Solid-Phase Synthesis of 2-Aminotetrahydropyrimidines

References and Notes

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• Typical procedure for the preparation of tetrahydropyrimidines 6. A solution of 100 mg of phenyl isothiocyanate (0.74 mmol) in 3mL of THF and 100 mg of resin 2 5b (0.074 mmol) was shaken for 0.5h. P(Ph)3 (194 mg, 0.74 mmol, 10-fold excess) was then added to the mixture, and shaking continued for another 2 hrs. The resulting resin was filtered, washed with THF and dichloromethane alternatively, dried, and treated with a solution of diethylamine (54 mg, 0.74 mmol, 10-fold excess) in 4 ml of N-methyl pyrrolidine. The mixture was shaken for 1–2 hrs. The reaction course was monitored on bead by the disappearance of the carbodiimide absorption at 2137 cm-1. The resin was filtered, washed with THF and dichloromethane alternatively, and dried. 5 ml of 95% TFA/H2O was added to the resin and the mixture shaken for one hour. The resin was filtered and washed with dichloromethane. The combined filtrate was evaporated and dried. 15 mg of product 6a was obtained (84% yield based on resin substitution). 1H NMR (CDCl3)δ 0.95 (t, 6H), 3.1 (m, 2H), 3.2 (m, 2H), 3.4 (m, 1H), 3.6 (m, 1H), 3.7 (m, 1H), 3.9 (m, 1H), 4.5 (m, 1H), 7.0 to 7.5 (m, 5H). MS (FAB) m/z 248.2 (MH+). Compound 7: Yield 98% (based on resin substitution). 1H NMR (CDCl3)δ 2.1 (m, 2H), 2.4 (m, 1H), 2.6 (m, 1H), 2.6 (m, 2H), 3.0 (m, 3H), 3.6 (m, 2H), 7.0 to 7.5 (m, 5H). MS (ESI) m/z 232 (MH+). The 96-member THP library was prepared using a similar procedure.
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• aaYields are based on the resin loading, obtained by elemental analysis for Nitrogen on 2 (FIG-1).
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• bPurity of the products were based on the the % area of the peak at dual wavelength in the HPLC (Shimadzu PDA, YMC-pack, Pro C18, 50 × 4.6 mm column, gradient 0% to 100% CH3CN:H2O over 7 min, monitored at 254 and 280 nm).
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• 2-Fluorophenyl isothiocyanate formed the carbodiimide intermediate but did not undergo amine addition. 3-trifluoromethyl isothiocyanate did not form the intermediate carbodiimide. t-Butylamine and 1-adamantylamine did not give satisfactory results.
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• Parallel Synthesis of 96 member THP Library, Y=Molecular ion of the expected product observed. N=Molecular ion of the expected product not observed. The above matrix represents the library format and the analysis of the cleaved products by MS (PE SCIEX API 50, flow injection).
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