Pd ( CH 3 CN ) 2 Cl 2 / Pipecolinic Acid as a Highly Efficient Catalytic System for Suzuki-Miyaura Cross-coupling Reaction of Bromoaryl Carboxylic Acids in Water

Abstract: In this study, a convenient and highly efficient catalytic system for the Suzuki-Miyaura coupling reaction was investigated under mild conditions. A combination of Pd(CH3CN)2Cl2 and pipecolinic acid showed excellent catalytic performance and afforded high turnover numbers; turnover numbers were up to 4.9 × 105 for the coupling reaction of 4-bromobenzoic acid and tetraphenylboron sodium. The catalytic system was also effective for the indexes of 4-bromobenzoic acid, and high turnover numbers were obtained.


Introduction
The C-C cross-coupling reaction, which is usually catalyzed by transition metals such as palladium [1] and gold [2,3], provides a powerful method for obtaining a biaryl scaffold.Among these catalysts, palladium is the most widely used, showing highly efficient catalytic performance.Impressive progress has been obtained in the enhancement of the catalytic performance of palladium in past decades [4].However, obtaining a highly efficient catalyst under room temperature conditions with no use of hazardous and expensive organic solvents still remains challenging.Nitrogen ligands have been used to complex and stimulate the palladium species instead of phosphine ligands, and excellent results have been reported [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].Most nitrogen ligands are stable in air and are easily available, which reveals their usefulness and appearance as a pertinent alternative.Primary, secondary, and tertiary amines have served as ligands to stimulate the palladium-catalyzed Suzuki-Miyaura coupling reaction of aryl halides and arylboronic acids [4][5][6].Pd(OAC) 2 /DABCO (triethylenediamine) has been reported as an efficient catalytic system for the Suzuki-Miyaura cross-coupling of p-nitroiodobenzene and phenylboronic acid, with turnover numbers (TONs) of up to 900,000 [7].However, 0.01-2 mol% of Pd(OAC) 2 /DABCO should be used to obtain a high yield in the coupling reaction of aryl bromides and phenylboronic acid.Recently, a ppm level of PdCl 2 has been developed for the Suzuki-Miyaura coupling reaction and in this process high-pressure and high-temperature water is necessary in order to gain a high yield [21].Amino acid complexes show good catalytic performance in C-C bond and C-N formation [18][19][20]22,23].Previous work has shown that Pd(NH 2 CH 2 COOH) 2 Cl 2 can catalyze the cross-coupling reaction.In order to obtain a high yield of the coupling products, 0.01-1 mol% Pd is necessary [23].Hence, pipecolinic acid, a kind of amino acid, was chosen as a ligand for the Pd-catalyzed Suzuki-Miyaura coupling reaction at room temperature in water, and a ppm level of Pd was enough to gain a high yield.

Optimization of Catalytic Conditions
The catalytic activities of Pd(CH 3 CN) 2 Cl 2 /L1-L3 in the Suzuki-Miyaura cross-coupling reaction were tested (Figure 1).The coupling reaction of 4-bromobenzoic acid and tetraphenylboron sodium was chosen as the model coupling reaction (Figure 1).The stimulation of the ligands (L1-L3) for the Pd-catalyzed cross-coupling reaction was evaluated.When 0.002 mol% Pd(CH 3 CN) 2 Cl 2 was used solely as the catalyst, 4.9% of the corresponding coupling product was detected by high performance liguid chromatography (HPLC) (Table 1, Entry 1).L1 was discovered as being able to trigger the cross-coupling reaction (

Optimization of Catalytic Conditions
The catalytic activities of Pd(CH3CN)2Cl2/L1-L3 in the Suzuki-Miyaura cross-coupling reaction were tested (Figure 1).The coupling reaction of 4-bromobenzoic acid and tetraphenylboron sodium was chosen as the model coupling reaction (Figure 1).The stimulation of the ligands (L1-L3) for the Pd-catalyzed cross-coupling reaction was evaluated.When 0.002 mol% Pd(CH3CN)2Cl2 was used solely as the catalyst, 4.9% of the corresponding coupling product was detected by high performance liguid chromatography (HPLC) (Table 1, Entry 1).L1 was discovered as being able to trigger the cross-coupling reaction (Table 1, Entry 4) but Pd(CH3CN)2Cl2/L2 and L3 showed poor catalytic activity within the cross-coupling reaction.A brown precipitate was formed when Pd(CH3CN)2Cl2/L2 or Pd(CH3CN)2Cl2/L3 was placed in water for about 20 minutes.The instability of the combination of Pd (CH3CN)2Cl2/L2 or Pd (CH3CN)2Cl2/L3 in water may be the main reason for their poor catalytic performance.The next step was to optimize the reaction conditions.As known, the base plays an important role in the Suzuki-Miyaura coupling reaction, so the effects of various inorganic bases on the coupling reaction were investigated first.Ninety-five percent (TON = 4.7 × 10 4 ) of the corresponding cross-coupling product was obtained when the coupling reaction proceeded for 6 h using 0.002 mol% Pd(CH 3 CN) 2 Cl 2 , 0.004 mol% L1, and 2.5 equiv of Na 2 CO 3 in water at room temperature, whereas in the presence of 2.5 equiv of NaF or NaOH, the yield decreased to 24% and 84%, respectively (Table 1,  Entry 4,5,7).Under similar conditions, when 2.5 equiv of NaHCO 3 was used, a yield identical to that using Na 2 CO 3 was obtained (Table 1, Entry 6).When the amount of catalyst increased to 0.004 mol%, an almost equivalent amount of cross-coupling product was obtained after 6 h (Table 1, Entry 8).A 24% (TON = 1.2 × 10 5 ) yield was observed after 6 h when the amount of catalyst decreased to 0.0002 mol% (Table 1, Entry 9), whereas, as the reaction time was extended to 22 h, a 97% (TON = 4.9 × 10 5 ) yield of the cross-coupling product was obtained (Table 1, Entry 10).Pd(CH 3 CN) 2 Cl 2 /L1 showed high catalytic activity at low catalytic loading.At low catalytic loading, the cross-coupling reaction of phenylboronic acid or potassium and 4-bromobenzoic acid could occur efficiently (Table 1, Entry 11,12).Under the same conditions, no cross-coupling product was isolated when bromobenzene reacted with tetraphenylboron sodium catalyzed by 0.0002 mol% Pd(CH 3 CN) 2 Cl 2 /L1 (Table 1, Entry 13).

Evaluation of the Scope of Pd(CH 3 CN) 2 Cl 2 /L1
The catalytic system Pd(CH 3 CN) 2 Cl 2 /L1 was also applied to various substrates (Figure 2), the results of which are shown in Table 2.At lower catalytic loading, such as at 0.002 mol%, Pd(CH 3 CN) 2 Cl 2 /L1 was exceptionally active for the Suzuki-Miyaura cross-coupling of various brominated aromatic carboxylic acids and tetraarylboron sodium.Using this system, high yields could be obtained for the coupling reactions of bromide aromatic carboxylic acids with electronwithdrawing and electron-donating substituents and tetraphenylboron sodium (Table 2, Entry 1-9).Ortho-substituted brominated aromatic carboxylic acids and tetraarylboron sodium reacted smoothly, though the yield of the corresponding coupling compounds slightly decreased (Table 2, Entry 4,6,9).This indicates that the steric hindrance of coupling partners had less influence on this Suzuki-Miyaura coupling reaction.Tetraarylboron sodium bearing methyl or methoxy groups converted to the corresponding products at high yield (Table 2, Entry 10-18).conditions: 1.0 mmol bromobenzene, 0.255 mmol tetraphenylboron sodium.e Detected by HPLC, with benzoic acid used as an internal standard.f Turnover number (TON): mole ratio of product with catalyst.
The next step was to optimize the reaction conditions.As known, the base plays an important role in the Suzuki-Miyaura coupling reaction, so the effects of various inorganic bases on the coupling reaction were investigated first.Ninety-five percent (TON = 4.7 × 10 4 ) of the corresponding crosscoupling product was obtained when the coupling reaction proceeded for 6 h using 0.002 mol% Pd(CH3CN)2Cl2, 0.004 mol% L1, and 2.5 equiv of Na2CO3 in water at room temperature, whereas in the presence of 2.5 equiv of NaF or NaOH, the yield decreased to 24% and 84%, respectively (Table 1, Entry 4,5,7).Under similar conditions, when 2.5 equiv of NaHCO3 was used, a yield identical to that using Na2CO3 was obtained (Table 1, Entry 6).When the amount of catalyst increased to 0.004 mol%, an almost equivalent amount of cross-coupling product was obtained after 6 h (Table 1, Entry 8).A 24% (TON = 1.2 × 10 5 ) yield was observed after 6 h when the amount of catalyst decreased to 0.0002 mol% (Table 1, Entry 9), whereas, as the reaction time was extended to 22 h, a 97% (TON = 4.9 × 10 5 ) yield of the cross-coupling product was obtained (Table 1, Entry 10).Pd(CH3CN)2Cl2/L1 showed high catalytic activity at low catalytic loading.At low catalytic loading, the cross-coupling reaction of phenylboronic acid or potassium phenyltrifluoroborate and 4-bromobenzoic acid could occur efficiently (Table 1, Entry 11,12).Under the same conditions, no cross-coupling product was isolated when bromobenzene reacted with tetraphenylboron sodium catalyzed by 0.0002 mol% Pd(CH3CN)2Cl2/L1 (Table 1, Entry 13).

Evaluation of the Scope of Pd(CH3CN)2Cl2 /L1
The catalytic system Pd(CH3CN)2Cl2/L1 was also applied to various substrates (Figure 2), the results of which are shown in Table 2.At lower catalytic loading, such as at 0.002 mol%, Pd(CH3CN)2Cl2/L1 was exceptionally active for the Suzuki-Miyaura cross-coupling of various brominated aromatic carboxylic acids and tetraarylboron sodium.Using this system, high yields could be obtained for the coupling reactions of bromide aromatic carboxylic acids with electronwithdrawing and electron-donating substituents and tetraphenylboron sodium (Table 2, Entry 1-9).Ortho-substituted brominated aromatic carboxylic acids and tetraarylboron sodium reacted smoothly, though the yield of the corresponding coupling compounds slightly decreased (Table 2, Entry 4,6,9).This indicates that the steric hindrance of coupling partners had less influence on this Suzuki-Miyaura coupling reaction.Tetraarylboron sodium bearing methyl or methoxy groups converted to the corresponding products at high yield (Table 2, Entry 10-18).

Table
, Entry 4) but Pd(CH 3 CN) 2 Cl 2 /L2 and L3 showed poor catalytic activity within the cross-coupling reaction.A brown precipitate was formed when Pd(CH 3 CN) 2 Cl 2 /L2 or Pd(CH 3 CN) 2 Cl 2 /L3 was placed in water for about 20 minutes.The instability of the combination of Pd (CH 3 CN) 2 Cl 2 /L2 or Pd (CH 3 CN) 2 Cl 2 /L3 in water may be the main reason for their poor catalytic performance.

Table 1 .
Optimization of reaction conditions.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Table 2 .
The scope of the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.