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

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][2][3][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 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][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Since the reports on transition metal-catalyzed direct arylation of polyfluorobenzenes by Fagnou (Figure 1b) [26], and others [27][28][29][30][31][32][33][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][36][37][38][39][40][41][42][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(C 3 H 5 )(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.
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, also smoothly reacted with 2,3,4-trifluorobenzenesulfonyl chloride to give 3 in 84% yield. Using the same reaction conditions, N-methylpyrrole affords the 1-methyl-2-(2,3,4-trifluorophenyl)pyrrole (4) in 91% yield. It is important to note that 4 equiv of N-methylpyrrole were used in order to prevent the formation of the 2,5-diarylated pyrrole as a side product. Finally, both 2-pentylthiophene and benzothiophene were arylated in 76% and 82% yields, respectively. Notably, the thiophene derivative was regioselectively arylated at the C4 position and the benzothiophene at the C3 position, which are challenging positions to functionalize using aryl bromides as the coupling partners [58].
Next, we investigated the reactivity of 1-methyl-2-(2,3,4-trifluorophenyl)pyrrole (4) in a second direct arylation (Scheme 3). Using of PdCl(C 3 H 5 )(dppb) catalyst and KOAc as base in DMA, the C5 position of the pyrrole unit was arylated in 82% yield with a complete regioselectivity; whereas the C-H bond at C5' position on the trifluorobenzene unit remained untouched. Moreover, under similar reaction conditions, using 4-bromobenzaldehyde or 4-bromopyridine as coupling partners, a C-H arylation on the trifluorobenzene moiety of 14 did not proceed.
Having demonstrated that palladium-catalyzed iterative direct arylations might be an efficient synthetic pathway for the synthesis of (hetero)aryl triads containing a trifluorobenzene unit, we decided then to turn our attention to the synthesis of (hetero)aryl triads containing a difluorobenzene unit. As previously, we synthesized a set of difluorobenzene-substituted heteroarenes using our previous palladium-catalyzed desulfitative arylation conditions (Scheme 5). 2,4-Difluorobenzenesulfonyl chloride was efficiently coupled with 2-n-butylfuran, benzofuran, and menthofuran to give the C2 arylated furans 19-21 in 64-82% yields. Next, 2-(4-methoxyphenyl)-1-methylpyrrole, in which one of the reactive C2 and C5 C-H bonds was already arylated, was subjected to the same reaction allowing the formation of C2,C5-diarylated pyrrole 22 in excellent yield. Then, 3,4-difluorobenzenesulfonyl chloride also shown an excellent reactivity as desulfitative coupling partner with menthofuran and 2-(4-methoxyphenyl)-1-methylpyrrole to furnish the arylated heteroarenes 23 and 24 in 82% and 79% yields, respectively. ortho-position to a fluorine atom might be arylated under this reaction conditions. Using 4-bromobenzaldehyde as coupling partner, a mixture of two regioisomers in 82:18 ratio was obtained, and the C5 arylation product 25 (major regioisomer) was isolated after flash chromatography in 53% yield as pure product. It is important to note that 25 results from the activation of the less hindered C-H bond. When the reaction was performed with 2-(2,4-difluorophenyl)menthofuran (21) methylpyrrole (24). As expected, in the presence of the 2,4difluorophenyl motif, the arylation exclusively took place between the two fluorine atoms to allow the formation of tetramer 29 in 51% yield.
We also investigated iterative direct arylations for the construction of (hetero)aryl triads or tetrads containing a mono-fluorinated phenyl motif (Scheme 7). In 2006, it has been already demonstrated that the palladium-catalyzed direct arylation of fluorobenzene proceeds in very low yield [26]. Based on our previous works, in which we have demonstrated that a halogen atom such as chlorine or bromine at the C3 or C4 position enhances its reactivity [65], we decided to use 2-chloro-4fluorobenzenesulfonyl chloride as the first arylating agent. We firstly selected menthofuran as starting material for the synthesis of (hetero)aryl triads (Scheme 7, top). Using our conditions for desulfitative arylation, 2-(2-chloro-4-fluorophenyl)menthofuran (30) was obtained in 74% yield. Then, a second arylation was performed using 2 mol % of PdCl(C 3 H 5 )(dppb) catalyst and KOAc in DMA. We were pleased to find that only one regioisomer was formed, as the arylation exclusively occurred at the C-H bond between fluorine and chlorine atoms. The desired (hetero)aryl triad 31 was isolated in moderate yield, due to the formation of a relatively large amount of homocoupling product of the aryl bromide partner. On the other hand, we also performed similar sequential C-H bond arylations from 2-pentylthiophene as starting material (Scheme 7, bottom). The desulfitative arylation occurred at the expected the C4-position to afford 4-(2-chloro-4-fluorophenyl)-2-pentylthiophene (32) in 78% yield. Then, we found that the thienyl C5-H bond reacted faster than the phenyl C-H bond at the ortho-position to chloro and fluorine atoms. Indeed Scheme 8: Reactivity of pentafluorobenzenesulfonyl chloride in Pd-catalyzed direct desulfitative arylation of heteroarenes. i) PdCl 2 (CH 3 CN) 2 (5 mol %), Li 2 CO 3 (3 equiv), 1,4-dioxane, 140 °C, 48 h. using 3-bromoquinoline, the (hetero)aryl triad 33 was obtained in 73% yield as a single regioisomer.
On the other hand, Zhang and co-workers developed a straightforward and practical method for the synthesis of end-capped pentafluorobenzene-substituted heteroarenes, which are an important class of materials, through palladium-catalyzed oxidative cross-coupling of perfluoroarenes with aromatic heterocycles [36]. Therefore, we decided to investigate the reactivity of pentafluorobenzenesulfonyl chloride for the construction of end-capped pentafluorobenzene-substituted heteroarenes through direct desulfitative arylation (Scheme 8).
We were pleased to find that using standard reaction conditions, 2-n-butylfuran and benzofuran were arylated at C5-or C2-positions in high yields. Moreover, this methodology allowed the synthesis of challenging C4-arylated thiophene 36 in 73% yield.

Conclusion
In summary, we have developed an efficient synthesis of complex heteroaryl triads and tetrads through palladium-catalyzed iterative direct arylations. Tri-, di-, and monofluorophenylsubstituted heteroarenes were synthesized in high yields and high regioselectivities through a desulfitative direct arylation of several heteroarenes using fluorinated arylsulfonyl chlorides. Then, direct arylation of the (poly)fluorophenyl units was performed using aryl bromides as coupling partners. In some specific cases, we have demonstrated that C2−H bonds of (benzo)thiophene, C5−H bonds of pyrrole, and C3−H bonds of (benzo)furans are more reactive than the C−H bonds of tri-and fluorobenzenes toward palladium-catalyzed direct arylation. This strategy allows the straightforward synthesis of heteroarylated polyfluorobiphenyls in good yields via two or three sequential iterative palladium-catalyzed direct arylations.

Supporting Information
Supporting Information File 1 Experimental and analytical data.