Multi-Component One-Pot Reaction of Aromatic Carbonyl Compounds, Tosylhydrazide, and Arylboronic Acids

In this paper, we developed a new method using 4-bromoacetophenone as the starting material, with tosylhydrazide and two arylboronic acids using Barluenga and Suzuki couplings in a four-component one-pot reaction to afford the target product 4-benzyl-1,1′-biphenyls. This system that we have developed enables the use of easily accessible starting materials and can be employed on a wide variety of substrates with good functional group tolerance. In particular, this protocol can be applied to the synthesis of 4-(1-([1,1′-biphenyl]-4-yl)ethyl)pyridine derivatives, a class of potential analogs of CPY17 inhibitors of prostate cancer.


Introduction
4-Benzyl-1,1 -biphenyl derivatives are important structural units in numerous thermal recording materials, electrophotographic photoreceptors and biologically active molecules, including a number of anticancer agents [1][2][3][4][5][6][7][8][9][10][11].Typically, the Friedel-Crafts reaction (Scheme 1, Method 1) is employed for the synthesis of such compounds, which may be catalyzed by solid acid catalysts [12][13][14].Particularly, patents have been reported on the synthesis of benzyl-1,1 -biphenyl derivatives starting from biphenyl and benzyl chloride using catalysts such as montmorillonite and zeolites [15,16].Previously, the kinetics of the reaction between biphenyl and benzyl chloride over dealuminated HY zeolites has been reported [17].In addition, the Suzuki-Miyaura reaction, which involves the coupling of an arylboronic acid derivative and an organohalide, proved to be an extremely useful synthetic tool for the construction of a biphenyl scaffold.Among others, some convenient features involved in the use of arylboronic acid precursors in these reactions are as follows: arylboronic acid derivatives demonstrate air and moisture stability, relatively low toxicity and high compatibility to various functional groups [18][19][20][21].However, the synthesis of 4-benzyl-1,1 -biphenyl derivatives by the Suzuki-Miyaura reaction is more challenging (Scheme 1, Method 2).More often, this protocol suffers from poor selectivity in the first step, resulting in a mixture of mono-and bis-coupled products, thereby necessitating the purification of the intermediate.Chemoselectivity is crucial if sequential cross-coupling reactions are to be effective.It may be achieved using precursors containing activating groups of different reactivities, such as 1-bromo-4-(halomethyl)benzene [22,23].Multicomponent reactions (MCRs) are ideal synthetic tools for generating complex molecules from readily available starting materials in a single synthetic operation; hence, they minimize waste generation, rendering green transformations [24][25][26][27].The separation and purification of this step raises the cost and decrease the efficiency of this synthesis method.Therefore, it is desirable to develop a more efficient synthetic path.
the cost and decrease the efficiency of this synthesis method.Therefore, it is desirable to develop a more efficient synthetic path.

Results and Discussion
First, from the structural analysis of the 4-(1-phenylethyl)-1,1′-biphenyl skeleton (Figure 1), Csp 2 -Csp 2 bond and Csp 2 -Csp 3 bonds were constructed for building such a molecular structure.The Csp 2 -Csp 3 bond is well known to be obtained by the reductive coupling reaction of aryl hydrazone with an aryl boronic acid, and the Csp 2 -Csp 2 bond is formed by the palladium-catalyzed Suzuki coupling of aryl halide with an arylboronic acid.One common factor between these two reactions is the use of a base, but the Suzuki coupling reaction usually requires the involvement of a palladium catalyst.Hence, if we use the 4′-halo-acetophenone as starting reactants, and optimize the reaction conditions, it is possible to easily achieve access to 4-benzyl-1,1′-biphenyl derivatives by a one-pot multi-step reaction.It is an ideal route to synthesis of the target compound by a simple and efficient way.Based on the above considerations, we decided to use cost-effective, readily available 4-bromoacetophenone as the starting material.N-tosylhydrazones were generated in situ using TsNHNH2, reacted with an arylboronic acid to afford a 4-bromo-diarylmethane intermediate by reductive coupling, leading to the formation of a Csp 2 -Csp 3 bond.With treatment using a transition-metal palladium catalyst, without isolation, the intermediate product was treated with another arylboronic acid by Suzuki coupling to construct the Csp 2 -Csp 2 bond, ultimately affording 4-benzyl-1,1′-biphenyl derivatives (Scheme 2).Scheme 1. Synthetic methods for 4-benzyl-1,1 -biphenyl derivatives.

Results and Discussion
First, from the structural analysis of the 4-(1-phenylethyl)-1,1 -biphenyl skeleton (Figure 1), Csp 2 -Csp 2 bond and Csp 2 -Csp 3 bonds were constructed for building such a molecular structure.The Csp 2 -Csp 3 bond is well known to be obtained by the reductive coupling reaction of aryl hydrazone with an aryl boronic acid, and the Csp 2 -Csp 2 bond is formed by the palladium-catalyzed Suzuki coupling of aryl halide with an arylboronic acid.One common factor between these two reactions is the use of a base, but the Suzuki coupling reaction usually requires the involvement of a palladium catalyst.Hence, if we use the 4 -halo-acetophenone as starting reactants, and optimize the reaction conditions, it is possible to easily achieve access to 4-benzyl-1,1 -biphenyl derivatives by a one-pot multi-step reaction.It is an ideal route to synthesis of the target compound by a simple and efficient way.
the cost and decrease the efficiency of this synthesis method.Therefore, it is desirable to develop a more efficient synthetic path.

Results and Discussion
First, from the structural analysis of the 4-(1-phenylethyl)-1,1′-biphenyl skeleton (Figure 1), Csp 2 -Csp 2 bond and Csp 2 -Csp 3 bonds were constructed for building such a molecular structure.The Csp 2 -Csp 3 bond is well known to be obtained by the reductive coupling reaction of aryl hydrazone with an aryl boronic acid, and the Csp 2 -Csp 2 bond is formed by the palladium-catalyzed Suzuki coupling of aryl halide with an arylboronic acid.One common factor between these two reactions is the use of a base, but the Suzuki coupling reaction usually requires the involvement of a palladium catalyst.Hence, if we use the 4′-halo-acetophenone as starting reactants, and optimize the reaction conditions, it is possible to easily achieve access to 4-benzyl-1,1′-biphenyl derivatives by a one-pot multi-step reaction.It is an ideal route to synthesis of the target compound by a simple and efficient way.Based on the above considerations, we decided to use cost-effective, readily available 4-bromoacetophenone as the starting material.N-tosylhydrazones were generated in situ using TsNHNH2, reacted with an arylboronic acid to afford a 4-bromo-diarylmethane intermediate by reductive coupling, leading to the formation of a Csp 2 -Csp 3 bond.With treatment using a transition-metal palladium catalyst, without isolation, the intermediate product was treated with another arylboronic acid by Suzuki coupling to construct the Csp 2 -Csp 2 bond, ultimately affording 4-benzyl-1,1′-biphenyl derivatives (Scheme 2).Based on the above considerations, we decided to use cost-effective, readily available 4-bromoacetophenone as the starting material.N-tosylhydrazones were generated in situ using TsNHNH 2 , reacted with an arylboronic acid to afford a 4-bromo-diarylmethane intermediate by reductive coupling, leading to the formation of a Csp 2 -Csp 3 bond.With treatment using a transition-metal palladium catalyst, without isolation, the intermediate product was treated with another arylboronic acid by Suzuki coupling to construct the Csp 2 -Csp 2 bond, ultimately affording 4-benzyl-1,1 -biphenyl derivatives (Scheme 2).Scheme 2. One-pot, multi-step, multi-component reactions of 4-bromoacetophenone, tosylhydrazide, with two arylboronic acids.
On the basis of their study and our previous work [17], the reaction conditions of the third step were optimized, namely, the effects of ligand, base and temperature on the Suzuki coupling reaction were examined.Initially, the coupling reaction of 4-bromoacetophenone, TsNHNH2 and phenylboronic acid was selected as a model reaction to optimize the reaction conditions.Table 1 summarizes the results.The use of only Pd(OAc)2 as the catalyst and K2CO3 as the base in 1,4-dioxane at 110 °C produced the desired product 3a in only 15% yield (entry 1).The phosphine ligands were screened for this reaction, and PCy3•HBF4 was found to be the most effective one for forming coupling product 3a (entry 3).Among the various bases examined, organic bases (Et3N), and inorganic bases (K3PO4•H2O and NaOH) gave the desired product in moderate yields (63-72%, entries 4-6, respectively).Cs2CO3 was not effective, and corresponding product 3a was obtained in a low yield (entry 7).Gratifyingly, when the amounts of tosylhydrazide and phenylboronic acid were increased, the yield of the product dramatically increased to 89% (entry 8).In addition, when the amount of Pd(OAc)2 was increased to 2 mol %, the yield of product did not improve significantly (entry 9).When the temperature of the Suzuki coupling reaction was decreased to 80 °C, the product was isolated in only 52% yield (entry 10).Hence, the combination of 4-bromoacetophenone (0.5 mmol), tosylhydrazide (1.5 equiv.),phenylboronic acid (3.0 equiv.),Pd(OAc)2 (1 mol %), PCy3•HBF4 (4 mol %) and K2CO3 (3.0 equiv.) at T1 = 80 °C (t1 = 2 h), T2 = 110 °C (t2 = 5 h), and T3 = 110 °C (t3 = 12 h) in 1,4-dioxane (5 mL) were found to be the most suitable reaction conditions.With the optimized conditions, we further investigated the substrate scope of this one-pot, three-step reductive coupling reaction process.As shown in Figure 2, the 4-substituted arylboronic Scheme 2. One-pot, multi-step, multi-component reactions of 4-bromoacetophenone, tosylhydrazide, with two arylboronic acids.
On the basis of their study and our previous work [17], the reaction conditions of the third step were optimized, namely, the effects of ligand, base and temperature on the Suzuki coupling reaction were examined.Initially, the coupling reaction of 4-bromoacetophenone, TsNHNH 2 and phenylboronic acid was selected as a model reaction to optimize the reaction conditions.Table 1 summarizes the results.The use of only Pd(OAc) 2 as the catalyst and K 2 CO 3 as the base in 1,4-dioxane at 110 • C produced the desired product 3a in only 15% yield (entry 1).The phosphine ligands were screened for this reaction, and PCy 3 •HBF 4 was found to be the most effective one for forming coupling product 3a (entry 3).Among the various bases examined, organic bases (Et 3 N), and inorganic bases (K 3 PO 4 •H 2 O and NaOH) gave the desired product in moderate yields (63-72%, entries 4-6, respectively).Cs 2 CO 3 was not effective, and corresponding product 3a was obtained in a low yield (entry 7).Gratifyingly, when the amounts of tosylhydrazide and phenylboronic acid were increased, the yield of the product dramatically increased to 89% (entry 8).In addition, when the amount of Pd(OAc) 2 was increased to 2 mol %, the yield of product did not improve significantly (entry 9).When the temperature of the Suzuki coupling reaction was decreased to 80 • C, the product was isolated in only 52% yield (entry 10).Hence, the combination of 4-bromoacetophenone (0.5 mmol), tosylhydrazide (1.5 equiv.),phenylboronic acid (3.0 equiv.),Pd(OAc) 2 (1 mol %), PCy 3 •HBF 4 (4 mol %) and K 2 CO 3 (3.0equiv.) at T 1 = 80 • C (t 1 = 2 h), T 2 = 110 • C (t 2 = 5 h), and T 3 = 110 • C (t 3 = 12 h) in 1,4-dioxane (5 mL) were found to be the most suitable reaction conditions.Scheme 2. One-pot, multi-step, multi-component reactions of 4-bromoacetophenone, tosylhydrazide, with two arylboronic acids.
On the basis of their study and our previous work [17], the reaction conditions of the third step were optimized, namely, the effects of ligand, base and temperature on the Suzuki coupling reaction were examined.Initially, the coupling reaction of 4-bromoacetophenone, TsNHNH2 and phenylboronic acid was selected as a model reaction to optimize the reaction conditions.Table 1 summarizes the results.The use of only Pd(OAc)2 as the catalyst and K2CO3 as the base in 1,4-dioxane at 110 °C produced the desired product 3a in only 15% yield (entry 1).The phosphine ligands were screened for this reaction, and PCy3•HBF4 was found to be the most effective one for forming coupling product 3a (entry 3).Among the various bases examined, organic bases (Et3N), and inorganic bases (K3PO4•H2O and NaOH) gave the desired product in moderate yields (63-72%, entries 4-6, respectively).Cs2CO3 was not effective, and corresponding product 3a was obtained in a low yield (entry 7).Gratifyingly, when the amounts of tosylhydrazide and phenylboronic acid were increased, the yield of the product dramatically increased to 89% (entry 8).In addition, when the amount of Pd(OAc)2 was increased to 2 mol %, the yield of product did not improve significantly (entry 9).When the temperature of the Suzuki coupling reaction was decreased to 80 °C, the product was isolated in only 52% yield (entry 10).Hence, the combination of 4-bromoacetophenone (0.5 mmol), tosylhydrazide (1.5 equiv.),phenylboronic acid (3.0 equiv.),Pd(OAc)2 (1 mol %), PCy3•HBF4 (4 mol %) and K2CO3 (3.0 equiv.) at T1 = 80 °C (t1 = 2 h), T2 = 110 °C (t2 = 5 h), and T3 = 110 °C (t3 = 12 h) in 1,4-dioxane (5 mL) were found to be the most suitable reaction conditions.With the optimized conditions, we further investigated the substrate scope of this one-pot, three-step reductive coupling reaction process.As shown in Figure 2, the 4-substituted arylboronic  With the optimized conditions, we further investigated the substrate scope of this one-pot, three-step reductive coupling reaction process.As shown in Figure 2, the 4-substituted arylboronic acid substrates bearing electron-withdrawing or electron-donating groups effectively afforded desired products 3b-3f in good yields (77-87%).Moreover, m-tolylboronic acid, (3-methoxyphenyl)boronic acid and (3,4,5-trifluorophenyl)boronic acid were found to produce desired coupling products 3g-3i in 56-94% yields, respectively.Furthermore, the reductive coupling reactions involving ortho-substituted arylboronic acids were investigated.Both electronic properties and steric hindrance of the substrates affect the coupling reaction.For example, the coupling reaction of o-tolylboronic acid with 4-bromoacetophenone and TsNHNH 2 afforded 3j in 92% yield.Naphthalene-2-ylboronic acid used as the coupling partner afforded 3k in 83% yield.Moreover, 3-bromoacetophenone and 4-bromobenzaldehyde also reacted with m-tolylboronic acid affording target products 3l and 3m in 82% and 74% yields.In contrast, 2-bromobenzaldehyde as the substrate reacted with m-tolylboronic acid affording the desired product 3n in only 29% yield.Notably, the gram-scale synthesis of 3g was performed to verify the practical application of this synthesis system.Fortunately, the reaction was performed using 5 mmol of 4-bromoacetophenone, 7.5 mmol TsNHNH 2 and 15 mmol m-tolylboronic acid, affording product 3g in 88% yield (1.254 g).
In response to the challenges above, we also attempted to synthesize 3x by an alternative route (Scheme 4).Using 4-acetylpyridine as the starting material, first reacted with TsNHNH2, generates the corresponding hydrazine, then, to reductive coupling with 4-bromophenylboronic acid.In the Scheme 3. Synthesis of 3x by three-step, four-component reactions.
In response to the challenges above, we also attempted to synthesize 3x by an alternative route (Scheme 4).Using 4-acetylpyridine as the starting material, first reacted with TsNHNH 2 , generates the corresponding hydrazine, then, to reductive coupling with 4-bromophenylboronic acid.In the third step, the second phenylboronic acid with a palladium catalyst were added to the above reaction solution, after the Suzuki coupling reaction, the ultimate product 3x formed with 60% yield directly without the need to isolate any of the reaction intermediates.Similarly, methoxy substituted product 3y was also obtained with 51% yield by this method.
Molecules 2017, 22, 2168 6 of 13 third step, the second phenylboronic acid with a palladium catalyst were added to the above reaction solution, after the Suzuki coupling reaction, the ultimate product 3x formed with 60% yield directly without the need to isolate any of the reaction intermediates.Similarly, methoxy substituted product 3y was also obtained with 51% yield by this method.
Scheme 4. Synthesis of 3x and 3y by one-pot, three-step, four-component reactions.

Materials and Methods
Chemicals were obtained commercially and used as received.NMR spectra were recorded on a Bruker DPX-400 spectrometer using TMS as the internal standard.EI-Mass spectra were measured on a LC/Q-TOF MS (Micromass, Wilmslow, UK) (see Supplementary Materials).All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleumether (60-90 °C) as mobile phase, unless otherwise noted.4-Bromoacetophenone derivatives, and arylboronic acids were of analytical grade quality, purchased from Adamas-beta Pharmaceuticals, Inc. (Shanghai, China).

General Procedure for the One-Pot, Four-Component Reactions of 4-Bromoacetophenone, TsNHNH2, and Two Same Arylboronic Acids
A solution of 4-bromoacetophenone or 4-bromobenzaldehyde derivatives (0.5 mmol) and tosylhydrazide (0.75 mmol) in 4 mL of 1,4-dioxane was stirred at 80 °C for 2 h in a reaction tube.Second, potassium carbonate (1.5 mmol) and the appropriate arylboronic acid (1.1 mmol) were added to the reaction mixture.Third, the reaction system was refluxed at 110 °C for 5 h with stirring.Next, 2 mol % Pd(OAc)2, and 4mol % PCy3•HBF4 were added, and the reaction was continued for 12 h at 110 °C.Then, the reaction was completed, and the crude mixture was allowed to reach room temperature.Finally, dichloromethane and a saturated solution of NaHCO3 were added, and the layers were separated.The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with two portions of a saturated NaHCO3 solution and one portion of brine, and then dried over anhydrous MgSO4 and filtered.The solvent was removed under reduced pressure.The products were purified by silica gel chromatography.

General Procedure for the One-Pot, Four-Step, Four-Component Reactions of 4-Acetylbiphenylderivatives, TsNHNH2, and Two Different Arylboronic Acids
A solution of 4-bromoacetophenone derivatives (0.5 mmol) and tosylhydrazide (0.75 mmol) in 4 mL of 1,4-dioxane was stirred at 80 °C for 2 h in a reaction tube.Then, potassium carbonate (1.5 mmol) and the appropriate arylboronic acid (0.6 mmol) were added to the reaction mixture.The system was refluxed at 110 °C for 5 h with stirring.Third, 2 mol % Pd(OAc)2, 4 mol % PCy3•HBF4, and another arylboronic acid (0.75 mmol) were added, and the reaction was continued for 12 h at 110 °C.After the reaction was completed, the crude mixture was allowed to reach room temperature.Finally, dichloromethane and a saturated solution of NaHCO3 were added, and the layers were separated.The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with two portions of a saturated NaHCO3 solution and one portion of brine, and then dried over anhydrous MgSO4 and filtered.The solvent was removed under reduced pressure.The products were purified by silica gel chromatography.

Materials and Methods
Chemicals were obtained commercially and used as received.NMR spectra were recorded on a Bruker DPX-400 spectrometer using TMS as the internal standard.EI-Mass spectra were measured on a LC/Q-TOF MS (Micromass, Wilmslow, UK) (see Supplementary Materials).All products were isolated by short chromatography on a silica gel (200-300 mesh) column using petroleumether (60-90 • C) as mobile phase, unless otherwise noted.4-Bromoacetophenone derivatives, and arylboronic acids were of analytical grade quality, purchased from Adamas-beta Pharmaceuticals, Inc. (Shanghai, China).
3.1.General Procedure for the One-Pot, Four-Component Reactions of 4-Bromoacetophenone, TsNHNH 2 , and Two Same Arylboronic Acids A solution of 4-bromoacetophenone or 4-bromobenzaldehyde derivatives (0.5 mmol) and tosylhydrazide (0.75 mmol) in 4 mL of 1,4-dioxane was stirred at 80 • C for 2 h in a reaction tube.Second, potassium carbonate (1.5 mmol) and the appropriate arylboronic acid (1.1 mmol) were added to the reaction mixture.Third, the reaction system was refluxed at 110 • C for 5 h with stirring.Next, 2 mol % Pd(OAc) 2 , and 4mol % PCy 3 •HBF 4 were added, and the reaction was continued for 12 h at 110 • C.Then, the reaction was completed, and the crude mixture was allowed to reach room temperature.Finally, dichloromethane and a saturated solution of NaHCO 3 were added, and the layers were separated.The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with two portions of a saturated NaHCO 3 solution and one portion of brine, and then dried over anhydrous MgSO 4 and filtered.The solvent was removed under reduced pressure.The products were purified by silica gel chromatography.

General
Procedure for the One-Pot, Four-Step, Four-Component Reactions of 4-Acetylbiphenylderivatives, TsNHNH 2 , and Two Different Arylboronic Acids A solution of 4-bromoacetophenone derivatives (0.5 mmol) and tosylhydrazide (0.75 mmol) in 4 mL of 1,4-dioxane was stirred at 80 • C for 2 h in a reaction tube.Then, potassium carbonate (1.5 mmol) and the appropriate arylboronic acid (0.6 mmol) were added to the reaction mixture.The system was refluxed at 110 • C for 5 h with stirring.Third, 2 mol % Pd(OAc) 2 , 4 mol % PCy 3 •HBF 4 , and another arylboronic acid (0.75 mmol) were added, and the reaction was continued for 12 h at 110 • C.After the reaction was completed, the crude mixture was allowed to reach room temperature.Finally, dichloromethane and a saturated solution of NaHCO 3 were added, and the layers were separated.The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with two portions of a saturated NaHCO 3 solution and one portion of brine, and then dried over anhydrous MgSO 4 and filtered.The solvent was removed under reduced pressure.The products were purified by silica gel chromatography.

General Procedure for the Synthesis of 3x and 3y
A solution of 4-acetylpyridine (0.5 mmol) and tosylhydrazide (0.75 mmol) in 4 mL of 1,4-dioxane was stirred at 80 • C for 3 h in a reaction tube.Then, potassium carbonate (1.5 mmol) and 4-bromophenylboronic acid (0.55 mmol) were added to the reaction mixture.The system was refluxed at 110 • C for 7 h with stirring.Third, 1 mol % Pd(OAc) 2 , 4 mol % PCy 3 •HBF 4 , and another arylboronic acid (0.75 mmol) were added, and the reaction was continued for 10 h at 110 • C.After the reaction was completed, the crude mixture was allowed to reach room temperature.Finally, dichloromethane and a saturated solution of NaHCO 3 were added, and the layers were separated.The aqueous phase was extracted three times with dichloromethane, and the combined organic layers were washed with two portions of a saturated NaHCO 3 solution and one portion of brine, and then dried over anhydrous MgSO 4 and filtered.The solvent was removed under reduced pressure.The products were purified by silica gel chromatography.

Table 1 .
Optimization of one-pot, multi-step reaction conditions a .

Table 1 .
Optimization of one-pot, multi-step reaction conditions a .

Table 1 .
Optimization of one-pot, multi-step reaction conditions a .