Repetitive Two-Step Method for o,o,p- and o,p-Oligophenylene Synthesis through Pd-Catalyzed Cross-Coupling of Hydroxyterphenylboronic Acid

A repetitive two-step method involving the Pd-catalyzed Suzuki-Miyaura coupling of hydroxyterphenylboronic acid and the subsequent nonaflation of the hydroxy group has been developed for the synthesis of oligophenylenes. This method readily afforded o,o,p- and o,p-oligophenylenes with defined chain lengths. X-ray crystallography was employed to obtain the structure of the o,p-oligophenylene 9-mer.


Introduction
Oligophenylenes, which are composed of benzene rings connected through single bonds, have attracted considerable attention as an important class of oligomers [1][2][3][4][5]. Oligophenylenes are widely used architectures in electronic devices [6] and are employed as self-assembling [7][8][9], biologically active [10], and catalytic molecules [11,12]. In addition, oligophenylenes can be used as building blocks for the synthesis of well-defined graphite subunits [13]. The conformational and electronic properties of oligophenylenes have also been subjects of intensive research [14][15][16][17][18]. Owing to such widespread interest, it is crucial to develope synthetic methods that can produce oligophenylenes with the desired chain length and connectivity pattern. Although one-step syntheses of long polyphenylenes have been reported [2], the resulting compounds are obtained as mixtures of varying chain lengths OPEN ACCESS rather than a single species. In order to synthesize oligophenylenes with structural homogeneity, stepwise synthetic methods are necessary. However, while several synthetic protocols for the preparation of such molecules have been reported [11,19], the development of efficient methods still remains a challenging task.
We previously developed a method for oligophenylene synthesis via repetitive Suzuki-Miyaura coupling [20,21] of hydroxyphenylboronic acids with sebsequent triflation of the hydroxy group (Scheme 1a) [22,23]. While this repetitive two-step method realizes the facile synthesis of a variety of oligophenylenes with a specific chain length and different functional groups, it was only able to introduce one benzene unit in a single Suzuki-Miyaura coupling step. Based on this two-step protocol, Hartley et al. developed an improved method in which two benzene units could be introduced in a single step [15]. However, the development of more efficient methods for synthesizing longer oligophenylenes is still needed. Herein, we describe a new version of the repetitive two-step method, which utilizes hydroxyterphenylboronic acid 1 and enables the introduction of three benzene units in one step (Scheme 1b). By employing this method, oligophenylenes with two different types of connectivity pattern, o,o,p-and o,p-oligophenylenes, were successfully synthesized in a small number of steps.

Results and Discussion
The key boronic acid, hydroxyterphenylboronic acid 1, was easily prepared according to the route shown in Scheme 2. Compound 2 [24] was treated with BuLi in Et 2 O at −78 °C, and then THF was added. This sequential use of the two solvents (Et 2 O and THF) ensured satisfactory conversion to the dilithiated compound, without the formation of a significant amount of the byproduct protonated at the lithiated carbon [25]. This was possible because the Li-Br exchange occurred only after the addition of THF [26]. The dilithiated compound was then boronated to give 1 in good yield (72%).

Scheme 2. Preparation of hydroxyterphenylboronic acid 1.
Boronic acid 1 was first applied to the synthesis of o,o,p-oligophenylenes, composed of benzene rings connected in the order of ortho, ortho, and then para. These were envisioned to make up a new structural motif of folding oligophenylenes [27]. While o,o,p-oligophenylenes could be synthesized using our previous reported method [27] involving the C-H arylation of bipheny-2-ols as the key step, the present method using 1 would be more efficient for synthesis of longer oligomers.
Thus, we started with compound 3 (Scheme 3), with dodecanoyl groups introduced in order to increase the solubility of the oligomers in organic solvents. While the triflyl group (Tf, -SO 2 CF 3 ) was used to activate hydroxy groups in the previous work (Scheme 1a), we decided to use the nonaflyl group (Nf, -SO 2 C 4 F 9 ) [27,28], as this is more stable against O-SO 2 bond cleavage [29,30] and can be prepared with NfF, which is usually less expensive than the commonly used triflating agent, Tf 2 O. Nonaflation of 3 gave bisnonaflate 4, which was then subjected to Suzuki-Miyaura coupling with 1 in the presence of a Pd/SPhos catalyst [31]. Double Suzuki-Miyaura coupling introduced two terphenyl units to give 5 in good yield (72%). Repetition of the nonaflation/Suzuki-Miyaura-coupling sequence twice afforded symmetric o,o,p-oligophenylene 9. It should be emphasized that only six steps were required to synthesize 21-mer oligophenylene 9 from 3. Although these o,o,p-oligophenylenes showed complicated 1 H-and 13 C-NMR spectra because of the existence of rotamers, even at 100 °C, high-resolution mass spectrometry (HRMS) and high performance liquid chromatography (HPLC) analysis verified the identities and the purities of the oligomers.
We next turned our attention to combining the previous and present strategies (Scheme 1a,b) to facilitate synthesis of another type of oligophenylenes. o,p-Oligophenylenes, which are used as precursors in bottom-up synthesis of graphene nanoribbons [32], were selected as the model target [33] in order to demonstrate the feasibility of the combined strategy.
The synthesis commenced using 1,4-dibromobenzene, which was subjected to Suzuki-Miyaura coupling with 1 (Scheme 4). Although the reaction was slow at rt, raising the temperature to 70 °C resulted in a good yield of 7-mer 10 (72%). After nonaflation, Suzuki-Miyaura-coupling with 4-hydroxyphenylboronic acid was conducted, affording 9-mer 12. While nonaflation of 12 in CH 3 CN resulted in a low yield due to the low solubility of 12 in this particular solvent, use of a mixed solvent (CH 3 CN/CH 2 Cl 2 ) improved the yield to 77%. For the final Suzuki-Miyaura-coupling step, it was necessary to change the reaction conditions, as the low solubility of 13 in THF/H 2 O hampered the reaction under the previous employed conditions. Finally, we found that the use of K 3 PO 4 ·nH 2 O in toluene gave 15-mer 14 in a modest yield (43%). In contrast to the o,o,p-oligophenylenes, rotamers were not observed in the NMR spectra of the o,p-oligophenylenes at room temperature. The synthesis shown in Scheme 4 clearly demonstrates that o,p-oligophenylenes with a specific chain length can be easily synthesized through this strategy.

Scheme 4. Synthesis of o,p-oligophenylenes.
Crystals of 9-mer 12 suitable for X-ray analysis were obtained by recrystallization from CH 3 CN, with the resulting structure shown in Figure 1 [34]. This is the first X-ray structure of o,p-oligophenylenes that has been obtained. The 9-mer can be seen adopt an S-shaped, centrosymmetric conformation in which the inversion center is located at the central benzene ring. Both of the hydroxy groups were observed to form hydrogen bonds with CH 3 CN molecules. Figure 1. ORTEP representation (50% ellipsoid probability) of the X-ray structure of 12·2CH 3 CN. Only one CH 3 CN molecule is shown. Left, front view; Right, side view.
Anhydrous solvents (except for acetonitrile) were purchased from Kanto Chemical (Tokyo, Japan) and used without further purification. Acetonitrile was purchased from Wako Pure Chemical Industries (Osaka, Japan) and distilled from CaH 2 under argon. All other chemicals were purchased from Wako Pure Chemical Industries, Kanto Chemical, Tokyo Chemical Industry (Tokyo, Japan), and Aldrich (Milwaukee, US) and used without further purification.
HPLC charts of 5-9 and 1 H-and 13 C-NMR spectra of 1, 3-14 are shown in Supplementary Materials.

15-mer (OH) (7)
Nonaflate 6 (0.972 g, 0.590 mmol), 1 (0.514 g, 1.77 mmol), KF (0.257 g, 4.43 mmol), Pd(OAc) 2 (13.2 mg, 0.0590 mmol), and SPhos (29.1 mg, 0.0708 mmol) were placed in a flask, which was then evacuated and backfilled with Ar. A mixture of THF/H 2 O (4:1, 0.59 mL) was then added. The tube was sealed, and the mixture was stirred at 70 °C for 17 h. After the reaction was complete, H 2 O (5.0 mL) was added. The mixture was extracted with CH 2 Cl 2 , and the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified using silica gel chromatography (hexane/EtOAc = 10:1) to give 7 (0.   The tube was sealed, and the mixture was stirred at 70 °C for 17 h. After the reaction was complete, H 2 O (5.0 mL) was added. The mixture was extracted with CH 2 Cl 2 , and the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified using silica gel chromatography (hexane/CH 2 Cl 2 = 1:2) to give 9 (76. 3  3.11. 7-mer (ONf) (11) Perfluorobutanesulfonyl fluoride (1.65 mL, 9.40 mmol) was added over 1 min to a solution of 10 (1.31 g, 2.31 mmol) and Et 3 N (2.6 mL, 18.7 mmol) in MeCN (7.9 mL) at room temperature, and the mixture was stirred for 2 h at the same temperature. After the reaction was complete, aqueous HCl (1 M, 20.0 mL) was added. The mixture was extracted with EtOAc, and the organic layer was washed with H 2 O and brine, dried over MgSO 4 , and concentrated in vacuo. MeOH was then added to the residue. After stirring, filtration gave 11 (1.65 g, 63%) as a white solid. mp. 198.

Conclusions
In conclusion, a repetitive two-step method for oligophenylene synthesis using hydroxyterphenylboronic acid 1 has been developed. By employing this method, o,o,p-oligophenylenes with precise chain lengths were readily synthesized. Furthermore, the combined use of 1 and 4-hydroxyphenylboronic acid efficiently gave o,p-oligophenylenes. The X-ray structure of 9-mer 12 was also determined. The synthetic strategy presented here is applicable to oligophenylenes with various connectivity patterns. By introducing a substituent on the benzene rings of the boronic acids, it would be also possible to synthesize oligophenylenes with substituents at a desired position. The present work not only contributes to the progress of oligophenylene chemistry, but also extends the applicability of Pd-catalyzed cross coupling.