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1 Kobe University Repository : Kernel タイトル Title 著者 Author(s) 掲載誌 巻号 ページ Citation 刊行日 Issue date 資源タイプ Resource Type 版区分 Resource Version 権利 Rights DI JaLCDI URL ynthesis of thiophene derivatives via palladium-catalyzed coupling reactions Arai, Nobumichi / Miyaoku, Takayuki / Teruya, hota / Mori, Atsunori Tetrahedron Letters,49(6): Journal Article / 学術雑誌論文 author /j.tetlet PD issue:

2 Tetrahedron Letters 1 ynthesis of thiophene derivatives via palladium-catalyzed coupling reactions Nobumichi Arai, Takayuki Miyaoku, hota Teruya and Atsunori Mori * Department of Chemical cience and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe , Japan Abstract Thiophene derivatives with multiple substitutions are prepared from vinylidene bromide, which is synthesized by the reaction of thiophene-2-carboxaldehyde with carbon tetrabromide in the presence of PPh 3, as a core molecule through several coupling reactions such as uzuki-miyaura coupling and palladium-catalyzed CH arylation. The reactions with a wide variety of organic halides lead to a series of substituted thiophene derivatives in moderate to good yields Elsevier cience. All rights reserved Thiophenes attract considerable attention in advanced materials such as organic TTs, light emitting devices, and dye-sensitized organic solar cells. A wide variety of thiophene derivatives have revealed to be interesting in spectroscopic properties, electrochemical behaviors, and liquid crystalline characteristics. 1 Development of synthetic protocols for thiophenes, which enable to afford a wide variety of derivatives in a combinatorial manner, has therefore been a major concern in organic synthesis. 2 We herein describe new synthesis of substituted thiophene derivatives with transition metal-catalyzed coupling methodologies, which involve uzuki-miyaura coupling 3 and palladium-catalyzed CH arylation. 4 ynthesis of 1 was carried out by Corey-uchs reaction, which is the reaction of thiophene-2-carboxaldehyde with 6 carbon tetrabromide in the presence of PPh 3. The reaction proceeded smoothly to afford 1 in an excellent yield as shown in cheme 1. CH C 4 2PPh 3 CH2Cl 2 90% cheme 1 1 The starting mateial for the thiophene derivative is vinylidene bromide 1, which is readily synthesized from commercially available thiophene-2-carboxaldehyde. ince 1 involves multiple reaction points as shown in Chart 1, synthesis of a wide variety of substituted thiophenes can be performed with transition metal-catalyzed carbon-carbon bond-forming reactions. 5 Chart 1 * Corresponding author. Tel.: ; fax: ; We first envisaged the cross-coupling reaction of 1 at the carbon-bromine bond with several organometallic reagents in the presence of a palladium or nickel catalyst. 7 The reaction of arylmagnesium reagent with 1 has been attempted using a catalytic amount of Pd(Ac) 2-4PPh 3 or NiCl 2 (dppb) at room temperature to 50 ºC to result in giving unidentified products and no desired coupling product 2 was obtained. Migita-Kosugi-tille coupling with arylstannane also afforded undesired products. 8 Altough the reaction proceeded under certain conditions, the major product was found to be the disubstituted alkyne 3, which would be obtained by the coupling reaction and following dehydrobromination or vice versa. The results are summarized in Table 1. y contrast, it was found that the uzuki-miyaura coupling with arylboronic acid esters as an organometallic reagent afforded the desired coupling product in a reasonable yield. 3 As summarized in Table 2, the reaction of 1 with 3 molar am ounts of arylb oronate 4a in the presence of aqueous potassium carbonate under reflux conditions for 24

3 2 Tetrahedron Letters Table 1. Coupling reaction of 1 with an organometallic reagent. a M cat M catalyst (mol%) solvent time, ºC time, h yield of 2 yield of 3 Mg Pd(Ac) 2-4PPh 3 TH (3) NiCl 2 (dppb) (1) TH rt b nu 3 Pd(dba) 2 (3) 1,4-dioxane a Unless noted, the reaction was carried out with 2-3 equivalents of the organometallic reagent. b As an additive, 2.2 equivalents of Cs was added Table 2. uzuki-miyaura coupling of 1 with boronic acid ester 4 a 1 4a Pd(Ac) 2-4PPh 3 K 2 C 3 TH-H 2 reflux 2a 5a entry boron reagent, eq K 2 C 3 amount, eq time, h yield, % 2a 5a >99 0 a The reaction was carried out with 5 mol% of the palladium catalyst in TH-H 2 h afforded the desired coupling product 2a in a quantitative yield. n the other hand, reducing the amount of potassium carbonate and the boro n reagent furnished the monosubstituted product 5a. It was found that mono/bissubstitution was controllable by the employed amount of potassium carbonate. Even with 2.2 molar amounts of 4a, mono-substituted product 5a was obtained in 80% yield in the presence of 3 mol amounts of potassium carbonate. It seems to react smoothly when TH-H 2 is employed as the solvent system, which would avoid undesired elimination to alkyne in the presence of a base. Although the use of an organic solvent such as toluene, ethanol, DME was preliminary examined, the reactions were found to be unsuccessful to result in no reaction or in giving a mixture of 2, 3, and 5. The finding that mono-substituted product 5 has been selectively obtained under a certain condition enables the coupling reaction to synthsize differently-substituted thiophene derivatives in a facile manner. When 5a was treated with 4a in the presence of a palladium catalyst and potassium carbonate, disubstituted 2a was obtained in an excellent yield. (cheme 2) However, treatment of arylstannane instead of 4a afforded the internal alkyne 3a as a major product, while disubstituted 2a was not obtained at all. The reaction with other arylboronate 4b also proceeded smoothly to afford the differently substituted 6 in 95% yield. (cheme 3) 5a Pd(Ac) 2 (5 mol%) PPh 3 (20 mol%) K 2 C 3 (3.0 eq) TH-H 2, reflux, 10 h cheme 2 4a 2a, 91%

4 Tetrahedron Letters 3 The disubstituted thiophene derivatives 2 were synthesized in a similar manner. As shown in Table 3, various boron reagents 4 were employed for the reaction to obtain thiophene derivatives bearing electron-donating or electron-withdrawing substituents in excellent yields under similar conditions to the synthesis of 2a. stereochemistry of the double bond was observed to some extent under the conditions shown in Table 4. urther studies would be required to undergo the reaction with retention of the stereochemistry. 5a 4b 2 ' I Pd(Ac) 2 (5 mol%) PPh 3 (20 mol%) K 2 C 3 (3.0 eq) TH-H 2, reflux, 10 h 6, 95% Pd cat. (3-5 mol%) AgN 3 -K DM, 100 C, 24 h ' cheme 4 7 cheme 3 Table 3. Coupling reaction of 1 with arylboronates a entry (eq) time, h %yield 1 24 > a (3) 4b (3) 46 4c (2.4) 4d (2.2) 5 24 >99 The thiophene derivatives 2 were then subjected to the functionalization at the 5-position of the thiophene ring with the palladium-catalyzed CH arylation reaction in the presence of AgN 3 /K as an activator (cheme 4). 2b Table 4 summarizes the results. The products bearing a variety of substituents 7 were obtained in moderate to good yields. The reaction with an aryl halide bearing an electronwithdrawing substituent proceeded in a relatively higher yields than that bearing electron-donating group. The reaction of 6 bearing different aryl groups as substituents has also been attempted and found that CH arylation reaction took place. However, scrambling of the >99 4e (3) 6 N f (2.4) a The reaction was carried out under the similar conditions to those for the entry 3 of Teble 2 Table 4. Palladium-catalyzed CH arylation of thiophene derivative 2 product product (yield) (yield) Et Et 45% 41% 57% 50% In summary, we have demonstrated the preparation of multiply substituted thiophene derivatives starting from vinylidene bromide 1 using uzuki-miyaura coupling and the palladium-catalyzed CH arylation strateties. The method allowed to synthesize a variety of trisubstituted Et 80% 78% 37% 26% 86% 32% a The reaction was carried out with 2 (0.3 mmol) and aryl iodide (0.36 mmol) in DM (1.8 ml) under nitrogen atmosphere with PdCl 2 (PPh 3 ) 2 (5 mol%) or PdCl 2 (dppb) (3 mol%) C 3 C3 C 3 C 3 C 3 C 3 C 3

5 4 Tetrahedron Letters thiophene derivatives 7 in a combinatorial manner. These molecules exhibited extended π-conjugation. urther studies on the properties of the thiophene derivative 6 leading to find the utility of these molecules as advanced materials are under way. Acknowledgments This work was partly supported by KRI Co. Ltd and a Grant-in-Aid for cientific Reserch on Priority Areas Advanced Molecular Transformation of Carbon Resources (No ) from the Ministry of Education, Culture, ports, cience and Technology, Japan. The authors thank Dr. higeru Yamaki and Dr. Masahiro ato of the KRI for fruitful discussion. References 1. (a) Koumura, N.; Wang, Z.-.; Mori,.; Miyashita, M.; uzuki, E.; Hara, K. J. Am. Chem. oc. 2006, 128, (b) unahashi, M.; Zhang,.; Tamaoki, N. Adv. Mater. 2007, 19, 353. (c) Yasuda,,.; Yoshida,.; asaki, J.; kutsu, Y.; Nakamura, T.; Taninaka, A.; Takeuchi,.; higekawa, H. J. Am. Chem. oc. 2006, 128, (d) Yamahiro, T.; Aso, Y.; tsubo, T.; Tang, H.; Harima, Y.; Yamashita, K. Chem. Lett. 1999, 443. (e) Tour, J. M. Chem. Rev. 1996, 96, 537. (f) acchetti, A.; Yoon, M.-H.; tern, C. L.; Katz, H. E.; Marks, T. J. Angew. Chem., Int. Ed. 2003, 42, (g) McCullough, R. D. Adv. Mater. 1998, 10, (h) Murphy, A. R.; Liu, J.; Luscombe, C.; Kavulak, D.; réchet, J. M. J.; Kline, R. J.; McGehee, M. D. Chem. Mater. 2005, 17, (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. oc. 2004, 126, (b) ugie, A.; Kobayashi, K.; uzaki, Y.; sakada, K.; Mori, A. Chem. Lett. 2006, 35, (c) Takahashi, M.; Masui, K.; ekiguchi, A.; Kobayashi, N.; Mori, A.; unahashi, M.; Tamaoki, N. J. Am. Chem. oc. 2006, 128, (d) Kobayashi, K.; Mohamed-Ahmed, M..; Mori, A. Tetrahedron 2006, 62, (e) iehn, C. A.; hiedel, M..; onsen, E. M.; chuhmann, W.; äuerle, P. Angew. Chem., Int. Ed. 2001, 40, (f) Yokooji, A.; atoh, T.; Miura, M.; Nomura, M. Tetrahedron 2004, 60, (g) Zhang,.; äuerle, P. J. Am. Chem. oc. 2007, 129, (h) Hassan, J.; Gozzi, C.; chulz, E.; Lemaire, M. J. rganomet. Chem. 2003, 687, 280. (i) Izumi, T.; Kobashi,.; Takimiya, K.; Aso, Y.; tsubo, T. J. Am. Chem. oc. 2003, 125, or a review: (j) atoh, T.; Miura, M. Chem. Lett. 2007, 36, (a) Miyaura, N.; uzuki, A. Chem. Rev. 1995, 95, (b) uzuki, A. J. rganomet. Chem. 1999, 576, (a) Mori, A.; ekiguchi, A.; Masui, K.; himada, T.; Horie, M.; sakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. oc. 2003, 125, (b) Masui, K.; Mori, A.; kano, K.; Takamura, K.; Kinoshita, M.; Ikeda, T. rg. Lett., 6 (12), 2011, (c) Kobayashi, K.; ugie, A.; Masui, K.; Takahashi, M.; Mori, A. rg. Lett. 2005, 7, (d) hikuma, J.; Mori, A.; Masui, K.; Matsuura, R.; ekiguchi, A.; Ikegami, H.; Kawamoto, M.; Ikeda, T. Chem. Asian J. 2007, 2, 301. (e) Arai, N.; Takahashi, M.; Mitani, M.; Mori, A. ynlett 2006, (f) Pivsa-Art,.; atoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. ull. Chem. oc. Jpn. 1998, 71, 467. (g) Kondo, Y.; Komine, T. akamoto, T. rg. Lett. 2000, 2, (h) tuart, D. R.; agnou, K. cience 2007, 316, (i) Gokula, K.; ames, D. cience 2006, 312, (a) hen, W.; Wang, L. J. rg. Chem. 1999, 64, (b) hen, W.; Wang, L. Tetrahedron Lett. 1998, 39, Corey, E. J.; uchs, P. L. Tetrahedron Lett. 1972, (a) Tamao, K.; umitani, M.; Kumada, M. J. Am. Chem. oc. 1972, 94, (b) Corriu, R. J.; Masse, J. P. J. Chem. oc.,chem. Commun. 1972, (a) Milstein, D.; tille, J. K. J. Am. Chem. oc. 1978, 100, thiophene; Corey-uchs reaction; palladium catalyst; uzuki-miyaura coupling, CH arylation;

6 Graphical Abstract To create your abstract, type over the instructions in the template box below. onts or abstract dimensions should not be changed or altered. ynthesis of thiophene derivatives via palladium-catalyzed coupling reactions Nobumichi Arai, Takayuki Miyaoku, hota Teruya, Atsunori Mori Department of Chemical cience and Engineering, Kobe University, Kobe, Japan X CH arylation Thiophene derivatives with multiple substitutions are prepared from vinylidene bromide with uzuki-miyaura coupling and palladium-catalyzed CH arylation. Leave this area blank for abstract info. uzuki-miyaura coupling