Catalytic activity of some oxime-based Pd(II)-complexes in Suzuki coupling of aryl and heteroaryl bromides in water

2.1 Materials and methods

Melting points were determined in open glass capillaries with a Gallenkamp apparatus and are uncorrected. The infrared spectra were recorded in potassium bromide disks on a Pye-Unicam SP 3–300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 MHz (¹H NMR) and at 75.46 MHz (¹³C NMR) using deuterated chloroform (CDCl₃) or dimethylsulfoxide (DMSO-d₆). Chemical shifts are quoted in δ and were related to that of the solvents. Mass spectra (EI) were obtained at 70 eV with a type Shimadzu GCMQP 1000 EX spectrometer. Microwave experiments were carried out using a CEM Discover Labmate^™ microwave apparatus (300 W with Chem Driver^™ Software). Syntheses of the Pd(II)-complexes 1 (Dawood, 2007), 2 (Darweesh et al., 2010), 3 (Dawood and El-Deftar, 2010), and 4 (Dawood et al., 2009), were accomplished following the reported literature procedures.

2.2 Suzuki cross-coupling of aryl and heteroaryl bromides with arylboronic acids under thermal heating

General procedure: A mixture of the appropriate aryl or heteroaryl bromide 6, 8, 10, 12 and 14 (1 mmol) and the appropriate arylboronic acid 5, 16–20 (1.2 mmol), tetrabutylammonium bromide (TBAB) (194 mg, 0.6 mmol), the appropriate palladium(II)-complexes 1, 2, 3 and 4 (1 mol%), KOH (112 mg, 2 mmol) in water (3 mL) was refluxed for 1 h. The same experiment was repeated under a typical reaction condition using palladium complexes 1, 2, 3 and 4 in 0.5 mol%. The amount (mol%) of the palladium complexes 1, 2, 3 and 4 was changed with respect to the aryl bromides to be: (0.25, 0.125, 0.05, 0.03, 0.01 and 0.00 mol% of Pd- complexes with scales: 1, 2, 2, 5 and 10 mmol of the appropriate aryl bromides, respectively). The molar ratio of the reaction components was in all cases as follows; aryl bromide, arylboronic acid, TBAB, KOH, water: 1/1.2/0.6/2/3 mL water. After the reaction was almost completed, the cross-coupled products were then extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over anhydrous MgSO₄ then filtered and the solvent was evaporated under reduced pressure. The residue was then subjected to separation via flash column chromatography with n-hexane/EtOAc (10:1) as an eluent to give the corresponding pure cross-coupled products 7, 9, 11, 13, 15 and 21–25. The yield % versus concentrations of the palladium complexes are outlined in Tables 1–6.

Table 1 Effect of concentrations of different Pd-complexes 1, 2, 3 and 4 on the coupling of p-bromoacetophenone.

Entry	Cat. mol%	Cat. 1a,b	Cat. 2a,b	Cat. 3a,b	Cat. 4a,b
1	1	100 (94)	100 (92)	100 (95)	100 (90)
2	0.5	100	100	100	100
3	0.25	100	100	100	100
4	0.125	100	100	100	10
5	0.05	100 (90)	100 (94)	100 (87)	100 (88)
6	0.03	100	100	90c	100
7	0.01	100	100	60c	100
8	0.00	0	0	0	0

a Conditions: Bromide/boronic acid/KOH/TBAB/water (3 mL): 1/1.2/2/0.6, at 100 °C for 1 h.

b Conversions were based on ¹H NMR of the crude product and the values between parentheses refer to the isolated yields.

c Traces of the reactants were detected using TLC.

Table 2 Effect of concentrations of different Pd(II)-complexes on the coupling of p-bromoanisole.

Entry	Cat. mol%	Cat. 1a,b	Cat. 2a,b	Cat. 3a,b	Cat. 4a,b
1	1	100 (90)	100 (87)	100 (94)	100 (83)
2	0.5	100	100	100	100
3	0.25	100	100	100	100
4	0.125	100	100	100	100
5	0.05	100 (89)	100 (91)	100 (90)	100 (78)
6	0.03	100	100	100	100
7	0.01	100	100	75	100
8	0.00	0	0	0	0

a Conditions: Bromide/boronic acid/KOH/TBAB/water (3 mL): 1/1.2/2/0.6, at 100 °C for 1 h.

b Conversions were based on ¹H NMR of the crude product and the values between parentheses refer to the isolated yields.

Table 3 Catalytic activity of the Pd-complexes 1, 2, 3 and 4 on the coupling of 3-bromoquinoline 10 with phenylboronic acid.

Entry	Cat. mol%	Cat. 1a,b	Cat. 2a,b	Cat. 3a,b	Cat. 4a,b
1	1	100 (93)	100	100 (92)	100 (96)
2	0.5	100	100 (96)	100	100
3	0.25	100	100	100	100
4	0.125	100	100	100	100
5	0.05	100 (93)	100 (94)	100 (86)	100 (91)
6	0.03	100	100	100	100
7	0.01	100	100	90c	100
8	00.0	0	0	0	0

a Conditions: Bromide/boronic acid/KOH/TBAB/water (3 mL): 1/1.2/2/0.6, at 100 °C for 1 h.

b Conversions were based on ¹H NMR of crude product and the values between parentheses refer to the isolated yields.

c Starting bromide 10 was detected by TLC.

Table 4 Effect of concentration of Pd-complexes 1–4 on the coupling of 2-bromothiophene with phenylboronic acid in water under thermal heating.

Entry	Cat. mol%	Cat. 1a,b	Cat. 2a,b	Cat. 3a,b	Cat. 4a,b
1	1	100 (93)	100 (97)	100 (90)	100 (96)
2	0.75	100	100	100	100
3	0.5	100	100	80	100
4	0.25	100	100	40	100
5	0.125	50b	100	10	100
6	0.05	10	100 (92)	0	100 (95)
7	0.025	0	84b,c	0	60b,c
8	0.00	0	0	0	0

a Conditions: Bromide/boronic acid/KOH/TBAB/water (3 mL): 1/1.2/2/0.6, at 100 °C for 3 h.

b Conversions were based on ¹H NMR of crude product and the values between parentheses refer to the isolated yields.

c Starting bromide 12 was detected by TLC.

Table 5 Catalytic activity of Pd(II)-complexes 1–4 in Suzuki coupling of 2-acetyl-5-bromothiophene (14) with phenylboronic acid under thermal heating.

Entry	Cat. mol%	Cat. 1a,b	Cat. 2a,b	Cat. 3a,b	Cat. 4a,b
1	1	100(89)	100(96)	100(91)	100 (93)
2	0.75	100	100	100	100
3	0.5	100	100	80	100
4	0.25	100c	100	50	100
5	0.125	65	100	0	100
6	0.05	10	100(86)	–	100(78)
7	0.025	0	100c	–	100c
8	0	–	0	–	0

a Conditions: Bromide 14/boronic acid 5/KOH/TBAB/water (3 mL): 1/1.2/2/0.6, at 100 °C for 1 h.

b Conversions were based on ¹H NMR of crude product and the values between parentheses refer to the isolated yields.

c When the reaction was repeated under microwave irradiation at 160 °C and 250 W for two min, full conversion to product 15 was detected by TLC.

Table 6 Suzuki coupling of 2-bromothiophene with arylboronic acids using complex 2 under thermal heating as well as microwave irradiation.

Entry	Het(Ar)-B(OH)2	Product	Thermal heating time/h yield % a,b		MW heating time/min yield % a,b
1	5	13	1	100(97)	2	100(94)
2	16	21	4	100(91)	5	100(95)
3	17	22	5	100(87)	5	100(90)
4	18	23	5	100(82)	6	100(92)
5	19	24	6	100(86)	6	100(90)
6	20	25	5	100(96)	6	10(90)

a Conditions: Bromide: 1 mmol; phenylboronic acid: 1.2 mmol; TBAB: 0.6 mmol; KOH: 2 mmol; water: 3 mL, Pd-complex: 2: 0.25 mol%, microwave heating (250 W) at 160 °C and thermal heating at 100 °C.

b The values between parentheses refer to the isolated yields.

2.3 Suzuki–Miyaura coupling of 2-bromothiophene with arylboronic acids in water under microwave irradiation condition

A mixture of 2-bromothiophene 12 (1 mmol) and the appropriate arylboronic acid 5, 16–20 (1.2 mmol), tetrabutylammonium bromide (TBAB) (194 mg, 0.6 mmol), the appropriate palladium(II)-complexes 1, 2, 3 and 4 (1 mol%), KOH (112 mg, 2 mmol) in water (3 mL) was mixed in a process glass vial. The vial was capped properly and thereafter the mixture was heated under microwave irradiating conditions at 160 °C and 250 W for the appropriate reaction times as shown in Table 5. After the reaction was almost completed, the cross-coupled products were then extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over anhydrous MgSO₄ then filtered and the solvent was evaporated under reduced pressure. The residue was then subjected to separation via flash column chromatography with n-hexane/EtOAc (10:1) as an eluent to give the corresponding pure cross-coupled products 2-aryl(heteroaryl)thiophenes 13 and 21–25.

3.1 Concentration effect of the Pd(II)-complexes 1–4 on the Suzuki coupling of aryl and heteroaryl bromides with phenylboronic acid in water

Although we reported the precatalysts 1–4 earlier, their comparative catalytic activities for certain substrates (arylboronic acids and aryl halides) under certain condition (heating mode, time, concentration and solvent) in parallel were not examined so far. Therefore, a detailed comparative study for the effect of concentration of palladium(II)-complexes 1, 2, 3 and 4 on the cross-coupling reaction between phenylboronic acid (5) and p-bromoacetophenone (6) was firstly evaluated. The reaction was performed in water under different concentrations of the catalysts using potassium hydroxide as a base and tetrabutylammonium bromide (TBAB) as a co-catalyst under thermal conditions at 100 °C for 1 h and the results are outlined in Table 1. At first, 1 mol% of the complexes 1, 2, 3 and 4 was employed in the reaction with a molar ratio of p-bromoacetophenone (6)/phenylboronic acid (5)/TBAB/KOH: 1/1.2/0.6/2, to give, in all cases, 100% conversion of 4-acetyl-1,1′-biphenyl (7) based on TLC and ¹H NMR analysis. In the second experiment, 0.5 mol% of each of the precatalysts 1, 2, 3 and 4 was used to give also, in all cases, full conversion after 1 h heating at 100 °C. The reaction was repeated again with different concentrations (mol%) of the Pd(II)-complexes 1, 2, 3 and 4 as shown in Table 1. From the obtained results it can be noticed that Pd(II)-complexes 1, 2 and 4 gave full conversion when they were used in 0.25, 0.125, 0.05, 0.03 and 0.01 mol%, respectively. However, Pd(II)-complex 3 was active enough and gave full conversion when it was used in 0.25%, 0.125%, 0.05% only and the conversion was then decreased to be 90% and 60% when the catalyst was used in 0.03 and 0.01 mol%, respectively. It can be concluded from the data in Table 1 that the Pd-complexes 1, 2 and 4 are more efficient than Pd-complex 3. Noteworthy to mention that, p-bromoacetophenone (6) as starting material was completely recovered unchanged when the reaction was carried out without any of the Pd-complexes 1, 2, 3 and 4 (entry 8, Table 1).

Next, the effect of concentration of palladium(II)-complexes 1, 2, 3 and 4 on the cross-coupling reaction between phenylboronic acid (5) and the deactivated p-bromoanisole (8), in water using potassium hydroxide as a base and tetrabutylammonium bromide (TBAB) as a co-catalyst under thermal conditions at 100 °C for 1 h, was evaluated as shown in Table 2. At first, the reaction was conducted using 1 mol% of the complexes 1, 2, 3 and 4 with a molar ratio of p-bromoanisole (8)/phenylboronic acid (5)/TBAB/KOH: 1/1.2/0.6/2 to give 100% conversion of 4-methoxy-1,1′-biphenyl (9) based on TLC and ¹H NMR analysis. In the second experiment, 0.5 mol% of the catalysts 1, 2, 3 and 4 was used to give full conversion after 1 h heating at 100 °C. The reaction was repeated with different concentrations (mol%) of 1, 2, 3 and 4 as shown in Table 2. In all cases, full conversions were obtained till 0.01 mol% of the complexes 1, 2 and 4. As shown in Table 2, all Pd-complexes are efficient except Pd-complex 3 for the cross-coupling of 8 with 5 at the concentration 0.01 mol% catalyst.

3.2 Effect of concentrations of the Pd(II)-complexes 1–4 on the coupling of heterocyclic bromides with phenylboronic acid

The Suzuki cross coupling of heterocyclic bromides with phenylboronic acid under different of concentration of palladium(II)-complexes 1, 2, 3 and 4 was also extensively studied. The cross-coupling of 3-bromoquinoline (10) with phenylboronic acid (5) under thermal conditions at 100 °C for 1 h in water/TBAB/KOH as catalytic system using different concentrations of the Pd-catalyst was examined and the results are illustrated in Table 3. In all cases, almost full conversions of 3-bromoquinoline (10) into 3-phenylquinoline (11) were observed regardless of the applied concentration of the Pd-complexes 1–4.

Sulfur species are considered to be potential catalyst poisons that cause a substantial decrease in the catalytic activity of palladium catalysts (Dunleavy 2006). In addition, the thiophene ring is a π-electron-rich heterocycle and consequently 2-bromothiophene (12) is considered as deactivated bromide in Pd-catalyzed C–C coupling reactions. Herein, two sulfur-containing Pd(II)-complexes 1 and 2 are applied in Suzuki C–C coupling reaction of sulfur-containing substrate; 2-bromothiophene (12) in comparison with the sulfur-free complexes 3 and 4. Thus, the effect of concentration of Pd(II)-complexes 1–4 on the cross-coupling reaction between phenylboronic acid (5) and 2-bromothiophene (12), in water using potassium hydroxide as a base and tetrabutylammonium bromide (TBAB) as a co-catalyst under thermal conditions at 100 °C for 1 h, was evaluated as depicted in Table 4. At first, the reaction was conducted using, in each case, 1 mol% of the Pd(II)-complexes 1–4 with a molar ratio of 2-bromothiophene (12)/phenylboronic acid (5)/TBAB/KOH: 1/1.2/0.6/2, where full conversion of 2-phenylthiophene (13) was observed on the basis of TLC analysis. In the second experiment, we used 0.5 mol% of the precatalysts 1, 2, 3 and 4 to give full conversion after 1 h heating at 100 °C. The reaction was repeated with different concentrations (mol%) of 1, 2, 3 and 4 and the results are depicted in Table 4. It is clear that the reactivity of the Pd(II)-precatalysts is in the order: 2 > 4 > 1 > 3. From this finding, it can be concluded that the presence of sulfur atom in either the catalyst or the coupling substrate did not affect the catalytic activity of the Pd(II)-catalysts used.

2-Acetyl-5-bromothiophene (14), as a coupling candidate, was prepared from the bromination of 2-acetylthiophene with N-bromosuccinimide in a mixture of glacial acetic acid and acetic anhydride according to the reported literature (Smirnov and Lipkin, 1973). Then, the reactivity of the palladium(II)-complexes 1–4 in the Suzuki cross-coupling reaction between 2-acetyl-5-bromothiophene (14) and phenylboronic acid (5) in water using KOH as a base and TBAB under thermal conditions at 100 °C (one hour) as well as under microwave irradiation (two min) and the results is outlined in Table 5. At first, the reaction was conducted using 1 mol% of the Pd-complexes 1–4 with a molar ratio of 2- acetyl-5-bromothiophene (14)/phenylboronic acid (5)/TBAB/KOH: 1/1.2/0.6/2, to give in all cases full conversion into 2-acetyl-5-phenylthiophene (15). In the second experiment, 0.5 mol% of the precatalysts 1–4 was used to give also, in all cases, full conversion after 1 h heating at 100 °C. The reaction was again repeated with different concentrations (mol%) of 1–4 and the yield % are depicted in Table 5. From the obtained results it was clear that the free-oxime containing Pd-complexes 2 and 4 are more active than their benzylated analogs 1 and 3 when their concentrations were less than 0.25 mol% as shown in Table 5.

3.3 Suzuki coupling of 2-bromothiophene with arylboronic acids using complex 2 under thermal heating as well as microwave irradiation

The highly active Pd(II)-precatalyst 2 was next applied in the Suzuki coupling between 2-bromothiophene (12) and several arylboronic acids 5 and 16–20 under different heating modes; thermal heating as well as microwave irradiation conditions. The Suzuki–Miyaura reaction of 2-bromothiophene (12) with the arylboronic acids 5 and 16–20 was performed using the catalytic system: water/KOH/TBAB in the presence of 0.25 mol% of the precatalyst 2. As shown in Table 6, run 2, when the coupling reaction of 4-chlorophenylboronic acid (16) with 2-bromothiophene (12) was conducted using 0.25 mol% of the precatalyst 2 in water/KOH/TBAB under thermal heating at 100 °C for 1 h, full conversion was achieved and afforded 2-(4-chlorophenyl)thiophene (21) in 91% isolated yield. Conducting the same reaction above under microwave irradiation condition for 2 min at 160 °C (250 W), using 0.25 mol% of the precatalyst 2 in water/KOH/TBAB, resulted in full conversion into 2-(4-chlorophenyl)thiophene (21) which was isolated in 95% yield as shown in Table 6, run 2. Similarly, cross-coupling of 2-bromothiophene (12) with 4-methoxyphenylboronic acid (17), 4-methylphenylboronic acid (18), 2-thienylboronic acid (19) and 3,4-methylenedioxy-phenylboronic acid (20), was conducted using 0.25 mol% of Pd-precatalyst 2 in water/KOH/TBAB under thermal heating as well as microwave irradiation conditions, where the corresponding 2-aryl(heteroaryl)thiophenes 22–25 were obtained in excellent yields as outlined in Table 6, entries 3–6. The obtained results reflect the high activity of the precatalyst 2 toward the less reactive 2-bromothiophene (12) compared to the aryl bromide 6.