Synthesis of Fluoroalkoxy Substituted Arylboronic Esters by Iridium- Catalyzed Aromatic C−H Borylation Farhat Batool, †,∥ Shehla Parveen, † Abdul-Hamid Emwas, ‡ Salim Sioud, ‡ Xin Gao, § Munawar A. Munawar, ∥ and Ghayoor A. Chotana* ,† † Department of Chemistry, Syed Babar Ali School of Science & Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan ‡ Imaging and Characterization Core Lab, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia § Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia ∥ Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan * S Supporting Information ABSTRACT: The preparation of fluoroalkoxy arylboronic esters by iridium- catalyzed aromatic C−H borylation is described. The fluoroalkoxy groups employed include trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, and 2,2- difluoro-1,3-benzodioxole. The borylation reactions were carried out neat without the use of a glovebox or Schlenk line. The regioselectivities available through the iridium-catalyzed C−H borylation are complementary to those obtained by the electrophilic aromatic substitution reactions of fluoroalkoxy arenes. Fluoroalkoxy arylboronic esters can serve as versatile building blocks. F luorinated aromatic compounds have important applica- tions in the fields of pharmaceutical, 1 agrochemical, 2 and material sciences. 3 The incorporations of fluorine or fluorinated substituents could induce dramatic changes in the electronic, steric, and hydrophobic parameters of the target molecule. This can result in improved binding selectivity, metabolic stability, lipophilicity, etc. ultimately affecting the pharmacodynamic and pharmacokinetic properties of fluorinated molecules. Besides fluorine itself, the most commonly used fluorine-containing functional group is trifluoromethyl (CF 3 ). Recently, other fluorinated functional groups, especially the fluoroalkoxy substituents such as trifluoromethoxy (OCF 3 ), difluoromethoxy (OCF 2 H), and tetrafluoroethoxy (OCF 2 CF 2 H), etc. have also been explored in search of unique properties. 4 The fluoroalkoxy groups have interesting properties when compared with other fluorinated substituents. For example, the OCF 3 group is far more lipophilic (π = +1.04) than F (π = +0.14) and is even better than the CF 3 (π = +0.88) group. 5 The Hammett substituent constant σ I of OCF 3 (0.51) is greater than that of CF 3 (0.39) or SCF 3 (0.31) groups and is comparable to that of an SF 5 (0.55) group. 6 While the σ I value of OCF 2 CF 2 H (0.39) is comparable to that of F (0.45). The fluoroalkoxy groups can also induce particular conformational changes. The OCF 3 group in (trifluoromethoxy)benzene tends to adopt an orthogonal position with respect to the arene ring, in contrast with the methoxy group which normally lies in the plane of the arene. 4 Also, due to the diminished conjugation of the oxygen nonbonding electrons with the aromatic ring, the OCF 3 group can freely rotate out of the nucleus plane. 7 This enhanced conformational flexibility may allow better binding affinity. Like other fluorinated substituents, fluoroalkoxy groups also display higher metabolic and thermal stabilities. The OCF 3 and OCF 2 CF 2 H functional groups are stable to strong acids and bases. 8 Compared to the trifluoromethylsulfide (SCF 3 ) group, which readily undergoes oxygenation to the corresponding sulfoxides and sulfones, 9 the fluoroalkoxy substituents are quite stable to oxidative stress. Due to these interesting physical and chemical properties, the fluoroalkoxy functional groups may thus advantageously replace fluorine or CF 3 in many bioactive molecules. The intrinsic properties of the fluoroalkoxy substituents can potentially be very useful for the fine-tuning of biological as well as technical properties. As a result, fluoroalkoxy-substituted aromatics have found important commercial applications in the fields of pharmaceuticals, agrochemicals, and electro-optical displays (Figure 1). 4,10 Despite their interesting properties, the facile introduction of fluoroalkoxy functional groups is not trivial. Trifluoromethoxy- substituted aromatics were first synthesized by Yagupol’skii by the reaction of hydrogen fluoride or antimony fluorides with aryl trichloromethyl ethers. 11 Over the past few decades, various new transformations have been developed for the synthesis of fluoroalkoxy aromatics. 4,12 However, most of these approaches either are multistep or suffer from poor substrate Received: July 17, 2015 Letter pubs.acs.org/OrgLett © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.5b02050 Org. Lett. XXXX, XXX, XXX−XXX