Sterically Demanding Aryl Chlorides: No Longer a Problem for Borylations

Is it really surprising that yet another Highlight concerns the latest developments in boron chemistry? The past few decades have seen remarkable progress in both, inorganic and organic boron chemistry, with William Lipscomb and Herbert Brown, respectively, being awarded Nobel prizes for their groundbreaking research in these emerging areas.1 Professor Akira Suzuki is the latest Nobel laureate in boron chemistry for his outstanding work in cross-coupling reactions, where organoboranes have all but usurped their more toxic tin counterparts.2 The Suzuki–Miyaura reaction uses organoboranes [primarily aryl boronic acid derivatives—ArB(OH)₂] and organic halides (RX) in the presence of a catalyst (usually palladium-based systems) to generate new organic products containing a new CC bond (ArR). Borates are generated as relatively non-toxic and environmentally benign by-products. One of the synthetically limiting challenges of the Suzuki–Miyaura reaction has been the process of accessing sterically demanding aryl boronic acid derivatives. Although the starting organoboranes have traditionally been prepared by using organolithium or Grignard reagents, these methods frequently suffer from low yields, difficult isolation procedures, and they are not usually compatible with a variety of functional groups.

An alternative approach to the construction of BC bonds and generating these valuable precursors has evolved from the metal-catalyzed borylation of CH bonds.3 However, selectivity can be a problem in these reactions, when more than one type of CH bond is present. Complementary to this reaction is the remarkably selective metal-catalyzed borylation of aryl halides (Scheme 1).4 First reported in 1995 by Miyaura and coworkers,5 this reaction converted a series of aryl bromides and iodides into the corresponding aryl boronate esters by addition of bis(pinacolato)diborane (B₂pin₂) by using a catalytic amount of [PdCl₂(dppf)] (DPPF=1,1′-bis[diphenylphosphino]ferrocene) and the weak base KOAc. The nature of the base is essential for ensuring high selectivities in these reactions as further coupling of the aryl boronate ester products with any unreacted starting aryl halide is observed when a stronger base than KOAc is used to affect these transformations. Although significant advances have been made with these borylation reactions, only a few metal systems have been able to effectively catalyze the conversion of unactivated aryl chlorides.6 Aryl chlorides are less reactive than their bromide, iodide, and triflate counterparts, but the low cost and the availability of a wide range of these substrates makes the ability to transform them into organoboronate esters a remarkably valuable tool in synthetic chemistry.

Scheme 1. The metal-catalyzed borylation reaction using HBpin or B₂pin₂ to generate aryl boronate esters.

It was originally believed that the best catalyst systems for this borylation reaction were those based on a palladium source incorporating electron-rich and sterically demanding phosphane6 or carbene ligands.7 As mentioned previously, catalytic amounts of [PdCl₂(dppf)] were used in the initial study by Miyaura and coworkers, but subsequent studies focused on (dicyclohexylphosphino)biphenyl-type ligands such as X-Phos (1).

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In these later studies, only one of these bulky ligands was purported to coordinate to the metal center, which allows for a free coordination site needed to coordinate and activate the diboron species. More recently, this chemistry has been extended to include the use of the bulky anthracene derivative 2. A palladacycle derived from 2 was able to effectively catalyze the borylation of a number of aryl chlorides into the boronate esters in moderate to high yields. For example, reactions with 2-chloro-1,3-dimethylbenzene gave the corresponding aryl boron compound, but only with a yield of 53 % (entry 2, Table 1), which is comparable to results obtained using ligand 1.8

Table 1. The metal-catalyzed borylation of 2-chloro-1,3-dimethylbenzene using palladium phosphane complexes.

Entry	Phosphane	Yield [%]	Reference
[a] A mixture of dioxane/water (10:1) was used as solvent. [b] Conversion was 90% according to ^1H NMR spectroscopy.
1	1	62^[a]	8
2	2	53	4
3	3	82^[b]	9

In a recent publication, Sawamura and coworkers have utilized a slimmed-down phosphane ligand tethered to a silica support (3) in conjunction with a palladium source along with the traditional three equivalents of KOAc to affect the borylation of 4-chlorotoluene using B₂pin₂ at 60 °C after 10 h to give exclusive formation of the corresponding aryl boronate ester.9a Ligand 3 is a silicon-constrained monodentate trialkylphosphane ([silica]-SMAP) prepared by treating the starting phosphane Ph-SMAP with trifluoromethanesulfonic acid (TfOH) in benzene. This gives the corresponding silyl triflate species, which is further treated with HCl-activated silica gel in refluxing benzene, followed by filtration and elution of soluble materials and subsequent neutralization. The surface silanols that remain intact are capped with Me₃Si groups to give the resulting heterogeneous ligand 3.9b

The catalyst system is readily separated from the products by simple filtration through Celite, and catalyst leaching was reported to be below the detection limit. Unfortunately, attempts to reuse the immobilized catalyst have so far proved unsuccessful. Remarkably, the related homogeneous catalyst systems based on analogues of 3, such as Ph-SMAP, were reported to give none of the desired borylation products under otherwise identical conditions.

Sterically challenging ortho-substituted aryl chlorides were also effectively converted to the aryl boronate esters without the formation of any significant amount of the undesired homocoupled products. Using this new catalyst system, reactions with 2-chloro-1,3-dimethylbenzene gave the corresponding aryl boronate ester at 60 °C in 90 % yield (entry 3, Table 1), a marked improvement from previous results utilizing the well-established bulky phosphanes. Reactions with bulky 2-chloro-1,3-diphenylbenzene gave the corresponding aryl boronate ester in 80 % isolated yield, although temperatures of 90 °C were required to complete this transformation (Scheme 2). Reactions of 2-chloro-1,3,5-triisopropylbenzene proceeded at higher temperatures (110 °C), but afforded the desired product in 64 % isolated yield. The only other significant by-products in these reactions were the corresponding protonated arene rings, 1,3-diphenylbenzene and 1,3,5-triisopropylbenzene, respectively.

Scheme 2. The borylation of sterically-demanding aryl chlorides using B₂pin₂ and catalytic amounts of palladium [silica]-SMAP (3).

The authors suggest that the steric demand of the ligand is not required for a high catalytic activity in the palladium-catalyzed borylation of aryl chlorides, if a monodentate phosphane ligand is anchored to a solid support. This immobilization allows only one phosphane ligand to coordinate to the metal center, and future work will no doubt concentrate on altering the electronic and steric nature of the phosphane ligand. Deactivation of the borylation activity is believed to occur only when two phosphane ligands coordinate to the palladium center.

This current methodology is exciting, as it allows for a wide range of silica-supported phosphanes to be used in these borylation reactions. The scope of the substrate will also have to be investigated to see, if other CCl bonds (i.e., alkenyl chlorides) can be activated. The ultimate accomplishment for these reactions will be to use catalyst systems and a base to affect the initial borylation reaction and a second, stronger base to assist in a tandem-catalyzed Suzuki–Miyaura cross-coupling reaction by using only cheap and readily available aryl chlorides. Finally, borylations using B₂pin₂ suffer from one major drawback, in that one of the boron fragments is usually sacrificed for the good of the reaction. Borylations using the borane HBpin can be more atom economical, and it will be interesting to see, if this reagent can be used in reactions using palladium [silica]-SMAP.

Acknowledgements

Thanks are gratefully extended to the Natural Sciences and Engineering Research Council of Canada for financial support.