Synthesis of Trisubstituted Pyrimidines by Regioselective S_NAr and Suzuki Reactions of Polyhalopyrimidines

Abstract

An efficient, regioselective approach to the synthesis of trisubstituted pyrimidines was developed. Sequential functionalisation of commercially available polyhalopyrimidines provided the target compounds in moderate to good overall yields.

Key words

regioselectivity - palladium - pyrimidine - Suzuki - cross-coupling

References and Notes

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12

Analysis of the crude reaction mixture revealed that approximately 37% of the debrominated product was present. For all other coupling reactions of compound 5, the same side-product was generated in quantities of less than 13%.

14

Preparation of 6. To a solution of 5-bromo-2-chloro-4-(piperidin-1-yl)pyr-imidine (5, 500 mg, 1.8 mmol) and phenylboronic acid (236 mg, 1.94 mmol) in DME (15 mL) was added PdCl₂(dppf) (66 mg, 0.08 mmol, 4.4 mol%). Then, 1 M Na₂CO₃ solution (3.75 mL, 3.75 mmol) was added, and the mixture heated at 85 °C for 18 h under an atmosphere of nitrogen. The solution was then cooled, and filtered through a plug of silica, washing with 10% MeOH-CH₂Cl₂. The filtrate was dried (MgSO₄), concentrated in vacuo and purified by flash column chromatography to yield the desired product (331 mg, 75%); R _f = 0.13 (hexane-EtOAc, 19:1). ¹H NMR (250 MHz, CDCl₃): δ = 1.33-1.44 (4 H, m), 1.45-1.56 (2 H, m), 3.17-3.26 (4 H, m), 7.23-7.40 (5 H, m), 7.85 (1 H, s). ¹³C NMR (62.9 MHz, CDCl₃): δ = 24.1, 25.3, 48.3, 119.1, 127.5, 127.9, 129.1, 137.1, 158.6, 159.0, 162.8. LCMS: t _R = 7.49 min. MS (ESI) for C₁₅H₁₆Cl₁N₃: m/z = 274 [MH⁺].

16

Preparation of 15.
To a solution of 2,5-dichloro-4-(pyrimidin-1-yl)pyrimidine (4, 100 mg, 0.43 mmol) and 4-methoxyphenylboronic acid (74 mg, 0.607 mmol) in DME (3.6 mL) was added Pd(PPh₃)₄ (25 mg, 0.022 mmol, 5.0 mol%). Then, 1 M Na₂CO₃ solution (0.9 mL, 0.9 mmol) was then added, and the mixture heated at 85 °C for 4 h. The solution was then cooled to r.t., filtered through a plug of silica, washing with 10% MeOH-CH₂Cl₂. The solution was concentrated and then purified by flash column chromatography to yield the desired product (79 mg, 67%). R _f = 0.25 (hexane-EtOAc, 19:1). ¹H NMR (250 MHz, CDCl₃): δ = 1.60-1.70 (6 H, m), 3.62-3.70 (4 H, m), 3.80 (3 H, s), 6.88 (2 H, d, J = 9.0 Hz), 8.20 (1 H, s), 8.23 (2 H, d, J = 9.0 Hz). ¹³C NMR (62.9 MHz, CDCl₃): δ = 24.6, 25.9, 48.5, 55.4, 113.7, 114.3, 129.7, 130.0, 156.6, 160.0, 161.0, 161.6. LCMS: t _R = 8.27 min. MS (ESI) for C₁₆H₁₈Cl₁N₃O₁: m/z = 303 [M⁺].