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May 1, 2017 - supported by The Uehara Memorial Foundation and Terumo. Foundation for Life Sciences and Arts, and CREST, JST. □ REFERENCES...
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Regio- and Stereoselective Synthesis of Triarylalkene-Capped Rotaxanes via Palladium-Catalyzed Tandem Sonogashira/Hydroaryl Reaction of Terminal Alkynes Hiroshi Masai,† Wakana Matsuda,† Tetsuaki Fujihara,† Yasushi Tsuji,† and Jun Terao*,‡ †

Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan Department of Basic Science, Graduate School of Art and Sciences, The University of Tokyo, Tokyo 153-8902, Japan

‡

S Supporting Information *

ABSTRACT: Triarylalkene-capped conjugated rotaxanes were synthesized via a palladium-catalyzed tandem Sonogashira/hydroaryl reaction between aryl halides and terminal alkynes bearing two permethylated α-cyclodextrins (PM αCDs) with high regioselectivity because of the insulation effect of the PM α-CDs. Moreover, sequential Sonogashira coupling and hydroarylation reactions using different aryl substrates afforded a regio- and stereoselective trisubstituted alkene as a single product. This new class of rotaxane-forming reactions can be used to increase the diversity of rotaxane skeletons, and thereby the material functionalities of rotaxanes.

T

shira coupling reactions. Subsequently, triarylalkenes are formed through hydroaryl reactions. The mechanisms of Pdcatalyzed intermolecular hydroarylations of alkynes12−14 usually rely on the carbopalladation15 of aryl palladium species and the subsequent protonation of vinyl palladium or reductive elimination of palladium hydride (Scheme 2).8,9,14 Further-

riarylalkene moieties demonstrate significant biological activities1 and unique optical behaviors.2 Hence, they are important constituents of various natural and artificial compounds. Their properties are governed by the substitutions and configurations of their aryl groups.1,2 Thus, developing regio- and stereoselective syntheses of triarylalkenes bearing three different aryl groups is necessary to combinatorically determine the properties and functionalities of various triarylalkene structures.3 Recently, transition metal-catalyzed reactions have been successfully used to control the configurations of triarylalkenes by exploiting their steric and electronic properties, and by incorporating directing groups into the substrates.4,5 In particular, synthetic strategies using readily available terminal alkynes have been reported.6−10 Stepwise introductions of aryl groups, halides, or metals onto terminal alkynes have yielded selective triarylalkenes.6 Within the past decade, Pd-catalyzed stepwise and tandem Sonogashira/hydroaryl reactions have gained importance as facile synthetic techniques (Scheme 1).7−9,11 Terminal alkynes are converted to internal alkynes via these Pd-catalyzed Sonoga-

Scheme 2. Proposed Mechanisms of Pd-Catalyzed Intermolecular Hydroarylations12−14

more, reactions have been proposed that proceed via the insertion of palladium hydride into an alkyne, followed by the transmetalation of the arylmetal species.16 Brønsted acids7,13 and α-hydrogen in acids8,12b,17 and, rarely, in alcohols9,14 have been used as H-sources in these reactions. However, regioselective carbopalladation of unsymmetrical diarylalkynes has proven to be challenging because most carbopalladation reactions are not regiospecific;8,9,15,18 although some exceptions have been reported.7,13,14,16b This has been a significant barrier to using Sonogashira/hydroaryl reactions to prepare specific regio- and stereoisomers.

Scheme 1. Typical Syntheses of Triarylalkenes from Terminal Alkynes via Tandem or Sequential Cross Coupling/Hydroarylation7−9,11

Received: February 28, 2017 Published: May 1, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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The Journal of Organic Chemistry Scheme 3. Selective Syntheses of Insulated Conjugated Molecules 3a and 3a′

In addition to the target Sonogashira coupling product 3a, two byproducts were formed after reacting overnight, which were observed in the mass spectra of the reaction mixtures. Because of their similar polarities and molecular weights, these byproducts were found to be inseparable. Increasing the reaction time (to 7 days) and the concentrations of the Pd catalyst and 2a resulted in the convergence of the three products to form 3a′ (55% isolated yield), which was one of the byproducts mentioned above. The most significant byproducts in this reaction were Glaser-type oligomeric derivatives of 1. On the other hand, the typical Sonogashira coupling product 3a was selectively obtained in an aqueous acetone solvent system (57% isolated yield) even in the increased reaction time and the concentrated Pd-catalyst and 2a. Thus, selective syntheses of two products with different molecular masses (3a and 3a′) were successfully achieved by controlling the solvent systems. The chemical structures of the isolated products (3a and 3a′) were determined by 1H NMR (Figure 1). The aromatic regions of the spectra demonstrated their highly symmetrical structures. The characteristic downfield peaks (∼8.0 ppm) in both spectra (Figure 1a and b) indicate that the insulated structures of 3a and 3a′ were distinct from the uninsulated substrate 1 (7.5 ppm).24,26 The structural differences between 3a and 3a′ were

Insulated conjugated molecules, in which cyclic molecules surround the π-conjugated backbone, have unique optical and electrical properties.19 These molecules possess rotaxane structures, in which backbone axles are threaded through macrocycles.20,21 The macrocycles protect the conjugated backbone, prohibiting intermolecular π−π interactions, and enhancing their material properties.19a,22 Correspondingly, they have been used in novel functionalized molecular devices.23 Insulated conjugated molecules have been constructed via specific transition metal-catalyzed systems with high specificity that do not disrupt the weak interactions in the rotaxane precursors.21 These systems include Huisgen cycloaddition, olefin metathesis, Suzuki coupling, Sonogashira coupling, and Glaser coupling. Although many rotaxane structures have been reported, the varieties of structural moieties afforded in rotaxane-forming reactions are limited to, for example, triazole, alkene, biphenyl, phenylenevinylene, phenylene ethynylene, and diyne groups. Accordingly, the development of a new class of catalytic reactions for the synthesis of triarylalkene-bearing rotaxanes would enable the incorporation of additional functionalities into insulated conjugated molecules. During our synthetic studies on insulated molecules24 and polymers25 comprising a phenylene ethynylene (PE) backbone and permethylated α-cyclodextrin (PM α-CD) macrocycles, a palladium-catalyzed regioselective tandem Sonogashira/hydroaryl reaction was developed for the synthesis of insulated conjugated molecules from terminal alkynes using methanol as a hydride source. This method was suitable for synthesizing triarylalkene-capped insulated conjugated molecules. Synthesis of triarylalkene-capped insulated conjugated molecules is shown in Scheme 3. Oligo(phenylene ethynylene) 1 bearing two PM α-CDs was synthesized using a previously reported procedure.25a As shown in Scheme 3, 1 was quantitatively converted into 1′ using aqueous methanol as a high-polarity solvent. Sonogashira coupling reactions of 1 with iodoaryl derivatives 2 in aqueous methanol were developed to yield insulated molecules 3 with arylalkyne stoppers.24,25d,e These reactions were facilitated by Pd/Cu cocatalysts with an aqueous phosphine ligand, tris(4,6-dimethyl-3-sulfonatophenyl)phosphine trisodium salt (TXPTS). Herein, an iodoaryl derivative, 3,5-di-tert-butyliodobenzene 2a, was added in excess.

Figure 1. Partial 1H NMR (500 MHz) spectra of (a) 3a and (b) 3a′ (*residual CHCl3 peak). 5450

DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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The Journal of Organic Chemistry

derivative, 3,5-di-tert-butylbromobenzene (2d). This reaction produced 3a′ with a similar isolated yield to the equivalent iodoaryl species 2a. However, the reaction with the bromoaryl required an increased reaction temperature (55−65 °C) and time (16 days). Previously reported capping reactions conducted in aqueous methanol have selectively produced the Sonogashira coupling products (3).24,25d,e This may be attributable to the slow reaction rate of the hydroaryl reaction based on the low solubility of the aryl derivatives (2) in aqueous methanol. These factors meant that when the Sonogashira coupling product was obtained (after reacting overnight to several days), the tandem reaction did not proceed. The vinyl-proton in 3a′ produced in the tandem reaction was determined to originate from methanol, because the hydroaryl reaction did not proceed in acetone. To investigate the reaction mechanism, parallel reactions were conducted using aqueous CH3OH and CD3OH as the reaction solvents. Kinetic isotope effects (KIEs) were measured by 1H NMR analysis after quenching to prevent 3a being fully converted to 3a′. A product 3a′-D containing a vinyl deuteron (D: 74%) was yielded from the reaction in methanol-d3 (Figure S1).28,29 This was in agreement with previous reports concerning alcoholmediated hydroaryl reactions.9a,d,14b Furthermore, the KIE value was almost 1, indicating that C−H bonds were not involved in the rate-determining step of this reaction.30 The hydroaryl reaction proceeded with both PM α-CDsubstituted internal alkyne 3 and typical diarylalkynes. Diphenylacetylene 4 was converted into the hydroaryl product 4′ (69% isolated yield)31 by reaction with iodoaryl 2a (3 equiv), Pd(OAc)2 (5 mol%), TXPTS (10 mol%), and Cs2CO3 (5 equiv) in methanol at 70 °C for 21 ha relatively short reaction time compared to that of the tandem reaction of 1. As demonstrated in this reaction, amine and copper species were not necessary for hydroaryl reactions to occur during the tandem reactions.9,14 The hydroaryl reaction of 4 proceeded with high cis-selectivity,9a,b,d as did the reactions of cyclodextrin derivatives 3′. As in previous reactions, the phosphine ligand (TXPTS) was not essential for the hydroaryl reaction of 4.9,14 However, TXPTS protected the Pd species during the reaction of PM α-CD derivative 3, where sterically bulky CDs dramatically decreased the reaction rate. Notably, this hydroaryl reaction of general unsymmetrical alkenes afforded re-

confirmed by the number of peaks present in the spectra. The Sonogashira coupling product 3a possessed a single type of 1,3,5-trisubstituted benzene (Figure 1a) and tert-butyl groups (1.33 ppm). The novel product 3a′ possessed two distinct 1,3,5-trisubstituted benzene (Figure 1b) and tert-butyl groups (1.28 and 1.21 ppm). Furthermore, an additional peak was present in the aromatic region of the 3a′ that was assigned to a vinyl proton (proton 8). Accordingly, 3a′ was determined to be a triarylalkene-capped insulated conjugated molecule, based on its mass spectrum and its 1H NMR spectrum. Although tandem reactions of unsymmetrical diarylalkynes intrinsically afford two regioisomers,9 3a′ possessed a single regiostructure. This was attributed to steric repulsion between the protective PM α-CDs and the aryl groups in 2a. The 1H NMR spectrum of 3a′ provided evidence for this steric effect. The trisubstituted benzene in the cis-position of the insulated aryl group of 3a′ displayed a slightly broader proton peak (proton 6) than that in the trans-position (proton 4). This may be because of the rotational barrier arising from the bulkiness of the PM α-CDs. An optimized 3a′ structure calculated using ONIOM27 (B3LYP/6-31G(d,p)-PM6) contained twisted cis-benzenes due to steric repulsion with a PM α-CD unit (Figure S3). Table 1 details the substrates used in the tandem Sonogashira/hydroaryl reactions of 1. Despite requiring the Table 1. Substrates Used in Tandem Sonogashira/Hydroaryl Reactions of 1

formation of four C−C bonds with the terminal alkynes of 1, both the electron-withdrawing 4-acetyliodobenzene 2b and electron-donating 4-methoxyiodobenzene 2c afforded the corresponding triarylalkene-capped insulated products (3b′ and 3c′, respectively) with good yields (71% and 61%). In addition, the reaction was conducted with a bromoaryl

Figure 2. Possible hydroaryl reaction mechanisms of (a) diarylalkyne 4 and (b) cyclodextrin derivatives 3. 5451

DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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The Journal of Organic Chemistry Scheme 4. Regio- and Stereoselective Synthesis of 5

Table 2. Optical Properties of 3a, 3a′−c′, and 5a

gioisomers,9 in contrast to the reactions producing cyclodextrin derivatives 3, demonstrating the strong steric effect of the PM α-CDs. Zhu et al. reported hydroaryl reactions using an alcohol as a hydride source. They suggested that Pd−H was generated via β-elimination of Pd-alkoxide species.14b Accordingly, the reaction mechanism with diphenylacetylene 4 was proposed (Figure 2a). Initially, an aryl palladium species was generated via oxidative addition (step A) and inserted into 4 (step B). This was followed by halogen exchange with an alkoxide (step C). This palladium alkoxide afforded Pd−H species via βelimination into formaldehyde (step D). Finally, reductive elimination formed the hydroaryl product and regenerated Pd(0) (step E). This mechanism is similar to those of typical Pd-catalyzed hydroaryl reactions using alternative hydride sources.8,12,14 In the case of 3, obtained via the Pd−Cu cocatalyzed Sonogashira coupling reaction of 1, the insertion of palladium species into the germinal position of the insulated aryl group would be difficult because of steric repulsion with the lip of the PM α-CDs (Figure 2a, 3-Pd). This assertion was based on a previously reported crystal structure of 3.25d These steric effects may significantly decrease the reaction rate and alter the reaction mechanism shown in Figure 2a. Hence, an alternative mechanism was proposed (Figure 2b) in which Pd(II) species coordinated with an alkoxide (step A) and β-elimination occurred to form Pd−H (step B).32 The Pd−H species was then regio- and stereoselectively inserted into the unsymmetrical diarylalkyne 3 (step C).33 In the CD derivative, the bulky aryl palladium species is connected to the vacant side, and the small hydride is connected to the crowded side. Vinyl palladium was transmetalated with excess aryl palladium (step D)34 formed from Pd(0) and aryl halide (step F), while excess aryl halide 2 would cause the transmetalation to generate a biaryl as a byproduct, in addition to the vinyl target product, via the disproportionation of aryl palladium.35 Reductive elimination of arylvinyl palladium provided the target product 3′ and Pd(0) (step E). Pd(0) was oxidized to Pd(II) via oxidative addition of aryl iodide 2 (step F), then transmetalation proceeded as described above (step D) to close the catalytic cycle. This mechanism takes reasonable account of the steric effect of CDs and high reagent concentrations. The hydroaryl reaction can be conducted separately from the tandem reaction. A triarylalkene-capped species was produced regioselectively in a sequential Sonogashira/hydroaryl reaction (Scheme 4). 3a was prepared from 1 and 3,5-di-tertbutyliodobenzene 2a under aqueous acetone, then reacted with p-acetyliodobenzene 2b in methanol to form a triarylalkene 5. The second aryl group was selectively introduced onto the trans-position of the insulated aryl group, making the reaction regio- and stereoselective. UV−vis absorption and fluorescent measurements were used to determine the properties of the conjugated systems of diphenylethynyl- and triarylalkene-capped insulated molecules (3a, 3a′−c′, and 5) (Table 2 and Figure S2). The

absorption (λmax/nm) emission (λmax/nm)b

3a

3a′

3b′

3c′

5

365 401

382 435

386 448

391 452

386 450

a Spectra were recorded in CHCl3. bExcitation at maximum absorption wavelengths.

hydroarylation of 3a to form 3a′ increased the effective conjugation length, as shown by increased maximum absorption and emission wavelengths, because the hydroaryl reaction added phenylenevinylene moieties (3a′) to the phenylene ethynylene backbone of 3a. Accordingly, the hydroarylated product 3a′ possessed a narrower energy gap than phenylene ethynylene 3a produced via the Sonogashira coupling reaction. The electronic properties of the insulated conjugated backbones can be tuned by changing the aryl group in the triarylalkene moieties of 3a′−c′ and 5. Acetyl- (3b′) and methoxy-substituted (3c′) products displayed longer maximum absorption and emission wavelengths compared to that of 3a′. Although 5 contained two different aryl groups (2a and 2b), it displayed optical properties more similar to 3b′ than 3a′. This indicated that the conjugated system of 5 was controlled more strongly with the aryl groups on the trans-position (2b) of the insulated benzene moieties than with those on the cis-position (2a). We attributed this to the twisted conformation of the cisbenzene on the conjugated backbone (Figure S3). In conclusion, novel insulated conjugated molecules containing PM α-CDs and capped with triarylalkene moieties were synthesized using Pd-catalyzed tandem Sonogashira/ hydroaryl reactions. The reactions proceeded with high regioselectivity because of the steric insulation effect of PM α-CDs during the insertion of palladium species. Sequential Sonogashira/hydroaryl reactions afforded a regio- and stereoselective triarylalkene. This reaction produced a new rotaxane structure bearing triarylalkenes as a capping moiety. This is a new methodology for the regio- and stereocontrol of triarylalkene isomers in rotaxanes utilizing the steric hindrance of PM α-CD lips.

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EXPERIMENTAL SECTION

General Methods and Materials. Unless otherwise stated, commercially available chemicals were used as received. Reaction solvents were purified as follows: H2O, MeOH, and Et3N were degassed by argon bubbling before use. The precursors 125a and 3,5ditertbutyliodobenzene (2a)36 were prepared according to modified literature procedures. 1H NMR (400 or 500 MHz), 13C {1H} NMR (100 or 126 MHz), 1H−1H COSY NMR, and NOESY NMR were conducted with a JEOL ECX-400 spectrometer or a Bruker AVANCE500 spectrometer. The 1H NMR chemical shifts reported are relative to residual protonated solvent (7.26 ppm) in CDCl3. The 13C NMR chemical shifts reported are relative to 13CDCl3 (77.0 ppm). Melting points were measured with Yanako micro melting point apparatus MPJ3. Matrix assisted laser desorption/ionization (MALDI) mass spectra were obtained with Bruker ultraflex time-of-flight or Thermo Fisher Scientific LTQ orbitrap XL spectrometers using α-cyano-4-hydroxycinnamic acid as the sample matrix and Na+ as the cationization 5452

DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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The Journal of Organic Chemistry

Synthesis of 3b′. 1 (50.0 mg, 18.2 μmol) was dissolved in water (1.25 mL) and MeOH (2.5 mL). This solution was stirred at 45 °C for 1 h to form 1′ quantitatively. After cooling to ambient temperature, 4acetyliodobenzene (2b) (90.0 mg, 365 μmol), Pd(OAc)2 (0.8 mg, 4 μmol), TXPTS (4.8 mg, 7.3 μmol), CuI (0.2 mg, 1 μmol), Cs2CO3 (30.0 mg, 92.0 μmol), and Et3N (0.19 mL) were added under an argon atmosphere. The mixture was stirred at 45 °C for 6 days. 2b (90.0 mg, 365 μmol), Pd(OAc)2 (0.8 mg, 4 μmol), and TXPTS (4.8 mg, 7.3 μmol) were further added to the mixture and the mixture was stirred at 55 °C for 8 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/Et2O. The organic layer was separated and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3b′ as a pale brown solid (41.8 mg, 71%). m.p.: 238−242 °C. HRMS (MALDI) m/z [M+Na+]+ Calcd for C164H226O64Na 3242.4328; Found 3242.4284. 1H NMR (500 MHz, CDCl3, 298 K) δH = 7.92 (d, J = 8.2 Hz, 4H, ArH), 7.89 (d, J = 7.0 Hz, 8H, ArH), 7.41 (d, J = 8.2 Hz, 4H, ArH), 7.30−7.27 (m, 10H, ArH), 7.14 (d, J = 8.5 Hz, 4H, ArH), 6.93 (s, 2H, vinyl-H), 5.07−2.76 (m, 186H, CD-H, OCH3), 2.60 (s, 6H, COCH3), 2.59 (s, 6H, COCH3). 13C NMR (126 MHz, CDCl3, 298 K) δC = 197.3, 196.8, 158.5, 147.7, 144.2, 141.7, 137.0, 136.6, 136.5, 132.9, 130.1, 129.8, 129.7, 129.0, 128.5, 127.7, 126.3, 120.9, 118.5, 101.1, 100.6, 100.3, 100.0, 99.8, 97.8, 96.7, 87.1, 82.6, 82.5, 82.4, 82.3 (peaks overlapped), 82.1 (peaks overlapped), 82.0, 81.9, 81.8, 81.4, 81.34 (peaks overlapped), 81.26, 81.23, 81.15, 81.1, 80.8, 77.5, 72.3, 72.1, 71.9, 71.7 (peaks overlapped), 71.5, 71.1, 71.0 (peaks overlapped), 70.7, 70.1, 61.9, 61.9, 61.7, 61.6, 61.3, 60.9, 59.1, 59.02, 58.95, 58.91, 58.5 (peaks overlapped), 58.0, 57.9, 57.7, 57.5, 57.3, 26.6, 26.3. Synthesis of 3c′. 1 (50.0 mg, 18.2 μmol) was dissolved in water (1.25 mL) and MeOH (2.5 mL). This solution was stirred at 45 °C for 20 min to form 1′ quantitatively. After cooling to ambient temperature, 4-methoxyliodobenzene (2c) (85.0 mg, 363 μmol), Pd(OAc)2 (0.8 mg, 4 μmol), TXPTS (4.8 mg, 7.3 μmol), CuI (0.2 mg, 1 μmol), Cs2CO3 (30.0 mg, 92.0 μmol), and Et3N (0.18 mL) were added under an argon atmosphere. The mixture was stirred at 45 °C for 6 days. 2c (85.0 mg, 363 μmol), Pd(OAc)2 (0.8 mg, 4 μmol), and TXPTS (4.8 mg, 7.3 μmol) were further added to the mixture and the mixture was stirred at 45 °C for 7 days. Furthermore, 2c (85.0 mg, 363 μmol), Pd(OAc)2 (0.8 mg, 4 μmol), and TXPTS (4.8 mg, 7.3 μmol) were added to the mixture and the mixture was stirred at 55 °C for 7 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/Et2O. The organic layer was separated and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3c′ as a yellow solid (35.3 mg, 61%). m.p.: > 250 °C. HRMS (MALDI) m/z [M+Na+]+ Calcd for C160H226O64Na 3194.4328 ;Found 3194.4369. 1H NMR (500 MHz, CDCl3, 298 K) δH = 7.87 (d, J = 8.2 Hz, 4H, ArH), 7.41 (d, J = 8.2 Hz, 4H, ArH), 7.28 (s, 2H, ArH), 7.07 (d, J = 8.5 Hz, 4H, ArH), 7.04 (d, J = 8.5 Hz, 4H, ArH), 6.82 (d, J = 8.5 Hz, 4H, ArH), 6.77 (d, J = 8.5 Hz, 4H, ArH), 6.67 (s, 2H, vinyl-H), 5.08−2.83 (m, 198H, CD-H, OCH3). 13C NMR (126 MHz, CDCl3, 298 K) δC = 159.6, 159.1, 158.5, 143.2, 138.8, 136.9, 132.7, 132.1, 131.2, 130.7, 129.4, 128.9, 126.5, 126.1, 125.2, 119.3, 118.5, 114.0, 113.7, 101.2, 100.7, 100.4, 100.1, 99.8, 97.8, 97.3, 86.3, 82.9, 82.7, 82.5 (peaks overlapped), 82.41 (peaks overlapped), 82.2 (peaks overlapped), 82.0, 81.9, 81.6, 81.5, 81.4, 81.3, 81.2, 81.1, 81.0, 80.7, 77.5, 72.4, 72.1, 71.9, 71.8, 71.7, 71.5, 71.04, 70.96 (peaks overlapped), 70.8, 70.1, 62.2, 62.1, 61.9, 61.9, 61.6, 61.5, 59.1, 59.0, 58.9, 58.8, 58.5 (peaks overlapped), 57.9, 57.8, 57.6, 57.5, 57.2, 55.3, 54.8. Synthesis of 3a′ using bromoaryl substrate. 1 (50.0 mg, 18.2 μmol) was dissolved in water (1.3 mL) and MeOH (2.6 mL). This solution was stirred at 45 °C for 20 min to form 1′ quantitatively. After cooling to ambient temperature, 3,5-di-tert-butylbromobenzene (2d) (98.0 mg, 364 μmol), Pd(OAc)2 (0.4 mg, 2 μmol), TXPTS (2.4 mg, 3.6 μmol), CuI (0.2 mg, 1 μmol), Cs2CO3 (30.0 mg, 92.0 μmol), and Et3N (0.19 mL) were added under an argon atmosphere. The mixture was stirred at 55 °C for 2 days. 2d (98.0 mg, 364 μmol), Pd(OAc)2 (0.4 mg, 2 μmol), and TXPTS (2.4 mg, 3.6 μmol) were further added to the mixture and the mixture was stirred at 65 °C for 6 days. Then

agent. Electron ionization (EI) mass spectra were recorded on a JEOL JMS-SX102A instrument. Preparative recycling Gel Permeation Chromatography (GPC) was performed using UV and RI detection and CHCl3 at a flow rate of 14 mL min−1 as the eluent, with either a JAI LC9140 system equipped with JAIGEL-2.5H columns, a JAI UV DETECTOR 310, and a JAI RI DETECTOR RI-5, a JAI LC9130NEXT system equipped with JAIGEL-2H or -2.5H columns, a JAI UV-370 NEXT, and a JAI RI-700 NEXT, or a SHIMADZU LC20AP System equipped with a Shodex K-4003L, K-4002.5L, K-4002L, or K-4001L column, a SHIMADZU SPD-20A, and a SHIMADZU RID-10A. UV−vis absorption spectra were measured with a SHIMADZU UV-2600 spectrophotometer. Fluorescence spectra were measured with a HITACHI F-7000 fluorescence spectrophotometer model equipped with a 150 W xenon lamp. Optical measurements were conducted with 10−6−10−5 g mL−1 sample solutions in CHCl3. Synthesis of 3a. 1 (50.0 mg, 18.2 μmol) was dissolved in water (21.2 mL) and acetone (10.6 mL). This solution was stirred at 40 °C for 1 h to form 1′ quantitatively. After cooling to ambient temperature, 3,5-di-tert-butyliodobenzene (2a) (115 mg, 364 μmol), Pd(OAc)2 (0.4 mg, 2 μmol), TXPTS (2.4 mg, 3.7 μmol), CuI (0.2 mg, 1 μmol), Cs2CO3 (30 mg, 91 μmol), and Et3N (0.16 mL) were added under an argon atmosphere. The mixture was stirred at 40 °C for 6 days and the mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/Et2O. The organic layer was separated and washed with brine and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3a as a pale yellow solid (32.6 mg, 57%). m.p.: > 250 °C. HRMS (MALDI) m/z [M+Na+]+ Calcd for C160H238O60Na 3142.5470; Found 3142.5437. 1H NMR (500 MHz, CDCl3, 298 K) δH = 8.07 (d, J = 8.2 Hz, 4H, ArH), 7.72 (d, J = 8.2 Hz, 4H, ArH), 7.46 (s, 2H, ArH), 7.43 (t, J = 1.8 Hz, 2H, ArH), 7.27 (d, J = 1.8 Hz, 4H, ArH), 5.09−2.79 (m, 186H, CD-H, OCH3), 1.33 (s, 36H, CCH3). 13C NMR (126 MHz, CDCl3, 298 K) δC = 158.7, 151.1, 132.9, 131.6, 126.3, 125.6, 125.0, 123.3, 121.8, 121.0, 118.6, 101.3, 100.8, 100.4, 100.2, 100.0, 97.9, 96.5, 93.3, 87.6, 87.4, 83.1, 83.0, 82.9, 82.7, 82.6, 82.5, 82.13, 82.06, 81.9 (peaks overlapped), 81.8, 81.5, 81.41, 81.35, 81.3, 81.2, 80.9, 80.7, 77.5, 72.9, 72.6, 72.2, 71.8, 71.62, 71.58, 71.2, 71.1 (peaks overlapped), 70.8, 70.3, 62.13, 62.11, 62.0, 61.8, 61.54, 61.51, 59.2, 59.0, 58.9, 58.8, 58.5 (peaks overlapped), 58.1, 57.7, 57.6, 57.5, 57.4, 34.8, 31.2. Synthesis of 3a′ Using Iodoaryl Substrate. 1 (20.0 mg, 7.29 μmol) was dissolved in water (0.50 mL) and MeOH (1.0 mL). This solution was stirred at 40 °C for 20 min to form 1′ quantitatively. After cooling to ambient temperature, 3,5-di-tert-butyliodobenzene (2a) (48.1 mg, 146 μmol), Pd(OAc)2 (0.3 mg, 1 μmol), TXPTS (1.9 mg, 2.9 μmol), CuI (0.1 mg, 0.5 μmol), Cs2CO3 (11.9 mg, 37 μmol), and Et3N (0.075 mL) were added under an argon atmosphere. The mixture was stirred at 45 °C for 3 days. 2a (48.1 mg, 146 μmol), Pd(OAc)2 (0.3 mg, 1 μmol), and TXPTS (1.9 mg, 2.9 μmol) were further added to the mixture and the mixture was stirred at 45 °C for 4 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/ Et2O. The organic layer was separated and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3a′ as a pale yellow solid (13.9 mg, 55%). m.p.: > 250 °C. HRMS (MALDI) m/z [M+Na+]+ Calcd for C188H282O60Na 3522.8913; Found 3522.8849. 1H NMR (500 MHz, CDCl3, 298 K) δH = 7.89 (d, J = 7.9 Hz, 4H, ArH), 7.58 (d, J = 7.9 Hz, 4H, ArH), 7.35 (s, 2H, ArH), 7.31 (s, 2H, ArH), 7.22 (s, 2H, ArH), 7.00 (s, 4H, ArH), 6.95 (s, 2H, vinyl-H), 6.82 (s, 4H, ArH), 5.07−2.79 (m, 186H, CD-H, OCH3), 1.28 (s, 36H, CCH3), 1.21 (s, 36H, CCH3). 13C NMR (126 MHz, CDCl3, 298 K) δC = 158.5, 151.1, 150.3, 145.3, 143.4, 139.7, 138.9, 132.9, 129.8, 126.4, 125.4, 124.5, 121.9, 121.7, 121.6, 119.5, 118.6, 101.1, 100.9, 100.3 (peaks overlapped), 99.8, 97.8, 97.1, 86.2, 83.0, 82.9, 82.8, 82.5, 82.4, 82.30, 82.26, 82.2, 82.1, 82.00, 81.95, 81.6, 81.4, 81.3, 81.2, 81.0, 80.6, 80.5, 78.0, 72.3, 72.1, 71.9 (peaks overlapped), 71.8 71.0 (peaks overlapped), 70.8, 70.6, 70.1, 62.5, 62.4, 62.2, 61.9, 61.7, 60.9, 59.3, 59.2, 59.1, 59.0, 58.54, 58.49, 57.9, 57.8, 57.54, 57.45, 56.9, 34.77, 34.75, 31.5, 31.3. 5453

DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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The Journal of Organic Chemistry Pd(OAc)2 (0.4 mg, 2 μmol) and TXPTS (2.4 mg, 3.6 μmol) were further added to the mixture and the mixture was stirred at 65 °C for 8 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/Et2O. The organic layer was separated and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3a′ as an orange solid (36.1 mg, 57%). Spectra were in good agreement with 3a′ mentioned above. Synthesis of 3a′ -D. 1 (20.0 mg, 7.29 μmol) was dissolved in water (3.3 mL) and CD3OD (D 99.8%, 6.7 mL). 3,5-di-tert-butyliodobenzene (2a) (46.0 mg, 141 μmol), Pd(OAc)2 (0.2 mg, 1 μmol), TXPTS (1.0 mg, 1.5 μmol) and Cs2CO3 (23.8 mg, 73.0 μmol) were added to the solution under an argon atmosphere. This solution was stirred at 60 °C for 30 min to form 1′ quantitatively. After cooling to ambient temperature, CuI (0.1 mg, 0.5 μmol) and Et3N (0.5 mL) were added to the solution. The mixture was stirred at 45 °C for 3 days. 2a (46.0 mg, 141 μmol), Pd(OAc)2 (0.2 mg, 1 μmol), and TXPTS (1.0 mg, 1.5 μmol) were further added to the mixture and the mixture was stirred at 55 °C for 4 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3. The organic layer was separated and was washed with brine before dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 3a′ as a pale yellow solid (7.5 mg, 29%). HRMS (MALDI) m/z [M+Na+]+ Calcd for C188H280D2O60Na 3524.9033; Found 3524.9017. 1H NMR (400 MHz, CDCl3, 298 K) δH = 7.89 (d, J = 8.2 Hz, 4H, ArH), 7.58 (d, J = 8.6 Hz, 4H, ArH), 7.35 (s, 2H, ArH), 7.31 (s, 2H, ArH), 7.22 (s, 2H, ArH), 7.00 (s, 4H, ArH), 6.95 (s, 0.17H, vinyl-H), 6.82 (d, J = 1.8 Hz, 4H, ArH), 5.11−2.75 (m, 186H, CD-H, OCH3), 1.28 (s, 36H, CCH3), 1.21 (s, 36H, CCH3). Deuterium Experiment via Two Parallel Reactions. 1 (40.0 mg, 14.6 μmol) was dissolved in water (0.7 mL) and CH3OH (CD3OH: D 99.8%) (1.4 mL). The solution was stirred at 45 °C for 20 min to form 1′ quantitatively. After cooling to ambient temperature, 3,5-di-tertbutyliodobenzene (2a) (92.0 mg, 291 μmol), Pd(OAc)2 (1.0 mg, 4.4 μmol), TXPTS (5.7 mg, 8.7 μmol), CuI (0.1 mg, 0.5 μmol), Cs2CO3 (23.8 mg, 73.0 μmol), and Et3N (0.15 mL) were added under an argon atmosphere. The mixture was stirred at 45 °C for 18 h. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/ Et2O. The organic layer was separated and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield mixtures of a Sonogashira coupling product and a hydroarylation product as a pale yellow solid (CH3OH: 32.8 mg and CD3OH: 27.4 mg, respectively). Synthesis of 4′. Diphenylacetylene (4) (40.0 mg, 224 μmol), 3,5-ditert-butyliodobenzene (2a) (213 mg, 673 μmol), Pd(OAc)2 (2.5 mg, 11 μmol), TXPTS (14.7 mg, 22.5 μmol), and Cs2CO3 (366 mg, 1.12 mmol) were added into MeOH (2.0 mL) under an argon atmosphere. This solution was stirred at 70 °C for 21 h. The mixture was quenched with aqueous NH4Cl and then diluted with Et2O. The organic layer was separated and washed with brine and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 4′ as a white solid (57.0 mg, 69%). m.p.: 79−81 °C. HRMS (EI) m/z [M]+ Calcd for C28H32 368.2504; Found 368.2500. 1H NMR (400 MHz, CDCl3, 298 K) δH = 7.38 (t, J = 1.8 Hz, 1H, ArH), 7.33 (d, J = 2.3 Hz, 1H, ArH), 7.31 (d, J = 1.8 Hz, 2H, ArH), 7.25−7.22 (m, 2H, ArH), 7.18 (d, J = 1.8 Hz, 2H, ArH), 7.15−7.10 (m, 4H, ArH), 7.07 (d, J = 1.8 Hz, 1H, ArH), 7.05 (s, 1H, ArH), 1.31 (s, 18H, CCH3). 13C NMR (100 MHz, CDCl3, 298 K) δC = 150.4, 143.6, 142.6, 140.6, 137.7, 130.5, 129.5, 128.4, 127.9, 127.6, 127.2, 126.5, 122.0, 121.7, 34.9, 31.4. Synthesis of 5. 3a (26.1 mg, 8.36 μmol), 4-acetyliodobenzene (2b) (41.1 mg, 167 μmol), Pd(OAc)2 (0.3 mg, 1 μmol), TXPTS (1.6 mg, 2.5 μmol), and Cs2CO3 (13.6 mg, 41.8 μmol) were added into MeOH (1.0 mL) under an argon atmosphere. This solution was stirred at 55 °C for 7 days. The mixture was quenched with aqueous NH4Cl and then diluted with CHCl3/Et2O. The organic layer was separated and washed with brine and dried over MgSO4. The solvent was removed by evaporation, and the residue was purified by GPC with CHCl3 as the eluant to yield 5 as a yellow solid (26.6 mg, 95%). m.p.: > 250 °C. HRMS (MALDI) m/z [M+Na + ] + Calcd for C 176 H254 O 62 Na

3382.6615; Found 3382.6641. 1H NMR (500 MHz, CDCl3, 298 K) δH = 7.89 (d, J = 8.2 Hz, 4H, ArH), 7.85 (d, J = 8.2 Hz, 4H, ArH), 7.41−7.39 (m, 6H, ArH), 7.33 (d, J = 7.9 Hz, 4H, ArH), 7.29 (s, 2H, ArH), 6.94 (s, 4H, ArH), 6.92 (s, 2H, vinyl-H), 5.08−2.57 (m, 192H, CD-H, OCH3), 2.59 (s, 6H, COCH3), 1.24 (s, 36H, CCH3). 13C NMR (126 MHz, CDCl3, 298 K) δC = 197.1, 158.5, 150.9, 145.3, 143.6, 142.5, 138.0, 136.3, 132.9, 130.5, 129.7 128.7 127.9, 126.3, 122.6, 122.2 120.1 118.4, 101.2 100.7, 100.5, 100.1, 99.9, 97.9, 97.0, 86.8, 82.7, 82.7, 82.6 (peaks overlapped), 82.4, 82.22, 82.16, 82.1, 82.04, 81.98, 81.4 (peaks overlapped), 81.2, 81.1, 80.8, 77.5, 72.4, 72.2, 71.9, 71.8, 71.7, 71.5, 71.2, 71.0 (peaks overlapped), 70.8, 70.2, 62.2, 62.1, 61.9, 61.7, 61.6, 61.0, 59.2, 59.1 (peaks overlapped), 59.0, 58.6, 58.5, 58.0, 57.9, 57.7, 57.5, 57.2, 34.9, 31.3, 26.3. Calculation of Optimized 3a′ Structure. An optimized structure of 3a′ was determined using ONIOM27 calculations. The molecular system of 3a′ was divided into two layers. The high layers were assigned to the conjugated backbones, containing the phenylene ethynylene and triarylalkene moieties, for B3LYP/6-31G(d,p) calculations. The low layers containing PM α-CDs, including the ether linkages to the conjugated region, were subjected to semiempirical molecular orbital calculations using the PM6 method. All calculations were performed with Gaussian 09 software.37 Details of the optimized geometries are presented in Table S1.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00442. NMR spectra for obtained compounds, optical spectra, and optimized structures for 3a′ (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Jun Terao: 0000-0003-1867-791X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Funding Program for JSPS Research Fellow and Grant−in−Aid for Scientific Research (B), and JSPS KAKENHI Grant Numbers JP16H00834 and JP16H00965 from MEXT, Japan. This research was also supported by The Uehara Memorial Foundation and Terumo Foundation for Life Sciences and Arts, and CREST, JST.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455

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DOI: 10.1021/acs.joc.7b00442 J. Org. Chem. 2017, 82, 5449−5455