Ion-Pair-Directed Borylation of Aromatic Phosphonium Salts

Control of positional selectivity in C–H activation reactions remains a challenge for synthetic chemists. Noncovalent catalysis has the potential to be a powerful strategy to address this challenge. As a part of our ongoing investigations into the use of ion-pairing interactions in site-selective catalysis, we demonstrate that several classes of aromatic phosphonium salts undergo iridium-catalyzed C–H borylation with a high selectivity for the arene meta position. This is achieved using a bifunctional bipyridine ligand bearing a pendant sulfonate group, which had previously been successful for borylation of aromatic ammonium salts. In this case, the phosphonium salts give a higher meta selectivity than the corresponding ammonium salts. We propose that the high selectivity occurs due to an attractive electrostatic interaction between the substrate and the ligand in the transition state for borylation.

T he direct functionalization of arene C−H bonds using transition metal catalysis constitutes a highly effective method for elaboration of aromatic compounds. Numerous advances have been made, particularly over the last two decades. It is notable however that the majority of these advances result in a selective reaction at the arene ortho position, as a consequence of proximity to a directing group. Strategies that are able to reach further to the more remote meta and para positions are less common, and as a consequence, these positions are typically more difficult to access. 1 We and others have recently been exploring strategies that exploit a temporary noncovalent interaction between a substrate and ligand to guide the reactive transition metal to a particular position in the selectivity-determining transition state for C−H bond functionalization. 2 This approach builds on previous advances for controlling regioselectivity in reactions including aliphatic C−H activation, 3 hydroformylation, 4 and others. We have been particularly interested in applying this idea to control regioselectivity in arene C−H functionalization via C−H borylation, which has been investigated by a number of groups. 5−7 Specifically, we were curious to explore a scenario in which the catalyst engages in ion-pairing interactions with the substrate, as this is far rarer than using hydrogen bonding and relatively unexplored. 8 In our previous work, we developed an anionic bipyridine ligand (1) for application in iridium-catalyzed C−H borylation. 9 This ligand bears a pendant sulfonate group, which we hypothesized may engage in attractive electrostatic interactions with a quaternary ammonium moiety in the substrate, directing C−H borylation to occur at the arene meta position. Gratifyingly, a high meta selectivity was obtained with a variety of chain lengths between the quaternary ammonium group and the arene, despite initial concerns that substantial substrate flexibility may be incompatible with the relatively low directionality of ion-pairing interactions. However, in these studies, we only examined quaternary ammonium salts as cationic groups on the substrates.
Phosphonium salts have a number of important chemical applications as phase transfer catalysts, ionic liquids, and lipophilic cations. They can be transformed into reactive intermediates upon deprotonation to form ylides, as widely used in the Wittig reaction and variants. 10,11 Several recent studies have shown that certain phosphonium salts can also be used in cross-coupling reactions. 12 Hence, we were keen to explore whether our ion-pair-directed method for controlling regioselectivity in C−H borylation would be compatible with arenes bearing a phosphonium group, in order to demonstrate greater generality of the approach.
We began our studies with trifluoromethyl-substituted benzyl trimethyl phosphonium salt 3a, possessing a tosylate counterion (Table 1). An initial evaluation with the standard borylation ligand dtbpy gave no conversion in THF at 50°C (entry 1), but we found that switching to a more reactive tmphen ligand gave high conversion to a mixture of meta and para isomers with a poor selectivity, as expected (entry 2). We were happy to see that using our sulfonate ligand 1 in place of tmphen gave a good conversion with a 7:1 meta/para selectivity, in line with our hypothesis (entry 3). Under the same conditions, the same phosphonium cation but bearing bromide as the counteranion (2a) gave no conversion, presumably due to the very poor solubility of the starting material (entry 4); hence, we continued optimization using 3a. An evaluation of solvents revealed that in 1,4-dioxane the meta selectivity was greatly improved (>20:1) and with full conversion (entry 5). The selectivity was reasonably tolerant to solvent variations (entries 6−8), although nonpolar solvents were not suitable, likely due to solubility issues (entry 9). A control borylation of 3a in dioxane with tmphen revealed a slight bias toward para selectivity, highlighting the dramatic effect that our anionic ligand 1 has on this substrate's intrinsic selectivity toward C−H borylation (entry 10).
With optimal conditions in hand, we proceeded to evaluate the scope of the transformation. The substrates could be synthesized very readily from substituted benzyl bromides by benzylation of trimethylphosphine, followed by anion exchange with silver tosylate, both steps proceeding with generally high yields (Scheme 1). While the use of silver is not ideal from a cost standpoint, it is also possible to access these tosylate salts from benyl tosylates (see Scheme 3).
We first examined the 2-chloro-substituted salt and found that this also gave a high meta selectivity using ligand 1 (Scheme 2, 4b). Similarly to the CF 3 -substituted substrate, the use of tmphen gave some bias toward the para selectivity, in this case, 3.3:1 para/meta (see values in parentheses). A bromo-substituted variant also worked very well, giving 17:1 m/p selectivity (4c). In the case of the electron-donating methyl substituent, a higher catalyst loading of 6 mol % Ir was required for good conversion, and this substrate too gave a high selectivity (4d). The small size of fluorine resulted in substrate 4e giving a mixture of isomers under borylation with tmphen, but with ligand 1, only the meta-borylated isomer was observed (>20:1). Finally, an unsubstituted benzylphosphonium salt also performed well (4f). In this case, it was not The Journal of Organic Chemistry Note possible to stop at monoborylation, and so, 3 equiv of B 2 Pin 2 was used to obtain the dimeta-borylated product in a good yield. The iodo-substituted phosphonium salts 3g and 3h unfortunately were found to give no conversion with either tmphen or ligand 1. Interestingly, the triarylbenzylphosphonium salt 3i was also found to give no reaction with either ligand. It should be mentioned that in many cases small amounts of starting material were still present at the end of the reaction, and these were impossible to separate from the borylated products as the salts were not purifiable on silica and had to be precipitated. The yields quoted have been adjusted to reflect this based on the molar mass of the starting material (see Experimental Section).
Borylation of a pyridine-derived phosphonium salt was next examined to evaluate whether selectivity between the 4-and 5positions could be obtained. In this case, the counterion exchange according to the previous substrate synthesis using silver failed in the presence of the basic pyridine. So an alternative approach was taken via the intermediate tosylate, which allows substrates to be accessed from benzyl alcohols. This approach can be advantageous for some substrates as it installs tosylate directly as the counteranion (Scheme 3a). For the pyridine substrate 5a, it was quite challenging to prevent over borylation to 6c, but by stopping the reaction after 1 h, useful amounts of 6a, the product of borylation at C4, could be obtained and the C4/C5 ratio was 10:1 (corresponding to the m/p ratio in nonheteroarenes). In contrast, with tmphen, the C4/C5 ratio was ∼1:1 (Scheme 3b).
We next sought to vary the carbon chain of the phosphonium salt to evaluate whether selectivity would be maintained if it is either extended or reduced. We were pleased to find that trifluoromethyl-substituted phenethyl phosphonium salt 7a gave >20:1 m/p selectivity in a good yield (Scheme 4a). In contrast, control borylation of this substrate with tmphen as a ligand gave 1:2 m/p. While we did explore substituents apart from CF 3 in this class, we found that less electron-withdrawing substituents typically gave only moderate conversions and so these were not further pursued due to the challenges of separating the product from the unreacted starting material (vide supra). Phenyltrimethyl phosphonium tosylate (7b) gave an excellent meta selectivity, resulting in dimeta-borylated product 8b (Scheme 4b). These results provide encouragement that phosphonium salts are likely to be tolerant of a range of chain lengths, as we had previously seen with the corresponding ammonium salts, which gave a meta selectivity with both 2-and 3-carbon linker lengths. 9 Finally, we demonstrate the meta-selective borylation of 3b on a 1.0 mmol scale and telescope this with conversion of the BPin to a hydroxyl group followed by reduction of the phosphonium functionality with lithium aluminum hydride (Scheme 5). 13 This example of further elaboration highlights the potential of our method for the rapid access to complex arene building blocks.
In summary, we have demonstrated that aromatic phosphonium salts are compatible with our previously reported sulfonate ligand 1 to enable C−H borylation to be directed to the arene meta position. The selectivities are in general very high, and we envisage that this study provides further evidence of the utility of ion-pairing interactions in the design of new catalyst scaffolds for site-selective functionalization.

■ EXPERIMENTAL SECTION
Materials and Methods. All reagents, unless otherwise stated, were used as supplied from commercial sources without further purification. CH 2 Cl 2 , THF, and Et 2 O were purified by distillation on site under an inert atmosphere via the following processes: THF and Et 2 O were predried over a sodium wire and then distilled from calcium hydride and lithium aluminum hydride. CH 2 Cl 2 and n-hexane were distilled from calcium hydride. 1 H NMR spectra were recorded on a 600 MHz Bruker Avance DRX-600 spectrometer, 500 MHz Bruker DCH Cryoprobe, or 400 MHz QNP Cryoprobe. Chemical shifts are reported in parts per million (ppm), and the spectra are calibrated to the resonance resulting from incomplete deuteration of the solvent (CDCl 3 7.26 ppm, CD 3 OD 3.31 ppm, (CD 3 ) 2 SO 2.50 ppm). 13 C NMR spectra were recorded on the same spectrometers with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard ( 13 CDCl 3 77.16 ppm, t; 13 CD 3 OD 49.00 ppm, sept; DMSO-d 6 39.51 ppm, s). Data are reported as follows: chemical shift δ/ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet or combinations thereof; 13 C signals are singlets unless otherwise stated), coupling Scheme 3. Synthesis and Borylation of Pyridylphosphonium Salt 5a Scheme 4. Borylation of Longer Chain Phosphonium Salt 7a and Phenyltrimethyl Phosphonium Tosylate (7b)

Scheme 5. Larger Scale Reaction and Elaboration of the Product
The Journal of Organic Chemistry Note constants J in Hz, integration (1H only). 1 H−COSY, HSQC, HMBC, and NOESY were used where appropriate to facilitate structural determination. The carbon attached to boron was generally not observed by 13 C spectroscopy due to quadrupolar relaxation. 1 H NMR signals are reported to 2 decimal places and 13 C signals to 1 decimal place (2 decimals places if the peaks are not distinguishable with only 1 decimal place). 19 F NMR spectra were recorded on a 400 MHz Bruker Avance III HD spectrometer, and 19 F signals are reported to 2 decimal places. 31 P NMR spectra were recorded on a 600 MHz Bruker Avance DRX-600 spectrometer or a 400 MHz Bruker Avance III HD spectrometer, and 31 P signals are reported to 2 decimal places.
High-resolution mass spectra (HRMS) were recorded on a Waters Micromass LCT Premier TOF spectrometer using a positive electrospray ionization (ESI+). Measured values are reported to 4 decimal places and are within ±5 ppm of the calculated value. The calculated values are based on the most abundant isotope.
General Procedure for the Synthesis of Phosphonium 4-Methylbenzenesulfonates (GP1). The corresponding phosphonium bromide (or chloride) salt and silver p-toluenesulfonate (1.1 equiv) were dissolved in CHCl 3 . The reaction mixture was stirred at room temperature for 30 min and then filtered through MgSO 4 . The filtrate was collected, and the solvent was removed under reduced pressure to afford the product.
Calculation of the Yield in Borylation Reactions. In some cases, small amounts of the starting material remained in the reactions, which were inseparable from the borylated products. The following procedure was then used to determine the yield of the borylated products. The ratio of borylated products to starting material was determined by NMR analysis, using the NMR of the isolated product. This ratio was used to calculate an average molecular weight in order to determine the mmol of product obtained, such that an overall yield could be obtained. The yield of the borylated products was then obtained by multiplying the overall yield by the fraction of borylated products present.
Assignment of meta and para Products. When possible, the coupling patterns in the aromatic region were used to assign the respective isomers. Otherwise, assignments were done using information from 2D NMR experiments (COSY, HSQC, HMBC, NOESY). Data for the para product was usually obtained from the tmphen control experiments by subtracting the signals for the meta product and starting material from the spectra.