Azine and Diazine Functionalization Using 2,2,6,6-Tetramethylpiperidino-Based Lithium–Metal Combinations: Application to the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines

Abstract

The synthesis of triaryl methanols was investigated by reacting different 4-metalated 2-substituted pyrimidines with diaryl ketones, the latter being generated by deprotocupration–aroylation of azine and diazine substrates. Cyclization of the triaryl methanols thus obtained afforded pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines, which were evaluated for kinase inhibition and antiproliferative activities in melanoma cells.

Key words

diaryl ketone - pyrimidine - deprotometalation - mixed-metal amide - variolin analogue

• References and Notes

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• 12 2-Chloro-α-(2-chloro-3-pyridyl)-α-phenyl-4-pyrimidinemethanol (4b) i-PrMgCl·LiCl (about 1.3 M THF solution, 1.2 mmol) was stirred with 2,2,6,6-tetramethylpiperidine (0.21 mL, 1.2 mmol) at r.t. for 48 h. The resulting solution was cooled at –60 °C before introduction of a cooled solution of 2-chloropyrimidine (2, 0.11 g, 1.0 mmol) in THF (2 mL). After 2 h at –40 °C, a solution of the ketone 1a (0.26 g, 1.2 mmol) in THF (4 mL) was added at –60 °C. The mixture was stirred overnight at r.t. before addition of H₂O (0.5 mL) and dilution with EtOAc (20 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification was performed by chromatography on silica gel (eluent: heptane–EtOAc, 7:3) to afford 4b in 51% yield as a yellow powder; mp 90 °C. ¹H NMR (300 MHz, CDCl₃): δ = 4.97 (s, 1 H), 7.18 (dd, 1 H, J = 7.8, 4.7 Hz), 7.33 (dd, 1 H, J = 7.8, 1.9 Hz), 7.36 (d, 1 H, J = 5.2 Hz), 8.37 (dd, 1 H, J = 4.7, 1.9 Hz), 7.35–7.45 (m, 5 H), 8.60 (d, 1 H, J = 5.2 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 80.5 (C), 117.6 (CH), 122.3 (CH), 127.5 (2 CH), 128.7 (CH), 128.8 (2 CH), 138.2 (C), 139.9 (CH), 140.7 (C), 149.4 (CH), 150.8 (C), 160.1 (CH), 161.0 (C), 175.0 (C) ppm. ESI-HRMS: m/z calcd for C₁₆H₁₁ ³⁵Cl₂N₃NaO [M + Na]⁺: 354.0177; found: 354.0178.
• 13 4-Iodo-2-(methylthio)pyrimidine (5a) To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi (about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl₂·TMEDA⁷ (0.26 g, 1.0 mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-(methylthio)pyrimidine (3, 0.25 g, 2.0 mmol). After 2 h at this temperature, a solution of I₂ (0.76 g, 3.0 mmol) in THF (10 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solution of Na₂S₂O₃ (10 mL) and extraction with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification was performed by chromatography on silica gel (eluent: heptane–EtOAc, 95:5) to afford 5a in 77% yield as a beige powder; mp 52 °C (ref. 14: 52–53 °C). ¹H NMR (300 MHz, CDCl₃): δ = 2.54 (s, 3 H), 7.40 (d, 1 H, J = 5.1 Hz), 8.00 (d, 1 H, J = 5.1 Hz) ppm.
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