Development of Facile and Simple Processes for the Heterogeneous Pd-Catalyzed Ligand-Free Continuous-Flow Suzuki–Miyaura Coupling

: The Suzuki–Miyaura coupling reaction is one of the most widely utilized C–C bond forming methods to create (hetero)biaryl sca ﬀ olds. The continuous-ﬂow reaction using heterogeneous catalyst-packed cartridges is a practical and e ﬃ cient synthetic method to replace batch-type reactions. A continuous-ﬂow ligand-free Suzuki–Miyaura coupling reaction of (hetero)aryl iodides, bromides, and chlorides with (hetero)aryl boronic acids was developed using cartridges packed with spherical resin (tertiary amine-based chelate resin: WA30)-supported palladium catalysts (7% Pd / WA30). The void space in the cartridge caused by the spherical catalyst structures enables the smooth ﬂow of a homogeneously dissolved reaction solution that consists of a mixture of organic and aqueous solvents and is delivered by the use of a single syringe pump. Clogging or serious backpressure was not observed.

Continuous-flow reactions using a packed-bed cartridge filled with heterogeneous catalysts attracted considerable research interest as robust and reproducible reaction methods [23][24][25][26][27][28]. Because small amounts of substrate and reactants in the reaction solution were continuously introduced into the catalyst cartridge via a narrow tube and immediately contacted a large amount of catalyst, a higher reaction efficiency was achieved compared with the corresponding batch reactions using flasks and reaction vessels. Supported Pd catalysts packed in a cartridge can be safely utilized without deactivation or ignition because the catalyst is not exposed to air (especially atmospheric oxygen). Furthermore, the resulting reaction mixture is continuously collected at the outlet of the cartridge without the need of catalyst separation.

Continuous-Flow Suzuki-Miyaura Coupling of Aryl Iodides and Bromides with Aryl Boronic Acids
The solubility of a mixture of 4'-iodoacetophenone (1a, 0.5 mmol) and phenylboronic acid (3a, 1.2 eq., 0.6 mmol) with K3PO4, NaOH, or KOH (2.0 eq., 1.0 mmol) in a mixed solvent of H2O and various organic solvents was initially investigated (see Supplementary Materials). As a result, it was observed that the combined use of NaOH or KOH with H2O (0.5 mL) and 1,4-dioxane (1.5 mL) formed a homogeneously dissolved solution. In contrast, other combinations of bases with solvents resulted in an inhomogeneous mixture.
Next, continuous-flow Suzuki-Miyaura reaction efficiencies were investigated by transferring a solution of 1a (0.5 mmol), 3a (1.2 eq., 0.6 mmol), and NaOH or KOH (2.0 eq.) in H2O/1,4-dioxane (0.5 mL/1.5 mL) into the 7% Pd/WA30 (100 mg)-packed catalyst cartridge using a syringe pump at a flow rate of 0.05 mL/min ( Table 1). The coupling reaction proceeded smoothly at 25 °C to obtain the corresponding 4-acetylbiphenyl (4aa), and the use of KOH indicated a slightly higher reaction efficiency (95% yield) compared with NaOH (77% yield). However, both reactions were incomplete and a small amount of 1a (entry 1 vs. 2) remained unchanged. Compound 1a was completely coupled with 3a in the presence of KOH and increasing the amount of 7% Pd/WA30 from 100 mg to 200 mg generated 4aa in quantitative yield, accompanied by turnover number (TON) and turnover frequency (TOF) of 3.8 and 0.1 min −1 , respectively (entry 3). Furthermore, leached Pd species were never detected in the reaction mixture collected at the outlet of the cartridge using atomic absorption spectrophotometry (AAS, Pd detection limit: 1 ppm, see Supplementary Materials).

Continuous-Flow Suzuki-Miyaura Coupling of Aryl Iodides and Bromides with Aryl Boronic Acids
The solubility of a mixture of 4'-iodoacetophenone (1a, 0.5 mmol) and phenylboronic acid (3a, 1.2 eq., 0.6 mmol) with K 3 PO 4 , NaOH, or KOH (2.0 eq., 1.0 mmol) in a mixed solvent of H 2 O and various organic solvents was initially investigated (see Supplementary Materials). As a result, it was observed that the combined use of NaOH or KOH with H 2 O (0.5 mL) and 1,4-dioxane (1.5 mL) formed a homogeneously dissolved solution. In contrast, other combinations of bases with solvents resulted in an inhomogeneous mixture.
Next, continuous-flow Suzuki-Miyaura reaction efficiencies were investigated by transferring a solution of 1a (0.5 mmol), 3a (1.2 eq., 0.6 mmol), and NaOH or KOH (2.0 eq.) in H 2 O/1,4-dioxane (0.5 mL/1.5 mL) into the 7% Pd/WA30 (100 mg)-packed catalyst cartridge using a syringe pump at a flow rate of 0.05 mL/min ( Table 1). The coupling reaction proceeded smoothly at 25 • C to obtain the corresponding 4-acetylbiphenyl (4aa), and the use of KOH indicated a slightly higher reaction efficiency (95% yield) compared with NaOH (77% yield). However, both reactions were incomplete and a small amount of 1a (entry 1 vs. 2) remained unchanged. Compound 1a was completely coupled with 3a in the presence of KOH and increasing the amount of 7% Pd/WA30 from 100 mg to 200 mg generated 4aa in quantitative yield, accompanied by turnover number (TON) and turnover frequency (TOF) of 3.8 and 0.1 min −1 , respectively (entry 3). Furthermore, leached Pd species were never detected in the reaction mixture collected at the outlet of the cartridge using atomic absorption spectrophotometry (AAS, Pd detection limit: 1 ppm, see Supplementary Materials).
Using 4'-bromoacetophenone (2a) as a substrate, a higher reaction efficiency was achieved with NaOH compared with KOH to obtain 4aa in 68% yield (entry 4 vs. 5). The increase in the catalyst cartridge temperature effectively activates the C-Br bond 2a to produce 4aa in 74% yield at 60 • C (entry 6). Adding more 7% Pd/WA30 catalyst led to an increase in coupling selectivity and efficiency, resulting in a 95% yield with a TON and TOF of 3.6 and 0.1 min −1 , respectively (entry 7).

Continuous-Flow Suzuki-Miyaura Coupling of Aryl Chlorides with Aryl Boronic Acids
Next, the ligand-and backpressure-free continuous-flow Suzuki-Miyaura coupling reaction was conducted to link aryl chlorides with aryl boronic acids. A solution of 4'-chloroacetophenone (5a, 0.5 mmol); 3a (1.5 eq., 0.75 mmol); and NaOH, KOH, or NaOtBu (2.0 eq., 1.0 mmol) in H 2 O/1,4-dioxane (0.5 mL/1.5 mL) was transferred using a syringe pump at 0.05 mL/min flow rate into the 7% Pd/WA30 (100 mg)-packed catalyst cartridge, which was pre-heated at 80 • C in an oil bath ( Table 3, entries 1-3). The use of NaOH resulted in a higher yield (23%) of 4aa compared with that using KOH (19% yield) and NaOtBu (17% yield). An increase of 7% Pd/WA30 from 100 mg to 500 mg increased the conversion of 1a. However, the yield of the targeted 4aa was moderate at 45% (entry 4). Furthermore, a decrease in the flow rate from 0.05 mL/min to 0.02 mL/min was ineffective and generated the corresponding 4aa in 30% yield (entry 5). mixture of the reaction indicated in entry 6, leached Pd species were never detected with atomic absorption spectrophotometry (AAS, Pd detection limit: 1 ppm, see the Supplementary Materials). While 3'-chloroacetophenone (5b) was coupled with 3a to obtain 4ba in 68% yield, the phenylation of 2'-chloroacetophenone (5c) with 3a afforded 4ca in only 13% yield because of the steric hindrance of the acetyl group (Figure 3). The coupling of ethyl 4-chlorobenzoate (5d) with 3a resulted in a 74% isolated yield of 4da. Chlorobenzenes bearing 4-EtO2C (5e) and 4-Me (5f) groups reacted with 4-methoxy phenylboronic acid (3b), regardless of the electronic properties of the benzene ring, to generate the corresponding biaryls (4db and 4eb) in 42% and 57% yields, respectively. The continuous-flow Suzuki-Miyaura reaction was also applied to the coupling of heteroaryl chlorides. 4-Chloropyridine hydrochloride (5g) was phenylated, increasing the amount of TBAF (3.0 eq.) to obtain 4ha in 57% yield. An isolated yield of 80% of 4ae was obtained when using a reactive heteroaryl boronic acid (3e) as a coupling partner of 5a with a TON and TOF of 3.0 and 0.8 min −1 , respectively. Based on these results, the present continuous-flow Suzuki-Miyaura reaction using the 7% Pd/WA30-packed catalyst cartridge was applied to the coupling of various (hetero)aryl chlorides with (hetero)aryl boronic acids in the presence of TBAF instead of NaOH as an additive. However, the reaction efficiency was affected by the electronic properties of the aromatics and the steric hindrance. The combination of base and solvent was crucial for developing the continuous-flow Suzuki-Miyaura coupling reaction using 7% Pd/WA30-packed catalyst cartridges, not only to form a homogeneously dissolved reaction solution, but also to achieve a high reaction efficiency. Tetrabutylammonium fluoride (TBAF), which can act as a phase transfer catalyst and/or base, is used for the Pd-catalyzed Suzuki-Miyaura coupling reaction of aryl halides with aryl boronic acids and its esters to activate the Pd catalyst under batch conditions [51][52][53][54]. Based on these references, a variety of advantages of TBAF as a base, solubilizing agent, and activator of the 7% Pd/WA30 catalyst were utilized under continuous-flow conditions. After optimizing the reaction solvent (see the Supplementary Materials), it was observed that the addition of 2 equivalents of TBAF efficiently promoted the dissolution of 5a (0.25 mmol) and 3a (2.0 eq., 0.50 mmol) in THF (2 mL). Furthermore, the reaction efficiency was considerably increased to achieve a 68% isolated yield by merely transferring a THF solution of 5a, 3a, and TBAF over the 7% Pd/WA30 (100 mg)-packed catalyst cartridge (entry 6). Because the increase of 7% Pd/WA30 from 100 mg to 300 mg did not improve the reaction efficiency (entry 6 vs. 7), the combined use of TBAF with THF and 100 mg of 7% Pd/WA30 was adopted as Catalysts 2020, 10, 1209 7 of 13 optimized conditions and used in the substrate applicability study. In the crude mixture of the reaction indicated in entry 6, leached Pd species were never detected with atomic absorption spectrophotometry (AAS, Pd detection limit: 1 ppm, see the Supplementary Materials).
While 3'-chloroacetophenone (5b) was coupled with 3a to obtain 4ba in 68% yield, the phenylation of 2'-chloroacetophenone (5c) with 3a afforded 4ca in only 13% yield because of the steric hindrance of the acetyl group (Figure 3). The coupling of ethyl 4-chlorobenzoate (5d) with 3a resulted in a 74% isolated yield of 4da. Chlorobenzenes bearing 4-EtO 2 C (5e) and 4-Me (5f) groups reacted with 4-methoxy phenylboronic acid (3b), regardless of the electronic properties of the benzene ring, to generate the corresponding biaryls (4db and 4eb) in 42% and 57% yields, respectively. The continuous-flow Suzuki-Miyaura reaction was also applied to the coupling of heteroaryl chlorides. 4-Chloropyridine hydrochloride (5g) was phenylated, increasing the amount of TBAF (3.0 eq.) to obtain 4ha in 57% yield. An isolated yield of 80% of 4ae was obtained when using a reactive heteroaryl boronic acid (3e) as a coupling partner of 5a with a TON and TOF of 3.0 and 0.8 min −1 , respectively. Based on these results, the present continuous-flow Suzuki-Miyaura reaction using the 7% Pd/WA30-packed catalyst cartridge was applied to the coupling of various (hetero)aryl chlorides with (hetero)aryl boronic acids in the presence of TBAF instead of NaOH as an additive. However, the reaction efficiency was affected by the electronic properties of the aromatics and the steric hindrance.

Application of the Continuous-Flow Suzuki-Miyaura Coupling to Gram-Scale Synthesis
A prolonged backpressure-and ligand-free continuous-flow Suzuki-Miyaura reaction was developed using a 7% Pd/WA30-packed catalyst cartridge.   A prolonged backpressure-and ligand-free continuous-flow Suzuki-Miyaura reaction was developed using a 7% Pd/WA30-packed catalyst cartridge. 4'-Iodoacetophenone (1a, 10.0 mmol), phenylboronic acid (2a, 15.0 mmol), and KOH (20.0 mmol) were dissolved in a mixed solvent of H2O (10 mL) and 1,4-dioxane (30 mL). The homogeneously dissolved reaction solution was pumped through the cartridge packed with 200 mg of 7% Pd/WA30 at a flow rate of 0.05 mL/min (Scheme 1). The coupling efficiently and continuously proceeded for 14 h to obtain the corresponding 4aa in quantitative yield (2.0 g) with a TON and TOF of 76.1 and 5.4 h −1 and without catalyst deactivation during the entire reaction period. Therefore, the continuous-flow Suzuki-Miyaura coupling reaction can be easily applied for prolonged gram-scale biaryl syntheses.

General Information
All reagents and solvents were obtained from commercial sources (Tokyo Chemical Industry Co., Ltd, Chuo, Tokyo, Japan; FUJIFILM Wako Pure Chemical Industries, Ltd., Osaka, Japan; Sigma-Aldrich Japan Co., Meguro, Tokyo, Japan) and used without further purification. The

General Information
All reagents and solvents were obtained from commercial sources (Tokyo Chemical Industry Co., Ltd, Chuo, Tokyo, Japan; FUJIFILM Wako Pure Chemical Industries, Ltd., Osaka, Japan; Sigma-Aldrich Japan Co., Meguro, Tokyo, Japan) and used without further purification. The dimethylamine-immobilized polymer WA30 was obtained from Mitsubishi Chemical Corporation (Chiyoda, Tokyo, Japan). Pd(OAc) 2 was obtained from N.E. Chemcat Corporation (Minato, Tokyo, Japan). Flash column chromatography was performed using Silica Gel 60 N (Kanto Chemical Co. Inc., Chuo, Tokyo, Japan, 63-210 µm spherical, neutral). The 1 H and 13 C NMR spectra were recorded on a JEOL ECA-500 (500 MHz for 1 H NMR and 125 MHz for 13 C NMR) and ECZ-400 (400 MHz for 1 H NMR and 100 MHz for 13 C NMR) spectrometers. CDCl 3 was used as solvent for the NMR measurements (LEOL Ltd., Akishima, Tokyo, Japan). The chemical shifts (d) are expressed in parts per million and internally referenced (0.00 ppm for tetramethylsilane). All 1 H NMR spectra of known products were identical to those reported in the literature.

Preparation of 7% Pd/WA30
A suspension of dry WA30 (3.00 g, colorless particles) in an ethyl acetate solution (30 mL) of Pd(OAc) 2 (2.12 mmol (226 mg; palladium)) was stirred under argon atmosphere at 25 • C for 4 d. The resulting yellow solid was collected by filtration (1 mm filter paper), washed with H 2 O (10 mL × 3), ethyl acetate (10 mL × 3), and MeOH (10 mL × 3), and dried in vacuo for 24 h. The filtrate was transferred to a 100 mL volumetric flask and diluted to 100 mL with MeOH. Leached Pd species were not detected (detection limit: <1 ppm) in the diluted filtrate using atomic absorption spectrometry (SHIMADZU AA-7000). The collected solid was then stirred with hydrazine monohydrate (NH 2 NH 2 ·H 2 O) (310.0 µL, 6.37 µmol) in H 2 O (30 mL) for 24 h at 25 • C under argon atmosphere. A pale gray solid was collected by filtration (1 mm filter paper), washed with H 2 O (10 mL × 3) and MeOH (10 mL × 3), and dried in vacuo for 24 h to generate Pd/WA30 (3.23 g). The filtrate was transferred to a 100 mL volumetric flask and diluted to 100 mL with MeOH. Palladium species were not observed in the diluted filtrate (detection limit: <1 ppm). Palladium species absorbed on WA30 were not detected. Thus, the palladium content of Pd/WA30 (ethyl acetate) was estimated to be approximately 7% [(2260)/3230 × 100]. flow rate of 0.05 mL/min. After transferring the entire reaction solution, the catalyst cartridge was washed with an additional mixed solvent of H 2 O (5 mL) and 1,4-dioxane (15 mL). The combined reaction mixture and washing solution were extracted with ethyl acetate (40 mL × 2). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to produce the corresponding coupling product 4 (Tables 1 and 2 and Figure 2).

Procedure for the Continuous-Flow Suzuki-Miyaura Coupling of Aryl Chlorides with Aryl Boronic Acids
A solution of aryl chloride (5, 0.25 mmol), aryl boronic acid (3, 0.50 mmol), and tetrabutylammonium fluoride (0.50 mmol; 1 mol/L in THF solution) was moved through the 7% Pd/WA30-packed cartridge (Ø 4.6 × 50 mm, SUS-316) by a syringe pump (YMC, YSP-101) at a flow rate of 0.05 mL/min. After transferring the entire reaction solution, the catalyst cartridge was washed with additional THF (5 mL) and then ethyl acetate (15 mL). The combined reaction mixture and washing solution were concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to provide the corresponding coupling product 4 ( Table 3, entry 6 and Figure 3).

Conclusions
The continuous-flow Suzuki-Miyaura coupling reaction of (hetero)aromatic iodides, bromides, and chlorides with (hetero)aryl boronic acids was developed using 7% Pd/WA30-packed catalyst cartridges, where Pd was immobilized on the spherical chelate resin WA30. The present continuous-flow Suzuki-Miyaura reaction proceeded under ligand-and backpressure-free conditions. Coupling of aromatic iodides and bromides with aryl boronic acids was efficiently conducted by transferring a single reaction solution of aryl halides, aryl boronic acids, and inorganic bases dissolved in H 2 O/1,4-dioxane into a 7% Pd/WA30-packed catalyst cartridge using a syringe pump. Using aryl chlorides as substrates, the addition of TBAF in THF instead of the inorganic base significantly improved the reaction efficiency. The ligand-and backpressure-free continuous-flow Suzuki-Miyaura reaction was also applied to the coupling of heteroaryl halides with heteroaryl boronic acids. The combination of base and solvent is quite crucial for preparing a homogeneously dissolved reaction solution consisting of an aromatic halide, aryl boronic acid, and organic or inorganic base. Furthermore, the provided void space in the cartridge derived from the spherical structures of the 7% Pd/WA30 catalyst enables a smooth flow of the reaction solution using a single syringe pump. Clogging or serious backpressure was not observed. Therefore, the present ligand-and backpressure-free continuous-flow Suzuki-Miyaura coupling reaction is a facile and straightforward continuous-flow method for practical use in a variety of chemistry fields.