solution of ammonium chloride was added, and the mixture was extracted
with CH Cl . The organic layer was washed with water and brine, dried over anhydrous
2
2
MgSO , and concentrated under reduced pressure to give the crude product as a light
4
brown syrup (382 mg, M = 9210, M /M = 6.18). Purification of the crude product by
n
w
n
silica gel column chromatography (MeOH), followed by preparative HPLC afforded the
product (12 mg, M = 6230, M /M = 1.40).
n
w
n
Polymerization with Et SiH, CsF, and 18-crown-6. All glass apparatus was dried
3
1
8
ACS Paragon Plus Environment

Page 19 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
prior to use. Addition of reagents into the reaction flask was conducted via a syringe
from the three-way stopcock with a stream of nitrogen. Cesium fluoride (91.0 mg, 0.599
mmol) was placed in a round bottom flask equipped with a three-way stopcock, and
dried at 250 °C under reduced pressure. Then, the flask was cooled to room temperature
under an argon atmosphere. A solution of 1 (189 mg, 0.399 mmol, dried azeotropically
twice with toluene prior to use), triethylsilane (67.5 mg, 0.580 mmol), and 18-crown-6
(320 mg, 1.21 mmol, dried at 50 °C under reduced pressure overnight prior to use) in
dry THF (0.2 mL) was added to the flask at room temperature, and the mixture was
stirred at 50 °C in an oil bath for 36 h. After the mixture was cooled to room
temperature, an aqueous saturated solution of ammonium chloride was added, and the
mixture was extracted with CH Cl . The organic layer was washed with brine, dried
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
over anhydrous MgSO , and concentrated under reduced pressure to give the crude
4
product (M = 2490, M /M = 1.24).
n
w
n
Synthesis of Monomer 2. The monomer 2 was synthesized as shown in Scheme
S2.
(S)-4-Iodo-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)-N-(4-((triisopropylsilyl)
ethynyl)phenyl)benzamide (19). To a round bottom flask was added a solution of
4-iodobenzoyl chloride (4.62 g, 20.4 mmol) in dry CH Cl (17 mL), Et N (1.4 mL, 10
2
2
3
mmol), and a solution of 16 (3.50 g, 8.08 mmol) in dry CH Cl (16 mL), and the
2
2
mixture was stirred at room temperature for 17 h under an argon atmosphere. After
addition of water, the mixture was extracted with CH Cl , and the organic layer was
2
2
washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of NaHCO3,
and dried over anhydrous Na SO . Silica gel column chromatography (AcOEt/CH Cl =
2
4
2
2
1
6/1) gave 19 as a brown syrup (4.63 g, 94%); H NMR (500 MHz, CDCl ) δ 7.50 (d, J =
3
6
.9 Hz, 2H), 7.33 (d, J = 7.7 Hz, 2H), 7.06 (d, J = 7.2 Hz, 2H), 7.03–6.89 (m, 2H), 5.05
(br m, 1H), 3.71–3.62 (m, 5H), 3.59–3.53 (m, 3H), 3.47 (br m, 2H), 3.37 (s, 3H),
13
1
1
.14–1.08 (m, 24H); C{ H} NMR (151 MHz, CDCl ) δ 170.1, 139.7, 136.9, 136.4,
3
132.6, 130.2, 130.0, 122.8, 106.0, 95.7, 92.0, 72.0, 71.8, 70.6, 70.5, 70.2, 59.0, 52.2,
8.6, 15.3, 11.2; IR (neat) 2942, 2864, 2155, 1646, 1221, 1118, 1040, 882, 823, 501
1
−
1
+
+
cm . HRMS (ESI ) m/z calcd for C H INO Si [M + H] 664.2314, found 664.2308.
3
2
47
4
(S)-N-(4-Ethynylphenyl)-4-iodo-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)b
32
enzamide (2). In a round bottom flask, 19 (4.30 g, 6.48 mmol) was dissolved in dry
THF (6.2 mL), and the solution was stirred at 0 °C. A 1.0 M solution of
tetrabutylammonium fluoride in THF (8.4 mL, 8.4 mmol) was added, and the mixture
1
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was stirred at 0 °C for 24 h under an argon atmosphere. After addition of a saturated
aqueous solution of ammonium chloride and water, the mixture was extracted with Et O,
2
and the organic layer was washed with brine and dried over anhydrous Na SO . The
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
crude product was purified with silica gel column chromatography (AcOEt/hexane =
1
1/1), which afforded 2 as a pale yellow syrup (2.97 g, 90%); H NMR (500 MHz,
CDCl ) δ 7.48 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H),
3
7.04–6.84 (br m, 2H), 5.03 (br m, 1H), 3.71–3.61 (m, 5H), 3.59–3.42 (m, 5H), 3.37 (s,
13
1
3
H), 3.09 (s, 1H), 1.14 (d, J = 7.2 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 170.1,
3
140.3, 136.9, 136.3, 132.7, 130.3, 129.9, 121.4, 95.7, 82.6, 78.4, 71.9, 71.8, 70.6, 70.5,
0.2, 59.0, 52.4, 15.4; IR (neat) 3287, 2976, 2875, 1645, 1456, 1199, 1076, 1107, 1058,
7
−
1
822 cm .
25
Polymerization of Monomer 2. The monomer 2 (153 mg, 0.302 mmol) was
placed in a round bottom flask and dried azeotropically twice with toluene.
Pd(PPh ) Cl (8.9 mg, 0.013 mmol) was added, and the flask was degassed under
3
2
2
reduced pressure and filled with argon. Then Et N (0.14 mL, 1.0 mmol) was added via a
3
syringe from the three-way stopcock with a stream of nitrogen, and the mixture was
stirred at 70 °C in an oil bath for 4 h and then cooled to room temperature. Water was
added, and the mixture was extracted with CH Cl . The organic layer was washed with
2
2
1 M hydrochloric acid and waster, dried over anhydrous Na SO , and concentrated
2
4
under reduced pressure to give the crude product (M = 9380, M /M = 2.05).
n
w
n
Purification of the crude product by reprecipitation (CH Cl -hexane) followed by
2
2
1
preparative HPLC gave the polymer -DPA (51.6 mg, M = 14900, M /M = 1.58); H
n
w
n
NMR (500 MHz, CDCl ) δ 7.47–6.97 (m, 8H), 5.04 (br m, 1H), 3.72–3.41 (m, 10H),
3
13
1
3
.35 (s, 3H), 1.14 (d, J = 6.3 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 170.2, 140.0,
3
136.8, 132.0, 130.9, 130.3, 128.2, 123.7, 122.1, 89.8, 89.6, 71.9, 71.8, 70.6, 70.5, 70.1,
5
9.0, 52.3, 15.4.
Synthesis of Monomer 3. The monomer 3 was synthesized as shown in Scheme
S3.
3
3
4-((Triisopropylsilyl)ethynyl)aniline (20). In a round bottom flask equipped with a
three-way stopcock, 4-iodoaniline (110 mg, 0.502 mmol), Pd(PPh ) (29.8 mg, 0.0258
3
4
mmol), and CuI (10.1 mg, 0.0530 mmol) were placed, and the flask was degassed under
reduced pressure and filled with argon. Dry THF (5.0 mL) was added via a syringe from
the three-way stopcock with a stream of nitrogen, and the atmosphere in the flask was
replaced with argon again. Then (triisopropylsilyl)acetylene (0.13 mL, 0.58 mmol) and
distilled Et N (5.0 mL, 36 mmol) were added via syringes from the three-way stopcock
3
with a stream of nitrogen, and the atmosphere in the flask was replaced with argon again.
2
0
ACS Paragon Plus Environment

Page 21 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
After stirred at room temperature for 3 h, AcOEt was added, and the mixture was
filtered with Celite. The filtrate was washed with 1 M hydrochloric acid, water, and
brine, and dried over anhydrous MgSO . Purification with silica gel column
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography (AcOEt/hexane = 1/7) afforded 20 as a brown syrup (122 mg, 89%);
1
H NMR (600 MHz, CDCl ) δ 7.28 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 8.3 Hz, 2H), 3.78
3
13
1
(
br s, 2H), 1.13–1.11 (m, 21H); C{ H} NMR (126 MHz, CDCl ) δ 146.6, 133.4, 114.5,
3
113.1, 107.9, 87.5, 18.7, 11.4; IR (neat) 3480, 2148, 1886, 1621, 1606, 1512, 1463,
230, 1174, 1126 cm−1.
1
2-Nitro-N-(4-((triisopropylsilyl)ethynyl)phenyl)benzenesulfonamide (21).35
A
mixture of 20 (12.0 g, 42.8 mmol) in pyridine (125 mL, 1.55 mol) was stirred at 0 °C,
and 2-nitrobenzenesulfonyl chloride (12.7 g, 57.2 mmol) was added. The mixture was
stirred at room temperature for 1 day, and 1 M hydrochloric acid was added. The
mixture was extracted with CH Cl , and the organic layer was washed with water and
2
2
dried over anhydrous Na SO . The crude product was purified successively with silica
2
4
gel column chromatography (CH Cl /hexane = 1/1) and recrystallization from
2
2
1
CH Cl -hexane to give 21 as pale yellow needles (16.1 g, 83%); H NMR (600 MHz,
2
2
CDCl ) δ 7.86–7.84 (m, 2H), 7.70 (dt, J = 1.4 and 7.9 Hz, 1H), 7.58 (dt, J = 1.4 and 7.9
3
Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.31 (br s, 1H), 7.14 (d, J = 8.6 Hz, 2H), 1.12–1.04
1
3
1
(m, 21H); C{ H} NMR (151 MHz, CDCl ) δ 148.2, 135.3, 134.1, 133.2, 132.7, 132.0,
3
1
31.9, 125.4, 122.5, 121.7, 105.8, 91.7, 18.6, 11.2.
(S)-N-(1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)-2-nitro-N-(4-((triisopropylsilyl)
3
5
ethynyl)phenyl)benzenesulfonamide (22). To a mixture of 21 (15.0 g, 34.0 mmol),
S)-2-(methoxyethoxyethoxy)propanol21,36 (3.99 g, 22.4 mmol), and triphenylphosphine
(
(9.49 g, 36.2 mmol) in dry THF (150 mL) stirred at 0 °C was added a 2.2 M solution of
diethyl azodicarboxylate in toluene (17 mL, 37 mmol). The mixture was stirred at room
temperature for 1 day and concentrated under reduced pressure. The residue was
purified with silica gel column chromatography (AcOEt/hexane = 1/2) to afford 22 as a
1
yellow syrup (13.8 g, 99%); H NMR (600 MHz, CDCl ) δ 7.64–7.58 (m, 2H), 7.52 (dd,
3
J = 1.4 and 7.9 Hz, 1H), 7.47 (ddd, J = 1.4, 6.8, and 8.2 Hz, 1H), 7.38 (d, J = 8.6 Hz,
2H), 7.22 (d, J = 8.6 Hz, 2H), 3.85 (dd, J = 7.2 and 14.4 Hz, 1H), 3.76 (dd, J = 4.8 and
1
4.4 Hz, 1H), 3.62–3.57 (m, 3H), 3.54–3.49 (m, 5H), 3.43–3.40 (m, 1H), 3.36 (s, 3H),
1
3
1
1.17 (d, J = 6.2 Hz, 3H), 1.12–1.10 (m, 21H); C{ H} NMR (151 MHz, CDCl ) δ
3
1
47.9, 138.8, 133.6, 132.9, 132.1, 131.9, 131.1, 129.0, 123.8, 123.4, 105.9, 92.4, 74.5,
71.9, 70.6, 70.5, 68.2, 59.0, 56.9, 18.6, 17.3, 11.2.
2
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(S)-N-(1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)-4-((triisopropylsilyl)ethynyl)a
35
niline (23). Thiophenol (113 mg, 1.03 mmol) and Cs CO (1.44 g, 4.42 mmol) were
2
3
added to a mixture of 22 (501 mg, 0.810 mmol) in acetonitrile (8.5 mL), and the
mixture was stirred at 70 °C in an oil bath for 4 h, poured into water, and extracted with
CH Cl . The organic layer was washed with water and dried over anhydrous MgSO .
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
4
Silica gel column chromatography (AcOEt/hexane = 1/3) gave 23 as a yellow syrup
1
(311 mg, 89%); H NMR (600 MHz, CDCl ) δ 7.28 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 8.6
3
Hz, 2H), 4.51 (br m, 1H), 3.76–3.68 (m, 2H), 3.67–3.61 (m, 4H), 3.59–3.53 (m, 3H),
3.38 (s, 3H), 3.21 (br d, J = 12.4 Hz 1H), 3.03 (dd, J = 7.9 and 12.7 Hz, 1H) 1.21 (d, J =
13
1
6
.2 Hz, 3H), 1.12-1.10 (m, 21H); C{ H} NMR (151 MHz, CDCl ) δ 148.5, 133.3,
3
112.4, 111.4, 108.3, 87.0, 74.2, 71.9, 70.7, 70.5, 68.0, 59.0, 48.8, 18.7, 17.8, 11.4.
(S)-4-Iodo-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)-N-(4-((triisopropylsilyl)
ethynyl)phenyl)benzamide (24). To a round bottom flask was added a solution of
4-iodobenzoyl chloride (221 mg, 0.829 mmol) in dry CH Cl (1.2 mL), Et N (0.12 mL,
2
2
3
0
.87 mmol), and a solution of 23 (302 mg, 0.696 mmol) in dry CH Cl (1.1 mL), and
2 2
the mixture was stirred at room temperature for 2.5 h under an argon atmosphere. After
addition of water, the mixture was extracted with CH Cl , and the organic layer was
2
2
washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of NaHCO3,
and dried over anhydrous Na SO . Silica gel column chromatography (AcOEt/hexane =
2
4
1
1/2) gave 24 as a yellow syrup (405 mg, 88%); H NMR (600 MHz, CDCl ) δ 7.53 (d, J
3
=
8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz,
2H), 4.05 (d, J = 11.7 Hz, 1H), 3.90 (br m, 1H), 3.71 (ddd, J = 3.8, 5.5, and 10.3 Hz,
H), 3.64 (dd, J = 8.6 and 14.1 Hz, 1H), 3.62–3.54 (m, 4H), 3.52–3.47 (m, 3H), 3.35 (s,
1
1
3
1
3H), 1.18 (d, J = 6.2 Hz, 3H), 1.12–1.09 (m, 21H); C{ H} NMR (151 MHz, CDCl ) δ
3
1
69.6, 144.3, 137.1, 135.5, 132.7, 130.5, 127.4, 121.6, 106.1, 96.5, 91.5, 73.5, 71.9,
+
70.8, 70.5, 68.2, 59.0, 56.6, 18.6, 17.5, 11.2. HRMS (ESI ) m/z calcd for C H INO Si
3
2
47
4
+
[
M + H] 664.2314, found 664.2305.
(S)-N-(4-Ethynylphenyl)-4-iodo-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)b
3
2
enzamide (3). In a round bottom flask, 24 (5.00 g, 7.53 mmol) was dissolved in dry
THF (7.1 mL), and the solution was stirred at 0 °C. A 1.0 M solution of
tetrabutylammonium fluoride in THF (9.8 mL, 9.8 mmol) was added, and the mixture
was stirred at room temperature for 10 h under an argon atmosphere. After addition of a
saturated aqueous solution of ammonium chloride and water, the mixture was extracted
with Et O, and the organic layer was washed with brine and dried over anhydrous
2
2
2
ACS Paragon Plus Environment

Page 23 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Na SO . The crude product was purified with silica gel column chromatography
2
4
1
(
AcOEt/hexane = 2/1), which afforded 3 as a yellow syrup (3.38 g, 88%); H NMR (600
MHz, CDCl ) δ 7.52 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
H), 7.03 (d, J = 8.6 Hz, 2H), 4.13–4.04 (m, 1H), 3.96–3.89 (m, 1H), 3.73–3.70 (m, 1H),
3.64–3.53 (m, 5H), 3.52–3.47 (m, 3H), 3.35 (s, 3H), 3.06 (s, 1H), 1.19 (d, J = 6.2 Hz,
13
1
3
H); C{ H} NMR (151 MHz, CDCl ) δ 169.6, 144.8, 137.0, 135.4, 132.8, 130.4,
3
127.5, 120.1, 96.5, 82.8, 77.9, 73.4, 71.9, 70.7, 70.4, 68.2, 59.0, 56.6, 17.4.
25
Polymerization of Monomer 3. The monomer 3 (152 mg, 0.300 mmol) and
Pd(PPh ) Cl (10.4 mg, 0.0148 mmol) were placed in a round bottom flask, and the
3
2
2
flask was degassed under reduced pressure and filled with argon. Dry THF (0.4 mL)
and Et N (0.13 mL, 0.94 mmol) were added successively via syringes from the
3
three-way stopcock with a stream of nitrogen, and the mixture was stirred at 50 °C in an
oil bath for 1 h and then cooled to room temperature. Water was added, and the mixture
was extracted with CH Cl . The organic layer was washed with 1 M hydrochloric acid
2
2
and waster, dried over anhydrous Na SO , and concentrated under reduced pressure to
2
4
give the crude product (M = 6680, M /M = 1.87). Purification of the crude product by
n
w
n
1
preparative HPLC gave the polymer -DPA (34.3 mg, M = 14200, M /M = 1.31); H
n
w
n
NMR (600 MHz, CDCl ) δ 7.34–7.27 (m, 6H), 7.14 (d, J = 8.3 Hz, 2H), 4.16–4.03 (m,
3
1H), 3.94 (m, 1H), 3.74–3.46 (m, 9H), 3.35–3.27 (m, 3H), 1.20 (d, J = 6.2 Hz, 3H);
13
1
C{ H} NMR (151 MHz, CDCl ) δ 169.7, 144.6, 135.7, 132.2, 131.0, 128.8, 127.6,
3
124.5, 120.8, 90.2, 89.4, 73.5, 71.9, 70.8, 70.5, 68.3, 59.0, 56.5, 17.5.
Synthesis of 4. The compound 4 was synthesized as shown in Scheme S4.
(S)-4-((4-((1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)amino)phenyl)ethynyl)-N,
N-dimethylbenzamide (25).22,37 Dimethylamine hydrochloride (173 mg, 2.12 mmol)
and dry toluene (3.3 mL) were placed in a round bottom flask. The flask was degassed
under reduced pressure and filled with argon, and the mixture was stirred at 0 °C. A 2 M
solution of trimethylaluminum in toluene (1.1 mL, 2.2 mmol) was added dropwise, and
the mixture was stirred at room temperature for 1 h. Then, a solution of 1 (75.4 mg,
0
.159 mmol) in dry toluene (0.5 mL) was added, and the mixture was stirred at room
temperature for 40.5 h. After addition of 1 M hydrochloric acid, the mixture was
neutralized with a saturated aqueous solution of NaHCO and extracted with AcOEt.
3
The organic layer was washed with brine and dried over anhydrous MgSO . The crude
4
product was purified with silica gel column chromatography (AcOEt) to give 25 as a
1
yellow solid (380 mg, 84%); H NMR (500 MHz, CDCl ) δ 7.50 (d, J = 8.6 Hz, 2H),
3
7
.37 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.9 Hz, 2H), 4.32–4.10
2
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(br m, 1H), 3.72–3.60 (m, 7H), 3.56–3.49 (m, 4H), 3.39 (s, 3H), 3.11 (br s, 3H), 2.99 (br
13
1
s, 3H), 1.24 (d, J = 6.6 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 171.2, 147.8,
3
134.9, 133.0, 131.1, 127.1, 125.6, 112.8, 110.4, 92.1, 86.6, 74.3, 71.9, 70.7, 70.6, 70.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
9.0, 48.1, 39.5, 35.4, 17.7; IR (KBr) 3449, 2925, 2878, 2204, 1636, 1598, 1389, 1136,
−
1
1109, 824 cm .
(S)-4-((4-(N-(1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)acetamido)phenyl)ethy
nyl)-N,N-dimethylbenzamide (4). The compound 25 (39.8 mg, 0.0938 mmol) and dry
pyridine (19.1 mg, 0.241 mmol) were dissolved in dry CH Cl (0.24 mL) in a round
2
2
bottom flask equipped with a three-way stopcock, and the flask was degassed under
reduced pressure and filled with argon. The mixture was stirred at 0 °C, and a solution
of acetyl chloride (18 mg, 0.23 mmol) in dry CH Cl (2.2 mL) was added dropwise via
2
2
a syringe from the three-way stopcock with a stream of nitrogen. After the mixture was
stirred at room temperature for 1.5 h, water was added, and mixture was extracted with
CH Cl . The organic layer was washed with 1 M hydrochloric acid and a saturated
2
2
aqueous solution of NaHCO and dried over anhydrous MgSO . Silica gel column
3
4
chromatography (MeOH/AcOEt = 1/10) of the crude product afforded 4 as a yellow
1
syrup (29.5 mg, 67%); H NMR (500 MHz, CDCl ) δ 7.57–7.55 (m, 4H), 7.41 (d, J =
3
8.3 Hz, 2H), 7.23 (br m, 2H), 5.12–5.05 (m, 1H), 3.68–3.60 (m, 5H), 3.56–3.49 (m, 3H),
3
.38 (s, 3H), 3.33 (dd, J = 4.9 and 10.6 Hz, 1H), 3.27–3.23 (m, 1H), 3.11 (br s, 3H),
1
3
1
2.99 (br s, 3H), 1.76 (s, 3H), 1.02 (d, J = 7.2 Hz, 3H); C{ H} NMR (126 MHz,
CDCl ) δ 170.8, 170.4, 139.3, 136.1, 132.5, 131.5, 130.4, 127.2, 124.1, 123.1, 89.9,
3
89.5, 71.9, 71.8, 70.51, 70.46, 70.0, 59.0, 49.4, 39.5, 35.3, 23.5, 15.5; IR (neat) 2961,
925, 2873, 2218, 1656, 1637, 1451, 1327, 1102, 801 cm−1.
2
Synthesis of 5. The compound 5 was synthesized as shown in Scheme S5.
Phenyl
(S)-4-((4-(N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)acetamido)phenyl)ethy
nyl)benzoate (26). The compound 1 (449 mg, 0.948 mmol) and dry pyridine (0.15 mL,
1.9 mmol) were dissolved in dry CH Cl (2.8 mL) in a round bottom flask equipped
2
2
with a three-way stopcock, and the flask was degassed under reduced pressure and filled
with argon. The mixture was stirred at 0 °C, and a solution of acetyl chloride (153 mg,
1
.95 mmol) in dry CH Cl (1.9 mL) was added dropwise via a syringe from the
2 2
three-way stopcock with a stream of nitrogen. After the mixture was stirred at room
temperature for 14 h, water was added, and mixture was extracted with CH Cl . The
2
2
organic layer was washed with 1 M hydrochloric acid and a saturated aqueous solution
of NaHCO and dried over anhydrous MgSO . Silica gel column chromatography
3
4
2
4
ACS Paragon Plus Environment

Page 25 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
(AcOEt) of the crude product afforded 26 as a brown syrup (436 mg, 89%); H NMR
600 MHz, CDCl ) δ 8.20 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 8.9
(
3
Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H),
.40–7.07 (br m, 2H), 5.10 (sext, J = 6.9 Hz, 1H), 3.68–3.64 (m, 5H), 3.57–3.51 (m,
3H), 3.39 (s, 3H), 3.35 (br dd, J = 4.8 and 10.3 Hz, 1H), 3.27 (br t, J = 9.6 Hz, 1H), 1.78
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
13
1
(
s, 3H), 1.04 (d, J = 6.9 Hz, 3H); C{ H} NMR (126 MHz, CDCl ) δ 170.3, 164.6,
3
150.8, 139.7, 132.7, 131.7, 130.6, 130.1, 129.5, 129.1, 128.2, 126.0, 122.8, 121.6, 91.6,
9.7, 72.0, 71.8, 70.6, 70.5, 70.0, 59.0, 49.5, 23.6, 15.5; IR (neat) 2976, 2928, 2875,
8
−
1
+
2218, 1736, 1655, 1599, 1016, 763, 690 cm . HRMS (ESI ) m/z calcd for C H NO
6
3
1
34
+
[
M + H] 516.2381, found 516.2374.
(
S)-4-((4-(N-(1-(2-(2-Methoxyethoxy)ethoxy)propan-2-yl)acetamido)phenyl)ethy
nyl)benzoic acid (27). A mixture of 26 (193 mg, 0.375 mmol) and ground NaOH (88.8
mg, 2.22 mmol) in dry THF (1.5 mL) in a round bottom flask was stirred at room
temperature for 11 h. The mixture was acidified by the addition of 2 M hydrochloric
acid and extracted with CH Cl . The organic layer was dried over anhydrous MgSO .
2
2
4
Purification of the crude product by silica gel column chromatography (MeOH/AcOEt =
1
3
/10) gave 27 as a colorless solid (164 mg, quant); H NMR (500 MHz, CDCl ) δ 8.05
3
(br d, J = 8.0 Hz, 2H), 7.51 (br d, J = 8.9 Hz, 2H), 7.48 (br d, J = 8.0 Hz, 2H), 7.12 (br
m, 2H), 5.11–5.05 (m, 1H), 3.70–3.60 (m, 5H), 3.57–3.48 (m, 3H), 3.34 (s, 3H),
1
3
1
3.30–3.20 (m, 2H), 1.69 (s, 3H), 0.94 (br d, J = 6.9 Hz, 3H); C{ H} NMR (151 MHz,
CDCl ) δ 172.9, 170.7, 138.9, 136.2, 132.5, 130.9, 130.3, 129.7, 124.8, 123.3, 90.7,
3
89.5, 71.9, 71.7, 70.2, 69.8, 58.9, 49.2, 23.4, 15.4; IR (KBr) 3423, 2878, 2217, 1701,
−1
−
1
655, 1499, 1458, 1383, 1276, 789 cm . HRMS (ESI ) m/z calcd for C H NO [M −
25 28 6
−
H] 438.1922, found 438.1926.
The dimer 5. A mixture of 27 (65.7 mg, 0.149 mmol) in thionyl chloride (0.8 mL, 11
mmol) was stirred at room temperature for 1 day, and then concentrated under reduced
pressure. Dry CH Cl (0.22 mL) was added to the residue, and the mixture was stirred at
2
2
0 °C. Then, a solution of 25 (70.6 mg, 0.166 mmol) and dry pyridine (61.0 mg, 0.771
mmol) in dry CH Cl (0.54 mL) was added and the mixture was stirred at room
2
2
temperature for 2.5 h. After addition of water, the mixture was extracted with CH Cl .
2
2
The organic layer was washed with 1 M hydrochloric acid and a saturated aqueous
solution of NaHCO , and dried over anhydrous MgSO . Silica gel column
3
4
chromatography (MeOH/AcOEt = 1/9) of the crude product afforded 5 as a yellow solid
1
(35 mg, 28%); H NMR (500 MHz, CDCl ) δ 7.52–7.50 (m, 4H), 7.40–7.38 (m, 4H),
3
7
.35–7.03 (br m, 8H), 5.11–5.04 (m, 2H), 3.76–3.46 (m, 18H), 3.39 (s, 3H), 3.37 (s, 3H),
2
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3.32 (br dd, J = 5.2 and 10.3 Hz, 1H), 3.26–3.22 (br m, 1H), 3.11 (br s, 3H), 2.98 (br s,
13
1
3
H), 1.75 (s, 3H), 1.19 (br d, J = 6.9 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H); C{ H} NMR
(126 MHz, THF-d , 60 °C) δ 170.2, 169.7, 169.0, 142.2, 141.6, 138.6, 138.0, 132.8,
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
32.5, 131.7, 131.5, 131.4, 131.3, 129.3, 128.1, 124.8, 124.4, 123.6, 122.7, 90.4, 90.27,
90.26, 90.2, 72.91, 72.86, 72.85, 72.82, 71.4, 71.3, 71.24, 71.20, 71.1, 70.9, 58.75,
8.70, 54.0, 51.2, 30.4, 25.6, 23.1, 15.7, 15.5; IR (KBr) 2929, 2873, 2216, 1655, 1638,
5
−
1
1398, 1341, 1262, 1104, 1019 cm .
Synthesis of 6a and 7a. The compounds 6a and 7a were synthesized as shown in
Scheme S6.
Methyl 4-((trimethylsilyl)ethynyl)benzoate (28).23c Methyl p-iodobenzoate (205.4
mg, 0.78 mmol), Pd(PPh ) Cl (26.8 mg, 5 mol%), triphenylphosphine (20.3 mg, 10
3
2
2
mol%), CuI (15.7 mg, 10 mol%), and DMF (8 mL) were placed in a two-neck round
bottom flask. Then, vacuum was applied, which was cancelled with argon (five times).
Into the stirred mixture at room temperature was added Et N (0.3 mL, 2.8 equiv) and
3
(trimethylsilyl)acetylene (0.14 mL, 1.3 equiv), and the mixture was stirred at room
temperature for 3 h. Then saturated aqueous ammonium chloride was added, and the
mixture was extracted with Et O. The organic layer was washed with water and brine,
2
and dried over anhydrous Na SO . The crude product was purified by silica gel column
2
4
chromatography (CH Cl /hexane = 1/2) to give 28 as a pale yellow solid (200.4 mg,
2
2
1
quant.); H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H),
3
3.91 (s, 3H), 0.26 (s, 9H).
Methyl 4-ethynylbenzoate (29).23c A 1.0 M solution of tetrabutylammonium fluoride
in THF (1 mL, 1 mmol) was added to a stirred solution of 28 (182.1 mg, 0.78 mmol) in
THF (7 mL) at room temperature. After stirred at room temperature for 10 min, the
mixture was diluted with AcOEt, washed with water three times and brine, and dried
over anhydrous Na SO . Purification with silica gel column chromatography
2
4
1
(AcOEt/hexane = 1/2) afforded 29 as a colorless solid (96.4 mg, 78%); H NMR (400
MHz, CDCl ) δ 7.99 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H), 3.23 (s,
3
1H).
Methyl 4-((4-aminophenyl)ethynyl)benzoate (30). Sonogashira coupling reaction
of 29 with p-iodoaniline was carried out in a manner similar to the synthesis of 28 by
addition of Et N (0.23 mL, 2.8 equiv) and p-iodoaniline (171.3 mg, 1.3 equiv) to a
3
degassed stirred mixture of 29 (96.4 mg, 0.60 mmol), Pd(PPh ) Cl (20.9 mg, 5 mol%),
3
2
2
triphenylphosphine (15.6 mg, 10 mol%), and CuI (12.0 mg, 10 mol%) in DMF (7 mL)
at room temperature, followed by stirring at that temperature for 3 h. Then saturated
aqueous ammonium chloride was added, and the mixture was extracted with Et O. The
2
2
6
ACS Paragon Plus Environment

Page 27 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
organic layer was washed with water and brine, and dried over anhydrous Na SO . The
2
4
crude product was purified by silica gel column chromatography (AcOEt/hexane = 1/4)
1
to give 30 as a yellow solid (107.8 mg, 71%); H NMR (400 MHz, CDCl ) δ 7.99 (d, J
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.2 Hz,
2H), 3.92 (s, 3H), 3.87 (br, 2H).
Methyl 4-((4-benzamidophenyl)ethynyl)benzoate (31). Triethylamine (0.07 mL,
1.2 equiv) was added to a solution of 30 (107.8 mg, 0.43 mmol) in dichloromethane (5
mL), and the mixture was stirred at 0 °C. Benzoyl chloride (0.05 mL, 1.0 equiv) was
added to the cold amine solution and the mixture was stirred at room temperature for 4
h. The white precipitates were collected and dried to give 31 (132.3 mg, 87%) as a
1
white powder; H NMR (400 MHz, CDCl ) δ 8.02 (d, J = 7.8 Hz, 2H), 7.88 (br, 3H),
3
7
.68 (m, 2H), 7.59 (m, 5H), 7.53 (m, 2H), 3.93 (s, 3H).
4-((4-Benzamidophenyl)ethynyl)benzoic acid (32). 31 (107.6 mg, 0.30 mmol)
and LiOH·H O (23.5 mg, 7 equiv) were dissolved in a mixture of THF (10 mL),
2
methanol (4 mL), and water (4 mL). The mixture was stirred for 3 h at room
temperature, acidified with 2 M HCl, and extracted with AcOEt. The organic layer was
dried over MgSO , filtered, and concentrated in vacuo to give 32 (85.0 mg, 82%) as a
4
1
white solid; H NMR (600 MHz, DMSO-d ) δ 10.48 (s, 3H), 7.97 (d, J = 8.2 Hz, 2H),
6
7.96 (d, J = 7.3 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.62-7.53 (m,
13
1
5
H). C{ H} NMR (151 MHz, DMSO-d ) δ 166.8, 165.9, 140.2, 134.8, 132.3, 131.9,
6
+
131.5, 129.7, 128.6, 127.8, 126.9, 120.2, 116.5, 92.4, 88.2. HRMS (ESI ) m/z calcd for
+
C H NO [M + H] 342.1125, found 342.1121.
2
2
16
3
4-((4-Benzamidophenyl)ethynyl)-N-phenylbenzamide
-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97.5 mg, 2.0 equiv)
and N,N-dimethyl-4-aminopyridine (61.9 mg, 2.0 equiv) were added to a solution of 32
85.0 mg, 0.25 mmol) and aniline (0.03 mL, 1.3 equiv) in DMF (3.5 mL). The resulting
mixture was stirred for 18 h at room temperature. After removal of the solvent in vacuo,
(33).
1
(
2
M HCl was added and the white precipitates were collected and dried to give 33 (96.8
1
mg, 93%); H NMR (600 MHz, DMSO-d ) δ 10.48 (s, 1H), 10.34 (s, 1H), 8.01 (d, J =
6
8
.4 Hz, 2H), 7.96 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H),
7.70 (d, J = 7.8 Hz, 2H), 7.63–7.58 (m, 3H), 7.55 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 8.4 Hz,
13
1
2
H), 7.11 (t, J = 7.2 Hz, 1H). C{ H} NMR (151 MHz, DMSO-d ) δ 165.8, 164.7,
6
140.0, 139.0, 134.7, 134.4, 132.1, 131.7, 131.2, 128.6, 128.4, 128.0, 127.7, 125.6, 123.8,
+
+
1
20.4, 120.1, 116.6, 91.8, 88.2. HRMS (ESI ) m/z calcd for C H N O [M + H]
28 21 2 2
417.1598, found 417.1592.
The monomer 6a. A solution of 33 (120.7 mg, 0.29 mmol) in DMF (3.5 mL) was
2
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 59
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
added at 0 °C to a suspension of NaH (60 %, 38.4 mg, 3.3 equiv, washed with n-hexane
twice) in DMF (1 mL). The solution was stirred at room temperature for 15 min, and
iodomethane (0.05 mL, 2.8 equiv) was added at 0 °C. The resulting solution was stirred
at room temperature for 2.5 h. After removal of the solvent in vacuo, the residue was
poured into water, and extracted with AcOEt. The organic layer was washed with brine,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by
4
silica gel column chromatography (AcOEt/n-hexane = 1/1) to give 6a (96.0 mg, 74%)
1
as a white solid; H NMR (600 MHz, CDCl ) δ 7.32 (d, J = 8.0 Hz, 2H), 7.30–7.27 (m,
3
6H), 7.25–7.22 (m, 3H), 7.19–7.14 (m, 3H), 7.02 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0
13
1
Hz, 2H), 3.50 (s ,6H); C{ H} NMR (151 MHz, CDCl ) δ 170.7, 170.0, 145.1, 144.8,
3
135.9, 135.7, 132.5, 131.0, 130.0, 129.4, 129.0, 128.9, 128.0, 127.0, 126.8, 126.8, 124.3,
+
+
1
21.0, 90.0, 89.6, 38.5, 38.3. HRMS (ESI ) m/z calcd for C H N O [M + H]
30 25 2 2
445.1911, found 445.1904.
Methyl 4-((4-(N-methylbenzamido)phenyl)ethynyl)benzoate (34). A solution of
31 (200 mg, 0.56 mmol) in DMF (8 mL) was added at 0 °C to a suspension of NaH
(60 %, 27.1 mg, 1.2 equiv, washed with n-hexane twice) in DMF (1 mL). The solution
was stirred at room temperature for 15 min, and iodomethane (0.05 mL, 1.4 equiv) was
added at 0 °C. The resulting solution was stirred at room temperature for 1.5 h. After
removal of the solvent in vacuo, the residue was poured into water, and extracted with
AcOEt. The organic layer was washed with brine, dried over MgSO , filtered, and
4
concentrated in vacuo. The residue was purified by silica gel column chromatography
1
(
AcOEt/n-hexane = 1/1) to give 34 (191 mg, 91%) as a pale yellow solid; H NMR (600
MHz, CDCl ) δ 8.01 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz,
3
2
H), 7.29 (d, J = 7.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.01 (d,
1
3
1
J = 8.5 Hz, 2H), 3.92 (s, 3H), 3.51 (s, 3H); C{ H} NMR (151 MHz, CDCl ) δ 170.7,
3
1
66.6, 145.3, 135.7, 132.6, 131.6, 130.1, 129.7, 128.9, 128.1, 127.7, 126.8, 120.7, 119.9,
+
+
91.5, 89.4, 52.4, 38.3. HRMS (ESI ) m/z calcd for C H NO [M + H] 370.1438,
2
4
20
3
found 370.1434.
4-((4-(N-Methylbenzamido)phenyl)ethynyl)benzoic acid (35). 34 (829 mg, 2.2
mmol) and LiOH·H O (567 mg, 6 equiv) were dissolved in a mixture of THF (60 mL),
2
methanol (24 mL), and water (24 mL). The mixture was stirred for 3 h at room
temperature, acidified with 2 M HCl, and extracted with AcOEt. The organic layer was
dried over MgSO , filtered, and concentrated in vacuo to give 35 (757 mg, 95%) as a
4
1
pale yellow solid; H NMR (600 MHz, CDCl ) δ 8.07 (d, J = 8.0 Hz, 2H), 7.57 (d, J =
3
8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.30 (m, 3H), 7.20 (t, J = 7.2 Hz, 2H), 7.03 (d, J =
13
1
8
.4 Hz, 2H), 3.53 (s, 3H); C{ H} NMR (151 MHz, CDCl ) δ 170.8, 169.8, 145.4,
3
2
8
ACS Paragon Plus Environment

Page 29 of 59
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
135.7, 132.7, 131.7, 130.3, 130.1, 128.9, 128.6, 128.1, 126.9, 120.6, 92.0, 89.4, 38.3.
+
+
HRMS (ESI ) m/z calcd for C H NO [M + H] 356.1281, found 356.1272.
2
3
18
3
Methyl
-((4-(4-((4-(N-methylbenzamido)phenyl)ethynyl)benzamido)phenyl)ethynyl)ben
zoate (36). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.6 mg,
.9 equiv) and N,N-dimethyl-4-aminopyridine (1.4 mg, 5 mol%) were added to a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
1
solution of 35 (61.3 mg, 0.17 mmol) and 30 (43.4 mg, 1.0 equiv) in DMF (2 mL). The
resulting mixture was stirred for 2 days at room temperature. After removal of the
solvent in vacuo, 2 M HCl was added and the white precipitates were collected and
1
dried to give 36 (67.0 mg, 66%); H NMR (600 MHz, CDCl ) δ 8.02 (d, J = 8.4 Hz, 2H),
3
7.86 (d, J = 6.0 Hz, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.58 (d, J =
8
.4 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 6.6 Hz, 2H),
7.28 (t, J = 7.2 Hz, 1H), 7.21 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H), 3.93 (s, 3H), 3.53 (s,
1
3
H). 13C{ H} NMR (151 MHz, CDCl ) δ 170.8, 166.7, 164.9, 145.4, 138.4, 135.8,
3
134.2, 132.9, 132.7, 132.1, 131.7, 131.6, 130.1, 129.7, 129.6, 128.9, 128.2, 128.1, 127.3,
+
1
27.1, 126.9, 120.7, 120.0, 118.9, 92.2, 91.5, 89.2, 88.8, 52.4, 38.3. HRMS (ESI ) m/z
+
calcd for C H N O [M + H] 589.2122, found 589.2107.
3
9
29
2
4
Methyl
4-((4-(N-methyl-4-((4-(N-methylbenzamido)phenyl)ethynyl)benzamido)phenyl)et
hynyl)benzoate (13). A solution of 36 (124 mg, 0.21 mmol) in DMF (3 mL) was
added at 0 °C to a suspension of NaH (60 %, 22.4 mg, 2.6 equiv, washed with n-hexane
twice) in DMF (1 mL). The solution was stirred at room temperature for 15 min, and
iodomethane (123.1 mg, 4.1 equiv) was added at 0 °C. The resulting solution was stirred
at room temperature for 1.5 h. After removal of the solvent in vacuo, the residue was
poured into water, and extracted with AcOEt. The organic layer was washed with brine,
dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by
4
silica gel column chromatography (AcOEt/n-hexane = 1/1) to give 13 (54.7 mg, 43%)
1
as a yellow solid; H NMR (600 MHz, CD OD) δ 8.00 (d, J = 8.4 Hz, 2H), 7.60 (d, J =
3
6.6 Hz, 2H), 7.46 (d, J = 9.0 Hz, 2H), 7.37 (m, 4H), 7.30 (m, 5H), 7.23 (t, J = 7.2 Hz,
2
H), 7.19 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 3.92 (s, 3H), 3.50 (s, 3H), 3.47
1
3
1
(s, 3H); C{ H} NMR (151 MHz, CDCl ) δ 170.7, 169.9, 166.6, 145.1, 144.9, 135.7,
3
1
35.4, 132.7, 132.5, 131.6, 131.2, 130.0, 129.8, 129.7, 129.0, 128.9, 128.0, 127.7, 126.8,
+
126.8, 124.7, 121.0, 120.8, 91.3, 90.3, 89.6, 89.4, 52.4, 38.3. HRMS (ESI ) m/z calcd
+
for C H N O [M + H] 603.2278, found 603.2264.
4
0
31
2
4
4-((4-(N-Methyl-4-((4-(N-methylbenzamido)phenyl)ethynyl)benzamido)phenyl)et
2
9
ACS Paragon Plus Environment