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

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.

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.

<A NAME="RG14309ST-14">14</A>

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: [e-mail].).

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