Spontaneous Helix Formation of "meta"-Ethynylphenol Oligomers by

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Spontaneous Helix Formation of "meta"-Ethynylphenol Oligomers by Sequential Intramolecular Hydrogen-Bonding Inside the Cavities Tomoya Hayashi, Yuki Ohishi, So Hee-Soo, Hajime Abe, Shinya Matsumoto, and Masahiko Inouye J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00996 • Publication Date (Web): 01 Jun 2018 Downloaded from http://pubs.acs.org on June 1, 2018

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The Journal of Organic Chemistry

Spontaneous Helix Formation of "meta"-Ethynylphenol Oligomers by Sequential Intramolecular Hydrogen-Bonding Inside the Cavities

Tomoya Hayashi,† Yuki Ohishi,† So Hee-Soo,‡ Hajime Abe,†,§ Shinya Matsumoto,‡ and Masahiko Inouye*,†

†

Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan

‡

Graduate School of Environment and Information Sciences, Yokohama National University,

Yokohama, Kanagawa 240-8501, Japan §

Present address: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Kami-ohno,

Himeji, Hyogo 670-8524, Japan

e-mail: [email protected]

Abstract Phenol-based oligomers linked with acetylenes at their meta positions, "meta"-ethynylphenol oligomers were developed as a synthetic helical foldamer. The architecturally simple oligomers spontaneously formed helical higher-order structures by sequential intramolecular hydrogen bonds through the multiple phenolic hydroxy groups inside the cavities. The hydrogen bonds forced C–C≡C–C bond angles to largely bend toward the inside. Addition of chiral amines caused the

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helices to be chiral by electrostatic interactions between the resulting chiral ammonium cations and the phenolate anions.

"meta"-Connected oligo(arylene ethynylene)s have been attracted interests from the field of supramolecular chemistry for the construction of helical foldamers since milestone works by Moore and coworkers in 1990s’.1-5 Formation of the helical foldamers is usually promoted by the preference of cisoid conformation of aromatic rings to transoid one, and Moore’s oligomers have taken advantages of solvophobic effects to stabilize the cisoid structure. On the other hand, Hecht, Yashima, and coworkers have investigated helical structures of meta-phenylene ethynylene polymers applying chiral amide pendants to stabilize the chiral helices by hydrogen-bonding between the pendants.5a Hydrogen bonds in main-chains have also been utilized to stabilize helical structures of oligomers. Huc and Li reported aromatic oligoamides for helical oligomers, where cisoid conformations were constructed by intramolecular hydrogen bonds among amide N−H donors and hydrogen-bonding acceptors of aromatic units.6,7 These pioneer works used elaborate architectures in order to realize the cisoid conformation in the oligomers. We have been studying meta-arylene ethynylene oligomers alternatively consisting of pyridine and phenol rings for saccharide recognition.8 The pyridine and phenol moieties cooperatively worked as a hydrogen-bonding acceptor and donor in a push-pull fashion for the saccharide hydroxy groups. Therefore, the hydrogen-bonding network exists inside the cavities of the oligomers with the saccharides (Figure 1a). From different points of view, one might expect that such network may be constructed by simply arranging only phenols both as a hydrogen-bonding donor and acceptor (Figure 1b). Several related compounds consisted of phenol and acetylene moieties have been reported by other groups.9 Bis(4-trifluoromethyl-2-hydroxyphenyl)ethyne has been utilized as a ditopic protic catalyst.9b However, no phenol–acetylene alternating oligomers with more than three


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phenols have been reported to the best of our knowledge. Herein we report meta-ethynylphenol oligomers that form helical higher-order structures spontaneously by sequential intramolecular hydrogen-bonding through the multiple phenolic hydroxy groups inside the cavities.

R

(a) N

O

R

OH H O

H

O

O H N

= OH

OH

R R

(b) O H H

=

O

R

H O

R

Figure 1. (a) meta-Arylene ethynylene oligomers alternatively consisting of pyridine and phenol rings

and

helix formation by intermolecular hydrogen-bonding with saccharides. (b)

"meta"-Ethynylphenol oligomers and helix formation by intramolecular hydrogen-bonding.

In advance, relative stability of the cisoid conformation was estimated by DFT calculation against the corresponding transoid one by using an acetylene–phenol–acetylene–phenol–acetylene model compound 2c (Figure 2). Hereafter, arabic numerals in the compound numbers means the number of phenol rings of the oligomers. The cisoid conformer 2c(cis) proved to be more stable than the transoid one 2c(trans) by 5.15 kJ mol−1, and two hydroxy groups of 2c(cis) form an intramolecular hydrogen bond in the optimized structure (O−H ··· O−H : 2.45 Å). The preference to cisoid conformation is hopeful as a part of helix. Interestingly, the C–C≡C angles in 2c(cis) were largely



bent (171.57° and 175.34°) from 180° by the hydrogen-bonding, which would influence on the higher-order structure of the resulting helix. In the usual meta-phenylene ethynylene foldamers, five and half to six benzene rings were supposed to make one pitch of the helix.4 In the case of the present ethynylphenol oligomers, bending of the ethynylene bonds should make the helix narrower. Indeed, MacroModel-based Monte Carlo simulations suggested that a longer nonamer model 9b formed a helix with approximately five phenols in one pitch (Figure 3, S1 in Supporting Information). The model helix seems to be fixed not only by the expected hydrogen bonds but also by π-stacking interactions between pitches.

H

171.57° H O

CH3

175.34° CH3

H3C

O H H 3C

O H 2c(trans)

2.45 Å H

O H

H

H

2c(cis) 5.15 kJ/mol more stable

Figure 2. Calculated stability of cisoid conformation 2c(cis) related to transoid one 2c(trans). Conditions: DFT calculation, 6-31G+(2d,p) basis set, in vacuo.

Figure 3 showed the structures of meta-ethynylphenol dimer to nonamer 2a–9a investigated here. Phenol rings were linked at their 2,6-positions with acetylenes, and alkyl side chains were introduced at the 4-positions of the phenol moieties to tune solubility. The MOM-protected precursors 2a(MOM)–9a(MOM) were prepared from the combination of building block diiodides 1a(MOM)–3a(MOM) and diethynyl compounds 1f–3f (Scheme 1).10 For example, Sonogashira


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reaction using diyne 1f and an excess amount of 1a(MOM) gave trimeric diiodide 3a(MOM). The iodine atoms of 3a(MOM) were converted into ethynyl groups to give 3f via 3e, and further Sonogashira reaction using 3f and an excess amount of 3a(MOM) furnished 9a(MOM). The resulting MOM-protected oligomers 2a(MOM)–9a(MOM) were treated with HCl to give target 2a–9a. A methyl derivative 5b was also prepared similarly in order to subject it to X-ray structure

analysis, and the synthetic procedure was shown in Schemes S1 in Supporting Information.

R

OH

X

X

OH n-1 R X

R

I

n-C 5H 11

2a 3a 4a 5a 6a 7a 9a

H

CH 3

5b

n= 2 3

4 5 6 7 9

9b

Figure 3. “meta-Ethynylphenol” oligomers. 2a–9a, 5b, and 9b.



C5H11-n C5H 11-n OMOM I

I OMOM

I OMOM

n-1

H

1d

C5H 11-n 1a(MOM)−9a(MOM) (n = 1 ~ 9) C 5H 11-n

OMOM R

R

OMOM n-1 C 5 H11-n 2e and 3e (R = TMS, n = 2 and 3) 1f - 3f (R = H, n = 1 ~ 3)

1a(MOM) + 1d (excess) 2a(MOM)

48%

cond B 100%

1a(MOM) + 1f (excess) 3a(MOM)

cond A

cond A 51%

cond B 91%

1a(MOM) + 2f (excess) 1a(MOM) + 3f (excess) 2a(MOM) + 2f (excess) 3a(MOM) + 1f (excess) 3a(MOM) + 3f (excess)

2e

3e

cond A 38% cond A 51% cond A 48% cond A 83%

2a(MOM)

75%

2a

cond C 82% 3a(MOM)

2f cond D

3a

73%

cond C 96% 4a(MOM)

5a(MOM)

6a(MOM)

7a(MOM)

cond A 62%

cond D

3f cond D 35% cond D 89% cond D 96% cond D 72%

4a

5a

6a

7a

cond D 9a(MOM)

48%

9a

cond A = Pd(PPh 3) 4, CuI, K2 CO 3, i-Pr 2NH, THF cond B = TMSA, Pd(PPh 3) 4, CuI, K2CO3, i-Pr2 NH, THF cond C = K2CO3, MeOH, CH 2Cl2 cond D = 12N HCl, MeOH, CH 2Cl2

Scheme 1. Preparation of oligomers 2a–9a. TMSA = (trimethylsilyl)acetylene.

With the oligomers in hands, 1H NMR spectra of 2a–9a were compared (Figure 4). Aromatic and benzylic proton signals of the shorter oligomers 2a–4a were very simple and appeared at close range.


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However, those of the longer oligomers 5a–9a became more split and shifted upfield by increasing the chain lengths. The shifted aromatic protons would suffer anisotropic effect from a stacked phenol ring at an interval of one pitch by forming helical higher-order structures.11 The threshold between 4a and 5a means one pitch of the helices being made of four to five phenol units. Similar types of

length-dependent NMR anisotropy have been reported for other kinds of helical foldamers.3,5 The helix formation was completely disturbed by hydrogen-bonding inhibitors. When a 1H NMR spectrum of 7a was measured in a mixture of CDCl3/dimethyl sulfoxide-d6 (8:2 v/v), the anisotropic effects disappeared and the spectrum gets near to that of 3a in the same mixture (Figure S2). Of course, MOM-protected precursors hardly form higher-order structures, so that 3a(MOM), 7a(MOM), and 9a(MOM) showed similar spectra to those of 2a–4a (Figure S3).

Figure 4. 1H NMR spectra of oligomers 2a–9a. Conditions: [oligomer] = 1.0 × 10−3 M, CDCl3, 25 ºC,



400 MHz. X-ray crystallography assured the preference to cisoid conformation of the phenol–acetylene–phenol moieties. Pentamer 5b gave single crystals suitable for the analysis from a mixed solvent of CH2Cl2 and hexane. In the crystal structure, four phenol rings are located almost in the same plane nearly parallel to the ac plane, and a remaining ring was observed to be almost vertical to the others (Figure 5). The four phenolic hydroxy groups form intramolecular hydrogen bonds. Several C≡C–C bond angles were wound as predicted in Figure 2 (Figure S4). The most acute angle among them was 170.1°, meaning that the C≡C–C is remarkably bent in comparison with those of usual chain molecules.12

Figure 5. X-ray molecular structure of 5b viewed from the b (left) and c (right) axis . Details for conditions and parameters were described in Experimental and Supporting Information. ORTEP plot shown with Gaussian ellipsoids at 50% probability level.

Induction of chiral helical higher-order structures can be demonstrated by addition of chiral amines (Figure 6).13 Upon addition of (S)-phenethylamine to a solution of 9a in CH2Cl2, a new absorption band appeared around 420 nm in the UV-vis spectra. The UV-vis spectral changes suggested that 9a was deprotonated because addition of Et3N also caused a similar change (Figure S5). In the absence of chiral amines, the CD spectrum of 9a was silent as a matter of course. However, characteristic induced CD (ICD) signals emerged by the addition of (S)-phenethylamine in the wavelength region


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of the new absorption band for the oligomer.14 The ICD band gradually shifted to longer wavelength because of the successive deprotonation of 9a during the addition of (S)-phenethylamine. An enantiomeric amine, (R)-phenethylamine, induced a mirror image of the spectrum, confirming that the ICD signals of 9a arose from the chirality of the amines. Although the interaction mode between the oligomer and the amines remains to be seen, the entire helicity of the oligomers may be induced by electrostatic interactions at the end point of the oligomers between the resulting chiral ammonium cations and the phenolate anions (Figure S6). In the case of the shorter 3a, UV-vis spectra similarly changed, while no meaningful ICD signals appeared under the same conditions (Figure S7). The trimer 3a hardly forms a helical higher-order structure, so that the point chirality of the amine never influenced the chiral sense of the oligomer.

Figure 6. (a) UV-vis spectra of mixtures of oligomers 9a with (S)-phenethylamine. (b) CD spectra of mixtures of oligomers 9a with (S)-phenethylamine or (R)-phenethylamine. Conditions: [9a] = 7.8 × 10−6 M, [(S)-phenethylamine] = 0 to 7.8 × 10−2 M, [(R)-phenethylamine] = 7.8 × 10−2 M, CH2Cl2, 25 ºC, path length = 10 mm.

In conclusion, we developed "meta"-ethynylphenol oligomers as new types of synthetic foldamers. The longer oligomer spontaneously formed helical higher−order structures with approximately four to five phenols in one pitch. X-ray crystallography assured sequential intramolecular hydrogen



bonds among the phenolic hydroxy groups, which stabilized the cisoid conformation of the phenol–acetylene–phenol structure. The addition of chiral amine induced chiral helical higher-order structures of the nonamer. We are now studying catalytic functions of the oligomers as a multivalent Brønsted acid. Furthermore, the investigation of macrocyclic analogues are under way.

Experimental Section General methods. 1H and

13

C NMR spectra were collected on JEOL ECX400 or 500

spectrometers by using tetramethylsilane (TMS) as an internal reference at 400 or 500 MHz (1H) and 100 MHz (13C). Unfortunately, phenolic O‒H protons could not be identified because of overlapping with the C‒H signals and/or fast exchange with a small amount of concomitant water. ESI-HRMS analyses were carried out on a JEOL JMS-T100LC mass spectrometer by using CH2Cl2/MeOH mixed solutions of the analytes. IR, UV/Vis, and fluorescence spectra were measured by JASCO spectrometers FTIR-460 plus, V-560, and FP-6500, respectively. Melting points were measured on a Yanaco MP-500D apparatus and not corrected. THF was freshly distilled from sodium benzophenone ketyl before use. Four starting materials, 1,3-diiodo-2-(methoxymethoxy) -5-pentylbenzene15 (1a(MOM)), 1-ethynyl-3-iodo-2-(methoxymethoxy)-5-pentylbenzene15 (1d), 1,3-diethynyl-2-(methoxymethoxy)-5-pentylbenzene8b

(1f),

1,3-diiodo-2-(methoxymethoxy)-5

-methylbenzene16 (1g), 1-iodo-2-(methoxymethoxy)-5-methylbenzene17 (1j) were prepared by the procedures in the literature. MOM-protected Dimer 2a(MOM). A mixture of 1a(MOM)15 (6.42 g, 14 mmol), 1d15 (1.00 g,

2.79 mmol), Pd(PPh3)4 (64.5 mg, 5.58 × 10−2 mmol), CuI (5.3 mg, 2.8 × 10−2 mmol), K2CO3 (1.54 g, 11.2 mmol), i-Pr2NH (70 mL), and THF (70 mL) was stirred for 3 h at 60 °C. The resulting mixture was diluted with AcOEt (100 mL) and filtered through a Florisil bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2


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= 3:1) to give recovered 1a(MOM) and 2a(MOM) (0.92 g, 48%) as a yellow solid. mp 60–62 °C; 1

H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.3 Hz, 2H), 7.27 (d, J = 2.3 Hz, 2H), 5.32 (s, 4H), 3.69

(s, 6H), 2.51 (t, J = 7.8 Hz, 4H), 1.63–1.54 (m, 4H), 1.43–1.17 (m, 8H), 0.90 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 160.0, 144.8, 144.4, 138.0, 121.2, 104.2, 96.5, 94.3, 63.0, 38.8, 35.7, 35.2, 26.8, 18.4; IR (KBr) νmax 2952, 2925, 2854, 2078, 1591, 1545 cm−1; HRMS (ESI-TOF) m/z calcd for C28H36I2NaO4 [M + Na+]: 713.0601, found: 713.0618. 1,2-Bis[2-(methoxymethoxy)-5-pentyl-3-(trimethylsilylethynyl)phenyl]ethyne (2e). A mixture

of 2a(MOM) (0.400 g 5.79 × 10−1 mmol), TMSA (0.500 mL, 3.48 mmol), Pd(PPh3)4 (13.4 mg, 1.16 × 10−2 mmol), CuI (1.1 mg, 5.8 × 10−3 mmol), K2CO3 (0.32 g, 2.32 mmol), i-Pr2NH (15 mL), and THF (15 mL) was stirred for 10 h at 60 °C. The resulting mixture was diluted with AcOEt (30 mL) and filtered through a Florisil bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 100:1) to give 2e (0.383 g, quant.) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 1.8 Hz, 2H), 7.25 (d, J = 2.3 Hz, 2H), 5.40 (s, 4H), 3.68 (s, 6H), 2.51 (t, J = 7.8 Hz, 4H), 1.67–1.50 (m, 4H), 1.39–1.25 (m, 8H), 0.90 (t, J = 6.9 Hz, 6H), 0.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ157.3, 138.4, 134.4, 133.9, 117.5, 117.4, 101.5, 99.2, 98.8, 89.9, 57.8, 34.9, 31.4, 31.0, 22.6, 14.1, −0.05; IR (neat) νmax 2959, 2930, 2858, 2157, 2068, 1591 cm−1; HRMS (ESI-TOF) m/z calcd for C38H54NaO4Si2 [M + Na+]: 653.3458, found: 653.3482. 1,2-Bis[3-ethynyl-2-(methoxymethoxy)-5-pentylphenyl]ethyne (2f). A mixture of 2e (0.383 g,

5.94 × 10−1 mmol), K2CO3 (0.246 g, 1.78 mmol), MeOH (1.8 mL), and CH2Cl2 (1.8 mL) was stirred for 2 h at room temperature. The resulting mixture was washed with H2O and brine subsequently, dried over Na2SO4, concentrated with a rotary evaporator, and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 60:1) to give 2f (0.230 g, 82%) as a yellow solid. mp 97–100 °C; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 2.3 Hz, 2H), 7.28 (d, J = 2.3 Hz, 2H), 5.41 (s,



4H), 3.66 (s, 6H), 3.27 (s, 2H), 2.52 (t, J = 7.8 Hz, 4H), 1.67–1.52 (m, 4H), 1.41–1.21 (m, 8H), 0.90 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.5, 138.6, 134.6, 134.2, 117.4, 116.6, 99.4, 89.9, 81.4, 80.2, 77.5, 77.1, 76.8, 57.9, 34.8, 31.4, 30.9, 22.6, 14.1; IR (KBr) νmax 3255, 2950, 2932, 2856, 2104, 2079, 1595 cm−1; HRMS (ESI-TOF) m/z calcd for C32H38NaO4 [M + Na+]: 509.2668, found: 509.2692. MOM-protected Trimer 3a(MOM). A mixture of 1a(MOM)15 (22.0 g, 47.8 mmol), 1f8b (1.21 g,

4.78 mmol), Pd(PPh3)4 (110 mg, 9.55 × 10−1 mmol), CuI (9.1 mg, 4.8 × 10−2 mmol), K2CO3 (2.63 g, 19.0 mmol), i-Pr2NH (80 mL), and THF (120 ml) was stirred for 16 h at 60 °C. The resulting mixture was diluted with AcOEt (150 mL) and filtered through a Florisil bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 60:1) to give recovered 1a(MOM) and 3a(MOM) (2.25 g, 51%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.3 Hz, 2H), 7.30 (d, J = 1.8 Hz, 2H), 7.29 (s, 2H), 5.44 (s, 2H), 5.36 (s, 4H), 3.70 (s, 6H), 3.65 (s, 3H), 2.60–2.40 (m, 6H), 1.70–1.48 (m, 6H), 1.43–1.23 (m, 12H), 0.99–0.82 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.1, 138.7, 133.9, 117.4, 117.1, 99.9, 99.5, 92.3, 90.4, 89.8, 58.7, 58.0, 34.9, 34.6, 31.4, 31.0, 22.6, 14.1; IR (neat) νmax 2956, 2928, 2857, 2213, 2078, 1591, 1545 cm−1; HRMS (ESI-TOF) m/z calcd for C43H54I2NaO6 [M + Na+]: 943.1907, found: 943.1917. 1,3-Bis{[2-(methoxymethoxy)-5-pentyl-3-(trimethylsilylethynyl)phenyl]ethynyl}-2-(methoxy methoxy)-5-pentylbenzene (3e). A mixture of 3a(MOM) (0.500 g, 5.20 × 10−1 mmol), TMSA (0.44

ml, 3.12 mmol), Pd(PPh3)4 (12.0 mg, 1.04 × 10-2 mmol), CuI (0.99 mg, 5.2 × 10−3 mmol), K2CO3 (0.288 mg, 2.08 mmol), i-Pr2NH (10 ml), and THF (25 mL) was stirred for 5 h at 60 °C. The resulting mixture was diluted with AcOEt (30 mL) and filtered through a Florisil bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 80:1) to give 3e (0.410 mg, 91%) as a yellow oil. 1H NMR (400 MHz,


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CDCl3) δ 7.29 (s, 2H), 7.28 (d, J = 2.3 Hz, 2H), 7.26 (d, J = 1.4 Hz, 2H), 5.47 (s, 2H), 5.41 (s, 4H), 3.69 (s, 6H), 3.66 (s, 3H), 2.66–2.42 (m, 6H), 1.72–1.51 (m, 6H), 1.45–1.20 (m, 12H), 0.93–0.87 (m, 9H), 0.25 (s, 18H);

13

C NMR (100 MHz, CDCl3) δ 157.3, 156.9, 138.53, 138.46, 134.4, 133.9,

117.54, 117.47, 117.4, 101.4, 99.4, 99.2, 98.8, 58.0, 57.9, 34.9, 31.4, 31.0, 30.4, 29.0, 23.1, 22.6, 14.1, 0.0; IR (neat) νmax 2958, 2929, 2858, 2157, 1729, 1591 cm−1; HRMS (ESI-TOF) m/z calcd for C53H72NaO6Si2 [M + Na+]: 883.4765, found: 883.4780. 1,3-Bis{[3-ethynyl-2-(methoxymethoxy)-5-pentylphenyl]ethynyl}-2-(methoxymethoxy)-5-pen tylbenzene (3f). A mixture of 3e (0.211 g, 2.45 × 10−1 mmol), K2CO3 (0.102 g, 7.35 × 10−1 mmol),

MeOH (0.74 mL), and CH2Cl2 (0.74 mL) was stirred for 2h at room temperature. The resulting mixture was washed with H2O and brine subsequently, dried over Na2SO4, concentrated with a rotary evaporator, and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 30:1) to give 3f (169 mg, 96%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.3 Hz, 2H), 7.31 (s, 2H), 7.28 (d, J = 1.8 Hz, 2H), 5.46 (s, 2H), 5.42 (s, 4H), 3.68 (s, 6H), 3.67 (s, 3H), 3.27 (s, 2H), 2.69–2.43 (m, 6H), 1.82–1.51 (m, 6H), 1.44–1.11 (m, 12H), 1.05–0.69 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 157.5, 156.9, 138.6, 134.5, 134.2, 133.8, 117.5, 117.4, 116.7, 99.4, 90.1, 89.8, 81.4, 80.2, 58.0, 57.9, 34.9, 34.8, 31.7, 31.3, 30.9, 22.8, 22.6, 14.2, 14.1; IR (neat) νmax 3299, 2958, 2930, 2858, 2218, 2109, 1590 cm−1; HRMS(ESI-TOF) m/z calcd for C47H56NaO6 [M + Na+]: 739.3975, found: 739.4000. MOM-protected Tetramer 4a(MOM). A mixture of 1a(MOM)15 (0.567 g, 1.23 mmol), 2f (100

mg, 2.05 × 10−1 mmol), Pd(PPh3)4 (4.75 mg, 4.11 × 10−3 mmol), CuI (0.39 mg, 2.1 × 10−3 mmol), K2CO3 (0.114 g, 11.2 mmol), i-Pr2NH (12 mL), and THF (12 mL) was stirred for 22 h at 60 °C. The resulting mixture was diluted with AcOEt (30 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 2:1) to give recovered 1a(MOM) and 4a(MOM) (90 mg, 38%) as a yellow oil. 1H



NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.8 Hz, 2H), 7.31 (s, 2H), 7.30 (d, J = 1.8 Hz, 4H), 5.45 (s, 4H), 5.36 (s, 4H), 3.71 (s, 6H), 3.66 (s, 6H), 2.66−2.43 (m, 8H), 1.75–1.56 (m, 8H), 1.44−1.27 (m, 16H), 0.94−0.85 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.0, 138.7, 134.0, 133.8, 133.2, 117.5, 117.4, 117.1, 99.9, 99.5, 92.2, 90.4, 90.0, 89.7, 58.7, 58.1, 34.9, 34.6, 31.4, 31.0, 22.60, 22.57, 14.1; IR (KBr) νmax 2955, 2928, 2857, 2213, 2079, 1591, 1545 cm−1; HRMS (ESI-TOF): m/z calcd for C58H72I2NaO8 [M + Na+]: 1173.3214, found: 1173.3187. MOM-protected Pentamer 5a(MOM). A mixture of 1a(MOM)15 (1.04 g, 2.26 mmol), 3f (0.162

g, 2.26 × 10−1 mmol), Pd(PPh3)4 (10.4 mg, 9.04 × 10−3 mmol), CuI (0.86 mg, 4.5 × 10−3 mmol), K2CO3 (125 mg, 9.04 × 10−1 mmol), i-Pr2NH (20 mL), and THF (25 mL) was stirred for 12 h at 60 °C. The resulting mixture was diluted with AcOEt (50 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 30:1) to give recovered 1a(MOM) and 5a(MOM) (0.16 g, 51%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.3 Hz, 2H), 7.35–7.31 (m, 4H), 7.30 (d, J = 1.8 Hz, 4H), 5.48 (s, 2H), 5.46 (s, 4H), 5.37 (s, 4H), 3.71 (s, 6H), 3.69 (s, 3H), 3.67 (s, 6H), 2.69–2.37 (m, 10H), 1.79–1.47 (m, 10H), 1.45–1.27 (m, 20H), 1.00–0.78 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.0, 138.6, 133.9, 133.8, 117.5, 117.4, 117.0, 99.9, 99.4, 92.2, 90.4, 90.1, 90.0, 89.6, 58.7, 57.9, 34.9, 34.6, 31.4, 30.9, 22.6, 14.1; IR (KBr) νmax 2955, 2928, 2857, 2214, 2078, 1590, 1545 cm−1; HRMS (ESI-TOF) m/z calcd for C73H90I2NaO10 [M + Na+]: 1403.4521, found: 1403.4525. MOM-protected Hexamer 6a(MOM). A mixture of 2a(MOM) (0.51 g, 7.4 × 10−1 mmol), 2f

(59.9 mg, 1.23 × 10−1 mmol), Pd(PPh3)4 (5.69 mg, 4.92 × 10−3 mmol), CuI (0.47 mg, 2.5 × 10−3 mmol), K2CO3 (68.0 mg, 4.92 × 10−1 mmol), i-Pr2NH (12 mL), and THF (12 mL) was stirred for 8 h at 60 °C. The resulting mixture was diluted with AcOEt (30 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column


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chromatography (eluent: hexane/CH2Cl2 = 1:1) to give recovered 2a(MOM) and 6a(MOM) (96.0 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.8 Hz, 2H), 7.32 (d, J = 2.4 Hz, 6H), 7.30 (s, 4H), 5.48 (s, 4H), 5.46 (s, 4H), 5.37 (s, 4H), 3.71 (s, 6H), 3.68 (s, 6H), 3.66 (s, 6H), 2.81–2.34 (m, 12H), 1.80–1.51 (m, 12H), 1.45–1.20 (m, 24H), 1.00–0.79 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.0, 138.64, 138.61, 134.0, 133.8, 117.5, 117.4, 117.1, 99.9, 99.5, 92.2, 90.5, 90.0, 89.9, 89.7, 58.7, 58.0, 34.9, 34.6, 31.4, 31.4, 31.0, 22.6, 14.1; IR (neat) νmax 2955, 2928, 2857, 2215, 2080, 1590, 1539 cm−1; HRMS (ESI-TOF) m/z calcd for C88H108I2NaO12 [M + Na+]: 1633.5828, found: 1633.5797. MOM-protected Heptamer 7a(MOM). A mixture of 3a(MOM) (2.16 g, 2.34 mmol), 1f8b

(0.100 g, 3.90 × 10−1 mmol), Pd(PPh3)4 (18.0 mg, 1.56 × 10−2 mmol), CuI (1.49 mg, 7.80 × 10−3 mmol), K2CO3 (0.216 g, 1.56 mmol), i-Pr2NH (40 mL), and THF (40 mL) was stirred for 18 h at 60 °C. The resulting mixture was diluted with AcOEt (50 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 20:1) to give recovered 3a(MOM) and 7a(MOM) (0.600 g, 83%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.4 Hz, 2H), 7.38–7.31 (m, 8H), 7.30 (d, J = 1.8 Hz, 4H), 5.49 (s, 8H), 5.46 (s, 4H), 5.37 (s, 2H), 3.75–3.64 (m, 21H), 2.69–2.34 (m, 14H), 1.78–1.54 (m, 14H), 1.41–1.21 (m, 28H), 0.99–0.85 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.0, 138.64, 138.61, 134.0, 133.8, 117.6, 117.4, 117.1, 99.9, 99.5, 92.2, 90.5, 90.0, 89.9, 89.7, 58.7, 58.0, 34.9, 34.6, 31.4, 34.6, 31.4, 31.0, 23.1, 22.6, 14.1; IR (neat) νmax 2956, 2928, 2215, 2080, 1590, 1540 cm−1; HRMS (ESI-TOF) m/z calcd for C103H126I2NaO14 [M + Na+]: 1864.7168, found: 1864.7209. MOM-protected Nonamer 9a(MOM). A mixture of 3a(MOM) (0.402 g, 4.18 × 10−1 mmol), 3f

(50.0 mg, 6.97 × 10−2 mmol), Pd(PPh3)4 (3.20 mg, 2.79 × 10-3 mmol), CuI (0.13 mg, 7.0 × 10−3 mmol), K2CO3 (38.6 mg, 2.79 × 10−1 mmol), i-Pr2NH (10 mL), and THF (10 mL) was stirred for 7 h



at 60 °C. The resulting mixture was diluted with AcOEt (30 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/AcOEt = 10:1) to give recovered 3a(MOM) and 9a(MOM) (0.10 g, 62%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.3 Hz, 2H), 7.35–7.32 (m, 12H), 7.30 (d, J = 2.3 Hz, 4H), 5.50 (s, 12H), 5.47 (s, 4H), 5.37 (s, 2H), 3.80–3.68 (m, 24H), 3.68 (s, 3H), 2.65–2.40 (m, 18H), 1.75–1.49 (m, 18H), 1.41–1.24 (m, 36H), 1.00–0.83 (m, 27H); 13C NMR (100 MHz, CDCl3) δ 156.9, 155.7, 140.5, 140.0, 138.6, 134.0, 133.9, 117.6, 117.4,117.1, 99.9, 99.5, 92.2 90.5, 90.0, 89.7, 58.7, 58.0, 34.9, 34.6, 31.4, 31.0, 22.6, 14.1; IR (KBr) νmax 2955, 2928, 2856, 2213, 2080, 1590, 1559 cm−1; HRMS (ESI-TOF) m/z calcd for C133H162I2NaO18 [M + Na+]: 2324.9782, found: 2324.9790. Dimer 2a. A mixture of 2a(MOM) (20.0 mg, 2.90 × 10−2 mmol), 12N HCl (1.16 mL), MeOH

(0.58 mL), and CH2Cl2 (0.58 mL) and was stirred for 5h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 3:1) to give 2a (13 mg, 75%) as a yellow solid. mp 48–51 °C; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 1.8 Hz,

2H), 7.18 (d, J = 2.3 Hz, 2H), 2.49 (t, J = 7.8 Hz, 4H), 1.73-1.46 (m, 4H), 1.42–1.20 (m, 8H), 0.90 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 154.1, 139.4, 136.9, 130.9, 109.1, 91.1, 83.3, 34.5, 31.4, 31.1, 22.6, 14.1; IR (KBr): νmax 3473, 2955, 2927, 2856, 2204, 1558 cm−1; HRMS (ESI-TOF) m/z calcd for C24H28I2NaO2 [M + Na+]: 625.0076, found: 625.0087. Trimer 3a. A mixture of 3a(MOM) (20.0 mg, 2.10 × 10−2 mmol), 12N HCl (0.83 mL), MeOH

(0.42 mL), and CH2Cl2 (0.42 mL) and was stirred for 5 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 3:1) to give 3a (12 mg, 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 1.8 Hz, 2H), 7.22 (s,


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2H), 7.20 (d, J = 1.8 Hz, 2H), 2.71–2.35 (m, 6H), 1.67–1.53 (m, 6H), 1.43–1.25 (m, 12H), 0.90 (t, J = 6.9 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 156.0, 154.0, 139.5, 136.9, 135.2, 131.4, 130.9, 109.4, 109.2, 90.85, 90.77, 83.0, 34.8, 34.5, 31.4, 31.14, 31.08, 22.6, 14.1; IR (neat) νmax 3447, 2955, 2928, 2856, 2205, 1558 cm−1; HRMS (ESI-TOF): m/z calcd for C37H42I2NaO3 [M + Na+]: 811.1121, found: 811.1094. Tetramer 4a. A mixture of 4a(MOM) (20.0 mg, 1.74× 10−2 mmol), 12N HCl (0.70 mL), MeOH

(0.35 mL), and CH2Cl2 (0.35 mL) and was stirred for 10 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 3:1) to give 4a (6 mg, 35%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 2.3 Hz, 2H), 7.24 (d, J = 1.5 Hz, 4H), 7.22 (d, J = 2.3 Hz, 2H), 2.57–2.50 (m, 8H), 1.67–1.53 (m, 8H), 1.37–1.26 (m, 16H), 0.95–0.87 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 155.9, 154.1, 139.5, 136.8, 135.1, 131.65, 131.58, 131.0, 109.8, 109.6, 109.5, 91.3, 90.8, 90.5, 83.2, 34.8, 34.5, 31.4, 31.2, 31.1, 29.8, 22.6, 14.1; IR (neat) νmax 3354, 2955, 2926, 2855, 2204, 1649, 1550 cm−1; HRMS (ESI-TOF) m/z calcd for C50H56I2NaO4 [M + Na+]: 997.2166, found: 997.2145. Pentamer 5a. A mixture of 5a(MOM) (16.0 mg, 1.16 × 10−2 mmol), 12N HCl (0.46 mL), MeOH

(0.23 mL), and CH2Cl2 (0.23 mL) and was stirred for 8 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2) to give 5a (12 mg, 89%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 1.6 Hz, 2H), 7.26–7.22 (m, 6H), 7.15 (d, J = 2.0 Hz, 2H), 2.59–2.51 (m, 6H), 2.50–2.44 (m, 4H), 1.74–1.48 (m, 10H), 1.45–1.19 (m, 20H), 0.95–0.85 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 156.0, 155.9, 154.1, 139.4, 136.7, 135.1, 131.4, 131.3, 130.7, 109.6, 109.51, 109.49, 109.4, 91.5, 91.2, 90.73, 90.69, 82.8, 34.9, 34.5, 31.4, 31.1, 22.63, 22.60, 14.1; IR (neat) νmax 3361, 2955, 2927, 2855, 2204 1605, 1558 cm−1; HRMS



Page 18 of 25

(ESI-TOF) m/z calcd for C63H70I2NaO5 [M + Na+]:1183.3210, found: 1183.3189 . Hexamer 6a. A mixture of 6a(MOM) (26.0 mg, 1.61 × 10−2 mmol), 12N HCl (0. 65 mL), MeOH

(0.32 mL), and CH2Cl2 (0.32 mL) and was stirred for 8 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator to give 6a (21 mg, 96%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.6 Hz, 2H), 7.28–7.24 (m, 4H), 7.13 (d, J = 1.8 Hz, 2H), 7.06 (d, J = 1.6 Hz, 2H), 7.03 (d, J = 1.8 Hz, 2H), 2.57 (t, J = 7.6 Hz, 6H), 2.47 (t, J = 7.8 Hz, 4H), 2.40 (t, J = 7.8 Hz, 2H), 1.62–1.54 (m, 12H), 1.41–1.27 (m, 24H), 0.94–0.85 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 156.2, 156.0, 154.0, 139.2, 136.4, 135.0, 131.1, 130.8, 130.7, 130.6, 109.8, 109.7, 109.45, 109.37, 91.9, 91.5, 91.3, 90.7, 82.8, 34.92, 34.85, 34.5, 31.5, 31.4, 31.12, 31.08, 31.0, 22.6, 14.1; IR (neat) νmax 3372, 2955, 2926, 2855, 2204, 1558 cm−1; HRMS (ESI-TOF) m/z calcd for C76H84I2NaO6 [M + Na+]:1369.4255, found: 1369.4230. Heptamer 7a. A mixture of 7a(MOM) (50.0 mg, 2.71 × 10−2 mmol), 12N HCl (1.1 mL), MeOH

(0.54 mL), and CH2Cl2 (0.54 mL) and was stirred for 8 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: hexane/CH2Cl2 = 5:1) to give 7a (30 mg, 72%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.30–7.24 (m, 4H), 7.19–7.17 (m,

2H), 7.10–7.12 (m, 2H), 7.01–6.99 (m, 4H), 6.93–6.91 (m, 2H), 2.70–2.36 (m, 12H), 2.32 (t, J = 7.8 Hz, 2H), 1.78–1.43 (m, 14H), 1.45-1.18 (m, 28H), 1.04–0.65 (m, 21H);

13

C NMR (100 MHz,

CDCl3) δ 156.1, 156.0, 155.9, 154.0, 139.0, 136.3, 134.9, 134.7, 134.5, 134.1, 130.9, 130.7, 130.6, 130.5, 130.2, 130.1, 129.9, 110.0, 109.8, 109.7, 109.5, 109.3, 92.2, 92.0, 91.0, 82.6, 34.92, 34.86, 34.5, 31.6, 31.54, 31.46, 31.1, 31.0, 22.7, 22.6, 14.2; IR (neat) νmax 3373, 2955, 2925, 2855, 2203, 1558 cm−1; HRMS (ESI-TOF) m/z calcd for C89H98I2NaO7 [M + Na+]: 1556.5300, found: 1556.5308. Nonamer 9a. A mixture of 9a(MOM) (20.0 mg, 8.69 × 10−3 mmol), 12N HCl (0. 35 ml), MeOH


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(0.17 ml), and CH2Cl2 (0.17 ml) was stirred for 5 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator and subjected to preparative TLC (eluent: hexane/CH2Cl2 = 1:1) to give 9a (8.0 mg, 48%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 2.4 Hz, 2H), 7.08–7.02 (m, 6H), 6.98 (d, J = 2.3 Hz, 2H), 6.96 (d, J = 2.3 Hz, 2H), 6.92–6.87 (m, 6H), 2.60–2.22 (m, 18H), 1.77–1.45 (m, 18H), 1.44–1.28 (m, 36H), 1.08–0.77 (m, 27H); 13C NMR (100 MHz, CDCl3) δ 156.1, 155.9, 154.0, 138.9, 136.1, 134.3, 130.5, 130.1, 109.9, 109.8, 109.7, 109.5, 109.2, 92.1, 91.9, 91.6, 90.4, 82.4, 34.9, 34.8, 34.4, 31.6, 31.12, 31.06, 31.0, 22.7, 14.2; IR (neat) νmax 3387, 2953, 2925, 2854, 2206, 1602, 1558 cm−1; HRMS (ESI-TOF) m/z calcd for C115H126I2NaO9 [M + Na+]:1928.7423, found: 1928.7400. 1,3-Bis[(trimethylsilyl)ethynyl]-2-(methoxymethyl)-4-methylbenzene (1h). A mixture of

1,3-diiodo-2-(methoxymethoxy)-5-methylbenzene16 (1g, 0.500 g, 1.24 mmol), TMSA (1.05 mL, 7.43 mmol), Pd(PPh3)4 (28.6 mg, 2.48 × 10−2 mmol), CuI (2.4 mg, 1.2 × 10−2 mmol), K2CO3 (0.684 g, 4.95 mmol), i-Pr2NH (30 mL), and THF (30 mL) was stirred for 5 h at 60 °C. The resulting mixture was diluted with CH2Cl2 (50 mL) and filtered through a Florisil bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2) to give 1h (0.480 mg, quant.) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 5.33 (s, 2H), 3.68

(s, 3H), 2.21 (s, 3H), 0.22 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 157.6, 134.9, 133.2, 117.4, 101.2, 99.0, 57.7, 20.3, −0.1; IR (neat) νmax 2959, 2899, 2837, 2155, 1593 cm−1; HRMS (ESI-TOF) m/z calcd for C19H28NaO2Si2 [M + Na+]: 367.1526, found: 367.1537. 1,3-Diethynyl-2-(methoxymethoxy)-4-methylbenzene (1i). A mixture of 1h (0.480 g, 1.39

mmol), K2CO3 (0.578 g, 4.18 mmol), MeOH (4.20 mL), and CH2Cl2 (4.20 mL) was stirred for 1h at room temperature. The resulting mixture was washed with H2O and brine subsequently, dried over Na2SO4, concentrated with a rotary evaporator, and subjected to silica gel column chromatography



Page 20 of 25

(eluent: hexane/CH2Cl2 = 2:1) to give 1i (0.180 g, 75%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 2H), 5.33 (s, 2H), 3.65 (s, 3H), 3.26 (s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.0, 135.4, 133.5, 116.6, 99.3, 81.7, 79.9, 57.9, 20.3; IR (neat) νmax 3288, 2959, 2926, 2839, 2110, 1653 cm−1; HRMS (ESI-TOF) m/z calcd for C13H12KO2 [M + K+]: 239.0474, found: 239.0480. 1,3-Bis{[3-ethynyl-2-(methoxymethoxy)-5-methylphenyl]ethynyl}-2-(methoxymethoxy)-4-me thylbenzene (3i). A mixture of 1,3-diiodo-2-(methoxymethoxy)-5-methylbenzene16 (1g, 0.131 g,

3.25 × 10−1 mmol), 1i (0.390 g, 1.95 mmol), Pd(PPh3)4 (15.0 mg, 1.30 × 10−2 mmol), CuI (1.3 mg, 6.5 × 10−3 mmol), K2CO3 (0.179 g, 1.30 mmol), i-Pr2NH (30 mL), and THF (30 mL) was stirred for 3 h at 60 °C. The resulting mixture was diluted with CH2Cl2 (30 mL) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2) to give recovered 1i and 3i (90.0 mg, 51%) as a white solid. mp 118–120 °C; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 1.8 Hz, 2H), 7.29 (s, 2H), 7.28 (d, J = 1.8 Hz, 2H), 5.45 (s, 2H), 5.41 (s, 4H), 3.67 (s, 6H), 3.65 (s, 3H), 3.27 (s, 2H), 2.30 (s, 3H), 2.28 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 157.4, 156.8, 135.1, 134.7, 134.4, 133.5, 117.5, 117.4, 116.7, 99.4,

90.0, 89.8, 81.5, 80.0, 58.00, 57.96, 20.5, 20.4; IR (KBr) νmax 2960, 2924, 2827, 2209, 2109, 1594 cm−1; HRMS (ESI-TOF) m/z calcd for C35H32NaO6 [M + Na+]: 571.2097, found: 571.2119. MOM-protected,

Methyl-substituted

Pentamer

5b(MOM).

A

mixture

of

1-iodo

-2-(methoxymethoxy)-5-methylbenzene17 (1j, 3.04 g, 10.9 mmol), 3i (1.00 g, 1.82 mmol), Pd(PPh3)4 (84.3 mg, 7.29 × 10−2 mmol), CuI (6.9 mg, 3.7 × 10−2 mmol), K2CO3 (1.01 g, 7.29 mmol), i-Pr2NH (80 mL), and THF (80 mL) was stirred for 8 h at 60 °C. The resulting mixture was diluted with CH2Cl2 (100 ml) and filtered through a Celite bed. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH = 60:1) to give recovered 1j and 5b(MOM) (1.2 g, 77%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ


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7.34–7.28 (m, 8H), 7.08 (dd, J = 1.8, 8.6 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 5.53 (s, 4H), 5.50 (s, 2H), 5.25 (s, 4H), 3.71 (s, 6H), 3.69 (s, 3H), 3.52 (s, 6H), 2.30 (s, 9H), 2.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 156.8, 156.6, 155.9, 134.4, 134.0, 133.7, 133.4, 131.4, 130.6, 117.8, 117.7, 117.6, 115.4, 113.5, 99.4, 99.3, 95.2, 90.2, 89.8, 89.3, 58.0, 57.9, 56.3, 20.5; IR (KBr) νmax 2953, 2920, 2826, 2211, 2075, 1592 cm−1; HRMS (ESI-TOF) m/z calcd for C53H52NaO10 [M + Na+]: 871.3458, found: 871.3443. Methyl-substituted Pentamer 5b. A mixture of compound 5b(MOM) (0.400 g, 4.71 × 10−1

mmol), 12N HCl (19 mL), MeOH (9.4 mL), and CH2Cl2 (9.4 mL) and was stirred for 5 h at room temperature. The resulting mixture was washed with H2O, and dried over Na2SO4. The organic layer was concentrated with a rotary evaporator subjected to silica gel column chromatography (eluent: CH2Cl2/MeOH = 50:1) to give 5b (80 mg, 27%) as a white solid. mp 227–230 °C; 1H NMR (500 MHz, CDCl3) δ 7.26–7.21 (m, 6H), 7.12 (s, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.9 Hz, 2H), 2.31 (s, 9H), 2.22 (s, 6H);

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C NMR (100 MHz, CDCl3/CD3OD = 5:1) δ 155.2, 155.0, 132.6,

132.3, 131.6, 130.9, 129.5, 114.9, 110.4, 110.1, 109.6, 91.0, 90.4, 90.3, 90.0, 20.14, 20.06; IR (KBr) νmax 3421, 2951, 2919, 2865, 2210, 1592 cm−1; HRMS (ESI-TOF) m/z calcd for C43H32NaO5 [M + Na+]: 651.2147, found: 651.2156. X-ray Crystallography of 5b. Single crystals of 5b were crystallized by the vapor diffusion

method. A CH2Cl2/n-hexane (5:1) solution of 5b was left to stand under n-hexane vapor for three weeks at room temperature to give single crystals of 5b as blocks. The diffraction data for the single crystal of 5b were collected at 296 K on a Rigaku XtaLAB PRO diffractometer using graphite-monochromated Cu-Kα radiation (λ= 1.54187 Å) and data reduction was performed using CrysAlisPro.18 The structure of 5b was solved by direct methods using SHELXT19 and refined by full-matrix least-squares methods based on F2 using SHELXL.20 The single crystal of 5b was found to contain solvent molecules. Two of them could be determined



as CH2Cl2 molecules judging from the electron density and the bond distance. We then refined other remaining peaks using the SQUEEZE procedure21 implemented into PLATON software and the analysis was converged. All non-hydrogen atoms were anisotropically refined. The hydrogen atoms for hydroxy groups were found from the electron density map and refined their positions with constraint on their bond length. Other hydrogen atoms were located on the calculated positions and refined with the riding model.

Associated Content Supporting Information Crystallographic data for 5b, 1H and

13

C NMR and for new compounds, and data of the

DFT calculations and Monte Carlo simulations (PDF) X-ray data for 5b (CIF)

Acknowledgment This study was supported by JSPS KAKENHI Grant Numbers; JP17H05360 (HA), Coordination Asymmetry) and JP24350066 (HA), JST CREST Grant Number JPMJCR1522, and JSPS Core-to-Core Program, B. Asia-Africa Science Platforms.

References (1) Foldamers: Structures, Properties and Applications; Hecht, S.; Huc, I. Eds.; Wiley-VCH, 2007; Weinheim. (2) For general reviews of helical foldamers, see: (a) Gellman, S. H. Foldamers: A Manifesto. Acc. Chem. Res. 1998, 31, 173−180. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. A field Guide to Foldamers. Chem. Rev. 2001, 101, 3893−4012. (c) Saraogi, I.; Hamilton, A. D.


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Recent Advances in the Development of Aryl-Based Foldamers. Chem. Soc. Rev. 2009, 38, 1726–1743. (d) Juwarker, H.; Suk J.-m.; Jeong, K.-S. Folding with Helical Cavities for Binding Complementary Guests. Chem. Soc. Rev. 2009, 38, 3316−3325. (e) Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.; Ikai, T.; Maeda, K. Supramolecular Helical Systems: Helical Assemblies of Small Molecules, Foldamers, and Polymers with Chiral Amplification and Their Functions. Chem. Rev. 2016, 116, 13752–13990. (3) For reviews of arylene ethynylene structure-based foldamer, see: (a) Ni, B.-B.; Yan, Q.; Ma, Y.; Zhao, D. Recent Advances in Arylene Ethynylene Folding Systems: Toward Functioning. Coord. Chem. Rev. 2010, 254, 954–971. (b) Toya, M.; Ito, H.; Itami, K. Recent Advances in Acetylene-Based Helical Oligomers and Polymers: Synthesis, Structures, and Properties. Tetrahedron Lett. 2018, 59, 1531−1547. (4) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Solvophobically Driven Folding of Nonbiological Oligomers. Science 1997, 227, 1793−1796. (5) For oligo(meta-phenylene ethynylene) derivatives whose helical conformations are stabilized by intramolecular hydrogen bonds, see: (a) Cary, J. M.; Moore, J. S. Hydrogen Bond-Stabilized Helix Formation of m-Phenylene Ethynylene Oligomer. Org. Lett. 2002, 4, 4663−4666. (b) Yang, X.; Brown, A. L.; Furukawa, M.; Li, S.; Gardinier, W. E.; Bukowski, E. J.; Bright, F. V.; Zheng, C.; Zeng, X. C.; Gong, B. A New Strategy for Folding Oligo(m-phenylene ethynylenes). Chem. Commun. 2003, 56−57. (c) Banno, M; Yamaguchi, T; Nagai, K; Kaiser, C.; Hecht, S.; Yashima, E. Optically Active, Amphiphilic Poly(meta-phenylene ethynylene)s: Synthesis, Hydrogen-Bonding Enforced Helix Stability, and Direct AFM Observation of Their Helical Structures. J. Am. Chem. Soc. 2012, 134, 8718−8728.

(6) For reviews of aromatic amide helices, see: (a) Zhang, D.-W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Aromatic Amide Foldamers: Structures, Properties, and Functions. Chem. Rev. 2012, 112,



5271−5316. (b) Zhang, D.-W.; Wang, H.; Li, Z.-T. Polymeric Tubular Aromatic Amide Helices. Macromol. Rapid Commun. 2017, 38, 1700179. (7) (a) Jiang, H.; Léger, J.-M.; Huc, I. Aromatic δ-peptides J. Am. Chem. Soc. 2003, 125, 3448−3449. (b) Yi, H.-P.; Li, C.; Hou, J.-L.; Jiang, X.-K.; Li, Z.-T. Hydrogen-Bonding-Induced Oligoamide Foldamers. Synthesis, Characterization, and Complexation for Aliphatic Ammonium Ions. Tetrahedron 2005, 61, 7974−7980. (8) (a) Ohishi, Y.; Abe, H.; Inouye, M. Saccharide Recognition and Helix Formation in Water with an Amphiphilic Pyridine−Phenol Alternating Oligomer. Eur. J. Org. Chem. 2017, 6975−6979. (b) Ohishi, Y.; Abe, H.; Inouye, M. Native Mannose-Dominant Extraction by Pyridine−Phenol Alternating Oligomers Having an Extremely Efficient Repeating Motif of Hydrogen-Bonding Acceptors and Donors. Chem. - Eur. J. 2015, 21, 16504−16511. (9) (a) Sated, O.; Simard, M.; Wuest, J. D. A Complex in Which the Carbonyl Oxygen Atom of a Simple Ketone Accepts Two Intermolecular Hydrogen Bonds. J. Org. Chem. 1998, 63, 3756−3757. (b) Turkmen, Y. E.; Rawal, V. H. Exploring the Potential of Diarylacetylenediols as Hydrogen Bonding Catalysts. J. Org. Chem. 2013, 78, 8340−8353. (10) MOM groups were necessary to avoid side reaction to form benzofuran under Sonogashira reaction conditions. (11) The concentration-dependence of 7a was studied by 1H NMR spectroscopy (Figure S8). The spectral changes were not observed at concentration of

Spontaneous Helix Formation of "meta"-Ethynylphenol Oligomers by

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