Pd-Catalyzed, Highly Selective C(sp2)-Br Bond Coupling Reactions of o-(or m-, or p-) Chloromethyl Bromobenzene with Arylboronic Acids

Highly selective C(sp2)–C(sp2) cross-coupling of dihalogenated hydrocarbons comprising C(sp2)–Br and C(sp3)–Cl bonds with arylboronic acids is reported. This highly selective coupling reaction of the C(sp2)–Br bond is successfully achieved using Pd(OAc)2 and PCy3·HBF4 as the palladium source and ligand, respectively. A series of chloromethyl-1,1′-biphenyl compounds are obtained in moderate-to-excellent yields. Moreover, this protocol can be extended to the one-pot dual arylation of 1-bromo-4-(chloromethyl)benzene with two arylboronic acids, leading to diverse unsymmetrical 4-benzyl-1,1′-biphenyl derivatives.


Results and Discussion
Initially, 1-bromo-4-(chloromethyl)benzene and p-tolylboronic acid were selected as model substrates to optimize the reaction conditions. Table 1 summarizes the results obtained. The screened bases were examined by using PCy3·HBF4 and Pd(OAc)2 as the ligand and palladium source, respectively, in toluene/water (1/0.1) at 80 °C for 2 h; Cs2CO3 was the most effective base, affording the desired product in 99% yield (entry 5). On the other hand, other bases such as K2CO3, K3PO4·3H2O, NaOH, and NEt3 afforded the desired products in 16-84% yields (entries 1-4). Remarkably, the ligand was found to play an important role in this reaction, and PPh3 was not effective for this selective C(sp 2 )-C(sp 2 ) coupling reaction (entry 6). Moreover, with the decrease in the reaction temperature to 60 °C, the product was obtained in only 74% yield (entry 7). With the decrease in the catalyst amount from 1 mol % to 0.2 mol %, the desired product was still obtained in a gas chromatography-mass spectrometer (GC-MS) yield of 99% (entries 8-10). However, with the decrease in the catalyst loading to 0.1 mol %, the yield was significantly reduced (entry 11). Finally, the combination of Pd(OAc)2 (0.2 mol %)/PCy3·HBF4 (0.4 mol %) and Cs2CO3 (2 equiv.) at 80 °C for 2 h in toluene/water (1 mL/0.1 mL) was found to constitute the optimum reaction conditions. With the optimized reaction conditions in hand, the substrate scope of this selective Suzuki-Miyaura reaction was examined. First, the coupling reactions of 1-bromo-4-(chloromethyl)benzene with arylboronic acid were explored under the optimized reaction conditions. 4-Substituted arylboronic acids bearing electron-donating or electron-withdrawing groups selectively underwent the coupling reaction, affording corresponding products 3b-3g in 75-93% yields (Table 2). Furthermore, the selective coupling reaction of 1-bromo-4-(chloromethyl)benzene, with mtolylboronic acid, and (3-chlorophenyl)boronic acid afforded the desired products 3h and 3i in 98% and 73% yields, respectively. Sterically demanding ortho substituents, such as o-tolylboronic acid, did not impair the coupling reaction, affording the desired product 3j in 90% yield. However, (2,3difluorophenyl)boronic acid and (2,6-dimethylphenyl)boronic acid as substrates afforded coupling products 3k and 3l, respectively, in low yields. In addition, thiophen-3-ylboronic acid, naphthalen-2ylboronic acid, and 4-vinylphenylboronic acid were tolerated, affording desired products 3n-3p in 57-86% yields. Next, the selective coupling reactions of 1-bromo-3-(chloromethyl)benzene with various arylboronic acids were investigated ( Table 3). The results indicated that neither the electronic property nor the steric hindrance of the substrates clearly affects the coupling reaction: The desired products 4a-4h were obtained in 73-95% yields.  To further ascertain the application scope of the catalytic system, the reaction of 1-bromo-2-(chloromethyl)benzene with arylboronic acids was examined. The present catalytic method can be applied for the selective coupling of 1-bromo-2-(chloromethyl)benzene with arylboronic acids, affording the desired products 5a-5h in yields of 80-95% (Table 4). A one-pot dual Suzuki coupling reaction for successively substituting 4-bromobenzyl chloride with distinct aryl groups was contemplated, which could provide a straightforward route for obtaining diverse 4-benzyl-1,1′-biphenyl derivatives (Table 5). First, 4-bromobenzyl chloride was treated with 1.1 equivalent of p-tolylboronic acid in the presence of 2 mol % of Pd(OAc)2, 0.4 mol % of PCy3·HBF4, and 5.0 equiv. of Cs2CO3 in a mixture of toluene and water (10:1). After heating for 2 h at 80 °C, 1.0 equivalent of arylboronic acid and 4.0 mol % of PPh3 were added to the reaction system. The reaction mixture was stirred for 5 h at 80 °C, affording the desired products 6a-6d in 57-96% yields. Next, the coupling reactions of 1-bromo-4-(bromomethyl)benzene (1d) with p-tolylboronic acid (2a) were investigated under the optimized conditions. We found that the selective reaction of C(sp 2 )-Br bond with arylboronic acids could proceed smoothly to give 42% of the desired product 7a, also accompanied by 25% yield of bis-coupling product 7b (Scheme 2). This experimental result shows that the selectivity of the reaction depends not only on the regulatory effect of the phosphine ligand but also on the structure of the C(sp 3 )-X bond.
The selectivity depended exclusively on the palladium ligands. To demonstrate the importance of phosphine ligand for palladium-catalyzed selective coupling reactions of C(sp 2 )-Br bond or C(sp 3 )-Cl bond with arylboronic acid, the external competition experiment was performed. To this end, we designed an experiment in which mixtures of bromobenzene and (chloromethyl)benzene were allowed to react with p-tolylboronic acid (Scheme 3). As expected, the formation of the Csp 2 -Csp 2 cross-coupling product (7c) was achieved in the competitive experiment when PCy3·HBF4 was used as the phosphine ligand in the palladium catalyst.

Materials and Methods
Chemicals were obtained commercially and used as received. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DPX-400 spectrometer (Bruker Co., Billerica, MA, USA) S Me using tetramethylsilane (TMS) as the internal standard. Electric impact ionization (EI)-Mass spectrum was measured on a gas chromatography time of flight high resolution mass spectrometry (GCTOF-HRMS) (Waters Co, Milford, MA, USA). or GC-MS (Agilent 7890A/5975C, Santa Clara, CA, USA) instrument. Electrospray ionization (ESI)-Mass spectrum was measured on a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) (Bruker Co., Bremen, Germany). To all copies of 1H NMR, 13C NMR and HRMS spectra, please see Figures S2-S45 in Supplementary Materials. All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleum ether (60-90 °C), unless otherwise noted. Arylboronic acids and o-(or m-, or p-)chloromethyl bromobenzene were of analytical grade quality, purchased from Adamas-beta Pharmaceuticals, Inc. (Shanghai, China).

General Procedure for the Selective Coupling Reaction of o-(or m-, or p-)chloromethyl Bromobenzene with Arylboronic Acid
A Schlenk tube (20 mL) was charged with o-(or m-, or p-)chloromethyl bromobenzene (0.3 mmol), arylboronic acid (0.33 mmol), Pd(OAc)2 (0.2 mol %), PCy3·HBF4 (0.4 mol %), and Cs2CO3 (2 equiv.). The tube was degassed for 30 s and then was filled with argon. This operation was repeated three times. After toluene (1.0 mL) and H2O (0.1 mL) were added under argon atmosphere, the resulting reaction mixture was stirred at 80 °C for 2 h under argon. After the completion of the reaction, the reaction mixture was allowed to cool to room temperature. The solution was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4 and filtered, followed by solvent removal under reduced pressure. The residue was purified by flash column chromatography on silica gel using petroleum ether/EtOAc as the eluent.

General Procedure for One-Pot Dual Arylations of 1-Bromo-4-(chloromethyl)benzene
A Schlenk tube (20 mL) was charged with 1-bromo-4-(chloromethyl)benzene (0.3 mmol), arylboronic acid (0.33 mmol), 2 mol % Pd(OAc)2, 0.4 mol % PCy3·HBF4, and 5 equiv. Cs2CO3. The tube was degassed for 30 s and then was filled with argon. This operation was repeated for three times. After toluene (1.0 mL) and H2O (0.1 mL) were added under argon atmosphere, the resulting reaction mixture was stirred at 80 °C for 2 h under argon. After the completion of the reaction, the solution was allowed to cool to room temperature. Then, another arylboronic acid (0.33 mmol) and 4 mol % PPh3 were introduced under argon. The reaction mixture was heated at 80 °C for 5 h. The solution was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4, filtrated, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc as the eluent.