43 R1 44
Scheme 12. Synthesis of 5,6-dihydropyrimidine-2,4-diones.
A suspension ofWang resin (0.5 g( 0.88 mmol/g) in 4 mL of dry CH2CI2 was treated twice with triethylamine (200 (xL) followed by acryloyl chloride (100 nL) and allowed to stir for 2 h at rt. After filtration, the resin 41 was washed three times each with the following solvents: CH2CI2, methanol, DMF, methanol, DMSO. The resin 41 was treated with DMSO (2 mL) and benzylamine (0.28 g, 2.6 mmol) and allowed to stir for 24 h.The resin 42 (R1 = Bn) was washed three times each with DMSO, methanol, CH2CI2 and dried.The resin 42 (0.42 g, 0.31 mmol) was suspended in CH2CI2 (3 mL) and reacted with phenyl iso-cyanate(0.1 g,0.8 mmol) at room temperature for 4 h and washed three times each with CH2CI2, methanol, CH2CI2 and diethylether to afford 43. This resin was placed in a glass vial with 4 mL of a saturated solution of HCI in toluene, capped and heated to 95° C for 4 h.The resin was filtered and washed three times with methanol and CH2CI2.The combined filtrates were concentrated, the crude product was purified by silica gel chromatography (diethylether/CH2CI2,1:1) to afford 39.7 mg (46 %) of 44 (R1 = Bn, R2 = Ph).
The synthesis of this scaffold requires a set of diverse anthranilic acids 46 of which only a few are available commercially. A variety of these was prepared by nucleophilic substitution of 2-
chlorobenzoic acid 45 with a range of primary amines (alkyl, benzyl, phenyl). These an-thranilic acids 46 were bound to a polystyrene/ triethyleneglycol chloroformate resin via the amine group (47). Amidation of the carboxylic acid function gave 48 and reaction at 125° C in DMF gave the cyclized product 49 (Scheme 13) .
Was this article helpful?