Iron-Catalyzed Direct Arylation of Aryl Pyridines and Imines Using Oxygen as an Oxidant

Abstract

An iron-catalyzed ortho C-H bond arylation reaction of an aryl pyridine or imine with an arylzinc reagent, which previously required the use of a rather expensive organodichloride as an oxidant, can now be achieved under oxygen atmosphere. By slowly introducing oxygen into the reaction, oxidative cross-coupling of the two reactants took place smoothly to give a biaryl product in moderate to good yield.

Key words

iron - C-H bond activation - cross-coupling - biaryls

References and Notes

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1

Present address: N. Yoshikai, Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.

10

The reaction needs 1 equiv of the zinc reagent for removal of the ortho hydrogen atom, 1 equiv for arylation, and small amount for generation of the active catalyst.^9a

12

The yields of biphenyl and phenol were typically in the range of 50-150% and 120-180%, respectively (based on the substrate).

16

A Typical Procedure for Arylation of 2-Arylpyridine An oven-dried Schlenk tube was charged with ZnCl₂˙TMEDA (505 mg, 2.0 mmol), 2,2′-bipyridine (9.3 mg, 60 µmol), and 2-arylpyridine (0.40 mmol) and cooled in an ice bath, followed by addition of a THF solution of PhMgBr (1.0 M, 4.0 mL, 4.0 mmol). After stirring for 1 h, a THF solution of FeCl₃ (0.10 M, 0.60 mL, 60 µmol) was added to the mixture. Then oxygen gas (10 mL, 0.45 mmol) was allowed to diffuse into the reaction by attaching a gastight syringe fitted with a 20G needle (38 mm). The reaction mixture was stirred for 36 h with gradual warming to r.t., while every 12 h the gastight syringe was filled with fresh O₂ gas. The reaction was quenched by the addition of sat. aq solution of Rochelle salt and extracted with EtOAc (3 × 5 mL). The organic solution was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford the arylation product.
A Typical Procedure for Arylation of Aryl Imine The reaction was carried out by the same procedure as above except for the use of 4,4′-di-tert-butyl-2,2′-bipyridine (16.1 mg, 60 µmol) instead of 2,2′-bipyridine. The reaction was quenched by the addition of 3 M HCl aq (5 mL), and the resulting mixture was stirred for 3 h at r.t. Further workup and purification was carried out in a similar manner as above to obtain the biaryl ketone product.
2-(4,5-Dimethoxybiphenyl-2-yl)pyridine (2f)
Mp 97.4-98.2 ˚C. IR (powder): 3062, 3035, 3008, 2964, 2933, 2838, 1688, 1598, 1580, 1520, 1478, 1453, 1441, 1385, 1351, 1320, 1273, 1260, 1243, 1179, 1113, 1081, 1038, 1011, 973, 924, 888, 818, 791, 770, 743, 702 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 8.54 (d, J = 5.8 Hz, 1 H), 7.24-7.21 (m, 2 H), 7.15-7.12 (m, 3 H), 7.09-7.07 (m, 2 H), 6.98-6.95 (m, 1 H), 6.82 (s, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 3.85 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 158.7, 149.2, 148.8, 148.3, 141.2, 135.0, 133.3, 131.8, 129.7 (2 C), 128.0 (2 C), 126.5, 125.5, 120.9, 113.3, 113.1, 55.9, 55.8. HRMS (APCI): m/z calcd for C₁₉H₁₈NO₂ ⁺ [M + H]⁺: 292.13375; found: 292.13331.
2-(5,6-Dimethoxybiphenyl-2-yl)pyridine (2g)
Mp 102.0-103.2 ˚C. IR (powder): 3058, 3000, 2962, 2931, 2834, 1582, 1563, 1519, 1485, 1428, 1407, 1279, 1256, 1219, 1162, 1117, 1108, 1009, 797, 776, 747, 718, 700, 685 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 8.56 (d, J = 5.2 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 1 H), 7.30-7.21 (m, 4 H), 7.18-7.16 (m, 2 H), 7.05 (d, J = 8.6 Hz, 1 H), 7.02-6.95 (m, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3 H), 3.50 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 158.6, 153.1, 149.1, 146.4, 136.5, 135.3, 134,9, 133.6, 130.8 (2 C), 127.6 (2 C), 126.7, 126.0, 125.2, 120.8, 111,6, 60.4, 55.9. HRMS (APCI): m/z calcd for C₁₉H₁₈NO₂ ⁺ [M + H]⁺: 292.13375; found: 292.13395.
1-(4′-Fluorobiphenyl-2-yl)ethanone (2l)
IR (neat): 3062, 3043, 3025, 3002, 2971, 1684, 1607, 1598, 1513, 1474, 1443, 1355, 1287, 1268, 1221, 1160, 1117, 1096, 1077, 1042, 1017, 1007, 955, 837, 820, 802, 750, 720, 671 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.56-7.54 (m, 1 H), 7.52-7.49 (m, 1 H), 7.43-7.40 (m, 1 H), 7.36-7.34 (m, 1 H), 7.32-7.29 (m, 2 H), 7.14-7.09 (m, 2 H), 2.05 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 204.4, 162.6 (d, ^¹ J _C-F = 246.8 Hz), 140.7, 139.3, 136.7 (d, ⁴ J _C-F = 3.6 Hz), 130.7, 130.4 (d, ^³ J _C-F = 8.4 Hz, 2 C), 130.3, 127.9, 127.5, 115.6 (d, ^² J _C-F = 21.5 Hz, 2 C), 30.3. HRMS (APCI): m/z calcd for C₁₄H₁₂FO⁺ [M + H]⁺: 215.0872; found: 215.0875.