Rapid and Efficient Synthesis of Functionalized Bipyridines

Abstract

The Negishi reaction affords a mild and efficient method to convert chloro- and bromo-pyridines into functionalized 2,2′-bipyridines using commercially available starting materials. This method also extends to the conversion of dibromopyridines to 5- and 6-bromobipyridines, which are powerful synthons for incorporation into larger supramolecular systems.

Key words

palladium - catalysis - organometallic reagents - cross-coupling - bipyridines

References

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General Procedure: A flame-dried Schlenk tube was charged with Pd(PPh₃)₄ and 2-halopyridine under argon. 2-Pyridylzinc bromide (THF solution) was then added by syringe. The mixture was stirred at r.t. for several hours, and was poured into an aq EDTA/Na₂CO₃ solution. After the precipitate had dissolved, the mixture was extracted with Et₂O (3 ¥ 50 mL), and dried over Na₂SO₄. The solvent was evaporated and the residue was chromatographed on an alumina column (neutral, Brockmann I) with 10:1 hexane:EtOAc.

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Compound 3c: 1: 4.5 mmol; 2c: 2.91 mmol; Pd(PPh₃)₄: 0.06 mmol. Chromatographed with 10:1 hexane:EtOAc as eluent to yield a colorless liquid. ¹H NMR (300 MHz, CDCl₃): δ = 8.64 (d, J = 4.8 Hz, 1 H, H_{6 ′}), 8.49 (d, J = 4.4 Hz, 1 H, H₆), 7.80-7.73 (m, 2 H, H_{3 ′ ,4 ′}), 7.56 (d, J = 7.7 Hz, 1 H, H ₄), 7.27-2.22 (m, 1 H, H_{5 ′}), 7.18 (d, J = 7.8, 4.7 Hz, 1 H, H_{5 ′}), 2.46 (s, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 159.0, 156.4, 148.6, 146.8, 139.2, 136.6, 132.3, 124.2, 123.1, 122.7, 20.0. FAB/NBA: 171.1 [MH⁺]. Compounds 3d-f: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported. [30]

21

Pd₂(dba)₃ and P(o-tolyl)₃ or P(2-furyl)₃ were tested as catalysts giving conversions of less than 20% with the same reaction conditions. Although recent results showed that Pd[P(t-Bu)₃]₂ is a powerful catalyst for coupling a broad range of aryl chlorides and organozinc halides, [22] the cost and the availability of the catalyst are a concern.

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Compound 3g: 4.3 mmol scale with 3 mol% Pd(PPh₃)₄, chromatographed with a hexane:EtOAc solvent gradient (10:1 to 3:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.80 (d, J = 4.9 Hz, 1 H), 8.68 (br, 2 H), 8.40 (d, J = 7.9 Hz, 1 H), 7.83 (td, J ^t = 7.7 Hz, J ^d = 1.5 Hz, 1 H), 7.49 (dd, J = 4.9, 1.2 Hz, 1 H), 7.35 (dd, J = 7.3, 4.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.6, 154.1, 150.1, 149.5, 137.3, 124.9, 124.8, 123.0, 121.4. 121.3, 116.8. Compound 3h: 1.0 mmol scale with 3 mol% Pd(PPh₃)₄. Extracted with CH₂Cl₂ and chromatographed with a hexane:EtOAc solvent gradient (10:1 to 3:1 to 1:1). Mp: 174-175 °C (EtOH). ¹H NMR (300 MHz, CDCl₃): δ = 9.42 (s, 1 H), 9.08 (s, 2 H), 8.84 (d, J = 5.0 Hz, 1 H), 8.75 (d, J = 4.6 Hz, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.33 (d, J = 4.1 Hz, 1 H), 7.83 (t, J = 7.7 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 2 H, Ph), 7.56-7.45 (m, 3 H, Ph), 7.32 (dd, J = 7.4, 4.8 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 161.7, 157.2, 156.1, 155.4, 150.1, 149.5, 145.7, 137.0, 134.2, 133.2, 129.6, 129.2, 127.0, 123.9, 121.9, 121.2, 119.7. FAB/NBA: 311.1 [MH⁺]. Compound 3i: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 13:1 hexane:EtOAc. NMR spectra are identical to those previously reported.²⁴

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Compound 5: 3.0 mmol scale with 2 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported.⁶

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Compound 8: 2.0 mmol scale with 3 mol% Pd(PPh₃)₄, chromatographed with 10:1 hexane:EtOAc. NMR spectra are identical to those previously reported.²⁸