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.

regioselectivity - palladium - pyrimidine - Suzuki - cross-coupling

References and Notes

1 Metal-Catalysed Cross-Coupling Reactions   2nd ed., Vol. 1 and 2:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 

2a Collins I. J. Chem. Soc., Perkin Trans. 1  2002,  1921 

2b Collins I. J. Chem. Soc., Perkin Trans. 1  2000,  2845 

For selected recent examples, see:

3a Witulski B. Azcon JR. Alayrac C. Arnautu A. Collot V. Rault S. Synthesis  2005,  771 

3b Bourrain S. Ridgill M. Collins I. Synlett  2004,  795 

3c Gudmundsson KS. Johns BA. Org. Lett.  2003,  5:  1369 

3d Johns BA. Gudmundsson KS. Turner EM. Allen SH. Jung DK. Sexton CJ. Boyd FL. Peel MR. Tetrahedron  2003,  59:  9001 

4 For an excellent recent review, see: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 

For selected recent examples, see:

5a Schröter S. Bach T. Synlett  2005,  1957 

5b Wu J. Zhang L. Sun X. Chem. Lett.  2005,  34:  550 

5c Comins DL. Nolan JM. Bori ID. Tetrahedron Lett.  2005,  46:  6697 

5d Bookser BC. Matelich MC. Ollis K. Ugarkar BG. J. Med. Chem.  2005,  48:  3389 

6 Solberg J. Undheim K. Acta Chem. Scand.  1989,  43:  62 

7 Simkovsky NM. Ermann M. Roberts SM. Parry DM. Baxter AD. J. Chem. Soc., Perkin Trans. 1  2002,  1847 

8 Schomaker JM. Delia TJ. J. Org. Chem.  2001,  66:  7125 

9 Hughes G. Wang C. Batsanov AS. Fern M. Frank S. Bryce MR. Perepichka IF. Monkman AP. Lyons BP. Org. Biomol. Chem.  2003,  3069 

10 Strekowski L. Dworniczak M. Kowalewski A. Pol. J. Chem.  1980,  54:  1557 

11a Bedford RB. Cazin CSJ. Chem. Commun.  2001,  1540 

11b Bedford RB. Cazin CSJ. Coles SJ. Gelbrich T. Horton PN. Hursthouse MB. Light ME. Organometallics  2003,  22:  987 

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%.

13 The effective use of this catalyst in the coupling of electron-deficient heteroaryl halides has been reported. See: Ali NM. McKillop A. Mitchell MB. Rebelo RA. Wallbank PJ. Tetrahedron  1992,  48:  8117 

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⁺].

15a Wei H. Sudini R. Yin H. Org. Process Res. Dev.  2004,  8:  955 

15b Ishikura M. Kamada M. Terashima M. Heterocycles  1984,  22:  265 

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⁺].

17 Stambuli JP. Kuwano R. Hartwig JF. Angew. Chem. Int. Ed.  2002,  41:  4746 

18 Littke AF. Schwarz L. Fu GC. J. Am. Chem. Soc.  2002,  124:  6343