Suzuki–Miyaura Coupling Using Monolithic Pd Reactors and Scaling-up by Series Connection of the Reactors

The space integration of the lithiation of aryl halides, the borylation of aryllithiums, and Suzuki–Miyaura coupling using a Pd catalyst supported by a polymer monolith flow reactor without using an intentionally added base was achieved. To scale up the process, a series connection of the monolith Pd reactor was examined. To suppress the increase in the pressure drop caused by the series connection, a monolith reactor having larger pore sizes was developed by varying the temperature of the monolith preparation. The monolithic Pd reactor having larger pore sizes enabled Suzuki–Miyaura coupling at a higher flow rate because of a lower pressure drop and, therefore, an increase in productivity. The present study indicates that series connection of the reactors with a higher flow rate serves as a good method for increasing the productivity without decreasing the yields.


Introduction
Recently the chemical synthesis using continuous flow reactors has received significant research interests from both academia and the industry .Because of better heat and mass transfer and a shorter residence time, flow processes offer various benefits over conventional batch processes, including increased controllability, safety, and selectivity.A number of synthetic transformations that are difficult or impossible for conventional batch processes have been developed using flow processes [48][49][50][51][52][53][54][55][56][57][58].
Polymer monoliths [114][115][116][117][118][119] serve as ideal supports for reagents and catalysts for continuous flow processes because of their high controllability of surface properties associated with the formation of nano-, micro-, and mesoporous structures.The contact time and temperature can be spatially and temporally controlled throughout the channels.In a preliminary communication, we reported that the space integration [120][121][122] of the preparation of arylboronic esters and Suzuki-Miyaura coupling using a flow reactor packed with the polymer monolith containing an immobilized Pd catalyst [123].Herein, we report the full details of this study and the process by the series connection of the reactors with high flow rates (Scheme 1).
Catalysts 2019, 9, x FOR PEER REVIEW 2 of 25 the integration of the preparation of boronic acids and the Suzuki-Miyaura coupling improves the efficiency of the overall transformation.Recently, Buchwald et al. reported the space integration of the preparation of boronic esters by lithiation, borylation, and Suzuki-Miyaura coupling [106].We have also reported the space integration of the preparation of arylboronic esters bearing electrophilic functional groups based on flash chemistry [107][108][109][110][111][112] using flow microreactors [113].The overall transformation enables the cross-coupling of two aryl halides bearing electrophilic functional groups.However, homogeneous Pd catalysts are used in both processes.Therefore, it was highly desirable to develop a similar process using heterogeneous Pd catalysts which enable the easy separation and recycling of the catalyst.
Polymer monoliths [114][115][116][117][118][119] serve as ideal supports for reagents and catalysts for continuous flow processes because of their high controllability of surface properties associated with the formation of nano-, micro-, and mesoporous structures.The contact time and temperature can be spatially and temporally controlled throughout the channels.In a preliminary communication, we reported that the space integration [120][121][122] of the preparation of arylboronic esters and Suzuki-Miyaura coupling using a flow reactor packed with the polymer monolith containing an immobilized Pd catalyst [123].Herein, we report the full details of this study and the process by the series connection of the reactors with high flow rates (Scheme 1).
Scheme 1.The space integration of the preparation of arylboronic esters and Suzuki-Miyaura coupling by the series connection of a flow reactor packed with the polymer monolith containing an immobilized Pd catalyst.

Preparation of Lithium Arylborates Using Flow Microreactors
Prior to studying the Suzuki-Miyaura coupling, we studied the preparation of lithium arylborates by the lithiation of aryl halides followed by the borylation of aryllithiums [113].The reactions were carried out using a flow microreactor system consisting of two T-shaped micromixers (M1 and M2) and two microtube reactors (R1 and R2) (Figure 1).For example, a solution of bromobenzene (0.10 M in THF, 6.0 mL/min) and a solution of n-BuLi (0.60 M in hexane, 1.0 mL/min) were introduced to M1 (φ = 500 μm) at 0 °C by syringe pumps.The resulting solution was passed through R1 (φ = 1000 μm, L = 25 cm (t R1 = 1.7 s)) and was mixed with a solution of trimethoxyborane (0.12 M in THF, 5.0 mL/min) in M2 (φ = 500 μm).The resulting solution was then passed through R2 (φ = 1000 μm, L = 50 cm (t R2 = 2.0 s)).A cloudy mixture was obtained, presumably because of an insufficient solubility of the resulting lithium arylborate (Figure 2a).Various solvents including THF, methanol, and ethanol were examined to solubilize the lithium arylborate, and a clear solution was obtained when methanol was added (Figure 2b).Scheme 1.The space integration of the preparation of arylboronic esters and Suzuki-Miyaura coupling by the series connection of a flow reactor packed with the polymer monolith containing an immobilized Pd catalyst.

Preparation of Lithium Arylborates Using Flow Microreactors
Prior to studying the Suzuki-Miyaura coupling, we studied the preparation of lithium arylborates by the lithiation of aryl halides followed by the borylation of aryllithiums [113].The reactions were carried out using a flow microreactor system consisting of two T-shaped micromixers (M1 and M2) and two microtube reactors (R1 and R2) (Figure 1).For example, a solution of bromobenzene (0.10 M in THF, 6.0 mL/min) and a solution of n-BuLi (0.60 M in hexane, 1.0 mL/min) were introduced to M1 (φ = 500 µm) at 0 • C by syringe pumps.The resulting solution was passed through R1 (φ = 1000 µm, L = 25 cm (t R1 = 1.7 s)) and was mixed with a solution of trimethoxyborane (0.12 M in THF, 5.0 mL/min) in M2 (φ = 500 µm).The resulting solution was then passed through R2 (φ = 1000 µm, L = 50 cm (t R2 = 2.0 s)).A cloudy mixture was obtained, presumably because of an insufficient solubility of the resulting lithium arylborate (Figure 2a).Various solvents including THF, methanol, and ethanol were examined to solubilize the lithium arylborate, and a clear solution was obtained when methanol was added (Figure 2b).

Preparation of Polymer Monolith and Immobilization of Pd Catalyst
The preparation of a polymer monolith and the immobilization of a Pd catalyst were carried out as follows (Figure 3).1,3-Bis(N,N-diglycidylaminomethyl)cyclohexane was added to a solution of poly(ethylene glycol) (PEG, molecular mass = 200), 4,4'-diaminodicyclohexyl-methane, and 6-(phenylamino)-1,3,5-triazine-2,4-dithiol, and the mixture was stirred at room temperature for 30 min.The resultant homogeneous solution was poured into a cylindrical stainless-steel reactor (an empty HPLC column, 4.6 mm ID x 150 mm length).The reactor was annealed to produce epoxy monolithic gels inside.Polymer monolith A was produced by annealing at 100 °C, whereas polymer monolith B was produced by annealing at 85 °C (vide infra).The gelation occurred within 30 min, and the samples were aged at the same temperature for a day.The resulting epoxy monoliths were washed with tetrahydrofuran by using an HPLC pump at 0.1 mL/min for an hour and dried under a vacuum.As shown in Figure 4, the pore size of the gel depends on the annealing temperature.The pore size of monolith B was larger than that of monolith A. Then, monolith A and B were treated with a solution of palladium acetate and were reduced with sodium borohydride.The resulting monolith reactors containing the Pd catalyst were used for Suzuki-Miyaura coupling.

Preparation of Polymer Monolith and Immobilization of Pd Catalyst
The preparation of a polymer monolith and the immobilization of a Pd catalyst were carried out as follows (Figure 3).1,3-Bis(N,N-diglycidylaminomethyl)cyclohexane was added to a solution of poly(ethylene glycol) (PEG, molecular mass = 200), 4,4 -diaminodicyclohexyl-methane, and 6-(phenylamino)-1,3,5-triazine-2,4-dithiol, and the mixture was stirred at room temperature for 30 min.The resultant homogeneous solution was poured into a cylindrical stainless-steel reactor (an empty HPLC column, 4.6 mm ID × 150 mm length).The reactor was annealed to produce epoxy monolithic gels inside.Polymer monolith A was produced by annealing at 100 • C, whereas polymer monolith B was produced by annealing at 85 • C (vide infra).The gelation occurred within 30 min, and the samples were aged at the same temperature for a day.The resulting epoxy monoliths were washed with tetrahydrofuran by using an HPLC pump at 0.1 mL/min for an hour and dried under a vacuum.As shown in Figure 4, the pore size of the gel depends on the annealing temperature.The pore size of monolith B was larger than that of monolith A. Then, monolith A and B were treated with a solution of palladium acetate and were reduced with sodium borohydride.The resulting monolith reactors containing the Pd catalyst were used for Suzuki-Miyaura coupling.

Preparation of Polymer Monolith and Immobilization of Pd Catalyst
The preparation of a polymer monolith and the immobilization of a Pd catalyst were carried out as follows (Figure 3).1,3-Bis(N,N-diglycidylaminomethyl)cyclohexane was added to a solution of poly(ethylene glycol) (PEG, molecular mass = 200), 4,4'-diaminodicyclohexyl-methane, and 6-(phenylamino)-1,3,5-triazine-2,4-dithiol, and the mixture was stirred at room temperature for 30 min.The resultant homogeneous solution was poured into a cylindrical stainless-steel reactor (an empty HPLC column, 4.6 mm ID x 150 mm length).The reactor was annealed to produce epoxy monolithic gels inside.Polymer monolith A was produced by annealing at 100 °C, whereas polymer monolith B was produced by annealing at 85 °C (vide infra).The gelation occurred within 30 min, and the samples were aged at the same temperature for a day.The resulting epoxy monoliths were washed with tetrahydrofuran by using an HPLC pump at 0.1 mL/min for an hour and dried under a vacuum.As shown in Figure 4, the pore size of the gel depends on the annealing temperature.The pore size of monolith B was larger than that of monolith A. Then, monolith A and B were treated with a solution of palladium acetate and were reduced with sodium borohydride.The resulting monolith reactors containing the Pd catalyst were used for Suzuki-Miyaura coupling.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Polymer Monolith A
Next, we examined the reaction integration of the lithiation of bromobenzene (Ar 1 -X: Ar 1 = C6H5-, X = Br), the arylation of phenyllithiums, and the Suzuki-Miyaura coupling with p-iodobenzonitrile (Figure 5).To the resulting solution of lithium trimethoxy(phenyl)borate was added a solution of piodobenzonitrile (Ar 2 -X: Ar 2 = p-NC C6H4-, X = I) (0.033 M in MeOH), and the mixture was passed through the reactor containing the Pd catalyst supported by monolith A at T °C using a plunger pump.The reactions were carried out with various residence times (t R ) in the monolith reactor and at various temperatures (T).The residence times were estimated based on the void volume of the reactor.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Polymer Monolith A
Next, we examined the reaction integration of the lithiation of bromobenzene (Ar 1 -X: Ar 1 = C 6 H 5 -, X = Br), the arylation of phenyllithiums, and the Suzuki-Miyaura coupling with p-iodobenzonitrile (Figure 5).To the resulting solution of lithium trimethoxy(phenyl)borate was added a solution of p-iodobenzonitrile (Ar 2 -X: Ar 2 = p-NC C 6 H 4 -, X = I) (0.033 M in MeOH), and the mixture was passed through the reactor containing the Pd catalyst supported by monolith A at T • C using a plunger pump.The reactions were carried out with various residence times (t R ) in the monolith reactor and at various temperatures (T).The residence times were estimated based on the void volume of the reactor.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Polymer Monolith A
Next, we examined the reaction integration of the lithiation of bromobenzene (Ar 1 -X: Ar 1 = C6H5-, X = Br), the arylation of phenyllithiums, and the Suzuki-Miyaura coupling with p-iodobenzonitrile (Figure 5).To the resulting solution of lithium trimethoxy(phenyl)borate was added a solution of piodobenzonitrile (Ar 2 -X: Ar 2 = p-NC C6H4-, X = I) (0.033 M in MeOH), and the mixture was passed through the reactor containing the Pd catalyst supported by monolith A at T °C using a plunger pump.The reactions were carried out with various residence times (t R ) in the monolith reactor and at various temperatures (T).The residence times were estimated based on the void volume of the reactor.As profiled in Figure 6, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 • C, the yield increased with an increase in t R .The coupling product was obtained in good yields (>93%) with t R longer than 4.7 min.The reaction at 120 • C resulted in a slightly better yield (t R = 9.4 min, quantitative yield).Notably, the reaction was complete within a few minutes without using an intentionally added base.Thereafter, the reactions were carried out under two conditions: condition (a) (T = 100 • C, t R = 4.7 min) and condition (b) (T = 120 • C, t R = 9.4 min) for the monolith A catalyst.
T and t R .At 100 °C, the yield increased with an increase in t R .The coupling product was obtained in good yields (>93%) with t R longer than 4.7 min.The reaction at 120 °C resulted in a slightly better yield (t R = 9.4 min, quantitative yield).Notably, the reaction was complete within a few minutes without using an intentionally added base.Thereafter, the reactions were carried out under two conditions: condition (a) (T = 100 °C, t R = 4.7 min) and condition (b) (T = 120 °C, t R = 9.4 min) for the monolith A catalyst.The present method was successfully applied to the cross-coupling of various functional aryl and heteroaryl iodides as coupling partners (Table 1).However, the use of phenyl iodide and aryl iodide having an electron-donating group resulted in much lower yields because the coupling reactions for these compounds were much slower.The use of substrates containing an orthosubstituent also showed a similar tendency.The yields for such reactions would be improved with a longer reaction time by connecting the reactors in serial.Notably, a cyano group tolerated the optimized conditions [124], although such functional groups easily undergo decomposition in conventional batch reactions.Therefore, biaryls bearing electrophilic functional groups on both aromatic rings can be synthesized in one flow.In addition, similar present transformations via lithiated heteroaromatics also took place effectively to give the corresponding heterobiaryls in good yields.Furthermore, a triaryl compound having one bromine atom on one of the aromatic rings was also synthesized via the lithiation of 4,4'-dibromobiphenyl, although such a transformation is very difficult when using conventional batch reactors because of the formation of a significant amount of dilithiated species [125].The present method was successfully applied to the cross-coupling of various functional aryl and heteroaryl iodides as coupling partners (Table 1).However, the use of phenyl iodide and aryl iodide having an electron-donating group resulted in much lower yields because the coupling reactions for these compounds were much slower.The use of substrates containing an ortho-substituent also showed a similar tendency.The yields for such reactions would be improved with a longer reaction time by connecting the reactors in serial.Notably, a cyano group tolerated the optimized conditions [124], although such functional groups easily undergo decomposition in conventional batch reactions.Therefore, biaryls bearing electrophilic functional groups on both aromatic rings can be synthesized in one flow.In addition, similar present transformations via lithiated heteroaromatics also took place effectively to give the corresponding heterobiaryls in good yields.Furthermore, a triaryl compound having one bromine atom on one of the aromatic rings was also synthesized via the lithiation of 4,4 -dibromobiphenyl, although such a transformation is very difficult when using conventional batch reactors because of the formation of a significant amount of dilithiated species [125].
Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.Table 1.The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 °C and monolith B for temperature at 85 °C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 °C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.

Suzuki-Miyaura Coupling Using the Pd Catalyst Supported by Monolith B
The operation of integrated systems consisting of multiple monolithic reactors in series at higher flow rates suffers from a high pressure drop.To solve this problem, a polymer monolith (monolith B) with wider pore sizes was synthesized by changing reaction temperatures when prepared (monolith A for temperature at 100 • C and monolith B for temperature at 85 • C) (vide supra).Generally, the pressure drop depends on the pore size.In fact, the pressure drop of monolith A of a smaller pore size was larger than that of monolith B of a larger pore size.For example, the operation using a monolith A reactor at 60 • C with the flow rate of 1.5 mL/min led to 8.2 Pa, whereas that using a monolith B reactor lead to 0.8 Pa.
Before studying the series connection of the reactors, the reaction using a single monolith B reactor was examined.To a solution of lithium trimethoxy(phenyl)borate prepared by the flow method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 • C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.
method (Figure 3) was added a solution of p-iodobenzonitrile (0.033 M in MeOH), and the mixture was passed through a reactor containing a Pd catalyst supported by monolith B using a plunger pump (Figure 5).The reactions were carried out with various residence times (t R ) at various temperatures (T).As profiled in Figure 7, the yield of biphenyl-4-carbonitrile was significantly influenced by both T and t R .At 100 °C, the yield increased with an increase in t R , and the reaction was complete within a few minutes.
Figure 7.The temperature (T)-residence time (t R ) map for the cross-coupling of bromobenzene and pbromobenzonitrile using the Pd catalyst supported by monolith B: the contour plots with a scattered overlay of the yields of biphenyl-4-carbonitrile (%), which are indicated by small circles.

Series Connection
Figure 7.The temperature (T)-residence time (t R ) map for the cross-coupling of bromobenzene and p-bromobenzonitrile using the Pd catalyst supported by monolith B: the contour plots with a scattered overlay of the yields of biphenyl-4-carbonitrile (%), which are indicated by small circles.

Series Connection
In general, the productivity can be increased by increasing the flow rate in a single flow reactor (Figure 8a).However, the increase in the flow rate often causes a decrease in the conversion because the residence time in the reactor becomes shorter.Therefore, the numbering-up method with a parallel connection of the flow reactors serves as a common approach to improve the productivity [126-130] (Figure 8b).However, the method often suffers from a poor uniformity in fluid distribution [131,132].Therefore, various types of flow distributors such as manifold- [133,134], bifurcation-, and split-and-recombine-type flow distributors have been developed to improve the uniformity of the fluid distribution.In general, the productivity can be increased by increasing the flow rate in a single flow reactor (Figure 8a).However, the increase in the flow rate often causes a decrease in the conversion because the residence time in the reactor becomes shorter.Therefore, the numbering-up method with a parallel connection of the flow reactors serves as a common approach to improve the productivity [126-130] (Figure 8b).However, the method often suffers from a poor uniformity in fluid distribution [131,132].Therefore, various types of flow distributors such as manifold- [133,134], bifurcation-, and split-and-recombine-type flow distributors have been developed to improve the uniformity of the fluid distribution.
We envisaged that the numbering-up method with a series connection of the flow reactors [135] could serve as a method for increasing productivity (Figure 8c).The residence time can be kept constant by a series connection of the reactors even with higher flow rates.A major obstacle of this approach is, however, the increase in the pressure drop with an increase in the number of the reactors in the series.The use of the monolith B reactor solved the problem.Their use in series enabled operation at high flow rates with a low pressure drop.The reactions were carried out with various flow rates to control the residence time at 100 °C (Figure 9).When a single monolith A reactor was used, the yield of biphenyl-4-carbonitrile was significantly influenced by the flow rate (Table 2, n = 1).The increase in the residence time by decreasing the flow rate caused an increase in the yield.The use of a single monolith B reactor also led to a similar result.Because of the larger pore size, the pressure drop for the monolith B reactor was much lower than that of the monolith A reactor.The product was obtained in a quantitative yield with the flow rate of 0.4 mL/min, although the increase in the flow rate caused a decrease in the yield, presumably because a shorter residence time leads to an incomplete conversion of the substrate.
Next, the reactions were carried out using multiple monolith B reactors connected in series (Table 2, n = 3 and 5).The use of multiple reactors connected in series often caused a higher pressure drop, which might be an obstacle for practical continuous production.However, the pressure drop was acceptable in this case because of larger pore size of monolith B. Notably, by using three reactors We envisaged that the numbering-up method with a series connection of the flow reactors [135] could serve as a method for increasing productivity (Figure 8c).The residence time can be kept constant by a series connection of the reactors even with higher flow rates.A major obstacle of this approach is, however, the increase in the pressure drop with an increase in the number of the reactors in the series.The use of the monolith B reactor solved the problem.Their use in series enabled operation at high flow rates with a low pressure drop.
The reactions were carried out with various flow rates to control the residence time at 100 • C (Figure 9).When a single monolith A reactor was used, the yield of biphenyl-4-carbonitrile was significantly influenced by the flow rate (Table 2, n = 1).The increase in the residence time by decreasing the flow rate caused an increase in the yield.The use of a single monolith B reactor also led to a similar result.Because of the larger pore size, the pressure drop for the monolith B reactor was much lower than that of the monolith A reactor.The product was obtained in a quantitative yield with the flow rate of 0.4 mL/min, although the increase in the flow rate caused a decrease in the yield, presumably because a shorter residence time leads to an incomplete conversion of the substrate.
Next, the reactions were carried out using multiple monolith B reactors connected in series (Table 2, n = 3 and 5).The use of multiple reactors connected in series often caused a higher pressure drop, which might be an obstacle for practical continuous production.However, the pressure drop was acceptable in this case because of larger pore size of monolith B. Notably, by using three reactors connected in series, the product was obtained in a quantitative yield with a flow rate three times larger than that for a single reactor (1.2 mL/min).Therefore, the productivity can be three times higher than that for a single reactor.Similarly, by using five reactors connected in series, the product was obtained in a quantitative yield with a flow rate five times larger than that for a single reactor (2.0 mL/min).Therefore, the productivity was five times larger than that for a single reactor.The increase in the flow rate caused a decrease in the yield because of an incomplete conversion.The series connection method is also effective in performing reactions which require longer reaction times.For example, the yields of the reactions with iodobenzene and 1-iodo-4methoxybenzene as an electron-donating coupling partner could be increased by the series connection of three monolith B reactors (Table 3).Other examples are also shown in Table 3.The series connection method is also effective in performing reactions which require longer reaction times.For example, the yields of the reactions with iodobenzene and 1-iodo-4-methoxybenzene as an electron-donating coupling partner could be increased by the series connection of three monolith B reactors (Table 3).Other examples are also shown in Table 3.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.

24
Catalysts 2019, 9, x FOR PEER REVIEW 10 of 25 Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2propanediol gave adapalene in an 89% yield.Moreover, the present method was successfully applied to a gram-scale synthesis of adapalene, which has been used for the treatment of acne, psoriasis, and photoaging (Figure 10).When the coupling of lithium (3-(1-adamantyl)-4-methoxyphenyl)trimethoxyborate and methyl 6-iodo-2-naphthoate was carried out using a single polymer monolith A reactor, a gram scale synthesis was achieved by a 21 h operation (1.55 g, 86% yield).In contrast, by using five monolith B reactors connected in series, a gram scale synthesis was achieved by a 4 h operation (1.49 g, 87% yield).The productivity increased by five times.The hydrolysis of the coupling product with NaOH in 1,2-propanediol gave adapalene in an 89% yield.

Recyclability of Monolithic Pd Catalysts
The leaching of a catalyst into the reaction stream causing the loss of activity due to the decrease in the catalyst loading is one of the potential problems of flow synthesis using supported catalysts.This is particularly problematic for pharmaceutical production.Thus, there is a great demand for developing robustly supported catalysts.To evaluate the recyclability of the catalyst, the reaction followed by washing with THF was repeated fifteen times, and no significant loss of activity was

Recyclability of Monolithic Pd Catalysts
The leaching of a catalyst into the reaction stream causing the loss of activity due to the decrease in the catalyst loading is one of the potential problems of flow synthesis using supported catalysts.This is particularly problematic for pharmaceutical production.Thus, there is a great demand for developing robustly supported catalysts.To evaluate the recyclability of the catalyst, the reaction followed by washing with THF was repeated fifteen times, and no significant loss of activity was observed based on the yields of the product as shown in Table 4, indicating that the Pd catalysts supported by the polymer monoliths A and B possess a sufficient stability under the reaction conditions.Therefore, these results mean that Pd leaching would not occur under the present experimental conditions.
Stainless-steel (SUS304) T-shaped micromixers with inner diameters of 250 and 500 µm were manufactured by Sanko Seiki Co., Inc. (Tokyo, Japan).Stainless-steel (SUS316) microtube reactors with inner diameters of 500 and 1000 µm were purchased from GL Sciences (Tokyo, Japan) and were cut into appropriate lengths (3.5, 25, 50, 100, and 300 cm).The micromixers and microtube reactors were connected with stainless steel fittings (GL Sciences, 1/16 OUW) to construct the flow microreactor systems.The flow microreactor system was dipped in the bath to control the temperature.The solutions were continuously introduced to the flow microreactor system using syringe pumps, Harvard PHD 2000, equipped with gastight syringes purchased from SGE or a plunger pump, shimadzu LC-20AT (Tokyo, Japan).
3.2.Preparation of the Pd Catalysts Supported by Monolith A and Monolith B 1,3-Bis(N,N-diglycidylaminomethyl)cyclohexane was added to a solution of poly(ethylene glycol) (PEG, molecular mass = 200) with 4,4 -diaminodicyclohexylmethane and 6-(phenylamino)-1,3,5-triazine-2,4-dithiol, and the mixture was stirred at room temperature for 30 min.The resultant homogeneous solution was poured into a cylindrical stainless-steel reactor (an empty HPLC column, 4.6 mm ID × 150 mm length).The reactor was annealed to the procedure, epoxy monolithic gels inside.Monolith A was produced by annealing at 100 • C, whereas monolith B was produced by annealing at 85 • C. The gelation occurred within 30 min, and the samples were subsequently aged at the same temperature for a day.The epoxy monoliths were washed with THF by an HPLC pump at 0.1 mL/min for an hour and dried under a vacuum.Then, a THF solution of palladium acetate (0.5 wt%, 5 mL) was injected into the monolith reactor at 0.05 mL/min.The monolith reactor adsorbed with palladium acetate was immersed in PEG (molecular mass = 300), heat-treated at 100 • C for 4 h, and was allowed to stand still for overnight at room temperature.THF in the reactor was replaced by PEG300, and the reactor was heat-treated at 200 • C for 4 h and was washed with THF (1 h) and water (1 h) using an HPLC pump at 0.1 mL/min.An aqueous solution of sodium borohydride (0.5 wt%, 5 mL) was injected into the reactor at 0.05 mL/min to reduce palladium ions adsorbed on the surface of the monolith.Then, the reactor was washed with methanol.
Then, a solution of methyl 6-iodo-2-naphthoate (0.033 M in THF/MeOH = 1.5:1) was added, and the mixing solution was passed through a monolithic reactor at 120 • C by a plunger pump.The reaction was carried out using a single monolith A reactor (flow rate: 0.2 mL/min) (residence time: 9.4 min) or five monolith B reactors (flow rate: 1.0 mL/min) (residence time: 9.5 min).After a steady state was reached, the product solution was collected in 21 h (a single monolith A reactor) or 4 h (five monolith B reactors).After the evaporation of the solvents, the crude product was thoroughly washed with MeOH (2 × 150 mL) to give methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate (1.55 g (one single monolith A reactor), 1.49 g (five monolith B reactors)).
Methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate (0.517 g) and 20 mL of 1,2-propanediol were placed in a flask, and the mixture was heated to 190 • C. The resulting transparent solution was supplemented with 0.534 g of sodium hydroxide in two portions and mixed for 20 min.The mixture was acidified until pH 1 with 6 N HCl.The resulting suspension was mixed for 30 min and washed with hot water (2 × 50 mL).After drying for 12 h at 120 • C, the yield was 0.458 g (89%).

Recyclability of the Polymer Monolith A and Monolith B Reactors
The mixing solution of phenyllithium (0.050 M in Et 2 O/THF = 1:19 (1.00 eq)), trimethoxyborane (0.050 M in Et 2 O/THF = 1:19 (1.00 eq)), and p-cyanoiodobenzene (0.033 M in MeOH (0.67 eq)) was passed through a flow reactor packed with a Pd catalyst supported by monolith A or monolith B by using a plunger pump (120 • C, 0.20 mL/min).After a steady state was reached, the product solution was collected (10 min).Then, the monolithic reactor was washed with THF (30 mL).Fifteen cycles of reactions and washings were carried out in the same way.The yields of the product were determined by a GC analysis.The results were summarized in Table 4.

Conclusions
An efficient synthetic method of unsymmetrical biaryls was developed by integrating lithiation, borylation, and Suzuki-Miyaura coupling using a flow reactor packed a Pd catalyst supported by the polymer monolith.In addition, a series connection of the flow reactors was proved to be a method for the numbering-up of the flow reactors for a scale-up.The method was successfully applied to various coupling reactions including the synthesis of adapalene.Because both the series connection approach and the conventional parallel connection approach have practical limits of the number of reactors, both approaches will hopefully work together to affect large-scale productions in a continuous flow mode in the industry.

Figure 3 .
Figure 3.The immobilization of Pd on the polymer monolith in a flow reactor.

Figure 2 .
Figure 2. A solution of lithium trimethoxy(phenyl)borate (a) before the addition of methanol and (b) after the addition of methanol.

Figure 3 .
Figure 3.The immobilization of Pd on the polymer monolith in a flow reactor.Figure 3. The immobilization of Pd on the polymer monolith in a flow reactor.

Figure 3 .
Figure 3.The immobilization of Pd on the polymer monolith in a flow reactor.Figure 3. The immobilization of Pd on the polymer monolith in a flow reactor.Catalysts 2019, 9, x FOR PEER REVIEW 4 of 25

Figure 4 .
Figure 4. (a) A SEM image of monolith A before treatment with Pd(OAc)2, (b) a SEM image of monolith B before treatment with Pd(OAc)2, (c) a SEM image of monolith A after treatment with Pd(OAc)2 followed by a reduction with NaBH4, (d) a TEM image of the cross section of monolith A, and (e) an appearance of the flow reactor containing the Pd catalyst supported by the monolith (size: 4.6 mm ID × 150 mm length).

Figure 4 .
Figure 4. (a) A SEM image of monolith A before treatment with Pd(OAc) 2 , (b) a SEM image of monolith B before treatment with Pd(OAc) 2 , (c) a SEM image of monolith A after treatment with Pd(OAc) 2 followed by a reduction with NaBH 4 , (d) a TEM image of the cross section of monolith A, and (e) an appearance of the flow reactor containing the Pd catalyst supported by the monolith (size: 4.6 mm ID × 150 mm length).

Figure 4 .
Figure 4. (a) A SEM image of monolith A before treatment with Pd(OAc)2, (b) a SEM image of monolith B before treatment with Pd(OAc)2, (c) a SEM image of monolith A after treatment with Pd(OAc)2 followed by a reduction with NaBH4, (d) a TEM image of the cross section of monolith A, and (e) an appearance of the flow reactor containing the Pd catalyst supported by the monolith (size: 4.6 mm ID × 150 mm length).

Figure 6 .
Figure 6.The temperature (T)-residence time (t R ) map for the cross-coupling of bromobenzene and pbromobenzonitrile using the Pd catalyst supported by monolith A: the contour plots with a scattered overlay of the yields of biphenyl-4-carbonitrile (%), which are indicated by small circles.

Figure 6 .
Figure 6.The temperature (T)-residence time (t R ) map for the cross-coupling of bromobenzene and p-bromobenzonitrile using the Pd catalyst supported by monolith A: the contour plots with a scattered overlay of the yields of biphenyl-4-carbonitrile (%), which are indicated by small circles.

Figure 8 .
Figure 8.The increasing productivity of a continuous flow reaction keeping the residence time constant, (a) a single reactor, (b) the numbering-up by parallel connection of the reactors, and (c) the numbering-up by series connection of the reactors.

Figure 8 .
Figure 8.The increasing productivity of a continuous flow reaction keeping the residence time constant, (a) a single reactor, (b) the numbering-up by parallel connection of the reactors, and (c) the numbering-up by series connection of the reactors.

43 82 a
Determined by GC.

Figure 10 .
Figure 10.The gram scale synthesis of adapalene.

Table 1 . The cross-coupling of Ar 1 -X and Ar 2 -X using the polymer monolith A containing an immobilized Pd catalyst. Ar 1 -X conditions of lithiation and borylation Ar 2 -X product yield (%) a t R1 (s) temperature ( o C) condition (a) c condition (b) d
Catalysts 2019, 9, x FOR PEER REVIEW 6 of 25

Table 2 .
The effect of the flow rate for the cross-coupling of bromobenzene and p-iodobenzonitrile using a single monolith reactor and multiple monolith reactors connected in series.
a Determined by GC.

Table 2 .
The effect of the flow rate for the cross-coupling of bromobenzene and p-iodobenzonitrile using a single monolith reactor and multiple monolith reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 3 .
The cross-coupling of Ar 1 -X and Ar 2 -X using a single monolith B reactor or multiple monolith B reactors connected in series.
a Determined by GC.

Table 4 .
The recyclability of the polymer monolith A and monolith B containing an immobilized Pd catalyst.
a Determined by GC.

Table 5 .
The cross-coupling of bromobenzene and p-iodobenzonitrile by the sequence of lithiation, borylation, and Suzuki-Miyaura coupling in a flow (monolith A reactor).

Table 6 .
The cross-coupling of bromobenzene and p-iodobenzonitrile by the sequence of lithiation, borylation, and Suzuki-Miyaura coupling in a flow (monolith B reactor).