Efficient synthesis of π-conjugated molecules incorporating fluorinated phenylene units through palladium-catalyzed iterative C(sp2)–H bond arylations

Efficient synthesis of π-conjugated molecules incorporating fluorinated phenylene units through palladium-catalyzed iterative C(sp2)–H bond arylations Fatiha Abdelmalek1,2, Fazia Derridj1,2,3, Safia Djebbar3, 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 1 "Organométalliques, Matériaux et Catalyse", Campus de Beaulieu, 35042 Rennes, France, 2Département de Chimie, UMMTO, University, BP 17 RP, 15000 Tizi-Ouzou, Algeria and 3Laboratoire d’hydrométallurgie et chimie inorganique moléculaire, Faculté de Chimie, U.S.T.H.B. Bab-Ezzouar, Algeria Beilstein J. Org. Chem. 2015, 11, 2012–2020. doi:10.3762/bjoc.11.218 Email: Jean-François Soulé* - ; Henri Doucet* - © 2015 Abdelmalek et al; licensee Beilstein-Institut. License and terms: see end of document. Received: 22 June 2015 Accepted: 07 October 2015 Published: 28 October 2015 Associate Editor: M. Rueping * Corresponding author Keywords: catalysis; C–H bond arylations; desulfitative; fluorine; palladium Abstract We report herein a two or three step synthesis of fluorinated π-conjugated oligomers through iterative C–H bond arylations. Palladium-catalyzed desulfitative arylation of heteroarenes allowed in a first step the synthesis of fluoroaryl-heteroarene units in high yields. Then, the next steps involve direct arylation with aryl bromides catalyzed by PdCl(C3H5)(dppb) to afford triad or tetrad heteroaromatic compounds via regioselective activation of C(sp2)–H bonds. Introduction Fluorinated π-conjugated oligomers increasingly receive recent interest owing to their particular applications as electronic devices (e.g., in organic solar cells) [1-4]. In addition, several fluorinated heterobiaryls such as atorvastatin, rosuvastatin, or pitavastatin have been developed as drugs and commercialized by pharmaceutical companies [5]. In both areas, fluorine atoms can modify the properties of organic compounds. It is established that fluorine atoms dramatically influence both chemical properties and reactivities owing to its electronegativity, size, lipophilicity, and electrostatic interactions. For example, introduction of fluorine into natural products can result in beneficial biological properties [6]. On the other hand, fluorinated 2012 Beilstein J. Org. Chem. 2015, 11, 2012–2020. π-conjugated oligomers have unique π-staking arrangement resulting sometimes in specific electronic properties [3]. Hence, a practical method for the synthesis of fluorinated π-conjugated oligomers that will use the specificity of fluorine atoms is highly desirable for the chemist community. Palladiumcatalyzed cross-coupling reactions are one of the most powerful technologies for the efficient synthesis of π-conjugated oligomers. As example, a π-conjugated thiophene triad incorporating a difluorinated phenylene unit has been previously synthesized in 60% yield using the Stille reaction of trimethyl(thiophen-2-yl)stannane and 1,4-difluoro-2,5diiodobenzene (Figure 1a) [3]. However, this methodology required the pre-synthesis of the stannane derivative, which is not eco-friendly. More recently, the direct C–H bond arylation has appeared as one of the most sustainable protocols for the synthesis of poly(hetero)arenes in high yields in only a few steps with the respect of the environment [7-25]. Since the reports on transition metal-catalyzed direct arylation of polyfluorobenzenes by Fagnou (Figure 1b) [26], and others [27-34], this technology has been increasingly employed for the synthesis of fluorinated π-conjugated materials, but this strategy was limited to the synthesis of end-caped fluorene oligomers [35-43]. Organic molecules containing polyfluoroaryl groups have been also synthetized through direct olefination [44]. In 2012, Zhang and co-workers reported one example of the use of 3-bromo-1,2,4,5-tetrafluorobenzene with iodoanisole as coupling partner (Figure 1c) [45]. The reaction conditions tolerate the C–Br bond on the polyfluorobenzene allowing the synthesis of (hetero)aryl triads with a fluoroarene unit. More recently, our research group also reported the synthesis of (hetero)aryl triads from fluorinated arenes bearing a C–Br bond using iterative palladium-catalyzed direct arylations (Figure 1d) [46]. In a first step, the C–Br bond of fluorinated phenylene units was involved in palladium-catalyzed direct arylations with a set of heteroarenes (e.g., thiophenes, thiazoles, furans). Then, the resulting heteroarylated polyfluorobenzenes were arylated using PdCl(C3H5)(dppb) catalyst in the presence of KOAc as the base in DMA at 150 °C using a wide range of aryl bromides as coupling partners. On the other hand, benzenesulfonyl chlorides were recently introduced as powerful arylating agents, through metalcatalyzed C–H bond activation [47-55]. Such desulfitative direct arylations sometimes offered different regioselectivities, e.g., thiophenes were arylated in β-position instead of α-position with the classical procedure employing aryl halides as coupling partners [53,55] and benzofuran regioselectively led to C2 arylated compounds instead of the mixtures of C2 and C3 arylated products obtained with aryl bromides [56]. Moreover, these processes are very chemoselective, as the reactions only involve desulfitative coupling even in the presence of Figure 1: Different pathways for the synthesis of π-conjugated molecules incorporating fluorinated phenylene units. i) Pd(OAc)2, KOAc, DMA, 150 °C. ii) PdCl(C3H5)(dppb), KOAc, DMA, 150 °C ; ii) PdCl(C3H5)(dppb), KOAc, DMA, 150 °C; iii) PdCl2(CH3CN)2, Li2CO3, 1,4-dioxane, 140 °C. C–halogen bonds [57], which allow further orthogonal transformations. Moreover, a wide scope of benzenesulfonyl chlorides is commercially available at an affordable cost. 2013 Beilstein J. Org. Chem. 2015, 11, 2012–2020. We report herein, a new synthetic pathway for fluorinated π-conjugated oligomers (i.e., dyads, triads, and tetrads). This novel strategy involves only palladium-catalyzed iterative C–H bond arylations. In a first step, PdCl 2 (CH 3 CN) 2 -catalyzed desulfitative regioselective arylations of heteroarenes using fluorinated benzenesulfonyl chlorides as coupling partners allowed the formation of heteroarylated polyfluorobenzenes. Then, in a second and third step, the PdCl(C 3 H 5 )(dppb)catalyzed regioselective arylations using aryl halides as coupling partners furnished the desired triads or tetrads. Results and Discussion We started our investigation with the synthesis of a set of heteroarenes bearing a 1,2,3-trifluorobenzene motif (Scheme 1). Using our previous reaction conditions, namely 5 mol % PdCl 2 (CH 3 CN) 2 in the presence of 3 equiv of Li 2 CO 3 in dioxane at 140 °C, both 2-n-butylfuran and benzofuran reacted with 2,3,4-trifluorobenzenesulfonyl chloride to give the C5- and C2-arylated products 1 and 2 in 86% and 78% yields. Menthofuran, in which only the C2 position is available, (...truncated)