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DOI: 10.1055/s-2006-939050
Synthesis of Trisubstituted Pyrimidines by Regioselective SNAr and Suzuki Reactions of Polyhalopyrimidines
Publication History
Publication Date:
14 March 2006 (online)
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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
- 1
Metal-Catalysed Cross-Coupling Reactions
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References and Notes
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%.
14Preparation 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+].