Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes with Aryl Halides

: The synthesis of arylCF 2 CF 2 SiMe 3 and their reactivity in cross-coupling reactions with aryl iodides and aryl bromides to afford a range of 1,1,2,2-tetrafluoro-1,2-arylethanes is reported. The use of pyridine as an alternative to phenanthroline, and the ability to carry out the reaction at 60 °C or room temperature are the key features of this Cu−Ag mediated cross-coupling methodology. The chemistry is compatible with (hetero)aryl halides, offering a platform to develop products of interest in material and medic-inal chemistry. 2

after two steps. The subsequent reaction, a magnesium-mediated trimethylsilylation, was less efficient but this process was readily scalable, delivering more than two grams of [2-(biphenyl-4-yl)-1,1,2,2-tetrafluoroethyl](trimethyl)silane 1a; this compound is a white crystalline solid found suitable for single crystal X-ray diffraction analysis. 11,12 The additional [2aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes 1b and 1c used in this study were prepared following a similar reaction sequence. For 1c, lithium halogen exchange was preferable to Grignard formation for the trimethylsilylation step. 12 In the first instance, the reactivity of 1a was probed with a benchmark reaction, a fluoride-mediated addition to enolizable and non-enolizable aldehydes (Scheme 3).
We focused next on the Cu-mediated cross-coupling of 1a with 1-iodo-2-methoxy-4-nitrobenzene (Table 1). Our investigation began with the coupling of 1a and our model aryl iodide in DMF with 1.5 equiv of KF and CuI at 60 °C for 16 h (Table1, entry 1). These conditions led to the desired product 3aa in 26% yield along with 35% of 4-(1,1,2,2tetrafluoroethyl)-1,1'-biphenyl 4a resulting from competitive protodesilylation. The two additional side products observed in the crude reaction mixture were the iodo derivative 5a formed in 31% yield along with 18% of alkene 6a. A similar product distribution was obtained using NMP, but the use of DMSO proved beneficial (Table 1, entries 2-3). AgF was the most efficient activator affording the desired coupling product in 53% yield (Table 1, entry 6). The cooperative effect of silver in the Cu-catalyzed trifluoromethylation of aryl iodides with CF3TMS has been reported for other systems by Weng and co-workers. 4e Alternative sources of Cu(I) such as CuBr or CuCl were less effective (Table 1, entries 7-8). 14 The reaction did proceed with a catalytic amount of CuI, however a substantial amount of by-product formation was observed (entry 9). Several additives were considered next. With the Ruppert-Prakash reagent CF3SiMe3, B(OMe)3 was shown to stabilize the CF3 anion in copper mediated cross-coupling, thus minimizing the formation of protodesilylated by-product; 4j no beneficial effect was observed with 1a (Table 1, entry 10). As anticipated, we found that 1,10-phenanthroline and bipyridine were superior to TMEDA, but these ligands afforded product 3aa in only low to moderate conversion (Table 1, entries 11-13); the more electron rich 4,4'-di-tert-butyl-2,2'-bipyridine ligand gave 3aa in 64% (Table 1, entry 14) and pyridine afforded 3aa in 63% (Table 1, entry 15). Cost-effective pyridine was identified as the best additive for cross-coupling (Table  1, entries [15][16]. The use of pyridine as a preferential ligand for copper-mediated cross-coupling methodologies for perfluoroalkylation is not common, but its advantage over other ligands has been documented in the context of flow chemistry. 15 Monitoring the reaction by NMR indicated that the starting material was consumed after 6 h (Table 1, entry 17). Applying our best conditions consisting of CuI (1.5 equiv), AgF (1.5 equiv), pyridine (5.0 equiv) in DMSO at 60 °C for 6 h, 3aa was isolated in 78% yield (Table 1, entry 18). Similar conditions using 20 mol % of CuI instead of 1.5 equiv led to inferior results, so these conditions using sub-stoichiometric amount of CuI were not retained to study the scope of this cross-coupling reaction (Table 1, entry 19).
The substrate scope was investigated next (Scheme 4). Numerous functionalized aryl iodides underwent cross-coupling with 1a. Ketone, nitro, cyano, ether, ester, and bromo substituents are well tolerated with good conversions obtained for both electron-donating and electron-withdrawing substitu-Scheme 4. Copper-mediated Cross Coupling of 1a with (Hetero)aryl Iodides a a 1.2 equiv of 1 and 1.0 equiv of aryl iodide (0.2 mmol scale); All yields are for isolated products. b Reaction performed at room temperature for 6 h. c chemical purity 91%. d 0.5 mmol scale. c chemical purity 90%.
ents. This methodology can be extended to a vinyl iodide as well as a range of heteroaryl iodides including thiophene, pyrazine, indole and pyridine derivatives. The reaction also proceeds with alternative 2-substituted trimethyl(1,1,2,2-tetrafluoroethyl)silanes, as exemplified by the synthesis of 3bg, 3cg and 3ce. Compound 3ce is an advanced precursor for the synthesis of a liquid crystalline compound. 6c We noted that this protocol allowed for the coupling of CF3CF2TMS with 1iodo-2-methoxy-4-nitrobenzene and HCF2TMS with 1-tertbutyl-4-iodobenzene affording the desired products in 82% (yield of isolated product) and 59% ( 19 F NMR yield), respectively. This is an improvement over current methods reported in the literature because of the mildness of our reaction conditions. 4h, 16 The cross-coupling of 1a with aryl iodides could also be performed at room temperature, but the yields of the isolated products were generally lower under these conditions (Scheme 4). The diaryl derivatives 3ac, 3aq and 3as stand out as candidates for further derivatization via cross-coupling or metathesis.
The difference in availability and price of (hetero)aryl iodides and bromides prompted us to study the coupling of representative (hetero)aryl bromides (Scheme 5). These reactions Scheme 5. Copper-mediated Cross Coupling of 1a with (Hetero)aryl Bromides. a a 1.2 equiv of 1a and 1.0 equiv of aryl iodide (0.2 mmol scale); yields of isolated products unless stated otherwise. b 19 F NMR yields, determined by integration of the product peak(s) using PhCF3 as the internal standard.
were performed using CuI (1.5 equiv), AgF (1.5 equiv), pyridine (5.0 equiv) in DMSO at 60 °C for 6 h. We found that this reaction does not proceed for electron rich cross-coupling partners such as 1-bromo-4-methoxybenzene. For electron deficient aryl bromides, cross-coupling proceeded under the reaction conditions applied to aryl iodides with yields of isolated products reaching up to 68%. 2-Bromopyridine was more reactive than 3-bromopyridine, a reactivity order allowing for the exclusive formation of product 3aq from 2,3-dibromopyridine.
In summary, we have developed a simple synthetic procedure for the generation of 1,1,2,2-tetrafluoro-1,2-arylethanes from the reaction of stable arylCF2CF2SiMe3 Ruppert-Prakash type reagents with (hetero)aryl iodides or bromides. These reactions are an improvement over current fluoroalkylation reactions due to the mildness of the reaction conditions applied. However, improved routes towards arylCF2CF2SiMe3 will be necessary to progress this methodology from research to process. The use of pyridine as an alternative to phenanthroline and the ability to carry out the reaction at 60 o C or room temperature for aryl iodides are the key features of this cross-coupling methodology. An additional characteristic is the range of (hetero)aryl halides amenable to cross-coupling under such mild reaction conditions. We anticipate that this process will facilitate research programs focusing on the discovery of high performance materials.

Supporting Information
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Notes
The authors declare no competing financial interest.