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Synlett 2009(13): 2137-2142  
DOI: 10.1055/s-0029-1217699
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Efficient Palladium-Catalyzed Aminations of Pyrimidines, 1,2,4-Triazines and Tetrazines by Original Methyl Sulfur Release

Laurent Pellegattia, Emeline Vedrennea, Jean-Michel Legerb, Christian Jarryb, Sylvain Routier*a
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005,Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
b EA 4138, Pharmacochimie, Université Victor Segalen Bordeaux II, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France
Fax: +33(234)17281; e-Mail: sylvain.routier@univ-orleans.fr;
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Publication History

Received 27 April 2009
Publication Date:
16 July 2009 (online)

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Abstract

The efficient and original palladium-catalyzed amination of pyrimidines, 1,2,4-triazines and tetrazines is reported. Starting from triazine 1, a Buchwald-Hartwig-type reaction leads to the formation of heterocycle 2 via methyl sulfur release. This reaction was generalized to the use of a wide range of amines in good to excellent yields.

Key words

aminations - cross-coupling - palladium - copper - sulfur

    References and Notes

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General Procedure for the Heterocyclic Amination: In a sealed microwave vial were successively added the SMe derivative, the amine (1.2 equiv), copper(I) methylsalicylate (2.0 equiv), Cs2CO3 (2.2 equiv), Pd(OAc)2 (10 mol%) and xantphos (20 mol%). Anhydrous toluene was added and the suspension was subjected to MW irradiation at 170 ˚C for 2 h. The reaction mixture was cooled to r.t. and the solvent was removed under reduced pressure. The crude material was immediately purified by chromatography on silica gel (CH2Cl2) to afford the attempted compound. Compound 2: R f 0.65 (CH2Cl2-MeOH, 95:5); mp 164-165 ˚C (CH2Cl2). IR (ATR diamond): 3196, 2961, 1595, 1574, 1507, 1447, 1323, 1291, 1107, 1025, 890, 810 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 3.82 (s, 3 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.54 (d, J = 9.0 Hz, 2 H), 7.78 (br s, 1 H), 8.22 (d, J = 2.3 Hz, 1 H), 8.68 (d, J = 2.3 Hz, 1 H). ¹³C NMR (62.5 MHz, CDCl3): δ = 55.5 (Me), 114.3 (2 × CH), 122.5 (2 × CH), 130.9 (Cq), 141.8 (CH), 149.1 (CH), 156.3 (Cq), 160.9 (Cq). HRMS (EI-MS): m/z [M + H+] calcd for C10H11N4O: 203.0933; found: 203.0946.

14

Crystallographic Study: The structure of compound 2 has been established by X-ray crystallography (Figure  [¹] ). Colorless single crystals of 2 were obtained by slow evaporation from a methanol-chloroform (20:80) solution. The unit cell dimensions were determined using the least-squares fit from 25 reflections (25˚ < θ < 35˚): a = 5.628 (1) Å, b = 8.211 (5) Å, c = 10.741 (2) Å, α = 101.05 (3)˚, β = 84.27 (1)˚, γ = 91.47 (3)˚. Space group: P-1, Z = 2, µ(Cu, Kα) = 0.783 mm-¹. 1740 unique reflections were measured; final R = 4.27% (all data). Intensities were collected with
an Enraf-Nonius CAD-4 diffractometer using the CuKα radiation and a graphite monochromator up to θ = 68.91˚. The data were corrected for Lorentz and polarization effects and for empirical absorption correction.¹5 The structure was solved by direct methods Shelx 86 and refined using Shelx 97 suite of programs.¹6,¹7 An intermolecular hydrogen bond partially contributed to the crystal cohesion. Indeed, the linker N7 (I) acts as a donor to the N1 (II) of the triazine moiety. The distance between N7 (I) and N1 (II), and the N7-H7 (I)˙˙˙N1 (II) angle were found to be 2.978 (2) Å and 168.55˚, respectively. Symmetry code of intermolecular hydrogen bond is: I (x, y, z); II (1-x, 1-y, 1-z).
CCDC 726564 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.uk/conts/retrieving.html (or from Cambridge Crystallographic Data Centre, University Chemical Lab, 12 Union Road, Cambridge,CB2 1EZ, U.K.; E-mail: deposit@ccdc.cam.ac.uk.).