Directed Palladium-Catalyzed Oxidative C-H Arylation of (Hetero)arenes with Arylboronic Acids by Using TEMPO

Abstract

Oxidative coupling of three different arenes and a thiophene derivative with various arylboronic acids with Pd(OAc)₂ and the commercially available 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an oxidant are reported. A 2-pyridyl group on the substrates serves as ortho-directing group to mediate the C-H arylation. Mechanistic studies are provided.

biaryls - boronic acids - C-H arylation - nitroxides - palladium

References and Notes

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14

Shi and Yu used Cu(II) salts as stoichiometric oxidants, see refs. 10 and 11.

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16

General Experimental Procedure
The corresponding boronic acid (1.00 mmol), TEMPO (156 mg, 1.00 mmol), KF (58 mg, 1.0 mmol), Pd(OAc)₂ (5.6 mg, 25 µmol), the pyridine derivative (0.25 mmol), and AcOH (1 mL) were stirred in a sealed tube at 50 ˚C for 24 h or 72 h, respectively. Water (3 mL) and brine (1 mL) were added and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried over MgSO₄ and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography.

17a Lafrance M. Fagnou K. J. Am. Chem. Soc.  2006,  128:  16496 

17b Garcia-Cuadrado D. de Mendoza P. Braga AAC. Maseras F. Echavarren AM. J. Am. Chem. Soc.  2007,  129:  6880 

18 Gómez M. Granell J. Martinez M. J. Chem. Soc., Dalton Trans.  1998,  37 

19

Determination of the Kinetic Isotope Effects
According to the general experimental procedure with 2-(2-deuterophenyl)pyridine (D-1, 39 mg, 0.25 mmol) and phenylboronic acid (122 mg, 1.00 mmol) for 72 h. Flash chromatography (pentane-EtOAc, 20:1 → 10:1) gave a mixture of 2a and D-2a as a yellow oil (17 mg, 65%). The isotope effect was determined by integration of the ESI-HRMS data in consideration of the isotope pattern of 2a. The deuterated species D-2a and compound 2a were obtained in a ratio of 4.5:1. According to GP 1 with 2-ethoxy-2-phenylpyridine (6, 10 mg, 50 µmol), 2-(2-ethoxy-6-deuterophenyl)pyridine (D-6, 10 mg, 50 µmol) and phenylboronic acid (24 mg, 0.2 mmol) for 4 h. The ratios of D-6 to 6 (0.87:1) were determined before the reaction (0 h) and after a reaction time of 4 h (1.05:1) by integration of the corresponding ESI-HRMS data in consideration of the isotope pattern of 6. The kinetic isotope effect was calculated to be 1.21.

20

As a side product the doubly arylated product is always formed (<15% with respect to the monoarylated compound). We assume that the primary kinetic isotope effect for the second arylation and the first arylation should be similar. Therefore, the measured value of 4.5 is slightly too high since 2a is consumed faster than D-2a. However, the error should be smaller than 12%. Hence the primary kinetic isotope effect for the first arylation is about 4.0-4.5 to 1.

21

2-(2,6-Dideuterophenyl)pyridine (D ₂ -1) and 2-(2,6-Dibromophenyl)pyridine
2-(2-Bromophenyl)pyridine^²² (466 mg, 2.0 mmol), Cu(OAc)₂ (363 mg, 2.0 mmol), and 1,1,2,2-tetra-bromo-ethane were heated in a sealed reaction tube at 130 ˚C for 24 h.^²³ Dichloromethane (10 mL) and Na₂S (aq sat., 10 mL) were added. The mixture was filtered over Celite and the filtrate was washed with brine (2 × 10 mL). The combined organic layers were dried over MgSO₄ and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (pentane-MTBE, 20:1).
2-(2-Bromo-6-deuterophenyl)pyridine
To a solution of 2-(2,6-dibromophenyl)pyridine (313 mg, 1.0 mmol) in THF (20 mL) at -78 ˚C was added dropwise
n-BuLi (1.68 M solution in hexanes, 0.60 mL, 1.00 mmol).^²³ The mixture was stirred for 30 min. Then, D₂O (2.0 mL) was added and stirring was continued for additional 30 min. The mixture was allowed to warm to r.t., and EtOAc (10 mL) and brine (20 mL) were added. The mixture was extracted with EtOAc (3 × 20 mL), dried over MgSO₄, and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (pentane-MTBE, 50:1) and the product was obtained as a yellow oil (0.181 g, 0.68 mmol, 77%). The product was used without any further characterization.
2-(2,6-Dideuterophenyl)pyridine (D ₂ -1)
To a solution of 2-(2-bromo-6-deuterophenyl)pyridine (160 mg, 0.68 mmol) in THF (10 mL) at -78 ˚C was added dropwise n-BuLi (1.68 M solution in hexanes, 0.4 mL, 0.68 mmol).^²³ The mixture was stirred for 30 min. Then, D₂O (1.0 mL) was added and stirring was continued for additional 30 min. The mixture was allowed to warm to r.t., and EtOAc
(5 mL) and brine (10 mL) were added. The mixture was extracted with EtOAc (3 × 10 mL), dried over MgSO₄, and the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (pentane-MTBE, 50:1) and the product was obtained as a colorless oil (0.104 g, 0.66 mmol, 97%, 88 atom% D). ^¹H NMR (300 MHz, CDCl₃): δ = 8.68 (d, J = 4.78 Hz, 1 H, aryl-H), 7.69 (d, J = 3.52 Hz, 2 H, aryl-H), 7.42 (m, 3 H, aryl-H), 7.19 (m, 1 H, aryl-H). ^¹³C NMR (75 MHz, CDCl₃): δ = 157.4 (C), 149.7 (C-H), 139.3 (C), 136.7 (CH), 129.0 (CH), 128.7 (CH), 126.6 (J = 23 Hz, CD), 122.1 (CH), 120.5 (CH). ESI-HRMS: m/z calcd for C₁₁H₇D₂N [M + H]⁺: 157.0933; found: 157.0939.
2-(2-Ethoxy-6-deuterophenyl)pyridine (D-6)
2-(2-Ethoxyphenyl)pyridine (6, 93 mg, 0.47 mmol), NBS (0.10 g, 0.56 mmol) and Pd(OAc)₂ (5.4 mg, 24 mol) in MeCN (10 mL) were heated in a reaction tube at 120 ˚C for 10 h.^²² The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (pentane-MTBE, 10:1). Crude 2-(2-bromo-6-ethoxy-phenyl)pyridine was obtained as a pale yellow oil (96 mg) and used for the next reaction without any further characterization. To a solution of crude 2-(2-bromo-6-ethoxyphenyl)pyridine (86 mg, 0.31 mmol) in THF (10 mL) at -78 ˚C was added dropwise n-BuLi (1.3 M solution in hexanes, 0.48 mL, 0.62 mmol).^²³ The mixture was allowed to warm to -40 ˚C and stirred for 30 min. Then, D₂O (0.5 mL) was added and stirring was continued for additional 30 min. The mixture was allowed to warm to r.t., and EtOAc (5 mL) was added. The organic layer was washed with brine, dried over MgSO₄, and the volatiles were removed under reduced pressure. The crude product was purified by flash chromatography (pentane-MTBE, 20:1) and D-6 was obtained as a pale yellow oil (43 mg, 46% over two steps, 94 atom% D determined via ESI-MS). IR (neat): 3036, 2980, 2933, 2881, 2363, 2341, 1578, 1474, 1452, 1421, 1391, 1285, 1250, 1190, 1138, 1111, 1088, 1040, 1026, 990, 924, 874, 812, 795, 746, 733, 679, 611, 552 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.68 (m, 1 H, aryl-H), 7.88 (m, 1 H, aryl-H), 7.66 (m, 1 H, aryl-H), 7.32 (m, 1 H, aryl-H), 7.16 (m,
1 H, aryl-H), 7.05 (m, 1 H, aryl-H), 6.96 (m, 1 H, aryl-H), 4.07 (q, J = 6.9 Hz, 2 H, CH₂), 1.36 (t, J = 6.9 Hz, 2 H, CH₃). ^¹³C NMR (600 MHz, CDCl₃): δ = 156.3 (C), 156.0 (C), 149.3 (CH), 135.4 (CH), 130.8 (C), 129.7 (CH), 129.0 (C), 125.1 (CH), 121.5 (CH), 120.9 (CH), 112.5 (CH), 64.1 (CH₂), 14.8 (CH₃). ^¹H{^¹H} 1D-TOCSY (600 MHz, CDCl₃): δ(^¹H)_irr/δ(^¹H)_res = 6.96/7.32, 7.05; 8.68/7.88, 7.66, 7.16. ^¹H,^¹H GCOSY (600 MHz, CDCl₃): δ(^¹H)/δ(^¹H) = 8.86/7.16; 7.88/7.66; 7.66/7.88, 7.16; 7.32/7.05, 6.96; 7.16/8.68, 7.66; 7.05/7.32; 6.96/7.32. ^¹H,^¹³C GHSQC (600 MHz, CDCl₃): δ(^¹H)/δ(^¹³C) = 149.3/8.68; 135.4/7.66; 129.7/7.32; 125.1/7.88; 121.5/7.16; 120.9/7.05; 112.5/6.96; 64.1/4.07; 14.8/1.36. ^¹H,^¹³C GHMBC (600 MHz, CDCl₃): δ(^¹H)/δ(^¹³C) =
 156.3/7.80, 7.32, 7.05, 6.96, 4.07; 156.0/7.868, 7.88, 7.66; 149.3/7.66, 7.16; 135.4/8.68, 7.88, 7.80, 7.52; 129.7/7.05; 129.0/7.88, 7.32, 7.05, 6.96; 125.1/8.68, 7.66, 7.16; 121.5/8.68, 7.88, 7.66; 120.9/6.96; 112.5/7.32, 7.05; 64.1/1.35; 14.8/4.05. ESI-HRMS: m/z calcd for C₁₃H₁₂DNO [M + H]⁺: 201.1133; found: 201.1129.

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23 Chen X. Hao X.-S. Goodhue CE. Yu J.-Q. J. Am. Chem. Soc.  2006,  128:  6790