Regiocontroled Pd-catalysed C5-arylation of 3-substituted thiophene derivatives using a bromo-substituent as blocking group

Regiocontroled Pd-catalysed C5-arylation of 3-substituted thiophene derivatives using a bromo-substituent as blocking group Mariem Brahim1,2, Hamed Ben Ammar*2, Jean-François Soulé*1 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 and 2Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, (UR 11ES56) Université de Monastir, Faculté des Sciences de Monastir, avenue de l’environnement, Monastir 5000, Tunisia Beilstein J. Org. Chem. 2016, 12, 2197–2203. doi:10.3762/bjoc.12.210 Email: Hamed Ben Ammar* - ; Jean-François Soulé* - ; Henri Doucet* - Guest Editor: L. Vaccaro Received: 25 July 2016 Accepted: 27 September 2016 Published: 17 October 2016 This article is part of the Thematic Series "Green chemistry". © 2016 Brahim et al.; licensee Beilstein-Institut. License and terms: see end of document. * Corresponding author Keywords: aryl bromides; C–H bond activation; catalysis; direct arylation; palladium; thiophenes Abstract The use of a bromo-substituent as blocking group at the C2-position of 3-substituted thiophenes allows the regioselective introduction of aryl substituents at C5-position via Pd-catalysed direct arylation. With 1 mol % of a phosphine-free Pd catalyst, KOAc as the base and DMA as the solvent and various electron-deficient aryl bromides as aryl sources, C5-(hetero)arylated thiophenes were synthesized in moderate to high yields, without cleavage of the thienyl C–Br bond. Moreover, sequential direct thienyl C5-arylation followed by Pd-catalysed direct arylation or Suzuki coupling at the C2-position allows to prepare 2,5-di(hetero)arylated thiophenes bearing two different (hetero)aryl units in only two steps. This method provides a “green” access to arylated thiophene derivatives as it reduces the number of steps to prepare these compounds and also the formation of wastes. Introduction Thiophene derivatives bearing aryl substituents are important structures because of their biological and/or physical properties. Among them, 3-substituted 5-arylthiophenes are widely used as building blocks for the synthesis of semi-conductors [1-3]. Therefore, the discovery of more direct and selective procedures for access to 5-arylated 3-substituted thiophene derivatives is an important topic in sustainable chemistry [4]. Stille or Suzuki palladium-catalysed coupling reactions [5-10] are some 2197 Beilstein J. Org. Chem. 2016, 12, 2197–2203. of the most efficient methods for the preparation of 5-arylated 3-substituted thiophenes [11-14]. However, before these coupling reactions can be performed, an organometallic compound must be synthesized. In 1990, Ohta and co-workers described the Pd-catalysed direct arylation of thiophene derivatives by coupling reaction with aryl halides [15,16]. This is a highly powerful method for a greener access to a very broad range of arylated thiophenes [17-25]. The method is very attractive in terms of green chemistry, because its major by-products are not metal salts but a base associated to HX, and synthesis of an organometallic derivative can be avoided. However, for C3-substituted thiophenes, arylation generally occurred at the C2-position or gave mixtures of C2- and C5-arylated products [26-33]. The introduction of blocking groups at C2-position on thiophene derivatives in order to arylate regiospecifically the C5-positions had been reported (Figure 1). Scheme 1: Blocking groups allowing regioselective C5-arylation of thiophenes. C–Br bond, ii) on the reaction scope using a set of aryl bromides and 2-bromo-3-substituted thiophenes, iii) conditions allowing either the sequential C5-arylation followed by C2-arylation or C2-heteroarylation followed by C5-arylation of C3-substituted thiophenes. Figure 1: Regioselectivity of the arylation of 3-substituted thiophenes. In 2010, Fagnou et al. attached a 2-chloro-substituent to the thiophene ring to selectively perform a Pd-catalysed direct arylation of 3-hexylthiophene at the C5-position (Scheme 1, top) [34]. An ester moiety as blocking group at the C2-position of 3-substituted thiophene could also direct regioselectivity of Pd-catalysed direct arylation to the C5-position (Scheme 1, middle) [35]. Mori et al. also reported two examples of C5-arylation of 2-bromo-3-methylthiophene with aryl iodides as aryl sources with 5 mol % PdCl2(PPh3)2 catalyst and AgNO3–KF as the base in DMSO (Scheme 1, bottom) [36]. Herein, we wish to report on green conditions in terms of number of steps, base nature, use of a phosphine-free catalyst at low loading and a quite “atom economic” aryl source promoting such a C5-arylation using C3-substituted 2-bromothiophenes. We report i) that only 1 mol % of air-stable Pd(OAc)2 catalyst associated to KOAc promotes the regiospecific access to C5-arylated 2-bromothiophenes without cleavage of the thienyl Results and Discussion Based on some of our previous results on Pd-catalysed direct arylation, for this study, DMA and KOAc were selected as the solvent and base [35]. The reaction of 2 equiv of 2-bromothiophene with 1 equiv of 4-bromonitrobenzene using 1 mol % of phosphine-free Pd(OAc)2 catalyst performed at 110 °C, only afforded the desired product 1 in a trace amount, but a complete conversion of 2-bromothiophene was observed, revealing the high reactivity of the thienyl C–Br bond under these conditions (Table 1, entry 1). Using a lower reaction temperature of 80 °C, and a reaction time of 15 h, the desired C5-arylated product 1 was formed in only 8% yield due again to the formation of several degradation products (Table 1, entry 2). Then, we examined the influence of the reaction time. After 2 or 4 h, higher yields of 1 (55% and 48%) were obtained, respectively; whereas, a very short reaction time of 0.5 h led to a lower yield of 27% due to the poor conversion of 4-bromonitrobenzene (Table 1, entries 3–6). The use of 0.5 mol % Pd(OAc)2 catalyst at 80 °C during 2 h also afforded 1 in a lower yield of 35%. Again, a large amount of 4-bromonitrobenzene was recovered (Table 1, entry 7). When CsOAc, NaOAc or K2CO3 were em2198 Beilstein J. Org. Chem. 2016, 12, 2197–2203. ployed as bases instead of KOAc, in the presence of 1 mol % Pd(OAc)2 catalyst during 2 h, a partial conversion of 4-bromonitrobenzene was observed and 1 was isolated in 32–40% yield (Table 1, entries 8–10). It should be noted that in the presence of cyclopentyl methyl ether or diethyl carbonate as solvents, no formation of 1 was observed, and 4-bromonitrobenzene was recovered unreacted (Table 1, entries 11 and 12). Table 1: Influence of the reaction conditions for the palladium-catalysed direct C5-arylation of 2-bromothiophene with 4-bromonitrobenzene.a Entry Pd(OAc)2 (mol %) Base Temp (°C) Time (h) Yield in 1 (%) 1 2 3 4 5 6 7 8 9 10 11 12 1 1 1 1 1 1 0.5 1 1 1 1 1 (...truncated)