Copper‐Catalysed Suzuki‐Miyaura Cross‐Coupling of Highly Fluorinated Aryl Boronate Esters with Aryl Iodides and Bromides and Fluoroarene−Arene π‐Stacking Interactions in the Products

A combination of copper iodide and phenanthroline as the ligand is an efficient catalyst for Suzuki‐Miyaura cross‐coupling of highly fluorinated boronate esters (aryl−Bpin) with aryl iodides and bromides to generate fluorinated biaryls in good to excellent yields. This method represents a nice alternative to traditional cross‐coupling methods which require palladium catalysts and stoichiometric amounts of silver oxide. We note that π⋅⋅⋅π stacking interactions dominate the molecular packing in the partly fluorinated biaryl crystals investigated herein. They are present either between the arene and perfluoroarene, or solely between arenes or perfluoroarenes, respectively.


Introduction
The conversion of highly fluorinated aromatics into fluorinated arylboronate esters is desirable as arylboronate esters are useful building blocks for organic synthesis. [1] We recently reported the successful defluoroborylation of polyfluorinated aromatics using an NHC nickel complex (NHC = N-Heterocyclic Carbene) as a catalyst and the diboron(4) compound B 2 pin 2 (pin = pinacolato) as the boron source. [2] Having a good source of fluorinated arylboronates in hand, we were interested to explore the chemistry of these electron poor aromatics, especially in Suzuki-Miyaura cross-coupling reactions which are employed in various fields, from the synthesis of natural products to materials chemistry, including large-scale production. [3] Applications of polyfluorobiphenyls are quite numerous including medicinal chemistry, [4] organic light emitting diodes, [5] electron-transport materials, [6] crystal engineering, [7] metal-organic frameworks (MOFs), [8] and supramolecular chemistry. [9] However, Suzuki-Miyaura cross-coupling of highly fluorinated boronate esters, especially pentafluorophenyl boronates is highly challenging under typical palladium catalysed Suzuki-Miyaura conditions, [10] as the transfer of C 6 F 5 to the palladium centre in the transmetalation step is usually inefficient. [11c] In many cases, stoichiometric amounts of costly silver oxide (Ag 2 O) were added in addition to the palladium catalyst to enhance the transmetalation step and thus to obtain the desired coupling product in fair to good yield. [11] In 1987, it was initially reported by Kishi et al. that Ag 2 O can accelerate the rate of palladium-catalysed Suzuki-Miyaura cross-coupling of alkenylboronic acids with alkenyl iodides with the relative rate being 30 times faster than that using common bases such as KOH. [12] Inspired by that, in 2002, Adonin et al. used 1.2 equivalents of Ag 2 O to enhance the efficiency of Pd(OAc) 2 /PPh 3 / K 2 CO 3 to catalyse the Suzuki-Miyaura cross-coupling of C 6 F 5 B (OMe) 3 Li [11f] or C 6 F 5 BF 3 K [11g] with aryl iodides in toluene. In 2005, Korenaga et al. [11c] reported an effective method for coupling of C 6 F 5 B(OH) 2 with aryl iodides using Pd(PPh 3 ) 4 /CsF in DMF and for coupling with aryl bromides using Pd 2 (dba) 3 /P(t-Bu) 3 /CsF in DMF, in both cases requiring 1.2 equivalents of Ag 2 O. In 2005, Adonin et al. extended their previous studies [11g] to the coupling of C 6 F 5 BF 3 K with aryl bromides instead of iodides employing Pd (OAc) 2 /P(t-Bu) 3 /K 2 CO 3 in toluene, but this was still only effective in the presence of 1.2 equivalents of Ag 2 O. [11b] Osakada et al. reported that Ag 2 O has the ability to replace the halide ligand of the catalyst to generate an hydroxyÀ palladium species, which shows higher reactivity in the transmetalation step with aryl boronates. The reaction of trans-[Pd(PEt 3 ) 2 (C 6 F 5 )I] with Ag 2 O in tolueneÀ water, for example, generates the complex trans-[Pd (PEt 3 ) 2 (C 6 F 5 )(OH)], which undergoes transmetalation with the boronic acid 4-MeOC 6 H 4 B(OH) 2 . [13] In 2010, Buchwald et al. reported the precatalyst XPhosÀ PdÀ G2 to solve the problem, and this works without additional Ag 2 O to catalyse the coupling of C 6 F 5 B(OH) 2 with aryl chlorides, bromides, and triflates but, interestingly, did not work for aryl iodides. [11h] However, this palladium catalyst is quite expensive or at least requires a multistep synthesis.
Previously, Osakada et al. [13] showed that 2,4,6-trifluorophenyl-B(OH) 2 reacts with trans-[Pd(C 6 F 5 )(PEt 3 ) 2 I] in the presence of Ag 2 O in toluene and H 2 O (Scheme 1), but the reaction stops with generation of the stable intermediate trans-[Pd(C 6 F 5 )(2,4,6-C 6 F 3 H 2 )(PEt 3 ) 2 ] as reductive elimination was not observed for this complex. Thus, for palladium complexes [L 2 Pd(Ar)(Ar')], if both Ar and Ar' are highly electron deficient, the reductive elimination step becomes much more difficult, as the PdÀ Ar bonds are strong. [14] Those reports show the current challenge for the palladium-catalysed Suzuki-Miyaura cross-coupling of C 6 F 5 À boronates with fluorinated aryl halides (Ar F À X), especially if the CÀ X bond flanked by two CÀ F bonds.
Polyfluorinated biaryls can be synthesised via Suzuki-Miyaura cross-coupling of polyfluorinated aryl boronic acid esters and polyfluorinated aryl iodides, as reported by Bulfield and Huber [10d] using palladium catalysts. They employed both fluoroaryl boronate and fluoroaryl halide substrates as coupling partners using a combination of palladium sources and various phosphine ligands. Although this reaction works in some cases, they had to optimise each reaction separately for the corresponding aryl boronate and aryl halide, using different types of expensive phosphine ligands. These reactions all required long reaction times (over 60 hours) and a procedure that would work for C 6 F 5 B(OH) 2 was not developed.
Recently, research to replace precious metal catalysts with cheaper and Earth-abundant metals [15] as well as metals of lower toxicity [16] has attracted much attention. Several groups have developed Cu(I) catalysts for Suzuki-Miyaura cross-coupling reactions. [17] For example, Li et al. have developed a copper/DABCO ligand catalyst system, but the reaction, however, does not work for sterically hindered and electrondeficient aryl boronic acids. [17c,d] Brown et al. reported that a combination of CuCl with Xantphos can effectively catalyse Suzuki-Miyaura cross-coupling of aryl iodides with aryl boronic acid neopentylglycol ester (Bneop) [17a] and later using Cy 3 PCuCl catalyst for a cross-coupling of arylÀ Bpin with heteroaryl bromides. [17h] Other systems involve the use of copper nanoclusters [17e] or copper powder in polyethylene glycol solvents. [17f] Giri et al. reported an efficient system employing CuI and (o-(di-tert-butylphosphino)-N,N-dimethylaniline (PN) as the ligand for efficient Suzuki-Miyaura cross-coupling of arylÀ Bneop with aryl iodides [17b] and extended with electron deficient aryl bromides. [17h] However, to the best of our knowledge, there are no reports of copper-catalysed Suzuki-Miyaura cross-coupling reaction of electron deficient, highly fluorinated aryl boronate esters, and only a few examples of the use of aryl bromides in Cu-catalysed Suzuki-Miyaura reactions. [17f,g,h] On the other hand, the optimised conditions for Cu-catalysed Suzuki-Miyaura cross-coupling employing arylÀ Bpin and aryl iodide as coupling partners is still challenging, as Brown et al. [17a] and Giri et al. [17b] reported that their optimised methods to employ arylÀ Bpin instead of arylÀ Bneop only afforded fair yields.
Herein, we report Suzuki-Miyaura cross-coupling of aryl iodides and bromides with highly fluorinated arylboronate esters (Ar F À Bpin), catalysed by phenanthroline-ligated copper complexes. Notably, Cu(I)-catalysed Suzuki-Miyaura cross-coupling of C 6 F 5 Bpin does not require the addition of silver oxide to achieve quantitative yields.

Result and Discussion
We began our investigation using the most electron deficient compound, C 6 F 5 Bpin (1 a), which was synthesised via an Ircatalysed CÀ H borylation reaction. [18] Coupling of C 6 F 5 Bpin with phenyl iodide (2 a) to give 2,3,4,5,6-pentafluoro biphenyl (3 a) was chosen as a model reaction. Giri et al. [17g] studied the mechanism of Cu(I)-catalysed Suzuki-Miyaura cross-coupling and showed that, after the formation of [(PN)CuI] 2 , the addition of CsF led to the formation of [(PN)CuF] 2 , which then yielded Scheme 1. Recent challenges for Pd-catalysed Suzuki-Miyaura cross-coupling to achieve polyfluorinated biaryls.
[(PN)CuPh] after transmetalation with an arylÀ Bneop reagent. Inspired by that work, we screened Cu(I) salts with different ligands, bases and solvents.
CuCl and CuBr, in place of CuI, were also tested but led to a decrease of the isolated yields to 55 % and 36 %, respectively (Table 1, entries 6 and 7). It is important to note that hydroxide and alkoxide bases must be avoided as the para-carbon atom of C 6 F 6 Bpin is susceptible to nucleophilic attack by these bases and they can replace the para-fluoro-substituent on the perfluorinated boronate substrate. [17] Thus, we examined fluorides and phosphates as bases and found that CsF gave the best results. Similarly, Korenaga et al. [11c] observed that CsF gave the highest yield for the Suzuki-Miyaura cross-coupling of C 6 F 5 B (OH) 2 with aryl halides using a Pd-catalyst. Using KF instead of CsF also gave a good yield of 68 % (Table 1, entry 7), whereas NMe 4 F afforded the product in only 29 % yield (Table 1, entry 8). Non-fluoride bases such as K 3 PO 4 resulted in a poor yield of 3 % (Table 1, entry 10).
Toluene and THF were ineffective solvents at temperatures close to their boiling points (Table 1, entries 11 and 12). It is interesting to note that without any additional ligand, the copper catalyst still gave a 26 % yield (Table 1, entry 13) and was more active than the system employing PN as the ligand (Table 1, entry 1). The absence of either CsF or CuI resulted in no product formation, indicating that both base and catalyst are required. A combination of CuI and phenanthroline generates [(Phen)CuI] [20] as using preformed [(Phen)CuI] gave an excellent yield (Table 1, entry 16). CsF reacts as a nucleophile and exchanges the halide ligand at Cu(I) to generate a CuF complex, [15b] which reacts more readily with the aryl boronate ester in the transmetalation step and thus accelerates the transfer of the aryl group to the metal. [10c,15b] CuI gave better result than CuBr or CuCl probably because the low bond energy [19] led to a more efficient anion exchange with CsF. It is also known that the reaction of [(phen)CuI] and CsF in DMF gives [(phen)CuF]. [20] Thus a combination of 10 mol% of CuI/ phenanthroline, and 2 equiv. of CsF, in DMF at 130°C emerged as the ideal conditions for the Suzuki-Miyaura cross-coupling of C 6 F 5 Bpin with aryl iodide. The use of organotrifluoroborates is attractive as these are inexpensive and more stable towards air and moisture than organoboronate substrates. [21] Thus, we also employed C 6 F 5 BF 3 K [11b,f] for the Suzuki-Miyaura cross-coupling and found that this also produced C 6 F 5 À C 6 H 5 in an almost quantitative yield of 99 % (Table 1, entry 4). While the use of aryl bromides and aryl boronate substrates for Cu-catalysed Suzuki-Miyaura cross-coupling has been reported, [17g] the reaction of aryl bromides with electrondeficient aryl boronate substrates was found to be difficult. [17g] We found that phenyl bromide was effective in reactions with C 6 F 5 Bpin in a mixed solvent system such as DMF : toluene (1 : 1) by increasing the loading of CuI/phenanthroline to 30 mol%, generating the cross-coupling product in 87 % yield (Scheme 2).
These conditions can be used to prepare polyfluorinated biaryl products on a gram scale. Thus, the coupling of C 6 F 5 Bpin with 1,2,3-trifluoro-5-iodobenzene (3 o) was conducted without any difficulty using the standard conditions to provide a 98 % yield of the unsymmetrical octafluoro biphenyl product (Scheme 4). Table 2. Cu-catalysed cross-coupling of C 6 F 5 Bpin with ArÀ X (X = I or Br). [a] Entry ArÀ X Product Yield [%] [b] 1 90   [c]

Molecular and Crystal Structures: Intermolecular π···π Stacking Interactions
The crystal structures of the polyfluorinated biaryls 3 d, 3 n, 3 o, and 5 d were analysed using single-crystal X-ray diffraction. A comparison of the molecular geometries of these compounds in their crystal structures ( Figure 1) shows a small influence of the steric demand of the hydrogenated aryl group in the vicinity of the CÀ C bonds joining the rings and, hence, of the repulsion between both groups of the biaryl units on their Table 4. Cross-coupling of 2,4,6-F 3 C 6 H 2 Bpin and 2,3,5,6-F 4 C 6 HBpin with PhX (X = I or Br). [a] Entry Ar F À Bpin Product and Yield [%] [b] 1 Scheme 4. Gram scale reaction. Reaction conditions: C 6 F 5 Bpin (1.47 g, 5 mmol), 1,2,3-trifluoro-5-iodobenzene (1.80 g, 7 mmol), (95 mg, 0.50 mmol, 10 mol%), phenanthroline (90 mg, 0.50 mmol, 10 mol%), CsF (1.52 g, 10.0 mmol, 2 equiv), and DMF (30 mL), 130°C, 18 h, under argon. [b] Isolated yield after column chromatography. geometries. The central CÀ C bond is in the range 1.483(4)-1.495(2) Å (Table 5) which is typical of biphenyl compounds. [24] It is slightly longer in compounds 3 d and 3 o than in 3 n and 5 d, although only within 1-2 su. The twist between the aryl moieties of the biaryl is slightly stronger in compounds 3 d and 3 o (61.66(5) and 64.28(5)°) than in 3 n and 5 d (51.23(15) and 49.76(7)°) ( Table 5). These small differences are likely due to the substitution at the ortho position of the non-fluorinated phenyl ring. In 3 d, a methyl group is bonded at the ortho position and in 3 o, the central phenyl ring of the anthracene moiety is bonded to the fluorinated phenyl ring. This increases the bulkiness of these aryl moieties in close vicinity to the central CÀ C bond and, hence, to the respective fluorinated phenyl rings. Large twist angles are also reported in the bulky biaryl compounds with a pentafluorophenyl group bonded to benzo [h]quinoline (67°), [25a] in 9,10-bis(pentafluorophenyl)anthracene (68°), [25b] and in 5-perfluorophenyl-11-phenyltetracene (72°). [25c] Particularly interesting in the crystal structure analyses are the intermolecular interactions and, hence, molecular packing in these compounds. The presence of both fluorinated and nonfluorinated aryl groups leads to the formation of opposite multipoles of these moieties due to the differences in electronegativity of hydrogen and fluorine atoms with respect to the carbon atoms. This often results in attractive multipole forces between the aromatic and perfluoroaromatic groups, also called the areneÀ perfluoroarene interaction, and, hence, in face-toface π-stacking with mean interplanar distances between 3.3 and 3.6 Å. [26] This type of interaction is mostly found in cocrystals of arenes and perfluoroarenes, which form highly oriented, π-stacked systems. [26c,27] However, also self-complementary compounds that contain both perfluorinated and nonfluorinated aryl groups, such as 2, 3,4,5,6-pentafluorobiphenyl and 1-pentafluorophenyl-2-phenylacetylene, form areneÀ perfluoroarene interactions. [27d,28a] This is also the case in the polyfluorinated biaryl compounds 3 n and 5 d in which the areneÀ perfluoroarene interaction determines the packing of the molecules (Table 6).

Conclusion
In summary, a combination of copper (I) iodide with phenanthroline as the ligand is an efficient catalyst for Suzuki-Miyaura cross-coupling reactions of electron deficient C 6 F 5 Bpin with aryl iodides and bromides in up to quantitative yield. Thus, the reaction proceeds using a non-toxic and inexpensive Earthabundant metal catalyst, replacing the traditional palladium catalysts which require large amounts of silver oxide as an additive. This reaction is also viable for cross-coupling a wide range of fluorinated phenyl boronic acid pinacol esters with aryl iodides or bromides. Notably, for aryl iodides, it can be used not only for coupling with electron deficient fluoroaryl boronates, but also for electron rich aryl boronates giving excellent yields.
A diverse range of π···π stacking interactions is observed in the partly perfluorinated biaryl compounds investigated herein, ranging from areneÀ perfluoroarene interactions (3 n, 5 d) to areneÀ arene (3 o) and perfluoroareneÀ perfluoroarene (3 d) interactions. Other applications of highly fluorinated aryl boronate substrates are under investigation in our laboratory.

Experimental Section
General procedure for the coupling reactions: unless otherwise noted, inside a glovebox, fluorinated phenyl boronic acid pinacol ester (0.4 mmol), the arylhalide (ArÀ X) (0.6 mmol), CuI (10 mol% if X = iodide; 30-50 mol% if X = bromide), phenanthroline (10 mol% if X = iodide; 30-50 mol% if X = bromide), CsF (0.8 mmol, 2 equiv), were added to a Schlenk flask that equipped with a stirring bar. The flask was capped and taken out of the glovebox. Solvent (DMF 3 mL if X = iodide; 1/1 mixture of DMF and toluene, 4 mL if X = bromide) were added under an argon atmosphere using a Schlenk vacuum line. The reaction was heated and stirred at 130°C for 18 h if X = iodide or at 140°C for 36 h if X = bromide. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was finally purified by flash column chromatography on silica gel (hexane). After concentrating the fractions containing the product, the residue was dried under reduced pressure to yield the pure product. Full experimental details as well as characterisation data and spectra of the products are provided in the Supporting Information.

Crystallographic Details
Crystal data collection and processing parameters are given in the Supporting Information. CCDC-1917134 (3 d