A Concise Synthesis of Fused Tricyclic Pyrrolo[3,2-d]pyrimidines

Abstract

A concise approach to partially saturated fused tricyclic pyrrolo[3,2-d]pyrimidines has been developed. Herein, we report a three-step route to the core templates, starting with a Sonogashira coupling and utilising either a CuI-catalysed or base-mediated 5-endo-dig cyclisation to form the pyrrolopyrimidine ring, followed by Mitsunobu cyclisation to afford the tricyclic system. This method facilitates synthetic access to a structural class with limited representation in the literature and is amenable to further elaboration by virtue of a halide incorporated at the 4-position.

Key words

pyrrolopyrimidines - partially saturated heterocycles - Sonogashira - Mitsunobu

• References and Notes

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• 8 Experimental Procedures: 5-(5-Amino-6-chloropyrimidin-4-yl)pent-4-yn-1-ol (11a): Et₃N (32.3 mL, 231.72 mmol) was added to a stirred solution of 4,6-dichloropyrimidin-5-amine (3.80 g, 23.17 mmol), CuI (88 mg, 0.46 mmol) and (PPh₃)₂PdCl₂ (0.651 g, 0.93 mmol) in THF (90 mL) under nitrogen. The solution was degassed with a stream of nitrogen. Pent-4-yn-1-ol (2.16 mL, 23.17 mmol) was added and the mixture was then heated at 65 °C for 3 h. The reaction mixture was adsorbed onto silica, dried under vacuum and purified by silica chromatography, eluting with 30% to 100% EtOAc in heptane. Product fractions were evaporated to dryness to afford a yellow gum, further purified by silica chromatography, elution gradient 0% to 5% MeOH in CH₂Cl₂. Pure fractions were evaporated to dryness to afford 11a (2.40 g, 49%) as a pale yellow solid; mp 94–96 °C. ¹H NMR (400 MHz, DMSO): δ = 1.69–1.78 (m, 2 H), 2.56–2.62 (m, 2 H), 3.48–3.55 (m, 2 H), 4.63 (t, J = 5.2 Hz, 1 H), 5.94 (s, 2 H), 8.13 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 15.9, 30.9, 59.6, 75.4, 101.9, 133.6, 140.3, 143.0, 145.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₀ClN₃O + H: 212.05852; found: 212.05867. 3-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)propan-1-ol (12a): 5-(5-Amino-6-chloropyrimidin-4-yl)pent-4-yn-1-ol (11a; 1.56 g, 6.63 mmol) was dissolved in DMF (25 mL) and the solution was degassed with a stream of nitrogen. CuI (0.190 g, 1.00 mmol) was added to the stirred solution, before heating at 110 °C for 35 min. The solution was allowed to cool to r.t., then diluted with CH₂Cl₂ and purified by ion-exchange chromatography, using an SCX column, eluting with MeOH then 10% 7 N NH₃/MeOH in CH₂Cl₂. The product containing fraction was evaporated to dryness and the crude product was purified by silica chromatography, elution gradient 0% to 10% MeOH in CH₂Cl₂. Pure fractions were evaporated to dryness and dried under high vacuum overnight to afford 12a (1.30 g, 93%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO): δ = 1.82–1.92 (m, 2 H), 2.83–2.91 (m, 2 H), 3.42–3.50 (m, 2 H), 4.60 (t, J = 5.1 Hz, 1 H), 6.50 (d, J = 1.8 Hz, 1 H), 8.54 (s, 1 H), 12.20 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 24.6, 31.5, 59.9, 99.9, 124.0, 140.0, 149.1, 150.8, 151.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₀ClN₃O + H: 212.05852; found: 212.05861. 4-Chloro-7,8-dihydro-6H-pyrimido[4,5-b]pyrrolizine (10a): (E)-Diisopropyl diazene-1,2-dicarboxylate (1.33 mL, 6.76 mmol) was added to solution of 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)propan-1-ol (12a; 1.30 g, 6.14 mmol) and Ph₃P (1.77 g, 6.76 mmol) in THF (40 mL), stirred under nitrogen at r.t. Stirring was continued for 2 h, then the crude reaction mixture was purified by ion-exchange chromatography, using an SCX column. The column was washed through with MeOH, before eluting the desired product using 1 M NH₃/MeOH. Product fractions were adsorbed onto silica and further purified by silica chromatography, eluting with 20% to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 10a (0.86 g, 72%) as a white solid; mp 118–119 °C. ¹H NMR (400 MHz, DMSO): δ = 2.52–2.62 (m, 2 H), 3.05–3.12 (m, 2 H), 4.36–4.43 (m, 2 H), 6.46 (t, J = 0.9 Hz, 1 H), 8.52 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 24.6, 26.4, 46.7, 94.1, 120.9, 139.8, 148.9, 154.5, 154.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₈ClN₃ + H: 194.04795; found: 194.04781. See Supporting Information for full details of other compounds exemplified.
• 9 A single regioisomer, 11d, was isolated from the Sonogashira reaction in step a, confirmed as the isomer shown by hydrogenation of 10d to afford the corresponding des-chloro analogue, shown by NMR analysis to be 7,8,9,10-tetrahydro-6H-pyrido[2′,3′:4,5]pyrrolo[1,2-a]azepine. See Supporting Information for experimental details.

For the synthesis of related des-chloro 5,6,5- and 6,5,6-tricyclic pyrrolo[3,2-b]pyridines ring systems, see:
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