One or Two-Step Bohlmann-Rahtz Heteroannulation of 6-Aminouracil Derivatives for the Synthesis of Pyrido[2,3-d]pyrimidines

Abstract

The Michael addition-cyclodehydration of a 6-aminouracil and alkynone proceeds to give 5-deazapterin derivatives with total control of regiochemistry. This simple and facile cyclocondensation process is catalyzed by zinc(II) bromide or ytterbium(III) trifluoromethanesulfonate at 110 °C, providing the heteroannulated products in up to 94% yield.

Key words

pyridopyrimidines - uracil derivatives - Bohlmann-Rahtz heteroannulation - heterocycles - Lewis acids

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17

In a typical experimental procedure, 4-(trimethylsilyl)but-3-yn-2-one 4a (0.34 g, 2.4 mmol) was added to a stirred solution of 6-aminouracil 3a (0.31 g, 2.4 mmol) and zinc(II) bromide (55 mg, 0.24 mmol) in DMSO (5 mL). The mixture was stirred at 110 °C for 72 hours, allowed to cool and water (30 mL) was added. The precipitated solid was washed with water and dried to give 6a (0.26 g, 60%) as a pale yellow solid, mp >260 °C (decomp.) (Found: C, 54.66; H, 4.27; N, 23.56. Calc. for C₈H₇N₃O₂: C, 54.24; H, 3.98; N, 23.72%) (Found MH⁺, 178.0619. C₈H₇N₃O₂ requires 178.0616); IR(nujol)/cm^-1: 3310, 3120, 1705, 1695; ¹H NMR (d ₆ -DMSO, 400 MHz) δ(ppm) 11.41 (1 H, s, NH), 11.12 (1 H, s, NH), 7.96 (1 H, d, J = 7.9 Hz, 5-H), 6.92 (1 H, d, J = 7.9 Hz, 6-H), 2.33 (3 H, s, Me); ¹³C NMR (d ₆ -DMSO, 100 MHz)
δ (ppm) 163.9 (C), 161.8 (C), 151.5 (C), 149.9 (C), 135.9 (CH), 118.1 (CH), 106.8 (C), 23.8 (Me); m/z (CI) 178 (MH⁺, 24%).