Sequentially Catalyzed Three-Component Masuda–Suzuki–Sonogashira Synthesis of Fluorescent 2-Alkynyl-4-(7-azaindol-3-yl)pyrimidines: Three Palladium-Catalyzed Processes in a One-Pot Fashion

Abstract

The Masuda–Suzuki–Sonogashira sequence efficiently unites, in a one-pot fashion, a borylation, an arylation, and an alkynylation in the sense of a sequentially Pd-catalyzed three-component reaction to give fluorescent 2-alkynyl-4-(7-azaindol-3-yl) pyrimidines in yields of 24–83% (14 examples). Time-dependent density-functional theory calculations supported the electronic structure of the longest wavelength absorption bands, revealing that this novel consecutive three-component synthesis opens an efficient access to alkynyl meriolins, a novel class of potential inducers of apoptosis.

Key words

arylation - alkynylation - borylation - fluorescence - multicomponent reaction - meriolins

• References and Notes

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• 12 Products 5a–m; General Procedure 7-azaindole 1a (398 mg, 1.00 mmol) and (Ph₃P)₄Pd (35.0 mg, 0.03 mmol) were placed in a dry screw-cap vessel equipped with a magnetic stirrer bar. The vessel was evacuated and refilled with argon three times, then anhyd 1,4-dioxane (5.00 mL) was added and the resulting mixture was degassed with argon for 10 min. Dry Et₃N (1.40 mL, 10.0 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 mL, 1.70 mmol) were successively added and the mixture was stirred in a preheated oil bath at 80 °C for 4 h then cooled to r.t. (water bath). Dry 1,2-dimethoxyethane (9.00 mL) and H₂O (1.00 mL) were added, and the mixture was stirred at r.t. for 10 min. 2,4-Dichloropyrimidine (2; 149 mg, 1.00 mmol) and Cs₂CO₃ (823 mg, 2.50 mmol) were then added, and the mixture was stirred in a preheated oil bath at 80 °C for 18 h. When the Suzuki coupling was complete, the mixture was cooled to r.t. (water bath), and CuI (19.0 mg, 0.10 mmol) and the appropriate alkyne 4 (1.20 mmol) were added. The mixture was stirred at 45–80 °C for 18 h. When the Sonogashira coupling was complete (TLC), the mixture was cooled to r.t. (water bath), the solvents were removed in vacuo, and the residue was absorbed onto Celite. After purification by chromatography (silica gel, hexane–acetone), the product was sonicated in hexane–acetone (95:5) for further purification. The solvent was removed and the residue was dried in vacuo at 70 °C for 42 h. 1-[(4-Methylphenyl)sulfonyl]-3-[2-(phenylethynyl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine (5a) The final Sonogashira step was carried out at 80 °C for 18 h to give a yellow solid; yield: 310 mg (0.68 mmol, 68%); mp 200.3–202.7 °C; R_f = 0.48 (CH₂Cl₂–acetone, 6:4). IR (neat): 3379 (w), 3107 (w), 3090 (w), 3026 (w), 2918 (w), 2218 (w), 1593 (m), 1570 (s), 1555 (w), 1533 (s), 1491 (m), 1479 (w), 1425 (w), 1398 (s), 1381 (m), 1368 (s), 1335 (w), 1302 (m), 1262 (m), 1244 (m), 1186 (s), 1171 (s), 1155 (s), 1123 (w), 1075 (w), 1036 (m), 1017 (m), 999 (w), 961 (s), 918 (w), 883 (m), 866 (w), 849 (w), 837 (m), 822 (m), 802 (m), 775 (s), 756 (s), 732 (s), 675 (s), 654 (s), 633 (w) cm^–1. ¹H NMR (600 MHz, DMSO-d ₆): δ = 2.35 (s, 3 H, CH₃), 7.44–7.54 (m, 6 H, CHAr), 7.72 (d, ³ J _HH = 6.7 Hz, 2 H, CHAr), 8.09 (d, ³ J _HH = 8.5 Hz, 2 H, CHAr), 8.23 (d, ³ J _HH = 5.4 Hz, 1 H, CHAr), 8.48 (dd, ³ J _HH = 4.7 Hz, ⁴ J _HH = 1.6 Hz, 1 H, CHAr), 8.85 (d, ³ J _HH = 5.4 Hz, 1 H, CHAr), 8.88 (dd, ³ J _HH = 8.0 Hz, ⁴ J _HH = 1.6 Hz, 1 H, CHAr), 9.03 (s, 1 H, CHAr). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 21.1 (CH₃), 86.2 (C_quat), 88.6 (C_quat), 115.5 (C_quat), 116.4 (CH), 119.8 (CH), 120.4 (C_quat), 120.5 (C_quat), 128.0 (CH), 129.0 (CH), 129.2 (CH), 130.1 (CH), 130.2 (CH), 131.7 (CH), 132.2 (CH), 134.0 (C_quat), 145.7 (CH), 146.2 (C_quat), 146.9 (C_quat), 152.0 (C_quat), 157.8 (CH), 159.8 (C_quat). EI MS: m/z (%) = 450 (21) [M+], 386 (100) [C₂₁H₁₄N₄O₂S⁺], 385 (36), 296 (11), 268 (12), 267 (19), 155 (13) [C₇H₇O₂S⁺], 142 (14), 141 (12) [C₉H₅N₂ ⁺], 127 (11), 114 (14) [C₉H₆ ⁺], 91 (90) [C₇H₇ ⁺], 65 (14) [C₅H₅ ⁺]. Anal. Calcd for C₂₆H₁₈N₄O₂S (450.5): C, 69.32; H, 4.03; N, 12.44; S, 7.12. Found: C, 69.11; H, 3.75; N, 12.19; S, 7.31.