Palladium-catalyzed 2,5-diheteroarylation of 2,5-dibromothiophene derivatives

Palladium-catalyzed 2,5-diheteroarylation of 2,5-dibromothiophene derivatives Fatma Belkessam1,2, Aidene Mohand2, Jean-François Soulé1, Abdelhamid Elias*1,2 and Henri Doucet*1 Full Research Paper Open Access Address: 1Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes, "Organométalliques: Matériaux et Catalyse", Campus de Beaulieu, 35042 Rennes, France, Tel.: 00-33-2-23-23-63-84, Fax 00-33-2-23-23-69-39 and 2Département de chimie, Tizi Ouzou University, BP 17 RP 15000 Tizi-Ouzou, Algeria Beilstein J. Org. Chem. 2014, 10, 2912–2919. doi:10.3762/bjoc.10.309 Email: Abdelhamid Elias* - ; Henri Doucet* Associate Editor: C. Stephenson Received: 13 October 2014 Accepted: 27 November 2014 Published: 09 December 2014 © 2014 Belkessam et al; licensee Beilstein-Institut. License and terms: see end of document. * Corresponding author Keywords: aryl halides; catalysis; C–H bond activation; direct arylation; heteroarenes; palladium Abstract Conditions allowing the one pot 2,5-diheteroarylation of 2,5-dibromothiophene derivatives in the presence of palladium catalysts are reported. Using KOAc as the base, DMA as the solvent and only 0.5–2 mol % palladium catalysts, the target 2,5-diheteroarylated thiophenes were obtained in moderate to good yields and with a wide variety of heteroarenes such as thiazoles, thiophenes, furans, pyrroles, pyrazoles or isoxazoles. Moreover, sequential heteroarylation reactions allow the access to 2,5-diheteroarylated thiophenes bearing two different heteroaryl units. Introduction 2,2':5',2"-Terthiophene (or 2,5-di(2-thienyl)thiophene) (Figure 1) and many of its derivatives are important structures due to their biological and/or physical properties. For example, 2,2':5',2"-terthiophene itself is a pigment of Tagetes minuta. Some 2,2':5',2"-terthiophene derivatives such as 5,5''-dichloroα-terthiophene also occur naturally [1]. Moreover, terthiophenes are widely used as building blocks for the synthesis of semiconductors [2]. Due to these multiple uses, the discovery of a simpler access to terthiophene derivatives would be very useful. Figure 1: 2,2':5',2"-Terthiophene. Suzuki, Stille or Negishi Pd-catalyzed cross-coupling reactions represent some of the most efficient methods for the preparation of 2,5-diheteroarylated thiophenes [3-16]. However, an 2912 Beilstein J. Org. Chem. 2014, 10, 2912–2919. organometallic derivative must be prepared to perform such reactions. In 1990, Ohta and co-workers reported the Pd-catalyzed direct arylation of heteroaromatics using aryl halides as coupling partners via a C–H bond activation [17,18]. Since then Pd-catalyzed direct arylation of heteroaryls, especially with aryl halides as coupling partners, has been shown to be a very powerful method for an easier and greener access to a very broad range of arylated heterocycles [19-32]. This method is more attractive than other Pd-catalyzed cross-coupling reactions as it avoids the preparation of an organometallic derivative and also as the major byproducts of the reaction are not metallic salts but a base associated to HX. The metal-catalyzed direct arylation of a wide variety of heteroarenes using aryl halides as coupling partners has been reported in recent years [19-36]. However, to our knowledge, only a few examples of Pd-catalyzed direct arylations at both C2 and C5 carbons of 2,5-dihalothiophene derivatives have been described. In 2006, Borgese et al. reported the Pd-catalyzed coupling of 2,5-dibromothiophene with 3-methoxythiophene to afford the corresponding terthiophene in 29% yield [37]. From 2,5-diiodothiophene and benzoxazole, using 5 mol % Pd(phen)2(PF6)2 catalyst, the 2,5-diheteroarylated thiophene was obtained in 89% yield by Murai et al. [38]. A fluorescent π-conjugate thiophene derivative bearing spiro[fluorene-9,4’-[4H]indeno[1,2-b]furan] substituents at C2 and C5 has been prepared in 46% yield by this reaction using Pd(OAc)2 (5 mol %) associated to PPh3 (10 mol %) as catalytic system [39]. A pyrrole derivative was coupled with 2,5-dibromothiophene in the presence of Pd(OAc)2 (5 mol %) and PCy3 (10 mol %) catalyst to afford the 2,5-di(pyrrolyl)thiophene in 59% yield [40]. Finally, an indolizine was also successfully coupled with 2,5-dibromothiophene in 47% yield in the presence of Pd(OAc)2 as catalyst [41]. To our knowledge, so far sequential Pd-catalyzed direct couplings using 2,5-dihalothiophene derivatives have not been described. Therefore, the discovery of effective general conditions, for the direct coupling of heteroarenes at both C2 and C5 positions of 2,5-dihalothiophene derivatives, would constitute a considerable advantage allowing a simpler access to terthiophene derivatives. Here, we wish to report (i) that only 0.5–2 mol % of air-stable palladium catalysts associated to KOAc promote the direct access to 2,5-diheteroarylated thiophenes in one pot, (ii) on the reaction scope using a large set of heteroarenes, and (iii) conditions allowing the sequential diheteroarylation of 2,5-dibromothiophene. Results and Discussion Based on our previous results, DMA was initially chosen as the solvent and KOAc as the base for this study [42,43]. The reactions were conducted at 140 °C under inert conditions using PdCl(C 3 H 5 )(dppb) or Pd(OAc) 2 catalysts. Using only 0.5 mol % Pd(OAc)2, the reaction of 1 equiv of 2,5-dibromothiophene with 2 equiv 2-ethyl-4-methylthiazole as coupling partners affords the mono- and diarylation products 1a and 1b in a 2:98 ratio and the desired product 1b was isolated in 79% yield (Scheme 1, Table 1, entry 1). The use of 3 equiv of 2-ethyl-4methylthiazole afforded 1b in similar yield (Table 1, entry 2). Then, we examined the influence of the amount of catalyst and other parameters on the reaction. The use of 1 or 2 mol % PdCl(C3H5)(dppb) catalyst, which had been previously found to be very effective to promote the direct arylation of several hereroaromatics [42-44], also afforded 1b in high yields (Table 1, entries 3–5). Even at 100 °C, the desired product 1b was obtained in 78% yield (Table 1, entry 6). When CsOAc was employed as the base instead of KOAc, in the presence of 2 mol % PdCl(C3H5)(dppb) catalyst, 1b was isolated in 80% yield, whereas NaOAc led to target product 1b in only 68% yield and Cs2CO3 was ineffective (Table 1, entries 7–9). It should be noted that in the presence of an excess of 2,5-dibromothiophene (4 equiv) with 1 equiv of 2-ethyl-4-methylthiazole the products 1a and 1b were produced in a 72:28 ratio and 1a was isolated in 52% yield, without cleavage of the second C–Br bond on the thiophene ring allowing sequential arylations (Table 1, entry 10). Then, with the most effective reaction conditions in hand for diheteroarylation (DMA, KOAc, Pd(OAc)2 or PdCl(C3H5)(dppb), 100 or 140 °C, 20 h), we explored the scope of this reaction using a variety of heteroarenes as the coupling partner (Scheme 2). First, we investigated the reaction of 2,5-dibromothiophene with 4-me (...truncated)