Probing the Reactivity of 2,4-Dichlorofuro[3,4-d]pyrimidin-7-one: A Versatile and Underexploited Scaffold to Generate Substituted or Fused Pyrimidine Derivatives

In memory of Prof. Maurizio Botta, inspiring mentor, friend, and strong believer in chemistry-based drug discovery

Abstract

Herein, we describe the results of our investigation on the chemical reactivity and versatility of a poorly explored scaffold: 2,4-dichlorofuro[3,4-d]pyrimidin-7-one (3). Highly functionalized pyrimidines can be obtained with a divergent approach by reacting the key intermediate 3 with different amine nucleophiles under carefully controlled reaction conditions. The set-up of a microwave-assisted one-pot, two- or three-step protocol to rapidly generate 2,4,5,6-tetrasubstituted or fused pyrimidines is also reported.

Key words

orotic acid - pyrimidines - multicomponent reactions - microwave

• References and Notes

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• 23 General Procedure for the One-Pot, Two-Step Synthesis of N-Benzyl-5-(hydroxymethyl)-2-morpholino-6-[(4-sulfamoylphenyl)amino]pyrimidine-4-carboxamide (12) In a microwave tube, intermediate 7 (100 mg, 0.36 mmol) and benzylamine (198 μL, 1.80 mmol) were suspended in 2 mL of n-pentanol (or DME) and heated at 80 °C for 15 minutes (max μW power input: 250 W; ramp time: 1 minute; reaction time: 15 minutes; power max: off; maximum pressure: 250 psi). At the end of the irradiation, morpholine (93.1 μL, 1.08 mmol) was added and the reaction was submitted to a second irradiation cycle at 100 °C for 10 minutes (max μW power input: 250 W; ramp time: 1 minute; reaction time: 10 minutes; power max: off; maximum pressure: 250 psi). At the end of irradiation the reaction mixture was evaporated under vacuum and the crude material was purified by flash chromatography (CHCl₃/i-PrOH, 98:2) to obtain 12 in 55% yield. MS (ESI): m/z = 497.5 [M – H]^–. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.70 (m, 8 H), 4.46 (d, J = 8 Hz, 2 H), 4.83 (s, 2 H), 5.39 (br s, 1 H), 7.24 (br s, 3 H), 7.34 (s, 4 H), 7.80 (m, 4 H), 9.09 (m, 1 H), 9.17 (s, 1 H). ¹³C NMR (DMSO-d ₆, 100 MHz): δ = 42.64, 44.63, 55.33, 66.52, 107.19, 120.40, 127.02, 127.23, 127.56, 128.77, 137.78, 139.82, 143.00, 156.89, 159.66, 160.89, 166.45.
• 24 General Procedure for the One-Pot, Three-Step Synthesis of 4-[(6-Benzyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino]benzenesulfonamide (14) In a microwave tube, intermediate 7 (100 mg, 0.36 mmol) and benzylamine (198 μL, 1.80 mmol) were suspended in 2 mL of n-pentanol (or DME) and heated at 80 °C for 15 minutes (max μW power input: 250 W; ramp time: 1 minute; reaction time: 15 minutes; power max: off; maximum pressure: 250 psi). At the end of the irradiation, morpholine (93.1 μL, 1.08 mmol) was added and the reaction was submitted to a second irradiation cycle at 100 °C for 10 minutes (max μW power input: 250 W; ramp time: 1 minute; reaction time: 10 minutes; power max: off; maximum pressure: 250 psi). TFA (13.78 μL, 0.18 mmol) was then added and the reaction was heated in the microwave at 170 °C for 10 minutes (max μW power input: 300 W; ramp time: 1 minute; reaction time: 10 minutes; power max: off; maximum pressure: 250 psi). The resulting mixture was evaporated under vacuum and the crude material was purified by flash chromatography using DCM/EtOH abs/HCOOH 80% aq (9.4:03:03) to give 14 in 23% yield. MS (ESI): m/z = 479.1 [M – H]^–. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.7 (m, 8 H), 4.42 (s, 2 H), 4.74 (s, 2 H), 7.34 (m, 5 H), 7.21 (s, 2 H), 7.77 (dd, J = 8.76 Hz, 2 H), 7.86 (dd, J = 8.76 Hz, 2 H), 9.48 (s, 1 H). ¹³C NMR (DMSO-d ₆, 100 MHz): δ = 44.99, 46.08, 46.27, 66.47, 109.65, 120.15, 127.02, 128.01, 128.28, 129.26, 137.58, 137.87, 142.95, 155.96, 158.23, 162.91, 166.14.